NRM 2021 Abstract Booklet

doi:10.1177/0271678X211061050

. 2021 Dec 15;41(1 Suppl):11–309. doi: 10.1177/0271678X211061050

NRM 2021 Abstract Booklet

Editor: Pedro Rosa-Neto

PMCID: PMC8851538 PMID: 34905986

2021-01

In vivo PET imaging of mutant huntingtin using [¹¹C]CHDI-180R as candidate marker in a mouse model of Huntington’s Disease (#4)

Daniele Bertoglio¹, Jeroen Verhaeghe¹, Klaudia Cybulska^1,
2, Špela Korat^{1, 2}, Alan Miranda¹, Leonie Wyffels^1,
2, Sigrid Stroobants^{1, 2}, Vinod Khetarpal³, Ladislav Mrzljak³, Celia Dominguez³, Jonathan Bard³, Mette Skinbjerg³, Longbin Liu³, Ignacio Munoz-Sanjuan³ and Steven Staelens¹

¹Molecular Imaging Center Antwerp (MICA), University of Antwerp, Wilrijk, Belgium

²Department of Nuclear Medicine, Antwerp University Hospital, Edegem, Belgium

³CHDI Management/CHDI Foundation, Los Angeles, CA, USA

Abstract

Introduction: Huntington’s Disease (HD) is a progressive autosomal dominant neurodegenerative disorder caused by mutant huntingtin (mHTT). Although several promising therapeutic approaches aimed at decreasing cerebral mHTT levels are currently being developed, there is a major (pre)clinical need for a noninvasive marker to monitor mHTT changes. The aim of this study was to investigate the first in class mHTT PET radioligand, namely [¹¹C]CHDI-180R, for imaging of mHTT aggregates in the Q175DN mouse model of HD.

Methods: Dynamic microPET/CT imaging was performed longitudinally in heterozygous (HET) Q175DN mice (n = 23) and wild-type (WT) littermates (n = 20) at 3, 6, 9, and 13 months of age (M). The total volume of distribution (V_T) (Logan) was calculated noninvasively using an image-derived input function (IDIF) (V_{T (IDIF)}) for brain regional and voxel-wise analyses. Post-mortem autoradiography with [³H]CHDI-180 and mHTT immunohistochemistry (IHC) were performed at each time point (n = 10/genotype at 3, 6, 9, and 13M) to confirm the in vivo findings. Receiver operating characteristic (ROC) curves for assessment of diagnostic ability and sample size calculations at desired therapeutic effects were performed.

Results: Longitudinal PET imaging could discriminate HET from WT littermates as early as 3M (striatum: HET = 0.53 ± 0.03 mL/cm³, WT = 0.49 ± 0.03 mL/cm³; +6.5%, p < 0.001). Binding in HET mice increased successively over time, resulting in the largest difference between genotypes at 13M (striatum: HET = 0.87 ± 0.05 mL/cm³, WT = 0.48 ± 0.03 mL/cm³; +82.5%, p < 0.0001) (Figure 1). Post-mortem analyses supported the in vivo PET quantification demonstrating increased binding with age in HET mice, which was associated with disease progression (r > 0.89, p < 0.0001) as measured by in vitro [³H]CHDI-180 autoradiography and mHTT IHC. No age-related or disease progressive increase in PET signal was detectable in WT littermates. ROC curves revealed good accuracy already at 3M (AUC = 0.81). Sample size calculations showed that less than 10 animals per treatment group were required to detect a 30% therapeutic effect as of 6 (Figure 2).

Conclusion: We described the first radioligand to image mHTT in the living brain. These findings indicate [¹¹C]CHDI-180R PET imaging is a non-invasive candidate PET tracer suitable for monitoring HD progression and potentially for evaluating the efficacy of mHTT lowering therapies with future clinical application.

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2021-02

Data-driven, blood-free quantification of positron emission tomography radiotracers with irreversible kinetics using the publicly-available Source-to-Target Automatic Rotating Estimation (STARE): Validation with [¹⁸F]FDG data and simulations (#10)

Elizabeth A. Bartlett^{1, 2}, R. Todd Ogden^{1, 3}, John Mann^1,
4 and Francesca Zanderigo^{1, 2}

¹Molecular Imaging and Neuropathology Area, New York State Psychiatric Institute, New York, NY, USA

²Department of Psychiatry, Columbia University Medical Center, New York, NY, USA

³Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, NY, USA

⁴Department of Radiology, Columbia University Medical Center, New York, NY, USA

Abstract

Introduction: Full quantification of positron emission tomography (PET) data requires arterial blood sampling. We present STARE, Source-to-Target Automatic Rotating Estimation, which quantifies the absolute net influx rate (K_i) of PET radiotracers with irreversible kinetics. STARE operates on individual-level PET data in the absence of blood measurements and without relying on a reference region. STARE is validated here in N = 69 human [¹⁸F]FDG scans using arterial-based quantification, and its performance is assessed with simulations and across clinical populations (healthy control, Alzheimer’s Disease (AD) and mild cognitive impairment (MCI)).

Methods: STARE is a data-driven approach that uses a source-to-target tissue model, based on a two-tissue irreversible compartment model, where time activity curves of multiple “target” regions are expressed as a function of a common “source” region, and separates target regions’ K_i from source K_i by fitting this model across all target regions simultaneously. Data-driven, subject-specific anchoring ensures identifiability of the model, using the PET signal in an automatically-determined vasculature cluster in the field of view. The estimation repeats, allowing each region to act in turn as the source, and final K_i in each region is estimated by averaging across source rotations.

Results: STARE K_i estimates were in good agreement with arterial blood-based estimates (regression slope = 0.88, Pearson’s r = 0.80), and were precisely estimated (comparing STARE K_i estimates across runs of the nondeterministic algorithm; coefficient of variation = 6.74 ± 2.48%). STARE performance, relative to blood-based K_i estimation, did not differ between diagnostic groups (p = 0.17). In simulations, STARE K_i estimates were largely robust to factors that influence the subject-specific anchoring (e.g., kinetics and noise within the automatically-determined vasculature cluster).

Conclusion: Feasibility is demonstrated for STARE blood-free quantification of K_i in this sample of [¹⁸F]FDG scans. Preliminary analyses suggest that STARE may be robust across some clinical populations (AD, MCI). Further validation is required, including application to data from other scanners, populations, and radiotracers.

Acknowledgements

The National Institute of Biomedical Imaging and Bioengineering provided funding for this study (R01EB026481, PI: Francesca Zanderigo, PhD).

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2021-03

Novel data-driven method captures spatio-temporal patterns of neurodegeneration in Parkinson’s disease (#12)

Jessie Fanglu Fu^{1, 2}, Ivan S. Klyuzhin³, Tilman Wegener^1,
4, Martin McKeown^{3, 5}, A. Jon Stoessl^{3, 5} and Vesna Sossi^{1, 5}

¹Department of Physics and Astronomy, University of British Columbia, Vancouver, BC, Canada

²Department of Radiology, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA

³Division of Neurology, Department of Medicine, University of British Columbia, Vancouver, BC, Canada

⁴Department of Medical Engineering, University of Luebeck, Luebeck, Schleswig-Holstein, Germany

⁵Djavad Mowafaghian Centre for Brain Health, Pacific Parkinson’s Research Centre, University of British Columbia, Vancouver, BC, Canada

Abstract

Introduction: Most neurodegenerative disorders are characterized by progressive neurodegeneration following specific spatio-temporal patterns. To quantify these patterns, traditionally one often fits pre-defined models with spatial and temporal parameters.^1,2 We recently proposed a novel data-driven approach, dynamic mode decomposition (DMD),³ to decompose the overall putaminal dopaminergic changes of Parkinson’s disease (PD) patients into orthogonal spatio-temporal patterns.⁴ In this work, we extended the previous work by applying DMD to a distinct PD cohort scanned on a lower resolution scanner to examine the robustness of the DMD results and the effect of scanner resolution.

Methods: We applied DMD to [¹¹C]( ± )dihydrotetrabenazine (DTBZ) PET data in 70 PD patients (disease duration: 1 to 22 years) scanned on a CTI ECAT 953B scanner⁵ (resolution ∼8 mm³) and compared with previous results obtained in a cohort comprising 41 PD patients (disease duration: 1 to 16 years) scanned on the Siemens High Resolution Research Tomograph (HRRT)⁴ (resolution ∼2.5 mm³). DMD was applied to the parametric binding potential images (occipital cortex as the reference region) of the less and more affected putamen in the common space. Robustness was tested with leave-one-out cross-validation.

Results: DMD decomposed the ECAT data into two orthogonal spatio-temporal patterns (Figure 1): 1) an anterior-posterior gradient, with higher expression in the less affected putamen; the expression of which decreased gradually with disease progression. This pattern replicated the first DMD spatio-temporal pattern obtained from the HRRT data (Figure 2). 2) a dorsal-ventral gradient, with higher expression in the less affected putamen; the expression of which only existed in the early disease. This pattern was similar to the second DMD spatio-temporal pattern previously obtained with the HRRT data.

Conclusion: We showed the applicability and robustness of DMD for extracting spatio-temporal patterns of neurotransmitter changes using two PD cohorts on different scanners. The orthogonal temporal curves may reflect different mechanisms underlying disease progression and initiation. The slight differences in the second DMD modes may be related to scanner resolution and image registration quality differences. In principle, DMD can be easily extended to other PET studies and may help to elucidate disease mechanisms in more detail compared to traditional approaches.

Acknowledgements

The authors thank the UBC PET scanning and the TRIUMF radio-chemistry production staff. The volunteer subjects who generously donated their time to this research are also most gratefully acknowledged. The study was financially supported by the Natural Sciences and Engineering Research Council of Canada (NSERC), Brain Canada, and Canadian Institutes of Health Research (CIHR) and Michael Smith Foundation of Health Research. AJS is supported by the Canada Research Chairs program. JF receives scholarship funding from the Isotopes for Science and Medicine program (NSERC-CREATE). TW is supported by ENEN+ project that has received funding from the EURATOM research and training Work Programme 2016–2017 (1#755576) and the PROMOS Study or Internship Abroad Scholarships which has received funding from the German Academic Exchange Service (DAAD).

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References

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2021-04

A high-resolution in vivo atlas of the human brain’s benzodiazepine binding site of GABA_A receptors (#13)

Martin Nørgaard^{1, 2}, Vincent Beliveau³, Melanie Ganz^1,
4, Claus Svarer¹, Lars H. Pinborg^{1, 2}, Sune H. Keller⁵, Peter S. Jensen¹, Douglas N. Greve⁶ and Gitte M. Knudsen^{1, 2}

¹Neurobiology Research Unit & CIMBI, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark

²Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

³Medical University of Innsbruck, Innsbruck, Austria

⁴Department of Computer Science, University of Copenhagen, Copenhagen, Denmark

⁵Department of Clinical Physiology, Nuclear Medicine and PET, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark

⁶Athinoula A. Martinos Center for Biomedical Imaging, MGH/HMS, Boston, MA, USA

Abstract

Introduction: Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain, and plays a critical role for brain function and in neuropsychiatric disorders.¹ Benzodiazepines act as agonists on the benzodiazepine receptor binding site (BZR) which is located between the α1,2,3 or 5 and γ subunits in the pentameric constellation of the ionotropic GABA_A receptor (GABA_AR). Here, we present a quantitative high-resolution in vivo atlas of the human brain’s BZRs; this atlas can serve as a reference in future studies investigating disorders or pharmacological interventions on the BZR site.

Methods: Twenty-six unique Positron Emission Tomography (PET) scans were obtained using a Siemens HRRT scanner with the radioligand [¹¹C]flumazenil. The radioligand was given either as a bolus or as a bolus-infusion, and the metabolite-corrected arterial input function was measured. The PET data was quantified to estimate total distribution volumes (V_T) for each brain region; steady-state analysis was done for the bolus-infusion experiments and Logan analysis was done for the bolus experiments.^2,3 BZR density (pmol per gram protein in brain tissue) was obtained by normalizing V_T with the corresponding postmortem human brain [³H]diazepam autoradiography data.⁴ The non-displaceable distribution volume (V_ND) was estimated as the intercept (Figure 2(b)). The atlas was transformed to represent protein densities in pmol/ml (Figure 2(a)). Finally, the association between protein density and mRNA expression for the 19 GABA_AR subunits was assessed using the Allen Human Brain atlas.⁵

Results: The regional V_T’s and the postmortem human brain autoradiography were highly correlated (Pearson’s R = 0.96) and the intercept, V_ND, was low, in average 0.51 across subjects (range 0.04–1.31). The association between BZR densities and mRNA expression showed a high correlation for each of the subunits included in the commonly expressed pentameric GABA_AR subtype α₁β₂γ₂ (>50% expression in the brain) with Pearson’s R > 0.62 (range: 0.62–0.88, P < 0.0001) for all three subunits.

Conclusion: This high-resolution atlas of the spatial distribution of BZR densities in the healthy human brain provides insights into the association between mRNA expression for individual subunits in the GABA_AR and the BZR density at each location in the brain; in addition, it may be used to evaluate efficacy of pharmacological targets acting on the GABA_AR.C

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The regression is shown as the black line, and the intercept is the non-displaceable distribution volume (V_ND). The shaded area is the 95% confidence interval.

References

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2021-05

An algorithm for classifying neurotransmitter signals from future ultra-high sensitivity dynamic PET (#22)

Heather Liu^{1, 2} and Evan D. Morris^{1, 2}

¹Department of Biomedical Engineering, Yale University, New Haven, CT, USA

²Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, USA

³Department of Psychiatry, Yale University, New Haven, CT, USA

Abstract

Introduction: Innovations in solid-state detector technology will soon be leveraged to build the next-generation NeuroEXPLORER (NX) brain scanner, offering an order-of-magnitude improvement in detection sensitivity compared to the current state-of-the-art, Siemen’s HRRT. Our goal was to explore how increased sensitivity could be used with the linear-parametric neurotransmitter PET (lp-ntPET) model^1–4 to better detect transient dopamine (DA) events and classify DA signals.

Methods: Striatal ¹¹C-Raclopride PET data were simulated in the presence of varying DA signals⁵. DA signals were modeled with differing start times, peak times, and amplitudes. Measurement variance for the NX was scaled to 10% of the HRRT, to reflect an anticipated ten-fold sensitivity improvement. Time-activity curves were fitted with lp-ntPET. The detection sensitivity to each signal was calculated. Classification thresholds were evaluated for their accuracy in separating “early”- vs. “late”-peaking, and “low”- vs. “high”-amplitude events. A 4D phantom was constructed, with each voxel containing either a null signal or a positive signal, classified as high/low and early/late. A weighted k-nearest neighbors (wkNN) algorithm incorporated the 6-, 18-, and 26-voxel neighborhoods of each voxel to reclassify it. The certainty of classification of a voxel was given by the weighted vote of its neighbors. wkNN was applied to the phantom for detection and classification. Detection sensitivities and classification accuracies were calculated for both scanners.

Results: The NX would expand the range of detectable events to signals with amplitudes as low as 200% above baseline and peaking as early as 6 min post-stimulus (Figure 1(a)), compared to the minimum of 550% and 20 min necessary for detection by the HRRT (Figure 1(b)). NX sensitivity was 72.3% and specificity was 91.5%, compared with 31.4% and 88.9% for the HRRT. Application of wkNN increased sensitivity of the NX to 91.5%, with 100% specificity. Classification of high-amplitude and early-peaking signals had a positive predictive value > 97%. All classifications had a negative predictive value > 85% (Figure 2).

Conclusion: An ultra-high sensitivity NX scanner could greatly expand the range of detectable DA signals, compared to the current state-of-the-art. Higher detection sensitivity and a novel classification algorithm will make it possible to accurately classify DA signals according to their amplitude and timing. Inline graphic

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References

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2021-06

In vivo neuroimaging of histone deacetylases in multiple sclerosis using [¹¹C]Martinostat (#24)

Mary C. Catanese, Chieh-En J. Tseng, Valeria Barletta, Constantina A. Treaba, Elena Herranz Muelas, Nicole R. Zurcher Wimmer, Anjali J. Parmar, Baileigh G. Hightower, Ambica Mehndiratta, Changning Wang, Caterina Mainero and Jacob M. Hooker

Athinoula A. Martinos Center for Biomedical Imaging, Radiology, Charlestown, MA, USA

Abstract

Introduction: Multiple sclerosis (MS) is a demyelinating disease characterized by progressive neurological impairment and lesion formation. Magnetic resonance (MR) imaging enables identification of lesions and insight into their pathology, however, there are critical gaps in our molecular understanding. Histone deacetylases (HDACs) are considered therapeutic targets based on the consistent amelioration of symptom-like behavior in preclinical models of demyelination after treatment with HDAC inhibitors.^1–3 Moreover, HDAC expression is altered in postmortem lesion tissue.⁴ We previously demonstrated increased uptake in the HDAC-specific radiotracer, [¹¹C]Martinostat, in white matter (WM) with age,⁵ which correlated with decreased WM microstructure. We hypothesized that HDACs may become dysregulated in MS, as focal lesions are found in the WM.

Methods: In a pilot study [¹¹C]Martinostat uptake was measured in four individuals with relapsing remitting (RR) MS (2 female/2 male;53.5 ± 8.3years) and four age- and sex-matched controls (2 female/2 male;51.75 ± 9.9years). Dynamic positron emission tomography (PET) images were acquired after bolus injection (controls 5.22 ± 0.41Ci; MS5.37 ± 0.14mCi) using a combined 3-Tesla:MR-PET system. PET data were reconstructed in units of standard uptake value (SUV); six 5-min frames, 60–90min post-injection were processed using FreeSurfer and FSL. SUV was normalized to whole-brain mean (SUVR,60-90min). SUVR was registered to the corresponding T1-weighted image. Lesions segmented on Fluid-Attenuated-Inversion-Recovery (FLAIR) images (3-D-slicer-v4.2.0) were registered to the T1-weighted and SUVR images (FSL). SUVR in MS WM-lesions were compared to normal-appearing-WM (NAWM) and control-WM and MS-NAWM was compared to control-WM in GraphPad Prism (Mann-Whitney).

Results: Preliminary analysis of [¹¹C]Martinostat uptake found no significant differences in signal comparing WM-lesions to control-WM and MS-NAWM or comparing control-WM to MS-NAWM. It is possible that differences were not found in lesions due to partial volume effects (PVE) and low sample size.

Conclusion: Our study is the first to investigate HDAC expression in MS in vivo. Preliminary data revealed that [¹¹C]Martinostat uptake in MS-WM lesions is not different compared to control-WM and MS-NAWM. Studying molecular dysregulation underlying MS is complicated by lesion localization and by differences in lesion and disease subtype. We will account for PVE in further analyses and will increase our sample size, as well as study patients across MS-subtypes to determine whether HDACs are involved in MS-WM lesion pathology.

Acknowledgements

This research received funding from an internal pilot funding mechanism at the Athinoula A. Martinos Center for Biomedical Imaging and the Massachusetts General Hospital Research Scholar’s Program (Jacob M. Hooker).

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2021-07

Optimized synthesis of [¹⁸F]FPEB and preliminary neuroimaging of mGlur5 in transgenic mouse models (#25)

Cassis Varlow^{1, 2}, Nickeisha Stephenson^{2, 3}, Emily Murrell² and Neil Vasdev^{1, 2}

¹Institute of Medical Science, University of Toronto, Toronto, ON, Canada

²CAMH, Azrieli Centre for Neuro-Radiochemistry, Brain Health Imaging Centre, Toronto, ON, Canada

³Department of Chemistry, The University of West Indes at MONA, Kingston, Jamaica

Abstract

Introduction: 3-[¹⁸F]fluoro-5-[(pyridin-3-yl)ethynyl] benzonitrile ([¹⁸F]FPEB) is a radiopharmaceutical selective for metabotropic glutamate receptor subtype 5 (mGluR5). The present study aims to: 1) establish the optimal synthesis of [¹⁸F]FPEB and 2) to investigate changes in mGluR5 uptake via in vitro autoradiography and preclinical PET imaging in transgenic mouse models of neurological diseases (i.e., Alzheimer’s disease (AD).

Methods: ¹⁸F]FPEB was prepared through nucleophilic aromatic substitution with [¹⁸F]fluoride on an automated radiosynthesis unit (GE TRACERlab™ FX2N) using five precursors with varying leaving groups, namely: Cl, NO₂, spirocyclic iodonium ylide (SCIDY) with a cyclopentyl (SPI5) and a novel adamantyl (SPIAd) auxiliary; and a sulfonium salt precursor. Preliminary PET/CT imaging studies were conducted in B6C3-Tg (APPswe,PSEN1dE9)85Dbo/J (APP/PS1) mice, and data were compared with age-matched wild-type (WT) B6C3F1/J control mice (Figure 1).

Results: Complete radiosynthesis data summarized in Table 1. The chloro- and nitro-precursors produced [¹⁸F]FPEB in low radiochemical yield (<10% RCY), whereas both the SPI5 auxiliary SCIDY precursor and the sulfonium salt precursor resulted in the highest RCY (25 ± 2% and 36 ± 6%, respectively). The new SPIAd auxiliary successfully produced [¹⁸F]FPEB in 24% RCY, however, no advantage over SPI5 was observed and HPLC separation will require further optimization. Preliminary PET imaging data with [¹⁸F]FPEB shows an increased brain uptake in the transgenic model of AD vs. the age-matched controls (10 month data shown in Figure 1).

Conclusion: Of the five precursors evaluated, the SCIDY precursor with SPI5 auxiliary and the sulfonium salt precursor appear to the be the best suited for routine radiopharmaceutical production of [¹⁸F]FPEB. Increased uptake of [¹⁸F]FPEB in the APP/PS1 mouse model of AD compared with controls is consistent with results in patients with early mild cognitive impairment. Preclinical imaging studies with [¹⁸F]FPEB in Fragile X syndrome and mouse models of autism spectrum disorder are also underway to gain mechanistic insights for mGluR5 targeting therapeutics, and will be presented.

Acknowledgements

CV Thanks Dr. Jason Holland and Dr. Steven Liang for their contributions.

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Table 1. Radiofluorination of [18F]FPEB via five different precursors.

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2021-08

Estimating PET partial volume full-width-half-maximum directly from human data (#30)

Douglas N. Greve¹, Martin Schain², Melanie Ganz², Martin Nørgaard², Claus Svarer² and Gitte M. Knudsen²

¹Massachusetts General Hospital, Martinos Center, Charlestown, MA, USA

²Rigshospitalet, CIMBI & Neurobiology Research Unit, Copenhagen, Denmark

Abstract

Introduction: PET suffers from partial volume effects (PVEs) in which limited scanner resolution causes the activity to appear to spill out of one region and into another. PVEs cause false positives and negatives and inter-scanner variability. PV correction (PVC) methods exist but require a measure of the scanner resolution, usually obtained from a point source. This research introduces Adaptive PVC (APVC) which simultaneously estimates the scanner resolution and performs PVC.

Methods: APVC is based on the GTM,¹ an ROI-based PVC method in which PVE-free ROI means (b) are related to voxel-wise intensities (y) through a linear model (X): y = X*b. X = X(q) depends on a blurring function parameterized by q. Typically, q is a full-width-half-maximum (FWHM). With q measured from a point source, the GTM is inverted to compute b. In APVC, we simultaneously solve for both b and q by minimizing the residual variance of the linear model. We tested this method using 5 subjects scanned on GE Advance and Siemens HRRT using a 5HT4 tracer, the assumption being that the best method will yield closer BPnd across scanner. The blurring function was modeled as a Gaussian, with q being three FWHMs (one per dimension).

Results: The average estimated FWHMs were much larger than the nominal values: x = 8.5 mm ± 0.11 y = 9.0 mm ± 0.11 z = 8.3 mm ± 0.37 mm (Advance, nominal = 6 mm) and x = 5.1 mm ± 0.22 y = 4.5 mm ± 0.22 z = 4.7 mm ± 0.16 (HRRT, nominal = 4 mm). Figure 1 shows how the BP_ND for a single ROI differs between scanner/method. Without PVC, the BP_NDs differ by 58%. Using the nominal FWHM, the difference drops to 31%. However, with APVC, the difference drops to only 15%. Figure 2 shows the differences for 68 cortical ROIs with NoPVC having a very large difference (41% average), nominal PVC improving to 32%, and APVC improving still further to 17%.

Conclusion: APVC estimates the scanner resolution directly from human data while correcting for PVEs. Our results show that the APVC-measured FWHM was much higher than the nominal in two scanners. APVC resulted in a much better agreement in 5HT4 BP_NDs across the two scanners. While APVC uses the GTM, the output resolution measure can be used in any PVC method. Software available in FreeSurfer/PETsurfer.

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2021-09

Repurposing novel PET neuroimaging radioligands in xenograft mouse models of cancer (#32)

Amanda J. Boyle¹, Junchao Tong¹, Sami Goghbi², Victor W. Pike², Robert B. Innis² and Neil Vasdev¹ and partly submitted as a collaboration with the National Institute of Mental Health (NIMH)

¹Centre for Addiction and Mental Health, Brain Health Imaging Centre, & Azrieli Centre for Neuro-Radiochemistry, Toronto, ON, Canada

²National Institute of Mental Health, Bethesda, MD, USA

Abstract

Introduction: This study aims to explore the utility of PET radioligands that target biomarkers relevant to oncology but which, to date, have only been developed as neuroimaging agents for cyclooxygenases (COX-1 and COX-2) and glycogen synthase kinase-3 (GSK-3). Herein, we evaluate [¹¹C]PS13, [¹¹C]MC1, and [¹¹C]OCM-44, which target COX-1,¹ COX-2,¹ and GSK-3,² respectively, in ovarian, breast, and pancreatic xenograft tumour mouse models.

Methods: Radiosyntheses of [¹¹C]PS13, [¹¹C]MC1, and [¹¹C]OCM-44 were performed as previously described.^2–4 The radioligands were evaluated in a panel of xenograft mouse models prepared from ovarian, breast, and pancreatic cancer cell lines, OVCAR-3, MDA-MB-231, and PANC-1, respectively, via dynamic PET imaging. Blocking studies, ex vivo biodistribution, and radiometabolite analysis of tumour homogenates were also carried out.

Results: OVCAR-3 xenografts were well visualized with [¹¹C]PS13 (0–60 min average image; Figure 1(a)). Time-activity curves (TACs) revealed steady tumour radioactivity accumulation that plateaued from 40–60 min with an average uptake of 3.56 ± 0.81%ID/g (40–60 min), which was significantly reduced by pre-treatment with the known COX-1 inhibitor, ketoprofen, to 1.30 ± 0.18%ID/g (p = 0.0096), (Figure 1(b) and 1(c)). Preliminary radiometabolite analysis established the parent compound, [¹¹C]PS13, to account for 65% of radioactivity in the tumour at 40 min post-injection (p.i.) of the radioligand. PANC-1 xenografts were not visualized by [¹¹C]MC1 despite reported high expression of COX-2 but were successfully imaged with [¹¹C]OCM-44 (Figure 2(a)), yet blocking was unsuccessful and radiometabolite analysis showed that at 40 min p.i. less than 2% of the radioactivity was parent. MDA-MB-231 xenografts were not visualized by PET imaging with [¹¹C]PS13, [¹¹C]MC1, or [¹¹C]OCM-44 (Figure 2(b)), despite reported overexpression of COX-1, COX-2, and GSK-3.

Conclusion: [¹¹C]PS13 has a favorable radiobiological profile for studying the role of peripheral COX-1 and clinical translation of this radioligand in ovarian cancer is planned. Further evaluations of [¹¹C]MC1 and [¹¹C]OCM-44 are underway and will also be presented.

Acknowledgements

Ian Duffy for producing these radioligands at CAMH. Cassis Varlow for her careful skills in mouse catheterization.

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References

1.Kim MJ, Pike VW, Innis RB, et al. Evaluation of two potent and selective PET radioligands to image COX-1 and COX-2 in rhesus monkeys. J Nucl Med 2018; 59: 1907–1912. [DOI] [PMC free article] [PubMed] [Google Scholar]
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2021-10

[¹⁸F]MNI-1054, a novel PET ligand for lysine-specific histone demethylase 1A (LSD1): First-in-human validation including radiation dosimetry, kinetic modeling and test-retest variability (#39)

Adam J. Schwarz¹, Christine Sandiego², Cristian Constantinescu², Vincent Carroll², Olivier Barret², Roger N. Gunn³, Akihiro Takano⁴, Paul McQuade¹, Terry Brown¹, Johannes Tauscher¹ and David S. Russell²

¹Takeda Pharmaceuticals, Cambridge, MA, USA

²Invicro, New Haven, CT, USA

³Invicro, London, UK

⁴Takeda Pharmaceuticals, Osaka, Japan

Abstract

Introduction: The enzyme lysine-specific histone demethylase 1A (LSD1), involved in the control of gene expression and cell proliferation, is widely expressed in the human brain and specifically demethylates lysine residues on histone H3K4 and H3K9. This Phase 1 study aimed to assess the LSD1-targeting radiotracer [¹⁸F]MNI-1054 in healthy volunteers in terms of: (1) brain kinetics and quantitative tracer kinetic modeling; (2) test-retest reproducibility; and (3) safety, biodistribution and radiation absorbed dose burden.

Methods: Four male subjects had two 180-minute [¹⁸F]MNI-1054 dynamic brain PET scans, with arterial blood samples, up to 2 weeks apart (303 ± 67 MBq (8.2 ± 1.8 mCi)). Additionally, two male and two female subjects underwent single whole-body PET scans to determine biodistribution (352 ± 6 MBq (9.5 ± 0.2 mCi)). All scans were performed on a Siemens HR+ PET camera. [¹⁸F]MNI-1054 binds irreversibly to the LSD1 enzyme, so the PET data were analyzed with the irreversible 2-tissue compartment model, using the metabolite-corrected arterial plasma input function, to calculate the enzyme binding parameter K_i.

Results: [¹⁸F]MNI-1054 and the study procedures were well-tolerated with no safety concerns. The highest tracer binding was observed in the cerebellum (K_i∼0.04), with lower uptake in cerebral cortices, striatum and hippocampus (K_i∼0.02), and lowest in the pons (K_i∼0.01), consistent with the expected LSD1 distribution (Figure 1(a) and (b)). The average test-retest variability in K_i across the four subjects was ∼5% for the cerebellum and ∼10-15% in other brain regions (Figure 1(c)). Analysis using only the first 120 minutes of data resulted in good agreement with that using 180 min of dynamic data (R² = 0.88) and similar cerebellar test-retest variability of ∼5% (Figure 1(d)). The average whole-body effective dose was determined to be 0.026 ± 0.00228 mSv/MBq, or 4.18 ± 0.42 mSv per 185 MBq (5 mCi) tracer injection.

Conclusion: [¹⁸F]MNI-1054 exhibited good safety and technical characteristics suitable for repeated scans and use in occupancy studies.

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2021-11

Towards the development of PET tracers for the imaging of melatonin receptors (#43)

Alexey Kostikov¹, Thomas A. Singleton¹, Hussein Bdair¹, Karen Ross¹, Min-Su Kang², Arturo Aliaga², Tanpreet Kaur³, Allen F. Brooks³, Peter J.H. Scott³, Gabriella Gobbi⁴, Chawki Benkelfat⁴, Marco Leyton⁴, Saïd Yous⁵, Jean-Paul Soucy^{1, 6} and Pedro Rosa-Neto^{1, 2}

¹McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, QC, Canada

²Research Centre for Studies in Aging, McGill University, Douglas Institute, Montreal, QC, Canada

³Department of Radiology, University of Michigan Medical School, Ann Arbor, MI, USA

⁴Department of Psychiatry, McGill University, Montreal, QC, Canada

⁵Neurosciences and Cognition Research Center, University of Lille, Lille, France

⁶PERFORM Centre, Concordia University, Montreal, QC, Canada

Abstract

Introduction: The neurohormone melatonin modulates circadian rhythms and other physiological functions in mammals through the activation of melatonin type 1 and 2 receptors (MT₁ and MT₂), which are mainly expressed in the suprachiasmatic nucleus (SCN)¹ of the brain. Recently, the melatonergic system emerged as a promising therapeutic target for the treatment of sleep and mood disorders and to maximize the therapeutic potential of sleep in neurodegenerative conditions². Imaging tools for visualization and localization of melatonin receptors are highly sought after to study their role in various physiological and pathological conditions, and for the development of new drugs targeting melatonergic system.

Methods: We radiolabelled a series of four high affinity MT receptors ligands with either carbon-11 or fluorine-18 PET isotopes (Figure 1). In particular, [¹¹C]UCM765³ and [¹¹C]UCM1014⁴ were labelled by ¹¹C-methylation of the desmethoxy precursors, whereas [¹⁸F]3-fluoroagomelatine⁵ was produced via copper-mediated ¹⁸F-fluorination of the corresponding boronic pinacolate precursor and [¹⁸F]fluoroacetamidoagomelatine⁵ was labelled via nucleophilic ¹⁸F-fluorination of the bromoacetamide agomelatine derivative. All ligands were evaluated as PET tracer candidates in preclinical imaging studies in wild-type rats using the microPET R4 scanner.

Results: All four radioligands showed good to excellent brain permeability, in particular the [¹⁸F]fluoroagomelatine derivatives (SUV_max = 3.25 ± 0.31, Figure 2) and a fast washout rate in wild-type rats. However, blocking studies using selective MT ligands have not revealed reduction of the tracer uptake in the brains of rats. This could be due to the fast metabolism of these PET tracers in rodents, the small anatomical size of the SCN in rats or the nocturnal nature of these animals leading to decreased MT expression during daytime.

Conclusion: The high brain permeability of the radiolabelled ligands warrants their further investigation as PET tracer candidates for imaging of MT₁ and MT₂ receptors. However, rats do not appear to be suitable animal models for those further studies. Higher species, such as non-human primates, are required for subsequent imaging experiments using PET tracer candidates developed in our lab.

Acknowledgements

The authors thank the personnel of the cyclotron and radiochemistry facility at the Montreal Neurological Institute.

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2021-12

Nicotine patch reduces striatal smoking-induced dopamine release compared to placebo patch (#46)

Yasmin Zakiniaeiz^{1, 2}, Heather Liu³, Hong Gao^{1, 2}, Soheila Najafzadeh^{1, 2}, Jim Ropchan^{1, 2}, Nabeel Nabulsi^1,
2, Yiyun H. Huang^{1, 2}, Kelly P. Cosgrove^{2, 4} and Evan D. Morris^{2, 5}

¹Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, USA

²Yale Positron Emission Tomography (PET) Center, Yale University, New Haven, CT, USA

³Department of Biomedical Engineering, Yale University, New Haven, CT, USA

⁴Department of Psychiatry, Yale University, New Haven, CT, USA

⁵Invicro, New Haven, CT, USA

Abstract

Introduction: Tobacco smoking is a major public health concern. Smoking cessation treatments have limited success rates, including nicotine replacement therapy (NRT) which acts directly at nicotinic-acetylcholine receptors on dopamine (DA) terminals to release DA in the striatum. The goals of this study were to examine the strength of cigarette smoking-induced striatal DA release and to relate spatial extent of release to nicotine dependence in smokers under nicotine patch and placebo patch conditions. We hypothesized that nicotine patch would reduce spatial extent of release compared to placebo, and that smoking pack years would be associated with spatial extent in the striatum.

Methods: Twenty-eight tobacco smokers (13 Female) wore a nicotine patch (21mg, daily) for 1-week and a placebo patch for 1-week in a randomized, counter-balanced design. Following each condition plus an overnight abstinence, smokers participated in 90-minute [¹¹C]raclopride PET scans. They smoked a cigarette while lying in the scanner. We used lp-ntPET,^1-4 a model of tracer uptake containing a time-varying term, to identify highly localized DA transients in PET data at the voxel level. lp-ntPET was fitted (voxel-wise) to PET TACs in the pre-commissural striatum. DA responses were retained for voxels if the inclusion of the time-varying term improved the fit. “Probability of activation” maps were generated, summed by condition and divided by the number of group members.⁵ Participants were divided into low and high pack years groups using a median split analysis and probability of activation maps were made for each group.

Results: Thenicotine patch reduced the spatial extent of DA release and the probability of DA activation following cigarette smoking compared to placebo patch (Figure 1(a)). The high pack years group had higher spatial extent of DA release and probability of DA activation in the striatum during the placebo patch condition than the low pack years group (Figure 1(b)).

Conclusion: Consistent with our hypotheses, the nicotine patch reduced the strength of cigarette-induced striatal DA response compared to placebo patch, suggesting a potential mechanism for NRT on the rewarding response of cigarette-smoking. Pack years was associated with the strength of the striatal DA response, suggesting that nicotine dependence might contribute to DA response.

Acknowledgements

Research support provided by R01DA038709-03 (Morris) and T32DA022975 (Zakiniaeiz). We thank the Yale PET Center staff for imaging and chemistry support.

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2021-13

Distinct spatio-temporal patterns of putuminal dopamine processing in Parkinson’s disease: A multi-tracer positron emission tomography study (#47)

Jessie Fanglu Fu^{1, 2}, Tilman Wegener^{1, 3}, Ivan S. Klyuzhin⁴, Julia G. Mannheim^{1, 5}, Martin McKeown^{4, 6}, A. Jon Stoessl^{4, 6} and Vesna Sossi^{1, 6}

¹Department of Physics and Astronomy, University of British Columbia, Vancouver, BC, Canada

²Massachusetts General Hospital/Harvard Medical School, Radiology, Boston, MA, USA

³Department of Medical Engineering, University of Luebeck, Luebeck, Schleswig-Holstein, Germany

⁴Division of Neurology, Department of Medicine, University of British Columbia, Vancouver, BC, Canada

⁵Department of Preclinical Imaging and Radiopharmacy, Werner Siemens Imaging Center, Eberhard-Karls University Tuebingen, Tuebingen Baden-Württemberg, Germany

⁶Djavad Mowafaghian Centre for Brain Health, Pacific Parkinson’s Research Centre, University of British Columbia, Vancouver, BC, Canada

Abstract

Introduction: In Parkinson’s disease (PD), different aspects of putaminal dopaminergic processing (synthesis, release and turnover) may be affected differently at different disease stages, thus following distinct spatio-temporal patterns. Differences in the patterns may reflect unique contributions from each aspect of dopaminergic processing to disease initiation, disease progression and potential compensatory mechanisms.^1,2 In this work, we investigated if distinct spatio-temporal patterns exist in different aspects of presynaptic dopamine alteration as disease progresses using multi-tracer Positron Emission Tomography (PET) and a previously published data-driven approach – dynamic mode decomposition (DMD).³

Methods: We applied DMD to three presynaptic PET tracers: [¹¹C]dihydrotetrabenazine (DTBZ, estimates dopaminergic integrity) in 70 PD patients, [¹¹C] d-threo-methylphenidate (MP, estimates dopamine reuptake) in 74 PD patients, and [¹⁸F]fluoro-L-DOPA (FD, reflects dopamine synthesis and storage) in 61 PD patients (disease duration: 1 to 22 years). The PET images were acquired on the CTI ECAT 953B ECAT scanner⁴ and DMD was applied to the parametric binding maps on the less and more affected putamen in the common space.

Results: DMD modes of all three tracers showed extremely similar anterior-posterior gradients in the less and more affected putamen (Figure 1); expressions of which decreased gradually with disease progression for all tracers (Figure 2). However, the initial expressions (intercepts) were significantly different (p < 10⁻⁵) with FD showing the highest and DTBZ showing the lowest intercept. FD and MP also showed significantly higher rates of decline for the gradient expression compared to DTBZ (p < 10⁻¹²), while there was no significant difference between FD and MP.

Conclusion: With this novel approach, we showed the expression of the gradient is more sensitive to disease progression than mean putaminal binding, suggesting a differential disease impact on the anterior and posterior putamen. While DTBZ mainly reflected direct disease-induced dopamine denervation, distinct temporal progression curves obtained with MP and FD may suggest upregulation of dopamine synthesis in the anterior putamen and downregulation of dopamine reuptake in the posterior putamen in early PD, consistent with previous finding obtained with univariate analysis on the same subject cohort,² which may be of compensatory nature. This compensatory mechanism may breakdown as the disease progresses, which can potentially contribute to progression of motor symptoms in advanced disease.

Acknowledgements

The authors thank the UBC PET scanning and the TRIUMF radio-chemistry production staff. The volunteer subjects who generously donated their time to this research are also most gratefully acknowledged. The study was financially supported by the Natural Sciences and Engineering Research Council of Canada (NSERC), Brain Canada, and Canadian Institutes of Health Research (CIHR) and Michael Smith Foundation of Health Research. AJS is supported by the Canada Research Chairs program. JF receives scholarship funding from the Isotopes for Science and Medicine program (NSERC-CREATE). TW is supported by ENEN+ project that has received funding from the EURATOM research and training Work Programme 2016–2017 (1#755576) and the PROMOS Study or Internship Abroad Scholarships which has received funding from the German Academic Exchange Service (DAAD). Inline graphic

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2021-14

Ketanserin can block but not displace [¹¹C]Cimbi-36 binding in the pig brain (#68)

Hanne D. Hansen^{1, 2}, Lene L. Donovan^{1, 3}, Nakul R. Raval^1,
3, Arafat Nasser¹, Szabolcs Lehel⁴, Claus Svarer¹, Martin Schain¹ and Gitte M. Knudsen^{1, 3}

¹Neurobiology Research Unit, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark

²Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, USA

³Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

⁴Department of Clinical Physiology, Nuclear Medicine and PET, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark

Abstract

Introduction: Changes in cerebral target binding following an intervention are conventionally estimated by performing two PET scans. Using this experimental design, the serotonin 2A receptor (5-HT_2AR) agonist PET tracer [¹¹C]Cimbi-36 has been used to measure the occupancy of ketanserin¹ and psilocybin.² Here, we aimed to estimate the occupancy of the 5-HT_2AR receptor antagonist ketanserin based on a single [¹¹C]Cimbi-36 PET scan.

Methods: In three anesthetized pigs, [¹¹C]Cimbi-36 was administrated using either bolus or bolus-infusion paradigms. Emission data was acquired for 120 min. Each pig underwent two measurements, one baseline and one with ketanserin (5 mg/kg) administrated intravenously ∼60 min after tracer injection. Arterial input measurements and radio-HPLC analyses were performed to allow for kinetic modelling using the 2-tissue compartment model.

Results: Unexpectedly, when ketanserin was administered 60 min after [¹¹C]Cimbi-36 bolus injection, the [¹¹C]Cimbi-36 time-activity curves did not differ from those obtained from the preceding baseline scan (Figure 1(a)), and the 5-HT_2AR occupancy was negligible (Figure 1(b)). When we reversed the scan-order in the second animal and gave the ketanserin within-scan challenge first, the [¹¹C]Cimbi-36 time-activity curves still did not show signs of displacement (Figure 1(c)). In the subsequent scan, however, 71% occupancy of the 5-HT_2AR was observed (Figure 1(d)). In the third animal, we used a bolus-infusion protocol (K_bol of 120 min) to obtain steady-state in cortex and plasma and now the within-scan ketanserin challenge resulted in a transient increase in the cortical [¹¹C]Cimbi-36 time-activity curve followed by noticeable wash-out of tracer from the cortex (Figure 1(e)). The corresponding cortex to plasma ratios also decreased after the ketanserin challenge (Figure 1(f)), consistent with ketanserin being able to block newly infused [¹¹C]Cimbi-36 but not to displace already bound [¹¹C]Cimbi-36.

Conclusion: [¹¹C]Cimbi-36 time-activity curves are not visibly altered by within-scan ketanserin injection, suggesting that [¹¹C]Cimbi-36 cannot be displaced from the 5-HT_2AR. In contrast, the antagonist 5-HT_2AR tracers [¹⁸F]MH.MZ and [¹⁸F]altanserin can be displaced by ketanserin.^2,3 We speculate whether the agonist properties of [¹¹C]Cimbi-36 causes the 5-HT_2AR to internalize and undergo conformational changes, thereby rendering the receptor inaccessible for ketanserin displacement.

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References

1.Ettrup A, da Cunha-Bang S, McMahon B, et al. Serotonin 2A receptor agonist binding in the human brain with [¹¹C]Cimbi-36. J Cereb Blood Flow Metab 2014; 34(7): 1188–96. [DOI] [PMC free article] [PubMed]
2.Madsen MK, Fisher PM, Burmester D, et al. Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels. Neuropsychopharmacology 2019; 44(7): 1328–1334. [DOI] [PMC free article] [PubMed]
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4.Pinborg LH, Adams KH, Svarer C, et al. Quantification of 5-HT2A Receptors in the Human Brain Using [18F] Altanserin-PET and the Bolus/Infusion Approach. J Cereb Blood Flow Metab 2003; 23(8): 985–996. [DOI] [PubMed]

2021-15

Alpha-synuclein preformed fibril (PFF)-triggered synucleinopathy recapitulates neurochemical features of human PD: a PET study in rats (#71)

Vesna Sossi¹, Joseph R. Patterson², Christopher J. Kemp², Kathryn M. Miller², Anna C. Stoll², Megan F. Duffy², Kelvin C. Luk³ and Caryl E. Sortwell²

¹Physics and Astronomy, University of British Columbia, Vancouver, BC, Canada

²Translational Neuroscience, Michigan State University, Grand Rapids, MI, USA

³Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA

Abstract

Introduction: Multiple progressive dopaminergic alterations in prodromal/manifest Parkinson’s disease (PD) have been identified with PET. Dopamine (DA) turnover increase (estimated as its inverse, the effective DA turnover (EDV); ∼ 60% reduction compared to controls in the putamen at symptom onset),¹ and a reduction in DA transporter (DAT) function (¹¹C-MP BP_ND; ∼ 55% reduction)² have been observed. In contrast, DA synthesis and storage (¹⁸F-Fdopa K_occ) is relatively preserved (∼30% reduction), likely reflecting synthesis upregulation contributing to the delay between disease and symptom onset² A recently developed PD model, induced by intracerebral injection of alpha-synuclein (a-syn) preformed fibrils (PFFs) to trigger accumulation of pathological a-syn inclusions showed progressive dopaminergic degeneration using immunohistochemical methods in a cross-sectional approach,³ with motor impairments only detectable at 6 months after PFF injection. Here we investigate (i) dopaminergic deficit longitudinally and (ii) its similarity to human PD using translational PET imaging.

Methods: 16 male Fischer 344 rats received unilateral intrastriatal injections of a-syn PFFs (n = 8) or vehicle (n = 8). Scans with ¹⁸F-Fdopa (EDV ratio (EDVR) for turnover and K_occ for DA synthesis)⁴ and ¹¹C-MP (BP_ND) were performed on a Siemens Focus 120 at 2, 4, and 6 months following injection.

Results: A significant progressive decrease in DAT binding in the ipsilateral striatum (65% reduction at 6 months) compared to controls was found together with a progressive decrease in EDVR (55% reduction) with relatively preserved DA synthesis and storage (15% reduction) (Figures 1 and 2). Contralateral side values remained in the normal range.

Conclusion: This progressive rat model of PD shows remarkable similarities to human PD: dopaminergic deficit progression with relative preservation of DA synthesis and storage compared to DA turnover and DAT function and measurable dopaminergic deficit preceding detectable motor impairments. Synucleinopathy and degeneration induced in the a-syn PFF model may be appropriate/useful to investigate disease modifying treatments and possibly more complex disease mechanisms.

Acknowledgements

Supported by NS099416 (CES).

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2021-16

Evaluation of MAO-B and TSPO PET radiotracers in a lipopolysaccharide rat model of neuroinflammation (#72)

Junchao Tong¹, Vidya Narayanaswami¹, Amanda J. Boyle¹, Ashley C. Knight¹, Christin Schifani¹, Peter Bloomfield¹ and Neil Vasdev^{1, 2}

¹Centre for Addiction and Mental Health, Azrieli Centre for Neuro-Radiochemistry, Brain Health Imaging Centre, Toronto, ON, Canada

²Department of Psychiatry, University of Toronto, Toronto, ON, Canada

Abstract

Introduction: The dynamic and multi-stage nature of neuroinflammation has prompted major efforts towards positron emission tomography (PET) radiotracer discovery targeting microglia and astrocyte activation for mechanistic and therapeutic advances of human psychiatric and neurodegenerative conditions.¹ The goal of the current study is to apply our 2nd generation translocator protein 18kDa (TSPO) radiotracer, [¹⁸F]FEPPA, to characterize a lipopolysaccharide (LPS) rodent model of neuroinflammation and extend this paradigm to monoamine oxidase B (MAO-B) using [¹¹C]L-deprenyl and [¹¹C]SL25.1188, as putative biomarkers of astrocyte activation.

Methods: An acute model of neuroinflammation was developed by unilateral intra-striatal injection of LPS in adult rats (50µg/4µL). Longitudinal PET/MR (Mediso nanoScan PET/MR 3T) scans were acquired up to 1 month following surgery. Regional brain time activity curves (TACs) were extracted using a stereotaxic MRI atlas implemented in PMOD (v4.004). Tracer binding potentials (BP) for the ipsilateral striatum were estimated using simplified reference tissue model with the contralateral side as the reference tissue. Autoradiography studies were conducted to determine [³H]L-deprenyl binding in vitro in rat brain 6 months post intra-striatal LPS injection.

Results: TACs extracted from the dynamic PET data demonstrated significantly increased [¹⁸F]FEPPA uptake in the LPS-injected striatum (see static images Figure 1), with a peak BP of 1.1 at ∼1 week after surgery. [¹⁸F]FEPPA uptake in the injected side decreased gradually over time, with a BP of 0.37 1-month post LPS injection. In contrast, preliminary data showed that, whereas in vitro autoradiography showed increased specific [³H]L-deprenyl binding in the LPS-injected striatum (Figure 2), there was no increase in PET binding of [¹¹C]SL25.1188; for [¹¹C]L-deprenyl, however, a trend toward increased uptake was observed from 2–4 weeks.

Conclusion: The intra-striatal LPS rat model may serve as a preliminary screening tool for benchmarking newly developed tracers targeted towards distinct neuroinflammatory mechanisms. In this respect, [¹¹C]SL25.1188 or [¹¹C]L-deprenyl MAO-B PET imaging might not be of sufficient sensitivity for imaging astrocyte activation in vivo in rodents. Further studies are underway to extend the LPS preclinical neuroinflammatory paradigm for glial activation to alternate PET biomarkers, including MAO-B radioligands.

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Reference

1.Narayanaswami V, Dahl K, Bernard-Gauthier V, et al. Emerging PET radiotracers and targets for imaging of neuroinflammation in neurodegenerative diseases: outlook beyond TSPO. Mol Imaging 2018; 17: 1536012118792317. [DOI] [PMC free article] [PubMed] [Google Scholar]

2021-17

Clinical measures of upper motor neuron burden strongly associate with neuroimaging in amyotrophic lateral sclerosis (#73)

Meena M. Makary^{1, 2}, Baileigh G. Hightower¹, Paul M. Cernasov³, Beverly V. Reynolds³, James Chan⁴, Olivia R. Pijanowski³, Chieh-En J. Tseng¹, Sabrina Paganoni³, Sheena Chew³, Nicole R. Zürcher¹, Jacob M. Hooker¹, Nazem Atassi^{3, 5} and Suma Babu³

¹Department of Radiology, A. A. Martinos Center for Biomedical Imaging, Harvard Medical School, Massachusetts General Hospital, Charlestown, MA, USA

²System and Biomedical Engineering Department, Cairo University, Cairo, Egypt

³Department of Neurology, Sean M Healey & AMG Center for ALS, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA

⁴Department of Biostatistics, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA

⁵Sanofi Genzyme, Cambridge, MA, USA

Abstract

Introduction: Several quantitative rating scales are used to objectively measure upper motor neuron burden/dysfunction (UMNB) in patients with amyotrophic lateral sclerosis (ALS).^1–4 However, their clinical relevance and relationship to neuroimaging findings are unknown. In this study, we correlated the MGH-UMNB and UPenn-UMNB clinical scales to (a) in-vivo brain expression of translocator protein 18kDa (TSPO) using [¹¹C]PBR28-PET imaging, (b) diffusion-MR imaging, and (c) clinical disease severity using ALS Functional Rating Scale-Revised (ALSFRS-R).

Methods: Thirty ALS patients (52.12 ± 10.75 years (mean ± SD), 14 Females) underwent simultaneous PET/MR imaging. The ALSFRS-R (ranges 0–48 and measures motor, bulbar and respiratory functional ability), UPenn-UMNB (a longer and more comprehensive scale, ranges 0–32 and measures hyperreflexia, pseudobulbar affect and spasticity), MGH-UMNB (shorter scale, ranges 0–45 and measures hyperreflexia) scales were collected from all participants at a matching time-point. [¹¹C]PBR28 standardized uptake value ratio (SUVR_60-90) normalized to whole-brain mean uptake was calculated.² Voxel-wise whole-brain correlation analysis was conducted between SUVR and clinical scales using FSL FEAT (Z > 2.3, P_cluster < 0.05). The skeletonized Fractional anisotropy (FA) was quantified using FSL-FDT and tract-based spatial statistics (TBSS) toolbox. Voxel-wise correlation analysis was then performed using nonparametric permutation (P_FWE < 0.05). [¹¹C]PBR28 SUVR_60-90 extracted from the bilateral primary motor cortices (M1)/paracental lobule (PCL) and FA values extracted from corticospinal tract (CST) were correlated with each clinical score. All analyses were corrected for sex and TSPO genotype.

Results: Both MGH- and UPenn-UMNB scales significantly correlated with: (1) ALSFRS-R (Figure 1(a)); (2) [¹¹C]PBR28 SUVR_60-90 uptake within M1/PCL on voxel-wise whole-brain analyses (Figure 1(b)) and ROI analyses (Figure 1(c)). TBSS correlation analysis revealed that skeletonized FA (Figure 2(a)) and FA values extracted from CST (Figure 2(b)) are strongly correlated with UPenn- and MGH-UMNB scales.

Conclusion: In this cross-sectional ALS cohort, both UPenn- and MGH-UMNB scales correlate significantly against each other and localize UMN dysfunction to biologically relevant M1 brain region where glial activation and CNS axonal degeneration is known to occur. Both UPenn-, MGH-UMNB scales are significantly correlated with clinical disability status in ALS. Further evaluation in a larger and longitudinal sample is required to better characterize the usefulness and application of these scales for early diagnosis, responsiveness to change over time and prediction potential in ALS.

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References

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2021-18

Development of novel PET ligands to image the receptor interacting protein kinase 1 (#77)

Hiroshi Ikenuma¹, Aya Ogata^{1, 2}, Hiroko Koyama³, Takashi Yamada¹, Junichiro Abe¹, Masanori Ichise¹, Takashi Kato¹, Masaaki Suzuki¹, Kengo Ito¹ and Yasuyuki Kimura¹

¹Department of Clinical and Experimental Neuroimaging, National Center for Geriatrics and Gerontology, Morioka-machi, Obu, Japan

²Department of Pharmacy, Gifu University of Medical Science, Kani, Japan

³Department of Chemistry and Biomolecular Science, Gifu University, Gifu, Japan

Abstract

Introduction: Microglia is involved in the pathophysiology of neurodegenerative diseases including Alzheimer’s disease (AD). Receptor Interacting Protein Kinase 1 (RIPK1), a cell-death regulatory factor located at the plasma membrane as a part of complex I, is involved in the process of a phenotypic transition from the homeostatic microglia to the disease-associated microglia. Therefore, molecular imaging of RIPK1 could provide useful information on the phenotypic transition of microglia as well as potential mechanisms leading to neuronal death. The purpose of this study is to develop novel PET ligands to image RIPK1 in the brain.

Methods: We labeled RIPK1 inhibitor GSK’963 and its enantiomer GSK’962¹ with [¹¹C]CH₃ to synthesize ¹¹C-GG502 and ¹¹C-GG503 respectively, by rapid cross-coupling, [¹¹C]methylation of the corresponding boron precursors with [¹¹C]CH₃I. The affinities of ¹¹C-GG502 and ¹¹C-GG503 to RIPK1 were evaluated by binding assays using cell lysate overexpressing human RIPK1. Their pharmacokinetics were evaluated by PET imaging with metabolite analysis in healthy rats as well as rats with acute neuroinflammation.

Results: Both ¹¹C-GG502 and ¹¹C-GG503 showed a high affinity to human RIPK1 in binding assays. PET scans in rats showed a high initial brain uptake and rapid washout for both ¹¹C-GG502 and ¹¹C-GG503. No clear difference in pharmacokinetics was observed between the two ligands. Metabolite analysis of ¹¹C-GG502 showed three major radiometabolites in the plasma, two of which also being detected in the brain. The rats with neuroinflammation showed no increased ligand uptake.

Conclusion: We developed two novel PET ligands,¹¹C-GG502 and ¹¹C-GG503, to image RIPK1 in the brain. Both showed high affinities in vitro. Specific binding PET signal of these two ligands was somewhat small. Based on the knowledge obtained here, however, we are hopeful to further develop RIPK1 ligands with specific binding signal sufficiently high for PET imaging.

Acknowledgements

This work was supported in part by a Grant-in-Aid for Creative Scientific Research (B) (JP18964417) from the Japan Society for the Promotion of Science (JSPS) and Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan. We would like to thank Ms. K. Yamashita for her assistance to synthesize boron labeling precursors and nonradiolabeled authentic samples.

Reference

1.Berger SB, Harris P, Gough PJ, et al. Characterization of GSK’963: a structurally distinct, potent and selective inhibitor of RIP1 kinase. Cell Death Discov 2015; 1: 15009. [DOI] [PMC free article] [PubMed] [Google Scholar]

2021-19

[¹⁸F]NOS PET measurement of in vivo neuroinflammation in Parkinson’s disease and healthy humans (#93)

Robert K. Doot¹, Anthony J. Young¹, Tiffany L. Dominguez¹, Zeinab Helili¹, Hsiaoju Lee¹, Regan Sheffer¹, Suzanne M. Reichwein², Erin K. Schubert¹, Andrew D. Siderowf², Henry R. Kranzler³, Robert H. Mach¹, Ilya M. Nasrallah¹ and Jacob G. Dubroff¹

¹Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

²Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

³Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

Abstract

Introduction: Parkinson’s disease (PD) is a progressive neurodegenerative disorder affecting 2% of the population over 60 years old¹. PD symptoms are thought to result from abnormal protein accumulation that triggers events including neuroinflammation.¹ Positron Emission Tomography (PET) imaging studies that target translocator protein (TSPO) have been used to measure neuroinflammation in Parkinson’s disease², but TSPO radiotracers have limitations.² [¹⁸F]6-(2-fluoro-propyl)-4-methylpyridin-2-amine ([¹⁸F]NOS) binds the inducible isoform of nitric oxide synthase, whose expression is induced by pro-inflammatory mediators.^3,4 Our goal is to test the feasibility of using [¹⁸F]NOS images to measure differences in regional neuroinflammation between healthy controls and PD patients.

Methods: Ten volunteers provided informed consent, including 4 healthy controls (mean ± SD age = 73 ± 9 y, 2F+2M) and 6 PD patients (age = 64 ± 5 y, 2F+4M), and underwent a 0–60 minute dynamic brain scan in a Philips Ingenuity PET/CT following bolus injection of [¹⁸F]NOS (209 ± 21 MBq), with serial arterial blood sampling and metabolite analysis. Each participant also underwent magnetic resonance imaging for brain segmentation and co-registration of PET images to enable generation of 19 combined left & right regional brain time activity curves. Regional total distribution volumes (V_T) were estimated using Logan plot⁵ and 1-tissue compartment (1TC) kinetic analyses and 1TC V_T parameter maps were generated using Pmod v3.7 software. Two-sample, 2-tailed equal variances t-tests compared V_T for controls with that of PD patients (SPSS v25).

Results: Population control and PD [¹⁸F]NOS V_T parameter maps are in Figure 1. All 19 brain regions exhibited higher V_T in PD patients than in controls for both Logan and 1TC models (p ≤ 0.01). Representative V_T values from 11 regions are in Figure 2.

Conclusion: PD patients had higher average V_T than controls in all brain regions, suggesting that PD subjects have higher levels of neuroinflammation than healthy controls.

Acknowledgements

Authors appreciate the contributions of Drs. Terence Gade and Gregory Nadolski for insertion of arterial blood lines. Research support was provided by Michael J. Fox Foundation (RM) and the United States of America’s National Institute on Drug Abuse of the National Institutes of Health under Award Numbers P30 DA046345 (RM), Foundation of the American Society of Neuroradiology Boerger Research Fund for Alzheimer’s Disease and Neurocognitive Disorders (IN), K01 DA040023 (RD), and K23 DA038726 (JD). Inline graphic

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References

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2021-20

Functional changes in Alzheimer’s disease evaluated by multimodality PET/MRI imaging (#96)

Hidehiko Okazawa¹, Masamichi Ikawa^{1, 2}, Jung Minyoung^1,
3, Tetsuya Tsujikawa¹, Tetsuya Mori¹, Akira Makino¹, Yasushi Kiyono¹ and Hirotaka Kosaka^{1, 3}

¹Biomedical Imaging Research Center, University of Fukui, Eiheiji-cho, Japan

²Department of Neurology, University of Fukui, Eiheiji-cho, Japan

³Department of Psychiatry, University of Fukui, Eiheiji-cho, Japan

Abstract

Introduction: Multimodal image data simultaneously obtained by [¹¹C]Pittsburgh compound-B (PiB) and [⁶⁴Cu]ATSM PET/MRI in the early stage of Alzheimer’s disease (AD) were evaluated to observe pathophysiologic and functional changes, as well as alteration of volumes and connectivity in the brain. Various neurophysiologic parameters were compared with healthy controls (CTL).

Methods: Thirty patients with mild cognitive impairment and early dementia (69 ± 12y), and 17 age-matched CTL subjects (68 ± 11y) underwent [¹¹C]PiB and [⁶⁴Cu]ATSM PET/MRI with 70- and 40-min dynamic PET/MRI, respectively. PET data were reconstructed into multiple images to calculate cerebral blood flow (CBF) using the early phase data and the image-derived input function (IDIF) method, where time-activity curves of the arteries were extracted from PET images. Standardized uptake value ratio (SUVr) was calculated from the last 20-min PET data using the cerebellar cortex as a reference region. The MR images of 3D-T1WI, resting-state functional MRI (RS-fMRI), diffusion tensor image (DTI) and perfusion MRI from the arterial spin labeling (ASL) method acquired during the dynamic PET were also analyzed to evaluate various brain functions on MRI.

Results: All patients were determined as the early stage AD based on the result of [¹¹C]PiB-PET and clinical findings. PiB-SUVr values in all AD cerebral cortices were significantly greater than those of CTL. The regional PET-CBF values of AD showed significantly lower values in the bilateral parietal and right temporal lobes compared with CTL, but not in ASL-MRI; however, SPM showed regional differences in both PET- and ASL-CBF. SPM analysis of RS-fMRI delineated differences in the anterior cingulate cortex and in the left precuneus. VBM analysis showed atrophic changes of the AD brain in the bilateral hippocampus. However, analysis of fractional anisotropy calculated from DTI did not show differences between the two groups. [⁶⁴Cu]ATSM-SUVr images also showed differences between AD and CTL.

Conclusion: Multimodal analyses using PET/MRI scans showed differences in regional CBF, cortical volume and neuronal networks in different regions, indicating that pathophysiologic and functional changes in the AD brain can be observed in various aspects of neurophysiologic parameters. Assessment of multimodal images would be ideal to investigate pathophysiologic changes in patients with dementia and other neurodegenerative diseases.

Acknowledgements

This study was partly supported by JSPS (18H02763).

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References

1.Okazawa H, Higashino Y, Tsujikawa T, et al. Noninvasive method for measurement of cerebral blood flow using O-15 water PET/MRI with ASL correlation. Eur J Radiol 2018; 105: 102–109. [DOI] [PubMed] [Google Scholar]
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2021-21

PET imaging of [¹¹C]NCGG401 for colony stimulating factor 1 receptor (#111)

Aya Ogata^{1, 2}, Takashi Yamada¹, Junichiro Abe¹, Masanori Ichise¹, Hiroshi Ikenuma¹, Hiroko Koyama³, Masaaki Suzuki¹, Takashi Kato¹, Kengo Ito¹ and Yasuyuki Kimura¹

¹Department of Clinical and Experimental Neuroimaging, National Center for Geriatrics and Gerontology, Obu, Japan

²Department of Pharmacy, Gifu University of Medical Science, Kani, Japan

³Department of Chemistry and Biomolecular Science, Gifu University, Gifu, Japan

Abstract

Introduction: Activated microglia are involved in the pathophysiology of Alzheimer’s disease and other neurodegenerative diseases. These glial cells have recently been recognized as a promising target for the treatment of these diseases. Here, positron emission tomography (PET) imaging of specific molecules for microglia could provide useful information needed for developing drugs that target these cells. We have been developing a PET ligand for imaging the colony stimulating factor 1 receptor (CSF1R). CSF1R is expressed exclusively on microglia. In this study, we evaluated the potential of this novel PET ligand for imaging CSF1R in rat brains using models of brain inflammation.

Methods: [¹¹C]NCGG401, our PET ligand, which is modified from a specific CSF1R inhibitor BLZ945,¹ was synthesized with a high radiochemical purity (>99%). We conducted 120-min dynamic PET scans with radioactive metabolite analyses in healthy rats with or without pre-administration of unlabeled NCGG401. The total distribution volume was calculated with the dual-input graphical analysis.² Subsequently, we conducted PET scans in rats of brain inflammation to evaluate the ligand’s kinetics in the microglia activated brain. Also, the expression of CSF1R in the brain was evaluated ex-vivo and compared with the results of PET imaging.

Results: [¹¹C]NCGG401 brain radioactivity showed a fast initial peak and good washout thereafter in the healthy rats. Pre-administration of unlabeled NCGG401 increased the rate of washout. The whole brain distribution volume decreased by 20% with blocking. The model rats of brain inflammation showed increased expression of CSF1R and two-times higher distribution volumes than did the healthy rats. However, no regional difference was observed probably because of the very low total expression of CSF1R in the rat brain.

Conclusion: Further studies appear warranted to confirm our findings in other rat inflammation models. In addition, knowledge of the characteristics of [¹¹C]NCCC401, our initial CSF1R compound, we have obtained may be useful for further development and optimization of CSF1R radioligands for PET imaging of microglia.

Acknowledgements

We would like to thank Drs. Bin Ji, Maiko Ono, Chie Seki, Satoka Hashimoto, Yuji Nagai, Takafumi Minamimoto, Xaioyun Zhou, Makoto Higuchi from National Institutes for Quantum and Radiological Science and Technology. This work was supported in part by a Grant-in-Aid for Creative Scientific Research (B) (JP18964417) from the Japan Society for the Promotion of Science (JSPS) and Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan.

References

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2021-22

Development of ¹⁸F-labeled radioligands for the GluN2B subunits of NMDA receptors: Synthesis and evaluation in non-human primates (#123)

Ming-Qiang Zheng¹, Hazem Ahmed², Kelly Smart¹, Yuping Xu³, Li Zhang¹, Jim Ropchan¹, Hong Gao¹, Roger Schibli², Gilles Tamagnan¹, Richard E. Carson¹, Yiyun H. Huang¹ and Simon M. Ametamey²

¹Yale PET Center, Yale University, New Haven, CT, USA

²Institute of Pharmaceutical Sciences, ETH Zurich, Zürich, Switzerland

³Jiangsu Atomic Institute, Wuxi, China

Abstract

Introduction: There is a great interest in developing PET radioligands for the GluN2B subunits of the N-methyl-D-aspartate (NMDA) receptors in humans. Previous in vitro and in vivo studies in rodents have shown (R)- and (S)-¹⁸F-OF-Me-NB1 to have promising binding properties to the GluN2B subunits [1]. Here we report the evaluation of these two radioligands and their corresponding demethylated analogs ( ± )¹⁸F-OF-NB1 and (R)-¹⁸F-OF-NB1 in rhesus monkeys.

Methods: Enantiopure (R)- and (S)-¹⁸F-OF-Me-NB1 were synthesized using the corresponding chiral precursors as reported previously.¹ ( ± )-¹⁸F-OF-NB1 and enantiopure (R)-¹⁸F-OF-NB1 were prepared by copper-catalyzed ¹⁸F-ﬂuorination of the protected boronic precursor followed by cleavage of the protecting groups. PET scans of up to 180 min each in rhesus monkeys were conducted on the Focus 220 scanner. Metabolite analysis was performed and arterial input function was calculated. Regional brain time activity curves were generated and analyzed with the one-tissue compartment (1TC) model and multilinear analysis-1 (MA1) method to obtain the respective regional volumes of distribution (V_T).

Results: All radiotracers were prepared in > 95% radiochemical purity, and > 95% enantiomeric purity for the chiral compounds. In rhesus monkey metabolism was moderate with ∼30% of parent compound for (R)-¹⁸F-OF-Me-NB1 at 30 min post-injection, and ∼18% for (S)-¹⁸F-OF-Me-NB1. For ( ± )-¹⁸F-OF-NB1 and (R)-¹⁸F-OF-NB1, 26% and 57% of the parent radioligands were found at 30 min. All radiotracers displayed high uptake and similar pattern of regional distribution in the monkey brain. Highest uptake was observed in the putamen, hippocampus and thalamus, medium in the occipital cortex and cerebellum, and low in the white matter (centrum semiovale). Clearance from brain regions was the fastest for (R)- and (S)-¹⁸F-OF-Me-NB1, followed by ( ± )-¹⁸F-OF-NB1, and slowest for (R)-¹⁸F-OF-NB1 (Figure 1). Regional 1TC and MA1 V_T values for these four radioligands are listed in the table and higher for ( ± )-¹⁸F-OF-NB1 and (R)-¹⁸F-OF-NB1 than (R)- and (S)-¹⁸F-OF-Me-NB1.

Conclusion: We have successfully synthesized and evaluated four radioligands targeting the GluN2B subunits of NMDA receptors in non-human primate. Blocking studies are ongoing to assess their binding speciﬁcity and selectivity.

Acknowledgements

Research support1. The Swiss National Science Foundation Grant Nos. 310030E_160403/1 and 310030E_182872/1. 2. NIH grant U01MH107803

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References

1.Haider A, et al. Identification and Preclinical Evaluation of a Radiofluorinated Benzazepine Derivative for Imaging the GluN2B Subunit of the Ionotropic NMDA Receptor. J Nucl Med 2019; 60:259–266. [DOI] [PMC free article] [PubMed] [Google Scholar]

2021-23

Validation of PET-compatible chemogenetic tools in squirrel monkeys (#125)

Matthew Boehm^{1, 2}, Hank Jedema¹, Jordi Bonaventura¹, Omar Gharbawie³, Juan Gomez¹, Elliot Stein¹, Charles Bradberry¹ and Michael Michaelides^{1, 4}

¹National Institute on Drug Abuse, NIH Intramural Research Program, Baltimore, MD, USA

²Department of Neuroscience, Brown University, Providence, RI, USA

³Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA, USA

⁴Department of Psychiatry & Behavioral Sciences, Johns Hopkins Medicine, Baltimore, MD, USA

Abstract

Introduction: Chemogenetic technologies offer an innovative approach for modulating activity of specific cell types in targeted brain regions. Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), and the recently developed Pharmacologically Selective Actuator Modules (PSAMs), are two types of chemogenetic systems used to modulate neural activity. Current applications of these tools in primates and humans is limited in part by an inability to track the location and function of chemogenetic receptors in vivo. Positron emission tomography (PET) is a translational molecular imaging modality uniquely poised to enable in vivo confirmation of expression and function of chemogenetic systems. Recent studies have demonstrated the use of PET-reporter ligands for imaging chemogenetic receptors, namely [¹⁸F]-JHU37107 for DREADDs and [¹⁸F]-ASEM for PSAMs. In addition, newly developed actuator ligands JHU37160 and uPSEM⁸¹⁷ claim improved selectivity and potency at DREADDs and PSAMs, respectively. Here we employ PET imaging methods to test the function of these chemogenetic ligands in squirrel monkeys (Saimiri sciureus).

Methods: Four monkeys underwent baseline scans with the PET-reporter ligands [¹⁸F]-JHU37107 and [¹⁸F]-ASEM (∼1.5mCi, bolus i.v.). Baseline scans were also performed with [¹⁸F]-fluorodeoxyglucose (FDG) as a measure of brain activity following saline or pretreatment with JHU37160 or uPSEM⁸¹⁷ (0.1mg/kg, i.v.). Following baseline scans, monkeys were injected with AAV2/5-hSyn-HA-hM3Dq and AAV2/5-Syn1-PSAM⁴-GlyR in left hand/forelimb area of motor cortex. PET scans with [¹⁸F]-JHU37107, [¹⁸F]-ASEM and FDG will be repeated and compared with baseline scans to determine the location of chemogenetic receptors and their effects on brain activity.

Results: In baseline PET-reporter scans, [¹⁸F]-JHU37107 signal in the brain peaked at 10min post-injection and remained detectable after 90min, indicating some level of endogenous binding. Similarly, [¹⁸F]-ASEM signal peaked at 20min post-injection and remained detectable at 90min (n = 4). FDG-PET scans revealed rapid uptake of FDG in the brain, with over 95% occurring by 5min post-injection. In addition, scans following administration of JHU37160 or uPSEM⁸¹⁷ showed no significant differences compared to baseline saline scans, suggesting these ligands do not produce off-target effects on brain activity (n = 4).

Conclusion: These findings support the use of recently developed PET-reporters and actuator ligands for DREADDs and PSAMs.

Acknowledgements

This research was supported [in part] by the Intramural Research Program of the NIH, NIDA

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References

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2021-24

Increased cerebral glucose consumption during hypoglycemia in obese patients measured using dynamic bolus-injection ¹⁸F-FDG PET/MR during hyperinsulinemic euglycemic and hypoglycemic clamp (#138)

Mark Lubberink¹, Sofia Kvernby¹, Niklas Abrahamsson², Kristina Almby², Markus Fahlstrom¹, Malin Gingnell³, Sven Haller¹, Johan Wikström¹, Magnus Sundbom¹, Anders Karlsson² and Jan Eriksson²

¹Surgical Sciences/Radiology & Nuclear Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden

²Medical Sciences, Uppsala University Hospital, Uppsala University, Uppsala, Sweden

³Psychiatry, Uppsala University Hospital, Uppsala University, Uppsala, Sweden

Abstract

Introduction: Obese patients develop less symptoms and hormonal response during hypoglycemia after gastric bypass surgery (GBP) than before.¹ However, it is not known whether cerebral glucose consumption and/or blood flow (CBF), and their response to hypoglycemia, change in obese patients after gastric bypass surgery. The aim of the present work was to develop methodology and assess glucose metabolism and cerebral blood flow (CBF) response to hypoglycemia in obese patients using simultaneous PET/MR.

Methods: Eight non-diabetic obese subjects (BMI 35–45) underwent 120-min dynamic scans after bolus injection of 5 MBq/kg ¹⁸F-FDG on a Signa PET/MR. Plasma glucose levels were stabilized using a hyperinsulinemic-euglyclemic clamp, resulting in normal glycemia with a plasma glucose concentration of 5 mmol/L during the first 50 min of the scan. Between circa 50 and 80 min p.i., plasma glucose concentration was decreased to 2.7 mmol/L. Blood samples were taken to measure plasma glucose and radioactivity. Net uptake rate of ¹⁸F-FDG (K_i) and metabolic rate of glucose (MR_glu) during euglycemia and hypoglycemia were calculated using a dual-phase basis function implementation of the irreversible two-tissue compartment (2T3k) model allowing for a change in rate constants during the glucose reduction phase, both for whole brain grey matter and at the voxel level. Changes between euglycemic and hypoglycemic CBF were assessed using simultaneous pseudo-continuous arterial spin labelling (pcASL). Accuracy and precision of the dual-phase model were assessed using numerical simulations.

Results: Mean K_i increased significantly from 0.025 ± 0.003 mL/cm³/min during normal glycemia to 0.059 ± 0012 mL/cm³/min during hypoglycemia (p = 0.08, Wilcoxon), corresponding to a significant increase of MR_glu from 0.13 ± 0.01 to 0.16 ± 0.03 µmol/cm³/min (p = 0.015). No significant changes in CBF were found. Agreement between K_i values for normal glycemia based on the dual-phase model and 2T3k was high. Simulations showed a high correlation and agreement between simulated and fitted K_i values both at normal glycemia and hypoglycemia. Voxel-based results agreed well with whole brain gray matter results.

Conclusion: Simulations indicate that the dual-phase basis function method is able to robustly measure changes in glucose metabolism. Hypoglycemia appears to result in an overcompensation of glucose uptake rate in obese patients, resulting in slightly but significantly increased glucose metabolism compared to normal glycemia.

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Reference

1.Abrahamsson et al. Gastric Bypass Reduces Symptoms and Hormonal Responses in Hypoglycemia. Diabetes 2016; 65(9): 2667–2675. [DOI] [PubMed]

2021-25

Dopamine release after fear conditioning as measured using bolus-infusion¹¹C-raclopride PET-MRI (#139)

Mark Lubberink¹, Andreas Frick², Johannes Björkstrand³, Fredrik Åhs³ and Mats Fredriksson³

¹Surgical Sciences/Radiology & Nuclear Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden

²Neurology, Uppsala University Hospital, Uppsala University, Uppsala, Sweden

³Psychology, Uppsala University, Uppsala, Sweden

Abstract

Introduction: Dopamine transmission is suggested to be crucial for aversive learning, as has been shown in animal studies. However, studies on the importance of dopamine release in human fear conditioning are lacking. The aim of the present study was to investigate dopamine release in striatum and amygdala during fear conditioning in healthy humans. In addition to equilibrium analysis and lp-ntPET,¹ a nested version of SRTM² was evaluated for assessment of dopamine release.

Methods: Eighteen volunteers underwent 90 min ¹¹C-raclopride scans using a bolus-infusion protocol on a Signa PET/MR scanner (GE Healthcare). Fifty minutes after injection start, participants underwent a 20 min differential fear conditioning paradigm, pairing one cue (CS+) with an aversive electrical shock while another cue (CS-) was never paired with a shock. Changes in raclopride binding were assessed by equilibrium analysis, using lp-ntPET, and using a nested version of SRTM (SRTMnt). In this last case, BP_ND, R₁ and k’₂ were estimated for the first 45 min, and then R₁ and k’₂ were fixed for a fit to the last 20 min of data after conditioning. Accuracy and precision of SRTMnt were evaluated using simulations where dopamine release was described by gamma variate functions. Skin conductance response (SCR) to CS+ minus CS- served as the autonomic fear conditioning index.

Results: ¹¹C-raclopride BP_ND based on SRTMnt was significantly reduced following fear conditioning by 5.4, 5.1 and 13.4% in putamen, caudate and amygdala, respectively (p < 0.03). A significant correlation between changes in BP_ND across all three methods was found. Simulations showed that SRTMnt could accurately measure changes in BP_ND provided that dopamine release was persistent to the end of the scan, without requiring equilibrium, and that results were insensitive to changes in R₁. Changes in BP_ND based on SRTMnt and equilibrium analysis in amygdala correlated with SCR (r = 0.54, p = 0.22 for SRTMnt).

Conclusion: SRTMnt provided a robust, easily implemented alternative for assessment of dopamine release induced changes in BP_ND provided that increased dopamine concentrations are persistent, which has previously been shown to be the case by microdialysis in amygdala in similar fear conditioning experiments in rodents. A significant correlation between dopamine release induced changes in BP_ND in amygdala and fear conditioning was found.

References

1.Normandin MD, Schiffer WK, Morris ED. ▪▪▪. Neuroimage 2012; 59(3): 2689–99. [DOI] [PMC free article] [PubMed] [Google Scholar]
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2021-26

Analysis of the expression of norepinephrine transporter and neuronal plasticity-related proteins in social isolation model rats (#141)

Yasushi Kiyono¹, Naoto Omata², Hiyori Matsumoto³, Tomoyuki Mizuno³, Kayo Mita³, Hirotaka Kosaka³ and Hidehiko Okazawa¹

¹Biomedical Imaging Research Center, University of Fukui, Yoshida-Gun, Japan

²Department of Nursing, Fukui Health Science University, Fukui, Japan

³Department of Neuropsychiatry, University of Fukui, Yoshida-Gun, Japan

Abstract

Introduction: Social isolation (SI) is closely associated with depression, but extended SI particularly from the early stage of the development can cause violence or aggression. As the pathogenesis of mood disorder, the dysfunction of the central norepinephrine (NE) system or the damage in neuronal plasticity is thought to be involved. Abnormality of the brain norepinephrine transporter (NET) has been reported in several psychiatric and neuronal disorders. Recently we developed radiobromine-labeled (S,S)-2-(α-(2-bromophenoxy)benzyl)morpholine ((SS)-BPBM) as a PET probe for brain NET imaging. Therefore, we applied (SS)-BPBM to SI model rats for analyzing the expression of NET in this study. In addition, we evaluated the expression of the neuronal plasticity-related proteins in SI model rats.

Methods: SI was loaded by housing each rat individually for 3 weeks or 8 weeks, and the rats of control group were housed in group for same period as SI-loaded group. Elevated pulse maze test and forced swim test were performed to evaluate behavior of rats. For analyzing the expression of NET, ex vivo autoradiography using (SS)-[⁷⁷Br]BPBM were performed. NE metabolite (MHPG) in the blood was measured by HPLC combined with electrochemical detection. The expression of brain-derived neurotrophic factor (BDNF), phosphorylated cyclic AMP (cAMP) responsive element binding protein (pCREB), and post-synaptic density 95 (PSD95) was estimated by western blotting.

Results: After SI for 3 weeks, depressive-like behavior appeared. But paradoxically, the extension of SI to 8 weeks reduced depressive-like and anxiety-related behaviors than control. The expression of NET was not changed in each duration compared with control. SI for 3 weeks reduced the expression of BDNF than control in the hippocampus, and the changes of the expression of neuronal plasticity-related proteins were more prominent after SI for 8 weeks.

Conclusion: Brief SI induced depressive-like behavior and extended SI induced manic-like behavior in rats. Furthermore, accompanied by the extension of the duration of SI, the damage in neuronal plasticity became more severe, but the dysfunction of the central NE system was not observed.

Acknowledgements

This work was supported by JSPS KAKENHI Grant Number 16K10208, 18H02764, 18K15511, and 19K08030.

2021-27

Tau pathology is associated with synaptic loss and altered synaptic function: a combined [¹⁸F]flortaucipir, [¹¹C]UCB-J and magnetoencephalography study (#145)

Emma M. Coomans^{1, 2}, Deborah Schoonhoven^{2, 3}, Hayel Tuncel¹, Sander C.J. Verfaillie¹, Emma E. Wolters^{1, 2}, Ronald Boellaard¹, Rik Ossenkoppele^{2, 4}, Wiep Scheper^2,
5, Patrick Schober⁶, Steven P. Sweeney⁷, Michael J. Ryan⁷, Robert C. Schuit¹, Albert D. Windhorst¹, Frederik Barkhof^{1, 8}, Philip Scheltens², Sandeep S.V. Golla¹, Arjan Hillebrand³, Alida Gouw^{2, 3} and Bart N.M. van Berckel¹

¹Department of Radiology & Nuclear Medicine, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, Netherlands

²Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, Netherlands

³Department of Clinical Neurophysiology and MEG Center, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, Netherlands

⁴Clinical Memory Research Unit, Lund University, Lund, Sweden

⁵Center for Neurogenomics and Cognitive Research, Department of Functional Genomics, Faculty of Science, Vrije Universiteit Amsterdam, Amsterdam, Netherlands

⁶Department of Anaesthesiology, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, Netherlands

⁷Rodin Therapeutics Inc., Boston, MA, USA

⁸Institute of Neurology, UCL, London, UK

Abstract

Introduction: The mechanisms contributing to synaptic loss in Alzheimer’s disease (AD) are poorly understood and may be associated with tau pathology. In this combined positron emission tomography (PET) and magnetoencephalography (MEG) study, we therefore investigated associations between tau ([¹⁸F]flortaucipir PET), synaptic density (synaptic vesicle 2A [¹¹C]UCB-J PET) and synaptic function (MEG) in AD.

Methods: Seven amyloid-positive AD subjects (age 64.3 ± 8.2; 3/7 female; MMSE 24.1 ± 1.8) were included from the Amsterdam Dementia Cohort. All subjects underwent dynamic 130-min [¹⁸F]flortaucipir and 60-min [¹¹C]UCB-J PET with arterial sampling. Six subjects underwent 10-min eyes-closed 306-channel MEG. [¹⁸F]flortaucipir binding potential (BP_ND) was determined with receptor parametric mapping (reference region: cerebellar gray matter) with partial volume correction. [¹¹C]UCB-J BP_ND (DVR-1, plasma input-derived) was obtained using the centrum semi-ovale as reference region. [¹⁸F]flortaucipir BP_ND, [¹¹C]UCB-J BP_ND and MEG spectral measures (total power (0.5–48 Hz), peak frequency, and relative delta (0.5–4 Hz), theta (4–8 Hz) and alpha (8–13 Hz) power) were calculated in 12 bilateral a priori defined temporal, parietal, frontal and occipital region-of-interests (ROIs). We used Spearman correlations and generalized estimating equations (GEE), correcting for multiple ROIs per subject, to investigate associations between [¹⁸F]flortaucipir, [¹¹C]UCB-J and MEG. Analyses with MEG were stratified per brain lobe. Additionally, within-subject regional correlations (Spearman) between [¹⁸F]flortaucipir and [¹¹C]UCB-J were performed.

Results: Higher [¹⁸F]flortaucipir BP_ND was associated with lower [¹¹C]UCB-J BP_ND (β = -0.30, p < 0.001) (Figure 1(a) and (b)). Within subjects, negative associations were observed when neocortical tauwas high, while positive associations were observed when neocortical tau was low (Figure 1(c)). Additionally, higher [¹⁸F]flortaucipirwas strongly associated with oscillatory slowing, reflected by negative associations with peak frequency and alpha power, and positive associations with delta or theta power. In contrast, lower [¹¹C]UCB-J binding was associated with lower peak frequency and alpha power, and higher delta power, most clearly in the occipital lobe (Table 1).

Conclusion: Across subjects, higher regional tau pathology was associated with synaptic loss, while within subjects, this association depended on subjects’ neocortical tau levels. Moreover, higher tau pathology and synaptic loss were associated with oscillatory slowing. This suggests that tau is associated with synaptic loss and reduced synaptic activity, yet that a tau-threshold may need to be reached before regional synaptic loss occurs.

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2021-28

Effect of 5-day regular coffee consumption and subsequent abstention on A₁ adenosine receptor occupancy and availability (#156)

David Elmenhorst¹, Eva-Maria Elmenhorst², Denise Lange², Judith Fronczek-Poncelet¹, Diego M. Baur³, Simone Beer¹, Anna L. Pierling¹, Tina Kroll¹, Bernd Neumaier⁴, Daniel Aeschbach^{2, 5}, Andreas Bauer^{1, 6} and Hans-Peter Landolt³

¹Institute of Neuroscience and Medicine (INM-2), Forschungszentrum Jülich, Jülich, Germany

²German Aerospace Center, Institute of Aerospace Medicine, Cologne, Germany

³Institute of Pharmacology & Toxicology, University of Zurich, Zurich, Switzerland

⁴Forschungszentrum Jülich, Institute of Neuroscience and Medicine (INM-5), Jülich, Germany

⁵Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA

⁶Department of Neurology, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany

Abstract

Introduction: The stimulating effects of commonly consumed caffeine, the major psychostimulant ingredient of coffee, are evoked through non-selective antagonism at adenosine receptors. [¹⁸F]CPFPX is a highly selective and affine ligand at the A₁ adenosine receptor (A₁AR) and has been successfully implemented as PET ligand. Here, we quantified by [¹⁸F]CPFPX PET the in vivo brain occupancy of A₁AR after short-term coffee consumption during sleep restriction and subsequent abstinence in the human brain.

Methods: Nine healthy volunteers (29 ± 5 years, 4f/5m) completed an 8-day in-lab study including 3 x 110-min bolus plus constant infusion [¹⁸F]CPFPX PET experiments. After a baseline PET scan in the afternoon following 2 weeks of caffeine abstinence, participants consumed freshly brewed coffee for 5 consecutive days, while time in bed was restricted to 5 h per night. The administered coffee contained 200 mg caffeine at 7:30 h and 100 mg caffeine at 14:00 h. Subsequent PET scans were conducted at the same time of day as in baseline, roughly 7 h after final coffee intake in the morning and after ∼ 31 h of coffee abstention including an 8 h-sleep episode. Metabolite corrected blood samples were used to calculate steady-state distribution volumes (V_T) (i.e., 50–100 min after start of [¹⁸F]CPFPX administration). Caffeine levels in saliva were determined regularly. Occupancy levels were calculated by applying the Lassen plot including cortical and subcortical areas, cerebellum and pons.

Results: Dependent on the resulting plasma concentrations of caffeine, [¹⁸F]CPFPX binding was reduced between 7 and 38%. The caffeine-dose to A₁AR-occupancy relation was comparable to the previously estimated relation with an IC50 of 67 µM in plasma corresponding to 460 mg caffeine per 70 kg subject (approximately 4.5 cups of coffee). One day after coffee abstention, V_T values did not differ from baseline.

Conclusion: Our preliminary data suggest that the consumption of 3 cups of coffee for 5 days does not alter A₁AR brain availability after 24 h hours of caffeine abstention.

Acknowledgements

The work was supported by the Institute for Scientific Information on Coffee, the Swiss National Science Foundation (# 320030_163439) and respective institutional funds.

2021-29

The influence of scanning time window on 18F-FP-DTBZ PET in PD (#158)

Shu-Ying Liu^{1, 2}, Hong-Wen Qiao³, Cai-Yun Qi¹, Zhu-Qin Gu², Olivier Barret⁴, Gilles Tamagnan⁵ and Piu Chan^{1, 2}

¹Department of Neurology, Xuanwu Hospital Capital Medical University, Beijing, China

²National Clinical Research Center for Geriatric Disorders, Beijing, China

³Department of Nuclear Medicine, Xuanwu Hospital Capital Medical University, Beijing, China

⁴Molecular Imaging Research Center, French Atomic Energy Commission, Laboratory of Neurodegenerative Diseases, Fontenay-aux-roses, France

⁵XingImaging, LLC, New Haven, CT, USA

Abstract

Introduction: In this study, we investigate the influence of scanning time window on the standardized uptake value ratios (SUVR) of 18F-FP-DTBZ PET in PD patients.

Methods: 191 patients with Parkinson’s disease (Table 1) were recruited from the movement disorder clinics and ward in Xuanwu Hospital between January 2017 and August 2019. Participants were diagnosed by movement disorder neurologists on the basis of the 2015 movement disorder society criteria. Participants were scanned for 15 minutes at around 50, 70, 90 or 110 minutes after an intravenous bolus injection of 18F-FP-DTBZ. The primary outcome measure was the caudate and putamen SUVR using the occipital cortex as the reference. We applied generalized linear models to control for age, gender and MDSUPDRSIII scores.

Results: There were 84 participants scanned within 60 minutes, 68 scanned between 60 to 80 minutes, 28 scanned between 80 to 100 minutes, and 11 scanned after 100 minutes post injection. We did not observe between-group difference of caudate and putamen SUVR (P > 0.05, Table 2). The SUVR correlated with Hoehn & Yahr stages and MDSUPDRSIII scores, but was not influenced by the scanning time window after adjusted for gender and MDSUPDRSIII scores (Table 3).

Conclusion: The standardized uptake value ratios of ¹⁸F-FP-DTBZ PET was not influenced by the scanning time window after 30 minutes of injection as equilibrium could be reached early in this cohort of PD patients. Further work will investigate the SUVRs of different frames after injection and possibly with arterial sampling data.

Acknowledgements

The National Key R&D Program of China, No. 2018YFC1312001, 2017YFC0840105; National Natural Science Foundation of China, No. 81901285. 81701726; Beijing Municipal Science & Technology Commission No. Z171100000117013. Inline graphic

2021-30

Sex-related differences in cerebral A₁ adenosine receptor availability in the human brain (#160)

Anna L. Pierling¹, Eva-Maria Elmenhorst², Denise Lange², Eva Hennecke², Diego M. Baur³, Simone Beer¹, Tina Kroll¹, Bernd Neumaier⁴, Daniel Aeschbach^{2, 5}, Andreas Bauer^{1, 6}, Hans-Peter Landolt³ and David Elmenhorst¹

¹Institute of Neuroscience and Medicine (INM-2), Forschungszentrum Jülich, Jülich, Germany

²Institute of Aerospace Medicine, German Aerospace Center, Cologne, Germany

³Institute of Pharmacology & Toxicology, University of Zurich, Zürich, Switzerland

⁴Forschungszentrum Jülich, Institute of Neuroscience and Medicine (INM-5), Jülich, Germany

⁵Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA

⁶Department of Neurology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany

Abstract

Introduction: Sex differences have been reported in terms of sleep duration, sleep efficiency, and sleep phases. Adenosine and its cerebral receptors, A₁ adenosine receptor (A₁AR) and A_2A adenosine receptor (A_2AAR), play an important role in homeostatic sleep-wake regulation. During wakefulness adenosine concentration increases, whereas it decreases during sleep. We investigated sex differences in the adenosine A₁AR availability in human volunteers.

Methods: We used the radioligand [¹⁸F]CPFPX combined with positron emission tomography to quantify brain A₁AR availability in 50 volunteers (20 female, 30 male, 28 ± 5 years). Following a one-week ambulatory sleep satiation protocol (9 hours time in bed, TIB), scans were performed under well-rested conditions after at least three nights in the sleep lab with 8 hours TIB. The A₁AR availability was estimated in terms of the [¹⁸F]CPFPX binding potential (BP_ND) via the Logan’s reference tissue model (t* = 30 min) based on average k2’, resulting from the simplified reference tissue model. The cerebellum was used as a reference region. With independent t-tests we compared BP_ND between males and females.

Results: Grey matter was subdivided into 12 regions. BP_ND was regionally 12–29% higher in females than in males. Notably, in females, BP_ND was significantly higher in all brain regions indicating higher A₁AR availability in females. The differences in BP_ND were particularly noticeable in regions which belong to the limbic system or are closely associated with it, such as anterior cingulum (0.57 ± 0.11 in females, 0.45 ± 0.11 in males), hippocampus (0.55 ± 0.08 in females, 0.43 ± 0.11 in males), and amygdala (0.51 ± 0.10 in females, 0.41 ± 0.11 in males).

Conclusion: Females compared to males have a higher A₁AR availability in the human brain already under well-rested conditions, which could explain the known sex differences in habitual sleep duration.

Acknowledgements

We thank all volunteers for participating in the studies, and Sylvia Köhler-Dibowski from the Forschungszentrum Jülich and Annette von Waechter of the German Aerospace Center for their excellent technical assistance and support in study conductance.

2021-31

[18F]FDOPA PET imaging for prediction of treatment response in psychosis (#169)

Giovanna Nordio¹, Rubaida Easmin¹, Barbara Santangelo^1,
2, Sameer Jauhar², Enrico d’Ambrosio^{2, 3}, Arsime Demjaha², Hugh Salimbeni⁴, Jin Huajie⁵, Paul McCrone⁵, Federico E. Turkheimer¹, Oliver D. Howes² and Mattia Veronese^{1, 6}

¹Department of Neuroimaging/Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK

²Department of Psychosis Studies/Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK

³Psychiatric Neuroscience Group, University of Bari, Bari, Italy

⁴Department of Computing, Imperial College, Faculty of Engineering, London, UK

⁵King’s Health Economics, King’s College London, London, UK

⁶Department of Information Engineering, University of Padua, Padua, Italy

Abstract

Introduction: A substantial proportion of patients with psychosis shows limited or no response to antipsychotic treatment. Multiple evidences have shown that dopaminergic function measured with [18F]FDOPA PET imaging can be used to distinguish treatment responders from non-responders. However, the theragnostic potential of this method to identify patients who will not respond to first-line treatment has yet to be evaluated. In view of this, we aimed to evaluate this for the full [18F]FDOPA PET dynamic scan protocol (90 mins, dynamic acquisition) and for a simplified protocol (10 mins, static acquisition) that would be easier to implement in clinical practice.

Methods: The classification accuracy for treatment response of the standard dynamic measure of dopamine synthesis capacity (Gjedde-Patlak approach with cerebellum as reference region, Ki^cer) and a simplified index of FDOPA uptake (striatum to cerebellum activity ratio, SUVRc) was evaluated. Two independent datasets of patients and matched healthy controls were used. Reproducibility of SUVRc was also assessed in a different test-retest dataset of eight healthy volunteers.

Results: SUVRc calculated from a static 10-minute [18F]-FDOPA PET scan acquired after 75 minutes from tracer injection is strongly and significantly correlated with the standard Ki^cer (Spearman’s rho: 0.89, p < 0.0001 in whole striatum) (Figure 1). Both [18F]FDOPA PET approaches have good test-rest reproducibility (Ki^cer ICC:0.68–0.94, SUVRc ICC:0.76–0.91). Our classification model showed good predictive power to distinguish responders from non-responders (receiver operating curve area under the curve: Ki^cer = 0.80, SUVRc = 0.79) and similar sensitivity for identifying treatment non-responders with closed to 100% of specificity (Ki^cer:∼50%, SUVRc:40%-60%) (Figure 2).

Conclusion: Our study showed that [18F]FDOPA PET imaging provides reliable and reproducible measures of dopamine synthesis capacity and that it can be used to distinguish patients with schizophrenia who are unlikely to respond to first-line antipsychotic treatments from those who will respond at first episode. The classification accuracy of the simplified imaging method is comparable to the one obtained with a dynamic [18F]FDOPA PET scan. Preliminary economic analysis of [18F]FDOPA PET to fast-track treatment resistant patients to clozapine indicated a potential healthcare cost saving of ∼4,455 GBP per patient, supporting clinical applicability.

Acknowledgements

Supported by NIHR Maudsley BRC and Wellcome Trust Innovator Award (215747/Z/19/Z)

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2021-32

Tetrazine-functionalised clearing agent to increase contrast in antibody imaging (#182)

Eva Schlein¹, Johanna Rokka¹, Tobias Gustavsson¹, Jonas Eriksson^{2, 3}, Stina Syvänen¹ and Dag Sehlin¹

¹Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden

²PET Centre, Uppsala University, Uppsala, Sweden

³Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden

Abstract

Introduction: Antibodies, engineered to enter the brain, can reach concentrations up to 80-fold higher than unmodified antibodies, similar to those observed with small, lipophilic radioligands.¹ Due to the long biological half-life of a radiolabelled antibody, imaging of brain targets with antibody-based ligands must be performed several days after injection. To overcome this problem we have used clearing agents (CA), which induce accelerated peripheral clearance via hepatic glycoprotein receptors immediately after administration.^2,3 Here, we aimed to combine antibody-based imaging with a CA to allow imaging shortly after administration of an amyloid-β (Aβ) antibody.

Methods: The Aβ antibody RmAb158⁴ and its bispecific, brain penetrating variant RmAb158-scFv8D3 [1] were modified with mannose for direct increased clearance or with trans-Cyclooctene (TCO) for induced clearance. The mannose modified [¹²⁵I]antibody was studied in wildtype mice using ex vivo biodistribution 24 h after injection. Transgenic (tg-ArcSwe,⁵ Aβ pathology model) and wildtype mice were administered with [¹²⁵I]RmAb158-TCO and SPECT/CT scanned 3 days later. Immediately after, CA was administered and additional SPECT/CT scans were taken after 1 h and 1 day post CA injection. The tetrazine-functionalised CA reacts quickly with the TCO-modified antibody (invers electron-demand Diels-Adler reaction) to induce radioligand clearance from blood. Blood was sampled at defined time points after antibody injection for pharmacokinetic analysis. The perfused brain tissue was cryosectioned for subsequent ex vivo autoradiography analysis.

Results: Both strategies cleared efficiently, with a decrease of up to 90% of RmAb158. The bispecific RmAb158-scFv8D3 could not be cleared from the blood, likely due to its binding to blood cells. Hence we used RmAb158 for imaging, in combination with the tetrazine-functionalized CA, which was more efficient and has the advantage of inducible clearance. [¹²⁵I]RmAb158 SPECT/CT images obtained 3 days after antibody injection showed immediate liver accumulation upon CA administration, which substantially reduced antibody concentration in blood (Figure 1). Contrast of the brain derived signal increased after 1 h CA administration and further improved after 24 h (Figure 2).

Conclusion: Results indicate that the method works as intended and that the use of clearing agents may be a promising strategy for antibody-based imaging in combination with more short-lived radionuclides.

Acknowledgements

This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 813528. Inline graphic

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2021-33

Measure of metabolic and electric rat brain changes induced by kainic acid, an EEG and ¹⁸FDG-PET studio (#184)

Arturo Avendaño-Estrada^{1, 2}, Iñigo Aguirre-Aranda³, Miguel Ángel Ávila-Rodríguez², Camilo Rios³, Roberto Olayo¹, Juan Morales¹ and Araceli Díaz-Ruíz³

¹UAM, Physics, Mexico, Mexico

²UNAM, Unidad Radiofarmacia-Ciclotrón, Mexico, Mexico

³INNN, Neurochemistry, Insurgentes sur, Mexico, Mexico

Abstract

Introduction: The kainic acid (KA) rat model is useful to evaluate new treatments and to understand biological processes involved in epilepsy. Nevertheless, metabolic processes the first 24 h in this animal model are still uncharacterized; of 2-deoxy-2-(18F)fluoro-á´-glucose positron emission tomography (¹⁸FDG-PET) is suitable to in vivo evaluate glucose brain consumption non-invasively, allowing to follow up and characterize processes robustly and quantitatively. In the KA model, the gold standard to evaluate new and established treatments is electroencephalography (EEG), nevertheless it is an invasive technique that limits experimentation. This work aimed to relate metabolic and electric brain activity the first 24 h after KA administration in rat brains.

Methods: Sixteen healthy male Wistar rats underwent ¹⁸FDG-PET scans at baseline and after kainic acid (KA) administration (1 h, 2 h, 3 h, 4 h, 21 h, 22 h, 23 h, and 24 h). Brain PET images were normalized to an atlas and segmented to locate the hippocampal regions, hippocampus-to-pons standardized uptake value ratios (SUVr) were obtained at the evaluated point times. Besides, EEGs of 5 ratas were acquired to compare electrical and metabolic activity.

Results: PET data showed hypermetabolism in the whole hippocampus (mean SUVr = 1.61) at 2 h after KA, and a hypometabolism at 24 h after KA (mean SUVr = 1.01) compared with the basal value (mean SUVr = 1.14) (see Figures 1 and 2). EEG also showed atypical values at 2 h (mean spectral power = 433216.6 µV² and mean frequency = 4.42 Hz).

Conclusion: PET data can measure metabolic brain changes of the KA rat model the first 24 h, providing an accurate tool to in vivo and non-invasively evaluate new therapies at this phase, furthermore, PET data is more robust than EEG data. In this work, metabolic and electric changes after KA administration was characterized the first 24 h, showing PET potential to be used to evaluate in vivo, the rat model without damage the animal as EEG technique do.

Acknowledgements

The authors would like to acknowledge Victoria López and Dafne Garduño for microPET imaging; Fernando Trejo, Gabriela Contreras, Héctor Gama, Armando Flores, Adolfo Zárate, Juan C. Manríquez, Ruben Tecuapetla, Ulises Rabadan and Efraín Zamora for radiopharmaceutical production. To the Universidad Autónoma Metropolitana for the fellowship PRODEP number 740.2019.

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References

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2021-34

Simultaneous PET/fMRI reveals differential D1 and D2 receptor trafficking induced by amphetamine in NHP (#185)

Hanne D. Hansen^{1, 2}, Martin Schain¹, Helen P. Deng², Joseph B. Mandeville^{2, 3}, Bruce R. Rosen^{2, 3} and Christin Y. Sander^{2, 3}

¹Neurobiology Research Unit, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark

²Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, USA

³Harvard Medical School, Boston, MA, USA

Abstract

Introduction: Amphetamine is powerful dopamine releaser and has been shown to induce D2 receptor internalization^1,2 on timescales relevant to repeated drug use. Differences in D1 vs. D2 receptor trafficking have been suggested in vitro³ but remain largely unknown in vivo. Here, we use PET/fMRI to investigate the effects of repeated amphetamine administrations on dopamine receptor trafficking.

Methods: Three anesthetized rhesus macaques were scanned twice each in a PET/MR scanner. [¹¹C]Raclopride was administered as a bolus+infusion with a scan duration of 2 h. Amphetamine (0.6 mg/kg) was given intravenously at 40 min as a within-scan challenge, while functional MRI with iron oxide contrast agent was acquired simultaneously. A second amphetamine injection was given after 3 h using the same PET/fMRI acquisitions. In an analogous set of imaging sessions, the antagonist SCH23390 was administered to block D₁ receptors prior to radiotracer injection. FMRI data were analyzed with a general linear model and converted to relative changes in cerebral blood volume (CBV). Receptor availability (BP_ND) was quantified using a modified SRTM with a time-dependent binding term.^4,5

Results: Amphetamine caused a prolonged reduction in BP_ND (peak occupancy: 28 ± 8% (mean ± SD), n = 6, Figure 1(a)), together with a short-lived decrease in CBV (Figures 1(c) and 2(a)). Repeated amphetamine administration after 3 h caused a further reduction in BP_ND (peak occupancy: 19 ± 9%, n = 3, Figure 1(b)). In contrast, the second CBV response differed entirely from the first, showing a long-lasting increase in CBV (Figures 1(d) and 2(b)). Administration of SCH23390 did not alter the overall shape of the amphetamine-induced changes in CBV at 0 h (Figures 1(c) and 2(c)). However, the long-lasting positive CBV response at 3 h was reduced to a short-lived positive response (Figures 1(d) and 2(d)).

Conclusion: These results suggest that D1 receptors recycle and are functionally available within three hours, whereas D2 receptor availability stays decreased for 24–48 h after amphetamine exposure (1). Overall, this study provides novel insight into the differentially lasting effects of amphetamine exposure on D1 vs. D2 receptor dynamics in vivo. It highlights a potentially important role of not only D2 but also D1 receptor internalization mechanisms involved in substance use disorders.

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References

1.Narendran R, Slifstein M, et al. Amphetamine-induced dopamine release: duration of action as assessed with the D2/3 receptor agonist radiotracer (––)-N-[11C]propyl-norapomorphine ([11C]NPA) in an anesthetized nonhuman primate. Synapse 2007; 61: 106–109. [DOI] [PubMed] [Google Scholar]
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2021-35

In vivo evidence for disrupted association between synaptic and glutamatergic markers in depression – A combined [¹¹C]UCB-J and [¹⁸F]FPEB study (#188)

Sophie Holmes¹, Mika Naganawa², Jean-Dominique Gallezot², Takuya Toyonaga², Robert H. Pietrzak¹, Richard E. Carson² and Irina Esterlis¹

¹Psychiatry Department, Yale University, New Haven, CT, USA

²Radiology Department, Yale University, New Haven, CT, USA

Abstract

Introduction: Converging evidence implicates a loss of synaptic connections in depression.¹ A related pathophysiological mechanism is glutamate dysfunction, and the metabotropic glutamate receptor 5 (mGluR5) has been specifically implicated in symptoms of depression.² In two separate Positron Emission Tomography (PET) studies, we demonstrated lower synaptic density in individuals with major depressive disorder (MDD),³ and that modulation of mGluR5 can alleviate depressive symptoms.⁴ However, the relationship between synaptic density and the glutamatergic system has not been investigated in vivo. We examined the association between the densities of presynaptic SV2A and postsynaptic mGluR5 in the same subjects in both MDD and healthy controls (HC) groups.

Methods: Twelve healthy controls (mean ± SD = 44 ± 16yrs; 5 women) and 20 individuals with major depressive disorder (MDD; 40 ± 11yrs; 16 unmedicated; 10 women) participated in one [¹¹C]UCB-J and one [¹⁸F]FPEB scan (measuring SV2A density and mGluR5 availability, respectively). Outcome measure was volume of distribution (V_T) for both scans. Correlations between [¹¹C]UCB-J and [¹⁸F]FPEB V_T were assessed using Pearson’s rin 11 ROIs across the brain. Differences between correlations were assessed using Fisher’s r to z transformation.

Results: We observed multiple significant positive correlations between [¹¹C]UCB-J and [¹⁸F]FPEBV_Tin the HCs across regions (Figure 1(a)). The strongest correlations converged on dlPFC, cerebellum and posterior cingulate cortex (r’s > 0.60,p’s < 0.05). Conversely, in individuals with MDD, there were no significant correlations between SV2A and mGluR5 in any ROIs (all r’s < 0.1; Figure 1(b)). The difference in correlations between HC and MDD groups was significant across multiple ROI pairs, converging on the dlPFC and cerebellum (Figure 2).

Conclusion: We demonstrate a disconnect between synaptic density and glutamatergic tone in individuals with MDD across multiple ROIs. The significant correlation between SV2A and mGluR5 in HCs is in line with research indicating a relationship between mGluR5 and synaptic plasticity.⁵ The lack of association in MDD could reflect a disconnect between pre- and post-synaptic function, or an aberrant association between mGluR5 and synaptic plasticity in depression. Further work should evaluate whether synaptogenic treatments such as ketamine ameliorate coupling between synaptic markers and mGluR5.

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References

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2021-36

Translocator protein in occupational post-traumatic stress disorder: Preliminary findings using the [¹⁸F]FEPPA PET radioligand (#189)

Sarah E. Watling^{1, 2}, Talwinder Gill^{1, 2}, Erin Gaudette^1,
2, Junchao Tong^{1, 3}, Tina McCluskey^{1, 3}, Jeffrey Meyer^{1, 4}, Jerry Warsh^{1, 4}, Rakesh Jetly⁵, Don Richardson^{6, 7}, Pablo M. Rusjan^{1, 8}, Romina Mizrahi^1,
8, Sylvain Houle^{1, 4}, Stephen Kish^{1, 4}, Michael G. Hutchison⁹, Neil Vasdev^{1, 10}, Shawn Rhind¹¹ and Isabelle Boileau^{1, 4}

¹Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada

²Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada

³Campbell Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada

⁴Department of Psychiatry, University of Toronto, Toronto, ON, Canada

⁵Department of National Defence, Canadian Forces Health Services, Ottawa, ON, Canada

⁶Department of Psychiatry, University of Western ON, London, ON, Canada

⁷McDonald Franklin OSI Research Centre, Parwood Institute, London, ON, Canada

⁸Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada

⁹Faculty of Kinesiology and Physical Education, University of Toronto, Toronto, ON, Canada

¹⁰Azrieli Centre for Neuro-Radiochemistr, Centre for Addiction and Mental Health, Toronto, ON, Canada

¹¹Defence Research and Development Canada, Toronto Research Centre, Toronto, ON, Canada

¹²Parkwood Operational Stress Injury Clinic, London ON, Canada

Abstract

Introduction: Inflammation, and specifically, the 18 kDa mitochondrial translocator protein (TSPO, a marker of gliosis) has been implicated in the pathophysiology of Post-traumatic stress disorder (PTSD). To date, two positron emission tomography (PET) studies have investigated brain TSPO, reporting decreased TSPO in patients diagnosed with PTSD¹ and increased TSPO in 9/11 first responders experiencing PTSD symptoms.² Therefore, more research is required to characterize immune-dysregulation in PTSD. Accordingly, the purpose of this study was to utilize PET of the TSPO probe N-acetyl-N-(2-[18F]fluoroethoxyben-zyl)-2-phenoxy-5-pyridinamine ([¹⁸F]FEPPA) to investigate TSPO binding in humans with occupational related PTSD.

Methods: TSPO binding was measured with PET and arterial sampling in 15 patients diagnosed with PTSD and 17 healthy controls (HC). A magnetic resonance image was acquired for delineation of regions of interest (ROIs). A repeated-measures analysis of covariance (ANCOVA) was employed to evaluate group differences within 6 ROIs in the limbic-striatum (prefrontal cortex [PFC], anterior cingulate cortex [ACC], insula, striatum, hippocampus, amygdala), controlling for the TSPO polymorphism (rs6971).

Results: The PTSD (∼ 45 years) and HC (∼ 31 years) groups did not differ in sex, TSPO polymorphism, ethnicity, or body mass index (p > 0.05); however PTSD patients were significantly older than HCs (p = 0.005). A repeated-measures ANCOVA with TSPO polymorphism as a covariate revealed no significant difference in TSPO binding between PTSD and HCs (F_(1,26) = 0.220, p = 0.643) and no group by ROI interaction (F_{(2.543,66.109)} = 1.203, p = 0.313). Interestingly, there was a marginally significant group by genotype interaction (F_(1,23) = 2.87, p = 0.101), whereby TSPO binding was 34% lower in PTSD middle affinity binders (MABs) compared to HC MABs, and 46% higher in PTSD high affinity binders (HABs) compared to HC HABs. TSPO binding in the amygdala was correlated with Beck Depression Inventory scores (p = 0.023, R = 0.7).

Conclusion: The current study investigating TSPO binding in a cohort of patients with occupational related PTSD did not replicate the recent finding of decreased TSPO in PTSD. This finding highlights the importance of characterising type of trauma in study samples. Furthermore, the group by genotype interaction was an unexpected finding and merits further investigation to better understand the potential role this genotype may or may not have in PTSD.

References

1.Bhatt S, Hillmer AT, Girgenti MJ, et al. PTSD is associated with neuroimmune suppression: evidence from PET imaging and postmortem transcriptomic studies. Nat Commun 2020; 11: 1–11. [DOI] [PMC free article] [PubMed] [Google Scholar]
2.Deri Y, Clouston SA, DeLorenzo C, et al. Neuroinflammation in World Trade Center responders at midlife: a pilot study using [18F]-FEPPA PET imaging. Brain Behav Immun Health 2021; 16: 100287.. [DOI] [PMC free article] [PubMed] [Google Scholar]

2021-37

The PET radioligands ([¹¹C]NR2B-X; X = Me, R or S; X = SMe, S) are selective for binding to the NR2B subunit of NMDA over the s1 receptor in rat in vivo (#191)

Lisheng Cai, Jeih-San Liow, Cheryl Morse, Sanjay Telu, Riley Davies, Emily Feigen, Robert B. Innis and Victor W. Pike

Molecular Imaging Branch, NIMH, Bethesda, MD, USA

Abstract

Introduction: The NR2B subunit within the NMDA complex and sigma receptors (σ1, σ2) are physically intertwined.¹ In our effort to develop PET radioligands for PET imaging of the NR2B receptor, we found that some ligands have quite high affinities for s-receptors.² Here we used our candidate radioligands targetting NR2B ([¹¹C]NR2B; X-Me, R- or S-enantiomer; X = SMe; S-enantiomer) and an established radioligand targetting s1 receptors ([¹⁸F]FTC146)³ with various challenge agents to investigate whether s1 receptors influence the PET imaging of NR2B in rat brain.

Methods: PET imaging of brain was performed after intravenous administration of an [¹¹C]NR2B-X radioligand or [¹⁸F]FTC146 to rats at baseline and after intravenous administration of ligands putatively selective for NR2B, such as NR2B-SMe and Ro 25 6981, or σ1, such as FTC146, and BD1047 at a range of doses (each typically at 0.01 − 3 mg/kg), at 10 min before radioligand injection. For each radioligand, a dose-response curve was established for each blocking agent.

Results: FTC146 gave an ED₅₀ value of 46 nmol/kg body for self-blockade of [¹⁸F]FTC146 binding in rat brain, whereas ED₅₀ values were far lower for blockade of the three tested NR2B radioligands depending on radioligand (i.e., 2571, 725, or > 1000 nmol/kg). Similarly, BD1047 gave an ED₅₀ of 169 nmol/kg for blockade of [¹⁸F]FTC146, and far lower ED₅₀ values for blockade of the three NR2B radioligands (>1000, 555, or 900 nmol/kg). NR2B-SMe, gave a weak ED₅₀ of 1064 nmol/kg against [¹⁸F]FTC146 and a strong ED₅₀ value of 9.5 nmol/kg against [¹¹C](S)-NR2B-SMe (Figure 1).

Conclusion: The ED₅₀ values of FTC146, BD1047, and NR2B-SMe depended on the radioligand used in PET imaging of rat brain. Both FTC146 and BD1047 potently blocked rat brain s1 receptors, affirming the reported high s1 selectivity of [¹⁸F]FTC146. FTC146 was extremely weak at blocking the NR2B radioligands. (S)-NR2B-SMe potently blocked the test NR2B radioligand [¹¹C](S)-NR2B-SMe, but not [¹⁸F]FTC146. Taken together the data indicate that the influence of s1 receptors on the PET imaging of NR2B receptors with the tested [¹¹C]NR2B radioligands is likely negligible.

Acknowledgements

Intramural Research Program of the National Institutes of Health (NIMH).

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References

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2021-38

Generation of a normative dopamine neuroreceptor template from [11C]PHNO PET imaging modelling population variability (#195)

Alessio Giacomel^{1, 2}, Ottavia Dipasquale¹, Robert Mccutcheon³, Tarik Dahoun³, Matthew Nour³, Oliver D. Howes³, Alessandra Bertoldo², Federico E. Turkheimer¹ and Mattia Veronese¹

¹Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK

²Department of Information Engineering, Padova University, Padova, Italy

³Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK

Abstract

Introduction: Brain normative templates are becoming more and more popular for detecting structural and functional abnormalities in brain disorders,¹ as well as to characterise pharmacological response² in imaging studies. In this work we tested and validated a non-hierarchical multiple linear modelling approach for the generation of a normative template for the dopamine neuroreceptor system as measure with [11C]PHNO PET imaging. The aim was to investigate the importance of modelling the population variability when comparing individual data with normative templates.

Methods: 90 minutes [11C]PHNO Brain PET scans (age: 26.09 ± 7.17 years, BMI: 28.28 ± 2.63 kg/m², 19/25 Females/Males) of forty-four healthy controls were reanalysed from previous studies of our internal database.³ Individual BPND generated with SRTM were normalised into standard MNI space via individual MRI transformations. Regional BPND values in cortical and subcortical regions (Striatum, Thalamus, Midbrain, Substantia Nigra and Hippocampus) we correlated with individual covariates (age, gender and BMI) that are known to be associated with dopamine function.^4,5 Based on these analyses and these covariates we formulated seven BPND population models using linear-mixed effect modelling. We compared the predicted parametric BPND maps of these models with the average maps using a leave-one-out cross validation approach. Mean absolute error (MAE) computed from the distribution of voxel residuals was used as a performance index.

Results: Regional BPND estimates were significantly associated to age (r > 0.46, Cortex and Striatum) and BMI (r = 0.30 Cortex) (Figure 1), while gender did not reach statistical significance (highest correlation in the Striatum, r = 0.28, p = 0.07). The best performing model used a combination of all these variables as described by BPND = θ+αAge+βBMI+δSex, where the effects of BMI and gender were modulated depending on the voxel anatomical location (Figure 2). Cross-validation showed that the model compared to the simple average improved prediction by 32% ± 30% in the whole brain, with regional improvement ranging from 4% ± 63% in hippocampus to 23% ± 18% in the Striatum.

Conclusion: We showed that including covariates in the creation of normative templates improves the prediction of individual data as compared to simple population mean. The same approach can be extended to other targets in order to obtain normative templates of different neurotransmitters.

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References

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2021-39

mGluR5 as a biomarker for suicidal behavior in trauma related disorders: Evidence from in vivoPET imaging studies (#200)

Margaret T. Davis, Ansel T. Hillmer, Sarah Debonee, Olivia Wilson, Nabeel Nabulsi, David Matuskey, Gustavo A. Angarita, Richard E. Carson and Irina Esterlis

Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA

Abstract

Introduction: Suicide remains a pressing public health concern, yet few pharmacological interventions are capable of reducing suicide risk.¹ Recent findings implicate dysregulation of mGluR5 – a metabotropic glutamate receptor – in the pathophysiology of suicidal behavior.^2,3 Using positron emission tomography (PET) with the tracer ¹⁸F-FPEB, we quantified mGluR5 availability in vivo in three clinical populations: post-traumatic stress and major depressive disorders (PTSD, MDD; Study 1), and borderline personality disorder (BPD; Study 2).

Methods: Study 1:Participants [(n = 29 PTSD, 14 with scan-day suicidal ideation (SI); n = 29 MDD, 15 with SI]. Study 2: [(n = 14 MDD, 8 with suicide attempt (SA) history; n = 14 BPD, 6 with SA history] completed a single ¹⁸F-FPEB PET scan to quantify mGluR5 availability in vivo. Radiotracer was injected as bolus plus constant infusion and subjects were scanned during steady state (90–120mins post-injection). All participants completed a comprehensive battery of psychiatric rating scales and cognitive testing. Volume of distribution (V_T: ratio of parent radioligand concentration in tissue relative to that in plasma) in grey matter regions was computed using a venous input function. Analyses focused on 5 fronto-limbic brain regions.

Results: Study 1: MANOVA with mGluR5 availability (V_T) in specified regions of interest as dependent variable (DV) and SI as independent variable (IV) revealed a main effect of SI for those with PTSD (p = .009) but not MDD. Post hoc analyses indicated PTSD-SI group had higher mGluR5 availability in all ROIs (p’s < .007, 21–29% difference; Figure 1). Study 2: MANOVA with V_T as DV, SA as IV revealed a main effect of SA in BPD; higher mGluR5 availability was associated with history of SA (p’s < .042, 19–23% difference; Figure 2) in BPD but not MDD. Relationships between SI and mGluR5 in Study 2 were non-significant.

Conclusion: Higher mGluR5 availability was associated with scan day SI in PTSD, and SA history in BPD. Observed differences in mGluR5 availability may reflect differences in glutamate neurotransmission between those who develop suicidal behavior in trauma-related disorders. Findings underscore the importance of continued investigation of mGluR5 as a target for intervention and suicide risk management in psychiatry.

Acknowledgements

This study was funded in part by the VA National Center for PTSD, and NIH grants R01MH104459 (PI: Esterlis) and 1K08MH117351-01 (PI: Davis).

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2021-40

Neuroinflammation in epilepsy: A systematic review of microglial activation imaging studies (#203)

Abhishekh H. Ashok^{1, 2} and Tomasz Matys^{1, 2}

¹Department of Radiology, University of Cambridge, Cambridge, UK

²Department of Radiology, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK

Abstract

Introduction: Magnetic resonance imaging (MRI) and FDG- Positron emission tomography (PET) is part of a standardized presurgical epilepsy imaging protocol in several centres. FDG-PET do not accurately predict seizure foci in a substantial number of patients, suggesting the need for novel imaging method. Preclinical studies have implicated neuroinflammation and microglial activation in epileptogenesis and pathophysiology of epilepsy. PET radiotracers which bind to the Translocator Protein (TSPO), an outer mitochondrial membrane protein expressed by microglia, have been used to evaluate neuroinflammation in vivo.¹ In this systematic review, we evaluated the studies which measured microglial activation in animal models and patients diagnosed with epilepsy.

Methods: Systematic review was conducted in PubMed/Medline with the following keyword: (Positron Emission Tomography OR PET OR Single photon emission tomography OR SPET OR Single Photon Emission Computed Tomography OR SPECT OR autoradiography) AND (epilepsy OR seizure) AND (microglia* OR microglia* activation OR TSPO OR Translocator protein OR peripheral benzodiazepine receptor OR peripheral benzodiazepine binding site). Out of the 60 articles, 14 preclinical, 4 human in-vitro and 3 human PET studies met the inclusion criteria.

Results: All of the preclinical studies consistently reported elevation of TSPO signal. Four in-vitro human studies conducted using post-mortem or surgically resected specimen showed elevated microglial activity. Three in-vivo TSPO studies detected increased uptake of radioactivity in the ipsilateral brain region to the seizure focus in patients with temporal lobe epilepsy. Two of these studies reported increased TSPO signal in patients compared to healthy controls. These studies were conducted with [11C]PBR28 radiotracer with a ratio of distribution volume to free fraction (VT/fP) as outcome parameter.

Conclusion: Preclinical studies consistently reported elevation of TSPO activity in epilepsy. In-vivo TSPO PET studies suggest a promising role of TSPO imaging in the evaluation of seizure foci. Future large-scale studies are needed to confirm these findings.

Acknowledgements

Dr Ashok would like to thank National Institute of Health Research (NIHR), UK for funding.

References

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2021-41

Towards an opioid receptor atlas of the human brain (#206)

Douglas N. Greve¹, Hsiao-Ying Wey¹, Lauri Tuominen², Tomi Karjalainen³ and Lauri Nummenmaa³

¹Massachusetts General Hospital, Martinos Center, Charlestown, MA, USA

²Royal’s Institute of Mental Health Research, Ontario, ON, Canada

³Turku PET Centre and Department of Psychology, University of Turku, Turku, Finland

Abstract

Introduction: The opioid system plays a fundamental role in human behavior and experience including addiction, depression, and anxiety.¹ This abstract describes an effort to create a publicly available atlas of the human opioid system to be made available through FreeSurfer/PETsurfer (surfer.nmr.mgh.harvard.edu/fswiki/PetSurfer).

Methods: Two opioid tracers were evaluated. 18 subjects (43 ± 11y, 8M/9F) were scanned using carfentanil (CFN, GE Discovery 690) and 7 subjects (3M/4F, 24.1 ± 2.7y) were scanned using diprenorphine (DPN, Siemens 3T-BrainPET). All subjects also had T1-weighted MRIs. All data were analyzed in FreeSurfer (FS)/PETsurfer.^2,3 After registering the PET to the MRI, the time activity curves (TACs) were mapped onto the common surface (fsaverage) where they were surface-smoothed; TACs were also mapped to the MNI152 through a nonlinear volume registration where a subcortical GM mask was applied prior to volume smoothing. TACs were also averaged in FS-defined ROIs. After mapping and smoothing or ROI-averaging, BP_ND was computed using MRTM1 using the individual’s FS-defined calcarine sulcus as the reference region.

Results: Figure 1 shows the cross-subject averages for each tracer on the surface (A and B) and in the volume with the subcortical results merged with the cortical maps. Generally, the maps have the typical spatial distribution expected from the m-opioid system (low in primary sensory areas and high in frontal, limbic, and basal ganglia). CFN and DPN are highly correlated across cortex (Figure 2) though there are some clear differences (e.g., middle temporal). Some differences are expected because DPN has some affinity for kappa and delta in addition to m receptors whereas CFN is exclusive to mu.

Conclusion: Brain atlases are a useful as a neuroscience resource.^4,5 The opioid atlases will consist of mean BP_ND maps in a common space (cortical surface and volume) as well as tables of average cortical and subcortical ROIs. They will be made publicly available through FreeSurfer/PETsurfer. It is our intention to gather opioid PET data from all available sources for all opioid receptor types to provide a comprehensive picture of the spatial distribution of opioid receptors in the human brain.

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References

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2021-42

DaTscan-based progression subtypes for Parkinson’s disease (#213)

Yuan Zhou¹, Sule Tinaz² and Hemant Tagare^{1, 3}

¹Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, USA

²Department of Neurology, Yale University, New Haven, CT, USA

³Department of Biomedical Engineering, Yale University, New Haven, CT, USA

Abstract

Introduction: Parkinson’s disease (PD) is known to progress heterogeneously.¹ We propose to use DaTscan images from the Parkinson’s Progression Marker Initiative (PPMI) to find PD progression subtypes using a mixture of linear dynamical systems (MLDS) model (see Figure 1).

Methods: We analyzed DaTscan images from 365 PPMI subjects scanned at baseline, and approximately at years 1,2,4,5 with some missing data (Male: 237, Female:128, Age: 62.6 ± 9.8 yrs.). Mean striatal binding ratios (SBRs)² for the left caudate (LC), left putamen (LP), right putamen (RP), and right caudate (RC) were extracted from the images. The MLDS model with K progression subtypes assumes that each progression subtype is a multi-variate differential equation with a fixed transition matrix, which models the coupled progression of the four SBRs (see Figure 2). A t-distributed model fitting error allows for outliers.³ The model is fitted to the image data using Bayesian inference with collapsed Gibbs sampling.⁴ This allows the identification of the number of subtypes as well as the transition matrix of each subtype. Finally, the total movement scores (TMS, sum of MDS-UPDRS Part III scores) within each progression subtype are evaluated for comparison.

Results: Bayesian model selection⁵ (as well as cross validation) identifies three progression subtypes in the PPMI dataset. The transition matrices of all subtypes have leading skew-symmetric eigenvectors and trailing symmetric eigenvectors. The leading eigenvalues in the three subtypes are -0.71, -0.37, -0.37 and the trailing eigenvalues are -0.20, -0.09, -0.02. Thus the subtypes are identified as fast (14.6% of the subjects), medium (61.2%), and slow (24.2%) progressing. The corresponding TMS progression rates of these subtypes are 4.11, 2.48 and 2.42 per year.

Conclusion: The MLDS model identifies three DaTscan-based progression subtypes from the PPMI dataset. In each subtype, the skew-symmetric eigenvector identifies the fastest progression time constant. This has the potential to serve as a reliable disease progression marker. The TMS of the subtypes also show analogous progression speeds providing clinical corroboration for the validity of our approach.

Acknowledgements

Funding source: R01NS107328.

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References

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2021-43

A single session of theta burst stimulation alters metabolic activity in the core depression network (#230)

Lauri Tuominen¹, Ines Jani¹, Cecelia Shvetz¹, Abir Gebara¹, Juho Joutsa² and Sara Tremblay¹

¹The Royal’s Institute of Mental Health Research, Ottawa, ON, Canada

²Turku PET Centre, Turku University Hospital, Turku, Finland

Abstract

Introduction: Intermittent theta burst stimulation (iTBS) to the left dorsolateral prefrontal cortex (DLPFC) has emerged as a promising new treatment for depression.¹ Effects of left DLPFC iTBS in humans however are not well understood. In this sham controlled double blind randomized cross-over study, we tested the effects of a single session of iTBS on [¹⁸F]FDG uptake and resting state fMRI (rsfMRI) in healthy individuals.

Methods: Planned unblinding and interim analyses were carried out on 8 healthy individuals (6 females, mean ± sd age 27.5 ± 8.2). All subjects underwent a standard iTBS stimulation (80% active motor threshold; 600 pulses) and a sham stimulation on separate days. iTBS was targeted to the DLPFC using neuronavigation (MNI coordinates -38, 44, 26).¹ [¹⁸F]FDG was injected as a bolus immediately after both stimulations. Between the bolus and data collection, subjects rested for 40 minutes eyes open in a quiet and dimly lit room. ^[18F]FDG emission data was collected for 30 minutes simultaneously with rsfMRI using a Siemens PET/MRI scanner. Difference between iTBS and sham in standardized uptake value ratio images and rsfMRI connectivity was calculated, and effects of stimulation were analyzed using voxel-wise one sample t-tests (Figure 1). All tests were thresholded at voxel-wise p-values < 0.01, uncorrected.

Results: Preliminary results suggest that compared to sham stimulation, iTBS increased [¹⁸F]FDG uptake in the pregenual anterior cingulate cortex (pgACC), in the anterior insula and in the left caudate. iTBS decreased [¹⁸F]FDG uptake in the somatosensory cortex. RsfMRI connectivity between the stimulation site and the pgACC was lower after iTBS than after sham stimulation.

Conclusion: To our knowledge this is the first PET/MRI study on iTBS. Our interim analysis suggests that a single session of iTBS is sufficient to modulate the metabolic activity of the core depression network. These results are in line with previous studies that have used a conventional repetitive transcranial magnetic stimulation. If these results are confirmed in the final analysis of a larger sample, they can be used to optimize and design more personalized iTBS treatments in clinical populations.

Acknowledgements

This work is supported by the eRIMh award to Dr. Tuominen.

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Reference

1.Blumberger DM, et al. Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): a randomised non-inferiority trial. Lancet 391.10131 (2018): 1683–1692. [DOI] [PubMed]

2021-44

MRI quantification of brain oxygenation and relationship with cerebrovascular reactivity in Moyamoya disease using simultaneous [¹⁵O]-water PET/MRI (#242)

Audrey P. Fan^{1, 2}, David Y.-T. Chen^{1, 3}, David D. Shin⁴, Moss Y. Zhao¹, Jun-Hyung Park¹, Bin Shen¹, Mohammad M. Khalighi¹, Dawn Holley¹, Kim Halbert¹, Gary K. Steinberg¹ and Greg Zaharchuk¹

¹Department of Radiology, Stanford University, Stanford, CA, USA

²Department of Biomedical Engineering and Neurology, University of California, Davis, Davis, CA, USA

³Department of Radiology, Taipei Medical University, Taipei, Taiwan

⁴GE Healthcare, CA, USA

⁵Department of Neurosurgery, Stanford University, Stanford, CA, USA

Abstract

Introduction: We compared two MRI approaches based on tissue R₂’ relaxation and vein magnetic susceptibility, respectively, to measure oxygen extraction fraction (OEF) abnormalities in Moyamoya disease,¹ a steno-occlusive disorder of intracranial arteries. MRI-derived OEF was compared for different stenosis severities, and correlated to [¹⁵O]-water PET of cerebral blood flow (CBF) using hybrid PET/MRI.

Methods: Simultaneous 3T PET/MRI was acquired in 15 Moyamoya patients (ages 32–62 years, 9 female). PET perfusion imaging with [¹⁵O]-water (550–925 MBq) was performed at baseline and after vasodilation with acetazolamide to observe the perfusion change (ΔCBF).² For baseline MRI of oxygenation, we calculated multi-parametric maps of R₂’, which are proportional to tissue OEF.^3,4 These scans included fast spin echo with 8 echoes (28–122ms) and multi-echo gradient echo with 10 echoes (11.1–42.4ms). We also acquired gradient echo scans (0.41x0.41x0.70 mm³) with flow compensation for quantitative susceptibility mapping (QSM) in veins.⁵ CBF, ΔCBF, and R₂’ were assessed within 10 vascular territories per hemisphere; QSM values were also evaluated in cortical veins draining these territories.

Results: Figure 1(a) shows PET/MRI in a 32-y.o. male Moyamoya patient with right middle cerebral artery (MCA) occlusion and impaired PET cerebrovascular reactivity after vasodilation (green arrows). Higher vein density and susceptibility on QSM maps (indicating elevated OEF), and higher white matter R₂’ were observed in the right hemisphere. In contrast, the 33-y.o. male patient in Figure 1(b) had healthy baseline PET perfusion and preserved reactivity. The corresponding QSM maps were normal, with symmetric vessel caliber and susceptibility, as were the R2’ oxygenation maps. Across patients, [¹⁵O]-water PET revealed 22.5% reduction in baseline CBF and 55.6% reduction in ΔCBF for MCA areas with severe stenosis compared to normal territories (Figure 2). Relative OEF assessed by vessel susceptibility was 20.4% higher for severe stenosis compared to normal areas (P = 0.007); and inversely correlated with PET baseline CBF and ΔCBF (P < 10⁻⁴). In contrast, R₂’ showed smaller abnormality (9.6%) in stenosed areas, and weaker correlations to PET perfusion.

Conclusion: Advanced MRI revealed abnormal, elevated OEF in Moyamoya disease, which inversely correlated with CBF and reactivity measured by simultaneous PET. Susceptibility MRI detected more robust OEF increases in areas of pathology than R₂’, with stronger correlation to perfusion deficits.

Acknowledgements

This study is funded by NIH grants 5K99NS102884-02 and R01EB025220-02.

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References

1.Ni WW, Christen T, Rosenberg J, et al. Imaging of cerebrovascular reserve and oxygenation in Moyamoya disease. J Cereb Blood Flow Metab 2017; 37: 1213–1222. [DOI] [PMC free article] [PubMed] [Google Scholar]
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2021-45

In vivo assessment of astroglial activation in cognitively impaired subjects using ¹¹C-BU99008 PET and its relationship with amyloid load (#247)

Paul Edison

Imperial College London, London, UK

Abstract

Introduction: Glial activation may play a major role in the cognitive function in Alzheimer’s disease. ¹¹C-BU99008 is a novel PET tracer selective for imidazoline I₂ binding sites (BS), which are found mainly in astroglial cells. The aim of this pilot study was to explore ¹¹C-BU99008 uptake in cognitively impaired subjects stratified as amyloid-positive or negative using ¹⁸F-florbetaben PET.

Methods: 11 cognitively impaired patients and 9 healthy controls (HC) underwent 3T MRI, ¹⁸F-florbetaben PET and ¹¹C-BU99008 PET. ¹¹C-BU99008 PET was analysed quantitatively using an arterial plasma input function while ¹⁸F-florbetaben uptake (referenced to that in the cerebellum) was used to define amyloid-positivity

Results: The 8/11 cognitively impaired subjects who were amyloid-positive had higher ¹¹C-BU99008 tracer uptake relative to the HC across the whole brain, but particularly in the frontal, occipital and medial temporal lobes. A positive voxel-wise correlation between ¹¹C-BU99008 and ¹⁸F-florbetaben uptake was observed. Autoradiography using ³H-BU99008 conducted in post mortem AD brains also showed an increase binding in AD patients compared with controls and this binding was not displaced by PiB or Florbetaben

Conclusion: Our results demonstrate increased I₂ receptor availability for ¹¹C-BU99008 in cognitively impaired amyloid-positive subjects neuroanatomically localised to cortical regions of highest amyloid deposition. Based on prior literature, the increased uptake is believed to reflect astroglial activation predominantly. This novel proof of principle study thus provides novel in vivo evidence for pathological astroglial activation with neurodegeneration and demonstrates ¹¹C-BU99008 PET as a potential new clinical research tool for its assessment.

Acknowledgements

The authors thank Invicro Centre for Imaging Sciences for the provision of ¹¹C-BU99008, scanning and blood analysis equipment. The authors also thank Piramal Life Sciences/Life Molecular Imaging for providing the ¹⁸F-florbetaben and permission to acquire unlabelled Florbetaben. We thank Dementia Platform UK (DPUK) and GSK for the generous funding for this project. This research was co-funded by the NIHR Imperial Biomedical Research Centre, and was supported by the NIHR Imperial Clinical Research Facility. The views expressed are those of the authors and not necessarily those of NHS, the NIHR or the Department of Health.

2021-46

Relations of EEG and α2-adrenoceptor availability in patients with Parkinson’s disease (#252)

Albert Gjedde¹, Adam F. Kemp¹, Martin B. Kinnerup² and Adjmal Nahimi³

¹Department of Nuclear Medicine, University of Southern Denmark, Odense, Denmark

²Department of Nuclear Medicine and PET Center, Aarhus University, Aarhus, Denmark

³Restorative Parkinson Unit, Lund University, Lund, Sweden

Abstract

Introduction: Alterations of electroencephalography (EEG) may be correlated to cognitive impairment and to predict dementia in patients with Parkinson’s disease. There is reason to believe that the cognitive impairment is related to degeneration of locus coeruleus (LC) as the primary source of noradrenergic innervation (NE) in CNS.¹ NE is essential for cognition and memory, and degeneration of LC unrelated to age has been detected in PD patients. Here, we claim that the alteration of EEG and the cognitive impairment both result from degeneration of LC.

Methods: We recruited 19 patients aged 53–80 years with a mean of 65 years (13 men) from the Department of Neurology, Aarhus University Hospital, Denmark, and 13 healthy control (HC) subjects aged 52–76 years with a mean of 66 years (6 men) by newspaper advertisement in Aarhus, Denmark. We used magnetic resonance imaging (MRI) and positron emission tomography (PET) with the α₂ adrenoceptor ligand [¹¹C]yohimbine to determine α2 adrenoceptor expression in thalamus and frontal cortex (FC) of 17 patients and the 13 HC subjects, and we calculated α₂ adrenoceptor density from binding potentials, specific activity, and the affinity of binding of the tracer.^2,3 We correlated the α₂ adrenoceptor density with EEG theta power bands in FC and thalamus by linear regression (Figure 1).

Results: On the day of tomography. the patients had UPDRS scores of 41 (range 17–55) in the "off" state with Hoehn & Yahr stage 2.5 and mean L-DOPA equivalent doses of 1052 (range 360–2057). Patients had more power in the EEG theta and delta bands compared to control subjects. Among the patients, the EEG theta power correlated with the α₂ adrenoceptor availability in both FC and thalamus . Age, gender and background rhythm frequency (BRF) correlated with α₂ adrenoceptor density in FC, and BRF correlated with α₂ adrenoceptor density in thalamus in HC subjects. BRF and theta power both correlated with α₂ adrenoceptor density in FC and thalamus when HC subjects and patients were analyzed as a single group.

Conclusion: The EEG theta power was related to α₂ adrenoceptor expression in frontal cortex and thalamus among patients with Parkinson’s disease. The evidence is consistent with the hypothesis of degeneration in LC as responsible for non-motor symptoms in PD, with EEG theta power predictive of some non-motor symptoms of PD.

Acknowledgements

Thanks to the staffs of Aarhus University Hospital’s Department of Nuclear Medicine and PET Center, and to Odense University Hospital’s Department of Nuclear Medicine.

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2021-47

Electroconvulsive stimulation differentially affects [¹¹C]MDL100907 binding to cortical and subcortical 5HT_2A receptors in porcine brain (#253)

Albert Gjedde^{1, 2}, Anne M. Landau^{3, 4}, Michael Winterdahl⁵, Ove Noer⁴, Aage O. Alstrup⁴, Hélène Audrain⁴, Poul Videbech^{6, 7}, Gregers Wegener³, Arne Møller⁸ and Doris J. Doudet⁹

¹Department of Nuclear Medicine, University of Southern Denmark, Odense, Denmark

²Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada

³Translational Neuropsychiatry Unit, Aarhus University, Aarhus, Denmark

⁴Department of Nuclear Medicine & PET Center, Aarhus University Hospital, Aarhus, Denmark

⁵Department of Nuclear Medicine and PET Center, Aarhus University, Aarhus, Denmark

⁶Center of Mental Health, Glostrup, Denmark

⁷University of Copenhagen, Copenhagen, Denmark

⁸Center of Functionally Integrative Neuroscience, Aarhus University, Aarhus, Denmark

⁹Department of Medicine & Neurology, University of British Columbia, Vancouver, BC, Canada

Abstract

Introduction: Electroconvulsive therapy is an effective therapy of depression. On the basis of past work in non-human primates,¹ we hypothesized that the beneficial effects are mediated partly by decreased serotonin receptor availability in the cortex. To test the hypothesis, we used positron emission tomography with the serotonin 5HT_2A receptor radioligand [¹¹C]MDL100907 to determine serotonin receptor availability in response to electroconvulsive stimulation (ECS), a design derived from previously reported primate studies.

Methods: Seven female Göttingen minipigs aged 16–18 months were deeply anaesthetized with intravenous pentobarbital and imaged at baseline before the onset of ECS with a clinical device, and at 1–2 and 8–10 days after the end of a clinical course of ECS, consisting of 10 sessions over 3.5 weeks, and post-ECS values were compared to baseline. Animals were prone during the experiments as previously described.² The ECS used 70 Hz frequency, 0.5 ms pulse width, and 0.9 A current with a maximum charge of 504 mC. Electrodes were placed bilaterally on each side of the head. One additional minipig was anaesthetized over 10 sessions without ECS, as a control. We analysed images in terms of binding potentials with the multilinear reference tissue method applied to the tracer binding in cortex and hippocampus, followed by whole-brain analysis by statistical non-parametric mapping.³

Results: We found significantly increased binding potential of [¹¹C]MDL100907 in the cortex and hippocampus 1–2 days after ECS, consistent with increased serotonin receptor availability compared to baseline. By 8–10 days after the final ECS, the average tracer binding had returned towards baseline. However, we also found significantly decreased tracer binding in the subcortical regions of olfactory bulb, pons, thalamus and striatum (Figures 1 and 2).

Conclusion: With ECS, minipigs, like rodents, have higher availability at cortical and hippocampal 5HT_2A receptors. Decreased tracer binding is consistent with reduced serotonin receptor availability as a differential effect of ECS on 5HT_2A receptors in subcortical regions of minipig brain. The cortical changes are consistent with previous studies in rodents but are opposite changes observed in human and non-human brains. The differences may account for differences of serotonergic modulation of subcortical versus cortical brain.

Acknowledgements

We are grateful for technical support from staff at the Aarhus University Hospital PET Center and from the staff at the Aarhus University Farm for help with handling and stimulation of the animals.

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2021-48

Network integration derived non-invasive biomarkers for early prediction of Alzheimer’s disease (#254)

Paule-Joanne Toussaint and Alan C. Evans

Department of Neurology and Neurosurgery, Faculty of Medicine, Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada

Abstract

Introduction: Development of preventive therapies and the design of disease-modifying treatments for neurodegenerative diseases such as Alzheimer’s (AD) require early diagnosis. Accurate identification of predictive patterns in the evolution of AD is essential, and recent evidence suggests that the degenerative process develops along anatomically well-defined functionally connected networks. We have devised a technique to identify early markers of conversion to AD in groups of cognitively healthy controls and individuals with mild cognitive impairment (MCI), to serve in a diagnostic procedure based on multivariate approaches.

Methods: Positron emission tomographic (PET) data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI; www.adni-info.org) were used. Participants from the ADNI1 with baseline ¹⁸F-FDG PET scans were selected (N = 399) and grouped based on their diagnosis at 18 months post- inclusion.¹ Spatial independent component analysis (ICA) was applied on the baseline PET maps of glucose metabolism to obtain common regions of greatest coherent activity between groups of controls, individuals with mild cognitive impairment (MCI), and patients with AD. Independent components were extracted using an InfoMax algorithm, followed by dimension reduction with principal component analysis and Bayesian model selection (NetBrainWork²).

Results: Patterns of correlated FDG-PET regional activity suggest that regions such as the cingulate and temporo-parietal areas (Figure 1) could be more susceptible to neurodegeneration linked to AD, as they show damage early in the progression of the pathology.

Conclusion: Networks of regional activity extracted from FDG-PET data show significant co-occurring changes in radioactivity patterns between controls, individuals with MCI, and patients with AD. These distinctive patterns can serve as biomarkers of the initial stages of AD in a predictive model based on anatomo-functional networks. The method provides novel information on the functional and anatomical features underlying the disturbed neuronal connectivity and altered vascular and cellular mechanisms, and assesses the extent to which these features are early predictors of neuronal circuitry dysfunction.

Acknowledgements

This work was supported by the Canadian Institutes of Health Research (CIHR) grant MOP-37754, and by the National Institutes of Health (NIH) operating grant 248216.

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References

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2021-49

Sucrose lowers µ-opioid and D2/3 dopamine receptor availability of porcine brain (#256)

Albert Gjedde^{1, 2}, Michael Winterdahl³, Ove Noer³, Dariusz Orlowski⁴, Anna M. Schacht³, Steen Jakobsen³, Aage O. Alstrup³ and Anne M. Landau⁵

¹Department of Nuclear Medicine, University of Southern Denmark, Odense, Denmark

²Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada

³Department of Nuclear Medicine and PET Center, Aarhus University, Aarhus, Denmark

⁴Department of Neurosurgery, Aarhus University, Aarhus University Hospital, Aarhus, Denmark

⁵Translational Neuropsychiatry Unit, Aarhus University, Aarhus, Denmark

Abstract

Introduction: The intake of sucrose as a palatable substance is known to release dopamine and induce dependency in rodents.¹ Excessive sucrose consumption elicits addiction-like craving that may therefore underpin the obesity epidemic. Opioids and dopamine mediate the rewarding effects of drugs of abuse, and of natural rewards from stimuli such as palatable food. We determined the effects of repeated intermittent access to sucrose on opioid and dopaminergic neurotransmission.

Methods: We investigated the effects of sucrose using positron emission tomography (PET) with [¹¹C] carfentanil (µ-opioid receptor agonist) and [¹¹C]raclopride (dopamine D_2/3 receptor antagonist) in seven anesthetized female Göttingen minipigs. We gave the seven minipigs access to a sucrose solution for one hour on 12 consecutive days and completed positron emission tomography again 24 hours after the final sucrose access. In a smaller sample of five minipigs, we completed an additional [¹¹C]carfentanil PET session after the first sucrose exposure. We calculated voxel-wise binding potentials (BP_ND) using the cerebellum as a region of non-displaceable (ND) binding, then analyzed differences with statistical non-parametric mapping, and carried out an analysis of separate regions of the brains.

Results: We obtained average parametric maps of [¹¹C]carfentanil and [¹¹C]raclopride binding potentials, as shown in Figure 1. After 12 days of sucrose access, the BP_ND of both tracers had declined significantly in striatum, nucleus accumbens, thalamus, amygdala, cingulate cortex, and prefrontal cortex, a result consistent with down-regulation of receptor densities, as increased saturation was judged to be unlikely (Figure 2). After a single exposure to sucrose, we found decreased binding of [¹¹C]carfentanil in nucleus accumbens and cingulate cortex, consistent with opioid release.

Conclusion: The results clearly demonstrate that sucrose affects reward mechanisms in a manner similar to that of drugs of abuse. The lower receptor availability of opioid and dopamine receptors may explain the addictive potential associated with intake of sucrose. Thus, excessive consumption of palatable food may both cause, and become the result of, addiction with direct consequences for health by obesity.

Acknowledgements

An Aarhus University "AU Ideas Project Development" grant to Anne M. Landau funded the study. We are grateful for the technical support from the staff at the Aarhus University Hospital PET Center and the Aarhus University Farm.

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2021-50

Nicotine attenuates age-related memory and learning impairment in D-galactose-induced senescence in mice (#258)

Albert Gjedde^{1, 2}, Alireza Majdi³, Saeed Sadigh-Eteghad³, Mahnaz Talebi³, Fereshteh Farajdokht³, Marjan Erfani³ and Javad Mahmoudi³

¹Department of Nuclear Medicine, University of Southern Denmark, Odense, Denmark

²Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada

³Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

Abstract

Introduction: Brain aging is a multifaceted process that results from changes of specific molecular pathways that may lead to cognitive dysfunction. Nicotine has been found to possess procognitive properties in animals and humans that may attenuate the changes.^1–3

Methods: Here, we tested the hypothesis that nicotine ameliorates learning and memory impairment in aging brains of mice, induced by d-galactose (DGal). We administered DGal at 500 mg/kg doses by subcutaneous (s.c.) injection for 6 weeks to induce the impairment. As treatment, we administered nicotine at doses of 0.1, 0.5 or 1 mg/kg by the s.c route, or at 0.1 mg/kg by the intranasal (i.n.) route into the aged animals. We evaluated animal anxiety and withdrawal signs by counting the number of somatic signs, and examining thermal hyperalgesia, elevated plus maze and open field tests. Also, we assessed spatial and recognition memories by means of novel object recognition and Barnes maze tasks. We measured reactive oxygen species, mitochondrial membrane potential, caspase-3, Bax, Bcl-2, cytochrome C, brain-derived neurotrophic factor, and nerve growth factor levels in the brain tissue of the aged mice.

Results: The results revealed that treatment of aged mice with nicotine at 0.5 mg/kg s.c,. and 0.1 mg/kg i.n., doses remarkably ameliorated spatial and episodic memory decline, compared with the decline of vehicle-injected aged mice. Nicotine at these doses also decreased mito-oxidative damage as well as apoptosis, and it increased neurotrophic factors in the aged animals, compared with the levels of vehicle-injected mice. We detected withdrawal signs only at the 1 mg/kg s.c. dose of nicotine, compared to the vehicle-injected mice. Figure 1 shows the means ± SEM, (n = 12), including significant differences yielded by two- (A) or one-way ANOVA followed by Tukey’s post hoc test; labeled as *P < 0.05 or **P < 0.01, compared to the control group, ^#P < 0.05 or ^##P < 0.01, compared to the DG+NS group, where NS is normal saline; DG is D-galactose; Nic is nicotine; s.c. is subcutaneous; i.n. is intranasal; MWM is Morris water maze; and NOR is novel object recognition

Conclusion: Nicotine at the examined doses and routes had the potential to ameliorate age-induced cognitive decline and affect related downstream pathways, i.e., mito-oxidation, apoptosis, and neurotrophic factors, without causing apparent development of dependence.

Acknowledgements

This research was in part supported by a grant from Neurosciences Research Center (NSRC), Tabriz University of Medical Sciences (TUOMS; grant number: 5/88/1523) to SS-E and grants from Department of Nuclear Medicine, Odense University Hospital, and from Alzheimer Foundation of Denmark to AG.

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References

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2021-51

Anesthetics differentially influence [¹¹C]MDL100907 binding to 5HT_2A receptors in porcine brain (#259)

Albert Gjedde^{1, 2}, Anne M. Landau^{3, 4}, Ove Noer³, Aage O. Alstrup³, Hélène Audrain³, Gregers Wegener⁴, Doris J. Doudet⁵ and Michael Winterdahl³

¹Department of Nuclear Medicine, University of Southern Denmark, Odense, Denmark

²Department of Neurology & Neurosurgery, McGill University, Montreal, QC, Canada

³Department of Nuclear Medicine and PET Center, Aarhus University, Aarhus, Denmark

⁴Translational Neuropsychiatry Unit, Aarhus University, Aarhus, Denmark

⁵Division of Neurology, Department of Medicine, University of British Columbia, Vancouver, BC, Canada

Abstract

Introduction: We previously considered data collected in Göttingen minipigs to compare the effects of two commonly used anesthetics routinely used in large animal positron emission tomography (PET), the inhalant isoflurane and the injectable ultrashort acting nonbarbiturate anaesthetic propofol, on the binding of two radioligands of the monoaminergic receptor systems. We evaluate the effects of the same two anesthetics on the binding of [¹¹C]MDL100907 to serotonin 5HT_2A receptors.

Methods: We imaged 14 Isoflurane- and propofol-anesthetized Göttingen minipigs with [¹¹C]MDL100907, an antagonist of 5HT_2A receptors. PET imaging was performed on the high-resolution research tomograph (HRRT, CTI/Siemens). After a brief transmission scan, the minipigs were imaged with [¹¹C]MDL100907. Parametric maps of the tracer’s binding potentials relative to non-displaceable reference activity (BP_ND) used a multilinear reference tissue kinetic approach and a white matter mask as reference region. The same kinetic modelling approach was applied to time-activity curves of specific regions of interest including the striatum, cortical areas, hippocampus and amygdala.

Results: In the striatal regions of the averaged parametric maps of brains of minipigs anesthetized with isoflurane, values of BP_ND of [¹¹C]MDL100907 exceeded those of minipigs anaesthetized with propofol (Figure 1). We performed region-of-interest analysis of primary data, and two-way ANOVA revealed a significant effect of type of anaesthetic (P < 0.001) and region (P < 0.0001). Post hoc Bonferroni testing revealed significantly higher binding potentials in striatum of minipigs anesthetized with isoflurane rather than with propofol (P < 0.01) (Figure 2). In order to evaluate the contribution of cerebral blood flow (CBF) changes to the higher binding potential observed in the striatum of the isoflurane anesthetized animals, we surrogate flow values and found significantly higher values with isoflurane than with propofol.

Conclusion: We found significant differences in striatal binding of [¹¹C]MDL100907 to 5HT_2A receptors in minipig brain under propofol compared to isoflurane anesthesia, and we attribute these differences, at least in part, to increases in blood flow inherent to the isoflurane condition. The effects of anesthesia on the serotonin system as well as interactions between radioligands and anesthesia must be considered when designing and interpreting experiments. The choice of anesthetic may mask potential differences or effects due to experimental manipulations (pharmacologic or behavioural) in a particular study or may exaggerate differences.

Acknowledgements

The Lundbeck Foundation and Danish Medical Research Council funded these experiments. We are grateful for the technical support from staff at the Aarhus University Hospital PET Center.

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References

1.Waaben J, Husum B, Hansen AJ, et al. Hypocapnia prevents the decrease in regional cerebral metabolism during isoflurane-induced hypotension. J Neurosurg Anesthesiol 1989; 1: 29–34. [DOI] [PubMed] [Google Scholar]
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2021-52

Transcranial photoacoustic imaging of NMDA-evoked focal circuit dynamics in rat hippocampus (#260)

Dean F. Wong¹, Albert Gjedde^{2, 3}, Shilpa D. Kadam⁴, Joshua S. Elmore⁵, Brennan J. Sullivan⁴, Heather Valentine¹, Adarsha P. Malla⁶, Maged M. Harraz⁶, Arman Rahmim¹, Jin U. Kang^{7, 8}, Leslie M. Loew⁹, Michael Baumann¹⁰, Anthony A. Grace¹¹, Emad M. Boctor⁷ and Jeeun Kang^{1, 7}

¹Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, Maryland, USA

²Department of Nuclear Medicine, University of Southern Denmark, Odense, Denmark

³Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada

⁴Johns Hopkins Medical Institutions, Hugo W. Moser Research Institute, Baltimore, Maryland, USA

⁵Dept of Radiology & Radiological Science, Johns Hopkins University, Baltimore, Maryland, USA

⁶Solomon H. Snyder Dept of Neuroscience, Johns Hopkins University, Baltimore, Maryland, USA

⁷Whitting School of Engineering, Johns Hopkins University, Baltimore, Maryland, USA

⁸Dept of Electrical and Computer Engineering, Johns Hopkins University, Baltimore, Maryland, USA

⁹Dept of Cell Biology, University of Connecticut Health, Farmington, Connecticut, USA

¹⁰Intramural Research Program, National Institute of Drug Abuse, Baltimore, Maryland, USA

¹¹Depts of Neuroscience, Psychatry and Psychology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

Abstract

Introduction: Transcranial functional photoacoustic (fPA) voltage-sensitive dye (VSD) imaging promises to overcome current temporal and spatial limitations of current neuroimaging modalities. The technique previously distinguished global seizure activity from control neural activity in groups of rats. To validate the focal specificity of transcranial fPA with VSD (IR780 perchlorate) imaging in vivo, we now present proofs-of-concept that the results differentiate N-methyl-D-aspartate (NMDA) evoked neural activity in rat hippocampus. Concurrent quantitative EEG (qEEG) and microdialysis recorded real-time circuit dynamics and glutamate concentration change, respectively. We hypothesized that location-specific fPA VSD contrast would identify the neural dynamics in hippocampus with the correlation to NMDA evoked focal glutamate release and time-specific EEG signals.

Methods: To test the hypothesis, we infused 0.3, 1, and 3 mM NMDA at 2 µl/min over 60 min via an implanted microdialysis probe. The dialysate samples collected every 20 minutes during the infusion were analyzed for focal changes in extracellular glutamate release and quantified by high-performance liquid chromatography (HPLC).

Results: Transcranial fPA VSD imaging provided NMDA evoked VSD responses at the contralateral side of the microdialysis probe, presenting positive correlation with glutamate increase during 3 mM NMDA infusion. On the other hand, insignificant VSD response and glutamate release were obtained during 0.3 mM NMDA infusion. Quantitative EEG (qEEG) successfully confirmed induction of focal seizure activity or low response during 3 mM and 0.3 mM NMDA infusion, respectively. This graded response suggests all-or-none gating system in the dentate gyrus (DG) in hippocampus.

Conclusion: We conclude that transcranial fPA VSD imaging distinguished graded DG gatekeeping functions, based on the VSD redistribution mechanism sensitive to electrophysiologic membrane potential. The results suggest the potential future use of this emerging technology in clinics and science as an innovative and significant functional neuroimaging modality.

Acknowledgements

This work was supported by the NIH Brain Initiative under Grant No. R24 MH106083-03 (DFW, AG, AR, AAG, EMB, HV, JE) and the NIH National Institute of Biomedical Imaging and Bioengineering under Grant No. R01EB01963. NIH National Institute of Child Health and Human Development (NICHD) for R01HD090884 (SDK). NIH National Institute of Heart, Lung and Blood (NHLBI) under grant number R01HL139543 (Jeeun K, APM, EMB). National Cancer Institute (NCI) under grant number R21CA202199 and its equipment supplement. Funding of the PA equipment via resources of Jin K and EB NSF Career award #1653322. Jeeun K was partially supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education #2018R1A6A3A03011551.

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References

1.Kang J, Kadam SD, Elmore J, et al. Transcranial photoacoustic imaging of NMDA-evoked focal circuit dynamics in rat hippocampus. J Neural Eng 2020; 17(2): 025001. [DOI] [PMC free article] [PubMed] [Google Scholar]
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2021-53

Intrinsic connectivity of the human brain provides scaffold for tau aggregation in Alzheimer’s disease (#262)

Joseph Therriault, Tharick A. Pascoal, Melissa Savard and Pedro Rosa-Neto

McGill, H4C 0B5, H4C 0B5 Montreal, QC, Canada

Abstract

Introduction: Preclinical models suggest that tau pathology spreads intracellularly, thought to explain the topographical distribution of tau observed in Alzheimer’s disease (AD). However, these findings have yet to be extended to humans.

Methods: We assessed 131 cognitively unimpaired elderly and 63 AD individuals who underwent amyloid-PET with [¹⁸F]AZD4694, tau-PET with [¹⁸F]MK6240, structural MRI, fMRI and diffusion-weighted MRI. Of the subjects with AD, 11 had behavioural/dysexecutive AD, 18 had PCA and 11 had Logopenic variant PPA, while 23 subjects had an amnestic presentation (all were Ab+/Tau+). A voxelwise multivariate regression model was employed to determine the peak difference in [¹⁸F]MK6240 SUVR between each AD variant and CU elderly, with each clinical diagnosis entered as a different categorical variable and correcting for age, gender and MMSE score. Within each AD variant, the peak voxels derived from the regression model were used to compute the correlation between [¹⁸F]MK6240 SUVR in the seed voxel and [¹⁸F]MK6240 SUVR in every voxel, thus generating an [¹⁸F]MK6240 covariance network for each AD group. The same seeds were also employed in functional connectivity and diffusion tractography analyses in the CU elderly group. To determine whether the topographical distribution of tau pathology is related to connectivity properties of the human brain, we applied regression models to assess the relationship between functional/structural connectivity values from the CU population and [¹⁸F]MK6240 in each variant of AD.

Results: Tau organization differed between AD groups, reflecting clinical phenotypes and organizing within distinct brain networks. Furthermore, structural (Figure 1) and functional (Figure 2) connectivity patterns of the human brain predicted in vivo [¹⁸F]MK6240 SUVR across the cerebral cortex in each variant of AD.

Conclusion: These results support a framework in which the intrinsic connectivity of the human brain provides a scaffold for tau pathology to spread to anatomically distant regions.

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2021-54

Correspondence between gene expression and neurotransmitter receptor and transporter density in the human cortex (#275)

Justine Y. Hansen¹, Ross D. Markello¹, Nicola Palomero-Gallagher^{2, 3}, Alain Dagher¹ and Bratislav Misic¹

¹Neurology and Neurosurgery, McGill University, Montreal, QC, Canada

²Institute of Neuroscience and Medicine (INM-1), Research Centre Julich, Julich, Germany

³C. and O. Vogt Institute for Brain Research, Heinrich Heine University Dusseldorf, Dusseldorf, Germany

Abstract

Introduction: Neurotransmitter receptors and transporters modulate neuronal excitability and firing rate, and are therefore critical for intercellular communication. As such, neurotransmitter receptors and transporters play a key role in shaping brain connectivity and dynamics.^1,2 Due to the lack of comprehensive open-source neurotransmitter receptor/transporter density datasets, microarray gene expression is often used as a proxy for these protein densities. Despite the frequent replacement of receptor/transporter densities with gene expression, the assumed correlation between gene expression and receptor/transporter density has yet to be comprehensively and formally tested across multiple neurotransmitter systems.

Methods: Here we investigate whether microarray gene expression can be used to estimate neurotransmitter receptor/transporter densities in the cortex. We use the Allen Human Brain Atlas for the expression levels of specific genes which code for specific neurotransmitter receptors or transporters.^3,4 Additionally, we use both PET- and autoradigoraphy-derived estimates of neurotransmitter receptor densities, which we collected for a total of 24 neurotransmitter receptors and transporters across 8 different neurotransmitter systems.⁵ We study the association between gene expression and neurotransmitter receptor densities at the level of the cortex, and across five bins along the unimodal-transmodal functional hierarchy. To ensure results are not biased by methodological choices, we repeat our analyses in a separate parcellation resolution and use a conservative spatial autocorrelation-preserving null model.

Results: We find poor spatial correspondences between gene expression and density for all neurotransmitter receptors except for three single-protein metabotropic receptors (5-HT1A, D2, and MOR; Figure 1). We find that genes with the greatest stability across brain samples are most closely associated with receptor density (Figure 2). Finally, we find variability in system-wide associations, with unimodal brain regions showing stronger gene-receptor associations and transmodal brain regions showing weaker gene-receptor associations.

Conclusion: Future efforts to map neurotransmitter receptor and transporter profiles to brain structure and function should verify the expression-density association when using microarray gene expression in place of receptor and transporter density. Altogether, we recommend using direct measures of receptor and transporter density when relating neurotransmitter systems to brain structure and function.

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2021-55

Mapping neurotransmitter receptor and transporter distributions to the connectivity and dynamics of the human neocortex (#276)

Justine Y. Hansen¹, Golia Shafiei¹, Ross D. Markello¹, Sylvia Cox¹⁰, Kelly Smart¹¹, Etienne Aumont², Stijn Servaes⁹, Stephanie Scala¹⁰, Gabriel Wainstein³, Gleb Bezgin⁹, Thomas Funck⁷, Marc-Andre Bedard^{1, 2}, R. Nathan Spreng¹, Jean-Paul Soucy¹, Synthia Guimond⁶, Jarmo Hietala⁵, Marco Leyton^{1, 10}, Pedro Rosa-Neto^{1, 9}, Richard E. Carson¹¹, Nicola Palomero-Gallagher^{7, 8}, Lauri Tuominen⁶, James M. Shine³, Alain Dagher¹ and Bratislav Misic¹

¹Neurology and Neurosurgery, McGill University, Montreal, QC, Canada

²UQAM, Cognitive Pharmacology Research Unit, Montreal, QC, Canada

³Brain and Mind Centre, University of Sydney, Sydney, Australia

⁴McGill University, Douglas Hospital, Montreal, QC, Canada

⁵University of Turku, Psychiatry, Turku, Finland

⁶Institute of Mental Health Research, University of Ottawa, Ottawa, ON, Canada

⁷Institute of Neuroscience and Medicine (INM-1), University of Julich, Julich, Germany

⁸C. and O. Vogt Institute for Brain Research, Heinrich Heine University Dusseldorf, Dusseldorf, Germany

⁹Research Centre for Studies in Aging, McGill University, Montreal, QC, Canada

¹⁰Psychiatry, McGill University, Montreal, QC, Canada

¹¹Yale, PET Centre, New Haven Connecticut, USA

Abstract

Introduction: The patterns of neural activity demonstrated by billions of neurons ultimately manifest as whole-brain connectivity and dynamics. Modulatory influences on neural activity occur due to the receptors that span the surface of each cell. The heterogeneous distribution of receptor densities across the cortex suggests a diversity of modulatory influence, and therefore also of signal integration, neural dynamics, and connectivity.^1,2

Methods: We used two recent state-of-the-art datasets (PET and autoradiography) of neurotransmitter receptor densities across the neocortex, which include a total of 27 receptors, receptor binding-sites, and transporters.³ First, we mapped receptor distributions to structural and functional connectivity, thereby profiling how receptors may influence whole-brain communication. Second, we used multiple linear regression models to predict magnetoencephalography power.⁴ Finally, we conducted a partial least squares analysis between receptor densities and Neurosynth-derived measures of functional association of 123 cognitive terms to uncover a latent axis of covariation across the cortex.⁵

Results: We find that the similarity of receptor profiles between two regions is greater for more proximal regions. Moreover, regions show more similar receptor distributions if they are physically connected with one another, and receptor distributions are highly similar in very densely connected brain regions. In terms of functional connectivity, we find that receptor distributions are more similar within regions of the same functional network rather than between regions of different functional networks. We also find that receptor similarity is significantly correlated to functional connectivity. We further find that receptor distributions augment structure-function coupling, particularly in the ventral temporal lobe. Interestingly, we find that receptor densities strongly predict all six MEG power bands. Finally, we extracted a significant axis of covariation between receptor densities and Neurosynth cognitive association, which indicates receptor densities and mood-related processes covary in the limbic and insular cortices.

Conclusion: Here, we show that the heterogeneous distribution of receptors across the human neocortex reflects structural and functional network architectures, shapes neural dynamics, and spatially covaries with neurocognitive functional activation. Altogether, we uncover the neurochemical infrastructure that shapes the brain’s connectivity and dynamics by comprehensively mapping receptor distributions to the structure and function of the human brain.

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References

1.Shine JM. Neuromodulatory influences on integration and segregation in the brain. Trends Cognitive Sci 2019; 23: 572–583. [DOI] [PubMed] [Google Scholar]
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3.Zilles K, Palomero-Gallagher N. Multiple transmitter receptors in regions and layers of the human cerebral cortex. Frontiers Neuroanatomy 2017; 11, 78. [DOI] [PMC free article] [PubMed] [Google Scholar]
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2021-56

A possible link between Fragile X mental retardation protein and metabotropic glutatmate receptor subtype 5 in men with fragile X syndrome (#277)

James R. Brasic¹, Jack A. Goodman², David S. Russell^3,
4, Danna Jennings^{3, 5}, Olivier Barret^{3, 6}, Ayon Nandi¹, Anil K. Mathur¹, Thomas W. Sedlak^{1, 7}, Keith Slifer^{7, 8}, Samuel D. Martin^{1, 9}, Elizabeth M. Berry-Kravis¹⁰, John P. Seibyl^{3, 4}, Dean F. Wong^{1, 11} and Dejan B. Budimirovic^{7, 12}

¹The Russell H. Morgan Department of Radiology and Radiological Science/Division of Nuclear Medicine and Molecular Imaging/Section of High Resolution Brain Positron Emission Tomography Imaging, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

²Frank H. Netter MD School of Medicine, Quinnipiac University, North Haven Connecticut, USA

³Institute for Neurodegenerative Disorders, New Haven Connecticut, USA

⁴Invicro, New Haven Connecticut, USA

⁵Denali Therapeutics, South San Francisco California, USA

⁶Commissariat à l’Énergie Atomique et aux Énergies Alternatives (CEA)/Université Paris-Saclay, Laboratoire des Maladies Neurodégénératives, Molecular Imaging Research Center (MIRCen)/Institut de Biologie François Jacob/Centre National de la Recherche Scientiﬁque (CNRS), Fontenay-aux-Roses, France

⁷Johns Hopkins University School of Medicine, Department of Psychiatry and Behavioral Sciences, Baltimore, Maryland, USA

⁸Johns Hopkins Medical Institutions, Department of Behavioral Psychology/Kennedy Krieger Institute, Baltimore, Maryland, USA

⁹Department of Neuroscience/Zanvyl Krieger School of Arts and Sciences, Johns Hopkins University, Baltimore, Maryland, USA

¹⁰Departments of Pediatrics, Neurological Sciences, and Biochemistry, Rush University Medical Center, Chicago Illinois, USA

¹¹Department of Radiology/Laboratory of Central Nervous System (CNS) Neuropsychopharmacology and Multimodal Imaging (CNAMI)/Mallinckrodt Institute of Radiology, Washington University School of Medicine, Saint Louis Missouri, USA

¹²Department of Psychiatry/Kennedy Krieger Institute, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA

Abstract

Introduction: Although animal models of fragile X syndrome (FXS) suggest a link between Fragile X Mental Retardation Protein (FRMP) and metabotropic glutamate receptor subtype 5 (mGluR₅) in the pathogenesis and pathophysiology of fragile X syndrome (FXS), numerous animal and human studies of FMRP and mGluR₅ provide inconsistent or conflicting findings about those relationships. We aimed to (A) compare and contrast FMRP levels and mGluR₅ expression by positron emission tomography (PET) with 3-[¹⁸F]fluoro-5-(2-pyridinylethynyl)benzonitrile ([¹⁸F]FPEB) in FXS and typical development (TD)^1–4 (Figure 1) and (B) show the preliminary value of measurement of FRMP and mGluR₅ expression for the application of precision medicine for the diagnosis and treatment of individuals with FXS and related conditions.

Methods: Two teams of investigators at the Institute for Neurodegenerative Disorders (IND), New Haven, Connecticut, and the Johns Hopkins University (JHU), Baltimore, Maryland, independently administered 3-[¹⁸F]fluoro-5-(2-pyridinylethynyl)benzonitrile ([¹⁸F]FPEB)⁴ to men with FXS [N = 7, age 27.67 + 4.28, range (22.3, 33.6)] and participants of both sexes with TD [N = 18, age 33,15 + 14.06, range (19, 62.4)].¹ Participants with FXS had a diagnosis of FXS based on FMR1 DNA gene testing by polymerase chain reaction (PCR)/Southern Blot on peripheral venous blood samples supplemented by clinical neurobehavioral profiling.^1–3

Results: The FMRP concentration (nanograms per microgram total protein) and the mGluR₅ uptake ([¹⁸F]FPEB BP_ND) in the cortical regions of all participants is plotted in Figure 2 (Graphpad Prism 9 for Mac, GraphPad Software, San Diego, California USA, www.graphpad.com). The FMRP value of 0.78 nanograms per microgram total protein, the average value of ten healthy people with typical development (TD) with normal CGG repeat sizes [range (20,37)] utilizing the same analyses as other participants, was used as the value for all participants with TD since none had undergone analysis for FMRP. There appears to be a positive correlation between mGluR₅ uptake in the cortical regions and FMRP concentrations in the cohorts of men with FXS and the cohorts of participants with TD (Figure 2).

Conclusion: This protocol to measure FMRP and mGluR₅^1–5 may facilitate future clinical trials of individuals with FXS and related conditions.

Acknowledgements

This research was made possible by a Radiology BRidge/Development Funding Initiative to STimulate and Advance Research (RAD BriteStar Bridge) Award from the Johns Hopkins University School of Medicine, Baltimore, Maryland to J.R.B. with the assistance of D.F.W.; and the Intellectual & Developmental Disabilities Research Center (U54 HD079123), Kennedy Krieger Institute, and Johns Hopkins Medical Institutions, Baltimore, Maryland, to J.R.B.

The authors thank the patients and families for their participation and dedication to these studies; they are the inspiration for our efforts at improving treatments. The authors thank the FORWARD Database and Registry of the National Fragile X Foundation (NFXF) funded by the Centers for Disease Control and Prevention (CDC), Atlanta, Georgia, for referral of participants.

The authors thank the teams of the Institute for Neurodegenerative Disorders and the Positron Emission Tomography (PET) Radiotracer Service Center of the Johns Hopkins University School of Medicine for conducting the scans. The authors thank Hiroto Kuwabara for PET analysis.

Earlier versions of this article were presented at the Undergraduate Research Symposium, Johns Hopkins University, Baltimore, Maryland, 28 October 2020, and the Society for Neuroscience Global Connectome, Virtual, 12 January 2021 (Martin et al.³).

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1.Brasic JR, Martin SD, Goodman JA, et al. Fragile X Mental Retardation Protein and cerebral expression of metabotropic glutamate receptor subtype 5 in men with fragile X syndrome, Zenodo, v1, Geneva, Switzerland: CERN European Organization for Nuclear Research, 2021. 10.5281/zenodo.5154217. [DOI]
2.Brasic JR, Nandi A, Russell DS, et al. Cerebral expression of metabotropic glutamate receptor subtype 5 in idiopathic autism spectrum disorder and fragile X syndrome: a pilot study. Int J Mol Sci 2021; 22: 2863. [DOI] [PMC free article] [PubMed] [Google Scholar]
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4.Wong DF, Waterhouse R, Kuwabara H, et al. ¹⁸F-FPEB, a PET radiopharmaceutical for quantifying metabotropic glutamate 5 receptors: a first-in-human study of radiochemical safety, biokinetics, and radiation dosimetry. J Nucl Med 2013; 54: 388–396. [DOI] [PMC free article] [PubMed] [Google Scholar]
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2021-57

A translational investigation of morphine-induced neuroimmune signaling: Implications for opioid use disorder (#278)

Eric A. Woodcock^{1, 2}, Gustavo A. Angarita^{2, 3}, David Matuskey^{2, 3}, Jim Ropchan³, Nabeel Nabulsi³, Yiyun H. Huang³, Ansel T. Hillmer^{2, 3}, Richard E. Carson³ and Kelly P. Cosgrove^{2, 3}

¹Psychiatry and Behavioral Neurosciences, Wayne State University, Detroit, Michigan, USA

²Psychiatry, Yale University, New Haven, Connecticut, USA

³Yale PET Center, Yale University, New Haven, Connecticut, USA

Abstract

Introduction: Preclinical studies indicate that opioids evoke pro-inflammatory responses in the periphery and brain. These pro-inflammatory signals influence appetitive and dysphoric addiction processes and thus, may influence development of opioid use disorder (OUD) and/or perpetuate continued use. Here, we investigated the neuroimmune effects of morphine using Positron Emission Tomography (PET) imaging with [¹¹C]PBR28. [¹¹C]PBR28 binds to the 18kDa translocator protein (TSPO), a marker that is sensitive to pro-inflammatory neuroimmune stimulation.

Methods: Study #1: Eight healthy individuals with prior medical opioid exposure (3F; 34.3yrs [range = 26-49yrs]; BMI = 24.8 [range = 20-30]) completed two 120-minute [¹¹C]PBR28 scans: before and 2-hours after intramuscular morphine (0.04mg/kg or 0.07mg/kg [‘low’ vs. ‘high’ dose]). Total volume of distribution (V_T; TSPO availability) was estimated in 12 brain regions of interest (ROIs) using multilinear analysis-1 (t* = 30) and the metabolite-corrected arterial input function. Linear mixed models were used to evaluate morphine’s effect on TSPO with rs6971 Genotype, Morphine Dose, and Time as fixed factors and regional [¹¹C]PBR28 V_T as the within-subject repeated factor. Subjective effects were measured via visual analogue scales. Study #2: Two adult male rhesus macaques completed identical neuroimaging procedures as Study #1 before/after intramuscular morphine (1mg/kg). One macaque was pre-treated with intravenous (+)-naloxone (1mg/kg), a Toll-like Receptor-4 antagonist (TLR4) with negligible binding affinity for opioid receptors, to investigate the putative neurobiological mechanism. Studies were approved by the Yale University IRB and IACUC.

Results: Study #1: Morphine increased TSPO availability by 25–32% across ROIs, F(1,203) = 282.2, p < .001, (Figure 1) and evoked a subjective ‘high’, F(4,24) = 3.06, p = .036 (Figure 2(a)). Controlling for morphine dose, the increase in TSPO availability in the caudate was positively correlated with subjective ‘high’ at post-scan (R² = 0.57, p = .03; Figure 2(b)). Study #2: Without pretreatment, morphine increased regional TSPO availability by 24–54%. Pretreatment with (+)-naloxone attenuated morphine’s effect on TSPO by 43%, on average, across ROIs.

Conclusion: Our findings indicate that morphine evokes a neuroimmune response in people and that morphine-induced ‘high’ is linearly related to neuroimmune signaling in the caudate. Given its well-established role in mesolimbic reward circuitry, our data suggest that neuroimmune signaling in the caudate may modulate opioid-induced euphoria. Finally, our non-human primate findings highlight TLR4 as a target for medication development.

Acknowledgements

The authors acknowledge the staff at the Yale University PET center, Jon Mikael Anderson, Aleksandra Rusowicz, Brittany LeVasseur, Dr. Stephen Baldassarri, Olivia Wilson, Nicole DellaGioia, Ryan Cool, Sarah DeBonee, Elizabeth Yanac, Daniel Holden, Krista Fowles, and Dr. Kenner Rice.

Funding

Funding was generously provided by the National Institute on Drug Abuse (NIDA K99/R00 DA048125; EAW), the National Institute of Mental Health (R01 MH110674; KPC), and the Veterans Affairs National Center for PTSD (KPC). (+)-Naloxone was provided by Dr. Kenner Rice in the Drug Design and Synthesis Section at NIDA. The work of the Drug Design and Synthesis Section, MTMDB, NIDA, and NIAAA was supported by the NIH Intramural Research Programs of the National Institute on Drug Abuse (NIDA) and the National Institute of Alcohol Abuse and Alcoholism (NIAAA). Inline graphic

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2021-58

[¹²⁴I]IBETA PET/CT studies in Alzheimer’s disease 5XFAD mouse model of β-amyloid (Aβ) Plaques (#279)

Christopher Liang, An N. Nguyen, Eunice Lee and Jogeshwar Mukherjee

Radiology, University of California, Irvine, California, USA

Abstract

Introduction: Several high affinity PET radiotracers for imaging Aβ plaques are currently being in the diagnosis of Alzheimer’s disease (AD).^1,2 Radioiodinated pyridyl benzofuran derivatives for SPECT imaging of Aβ plaques using 123I and 125I have been reported.³ Because of the long half life of iodine-124 and use in extended PET imaging,⁴ we have prepared the benzofuran, [124I]I-IBETA (Ki = 2.36 ± 0.53³) for use in PET imaging. Here we report our preliminary findings on [124I]I-IBETA in the 5XFAD AD mouse model.

Methods: [124I]Sodium Iodide (from 3D Imaging LLC) was used to prepare [124I]I-IBETA by electrophilic substitution of the tributyltin derivative (Figure 1) and purified by chromatography. Female hemizygous 5XFAD (n = 3) 7-month old mice obtained from MMRRC JAX were used for in vitro and in vivo study. Horizontal brain slices were incubated with [124I]I-IBETA and analyzed using Optiquant. In 5XFAD mice, [124I]I-IBETA was injected retroorbitally (0.9 MBq) under 2% isoflurane anesthesia. All mice underwent 15-minute PET scans (90 minutes and 24 hours post-injection) in a supine position with an accompanying 7-minute CT scan for attenuation correction. An Inveon Multimodality scanner was used for CT acquisitions in combined PET/CT experiments.

Results: Iodine-124 radiolabeling proceeded smoothly and purified [124I]I-IBETA was found to be stable for in vitro and in vivo studies. In vitro binding of [124I]I-IBETA in 5XFAD brain slices was high in thalamus, cortex and hippocampus, while cerebellum revealed very low levels of binding (Figure 2(b)). Ratio of regions versus cerebellum were > 10 (Figure 2(C) and (D)) suggesting high levels of Aβ plaques in these regions. In vivo PET/CT [124I]I-IBETA scans, uptake was non-uniform, but showed uptake in the thalamus and frontal cortex region as shown in Figure 2(e). At later time points, significant amount of activity was detected in the thyroid region, suggesting that some deiodination of [124I]I-IBETA in vivo.

Conclusion: Preliminary PET/CT scans and mouse brain slice autoradiography in 5XFAD mice have shown binding of [124I]I-IBETA to Aβ plaques consistent with 5XFAD mice model.⁵ There is potential for radioiodinated pyridyl benzofurans to be used as PET tracers to detect Aβ plaques.³ Further studies are planned to investigate drug effects and reversibility of binding of [124I]I-IBETA on Aβ plaques in vivo.

Acknowledgements

NIH/NIA RF1 AG029479 (JM), UCI UROP (AN)

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References

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2021-59

Examining kinetic spectrum of extracerebral signal and its contributions to reference regions of ¹⁸F-MK6240 PET (#280)

Jessie Fanglu Fu^{1, 2}, Cristina Lois^{2, 3}, Justin Sanchez³, Alex Becker^{2, 3}, Zoe Rubinstein³, Emma Thibault³, Andrew Salvatore¹, Hasan Sari^{1, 2}, Michelle Farrell², Marc Normandin^{2, 3}, Nicolas J. Guehl^{2, 3}, Georges El Fakhri^{2, 3}, Keith Johnson^{2, 3} and Julie C. Price^1,
2

¹Athinoula A. Martinos Center for Biomedical Research, Massachusetts General Hospital, Charlestown Massachusetts, USA

²Department of Radiology, Harvard Medical School, Boston, Massachusetts, USA

³Gordon Center for Medical Imaging, Massachusetts General Hospital, Division of Nuclear Medicine and Molecular Imaging, Boston Massachusetts, USA

Abstract

Introduction: Off-target ¹⁸F-MK-6240 binding to melanocytes (extracerebral signal (EC), Figure 1(a))^1,2 can contaminate cerebellar gray matter (CerGM) reference uptake and impact the detection of emergent tau signal in Alzheimer’s disease (AD)^3,4 by reference tissue methods. We compared ¹⁸F-MK6240 kinetic spectra quantified in EC, CerGM and alternative reference regions to inform reference region selection, across the AD spectrum.

Methods: Thirteen subjects (8 controls (CN)–63 ± 12yrs; 5 mild cognitive impairment (MCI) or AD–75 ± 9yrs) underwent 120 min ¹⁸F-MK6240 PET, MRI, and arterial blood sampling. Masks for EC (Figure 1(b) and (c)) and reference regions (CerGM, eroded CerGM 3 mm, inferior CerGM (InfCer), cerebral white matter (WM) and pons) were generated (Freesurfer). Region-level spectral analysis (SA)⁵ was applied to decompose total ¹⁸F-MK6240 uptake into spectral components with frequency band amplitude a. SA kinetic spectra were compared between EC and reference regions (T-tests, p < 0.05).

Results: SA indicated 2 reversible components in reference regions (Figure 2(a) and (b)): 1) b ∼0.03min⁻¹ (slow, non-displaceable uptake) and 2) b ∼0.18min⁻¹ (fast, tracer delivery). Compared to CerGM, EC SUV was 30% higher and constantly increasing in late frames (Figure 1(d)) and only exhibited a fast component with 90% lower amplitudes (P < 10E-5, Figure 2(d)). A trapping/irreversible component (b = 10E-5min⁻¹) was detected in all regions, with amplitudes significantly higher in EC (∼3-fold) than other regions (P < 0.05) except InfCer (Figure 2(e)). Compared to CerGM, trapping amplitudes were higher in InfCer (50%), but lower for WM and pons (60%) and eroded CerGM (18%).

Conclusion: SA supports a 2-tissue compartment configuration in reference regions. EC signal uniquely exhibited 1 reversible component and largest trapping amplitudes. The trapping component in reference regions likely reflects EC contamination, which was most evident in InfCer and less prevalent in WM and pons. Further studies will quantify the EC signal longitudinally and examine model-based methods to account for the EC signal as an alternative to partial-volume-correction.

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References

1.Betthauser TJ, Cody KA, Zammit MD, et al. In vivo characterization and quantification of neurofibrillary tau PET radioligand 18F-MK-6240 in humans from Alzheimer disease dementia to young controls. J Nucl Med 2019; 60: 93–99. [DOI] [PMC free article] [PubMed] [Google Scholar]
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2021-60

The relationship between glutamate, dopamine receptors, dopamine release and cortical grey matter: A simultaneous PET-MR study (#281)

Antoine Rogeau, Giovanna Nordio, Mattia Veronese, Oliver D. Howes and Robert McCutcheon

King’s College London, Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, London, UK

Abstract

Introduction: The relationship between cortical grey matter, striatal dopamine signalling and cortical glutamate levels is of interest given their frequent simultaneous disruption in neuropsychiatric disease. Simultaneous measurement of these systems is challenging given the different imaging modalities required for accurate assessment. The aim of this study is to find out whether correlations exist between these neural systems.

Methods: In the current study, twenty-eight healthy subjects were enrolled to undergo 2 simultaneous [11C]-PHNO PET-MRI scans after double-blind randomised placebo or amphetamine administration in a cross-over design. This allowed measurement of striatal dopamine release capacity, striatal dopamine receptor availability, anterior cingulate glutamine & glutamate levels, and cortical grey matter volumes (GMV). A multiple regression model was used with voxel-based morphometry to seek associations between neurochemical measures and GMV.

Results: Left associative striatum dopamine receptor availability demonstrated a significant positive correlation with the volume of a grey matter cluster in the right prefrontal cortex (pFWE corrected = 0.022 – Figure 1). In addition, a negative interaction effect between sensorimotor dopamine receptor availability and glutamate+glutamine (Glx) correlated with a right cluster in BA6 (pFWE corrected = 0.047 – Figure 2).

Conclusion: These results extend previous findings that showed association between prefrontal grey matter volume and striatal dopamine synthesis capacity in schizophrenia to demonstrate that even in healthy individuals striatal dopamine function and prefrontal GMV are linked. It also highlights an interaction effect of ACC glutamate and striatal dopamine on prefrontal GMV. This brings new insights to the relationship between dopaminergic and glutamatergic physiology, and their relationship with cortical structure.

Acknowledgements

Supported by NIHR Maudsley BRC and Wellcome Trust Innovator Award (215747/Z/19/Z).

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2021-61

Peripheral red blood cell (RBC) docosahexaenoic acid (DHA) and serum triglyceride levels influence [¹¹C]PBR28 binding to TSPO in the brain (#282)

Savannah Tollefson¹, Michael Himes¹, Katelyn Kozinski¹, Brian Lopresti¹, Neale S. Mason¹ and Rajesh Narendran^{1, 2}

¹School of Medicine, Department of Radiology, University of Pittsburgh, Pittsburgh Pennsylvania, USA

²School of Medicine, Department of Psychiatry, University of Pittsburgh, Pittsburgh Pennsylvania, USA

Abstract

Introduction: DHA, an omega-3 fatty acid, exhibits anti-inflammatory effects in the brain in basic investigations. DHA’s ability to modulate brain inflammation is of interest in Alzheimer’s disease and traumatic brain injury. We hypothesized that binding to the 18KDa translocator protein (TSPO), a proxy for M1-type microglia, will be higher in individuals with low relative to high DHA levels.

Methods: RBC DHA was measured in 320 healthy males. [¹¹C]PBR28 was used to measure TSPO binding in 38 and 32 males in the lowest and highest RBC DHA quartiles. Volumes of distribution expressed relative to total plasma ligand concentration (V_T) was derived using a two-tissue compartment kinetic analysis in fourteen brain regions (ROIs). Stress-resilience and cognitive assessments were conducted to correlate with V_T.

Results: Age, weight and body mass index (BMI) were not different between-groups. RBC DHA in the high and low groups were 3.27 ± 0.56% and 2.13 ± 0.35%. Trend-level negative associations between DHA and serum triglycerides was present.

Between-group differences in [¹¹C]PBR28 injected dose and mass, f_p and C_L were not present. V_T was significantly lower (by 12% and 20% in C/T and C/C rs6971 genotypes) in the low compared to high RBC DHA group (Linear Mixed Model: DHA group, p = 0.047; ROI, p < 0.001; genotype, p < 0.001). V_T was positively and negatively associated with high-density lipoproteins and triglycerides, respectively. Negative correlations between V_T and triglycerides (5/14 ROIs), but not high-density lipoproteins survived the Bonferroni correction. No relationships between V_T and BMI, or clinical assessments were present.

Conclusion: Contrary to our hypothesis, we found lower TSPObinding in low relative to high DHA subjects. It is unclear as to whether low TSPO binding reflects differences in microglia and/or triglyceride metabolism in this study. These results underscore the need to consider lipid parameters as a factor when interpreting TSPO PET clinical findings.

Funding

W81XWH-15-PRMRP-IIRA/Log Number: PR150716 from the US Department of Defense (DoD)

2021-62

Choroid plexus enlargement is associated with neuroinflammation and reduction of blood brain barrier permeability in depression (#283)

Noha S. Althubaity^{1, 2}, Julia J. Schubert¹, Daniel Martins¹, Tayyabah Yousaf¹, Maria A. Nettis³, Valeria Mondelli³, Carmine Pariante³, Neil A. Harrison^{4, 5}, Edward T. Bullmore^{6, 7}, Danai Dima^{1, 9}, Federico E. Turkheimer¹ and Mattia Veronese^{1, 10} and Neuroimmunology of Mood Disorders and Alzheimer’s Disease Consortium¹¹

¹Department of Neuroimaging, King’s College London, IoPPN, London, UK

²Radiological Sciences, College of Applied Medical Science, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia

³Department of Psychological Medicine, King’s College London, IoPPN, London, UK

⁴Brain Research Imaging Centre, Cardiff University, Cardiff, UK

⁵Department of Neuroscience, Brighton and Sussex Medical School, University of Sussex, Brighton, UK

⁶Department of Psychiatry, School of Clinical Medicine, University of Cambridge, Cambridge, UK

⁷Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge, UK

⁸GlaxoSmithKline R&D, Immuno-Psychiatry, Immuno-Inflammation Therapeutic Area Unit, Stevenage, UK

⁹Department of Psychology, School of Arts and Social Sciences, City University of London, London, UK

¹⁰Department of Information Engineering, University of Padua, Padua, Italy

¹¹Wellcome Trust Consortium for the Neuroimmunology of Mood Disorders and Alzheimer’s Disease, UK, UK

Abstract

Introduction: Depression is often associated with elevations of peripheral inflammatory markers¹ but the mechanisms linking peripheral inflammation and changes in the central nervous system are still under investigation. Recent studies have shown that choroid plexuses (CP) may be involved in the neuro-immune axes, playing a role in brain homeostasis, and mediating the interaction between central and peripheral inflammation.^2,3 Here we aimed to investigate CP volume alterations in depression and their associations with central brain inflammation.

Methods: 51 depressed participants (HDRS score > 13) and 25 age- and sex-matched healthy controls (HCs) from the Wellcome Trust NIMA consortium were re-analysed for the study. All the participants underwent full peripheral cytokine profiling and simultaneous [¹¹C]PK11195 PET/structural MRI imaging for measuring neuroinflammation and blood-to-CSF radiotracer exchange parameters, and CP volume, respectively. We leveraged transcriptomic data from the Allen Human Brain Atlas to explore possible associations between the brain map depicting the correlations between CP volume and TSPO with functional brain pathways.

Results: We found a significantly greater CP volume in depressed subjects compared to HCs (t₍₇₆₎ = +2.17, p = 0.03) that was positively correlated with [¹¹C]PK11195 binding in the anterior cingulate cortex (r = 0.28, p = 0.02), prefrontal cortex (r = 0.24, p = 0.04), and insular cortex (r = 0.24, p = 0.04) (Figure 1). The CP volume exhibited a negative association with the blood-to-CSF radiotracer exchange parameters (r = -0.28, p = 0.02). Integration of transcriptomic data with CP volume/TSPO imaging correlation map showed significant gene enrichment for several pathways involved in the neuroinflammatory response.

Conclusion: These results support the hypothesis that changes in brain barriers may cause reduction in solute exchanges between blood and CSF, disturbing brain homeostasis and ultimately contributing to inflammation in depression. Given that CP anomalies have been recently detected in other brain disorders^4,5 these results may not be specific to depression and might extend to other conditions with a peripheral inflammatory component.

Acknowledgements

The Wellcome Trust and NIHR Maudsley Biomedical Research Centre.

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2021-63

Evidence of blood-to-cerebrospinal fluid alterations in traumatic brain injury (#284)

Julia J. Schubert¹, Mattia Veronese¹, Gregory Scott², Oliver Cousins¹, Richard J. Greenwood^{3, 4}, Anil F. Ramlackhansingh², David J. Sharp² and Federico E. Turkheimer¹

¹Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK

²Department of Medicine, Imperial College London, London, UK

³University College London, London, UK

⁴MedTech West at Sahlgrenska University Hospital, Gothenburg, Sweden

Abstract

Introduction: The brain relies on cerebrospinal fluid (CSF) for delivery, movement, and removal of solutes.¹ CSF is mostly produced by choroid plexuses (CPs) lining the ventricular system and forming part of the blood-to-CSF barrier (BCSFB).² Reduced lateral ventricle (LV) PET signal has been observed in Alzheimer’s disease (AD),³ possibly attributed to reduced CSF-mediated tissue clearance. Given that traumatic brain injury (TBI) exhibits similar pathological features to AD,^4,5 we investigated whether blood-to-CSF dynamic alterations exist in TBI using existing PET data by comparing LV ¹¹C-PBR28 signal, perfusion rates, and CP volumes of TBI subjects and healthy controls (HC).

Methods: 14 moderate-severe TBI subjects and 44 HC underwent 90-minute dynamic ¹¹C-PBR28 PET with arterial input function and structural MRI. LV and CP segmentations were generated. LV ¹¹C-PBR28 signal was quantified as standard uptake value ratios (SUVRs) from 50–70 minutes using cerebellum grey matter reference. Compartmental modelling of LV ¹¹C-PBR28 signal was also performed to quantify input from plasma (K₁), clearance to plasma and the remaining ventricular system (kClearance), and rates of specific binding on (k_on) and off (k_off) LV binding sites (Figure 1). CP volume was calculated using FSL (FMRIB, Oxford UK).

Results: Significantly lower LV SUVRs (F(1,54) = 7.78, P = 0.007; Figure 2(a)) and K₁ (F(1,52) = 8.82, P = 0.004; Figure 2(b)) and significantly higher CP volumes (F(1,54) = 39.74, P < 0.001; Figure 2(c)) were observed in TBI compared to HC. No significant differences were observed in kClearance, k_on, or k_off.

Conclusion: We observed reduced LV signal and perfusion rates from plasma to LV in TBI, similar to previous results in AD.³ We also observed larger CP volume in TBI, demonstrating that the CP contribution of the BCSFB is altered in TBI. Blood-to-CSF transfer rate alterations may lead to reduced passage of small molecules into and through the CSF in TBI, contributing to early development of neurodegenerative disease.

Acknowledgements

Hammersmith Imanet provided radiotracers and scanning facilities used for data acquisition.

We gratefully acknowledge all study participants.

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2021-64

Comparison of Lewy body distribution and monoamine oxidase A in anterior cingulate of postmortem Parkinson’s disease brains (#286)

Reisha M. Ladwa, Rommani Mondal, Christopher Liang and Jogeshwar Mukherjee

Radiological Sciences, University of California, Irvine California, USA

Abstract

Introduction: Lewy bodies (LB) in anterior cingulate (AC) play a significant role in Parkinson’s disease (PD).¹ Imaging agents for LB or surrogate markers for LB will assist in earlier and accurate diagnosis of PD and LB dementia. The goal in this study is to evaluate LB using anti-ubiquitin immunohistochemistry (UIHC) in AC² (Figure 1) and correlate them to monoamine oxidase A (MAO-A) expression using the selective PET agent, [¹⁸F]FAZIN3.³

Methods: Human post-mortem brain slices of anterior cingulate and corpus callosum (controls (CN), n = 6; age 81–90 LB = 0 and PD, n = 6, age 77–89, LB = III-IV) were used. Brain slices were UIHC stained for LB and [¹⁸F]FAZIN3 for MAO-A.³ The UIHC image was analyzed using QuPath to create a heatmap of the image.⁴ Spatially aligned UIHC and autoradiograph images were processed in MATLAB to generate normalized image intensity plots through the cortical layers for quantitation. Autoradiography image intensity corresponded to [¹⁸F]FAZIN3 binding to MAO-A and QuPath image intensity corresponded to the presence of LB.

Results: Figure 2 shows relative intensity profiles of UIHC and autoradiography of one PD subject indicating a correlation of the increase in [¹⁸F]FAZIN3 binding with LB. This increased [¹⁸F]FAZIN3 binding and UIHC staining was observed in all PD subjects in the AC compared to the CN subjects. Outer cortical layers (I-III) had 21%, inner layers (IV-VI) had 75% and white matter (WM) had < 1% UIHC. In the CN subjects all grey matter (GM) and white matter (WM) had < 1% UIHC. [¹⁸F]FAZIN3 ratio in PD Figure 2(a) was GM/WM = 3.57 while CN subjects was GM/WM = 2.24. Increased LB in PD brains resulted in increased [¹⁸F]FAZIN3 binding to MAO-A.

Conclusion: A novel method QuPathRad (QPR) has been developed which allows quantitative comparative image analysis of IHC with autoradiography. QPR confirmed the increased [¹⁸F]FAZIN3 binding in the PD with the presence of LB in the inner cortical layers of AC. This suggests increased levels of MAO-A in LB, and possibly increased mitochondria in LB.⁵ Thus, MAO-A imaging using [¹⁸F]FAZIN3 may serve as an early diagnostic tool for PD.

Acknowledgements

NIH/NIA RF1 AG029479 (JM), UCI UROP (RML, RM). Banner Health Research Institute for brain samples and UCI Pathology for immunostaining.

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References

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2021-65

A multiple regression modelling approach to investigate the coupling between [¹⁸F]fluorodeoxyglucose positron emission tomography and resting-state functional MRI (#287)

Tommaso Volpi^{1, 2}, Erica Silvestri^{1, 3}, Marco Aiello⁴, Maurizio Corbetta^{1, 2} and Alessandra Bertoldo^1,
3

¹Padova Neuroscience Center, University of Padova, Padova, Italy

²Department of Neuroscience, University of Padova, Padova, Italy

³Department of Information Engineering, University of Padova, Padova, Italy

⁴IRCCS SDN, Napoli, Italy

Abstract

Introduction: Brain glucose metabolism as measured by [¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG) positron emission tomography (PET) is expected to be related to spontaneous activity and functional connectivity (FC) derived from resting-state functional MRI (rs-fMRI)¹, but their coupling model is not thoroughly understood.

Methods: Employing simultaneous acquisitions on a Siemens Biograph mMR scanner in 26 healthy individuals (59.8 ± 10.8 yrs),^2,3 we related [¹⁸F]FDG standard uptake value ratio (SUVR, relative to whole-brain average uptake) to 50 rs-fMRI features pertaining to 1) signal and local properties, 2) hemodynamic response function (HRF), 3) static FC (sFC), 4) time-varying FC (tvFC), and 5) phase synchronization (PC). Both [¹⁸F]FDG and rs-fMRI data were parcellated using the Schaefer cortical atlas⁴ supplemented by subcortical parcels (218 regions). To assess which rs-fMRI variables better describe SUVR across regions at the group median level, we performed feature selection using sparse regression approaches.

Results: Feature selection led to the choice of 9 rs-fMRI predictors out of 50. The combination of the selected predictors explained a significant proportion of the group-level SUVR variance across regions (R² = 0.41), with local rs-fMRI features (i.e., signal complexity, local coherence, number of high-amplitude events etc.) as more relevant with respect to large-scale network information, i.e. sFC and tvFC (Figure 1(a)). The region-wise model residuals are shown in Figure 1(b).

Conclusion: Using multiple regression modelling, we highlight that local rs-fMRI metrics are more tightly linked to SUVR than large-scale FC, possibly because of their inherent blood flow (CBF) information. Future work on [¹⁸F]FDG-fMRI coupling should aim at regressing out the CBF component from the rs-fMRI signal⁵, and performing PET kinetic modelling to disentangle influx of [¹⁸F]FDG (K₁) from its actual phosphorylation (k₃).

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References

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2021-66

Comparative sensitivity of PET radioligands to partial inhibition of P-glycoprotein at the blood-brain barrier (#288)

Louise Breuil^{1, 2}, Solène Marie^{1, 3}, Sébastien Goutal¹, Sylvain Auvity^{1, 4}, Charles Truillet¹, Wadad Saba¹, Oliver Langer⁵, Fabien Caillé¹ and Nicolas Tournier¹

¹Laboratoire d’Imagerie Biomédicale Multimodale (BIOMAPS), Université Paris-Saclay, CEA, CNRS, Inserm, Service Hospitalier Frédéric Joliot, Orsay, France

²Pharmacy Department, Robert-Debré Hospital, AP-HP, Université de Paris, Paris, France

³Pharmacy Department, Bicêtre Hospital, AP-HP, Université Paris-Saclay, Le Kremlin-Bicêtre, France

⁴Pharmacy Department, Necker Hospital, AP-HP, UMR-S 1144, Université de Paris, Paris, France

⁵Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria

Abstract

Introduction: P-glycoprotein (P-gp, ABCB1) is a major efflux transporter at the blood-brain barrier (BBB). Radiolabeled substrates used for quantitative determination of P-gp function at the BBB using PET were initially selected based on their ability to generate maximal contrast in response to complete P-gp inhibition. However, only partial deficiency or inhibition is likely to occur in pathophysiological situations or drug-drug interactions. This raises questions regarding the sensitivity of available PET probes to detect moderate but clinically relevant changes in P-gp function at the BBB.

Methods: The P-gp-mediated transport characteristics of the radiolabeled substrates ¹¹C-verapamil, ¹¹C-N-desmethyl-loperamide and ¹¹C-metoclopramide were compared in vitro and in vivo. Substrate uptake in MDCKII-MDR1 cells overexpressing human P-gp was compared in the increasing concentrations presence of the P-gp inhibitor tariquidar (0–200 nM, n = 4). Then, the impact of increasing doses of tariquidar (i.v, 1–8 mg/kg) on the brain exposure to selected substrates was assessed using PET imaging in rats.

Results: In vitro, the half-maximum inhibitory concentration (IC₅₀) of tariquidar was significantly different between ¹¹C-verapamil (44 nM [33–53 nM]), ¹¹C-N-desmethyl-loperamide (19 nM [13–25 nM]), and ¹¹C-metoclopramide (4 nM [2–8 nM]) (Figure vitro). Maximal increase in cellular uptake was 1.4 ± 0.1, 3.9 ± 0.7 and 1.4 ± 0.1-fold for ¹¹C-verapamil, ¹¹C-N-desmethyl-loperamide and ¹¹C-metoclopramide, respectively (p < 0.001). In vivo, half-maximum inhibition of P-gp-mediated transport of ¹¹C-metoclopramide at the BBB was achieved using 1 mg/kg [0.78–1.5 mg/kg] of tariquidar (p < 0.05, n = 4), corresponding to an IC₅₀ of 82 nM tariquidar in plasma and resulting in a 2.1-fold increase in brain exposure (Figure vivo). This dose increased the brain exposure of ¹¹C-verapamil to a similar extent (2.4-fold increase, p < 0.05, n = 4) but did not significantly increase the brain exposure of ¹¹C-N-desmethyl-loperamide (n = 4) compared with baseline.

Conclusion: This comparative in vitro/in vivo study showed differences in the “vulnerability” to P-gp inhibition among radiolabeled substrates, which was apparently unrelated to their maximal response to P-gp inhibition. We advocate that partial inhibition of transporter function, in addition to maximal inhibition, should be a primary criterion of evaluation regarding the sensitivity of radiolabeled substrates to detect moderate but physiologically-relevant changes in transporter function in vivo.

Acknowledgements

We thank Maud Goislard, Thierry Lekieffre, Christine Coulon and Kevin Pansavath for helpful technical assistance. Louise Breuil received funding from the joined AP-HP/CEA grant. This work was performed on a platform partially funded by the France Life Imaging network (grant ANR-11-INBS-0006).

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References

1.Kalvass JC, Polli JW, Bourdet DL, et al. Why clinical modulation of efflux transport at the human blood–brain barrier is unlikely: the ITC evidence-based position. Clin Pharmacol Therapeut 2013; 94: 80–94. [DOI] [PubMed] [Google Scholar]
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2021-67

Multimodal investigation of the synaptic and metabolic basis of low-frequency oscillations in the human brain: A [¹¹C]UCB-J, [¹⁸F]BCPP-EF and resting state fMRI study (#289)

Ekaterina Shatalina¹, Gaia Rizzo², Robert A. Comley⁶, Hideo Tsukada⁷, Oliver D. Howes^{1, 5}, Eugenii A. Rabiner^2,
5 and Matthew Wall^{2, 3}

¹MRC London Institute of Medical Sciences, Imperial College London, London, UK

²Invicro LLC, London, UK

³Clinical Psychopharmacology Unit, University College London, London, UK

⁴Faculty of Medicine, Imperial College London, London, UK

⁵Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK

⁶AbbVie, Chicago Illinois, USA

⁷Hamamatsu Photonics K.K., Hamamatsu, Japan

Abstract

Introduction: The neuronal basis of low-frequency blood oxygen level dependent (BOLD) signal oscillations in fMRI is not fully understood but may reflect synaptic firing or underlying metabolic activity. This multimodal imaging study combined [¹¹C]UCB-J and [¹⁸F]BCPP-EF PET and resting state fMRI to investigate the biological basis of BOLD fluctuations. [¹¹C]UCB-J, a purported marker of synaptic density, binds to synaptic vesicle protein 2A (SV2A), while [¹⁸F]BCPP-EF binds to mitochondrial complex I (MC1) and is assumed to be a marker of cellular metabolism. FMRI measures used were fractional Amplitude of Low Frequency Fluctuations (fALFF) and dual-regression analyses of functional connectivity.

Methods: 23 healthy subjects (12M,11F; age range 22–78, mean age 55.7 years) completed a resting state fMRI scan, a [¹⁸F]BCPP-EF scan, and a [¹¹C]UCB-J scan (n = 22). Eight standard resting-state networks (RSN) were used as regions of interest across all imaging modalities. FMRI data were processed using standard methods, with fALFF values and dual-regression analyses carried out subsequently. Parametric volume of distribution (V_T) images were generated using a one-tissue compartment model for [¹¹C]UCB-J and the Logan Graphical Analysis (LGA) for [¹⁸F]BCPP-EF. Average V_T values for the eight RSNs were estimated for both tracers. Data from all modalities was transformed into MNI152 space.

Results: FALFF values for three networks (default mode, ventral attention, and frontoparietal right) were significantly correlated with UCB-J V_T (multiple-comparisons corrected; all r > 0.5, p < 0.01). [¹⁸F]BCPP-EF V_T was not significantly correlated with fALFF in any RSN. Neither PET measure showed significant correlations with the dual-regression data.

Conclusion: Individual differences in synaptic density may contribute to BOLD low-frequency oscillations, however mitochondrial density may only have a secondary role. FALFF may also have potential as a useful proxy measure of synaptic activity in fMRI data. This is the first study investigating the synaptic and mitochondrial origins of BOLD fMRI signals in humans, with important implications for interpreting pathology-specific group differences seen in resting state fMRI

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2021-68

Receptor distribution associations to mRNA gene expression patterns in the human cerebral cortex (#290)

Matej Murgaš, Paul Michenthaler, Gregor Gryglewski and Rupert Lanzenberger

Department of Psychiatry and Psychotherapy, Medical University of Vienna, Wien Wien, Austria

Abstract

Introduction: Investigation of potential links between molecular mechanisms and neuroreceptor distributions in the human cerebral cortex could help to enable in vivo analysis of multi-receptor systems and therefore lead to more effective clinical applications. In this work, we present a multi-receptor comparison of mRNA gene expression patterns to neuroreceptor distribution associated with them in the human cerebral cortex.

Methods: To this end, we utilized publicly available proteomic autoradiography data¹ and transcriptomic data – normalized microarray (mA) and RNA sequencing (RNA-seq) data, published by Allan Brain institute² and interpolated mRNA expression patterns (int-mA).³ Spatial distribution of 15 receptors listed in literature¹ and 64 gene expression patterns associated with at least one of the receptors were represented by average regional values for 38 cytoarchitectonicaly distinct areas defined Julich-Brain atlas.⁴ Spearman’s rank correlation, together with the permutation test establishing significance, was used to measure the similarity of investigated data sets

Results: Solid positive associations between autoradiography and gene expression data sets were found for e.g. glutamate ionotropic receptor kainate type subunit 2 (int-mA: r = 0.63, mA: r = 0.60, RNA-seq: r = 0.56) or serotonin 1A receptor (int-mA: r = 0.71, mA: r = 0.60, RNA-seq: r = 0.54). Additionally, negative associations were found for e.g. GABA A receptor subunit beta 1 (int-mA: r = −0.58, mA: r = −0.54), GABA A receptor subunit theta (int-mA: r = −0.50, RNA-seq: r = −0.61) as well as for GABA A receptor subunit alpha 3 (int-mA: r = −0.64, mA: r = −0.62, RNA-seq: r = −0.49). However, most of the receptors showed low correlation values (int-mA: 60%, mA: 74%, RNA-seq: 76% of r < 0.35).

Conclusion: Comparison of mRNA gene expression patterns and proteomic data unveiled few strong positive links between neuroreceptor spatial distributions and molecular processes. Counterintuitively, most of the relations showed negative or no correlation, highlighting the importance of further studies on splicing variants and the potential role of mRNA markers associated with post-transcriptional and post-translational modifications.

Acknowledgements

M. Murgaš is funded by the Austrian Science Fund FWF, DOC 33-B27.

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2021-69

Altered neuroepigenetics in autism spectrum disorder: a [¹¹C]Martinostat PET brain imaging study (#292)

Chieh-En J. Tseng^{1, 2}, Baileigh G. Hightower¹, Anjali J. Parmar¹, Rachel E. Marcus^{1, 3}, Jennifer E. Mullett³, Christopher J. McDougle^{2, 3}, Jacob M. Hooker^{1, 2} and Nicole R. Zurcher Wimmer^{1, 2}

¹Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Department of Radiology, Charlestown Massachusetts, USA

²Harvard Medical School, Boston Massachusetts, USA

³Lurie Center for Autism, Massachusetts General Hospital, Lexington Massachusetts, USA

Abstract

Introduction: Prenatal exposure to histone deacetylase (HDAC) inhibitors leads to autism-like behavior in rodent models and has been associated with autism spectrum disorder (ASD) in humans,¹ suggesting that epigenetic HDAC enzymes may play a role in the etiology of ASD. Moreover, changes in HDACs have been demonstrated to affect core symptoms and comorbidities of ASD in preclinical studies^2,3 and HDACs interact with several risk genes for ASD.⁴ Postmortem work has shown altered acetylation in genes implicated in ASD in frontal and temporal cortices in children and adults with ASD.⁵ No study has yet investigated HDAC expression in individuals with ASD in vivo.

Methods: The radiotracer [¹¹C]Martinostat binds to HDAC1, 2, 3 and 6. Eight participants with ASD (5M/3F, age = 27.8 ± 7.6years) and eight controls (CON) matched for sex and age (5M/3F, age = 27 ± 5.6years) completed a [¹¹C]Martinostat PET-MRI scan on a 3T Siemens TIM Trio with PET insert at the A. A. Martinos Center for Biomedical Imaging. [¹¹C]Martinostat (ASD:5.3 ± 0.3mCi; CON:4.8 ± 0.4mCi) was injected as a bolus. A high-resolution T1-weighted anatomical scan with prospective motion correction was collected. PET data were reconstructed using the 3D ordinary Poisson ordered-subset expectation maximization (OP-OSEM) algorithmin units of standard uptake value (SUV), motion-corrected, and processed with FreeSurfer and FSL. SUV maps were normalized to the whole brain mean from 60–90 minutes post-injection (SUVR_60-90). Whole brain voxelwise analysis was performed using an unpaired t-test in FSL’s FEAT with ordinary least squares mixed-effects modeling, with age and sex as covariates (Z > 2.3, P_cluster < 0.05).

Results: Lower [¹¹C]Martinostat uptake was found in the bilateral orbitofrontal cortex, and right anterior cingulate cortex, right insula and right amygdala. These regions are associated with socio-cognitive processing and have previously been implicated in ASD in functional MRI studies.⁶ Additionally, higher [¹¹C]Martinostat uptake was found in the bilateral visual cortex in ASD compared to CON (Figure 1).

Conclusion: Preliminary findings show altered HDAC brain expression in ASD compared to CON. [¹¹C]Martinostat PET-MRI data from a larger sample size will be required to determine if HDAC alterations represent a common feature in ASD. This pilot study was conducted using SUVR_60-90 given the challenges associated with obtaining arterial blood in individuals with ASD. Future work will investigate whether regional alterations in HDAC levels are linked to ASD-related symptoms.

Acknowledgements

We wish to thank the physicians Dr. Christopher Keary and Dr. Michelle Palumbo for obtaining informed consent, Dr. Lisa Nowinski for neuropsychological assessments, nuclear medicine technologists Shirley Hsu, Regan Butterfield and Grae Arabasz for radiotracer injection and assistance with PET-MRI scans, Judit Sore, Phill Nielson, Daniela Bernales and the radiopharmacy team for radioligand production, and the nurse practitioners Amy Kendall and Natacha Nortelus for medical coverage. Funding for this study was provided by the Transatlantic Research Scholar and pilot funding from the Athinoula A. Martinos Center for Biomedical Imaging awarded to N.R.Z. and the Phyllis and Jerome Lyle Rappaport MGH Research Scholar awarded to J.M.H. This research was carried out at the Martinos Center, using resources provided by the Center for Functional Neuroimaging Technologies, P41EB015896, a P41 Biotechnology Resource Grant supported by the National Institute of Biomedical Imaging and Bioengineering (NIBIB), NIH. This work also involved the use of instrumentation supported by the NIH Shared Instrumentation Grant Program S10RR017208-01A1, S10RR026666, S10RR022976, S10RR019933, S10RR023043, S10RR023401, and 1S10OD023517-01A1. Inline graphic

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2021-70

Preclinical imaging of [¹¹C]colchicine, [¹¹C]verubulin, and [¹¹C]HD-800 for imaging microtubules (#293)

Anton Lindberg¹, Andrew V. Mossine², Arturo Aliaga³, Robert Hopewell⁴, Gassan Massarweh⁴, Pedro Rosa-Neto³, Xia Shao², Vadim Bernard-Gauthier^{1, 5}, Peter J.H. Scott² and Neil Vasdev^{1, 5}

¹CAMH, Brain Health Imaging Centre, Toronto, ON, Canada

²University of Michigan Medical School, Department of Radiology, Ann Arbor Michigan, USA

³McGill University, Translational Neuroimaging Laboratory, Montreal, QC, Canada

⁴McGill University, McConnell Brain Imaging Centre, Montreal, QC, Canada

⁵University of Toronto, Department of Psychiatry, Toronto, ON, Canada

Abstract

Introduction: [¹¹C]Verubulin (a.k.a.[¹¹C]MCP-6827), [¹¹C]HD-800 and [¹¹C]colchicine have been developed for imaging microtubules (MTs) with PET.^1,2 The objective of this work was to conduct an in vivo comparison of [¹¹C]verubulin for MT imaging in mouse and rat brain, as well as an in vitro study with this radiotracer in rodent and human Alzheimer’s Disease (AD) tissue. We also conducted the first comparative in vivo PET imaging study with all three of these radiotracers in a non-human primate (NHP).

Methods: [¹¹C]Colchicine, [¹¹C]verubulin, and [¹¹C]HD-800 were labeled by O-¹¹C-methylation from [¹¹C]CH₃OTf. [¹¹C]Verubulin was used for autoradiography in rat and AD and healthy control (HC) tissues with verubulin (50 mL, 500 µM) co-administrated in blocking studies. [¹¹C]Verubulin was used in PET measurements in rodents with verubulin (5 mg/kg) administered 20 min prior to radiotracer. [¹¹C]verubulin, [¹¹C]HD-800, and [¹¹C]colchicine were compared in preliminary baseline PET scans in rhesus monkey.

Results: [¹¹C]Verubulin, [¹¹C]HD-800 and [¹¹C]colchicine were obtained in 0.5–1.5% uncorrected radiochemical yields, 99% radiochemical purity and molar activitiesof 159–389 GBq/µmol. Autoradiography with [¹¹C]verubulin in rat tissue showed higher binding compared to blocking measurements and higher uptake in AD patient tissue was seen compared with HC. In PET imaging studies, [¹¹C]verubulin had decreased brain uptake in mouse, while increased brain uptake in rat was measured when pretreated with verubulin. In NHP PET imaging, [¹¹C]verubulin and [¹¹C]HD-800 entered the brain, and as expected [¹¹C]colchicine did not cross the blood-brain barrier.

Conclusion: Preliminary PET imaging studies of [¹¹C]verubulin in rodents revealed contradictory results between mouse and rat brain uptake under pretreatment conditions. [¹¹C]verubulin showed an unexpected higher uptake in AD patient tissue compared with HC. Both [¹¹C]Verubulin and [¹¹C]HD-800 require pharmacokinetic modeling and quantification studies to understand the role of how these radiotracers bind to MTs in the central nervous system before translation to human use.

Acknowledgements

The authors would like to thank Ashley Knight and Dr. Shil Patel for their input with [³H]colchicine binding assays, as well as Jenelle Stauff, Janna Arteaga and Phillip Sherman for assistance with preclinical imaging studies. The authors also thank members of the CAMH Brain Health Imaging Centre and the University of Michigan PET Center for support.

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2021-71

Task-specific dynamics of dopamine synthesis during monetary gain and loss (#294)

Andreas Hahn¹, Murray B. Reed¹, Verena Pichler^{2, 3}, Lucas Rischka¹, Godber M. Godbersen¹, Lukas Nics², Marcus Hacker² and Rupert Lanzenberger¹

¹Medical University of Vienna, Department of Psychiatry and Psychotherapy, Vienna Wien, Austria

²Medical University of Vienna, Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Vienna Wien, Austria

³University of Vienna, Department of Pharmaceutical Sciences, Division of Pharmaceutical Chemistry, Vienna, Austria

Abstract

Introduction: The competition model is well-established for the investigation of dopamine action. To overcome disadvantages inherent to the assessment of cognitive processes, we combine functional PET (fPET) and 6-[¹⁸F]FDOPA imaging into a novel approach. The technique is based on the dynamic regulation of dopamine synthesis by neuronal firing,¹ indicating a direct association with dopamine release² (Figure 1).

Methods: 16 healthy subjects (24.8 ± 4.8 years, 7 female) underwent one 6-[¹⁸F]FDOPA fPET (GE Advance, 5.5 MBq/kg as bolus+infusion, 70x43 s frames). Subjects completed the monetary incentive delay (MID) task with separate assessment of monetary gain and loss (4x5 min task blocks). Task effects were assessed by the general linear model and dopamine synthesis was quantified with the Gjedde-Patlak plot after correction for the 3-OMFD component.

Results: In men monetary gain induced stronger increases in dopamine synthesis than loss, but this pattern was reversed in women (all p < 0.001, Figure 2), resulting in a sex difference for the contrast gain vs. loss (p < 0.001). Task-specific changes ranged between Ki = 0.009 ± 0.004/min and Ki = 0.019 ± 0.004/min, corresponding to increases of 105 ± 31% to 165 ± 64% from baseline Ki. Individual changes in DA synthesis were associated with behavioral parameters of reward sensitivity in men (rho = −0.67, p = 0.059) and punishment sensitivity in women (rho = 0.79, p < 0.05).

Conclusion: Assuming that task effects were driven by k3, presumably reflecting AADC activity, and considering DOPA fractions available for dopamine synthesis,^3,4 reward processing seems to yield 56–107% of additionally synthesized dopamine, matching physiological values in rodents. Our approach enables the assessment of dopamine action during cognitive processing in a single scan with high temporal resolution and robust task-specific effect size.⁵ The findings provide a biological rationale for the well-known behavioral sex differences in reward and punishment processing. This may have important implications in psychiatric conditions with sex-specific prevalence rates, altered reward processing and dopamine signaling.

Acknowledgements

This research was supported by a grant from the Austrian Science Fund to A. Hahn (FWF KLI 610). L. Rischka and M.B. Reed are recipients of a DOC Fellowship of the Austrian Academy of Sciences at the Department of Psychiatry and Psychotherapy, Medical University of Vienna. The scientific project was performed with the support of the Medical Imaging Cluster of the Medical University of Vienna.

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2021-72

Interdependent adaptations of glucose metabolism and functional connectivity elicited through learning (#295)

Andreas Hahn¹, Sebastian Klug¹, Godber M. Godbersen¹, Lucas Rischka¹, Wolfgang Wadsak^{2, 3}, Verena Pichler^{2, 4}, Marcus Hacker² and Rupert Lanzenberger¹

¹Medical University of Vienna, Department of Psychiatry and Psychotherapy, Vienna Wien, Austria

²Medical University of Vienna, Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Vienna Wien, Austria

³Center for Biomarker Research in Medicine (CBmed), Graz Steiermark, Austria

⁴University of Vienna, Department of Pharmaceutical Sciences, Division of Pharmaceutical Chemistry, Vienna, Austria

Abstract

Introduction: Learning elicits numerous neuronal adaptations, but it is poorly understood how they act together to support improvements in cognitive processing. We employed metabolic connectivity mapping (MCM) to investigate learning-induced changes in the association of functional connectivity (FC) and the underlying glucose metabolism (CMRGlu), thereby enabling the computation of directional connectivity.¹

Methods: 41 healthy subjects (23.2 ± 3.3 years, 21 female) underwent two PET/MRI scans (Siemens mMR), while performing the video game Tetris® in two levels of difficulty (easy, hard). The training group (n = 21) practiced the task for 53.6 ± 5.2 min/day for 20.9 ± 1.5 days between the two scans. [¹⁸F]FDG was applied as bolus+infusion (5.1 MBq/kg, 104x30 s frames). Task effects were assessed by the general linear model and CMRGlu was quantified with the Gjedde-Patlak plot.^1,2 Simultaneous BOLD acquisition (TE/TR = 30/2000 ms, 6 min per condition) was used to compute FC at rest and during task performance.

Results: Compared to the control group, learning altered the directional connectivity (MCM) from the salience network (insula and dorsal anterior cingulate) to the occipital cortex, with increases during rest and decreases during task execution (group*time interactions, all p < 0.05 corrected, Figure 1). A higher divergence in MCM between rest and task was associated with better cognitive performance after learning. Simulations revealed that MCM changes at rest were driven by CMRGlu, but those during the task execution were dependent on FC.

Conclusion: Metabolism-driven increases in the association of CMRGlu and FC at rest potentially reflect learning-induced anchoring of glutamatergic AMPA receptors,³ which doubles the postsynaptic energy consumption.⁴ Retrieval of this metabolically expensive skill engram during task execution seems to enable the minimization of prediction errors⁵ between neuronal task representations between higher- (salience network) and lower-order (occipital cortex) brain regions. Disentangling the contribution of CMRGlu and FC in deficits of learning and cognition may provide novel insights in numerous patient populations.

Acknowledgements

This research was supported by a grant from the Austrian Science Fund to A. Hahn (FWF KLI 610). L. Rischka is recipient of a DOC Fellowship of the Austrian Academy of Sciences at the Department of Psychiatry and Psychotherapy, Medical University of Vienna. The scientific project was performed with the support of the Medical Imaging Cluster of the Medical University of Vienna.

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References

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2021-73

Harmonization of neuroimages acquired on two brain PET scanners (#296)

Jocelyn Hoye, Yasmin Zakiniaeiz, Takuya Toyonaga, Michelle Hampson and Evan D. Morris

Yale University, Radiology and Biomedical Imaging, New Haven Connecticut, USA

Abstract

Introduction: Two separate imaging studies were carried out with [11C]Raclopride to study striatal dopamine release in humans. Each human cohort was scanned with a different PET scanner. The purpose here was to develop an inter-scanner harmonization technique to allow for cohort comparison.

Methods: To develop the harmonization technique (experiment 1), the Iida brain phantom was filled with F-18 solution and scanned on two scanners (HRRT,HR+, Siemens/CTI). The HRRT images were filtered with isotropic gaussian filters of varying FWHM (0.5 mm-10 mm). Filtered HRRT images were matched to HR+ images by calculating the squared sum of the voxel-wise error (SSE) across voxels (using whole-brain or a mid-brain region alone). The gaussian filter that minimized SSE was deemed the optimal filter. To evaluate the harmonization on real data (experiment 2), inter-scanner variability was calculated using [11C]Raclopride scans of 2 human subjects on both the HRRT and HR+. Binding potential (BP_ND) in striatum was calculated for HR+ and HRRT (with various filters). Percent difference (PD) in striatal BP_ND was calculated between HR+ and HRRT (with various filters). Finally (experiment 3), PD was calculated for intra-scanner test-retest of striatal BP_ND (T/RT) for 8 human subjects scanned only on the HR+.

Results: Experiment 1 resulted in optimal whole-brain and mid-brain filters of 4.5 mm and 3.5 mm, respectively (Figure 1). Experiment 2 resulted in 15.89% PD for unfiltered HRRT, 9.25% for HRRT filtered with 3.5 mm gaussian, and 4.45% for HRRT filtered with 4.5 mm (Figure 2). Experiment 3 yielded 5.24% intra-scanner T/RT for HR+.

Conclusion: The mean inter-scanner difference for the HRRT with 4.5 mm filter was less than the mean intra-scanner T/RT for the HR+. The results indicate that BP_ND estimates from the HRRT can be combined with those from the HR+, with minimal addition to the overall variance, by using optimal gaussian smoothing of HRRT images.

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2021-74

PET simulations investigating the effect of off-target binding in [F-18]MK-6240 PET scans for the detection of early-stage Alzheimer’s disease (#298)

Andrew McVea^{1, 2}, Alexandra DiFilippo^{1, 2}, Max McLachlan^1,
2, Yangchun Xin², Sterling Johnson³, Tobey Betthauser³ and Bradley Christian^{1, 2}

¹University of Wisconsin – Madison, Medical Physics, Madison Wisconsin, USA

²Waisman Center, Madison Wisconsin, USA

³Wisconsin Alzheimer’s Disease Research Center, Madison Wisconsin, USA

Abstract

Introduction: PET imaging of AD-related tauopathies has made substantial contributions towards the understanding of spatial and temporal changes of this pathological feature. [F-18]MK-6240 is a next-generation radiotracer with favorable imaging characteristics for detecting early, pre-symptomatic accumulation of tau in the entorhinal cortex (ERC). However, off-target (OT) binding in the meninges and sinus may confound the ability to accurately quantify specific MK-6240 binding due to “spill-in" signal to the reference and target regions of the brain. The goal of this work is to simulate regional uptake of MK-6240 signal to examine the effects of OT binding on PET outcome measures.

Methods: Simulations were generated with PET-SORTEO (Reilhac, 2004), which uses Monte-Carlo methods to generate PET images based on input time-activity curves (TACs) for designated brain regions. Ten realizations were created for each set of four 5-minute frame (70–90 minutes) scans simulating the ECAT HR+ scanner (i.d. = 10mCi). The input TACs were derived from human MK-6240 scans at our center and used to generate emission maps based upon the Harvard-Oxford atlas with custom regions for early-stage elevated tau in the ERC. Simulation cohorts included: no meninges or sinus uptake (OT_0), low MK-6240 signal in both (OT_L) and high MK-6240 signal in both (OT_H) with separate tau(+) and tau(-) scans for each. The SUVR outcome measure used the inferior cerebellar grey matter reference region and anterior parahippocampal gyrus to represent the ERC.

Results: For OT_0 the average ERC SUVR was 0.94 ± 0.02 and 1.27 ± 0.02 for tau(-/+) groups, respectively. The ERC SUVR was 0.92 ± 0.02 and 0.93 ± 0.01 for tau(-) in OT_L and OT_H, respectively, and 1.23 ± 0.03 and 1.20 ± 0.02 for tau(+). In the tau(+) images compared to OT_0 there was an average cerebellum SUV increase of 11.47 ± 0.68% and 17.52 ± 0.93% for OT_L and OT_H and an ERC SUV increase of 10.54 ± 3.51% and 15.02 ± 2.33%.

Conclusion: A significant elevated spill-in signal from off-target uptake has been simulated for the reference and early Braak regions and may offset each other for the SUVR outcome. Investigation is ongoing to examine a greater variety of OT uptake patterns and the performance of partial volume correction methods for calculating accurate outcome measures.

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2021-75

Visual memory scores are associated with lateralization of tau in the medial temporal lobe (#299)

Jaime Fernández Arias^{1, 2}, Yi-Ting Wang^{1, 2}, Firoza Z. Lussier^{1, 2}, Cécile Tissot^{1, 2}, Joseph Therriault^{1, 2}, Tharick A. Pascoal^{3, 2}, Mira Chamoun², Min-Su Kang^{1, 2}, Gleb Bezgin², Stijn Servaes², Nina M. Poltronetti², Jenna Stevenson², Nesrine Rahmouni², Pedro Rosa-Neto^{1, 2} and Serge Gauthier^{1, 2}

¹McGill University, Medicine, Montreal, QC, Canada

²Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, Verdun, QC, Canada

³University of Pittsburgh, Psychiatry and Neurology, Pittsburgh Pennsylvania, USA

Abstract

Introduction: Aggie Figures Learning Test (AFLT) is a visual memory test that was conceived as an analogue of the widespread Rey Auditory Verbal Learning Test (RAVLT), which tests verbal memory. Previous research has indicated that performance may rely on the left medial temporal lobe (lMTL) for verbal memory and on the right medial temporal lobe (rMTL) for nonverbal memory, although evidence is inconclusive. The present study looks into the association between delayed recall (DR) scores in both tests and tau binding in the brain.

Methods: Tau PET ([18F]-MK6240) was acquired for 130 individuals for analysis involving AFLT, and 139 for analysis involving RAVLT. Demographic data is shown on Tables 1 and 2. MRI were segmented into probabilistic grey (GM) and white (WM) maps, non-linearly registered to the ADNI template using Dartel and smoothed with an 8 mm FWHM gaussian kernel. Voxel-wise linear regression models were applied, using VoxelStats, with either DR AFLT or DR RAVLT as dependent variables and tau as a predictor. We corrected for age, sex, diagnosis, apoe genotype, years of education, difference between scan date and neuropsychological assessment date, and amyloid load.

Results: We found negative associations between tau binding and DR RAVLT in the MTL bilaterally. Interestingly, we found a negative correlation between tau binding and DR AFLT scores that is remarkable in the rMTL and disappears in the lMTL

Conclusion: Our findings provide evidence in support of the lateralization of memory in the brain based on the learning modality. This dissociation is in line with previous findings; namely, that the rMTL is responsible for visual memory. However, these findings are not entirely in line with previous research since associations with RAVLT are found bilaterally. Of note, most of the previous research has been made in the context of epilepsy and/or patients with anterior MTL lesions. Here, however, we are investigating a totally different population and we are looking at a parameter that is specific to this population.

Inline graphic Figure 1. Demographic data. Demographics for the AFLT subsample (above) and for the RAVLT subsample (below)

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References

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2021-76

Investigating tauopathy in military occupational blast: a [¹⁸F]flortaucipir positron emission tomography study in Canadian armed forces members (#302)

Shamantha J. Lora^{2, 3}, Sarah E. Watling³, Jerry Warsh², Oshin Vartananian⁵, Neil Vasdev^{2, 7}, Iain Vergie⁶, Isabelle Vallee⁶, Tina McCluskey², Carmela Tartaglia⁴, Shawn Rhind⁵ and Isabelle Boileau^1,
2

¹University of Toronto, Psychiatry, Toronto, ON, Canada

²Centre for Addiction and Mental Health, Campbell Mental Health Research Institute, Toronto, ON, Canada

³University of Toronto, Institute of Medical Sciences, Toronto, ON, Canada

⁴University of Toronto, Tanz Centre for Research in Neurodegenerative Diseases, Toronto, ON, Canada

⁵Toronto Research Centre, Defence Research and Development Canada, Toronto, ON, Canada

⁶Canadian Armed Forces, Canadian Special Operation Forces Command, Ottawa, ON, Canada

⁷Centre for Addiction and Mental Health, Azrieli Centre for Neuro-Radiochemistry, Toronto, ON, Canada

Abstract

Introduction: Chronic traumatic encephalopathy (CTE), a tauopathy, is suspected to occur as a result of repetitive exposure to low-intensity blast overpressure during military training and operations. Although animal models putatively link explosive blast exposure with tau aggregation, studies in humans exposed to repeated low level blasts are limited. We used positron emission tomography (PET) imaging of [¹⁸F]flortaucipir (a.k.a [¹⁸F]TAUVID™, [¹⁸F]AV-1451; [¹⁸F]T807) to evaluate tau levels in Canadian Armed Forces (CAF) operators with significant career exposure to blast.

Methods: CAF members (5 males; 44.6 ± 6.2 years old) exposed to blast completed an MRI and a PET [¹⁸F]flortaucipir scan. Standardized Uptake Value ratio (SUVr) were calculated with the cerebellum as reference tissue. Participants performed a test of executive function (Stroop) and completed mood and clinical questionnaires.

Results: [¹⁸F]flortaucipir uptake was highest in midbrain/substantia nigra (SUVr range: 0.8 to 1.6), basal ganglia (SUVr range: 1.0 to 1.3), temporal (SUVr range: 0.8 to 1.13) and frontal cortices (SUVr range: 0.8 to 1.11). [¹⁸F]flortaucipir SUVr values were positively correlated with years of exposure to explosives and to years of breaching (r = 0.9; p-uncorrected < 0.05). Greater [¹⁸F]flortaucipir SUVr values in prefrontal regions were related to poorer performance on the Stroop test of executive function (r = 0.9; p < 0.05). [¹⁸F]flortaucipir SUVr did not correlate with mood or clinical symptoms.

Conclusion: Thesepreliminary results suggest that while [¹⁸F]flortaucipir uptake in CAF operators regularly exposed to low-intensity blast is within the range reported for normal mid-aged controls,¹ our study found that greater tau deposition is associated with years of exposure to blast, as noted previously.² Studies in a larger cohort should aim to model tau in order to understand what constitutes safe exposure to blast.

Acknowledgements

This work was funded by the Canadian Institute for Military and Veteran Health Research (CIMVHR) and the Canadian Department of National Defence (DND).

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References

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2021-77

In vivo imaging of microglial activation by positron emission tomography with ¹¹C-ER176 in a mouse model for post-infectious autoimmune encephalitis (#304)

Zeljko Tomljanovic^{1, 2}, Aubrey Johnson^{1, 2}, Charlotte Wayne², Tyler Cutforth², Maryann Platt², Mikhail Doubrovin³, Dritan Agalliu^{1, 4} and William C. Kreisl^1,
2

¹Columbia University, The Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, New York New York, USA

²Columbia University, Department of Neurology, New York New York, USA

³Columbia University, Department of Radiology, New York New York, USA

⁴Columbia Universit, Department of Pathology and Cell Biology, New York New York, USA

Abstract

Introduction: Group A Streptococcus (GAS) infections are associated with basal ganglia encephalitis (BGE), a syndrome producing movement and psychiatric sequelae. Human and animal studies have shown that aberrant cellular and humoral adaptive immune responses target the brain and elicit neurovascular damage. ¹¹C-ER176 is a third generation PET radioligand for the 18kDa translocator protein (TSPO) – a marker of activated microglia. We sought to evaluate the ability of ¹¹C-ER176 to detect differences in TSPO binding in an animal model for post-infectious BGE as an independent method to assess the degree of neuroinflammation.

Methods: Twenty-three four-week-old C57BL/6 female mice were infected intranasally weekly with either GAS-2W streptococci (treated) or PBS (control) for five weeks. Twenty-four hours after the last inoculation, mice were injected intravenously with ¹¹C-ER176 (110.11 ± 24.67 uCi) and PET images were acquired 0–60 minutes post-injection. Images were co-registered to CT and normalized using PMOD 4.2. Standardized uptake values ratios (SUVR) were calculated with rostral thalamus (rThal) as a “pseudo-reference” region. Statistical analysis was performed using frames from 30–60 min post-injection. Microglia activation was assessed in serial sections from the olfactory bulb (OB) in the subset of treated and untreated mice by immunofluorescence (IF) for Iba1.

Results: Treated mice (n = 12; 53.83 ± 4.55 days; weight 15.42 ± 2.61g) showed greater binding of ¹¹C-ER176 than control mice (n = 11; 52.18 ± 2.56 days; weight 17.82 ± 0.98g) in the OB (11.60%, p = 0.0274), and amygdala (16.33%, p = 0.0002) consistent with previous studies in this mouse model. IF image analysis of activated (Iba1⁺) microglia in OB revealed higher mean number of cells in treated (n = 4; 6.57 ± 1.05) than control (n = 4; 4.25 ± 0.79, p = 0.0137) mice. However, microglia activation by IF did not correlate with ¹¹C-ER176 SUVRs in any CNS region tested in the study.

Conclusion: GAS-treated C57BL/6 mice show increased binding of ¹¹C-ER176 in olfactory bulb and amygdala, demonstrating that TSPO can serve as an inflammatory biomarker in post-infectious BGE. Lack of correlation between PET and IF results may be due to small sample size; alternatively, there may not be a one-to-one relationship between the number of activated microglia and the density of TSPO in this model.

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References

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2021-78

Development of a novel carbon-11 radiotracer for brain PET imaging of sulfonylurea receptors 1 (#305)

Fabien Caillé, Wadad Saba, Sébastien Goutal, Louise Breuil, Maud Goislard, Bertrand Kuhnast and Nicolas Tournier

Université Paris-Saclay, CEA/CNRS/INSERM, Orsay, France

Abstract

Introduction: Sulfonylurea receptors 1 (SUR-1, ABCC8) are almost absent of the healthy brain but overexpressed in neurons and glial cells under cerebral ischemic or injury conditions and are therefore a potential biomarker for brain trauma PET imaging. Kharade et al. described VU0071063, a ligand with affinity and selectivity for SUR-1, able to cross the BBB.¹ Herein we report the isotopic labeling of VU0071063 and the in vivo PET imaging in the healthy rat brain.

Methods: The labeling precursor of VU0071063 was synthesized in one step. Radiomethylation with [¹¹C]CH₃I was realized in dimethylformamide with potassium carbonate at 100°C for 3 minutes using a TRACERlab® FX CPro module and the compound was purified by semi-preparative HPLC. Quality control including identity, radiochemical purity and molar activity was realized by analytical HPLC. Healthy male Wistar rats (365 ± 12 g, n = 4) were injected with [¹¹C]VU0071063 (36 ± 5 MBq) in the tail vein and brain PET images were recorded for 60 minutes using a µPET Inveon^®. Images were analyzed using the Pmod software to derive the time-activity curves expressed in % ID/cc over time in selected brain regions.

Results: The precursor was synthesized in one step from 3-methylxanthine in quantitative yield. Automated radiosynthesis of the precursor was realized within 35 minutes to afford ready-to-inject [¹¹C]VU0071063 in 12 ± 2% (n = 5) decay-corrected radiochemical yield. [¹¹C]VU0071063 was obtained in > 99% radiochemical purity with a molar activity of 85 ± 10 GBq/µmol. High and homogenous brain uptake was observed at early time points (0.95 ± 0.13% ID/cc from 0–10 min.) suggesting that [¹¹C]VU0071063 readily crosses the BBB. A rapid elimination of [¹¹C]VU0071063 was then observed with a low uptake at later time points (0.26 ± 0.03% ID/cc from 30–60 min.), consistent with the low expression of SUR-1 in the healthy brain.

Conclusion: A new radioligand targeting SUR-1 in the brain was designed and successfully radiolabeled with carbon-11. Preliminary study of this tracer in the healthy rat brain prompt us to pursue further investigation in animal models of brain injury with increased expression of SUR-1.

Acknowledgements

The authors thank the Atomic Energy Commission (CEA) for financial support.

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Reference

1.Kharade SV, Sanchez-Andres JV, Fulton MG, et al. Structure-activity relationships, pharmacokinetics, and pharmacodynamics of the Kir6.2/SUR1-specific channel opener VU0071063s. J Pharmacol Exp Ther 2019; 370: 350–359. [DOI] [PMC free article] [PubMed] [Google Scholar]

2021-79

Imaging the endogenous opioid response to acute cannabis smoking in humans (#307)

Kelly Smart¹, Jon Mikael Anderson², Patrick D. Skosnik², David Matuskey¹, Jim Ropchan¹, Zachary Felchner¹, Nabeel Nabulsi¹, Yiyun H. Huang¹, Kelly P. Cosgrove² and Ansel T. Hillmer^{1, 2}

¹Yale School of Medicine, Yale PET Center, New Haven Connecticut, USA

²Yale School of Medicine, Department of Psychiatry, New Haven Connecticut, USA

Abstract

Introduction: The major psychoactive compound in cannabis, Δ⁹-tetrahydrocannabinol (THC), acutely increases brain levels of endogenous in preclinical models, which may contribute to both analgesic and reinforcing effects. To translate these findings to human studies, our objective was to assess if endogenous opioid release is detected in healthy volunteers following cannabis smoking using positron emission tomography (PET) with the selective mu opioid receptor (MOR) agonist radioligand [¹¹C]carfentanil.

Methods: Eight healthy volunteers (29.3 ± 8.8 years, 4M/4F) with limited past recreational cannabis use completed PET scans with bolus injections of [¹¹C]carfentanil at baseline (529 ± 177 MBq) and 16 ± 8 minutes after smoking cannabis (524 ± 140 MBq; 5.6 ± 0.57% THC, 0.01 ± 0.00% cannabidiol). Ratings of subjective drug response were collected, and the Cold Pressor Task was performed to assess pain response pre- and post-cannabis.

[¹¹C]Carfentanil binding potential (BP_ND) was determined by the simplified reference tissue model in frontal cortex, anterior cingulate, insula, caudate, putamen, amygdala, and thalamus. Global BP_ND was determined as the average value across these regions. Change in BP_ND between baseline and post-cannabis scans was assessed as an index of endogenous opioid release. Secondary analyses explored correlations between baseline BP_ND, drug response, and pain tolerance.

Results: The post-cannabis change in [¹¹C]carfentanil BP_ND ranged from -2.2 ± 6.9% in frontal cortex to +4.5 ± 9.7% in anterior cingulate. This change was not statistically significant in any region (ps > 0.11).

Baseline global [¹¹C]carfentanil BP_ND was negatively correlated with ratings of ‘high’ post-cannabis (r = −0.79, p = 0.035), such that people with lower MOR availability at baseline had stronger subjective intoxication responses. This was driven by relationships in amygdala, caudate, thalamus, and insula (ps < 0.1). Baseline global BP_ND was positively correlated at trend-level with pain tolerance at baseline (p = 0.08) and post-cannabis (p = 0.07).

Conclusion: In healthy volunteers with low levels of recreational cannabis use, we did not find evidence of endogenous opioid release following smoked cannabis using [¹¹C]carfentanil PET. The relatively low THC content may have limited the ability to detect such effects. Baseline MOR availability in limbic brain regions, reflecting receptor expression or endogenous endorphin levels, may be linked to subjective cannabis response and pain tolerance.

2021-80

Comparative analysis of immunohistochemical and autoradiographic images of Tau in postmortem human Alzheimer’s disease brain (#308)

Rommani Mondal, Reisha M. Ladwa, Christopher Liang and Jogeshwar Mukherjee

University of California, Irvine, Preclinical Imaging, Radiological Sciences, Irvine California, USA

Abstract

Introduction: High resolution scans of immunohistochemical (IHC) stains of Alzheimer’s disease (AD) brain slices and autoradiography binding assays both give us information about the distribution of Tau protein. Accurate assessment of the amount and regional location of Tau is essential to understand AD pathology.¹ Our goal is to develop a quantitative method for analysis of coregistered IHC-autoradiography images. Here we report our results of AD hippocampus (HP) labeled with [¹²⁵I]IPPI and total Tau IHC.

Methods: Postmortem human HP from AD subjects were IHC stained for total Tau and [¹²⁵I]IPPI autoradiography for Tau as reported.² QuPath and a pixel thresholder was created to outline the IHC image.³ Adobe Photoshop was used to spatially align and crop the IHC and autoradiography images. A heatmap was generated in QuPath using SLIC superpixel method.³ The co-registered autoradiography and QuPath heatmap image were loaded into MATLAB, converted to grayscale intensity images with a range of 0–255 (Fig ure 1). Intensity quantification in both images was indicative of the presence of higher regional Tau.

Results: Figure 2(a) and (b) shows a detailed profile of [¹²⁵I]IPPI binding in the cortical fold showing four distinct peaks (1 to 4). Similarly, four peaks were observed in Tau QuPath in Fig 2(c) and (d). Peaks 1 and 3 were consistent in magnitude (>80%) and location, but intensity of peaks 2 and 4 were higher in QuPath. Intensity of Tau and IPPI binding on the slice using AutoPath were compared with the 2-D correlation coefficient matrix, image correlation coefficient (0.7317), ratio of peak locations (1.0006), and a visual graph of the intensity profiles. The variability of intensity between the two modalities may be due to the limited pixels measured by the line in Figure 2(a) and (c) and potential differences between total Tau measured in QuPath versus phosphorylated Tau (pTau) measured by [¹²⁵I]IPPI.⁴

Conclusion: Compared to semi-quantitative histopathological scoring, our novel method QuPathRad (QPR) has the potential for quantitative image analysis of IHC with autoradiography for Tau in AD. Since various pTau are present in the AD brain HP,⁵ efforts are underway to identify aggregate pTau as well as size differentiation of Tau using the QPR technique.

Acknowledgements

NIH/NIA RF1 AG029479 (JM), UCI UROP (RM, RML). Banner Health Research Institute for brain sections of hippocampus and UCI Pathology for immunostaining.

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2021-81

Evaluation in rat, monkey, and humans of [¹⁸F]PF-06445974, a PET radioligand for phosphodiesterase 4B (#309)

Yuichi Wakabayashi¹, Per Stenkrona³, Jeih-San Liow¹, Kevin P. Maresca², Thomas A. Chappie², Lei Zhang², Zoë A. Hughes², Christopher J. Schmidt², Shawn D. Doran², Ryosuke Arakawa³, Andrea Varrone³, Akihiro Takano³, Paolo Z. Fregonara¹, Sami S. Zoghbi¹, Maarten Ooms¹, Cheryl Morse¹, Victor W. Pike¹, Christer Halldin³ and Robert B. Innis¹

¹NIH – Bethesda, MD, Molecular Imaging Branch, Bethesda Maryland, USA

²Pfizer Inc, Worldwide Research, Development & Medicine, New York New York, USA

³Karolinska Institute and Stockholm County Council, Department of Clinical Neuroscience, Centre for Psychiatry Research, Stockholm, Sweden

Abstract

Introduction: Phosphodiesterase-4 (PDE4), which metabolizes the second messenger cyclic adenosine monophosphate (cAMP), has four isozymes: A, B, C, and D. PDE4B and PDE4D have the highest expression in brain and are associated with neuropsychiatric diseases such as major depressive disorder. This study evaluated the properties of the newly developed PDE4B-selective radioligand [¹⁸F]PF-06445974 in the brain of rats, rhesus monkeys, and humans

Methods: Three monkeys from two different institutions (NIMH and Karolinska Institute) were scanned with 180-min dynamic PET images and metabolite-corrected arterial input function. Five healthy volunteers from both institutions were scanned with 120-min dynamic PET and input function. [¹⁸F]PF-06445974 binding was quantified as total distribution volume (V_T) using a two-tissue compartment model. Radiochromatograms were performed in rat brain tissue 180 minutes after injection to assess the presence of radiometabolites.

Results: [¹⁸F]PF-06445974 readily distributes in the monkey brain, the highest binding being in thalamus. V_T was stable over time (<10% difference from 90 to 180 minutes). Similarly, [¹⁸F]PF-06445974 readily entered the human brain (Figure 1) and its V_T matched the distribution of mRNA expression derived from the Allen Brain Atlas. However, on average, V_T (value over the whole brain 9.5 ± 2.4 mL/cm⁻³) showed linear increase until the end of the scans (Figure 2). Radiochromatograms of rat brains found that 98.7% of the activity was due to the parent compound.

Conclusion: [¹⁸F]PF-06445974 successfully imaged PDE4B in monkey and human brain. V_T was stable over time in monkeys, but it linearly increased after 120 minutes in humans. Despite the lack of radiometabolites in the rat brain, they may accumulate in the human brain. This radioligand will be further assessed to understand whether the lack of time stability in humans is due to the presence of radiometabolites or to a slow equilibration time in the human brain.

Acknowledgements

Laboratories of Dr. Pike and Dr. Innis

NIMH veterinary staffs

Karolinska Institute scientists

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2021-82

Perfusion heterogeneity in extra-tumoural brain in grades III and IV glioma measured using positron emission tomography with radiolabelled water (#311)

Ana Jorge Gonçalves¹, Moudi Alotaibi¹, Alice R. Carlin¹, Yaonan Chen¹, Constance Y.W. Wong¹, Ibrahim K. Djoukhadar², Georgios Krokos¹, Alan Jackson¹, David Coope² and Marie-Claude Asselin¹

¹The University of Manchester, Manchester, UK

²Salford Royal NHS Foundation Trust, Manchester, UK

Abstract

Introduction: The impact of the disrupted neo-vasculature in glioma to the extra-tumoural brain has clinical interest since radiotherapy and drug delivery rely on adequate perfusion and perfusion may be predictive of areas of infiltration and recurrence. The aim of this study is to assess heterogeneity of cerebral blood flow (CBF) with distance from the tumour with a novel image sampling method.

Methods: Twelve glioma (5 grade III, 7 grade IV) patients (3 females) aged 51.0 ± 12.8 years underwent dynamic [¹⁵O]H₂O PET on the HRRT before treatment.¹ Parametric maps of absolute CBF were generated using generalised linear least squares² for the 1-tissue reversible compartment model with a sampled arterial blood input function. Tumour regions were manually delineated on MR images by an experienced neuroradiologist (ID). Extra-tumoural white matter (WM) and gray matter (GM) were segmented from the T1-weighted images and coregistered to the PET images using FSL. Concentric GM and WM shells growing away from the tumour edge were generated as explained in Figure 1. The asymmetry index (AI) was calculated to assess hemispherical CBF differences. The 95% confidence intervals of CBF and AI were determined from fifteen healthy volunteers (HV, 8 females) aged 43.5 ± 5.7 years.

Results: CBF was significantly different compared to HVs only in grade IV glioma (Figure 2(a)), being reduced in WM ipsilaterally by 18.5% (p = 0.01716) and contralaterally by 16.2% (p = 0.02128), but not in GM. In both grades, perfusion in GM and WM was not significantly different between ipsilateral and contralateral sides. Close to the tumour edge of several grade IV, CBF was very asymmetric (AI > 30%), either elevated or depleted relative to the contralateral side, and gradually became more symmetric moving away from the tumour (Figure 2(b)). This was most marked in WM but also observed in GM.

Conclusion: Gliomas can cause extra-tumoural alterations in CBF even on the normal-appearing contralateral hemisphere. The shells sampling method revealed sub-hemispheric heterogeneity, with asymmetry increasing towards the tumour edge. Future work aims to create similarly sized shell regions in the HVs to better estimate the normal variability and define the asymmetry patterns in the healthy brain.

Acknowledgements

The research leading to these results was financially supported by the Europeen Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement n° 201380 and by the Cancer Research UK and EPSRC Cancer Imaging Centre in Cambridge and Manchester under grant agreement C8742/A18097. AJG is funded by the EU H2020 MSCA-ITN-2018: INtegratingMagnetic Resonance SPectroscopyand Multimodal Imaging for Research and Education in MEDicine (INSPiRE-MED), funded by the European Commission under Grant Agreement #813120.

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References

1.Walker MD, Feldmann M, Matthews JC, et al. Optimization of methods for quantification of rCBF using high-resolution [¹⁵O]H₂O PET images. Phys Med Biol 2012; 57: 2251–2271. [DOI] [PubMed] [Google Scholar]
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2021-83

Expression of transduced estrogen receptor-α fragment fusion protein in rhesus monkey brain using [¹⁸F]FES as a PET reporter probe (#312)

Palak Wadhwa¹, Bing Li¹, Walter Lerchner¹, Paolo Zanotti-Fregonara¹, Jeih-San Liow¹, Mark A. G. Eldridge¹, Xuefeng Yan¹, Michael Michaelides², Sami S. Zoghbi¹, Barry J. Richmond¹ and Robert B. Innis¹

¹National Institutes of Health, Intramural Research Programs of NIMH, Bethesda Maryland, USA

²National Institutes of Health, Biobehavioral Imaging & Molecular Neuropsychopharmacology Unit, NIDA, Baltimore, Maryland, USA

Abstract

Introduction: Positron emission tomography (PET) reporter gene systems have contributed to progress in cell/gene therapy, and have improved our understanding of the molecular pathology of neurological diseases by providing an in vivo molecular imaging tool.^1,2,3,4 PET reporter gene systems comprise of: (1) a PET reporter gene which is linked to a therapeutic gene of interest, packaged within a viral vector that can transduce the targeted neural cell population and (2) a complementary PET reporter probe that can image the expression of the reporter proteins within the transduced cells.^2,3,4 This PET study is designed to assess whether [¹⁸F]FES can be used as a PET reporter probe to image an estrogen receptor-α (ER- α) fragment expressed from a fusion construct comprising Channelrhodopsin2 and the ER – α ligand binding domain (ChRERa) in the rhesus monkey brain.

Methods: Lentivirus expressing ChRERa under the control of a human synapsin promoter (Lenti-ChRERa) and Adeno-associated virus expressing ChRERa under the control of a human synapsin promoter (AAV-ChRERa) were injected intracerebrally within the right and left anterior caudate, respectively, of two rhesus monkeys.[¹⁸F]FES baseline PET scans were performed before and after the viral transduction in both rhesus monkeys, with measurement of the arterial input function. Specific binding was measured as the difference between the baseline scan and that blocked by estradiol (0.1 mg/kg). Volume of distribution (V_T) was calculated using Logan graphical analysis.

Results: Prior to viral transduction, [¹⁸F]FES uptake in the brain was similar between baseline and estradiol-blocked scans, showing that ER are not significantly expressed in the normal brain. High (and blockable) uptake was seen only in the hypophysis (a region known to have high ER density⁵). Viral transduction induced a focal tracer uptake at the Lenti-ChRERa injection site (with an estimated increase of at least 70% in plasma-free fraction corrected distribution volume, V_T/f_p, compared to baseline), but not at the AAV-ChRERa injection site.

Conclusion: The rhesus monkey brain has no significant baseline expression of ER, thus [¹⁸F]FES is a promising tracer to be used as a PET reporter probe. Intracerebral injection of Lenti-ChRERa successfully induced a detectable focal uptake of [¹⁸F]FES.

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References

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2021-84

Quantification of cerebral nicotinic α7 acetylcholine receptors (α7 nAChRs) under gastric stimulation of the vagus nerve in piglets (#313)

Michael Rullmann¹, Georg A. Becker¹, Anton Antonov², Bernhard Sattler¹, Tatjana Sattler^{3, 4}, Winnie Deuther-Conrad⁵, Stefan Schimpf⁶, Marianne Patt¹, Philipp M. Meyer¹, Rodrigo Teodoro⁵, Barbara Wenzel⁵, Matthias Scheunemann⁵, Swen Hesse¹, Peter Brust⁵, Marco Leitzke² and Osama Sabri¹

¹University of Leipzig, Department of Nuclear Medicine, Leipzig, Germany

²Helios Clinics, Department of Anaesthesiology, Leisnig, Germany

³University of Leipzig, Deparment of Claw Animals, Leipzig, Germany

⁴University of Leipzig, Albrecht-Daniel-Thaer-Institute of Agricultural Sciences, Leipzig, Germany

⁵Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Department of Neuroradiopharmaceuticals, Research Site Leipzig, Leipzig, Germany

⁶Dräger Medical GmbH, Lübeck, Germany

Abstract

Introduction: Electrical gastric vagus nerve stimulation (VNS) shifts the sympathetic-vagal balance toward a parasympathetic predominance.¹ We aim to assess central changes in α7 nAChR-mediated transmission and hypothesize that VNS changes the parasympathetic tone by changing the α7 nAChR availability in the nucleus tractus solitarii (NTS) and distinct cortical and subcortical regions.²

Methods: Following a standard 35-frames, 120-min protocol for dynamic brain PET imaging, data from eight piglets (15.6 ± 3.2 kg, ∼6 weeks) were acquired post injection of 194.8 ± 9.4 MBq of [¹⁸F]DBT-10³ followed by T1-MPRAGE MRI: three baseline, two with infusion of the acetylcholine esterase inhibitor physostigmine (0.04 mg/kg, 1 ml/min, at 10 min prior to tracer injection; 0.24 mg/kg, 1 ml/min, at tracer injection/scan start over 120 min) and three with VNS in repeated sequences of 0.5 Hz over 5 min, 5 min pause started at scan start. TACs were analyzed using a 2-tissue compartment model involving a metabolite-corrected arterial input function to generate individual total distribution volumes (V_T) as receptor parameter.

Results: Compared to baseline, we observed an increase of the mean V_T after physostigmine infusion (61%) as well as after VNS (28%) without major alterations of K₁ in the NTS (Figures 1 and 2).

Conclusion: These initial data indicate blood-flow-independent changes under VNS as compared with baseline suggesting an increase in α7 nAChR availability although the changes appear more heterogeneous in VNS as compared with physostigmine. The finding is in contrast to our hypothesis expecting lower α7 nAChR-availability as a result of increased acetylcholine release following VNS. We speculate that higher V_T under VNS may reflect an increase in affinity of the α7 nAChR or result in an upregulation of the α7 nAChR. Increase of V_T following physostigmine administration could be related to a positive allosteric effect on the α7 nAChR. Furthermore, the results of this study allow sample size estimations for further preclinical and clinical studies.

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References

1.Leitzke M, Schimpf S, Altrock M, et al. Afferent vagal stimulation via gastric electrical stimulation alters sympathetic-vagal balance in house pigs – a pilot trial. J Biol Regul Homeost Agents 2021; 35:11–24. [DOI] [PubMed] [Google Scholar]
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2021-85

Regional analysis demonstrates asymmetric binding with [¹¹C]-(R)-PK11195 positron emission tomography in normal brain (#315)

Bandar Q. Alfaifi^{1, 2}, Daniel Lewis^{3, 4}, Alan Jackson^1,
2, David Coope^{3, 4} and Rainer Hinz^{1, 2}

¹University of Manchester, Wolfson Molecular Imaging Centre, Manchester, UK

²University of Manchester, Division of Informatics, Imaging & Data Sciences, Manchester, UK

³University of Manchester, Division of Neuroscience and Experimental Psychology, Manchester, UK

⁴University of Manchester, Geoffrey Jefferson Brain Research Centre, Manchester, UK

Abstract

Introduction: An understanding of the normal translocator protein (TSPO) distribution in healthy brain is essential if physiological variation is to be distinguished from pathology associated changes in TSPO expression. In this study we investigated the distribution and expression of TSPO in human brains using [¹¹C]-(R)-PK11195 positron emission tomography (PET), evaluating hemispheric asymmetry in TSPO expression in one of the largest TSPO PET datasets of healthy subjects.

Methods: A total of 50 healthy subjects (mean ± SD = 41 ± 15) underwent MR and dynamic [¹¹C]-(R)-PK11195 PET scanning. [¹¹C]-(R)-PK11195 PET scans were acquired for 60-min post-injection using a HRRT scanner.¹ Summed [¹¹C]-(R)-PK11195 PET images were created and used for PET/MRI co-registration. Brain Hammers atlas² was used to permit quantification of [¹¹C](R)-PK11195 BP_ND with atlas-defined brain regions. Fourteen regions of interest were included (Table 1). Parametric images of [¹¹C]-(R]-PK11195 binding potential (BP_ND) were generated using the simplified reference tissue model and bilateral grey-matter cerebellar time-activity curve as an input function. Paired-t-test was performed to assess right/left asymmetry. At regional level, multiple comparison correction (Bonferroni-Dunn’s) was applied (P < 0.01 was considered significant).

Results: Significant asymmetry in mean [¹¹C]-(R)-PK11195 BP_ND values was observed, with both total right hemisphere (GM+WM) and right hemispheric GM showing higher [¹¹C]-(R)-PK11195 BP_ND (p < 0.001) values compared to the left side (Table 1). At the regional level, paired t-tests with Bonferroni multiple comparison correction showed that the mean [¹¹C]-(R)-PK11195 BP_ND in right hemispheric regions were significantly higher (p < 0.001) than left regions in all sampled regions except for the occipital cortex.

Conclusion: [¹¹C]-(R)-PK11195 BP_ND asymmetry was observed with right-brain regions showing higher BP_ND in all normal brain regions except of the occipital cortex. Only one reference tissue input function was considered here although similar asymmetry was found with alternative reference-tissue input functions. This identified asymmetry should be considered and accounted for when evaluating TSPO PET datasets in pathological conditions.

Acknowledgements

Bandar Alfaifi is a scholarship holder from AL JOUF University, Saudi Arabia.

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References

1.Su Z, Herholz K, Gerhard A, et al. [¹¹C]-(R) PK11195 tracer kinetics in the brain of glioma patients and a comparison of two referencing approaches. Eur J Nucl Med Mol Imaging 2013; 40: 1406–1419. [DOI] [PMC free article] [PubMed] [Google Scholar]
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2021-86

Impact of cerebral blood flow and amyloid load on SUVR bias (#316)

Fiona Heeman¹, Maqsood Yaqub¹, Janine Hendriks¹, Bart N.M. van Berckel¹, Lyduine E. Collij¹, Katherine R. Gray², Richard Manber², Robin Wolz², Valentina Garibotto^{3, 4}, Catriona Wimberley⁵, Craig Ritchie⁵, Frederik Barkhof^{1, 6}, Juan Domingo Gispert López^{7, 8}, David Vállez García¹, Isadora Lopes Alves¹ Adriaan A. Lammertsma¹ and on behalf of the AMYPAD consortium

¹Amsterdam UMC, Vrije Universiteit Amsterdam, Radiology & Nuclear Medicine, Amsterdam, Netherlands

²IXICO Plc, London, UK

³Geneva University, NIMTLab, Faculty of Medicine, Geneva, Switzerland

⁴Geneva University Hospitals, Division of Nuclear Medicine and Molecular Imaging, Geneva, Switzerland

⁵University of Edinburgh, Edinburgh Imaging, Queen’s Medical Research Institute, Edinburgh, UK

⁶UCL, Institutes of Neurology and Healthcare Engineering, London, UK

⁷Barcelonaβeta Brain Research Centre, Pasqual Maragall Foundation, Barcelona, Spain

⁸Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Madrid, Spain

⁹Universitat Pompeu Fabra, Department of Experimental and Health Sciences, Barcelona, Spain

¹⁰IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain

Abstract

Introduction: Despite the widespread use of static amyloid PET scans for clinical and research purposes, it is known that the standardized uptake value ratio (SUVR), calculated from a static scan, may be biased compared with the distribution volume ratio (DVR) derived from a dynamic scan.¹ This bias may be partially explained by changes in cerebral blood flow (CBF) and is likely to be also dependent on the severity of the underlying amyloid-β (Aβ) pathology.^2,3 To date, most Alzheimer’s disease (AD) studies have compared SUVR and DVR only at a diagnostic group level and not as a function of underlying Aβ pathology. The purpose of the present study was to compare SUVR with DVR and to evaluate the effects of underlying Aβ pathology and CBF on bias in SUVR in a group of mainly cognitively unimpaired participants.

Methods: Participants (N = 121) were scanned according to a dual-time window protocol,⁴ with either [¹⁸F]flutemetamol (N = 90) or [¹⁸F]florbetaben (N = 31). The validated voxel-based implementation of the two-step simplified reference tissue model was used to derive DVR and R₁ and SUVR was calculated for a 90–110 min post-injection uptake window, all with the cerebellar grey matter as reference tissue.⁵ First, linear regression and Bland-Altman analyses were used to compare SUVR with DVR. Then, Generalized Linear Models were applied to evaluate whether (bias in) SUVR relative to DVR could be explained by R₁ for four regions (i.e. global cortical average (GCA), precuneus, posterior cingulate, and orbitofrontal cortex).

Results: Parameter distributions for both tracers are depicted in Figure 1. Despite high correlations (GCA: R²≥0.85), large overestimation and proportional bias of SUVR relative to DVRwas observed (regression line of the proportional bias: GCA: [¹⁸F]flutemetamol R² = 0.69, slope = 0.56 and intercept = −0.48; [¹⁸F]florbetaben: R² = 0.65, slope = 0.31 and intercept = −0.20). Figure 2. Negative associations were observed between both SUVR or SUVR_bias and R_1, albeitnon-significant.

Conclusion: The present findings demonstrate that bias in SUVR relative to DVRis primarily due to underlying Aβ pathology. Furthermore, in a cohort consisting mainly of cognitively unimpaired individuals, the effect of CBF on bias in SUVR appears limited.

Acknowledgements

The authors would like to thank all staff of the various centres for skilful acquisition of the scans.

This work has received support from the EU-EFPIA Innovative Medicines Initiatives 2 Joint Undertaking (grant No 115952). This communication reflects the views of the authors and neither IMI nor the European Union and EFPIA are liable for any use that may be made of the information contained herein.

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References

1.Carson RE, Channing MA, Blasberg RG, et al. Comparison of bolus and infusion methods for receptor quantitation: application to [18F]Cyclofoxy and positron emission tomography. J Cerebral Blood Flow Metab 1993; 13:24–42. [DOI] [PubMed] [Google Scholar]
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2021-87

[¹⁸F]Flotaza and [¹²⁴I]IBETA, two new β-amyloid PET imaging agents in post-mortem human Alzheimer’s disease brain (#317)

An N. Nguyen, Christopher Liang, Harsimran Kaur and Jogeshwar Mukherjee

University of California, Irvine, Radiological Sciences, Irvine, USA

Abstract

Introduction: PET studies of amyloid β (Aβ) accumulation in Alzheimer’s disease (AD) have shown clinical utility.¹ Several fluorine-18 labeled PET radiotracers are being clinically used. The aim of this study was to develop and evaluate in vitro effectiveness of new fluorine-18 radiotracer, [¹⁸F]Flotaza² and long half-life iodine-124 radiotracer [¹²⁴I]IBETA³ (Figure 1), for Aβ plaque imaging in postmortem human AD brain slices.

Methods: Molecular docking was carried out using Autodock-Chimera on amyloid fibrils.⁴ Nucleophilic fluorine-18 was used to label tosylateprecursor.¹ [¹²⁴I]Sodium Iodide was used to prepare [¹²⁴I]IBETA by electrophilic substitution of the tributyltin derivative.⁵ Human AD (n = 6) post-mortem brain tissues consisting of anterior cingulate (AC) and corpus callosum (CC) were used. Brain slices (10 µm thick) were treated with [¹⁸F]Flotaza or [¹²⁴I]IBETA in 40% ethanol PBS buffer pH 7.4 at 25°C for 1.25 hr. The slices were then washed with cold PBS buffer, 50% ethanolic PBS buffer twice (90% ethanolic PBS buffer twice for [¹²⁴I]IBETA), PBS buffer and cold water. The brain sections were air-dried, exposed overnight on phosphor films and the extent of binding of [¹⁸F]Flotaza and [¹²⁴I]IBETA was measured in DLU/mm².

Results: Both [¹⁸F]Flotaza and [¹²⁴I]IBETA exhibit nanomolar affinities for Aβ plaques. Preferred binding sites of [¹⁸F]Flotaza and [¹²⁴I]IBETA on Aβ fibril were similar (Figure 1). For Aβ plaques, slices from all subjects were positively immunostained with anti-Aβ (Figure 2). High ratios (>100) of [¹⁸F]Flotaza in AC to CC was observed (Figure 2(b)) in all the 6 subjects while ratios with [¹²⁴I]IBETA (Figure 2(c)) were lower (<10). Very little white matter binding was seen when alcohol was used for washing. [¹⁸F]Flotaza and [¹²⁴I]IBETA binding in the AC strongly correlated with anti-Aβ immunostains (Figure 2(d)). In preliminary PET/CT studies, [¹⁸F]Flotaza was found to be stable in vivo in transgenic 5XFAD mice models and no bone uptake confirmed lack of defluorination, while some deiodination of [¹²⁴I]IBETA was observed.

Conclusion: [¹⁸F]Flotaza and [¹²⁴I]IBETA are new β-amyloid PET imaging agents which can be made in one-step radiosynthesis followed by HPLC purification. Both radiotracers exhibited high binding to Aβ plaques in postmortem human AD brains. Higher AC/CC ratios of [¹⁸F]Flotaza compared to [¹²⁴I]IBETA may be attributed to PEG functionality.

Acknowledgements

NIH/NIA RF1 AG029479 (JM), UCI UROP (AN, HK)

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2021-88

Multi-tracer PET joint correlation analysis reveals disease-specific patterns in both Parkinson’s disease and asymptomatic LRRK2 mutation carriers compared to healthy controls (#318)

Julia G. Mannheim^{1, 2}, Jessie Fanglu Fu^{1, 3}, Tilman Wegener^{1, 4}, Ivan S. Klyuzhin⁵, A. Jon Stoessl^{5, 6} and Vesna Sossi^{1, 6}

¹University of British Columbia, Department of Physics and Astronomy, Vancouver British Columbia, Canada

²Eberhard-Karls University Tuebingen, Department of Preclinical Imaging and Radiopharmacy, Tuebingen Baden-Württemberg, Germany

³Massachusetts General Hospital, Athinoula A. Martinos Center for Biomedical Research, Charlestown Massachusetts, USA

⁴University of Luebeck, Department of Medical Engineering, Luebeck Schleswig-Holstein, Germany

⁵University of British Columbia, Division of Neurology, Department of Medicine, Vancouver British Columbia, Canada

⁶University of British Columbia & Vancouver Coastal Health, Djavad Mowafaghian Centre for Brain Health, Pacific Parkinson’s Research Centre, Vancouver British Columbia, Canada

Abstract

Introduction: Parkinson’s disease (PD) is a neurodegenerative disorder associated with dopaminergic terminal loss.¹ We previously demonstrated the benefit of a joint pattern approach based on canonical correlation analysis (CCA) to extract PD-progression related spatial patterns.² This study extends the analysis to extract PD- and leucine-rich repeat kinase 2 (LRRK2) mutation-specific dopaminergic patterns in relation to healthy controls (HCs).

Methods: CCA was applied to: (i)sporadic PD (n = 40, disease duration:7.5 ± 5.9y), (ii)HC (n = 27) and (iii)asymptomatic LRRK2 mutation carriers (UC, n = 11) scanned with [¹¹C]dihydrotetrabenazine (DTBZ, VMAT2 marker) and [¹¹C]d-threo-methylphenidate (MP, DAT marker). DTBZ and MP binding potentials (BP_ND) were calculated for the caudate and putaminal (anterior-middle-posterior) regions on the less/more affected side for PD, and dominant/non-dominant side for HCs and UCs. CCA was applied to HCs pooled with UCs and to HCs pooled with UCs and PDs.

Results: CCA of pooled HCs and UCs revealed disease-associated patterns (component 1: overall denervation & anterior-posterior gradient, component 2: asymmetry, component 3: residual gradient for MP, Figure 1(a)) similar to PD-progression related patterns as previously described.² Subject scores for component 1 separated HCs from UCs for DTBZ and MP (Figure 2(a), p < 0.01). A significant age dependency was detected for both HC and UC subject scores along component 1 for MP (p < 0.05). Pooling all three cohorts revealed similar patterns (Figure 1(b)) with significantly different subject scores between the three cohorts along component 1 (Figure 2(b), p < 0.01). Interestingly, subject scores of UCs while consistent with HCs of younger age approached those of the PD subjects with increasing age, likely indicating preclinical disease.

Conclusion: CCA extracted patterns of topological dopaminergic denervation. Spatial patterns identified for UC revealed similarities compared to PD patterns, suggesting topological denervation similarity between preclinical and clinical disease stage. CCA-derived component 1 of the three-group analysis revealed a stronger separation of UCs and HCs compared to univariate analysis (data not shown) along with a correlation with disease risk/age for LRRK2 and HC, i.e. as age increases, the subject scores for HCs and especially UCs trend towards those obtained for PDs. These data may highlight age-related alterations in the dopaminergic system that may increase the risk of developing PD.

Acknowledgements

The authors would like to thank the UBC PET scanning team and the TRIUMF radio-chemistry production staff. All volunteer subjects, who generously donated their time to this research, are also most gratefully acknowledged.

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References

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2021-89

Quantification of cerebral blood flow by a non-invasive hybrid PET/MR method for extracting the ¹⁵O-water image-derived input function free of partial volume errors (#319)

Lucas Narciso^{1, 2}, Tracy Ssali^{1, 2}, Linshan Liu¹, Sarah Jesso^{1, 3}, Justin W. Hicks^{1, 2}, Udunna Anazodo^{1, 2}, Elizabeth Finger^{1, 3} and Keith St Lawrence^{1, 2}

¹Lawson Health Research Institute, London, ON, Canada

²Western University, Department of Medical Biophysics, London, ON, Canada

³Western University, Department of Clinical Neurological Sciences, London, ON, Canada

Abstract

Introduction: Efforts to avoid invasive arterial blood sampling required for imaging cerebral blood flow (CBF) by positron emission tomography (PET) generally focus on obtaining an image-derived input function (IDIF).¹ Hybrid PET/magnetic resonance imaging (MRI) offers an alternative in which MRI measurements of whole-brain (WB) CBF are used to calibrate ¹⁵O-water-PET.^2,3 Originally, a double integration method (PMRFlow_DIM) was proposed; however, PMRFlow_DIM does not account for activity from the arterial cerebral blood volume (CBV_a). Here, we present a modified version (PMRFlow_IDIF) that extracts the IDIF (Figure 1(a) and (b)) from the WB ¹⁵O-water time-activity curve, is free of partial volume errors and generates CBV_a images.

Methods: Data were collected in a PET/MR scanner (Siemens Biograph mMR) and included 5-min dynamic ¹⁵O-water-PET and phase-contrast MRI⁴ measurements. The accuracy of PMRFlow_IDIF was assessed in a porcine model (n = 12) by comparison to PET-only CBF measurements (weighted non-linear least squares fitting routine). CBF maps from healthy individuals (n = 13) were generated with both PMRFlow approaches to investigate the impact of CBV_a.

Results: CBF estimates from PMRFlow_IDIF (Figures 1(c) and 2(a)) were in excellent agreement with the corresponding PET estimates in the porcine experiments. In general, good agreement was observed between CBF measurements from the two PMFlow methods (Figure 1(d); e.g., grey matter CBF = 45.1 ± 6.6 and 44.6 ± 6.4 mL/100g/min for PMRFlow_DIM and PMRFlow_IDIF, respectively). However, closer inspection of the images revealed regional discrepancies were proportional to the regional-to-WB CBV_a differences (Figure 2(b); e.g. the cerebellum and insula).

Conclusion: The primary source of error of PMRFlow_IDIF is inaccuracies in WB CBF measured by MRI. As expected in the healthy brain, differences in regional CBF between the PMRFlow techniques were typically small (<10%) with the largest found in highly vascularized regions. Consequently, we would recommend applying PMRFlow_IDIF, rather than the simpler PMRFlow_DIM, when significant variations in regional CBV_a are expected, such as due to cerebrovascular disease.

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References

1.Zanotti-Fregonara P, Chen K, Liow JS, et al. Image-derived input function for brain PET studies: many challenges and few opportunities. J Cereb Blood Flow Metab 2011; 31: 1986–1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
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2021-90

Synaptic density measured by [¹⁸F]SynVesT-1 PET in ageing mice (#321)

Mengfei Xiong¹, Sahar Roshanbin¹, Dag Sehlin¹, Jonas Eriksson^{2, 3}, Johanna Rokka¹ and Stina Syvänen¹

¹Uppsala University, Public Health and Caring Science/Molecular Geriatrics, Uppsala, Sweden

²Uppsala University, Medicinal Chemistry, Uppsala, Sweden

³Uppsala University Hospital, PET Centre, Uppsala, Sweden

⁴Uppsala University, Department of Public Health and Caring Sciences, Uppsala, Sweden

Abstract

Introduction: Synaptic vesicle 2A protein (SV2A) imaging with positron emission tomography (PET) has linked the loss of functional synapses to many neurodegenerative diseases by comparing diseased subjects with healthy controls. However, synaptic density changes in healthy ageing populations remain unclear. A recent PET study reported no decline in synaptic density with age in healthy human brains, but a similar study has not been conducted preclinically. Thus, in the present study, SV2A PET ligand [¹⁸F]SynVesT-1 was used to quantify synaptic density in healthy mice of different ages.

Methods: Three age groups (4–5 months: n = 7, 12–14 months: n = 11, 17–19 months: n = 8) of C57BL/6J mice were PET scanned with [¹⁸F]SynVesT-1 for 60 min followed by a 3 min CT examination. Images were subsequently aligned with an MRI-based brain atlas.¹ Regions of interests (ROI) in the brain were extracted to obtain time-activity curves (TACs), and an image-derived input function (IDIF) was extracted from an ROI placed in the left ventricle of the heart.² Brain retention of [¹⁸F]SynVesT-1 was displayed as the model-independent AUC_brain/blood ratio and the volume of distribution (V_T). The area under the curves (AUC) were generated from TACs, whereas V_T was obtained through kinetic modelling with either one- or two-tissue compartment model (1TCM or 2TCM).³

Results: V_T from 1TCM suggested that brain uptake in the two younger groups were significantly higher than in the oldest group (Figure 1(e)). Interestingly, the highest brain retention appeared in mice aged 12–14 months. All age groups displayed the same blood concentrations. Thus, the difference in brain exposure was not due to differences in blood exposure. The 2TCM V_T was in excellent agreement with 1TCM V_T (Figure 1(f)) and AUC_brain/_blood (r = 0.9929, p < 0.0001).

Conclusion: Consistent with human PET data,⁴ our data suggest that the synaptic density in healthy ageing mice remains stable during the majority of the mouse life span and does not decrease until very old age. Even then, the decrease is moderate. This information is important as preclinical PET may be used to test novel drug compounds. Therefore, that data is also likely to be translatable to higher species.

Acknowledgements

This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 813528.

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References

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2021-91

The positron emission tomography brain imaging data structure (PET-BIDS) extension: A new standard for sharing PET data (#322)

Martin Norgaard^{1, 2}, Granville J. Matheson^{3, 4}, Hanne D. Hansen^{1, 5}, Adam Thomas⁶, Graham Searle⁷, Gaia Rizzo⁷, Mattia Veronese^{8, 9}, Alessio Giacomel⁸, Maqsood Yaqub¹⁰, Matteo Tonietto¹¹, Thomas Funck¹², Ashley Gillman¹³, Hugo Boniface¹⁴, Alexandre Routier¹⁵, Jelle R. Dalenberg¹⁶, Tobey Betthauser¹⁷, Franklin Feingold², Christopher J. Markiewicz², Krzysztof J. Gorgolewski², Ross W. Blair², Stefan Appelhoff¹⁸, Remi Gau¹⁹, Taylor Salo²⁰, Guiomar Niso²¹, Cyril Pernet¹, Christophe Phillips²², Robert Oostenveld^{23, 24}, Jean-Dominique Gallezot²⁵, Richard E. Carson²⁵, Gitte M. Knudsen¹, Robert B. Innis²⁶ and Melanie Ganz^{1, 27}

¹Univ. Copenhagen, Neurobiology Research Unit, Rigshospitalet, and Institute of Clinical Medicine, Copenhagen, Denmark

²Stanford University, Department of Psychology, Stanford California, USA

³Columbia University, Department of Psychiatry, New York New York, USA

⁴Karolinska Institutet and Stockholm Health Care Services, Centre for Psychiatry Research, Department of Clinical Neuroscience, Stockholm, Sweden

⁵Athinoula A. Martinos Center for Biomedical Imaging, MGH/HST, Charlestown Massachusetts, USA

⁶Intramural Research Program, NIMH, Bethesda, USA

⁷Imperial College London, Invicro and Division of Brain Sciences, London, UK

⁸King’s College London, Centre for Neuroimaging Sciences, London, UK

⁹University of Padua, Department of Information Engineering, Padua, Italy

¹⁰Amsterdam UMC, location VUmc, department of radiology and nuclear medicine, Amsterdam, Netherlands

¹¹Universite Paris-Saclay, CEA, CNRS, Inserm, BioMaps, Service Hospitalier Frederic Joliot, Orsay, France

¹²Juelich Forschungszentrum, INM-1, Juelich, Germany

¹³Commonwealth Scientific and Industrial Research Organisation, Australian eHealth Research Centre, Townsville, Australia

¹⁴CEA, Centre d’Acquisition et de Traitement des Images, Paris, France

¹⁵Inria, Aramis project-team, Sorbonne Universite, Institut du Cerveau – Paris Brain Institute – ICM, Inserm, CNRS,AP-HP, Hospital de la Pitie Salpetriere, Paris, France

¹⁶University of Groningen, University Medical Center Groningen, Department of Neurology, Groningen, Netherlands

¹⁷University of Wisconsin-Madison School of Medicine and Public Health, Wisconsin Alzheimer’s Disease Research Center, Division of Geriatrics, Department of Medicine, Madison Wisconsin, USA

¹⁸Max Planck Institute for Human Development, Center for Adaptive Rationality, Berlin, Germany

¹⁹Université catholique de Louvain, Institute of psychology, Louvain la Neuve, Belgium

²⁰Florida International University, Department of Psychology, Miami Florida, USA

²¹Indiana University, Psychological Brain Sciences, Bloomington Indiana, USA

²²University of Liege, GIGA Cyclotron Research Centre in vivo imaging, Liege, Belgium

²³Radboud University, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, Netherlands

²⁴Karolinska Institutet, NatMEG, Stockholm, Sweden

²⁵Yale University, Department of Radiology and Biomedical Imaging, New Haven, USA

²⁶National Institutes of Health, Molecular Imaging Branch, Bethesda, USA

²⁷University of Copenhagen, Department of Computer Science, Copenhagen, Denmark

Abstract

Introduction: The neuroimaging community has increasingly recognized the importance of data sharing. Reasons for this are the poor replicability of findings, the need for appropriate quality control, the greater statistical power provided by larger samples, and the higher scientific impact of multilateral collaborations. In addition, funding bodies and scientific journals increasingly require that data be shared. The Brain Imaging Data Structure (BIDS)¹ initiative has sought to establish consensus on how to organize and share data obtained in neuroimaging experiments. BIDS is being developed in an ongoing and inclusive community effort; many neuroscientists consult to ensure that BIDS covers most common neuroimaging experiments. While BIDS was originally based on functional and structural MRI acquisitions, it has now been extended to cover a wide range of different modalities.² In addition, a growing number of software tools (see http://bids-apps.neuroimaging.io/) can read data organized according to the BIDS structure.³

Methods: The new PET community data standard is now part of the BIDS specification and in detail described in literature.⁴ The data standard follows the community guidelines for the reporting of PET experiments⁵ and describes storage of all image and metadata needed to quantify PET data using uptake imaging or reference tissue modelling (RTM). It also specifies how to store blood data and how to convey the meta information related to it in a standardized fashion.

Results: Example data following the BIDS standard have been added to OpenNeuro to demonstrate feasibility. The interface is shown in Figure 1. Furthermore, we are currently developing converter software to facilitate easy conversion to PET BIDS based on different type of scanner files, e.g. dcm or ecat, that are distributed in an open-source GitHub repository for use by the community.

Conclusion: BIDS is intuitive and easy to adopt. The specification was intentionally based on existing file formats and intuitive folder structures to reflect current lab practices and make data machine-readable. The rapid and widespread adoption of this standard by the wider PET community will facilitate not only data sharing and aggregation, but also improve the applicability of software designed to accommodate this standard.

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References

1.Gorgolewski KJ, Auer T, Calhoun VD, et al. The brain imaging data structure, a format for organizing and describing outputs of neuroimaging experiments. Sci Data 2016; 3: 160044. [DOI] [PMC free article] [PubMed] [Google Scholar]
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5.Knudsen GM, Ganz M, Appelhoff S, et al. Guidelines for the content and format of PET brain data in publications and archives: a consensus paper. J Cerebral Blood Flow Metab 2020; 40: 1576–1585. [DOI] [PMC free article] [PubMed] [Google Scholar]

2021-92

Development of a novel PET ligand for receptor-interacting protein kinase 1 in brain (#323)

Takayuki Sakai¹, Takashi Yamada^{2, 1}, Hiroshi Ikenuma¹, Aya Ogata^{3, 1}, Masanori Ichise¹, Saori Hattori¹, Junichiro Abe¹, Masaaki Suzuki¹, Kengo Ito¹, Takashi Kato¹, Sinichi Imamura¹ and Yasuyuki Kimura¹

¹National Center for Geriatrics and Gerontology, Department of Clinical and Experimental Neuroimaging, Obu, Japan

²Nagoya University of Economics, Department of Human Life and Sciences, Nagoya, Japan

³Gifu University of Medical Science, Department of Pharmacy, kani, Japan

Abstract

Introduction: Microglia are the immune cells in the brain. Microglia play a critical role in neuroinflammation associated with neurodegenerative diseases, such as Alzheimer’s disease (AD). Recently, efforts in drug discovery for treatment of AD progression have focused on modifying the function of microglia. For example, one such effort has been focusing on receptor-interacting protein kinase 1 (RIPK1), which is a multifaceted kinase that controls cell death and inflammation. Inhibition of RIPK1 expressed in microglia is known to prevent phenotypic changes of microglia from the resting to disease-associated states. RIPK1 inhibitors are therefore considered to be of therapeutic values in treating AD progression. To monitor the effectiveness of this treatment strategy, in vivo imaging biomarker of RIPK1 would be of potential usefulness.

Methods: We chose one RIPK1 inhibitor, (3S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo-[3,4-c]pyridin-6-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxa-zepine-8-carbonitrile (1), from several candidates with a high RIPK1 inhibitory potency that would possess optimal characteristics for PET imaging of the brain. To radiolabel 1 with¹¹C, a precursor, N-desmethylated 1 (Dm-GG511), was synthesized from starting materials related to the 1 structure. Then, ¹¹CH₃ group was introduced to Dm-GG511 to the final product, ¹¹C-1 (¹¹C-GG511), by optimizing methylating processes. To evaluate if ¹¹C-GG511 has adequate properties as a PET ligand for imaging RIPK1, PET imaging was performed in normal and inflammation model rats including the evaluation of the presence of any of ¹¹C-GG511 specific binding by conducting in vivo blocking and in vitro brain tissue autoradiography experiments.

Results: In the normal rats, ¹¹C-GG511 showed overall good reversible brain uptake with a relatively higher uptake in the cerebellum, but otherwise no other regional uptake differences. In the inflammation model rats, no obvious ¹¹C-GG511 uptake differences were observed between the inflamed and contralateral striata or any healthy brain regions. The cerebellar uptake in the normal rats was minimally blocked, suggesting the presence of specific binding of ¹¹C-GG511 if any. However, the presence of any specific binding was not evident on autoradiography.

Conclusion: ¹¹C-GG511 shows a good overall brain uptake, but no clear evidence of specific binding in rats. Further studies are warranted to modify this ligand or try other related ligands for more optimal PET imaging of RIPK1.

Acknowledgements

We would like to thank Takeda Pharmaceutical Company Limited for providing chemical substance {Ethyl 1-Benzyl-5-chloro-4-(2-oxoethyl)-1H-pyrazole-3-carboxylate}, standard samples of labeling precursors (Dm-GG511) and nonradiolabeled authentic samples (1).

2021-93

Positron emission tomography imaging of alpha-synuclein?In vitro and in vivo evaluation of MODAG-005 (#324)

Ran Sing Saw¹, Sabrina Buss¹, Laura Kuebler¹, Sergey Ryazanov^{2, 3}, Andrei Leonov^{2, 3}, Federica Bonanno¹, Felix Schmidt², Viktoria Ruf⁴, Daniel Bleher¹, Marilena Poxleitner¹, Ann-Kathrin Grotegerd¹, Bernd J. Pichler¹, Gregory D. Bowden¹, Andreas Maurer¹, Christian Griesinger⁴, Armin Giese^{2, 4} and Kristina Herfert¹

¹Eberhard Karls University of Tübingen, Werner Siemens Imaging Center, Department of Preclinical Imaging & Radiopharmacy, Tübingen Baden-Württemberg, Germany

²MODAG GmbH, Wendelsheim Rhineland-Palatinate, Germany

³Max Planck Institute for Biophysical Chemistry, Göttingen Lower Saxony, Germany

⁴Ludwig Maximilians University, Center for Neuropathology and Prion Research, Munich Bavaria, Germany

Abstract

Introduction: Positron emission tomography (PET) imaging of alpha-synuclein (αSYN) aggregates would be invaluable for the non-invasive diagnosis of synucleinopathies as well as facilitating the development of novel treatment strategies. Here, we report the in vitro and in vivo evaluation of MODAG-005 as a promising αSYN PET tracer.

Methods: In vitro binding of [³H]MODAG-005 was determined using human recombinant αSYN, amyloid-beta_1-42 (Aβ)andtau fibrils. (Micro)autoradiography was performed in postmortem human brain tissues from multiple system atrophy (MSA), Parkinson’s disease (PD), Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), healthy controls, and in the transgenic αSYN(A30P) mouse model. Subsequently, the binding affinity to αSYN in human brain was determined in MSA tissues using autoradiography. In vivo pharmacokinetics and metabolism of [¹¹C]MODAG-005 were studied in healthy mice and rats, and in rats intrastriatally injected with αSYN fibrils. Time-activity curves were generated from dynamic 60-minute PET for the striata (target region) and cerebellum (reference), and the binding potential (BP_ND) values were calculated using Logan’s reference tissue model.

Results: Saturation binding assays revealed K_d values for [³H]MODAG-005 of 0.2 nM for αSYN, 7 nM for tau and > 100 nM for Aβ fibrils. Autoradiography in human brain tissues confirmed the high affinity binding of [³H]MODAG-005 to αSYN with a K_d of 0.25 nM in MSA, while showing a specific binding in the αSYN(A30P) mouse model. [¹¹C]MODAG-005 was obtained at high molar activities of > 200 GBq/µmol. The tracer showed an excellent blood-brain barrier penetration and a fast clearance from the brain. We observed one metabolite in the brain, with 96% and 79% of the parent compound remaining at 5 and 15 minutes post-injection. Increased tracer binding was detected in the fibril-injected striatum compared to the sham-injected striatum, whereas no difference was detected in non-injected rats.

Conclusion: Here, we present a novel PET tracer targeting αSYN in the human brain. MODAG-005 possesses a very high affinity to αSYN in MSA tissues, in line with the αSYN fibril binding assay. It also exhibits excellent brain availability, good kinetics, and sufficient signal-to-noise ratio in fibril-injected rats. Despite the lack of full selectivity, MODAG-005 is currently one of the most promising αSYN-targeting PET tracers.

Acknowledgements

We thank Ramona Stremme, Elena Kimmerle and Johannes Kinzler for the radiosynthesis. We also thank the technical assistants Linda Schramm, Maren Harant, Stacy Huang, Miriam Owczorz, Natalie Hermann and Isabel Sehnke for their experimental support. Additionally, we acknowledge Dr. Julia Mannheim, Dr. Rebecca Rock, Dr. Neele Hübner, Dr. Andreas Dieterich, Hans Jörg Rahm, Dr. Carsten Calaminus and Funda Cay for their administrative support.

In vitro evaluation of [3H]MODAG-005 NOT FOR PUBLICATION

In vivo evaluation of [11C]MODAG-005 NOT FOR PUBLICATION

2021-94

Simultaneous Multifactor Bayesian Analysis (SiMBA) of PET Time Activity Curve Data (#325)

Granville J. Matheson^{1, 2} and R. Todd Ogden^{1, 2}

¹Columbia University, Molecular Imaging and Neuropathology Division, New York New York, USA

²Columbia University, Department of Biostatistics, New York New York, USA

Abstract

Introduction: Positron emission tomography (PET) is essential for studying the neurochemical pathophysiology of psychiatric and neurological disease, however its high cost and exposure of participants to radiation limit the feasibility of large sample sizes. In clinical research, the major shortcoming of PET imaging has therefore been its lack of statistical power for studying clinically-relevant research questions. Here, we introduce a new method for performing PET quantification and analysis called SiMBA to make more effective use of PET time activity curve data.

Methods: SiMBA makes use of hierarchical, multifactor Bayesian modelling to exploit similarities both between individuals and among regions within individuals while applying the two-tissue compartment model. In this way, the model borrows strength across the whole dataset to improve stability and robustness to measurement error, as well as parameter identifiability and estimation accuracy, without sacrificing model interpretability. Furthermore, parameter estimation and statistical analysis are performed simultaneously using all measured data and its associated uncertainty, in contrast with the conventional approach of using point estimates. We tested this approach in simulated data in comparison with conventional nonlinear least squares modelling and subsequent statistical analysis.

Results: In simulated [¹¹C]WAY100635 data, this approach greatly improves both statistical power and the consistency of effect size estimation, equivalent to effectively doubling and quadrupling the sample size respectively, without affecting the false positive rate. This comes at the cost of increased computational expense, taking in the order of hours to days to fit for typical clinical datasets.

Conclusion: This method has the potential to make it possible to test clinically-relevant hypotheses which could not be studied before given the practical constraints. Furthermore, because this method does not require any additional information, it makes it possible to re-examine data which has already previously been collected. In the absence of dramatic advancements in PET image data quality, radiotracer development, or data sharing, PET imaging has been limited in the scope of research hypotheses which could be studied. This method, especially combined with the recent steps taken by the PET imaging community to embrace data sharing, will make it possible to further improve the research possibilities and clinical relevance of PET neuroimaging.

Acknowledgements

The work reported here has been partially supported by US NIH grants 5 P50 MH090964 and 5 R01 EB024526, and by the Hjärnfonden Postdoctoral Fellowship.

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2021-95

Investigating fatty acid amide hydrolase in mild traumatic brain injury; A PET study of [¹¹C]CURB in occupational posttraumatic stress disorder (#327)

Khadija N. Brouillette^{1, 2}, Erin Gaudette^{2, 3}, Sarah E. Watling^{2, 5}, Jerry Warsh^{2, 3}, Laura M. Best^{2, 5}, Duncan Green^{2, 5}, Tina McCluskey^{2, 3}, Shawn Rhind⁶, Rachel Tyndale^{3, 4}, Don Richardson^{7, 8}, Neil Vasdev^{3, 10}, Rakesh Jetly⁹, Stephen Kish^{2, 3} and Isabelle Boileau^2,
3

¹McMaster University, School of Interdisciplinary Sciences, Hamilton, ON, Canada

²Centre for Addiction and Mental Health, Brain Health Imaging Centre, Toronto, ON, Canada

³Centre for Addiction and Mental Health, Campbell Mental Health Research Institute, Toronto, ON, Canada

⁴University of Toronto, Pharmacology and Toxicology, Toronto, ON, Canada

⁵University of Toronto, Institute of Medical Sciences, Toronto, ON, Canada

⁶Toronto Research Centre, Defense Research and Development Canada, Toronto, ON, Canada

⁷St. Joseph’s Operational Stress Injury Clinic, London, ON, Canada

⁸University of Western Ontario, Department of Psychiatry, London, ON, Canada

⁹University of Ottawa, The Royal’s Institute of Mental Health Research and Department of Psychiatry, Ottawa, ON, Canada

¹⁰Centre for Addiction and Mental Health, Azrieli Centre for Neuro-Radiochemistry, Toronto, ON, Canada

Abstract

Introduction: Concussive head trauma or mild traumatic brain injuries (mTBI) are prevalent and impactful in individuals with occupational posttraumatic stress disorder (PTSD) and may affect the course and severity of disease. Higher levels of the major endocannabinoid anandamide have been shown in preclinical models of neuronal damage; putatively suggesting a possible neuroprotective role for anandamide. This study aimed to use positron emission tomography (PET) to test the hypothesis that levels of Fatty Acid Amide Hydrolase (FAAH), the enzyme that catabolizes anandamide, are lower in individuals with occupational PTSD with mTBI relative to those without.

Methods: Participants with occupational PTSD (e.g., Canadian Armed Forces members, veterans and first responders) (n = 16; 8 with an mTBI) completed a PET scan with arterial blood sampling following injection of the FAAH tracer [¹¹C]CURB. All participants were genotyped for the FAAH C385A polymorphism which affects [¹¹C]CURB binding. Clinical symptoms and cognitive function were assessed. A Repeated Measures ANCOVA (brain region of interest (ROI)¹ x GROUP² controlling for FAAH C385A) was conducted to assess whether FAAH levels were different in the brains of those with PTSD alone versus those with comorbid PTSD and mTBI.

Results: There were no group differences in age, sex, body mass, smoking status, FAAH C385A genotype or medication and clinical symptom scores were also not different (p’s > 0.94). However, PTSD with mTBI had marginally poorer performance on tests of executive function and verbal memory (trails B: p = 0.01; Hopkin’s Verbal Learning Test: p = 0.1). [C-11]CURB binding in all 10 ROIs was 12%-20% lower in the mTBI group (F(1,13) = 4.53, p = 0.05) with the most robust effects noted in the hippocampus and amygdala (∼20%; p(uncorrected) = 0.03). [C-11]CURB binding in the 10 ROIs did not correlate with clinical measures (p’s > 0.99).

Conclusion: These preliminary findings suggest that mTBI in PTSD may be associated with lower FAAH binding in the brain and lend support to preclinical evidence suggesting increased anandamide after neuronal damage. Future studies should systematically investigate the consequences of mTBI on endocannabinoid levels and their key hydrolytic enzymes, including FAAH, to gain a better understanding of their roles in recovery from trauma and the potential utility of endocannabinoid focused therapeutics (e.g., FAAH inhibitors).

Acknowledgements

This work was funded by the Canadian Institute for Health Research, Canadian Institute for Military and Veteran Health Research.

References

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2021-96

5HT1A receptor co-expression based polygenic score associates with 5HT1A predicted binding potential in frontal regions (#328)

Danusa M. Arcego^{1, 4}, Eve Peraldi³, Irina Pokhvisneva^1,
4, Zihan Wang^{1, 4}, Sachin Patel^{1, 4}, Barbara Barth^3,
4, Michael J. Meaney^{1, 4}, Andreas Hahn², Rupert Lanzenberger² and Patricia P. Silveira^{1, 4}

¹Douglas Mental Health University Institute/McGill university, Department of Psychiatry, Montréal, QC, Canada

²Medical University of Vienna, Department of Psychiatry and Psychotherapy, Vienna, Austria

³McGill University, Montreal, QC, Canada

⁴McGill University, Ludmer Center for Neuroinformatics and Mental Health, Montreal, QC, Canada

Abstract

Introduction: Serotonin is an important modulatory neurotransmitter with distinctive neuroplastic capabilities. Serotoninergic neuroplasticity dysfunctions can impact gray matter volume, which is associated with disruption of cognition and emotional functions. We aimed at evaluating if variations in the main inhibitory serotonin receptor (5HT1A) expression-based polygenic score (ePRS) in the frontal cortex associates with variations in the predicted binding potential for this receptor in participants from the UK Biobank.

Methods: The predicted binding potential was calculated based on a 5HT1A binding-gray matter reference atlas (measured by PET scan,¹). This information was used to predict 5HT1A binding potential in the UK Biobank individuals using the corresponding gray matter volume information for this sample. The ePRS was based on 5HT1A co-expression network using human RNA-sequencing data from BrainEAC (http://www.braineac.org) in the frontal cortex. Single-nucleotide polymorphisms mapped on the network genes (144 genes) were weighted by the association between genotype and gene expression using GTEx (http://www.gtexportal.org) (Figure 1).

Results: Regression models adjusted by population stratification, age and sex were used to investigate the association between the predicted 5HT1A binding potential and the frontal cortex 5HT1A ePRS, both calculated for UK Biobank participants. We observed that the frontal 5HT1A ePRS was significantly correlated with serotonin predicted binding potential in specific cortical regions (frontal orbital cortex, FDR adjusted p-value = 0.03, ß = 11.25; insular cortex, FDR = 0.03, ß = 7.45; precentral gyrus FDR = 0.03, ß = −24.72; cingulate gyrus FDR = 0.04, ß = −7.43; frontal pole, FDR = 0.04, ß = −32.85, N = 17,181, Figure 2).

Conclusion: We observed that frontal 5HT1A ePRS (based on a co-expression gene network) strongly associated with a functional brain measure (binding potential) specifically for this receptor in a large sample of individuals. This confirms the ability of the polygenic score to reflect biological differences in neurotransmitter systems in a brain region-specific manner.

Acknowledgements

JPB Foundation, Hope for Depression Research Foundation, and Canadian Institutes of Health Research (CIHR).

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Reference

1.Kraus C, Hahn A, Savli M, Kranz GS, Baldinger P, Höflich A, Spindelegger C, Ungersboeck J, Haeusler D, Mitterhauser M, Windischberger C. 2012. Serotonin-1A receptor binding is positively associated with gray matter volume—a multimodal neuroimaging study combining PET and structural MRI. Neuroimage, 63: 1091–1098. [DOI] [PubMed] [Google Scholar]

2021-97

[¹²⁴I]IPPI: Molecular modeling and autoradiographic study for binding to Taupathies (#329)

Taylor R. Moran, Reisha M. Ladwa, Rommani Mondal, Christopher Liang and Jogeshwar Mukherjee

University of California, Irvine, Preclinical Imaging, Radiological Sciences, Irvine California, USA

Abstract

Introduction: Tau isoforms 3R and 4R are present in Alzheimer’s disease (AD, 3/4R), Pick’s disease (PiD, 3R) and corticobasal degeneration (CBD, 4R).¹ Selective imaging agents for 3R and 4R will help in the development of differential diagnostic methods of various taupathies. We have docked the azaindole IPPI in Tau molecular stuctures to assess binding sites and developed [¹²⁴I]IPPI as a potential PET imaging and evaluated [¹²⁵I]IPPI in autoradiographic studies of human taupathies.

Methods: Molecular docking was carried out using Autodock-Chimera on AD Tau, PiD Tau and CBD Tau² [Figure 1]. [¹²⁴I]Sodium Iodide was used to prepare [¹²⁴I]IPPI by electrophilic substitution of the tributyltin derivative³ [Figure 2(a)]. Human AD post-mortem brain tissues consisting of anterior cingulate (AC) were used (n = 6). Brain slices (10 µm thick) were treated with [¹²⁴I]IPPI as reported previously with [¹²⁵I]IPPI.³ Preliminary autoradiographic studies were also carried out in PiD (n = 2) and CBD (n = 1) using [¹²⁵I]IPPI. Nonspecific binding was measured using 10 µM MK-6240. The brain sections were exposed overnight on a phosphor film and extent of binding [¹²⁴/¹²⁵I]IPPI was measured in DLU/mm². Adjacent sections were immunostained with anti-Tau antibody in AD brains (Figure 2(d)).

Results: IPPI exhibits nanomolar affinities for AD Tau.³ Four separate binding sites were found for AD Tau,³ CBD Tau and PiD Tau⁴ (Figure 1). Binding energies were found to be favorable for site 1 for each of the Tau (-9.7, -9.6, -10.8 Kcal/mol for AD, CBD, PiD). This suggested that IPPI is likely to bind to the different Tau forms in the three tauopathies. High binding of [¹²⁴IIPPI in AD brain slices was observed in AC in all subjects (Figure 2(c)) which was consistent with adjacent slice positively immunostained with anti-Tau (Figure 2(d)). This is similar to our reported findings with [¹²⁵I]IPPI.³ Preliminary results of [¹²⁵I]IPPI in PiD and CBD suggest some binding which was not displaceable by MK-6240. This is consistent with the finding that [¹⁸F]MK-6240 does not bind to PiD.⁵

Conclusion: [¹²⁴I]IPPI has been successfully prepared for PET imaging of taupathies. Additional studies are underway to confirm its binding to different forms of human Tau. Transgenic P301S mice models of Tau are currently being used for PET/CT imaging of [¹²⁴I]IPPI.

Acknowledgements

NIH/NIA RF1 AG029479 (JM), UCI UROP (TM, RML, RM). Banner Health Research Institute and UCI MIND for tissue samples and UCI Pathology for immunostaining.

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References

1.Katsumoto A, Takeuchi H, Tanaka F. Tau pathology in chronic traumatic encephalopathy and Alzheimer’s disease: similarities and differences. Front Neurol 2019; 10: 980. [DOI] [PMC free article] [PubMed] [Google Scholar]
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3.Mukherjee J, Liang C, Patel KK, et al. Development and evaluation [¹²⁵I]IPPI for tau imaging in post-mortem human Alzheimer’s disease brain. Synapse 2021; 74: e22183. [DOI] [PMC free article] [PubMed] [Google Scholar]
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2021-98

Increased Tau, Aβ amyloid, and monoamine oxidase-A in post-mortem human Alzheimer’s disease anterior cingulate (#330)

Amina U. Syed, Christopher Liang, Tonya Mukherjee, Krystal Patel and Jogeshwar Mukherjee

University of California, Irvine, Preclinical Imaging, Radiological Sciences, Irvine California, USA

Abstract

Introduction: Successful multitarget approaches are currently underway towards the accurate and early diagnosis of Alzheimer’s disease (AD).¹ Our ongoing multitarget approach involves Tau imaging with [¹²⁵I]IPPI,² Aβ plaque imaging with [¹⁸F]Flotaza,³ and [¹⁸F]FAZIN3 for imaging monoamine oxidase A (MAO-A).⁴ The role of monoamine oxidases (MAOs) in neurotransmitter breakdown, increased production of reactive oxygen species, and possible roles in microglia activation and inflammation have attracted much attention. To support role of MAO-A in AD, we reported [¹⁸F]fluoroethylharmol ([¹⁸F]FEH).⁵ Using anterior cingulate (AC) regions of the brain, we now correlate the three biomarkers for AD (Figure 1).

Methods: [¹²⁵I]IPPI, [¹⁸F]Flotaza, [¹⁸F]FAZIN3, and [¹⁸F]FEH were prepared as previously reported. For in vitro studies, human post-mortem brain tissues, consisting of AC and corpus collosum (CC) regions, from Banner Health, Sun City, Arizona were used. Brain slices (10 µm thick) were obtained on a Leica 1850 cryotome. Brain sections were incubated with [¹⁸F]FAZIN3 or [¹⁸F]FEH (approx. 1 µCi/cc) in PBS (pH 7.4) buffer at 25°C for 60 min and subsequently washed with PBS buffer, while [¹²⁵I]IPPI and [¹⁸F]Flotaza were washed with alcohol-PBS buffer. Using the Optiquant program, regions of interest were drawn in digital light units (DLU)/mm² to quantify the percentage binding of the radiotracers. Immunostaining with anti-Tau and anti-Aβ was carried on adjacent sections of all subjects.

Results: Autoradiography and immunostaining results support that Aβ, MAO-A, and Tau are upregulated in the AD brain (Figure 2). The gray matter (GM) were clearly delineated versus white matter (WM) in the AD autoradiographic images of [¹⁸F]FEH with an average GM/WM > 2 (Figure 2(c)) and [¹⁸F]FAZIN3 with an average GM/WM > 3 (Figure 2(b)) for the binding to MAO-A. MAO-A binding positively correlated with the high binding of [¹²⁵I]IPPI to Tau (GM/WM > 4) (Figure 2(e)) and [¹⁸F]Flotaza to Aβ plaques (GM/WM > 100) (Figure 2(h)), consistent with cortical binding corresponding to anti-Aβ (Figure 2(i)) and anti-Tau (Figure 2(f)). All cognitively normal (CN) subjects exhibited lower binding in the GM compared to AD subjects in autoradiography studies. Nonspecific binding of [¹⁸F]FEH was higher than [¹⁸F]FAZIN3.

Conclusion: Based on our results, increased [¹⁸F]FEH and [¹⁸F]FAZIN3 binding in AD brains suggests upregulation of MAO-A. Additionally, with increased [¹²⁵I]IPPI binding to Tau and [¹⁸F]Flotaza binding to Aβ in AD, our findings support a potential multitarget approach to AD determination.

Acknowledgements

NIH/NIA RF1 AG029479 (JM), UCI UROP (AS). Banner Health Research Institute and UCI MIND for tissue samples and UCI Pathology for immunostaining.

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References

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2021-99

A three-factor model of common early-onset psychiatric disorders: Temperament, adversity, and dopamine (#331)

Maisha Iqbal¹, Sylvia Cox², Natalia Jaworska³, Maria Tippler¹, Natalie Castellanos-Ryan⁶, Sophie Parent⁶, Alain Dagher¹, Frank Vitaro⁴, Mara Brendgen⁵, Michel Boivin⁷, Robert Pihl⁸, Sylvana Cote⁴, Richard Tremblay⁴, Jean Seguin⁴ and Marco Leyton^{1, 2}

¹McGill University, Neurology and Neurosurgery/Irving Ludmer Psychiatry Research and Training Building, Montreal, QC, Canada

²McGill University, Psychiatry, Montreal, QC, Canada

³University of Ottawa Institute of Mental Health Research, Ottawa, ON, Canada

⁴CHU Ste-Justine Research Center, Montreal, QC, Canada

⁵Université de Québec à Montréal, Department of Psychology, Montreal, QC, Canada

⁶Université de Montréal, School of Psychoeducation, Montreal, QC, Canada

⁷Tomsk State Universit, Institute of Genetic, Neurobiological and Social Foundations of Child Development, Tomsk, Russia

⁸McGill University, Department of Psychology, Montreal, QC, Canada

Abstract

Introduction: Commonly comorbid early-onset psychiatric disorders might reflect the varying expression of overlapping risk factors.¹ The mediating processes remain poorly understood, but three factors show some promise: adolescent externalizing (EXT) traits, early life adversity,² and midbrain dopamine autoreceptors.^3,4 Here, we investigated whether these features acquire greater predictive power when combined.

Methods: Participants were transitional aged youth who had been followed since birth and lived in the area of Montreal and Quebec City. They were invited to participate in the current study based on EXT trait scores between the ages of 10 to 16,⁵ as measured with the Social Behavioural Questionnaire. In early adulthood (age 18.5 ± 0.6 y.o.) participants were assessed with the Structured Clinical Interview for DSM-5, completed the Childhood Trauma Questionnaire (CTQ), and had a 90-min high-resolution positron emission tomography scan with [¹⁸F]fallypride. Fifty-two participants (30F, 22M) completed the study. Follow-up interviews were conducted 1, 2 and 3 years later. Binomial logistic regression analyses tested whether midbrain [¹⁸F]fallypride BP_ND values, EXT and CTQ scores predicted the presence of lifetime DSM-5 diagnoses. All analyses were run for diagnoses obtained at the time of or prior to the PET scan and again including diagnoses obtained during the follow-up interviews.

Results: The three-factor model predicted their presence with an overall accuracy of 90.4% (p = 2.4 x 10⁻⁵) and explained 91.5% of the area under the receiver operating characteristic curve [95% CI: .824, 1.000]. The model remained significant upon addition of new diagnoses that developed during the follow-up period (p = 3.5 x 10⁻⁵).

Conclusion: A combination of EXT traits, early life adversity, and poorly regulated dopamine transmission might increase the risk for diverse early-onset psychiatric disorders. The data reported here raise the possibility that these features can predict susceptibility prospectively.

References

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2021-100

[18F]2-fluoro-2-deoxy-sorbitol PET imaging for quantitative estimation of blood-brain barrier permeability in vivo (#332)

Gaëlle Hugon¹, Sébastien Goutal¹, Ambre Dauba¹, Louise Breuil¹, Benoit Larrat², Alexandra Winkeler¹, Anthony Novell¹ and Nicolas Tournier¹

¹Université Paris-Saclay, CEA, CNRS, Inserm, BioMaps, Orsay, France

²Université Paris-Saclay, CNRS, CEA, DRF/JOLIOT/NEUROSPIN/BAOBAB, Gif-sur-Yvette, France

Abstract

Introduction: The non-transported and non-metabolized sorbitol derivative [18F]-2-fluoro-2-deoxy-sorbitol ([18F]FDS) can be straightforwardly obtained from chemical reduction of commercial 18F-2-deoxy-2-fluoro-D-glucose ([18]FDG). Biodistribution ¹⁸F-FDS shows negligible baseline brain uptake. For the first time, [18F]FDS was evaluated as a small molecule (paracellular) marker of blood-brain barrier (BBB) integrity for PET imaging.

Methods: Five mice underwent focused ultrasound (FUS) to generate spatially controlled BBB disruption in the right brain hemisphere and three mice were used as a control without FUS protocol. Five min after FUS, the BBB integrity marker Evan’s blue (EB) and ¹⁸F-FDS (4.2 ± 0.7 MBq) were injected i.v, followed by 60 min brain microPET acquisition. Animals were then sacrificed and brain removed to visually check EB extravasation as a post-mortem marker of BBB disruption. Time-activity curves (TACs) were measured in the right and left hemisphere for each group. Area Under the TACs (AUC) and AUC_R using the non-sonicated hemisphere as a reference region were calculated. PET kinetics of [18F]FDS in each brain hemisphere were described by a 1-tissue compartment model using an image derived input function.

Results: Brain PET signal was visually increased in the sonicated brain region. Brain AUC was significantly higher in the hemisphere with disrupted BBB compared to contralateral hemisphere (2.2 ± 0.5-fold increase, p < 0.01); or corresponding (right) hemisphere of control mice (p < 0.05). A 2.4 ± 0.8-fold increase was observed in the brain distribution (V_T, p < 0.01) of [18F]-FDS in the sonicated area compared with the contralateral hemisphere in the FUS group but not in the control group, consistent with ex vivo brain distribution of EB extravasation. Enhanced brain uptake was associated with an increase in the influx transfer rate K1 (+1.4 ± 0.7-fold, p < 0.05) and a decrease in the efflux transfer rate k2 (-1.7 ± 0.4-fold, p < 0.01).

Conclusion: Thanks to the quantitative performance of PET compared with other neuroimaging techniques, [18F]FDS PET and kinetic modelling provides a readily available and sensitive method for non-invasive determination of BBB permeability in vivo.

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2021-101

Relative cerebral blood flow, amyloid burden and cognition in individuals with subjetive cognitive decline are closely associated (#333)

Jarith Ebenau¹, Denise Visser², Sander C.J. Verfaillie², Tessa Timmers², Mardou van Leeuwenstijn¹, Frederik Barkhof^{2, 3}, Philip Scheltens¹, Niels Prins^{1, 4}, Ronald Boellaard², Albert D. Windhorst², Wiesje M. van der Flier^{1, 5} and Bart N.M. van Berckel^{1, 2}

¹Amsterdam UMC, Alzheimer Center, Amsterdam, Netherlands

²Amsterdam UMC, Deparment of Radiology & Nuclear Medicine, Amsterdam, Netherlands

³UCL, London, UK

⁴Brain Research Center, Amsterdam, Netherlands

⁵Amsterdam UMC, Department of Epidemiology & Biostatistics, Amsterdam, Netherlands

Abstract

Introduction: The role of cerebral blood flow (CBF) in the early stages of Alzheimer’s disease (AD) is complex and studies provide conflicting results regarding its relationship with AD biomarkers. We investigated the cross-sectional and longitudinal relationships between amyloid burden, relative CBF (rCBF) and cognition, in individuals with subjective decline (SCD).

Methods: We included 187 individuals with SCD from the SCIENCe cohort (64 ± 8y, 39%F, MMSE 29 ± 1). Each underwent a dynamic [¹⁸F]florbetapir PET and T1-weighted MRI scan, enabling calculation of mean binding potential (BP_ND) and R₁ (measure of rCBF) in frontal, temporal, parietal, occipital and composite regions-of-interest. Eighty-three individuals underwent a second [¹⁸F]florbetapir PET (mean difference 2.6 ± 0.7y). Individuals annually underwent neuropsychological testing (follow-up time 3.8 ± 3.1y).

Results: Spearman’s correlation analyses showed a positive association between baseline BP_ND and R₁ in occipital regions, but not in other regions (Figure 1). Linear mixed models (LMM) showed that a low baseline R₁ was associated with an increase in BP_ND in frontal, temporal and composite regions. Vice versa, a high baseline BP_ND was associated with a decline in R₁ in all regions (Table 1). Furthermore, a low baseline R₁ was associated with a worse cognitive trajectory for tests for memory, attention and global cognition (range betas 0.01 to 0.28, p < 0.05). High BP_ND was associated with a worse cognitive trajectory for tests covering all domains (range betas -0.01 to -0.70, p < 0.05). When both predictors were simultaneously added to the model, associations remained comparable.

Conclusion: BP_ND and R₁ were both associated with cognitive test performance over time in individuals with SCD. Furthermore, their longitudinal trajectories were closely associated. Although our results do not provide evidence for a causal relationship, they suggest two pathways in the development of AD, starting with low rCBF or high amyloid burden, which are influenced by each other, and could eventually lead to further deterioration. Inline graphic

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2021-102

Genetically identical twins show comparable tau PET load and spatial distribution (#334)

Emma M. Coomans^{1, 2}, Jori Tomassen², Rik Ossenkoppele^2,
3, Sandeep S.V. Golla¹, Marijke E. den Hollander¹, Lyduine E. Collij¹, Emma Weltings¹, Sophie van der Landen², Emma E. Wolters¹, Albert D. Windhorst¹, Frederik Barkhof^{1, 4}, Eco J.C. de Geus5, Philip Scheltens², Pieter Jelle Visser^{2, 6}, Bart N.M. van Berckel¹ and Anouk den Braber^{2, 5}

¹Vrije Universiteit Amsterdam, Amsterdam UMC, Department of Radiology & Nuclear Medicine, Amsterdam Neuroscience, Amsterdam, Netherlands

²Vrije Universiteit Amsterdam, Amsterdam UMC, Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Amsterdam, Netherlands

³Lund University, Clinical Memory Research Unit, Lund, Sweden

⁴UCL, Institute of Neurology, London, UK

⁵Vrije Universiteit Amsterdam, Department of Biological Psychology, Amsterdam, Netherlands

⁶Maastricht University, Alzheimer Center Limburg, School for Mental Health and Neuroscience, Maastricht, Netherlands

⁷Karolinska Institutet, Department of Neurobiology, Care Sciences and Society, Division of Neurogeriatrics, Stockholm, Sweden

Abstract

Introduction: Tau accumulation starts during the preclinical phase of Alzheimer’s disease and is closely associated with cognitive decline. For preventive purposes, it is important to identify factors associated with tau accumulation and spread. Studying genetically identical twin-pairs may give insight into genetic and environmental contributions to tau pathology, as similarities in identical twin-pairs largely result from genetic factors, while differences can be attributed to non-shared, environmental factors. This study aimed to examine genetic and environmental contributions to 1) tau load and 2) spatial distribution of tau in a sample of cognitively unimpaired genetically identical twins.

Methods: We included 78 twins (39 pairs), aged 73.4 ± 5.9 years (51.3% female), who underwent dynamic [18F]flortaucipir-PET. We extracted binding potentials (BPND) in entorhinal (Braak-I), temporal (Braak-III-IV), neocortical (Braak-V-VI) and global (Braak-I-VI) regions, and examined within-pair similarities in BPND using intra-class correlations (Figure 1(a)). Furthermore, we correlated each participant’s voxel-by-voxel [18F]flortaucipir spatial distribution to that of every other participant using Spearman correlation models and tested, using an independent t-test, whether the average correlation coefficient obtained for twin-pairs was significantly higher (i.e. more similar spatial distribution) than for non-twin pairings of participants (Figure 2(a)). Last, we explored whether environmental (e.g. physical activity, obesity) risk factors could explain observed within-pair differences in [18F]flortaucipir-BPND.

Results: [18F]flortaucipir-BPND was correlated within twin-pairs in entorhinal (r = 0.40; p = 0.01), neocortical (r = 0.59; p < 0.01) and global (r = 0.56; p < 0.01) regions, but not in the temporal region (r = 0.20; p = 0.10) (Figure 1(b)). The [18F]flortaucipir distribution pattern was significantly more similar between twins of a pair (mean r = 0.27; SD = 0.09) than between non-twin pairings of participants (r = 0.01; SD = 0.10) (p < 0.01) (Figure 2(b)). Finally, within-pair differences in [18F]flortaucipir-BPND were associated with within-pair differences in depressive symptoms (0.37 < β < 0.56), physical activity (-0.41 < β < −0.42) and social activity (-0.32 < β < −0.36) (all p < 0.05).

Conclusion: Overall, identical twin-pairs were comparable in tau load and spatial distribution, highlighting the important role of genetic factors in the accumulation and spreading of tau pathology. Considering also the presence of dissimilarities in tau pathology in identical twin-pairs, our results additionally support a role for (potentially modifiable) environmental factors in the onset of Alzheimer’s disease pathological processes, which may be of interest for future prevention strategies.

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2021-103

Assessing neurobiological correlates of [¹¹C]WAY-100635 two-tissue compartment model parameters using SiMBA (#335)

Granville J. Matheson^{1, 2} and R. Todd Ogden^{1, 2}

¹Columbia University, Molecular Imaging and Neuropathology Division, New York New York, USA

²Columbia University, Department of Biostatistics, New York New York, USA

Abstract

Introduction: We have introduced a new method called SiMBA, which exploits similarities between both individuals and regions within individuals while applying the traditional two-tissue compartment (2TC) model in order to improve the identifiability and estimation of model parameters. Another important advantage of this approach is that estimation of model parameters is performed at the levels of individuals, regions, and individual TACs, allowing us to study the influence of different levels in isolation.

Methods: We applied SiMBA to a sample of 97 individuals measured using [¹¹C]WAY100635 using ten regions, and extracted regional estimates of measurement error, as well as blood volume fraction (v_B) and non-displaceable distribution volume (V_ND) from the 2TC. We assessed correlations between these estimated parameters and regional neurobiological attributes derived from average region size, as well as using the defined regions in MNI space to assess mean regional vascular partial volume from the VENAT atlas of vascular neuroanatomy¹ and myelin concentrations from the MWF atlas.²

Results: Firstly, it is widely known that smaller regions have greater measurement error, and that the magnitude of this relationship is useful for regional weighting. We observe a strong linear association between the natural logarithms of region size and estimated measurement error (β = −0.23, r = −0.96, p < 0.001), estimating that for every doubling of region size, the measurement error decreases by 15%. Next, we show a significant positive correlation between mean VENAT (1) regional vasculature partial volume and 2TC estimates of v_B (r = 0.70, p = 0.026). Lastly, examining 2TC estimates of V_ND, we observe a two-fold variance across regions (σ = 23%, 95% CI: 16–34%), with highest values in the parahippocampus (150% of the mean), and the lowest values in the cerebellum (72%). We show a significant positive correlation between MWF (2) regional myelin concentrations and V_ND estimates (r = 0.85, p = 0.008).

Conclusion: The current investigation not only sheds light on the neurobiological interpretation of the parameters of the 2TC in [¹¹C]WAY100635, but also serves to validate the performance and estimates of SiMBA using external sources.

Acknowledgements

The work reported here has been partially supported by US NIH grants 5 P50 MH090964 and 5 R01 EB024526, and by the Hjärnfonden Postdoctoral Fellowship.

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2021-104

[¹⁸F]FLUDA – A novel radiotracer for PET imaging of the adenosine A_2A receptor (A_2AR) (#337)

Thu Hang Lai^{1, 2}, Magali Toussaint¹, Rodrigo Teodoro¹, Daniel Gündel¹, Friedrich-Alexander Ludwig¹, Sladjana Dukić-Stefanović¹, Barbara Wenzel¹, Susann Schröder², Bernhard Sattler³, Rareş-Petru Moldovan¹, Osama Sabri³, Winnie Deuther-Conrad¹ and Peter Brust¹

¹Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Department of Neuroradiopharmaceuticals, Leipzig Saxony, Germany

²ROTOP Pharmaka GmbH, Department of Research and Development, Dresden Saxony, Germany

³University Hospital Leipzig, Department of Nuclear Medicine, Leipzig Saxony, Germany

Abstract

Introduction: Selective A_2AR antagonists have emerged as potential therapeutics for multiple diseases. With regard to Parkinson’s disease, adjunctive treatment of A_2AR antagonists potentially reduces adverse effects of long-term L-DOPA treatment. Therefore, imaging of receptor availability during the A_2AR-tailored therapy is of utmost importance. We recently developed [¹⁸F]FLUDA as an novel A_2AR-specific PET radiotracer.¹

Methods: [¹⁸F]FLUDA was synthesized by an automated procedure Biological evaluation was performed in healthy mice and piglets. In vitro autoradiography was performed with brain cryosections. In vivo metabolism was analysed by radio-HPLC of plasma and brain homogenate. Pharamcokinetics and biodistribution was assessed by dynamic PET imaging under control and blocking conditions (2.5 mg/kg tozadenant and/or 1.0 mg/kg istradefylline). SUV ratio (SUVr) of striatum-over-cerebellum was used as a metric for specific uptake. A single dose acute toxicity study was performed in Wistar rats according to the ICH guideline M3(R2). Radiation dosimetry was investigated in piglets.

Results: In vitro autoradiography revealed an A_2AR affinity (K_D) of 4.3 and 0.7 nM and an A_2AR density (B_max) of 556 and 218 fmol/mg in the striatum of mice and piglets. No radiometabolites were detected in the mouse brain at 15 min p.i., whereas radiometabolites were found in piglet plasma but are assumed to not cross the blood-brain barrier. PET demonstrated high specific binding of [¹⁸F]FLUDA in both species (Figure 1). Toxicity studies revealed no adverse effects up to a dose of 30 µg/kg (∼4000-fold of expected human dose). The ED to humans is 16.4 µSv/MBq, which is in the range of other ¹⁸F-labeled radiotracers.²

Conclusion: We have demonstrated that [¹⁸F]FLUDA is suitable for determination of the A_2AR availability in the striatum. No safety concerns are expected upon administration of [¹⁸F]FLUDA according to toxicity and dosimetry data. These results encourage the clinical translation of [¹⁸F]FLUDA.

Acknowledgements

This work (Project No. 100226753) has been funded by the European Regional Development Fund (ERDF) and Sächsische Aufbaubank (SAB).

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References

1.Lai TH, Toussaint M, Teodoro R, et al. Improved in vivo PET imaging of the adenosine A_2A receptor in the brain using [¹⁸F]FLUDA, a deuterated radiotracer with high metabolic stability. Eur J Nucl Med Mol Imaging 2021; 48: 2727–2736. [DOI] [PMC free article] [PubMed] [Google Scholar]
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2021-105

Development of a non-invasive PET/MRI method for quantifying cerebral glucose kinetics (#338)

Lucas Narciso^{1, 2}, Alaa Taha¹, Praveen Dassanayake^1,
2, Tommaso Volpi^{3, 4}, Linshan Liu¹, Andrea Soddu⁵, Udunna Anazodo^{1, 2}, Alessandra Bertoldo^{3, 6} and Keith St Lawrence^{1, 2}

¹Lawson Health Research Institute, London, ON, Canada

²Western University, Department of Medical Biophysics, London, ON, Canada

³University of Padua, Padova Neuroscience Centre, Padua, Italy

⁴University of Padua, Department of Neuroscience, Padua, Italy

⁵Western University, Department of Physics, London, ON, Canada

⁶University of Padua, Department of Information Engineering, Padua, Italy

Abstract

Introduction: Quantifying the kinetics of glucose metabolism by dynamic [¹⁸F]FDG PET is not commonly performed because of invasive nature of measuring the arterial input function (AIF).¹ Extracting an image-derived input function (IDIF) by vessel segmentation is one alternative but is sensitive to partial volume errors (PVEs).¹ We present a simultaneous estimation (SIME) approach that avoids PVEs by deriving the AIF from multiple brain time-activity curves (TACs). Unlike previous SIME methods that model the IDIF as a series of exponentials,² our method derives the IDIF from the two-compartment FDG model, which reduces the number of fitting parameters, and incorporates late timepoints from the superior sagittal sinus (SSS) TAC to constrain the optimization. The IDIF was combined with a Variational Bayesian (VB) method to generate images of the microparameters.³

Methods: Sixty min of dynamic [¹⁸F]FDG data were acquired from 10 healthy individuals on a Siemens Biograph mMR system. PET images were reconstructed using OSEM. Each IDIF was extracted from the whole-brain TAC by applying SIME to 10 TACs obtained by k-means clustering (500 iterations, 10 replicates; same clusters used for VB). SSS activity was obtained by MRI vessel segmentation,⁴ and one venous blood sample was collected at 60 min for comparison. Only SSS timepoints ≥ 45 min were used to ensure arterial-to-venous [¹⁸F]FDG equilibrium.⁵ Parametric maps of FDG microparameters were obtained from VB analysis using a lumped constant of 0.65 to calculate the cerebral metabolic rate of glucose (CMRGlu).

Results: No significant difference was found between venous blood and SSS activity (3.82 ± 0.57 vs 4.09 ± 1.02 kBq/ml). IDIFs were successfully extracted for all subjects. Figure 1 includes average microparameter values obtained by SIME. Figure 2 presents parametric maps of the rate constants and CMRGlu.

Conclusion: In this preliminary analysis, microparameter estimates from SIME were in good agreement with literature values,¹ and parametric maps were successfully generated with the VB approach. However, discrepancies were found between the SIME and VB estimates, indicating further work is required regarding optimal priors and clustering for VB analysis, as well as possible influence of noise in the IDIFs.

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References

1.Zanotti-Fregonara P, Chen K, Liow JS, et al. Image-derived input function for brain PET studies: many challenges and few opportunities. J Cereb Blood Flow Metab 2011; 31: 1986–1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
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2021-106

Positron emission tomography with [¹⁸F]ROStrace reveals increased oxidative stress in a mouse model of alpha synuclein aggregation (#339)

Evan Gallagher¹, Yi Zhu², Meagan McManus², Kelvin C. Luk³ and Robert H. Mach⁴

¹University of Pennsylvania, Neuroscience Graduate Group, Philadelphia Pennsylvania, USA

²Children’s Hospital of Philadelphia, Center for Mitochondrial and Epigenomic Medicine, Philadelphia Pennsylvania, USA

³Perelman School of Medicine, Department of Pathology and Laboratory Medicine, Philadelphia Pennsylvania, USA

⁴Perelman School of Medicine, Department of Radiology, Philadelphia Pennsylvania, USA

Abstract

Introduction: Parkinson’s disease (PD) is a debilitating neurodegenerative disorder characterized in part by the progressive accumulation of insoluble intraneuronal inclusions called Lewy Bodies (LBs). LBs are largely composed of oxidatively modified alpha-synuclein (aSyn), and oxidative stress is thought to be both a mediator and a consequence of aSyn aggregation in PD. Here, we aim to determine whether the recently developed positron emission tomography (PET) radioligand [¹⁸F]ROStrace¹ is capable of detecting increases in oxidative stress in vivo in a well-characterized mouse model of aSyn aggregation.

Methods: 3 month-old transgenic mice overexpressing the A53T mutant form of human aSyn (’A53T mice’)² were stereotactically injected with preformed aSyn fibrils (PFFs) in the right dorsal striatum to induce aSyn aggregation³. Groups of PFF-injected mice were then scanned with ROStrace at 1, 2, or 3 months post-injection (MPI) alongside age- and sex-matched saline-injected controls. Following the PET scans, the mice were euthanized, and the brains were extracted and histologically examined for aSyn aggregates and other markers of oxidative damage.

Results: PFF-injected animals showed significantly higher whole-brain average ROStrace signal at 2MPI compared to saline-injected animals (Figure 1). This increase in signal at 2MPI was accompanied by widespread formation of pathological aSyn aggregates in PFF-injected but not saline-injected mice (Figure 2). In PFF-injected mice, the aSyn aggregates were predominantly found in neurons, including dopaminergic neurons in the substantia nigra (white arrows in Figure 2).

Conclusion: In this study, we show that PFF-injected A53T mice display increased oxidative stress in brain compared to saline-injected mice, as measured by the recently developed PET probe [¹⁸F]ROStrace. These results support the idea that oxidative stress is associated with disease progression in PD and suggest that ROStrace could develop into a valuable tool for studying redox biology and antioxidant drug efficacy in vivo.

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References

1.Chu W, Chepetan A, Zhou D, et al. Development of a PET radiotracer for non-invasive imaging of the reactive oxygen species, superoxide, in vivo. Org Biomol Chem 2014; 12: 4421–4431. [DOI] [PMC free article] [PubMed] [Google Scholar]
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2021-107

Visual memory test equal to commonly used verbal memory test in predicting Tau in the medial temporal lobe (#340)

Nina M. Poltronetti^{1, 2}, Jaime Fernandez Arias^{7, 2}, Vanessa Pallen^{1, 2}, Nesrine Rahmouni^{7, 2}, Jenna Stevenson^{7, 2}, Joseph Therriault^{7, 2}, Sulantha Mathotaarachchi², Yi-Ting Wang^{7, 2}, Andréa L. Benedet^{4, 2}, Cécile Tissot^{7, 2}, Tharick A. Pascoal^{5, 2}, Firoza Z. Lussier^{3, 7}, Gleb Bezgin³, Serge Gauthier^{7, 2} and Pedro Rosa-Neto^7,
3

¹McGill University, Neuropsychology, Montreal, QC, Canada

²Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, Montreal, QC, Canada

³Translational Neuroimaging Laboratory, Montreal, QC, Canada

⁴University of Gothenburg, Gothenburg, Sweden

⁵University of Pittsburgh, Pittsburgh Pennsylvania, USA

⁶Douglas Mental Health University Institute, Montreal, QC, Canada

⁷McGill University, Neuroscience, Montreal, QC, Canada

Abstract

Introduction: The Aggie Figures Learning Test (AFLT) is a visual memory assessment tool, constructed as an analog to the Rey Auditory Verbal Learning Test (RAVLT). The AFLT includes three sequences of abstract drawings as stimuli –a primary set which is repeated across five trials, an interference set, and a recognition set. After about twenty minutes, the test assesses free delayed recall (DR) and delayed recognition of the learned material. This test is very similar to the RAVLT in terms of administration; therefore, the present study will evaluate whether the predictive value of DR scores from both tests is comparable in relation to Tau PET.

Methods: Tau PET ([18F]-MK6240) was acquired for 130 individuals for analysis involving only AFLT, 139 for analysis involving only RAVLT, and 127 individuals for analysis including both AFLT and RAVLT. Demographic data is shown on Tables 1, 2, and 3. MRI were segmented into probabilistic grey (GM) and white (WM) maps, non-linearly registered to the ADNI template using Dartel and smoothed with an 8 mm FWHM gaussian kernel. Voxel-wise linear regression models were applied, using VoxelStats, with Tau PET as the dependent variable and either DR AFLT or DR RAVLT as predictors. We ran three analyses where one included both DR scores. Additionally, we corrected for age, sex, diagnosis, APOE, and amyloid load. All other variables that were tested did not significantly contribute to predict Tau PET.

Results: We found negative associations between tau binding in the medial temporal lobe and both DR scores when looking at each of them separately. More importantly, we found that DR AFLT scores lose their predictive value when including DR RAVLT in the same model.

Conclusion: Our results support the use of both tests interchangeably when testing memory in elderly populations, even though they tap into two different modalities. This piece of evidence confirms what was reported by the authors who published the original AFLT article. Nonetheless, that article dealt with a sample whose demographics and clinical presentation strongly differed from those of our sample. Inline graphic

Figure 1. MK delayed recall on RAVLT & AFLT.

MK ∼ DR_AFLT + DR_RAVLT + amyloid + age + sex + apoe + diagnosis

MK ∼ DR_RAVLT + DR_AFLT + amyloid + age + sex + apoe + diagnosis

Figure 2. MK delayed recall on AFLT & RAVLT.

MK ∼ DR_AFLT + amyloid + age + sex + apoe + diagnosis

MK ∼ DR_RAVLT + amyloid + age + sex + apoe + diagnosis

References

1.Sziklas V, Jones-Gotman M. RAVLT and nonverbal analog: French forms and clinical findings. Can J Neurol Sci/J Can Des Sci Neurolog 2008; 35: 323–330. [DOI] [PubMed] [Google Scholar]
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2021-108

3D reconstruction of 20 neurotransmitter receptor atlases from 2D autoradiographs (#341)

Thomas Funck¹, Konrad Wagstyl², Claude Lepage³, Paule-Joanne Toussaint³, Mona Omidyeganeh³, Karl Zilles¹, Alexander Thiel⁴, Alan C. Evans³ and Nicola Palomero-Gallagher^{1, 5}

¹Forschungszentrum Jülich, INM-1, Julich North Rhine-Westphalia, Germany

²University College London, Wellcome Center for Human Neuroimaging, London, UK

³McGill University, Montreal Neurological Institute, Montreal, QC, Canada

⁴McGill University, Lady Davis Institute, Jewish General Hospital, Montreal, QC, Canada

⁵Heinrich-Heine-University, C. & O. Vogt Institute for Brain Research, Dusselforf, Germany

Abstract

Introduction: Quantitative atlases of neurotransmitter receptor densities in healthy and pathologic human brains are important for characterizing normal and pathologic brain function and behaviour. We present a 3D reconstruction pipeline for 2D autoradiographs¹ that will allow for the creation of the first ever set of ultra-high resolution (50µm) 3D atlases for 20 different neurotransmitter binding sites in the human brain. This pipeline was designed to overcome significant challenges in the data, including: non-linear deformations in the brain tissue, intensity variations between autoradiographs, variability in autoradiograph acquisitions, a large number of slices lost in sectioning, and non-orthogonal brain sections.

Methods: The reconstruction pipeline (Figure 1) is composed of 4 major processing stages: 1) automated cropping of the autoradiographs, 2) inter-autoradiograph 2D alignment, 3) iterative multi-resolution 3D volumetric followed by 2D section-wise alignment of autoradiographs to the donor’s MRI, 4) surface-based interpolation of receptor densities.^2–5 Two methods have been implemented to validate the quantitative accuracy of the reconstructed ligand values. Pixel intensities of sections in the reconstructed ligand volumes were compared to the raw autoradiographs. his is done to verify that the pipeline preserves the ligand binding densities. The second validation technique applies the surface-based interpolation algorithm within acquired autoradiographs.

Results: The reconstruction pipeline was successful in aligning the 2D sections to the donor’s MRI (Figure 2(a)). Some sections appear to extend over the cortical surfaces, indicating that some sections may be suboptimally aligned. The 3D cortical maps of receptor density are seen in Figure 2(b). Initial results indicate ∼90% accuracy for a flumazenil binding density volume at 0.6 mm resolution.

Conclusion: The methods presented here provide all the necessary processing steps to reconstruct a dataset of multiple neurotransmitter receptor atlases at 50µm for a full human brain. Moreover, as both hemispheres of 3 donor brains were acquired in Ref.¹, we will therefore reconstruct 20 neurotransmitter binding site atlases for each of the 3 human brains. This will provide a novel and unparalleled set of atlases for the neuroscience research community that will help better elucidate the functional anatomy of the human brain.

Inline graphic

References

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2021-109

Neuroimaging of M4 muscarinic acetylcholine receptors using [¹¹C]MK-6884 in rhesus macaques (#342)

Vasily Belov¹, Nicolas J. Guehl¹, Sridhar Duvvuri², Philip Iredale², Sung-Hyun Moon¹, Maeva Dhaynaut¹, Peter A. Rice¹, Daniel L. Yokell¹, John Renger², Georges El Fakhri¹ and Marc D. Normandin¹

¹Massachusetts General Hospital, Harvard Medical School, Gordon Center for Medical Imaging, Boston Massachusetts, USA

²Cerevel Therapeutics, LLC, Boston Massachusetts, USA

Abstract

Introduction: Quantitative imaging of M4 muscarinic acetylcholine receptors (mAChR) is important due to implications of mAChR in both neurodegenerative and psychiatric disorders.^1-3 Recently, a novel ¹¹C-radiolabeled PET ligand ([¹¹C]MK-6884), selectively binding to M4 mAChR as a positive allosteric modulator (PAM), was developed.⁴ Further detailed characterization of PET imaging and quantitative performance is required. The current study pursued this aim using a M4 PAM drug candidate (CVL-231) as a blocking agent.

Methods: Two rhesus macaques underwent six paired baseline-blocking 90-min PET scans. [¹¹C]MK-6884 was synthesized with high molar activity (187.2 ± 68.7 GBq/µmol) and radiochemical purity (100%). CVL-231 i.v. administration started 10 min prior the blocking scan and lasted until the end of scan. Arterial blood samples were serially collected for radiometabolites and radioactivity concentration analysis. Both blood-based (1T2k, 2T4k, Logan plot, MA1) and reference region-based (SRTM, MRTM2 and Logan DVR) modelling methods were applied to calculate distribution volume (V_T) and binding potential (BP_ND) in various cerebral regions (caudate nucleus, cerebellar grey matter, entire cortex, hippocampus, putamen, central white matter).⁵

Results: Blood data indicated the tracer’s fast bi-exponential plasma clearance (t_1/2,fast = 2.3 ± 0.5 min and t_1/2,slow = 66.7 ± 13.7 min), moderate metabolic stability (44.9 ± 7.6% parent in plasma at 30 min), and moderate binding to plasma proteins (plasma free fraction = 34 ± 10%). Estimates of regional V_T by different blood-based methods were highly correlated (R² > 0.95) and estimates of BP_ND by reference region methods were in strong agreement (R² = 1.00). Only caudate nucleus and putamen displayed statistically significant and reproducible tracer uptake (striatum V_T = 3.2 ± 0.5 ml/cc, BP_ND = 0.7 ± 0.3) and dose-dependent blockade by CVL-231. Truncation of the time interval to 60 min improved data stability and fitting robustness of all kinetic models. The data supported the use of the cerebellar grey matter as a reference region. Receptor occupancy determined by changes in BP_ND estimated by SRTM was in good agreement with Lassen plot for different blood-based methods (R²∼0.8), with dependence on the CVL-231 injected dose and plasma concentration described by a classical Hill dose-response function (ID₅₀ = 1.1 ± 0.1 mg/kg and IC₅₀ = 581.4 ± 54.9 ng/ml).

Conclusion: Kinetic modeling of [¹¹C]MK-6884 data using arterial and reference region methods can quantify M4 mAChR availability in the brain. Receptor occupancy estimates demonstrate dose-dependent blockade by the structurally distinct PAM CVL-231.

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References

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2021-110

Population-based input function for [¹¹C]PBR28 quantification in non-human primates (#343)

Lucero G. Aceves-Serrano¹, Vesna Sossi² and Doris J. Doudet¹

¹University of British Columbia, Department of Medicine/Neurology, Vancouver British Columbia, Canada

²University of British Columbia, Department of Physics and Astronomy, Vancouverr British Columbia, Canada

Abstract

Introduction: A significant caveat of [¹¹C]PBR28 studies is the need to compute an arterial input function (AIF) needing arterial cannulation for data quantification. Canulation makes scanning burdensome on the staff, uncomfortable for subjects, and very challenging in a clinical setting. Population-based input function (PBIF) can, in theory, be used to eliminate the need for arterial canulation. In this work, we evaluated the validity of different PBIF functions.

Methods: A total of 11 [¹¹C]PBR28 scans were acquired from 7 non-human primates. We acquired arterial blood samples from 10 scans and venous blood samples from one scan. Two venous blood curves from a different [¹¹C]PBR28 study were used for comparison between arterial and venous samples. AIFs were averaged to create a population template input function (TIF). PBIFs were created by scaling the TIF with injected activity per body weight (PBIF) or unmetabolized tracer activity in blood at 15-,30- and 60-minutes post-injection (PBIF15, PBIF30, PBIF60). Another population-derived function was created using total activity in plasma (in anticipation of an image-derived input function) and a template parent fraction curve scaled using metabolism at t = 30 (TPF30-IF). Total distribution volumes (V_T) estimates were calculated using PBIF, PBIF30, PBIF15, PBIF60, TPF30-IF, and the individual AIF (V_T^AIF).

Results: V_T-s computed using PBIF15 and PBIF30 showed the best correlation with V_T^AIF (r > 0.90), while V_T derived from PBIF60 and TPF30-IF yield lower correlation (r = 0.76 and r = 0.69). The blood-free scaled PBIF showed the worst correlation (r = 0.46). Venous and arterial metabolite fractions showed comparable values (Figure 1).

Conclusion: Population-based input functions scaled with a single blood sample might be a useful alternative to using AIF to compute [¹¹C]PBR28 binding in healthy NHPs. These results are in line with previous human work,^{1, 2} where authors demonstrated that a PBIF scaled using a blood sample (at 27min post-injection) outperformed the PBIF scaled using activity dose/weight.¹ Taken together this suggests, single blood samples could be used instead of multiple sampling, reducing the invasiveness of [¹¹C]PBR28 scanning. Single samples could be acquired using an arterial stick, which is significantly less invasive and technically demanding than arterial cannulation.

Acknowledgements

We thank the UBC/TRIUMF PET program staff for their contribution to this work: this study would not have been possible without Carolyn English and Siobhan McCormick’s assistance for the metabolite analyses radiochemistry laboratories at TRIUMF. Special thanks are due to Julian Kaye and the UBC Animal Care Facilities personnel for their animals’ outstanding care. Inline graphic

References

1.Buchert R, et al. Reliable quantification of 18F-GE-180 PET neuroinflammation studies using an individually scaled population-based input function or late tissue-to-blood ratio. Eur J Nucl Med Mol Imaging 2020; 47: 2887–2900. [DOI] [PMC free article] [PubMed] [Google Scholar]
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2021-111

[¹¹C]MC1 has adequate sensitivity to measure low density cyclooxygenase 2 (COX-2) in healthy human brain (#344)

Xuefeng Yan, Andrea Zhang, Sami S. Zoghbi, Jeih-San Liow, Cheryl Morse, Min-Jeong Kim, Maria Ferraris Araneta, Jose A. Montero Santamaria, Lester Manly, Madeline Jenkins, Maia Van Buskirk, Bruny Kenou, Sara Rubovits, William Miller, Victor W. Pike, Paolo Zanotti-Fregonara and Robert B. Innis

National Institutes of Health, Molecular Imaging Branch/National Institute of Mental Health, Bethesda Maryland, USA

Abstract

Introduction: Cyclooxygenase enzymes (COXs) are important targets for neuroinflammation. [¹¹C]MC1, a selective and high-affinity radioligand for COX-2, can detect elevated COX-2 in nonhuman primates after intracerebral lipopolysaccharide (LPS) injection and in patients with rheumatoid arthritis at the symptomatic joints¹. This study investigated whether COX-2 can be measured by [¹¹C]MC1 in healthy human brain.

Methods: Ten healthy participants were injected with [¹¹C]MC1 (730 ± 48 MBq). Each participant received two 120-minute brain PET scans, two hours apart—a baseline scan in the morning followed by a blockade scan with celecoxib (600 mg p.o.), a preferential COX-2 inhibitor. Both scans were performed with concurrent arterial sampling. Enzyme binding was calculated as total distribution volume corrected for free parent fraction in plasma (V_T/f_p) using a two-tissue compartment model (2TCM). Receptor occupancy was determined via Lassen plot.

Results: After [¹¹C]MC1 injection, the concentration of brain radioactivity peaked at 4.0 SUV at ∼2.8 minutes and declined to 16% of the peak at 120 minutes. The brain time-activity curve was reasonably well-fitted by a 2TCM. V_Ts were stable after 40 minutes. However, the measured V_T values after 60 minutes were higher than the fitted values, possibly reflecting accumulation of a small amount of radiometabolites in brain. Nine participants showed specific uptake (V_S), which was only ∼20% of total uptake. Based on the Lassen plot, celecoxib occupied 72% of available COX-2 in the brain. The occipital cortex, insula, and prefrontal cortex had the highest V_S. The distribution of V_S correlated well with regional mRNA transcripts of the COX-2 gene.

Conclusion: [¹¹C]MC1 uptake in healthy human brain reflected specific binding to COX-2 based on blockade by celecoxib and on the correlation between regional V_S values and the gene transcript. Together, the results demonstrate that [¹¹C]MC1 has adequate sensitivity to measure the low density of constitutively expressed COX-2 in healthy participants.

Acknowledgements

Intramural Research Program at the National Institute of Mental Health

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2021-112

Combining plasma p-Tau181 and p-Tau231 enhances Alzheimer’s disease in vivo classification (#346)

Pâmela C. Lukasewicz Ferreira¹, Wagner S. Brum², João Pedro Ferrari-Souza^{1, 2}, Cécile Tissot³, Bruna Bellaver^{1, 2}, Joseph Therriault³, Nicholas J. Ashton⁴, Andréa L. Benedet^3,
5, Stijn Servaes³, Firoza Z. Lussier³, Mira Chamoun³, Jenna Stevenson³, Nesrine Rahmouni³, Serge Gauthier³, Eugeen Vanmechelen³, Henrik Zetterberg⁴, Kaj Blennow⁶, Eduardo R. Zimmer², Thomas Karikari^{1, 5}, Pedro Rosa-Neto³ and Tharick A. Pascoal¹

¹University of Pittsburgh, Department of Psychiatry, Pittsburgh Pennsylvania, USA

²Universidade Federal do Rio Grande do Sul (UFRGS), Graduate Program in Biological Sciences: Biochemistry, Porto Alegre, Brazil

³McGill University, Montreal, QC, Canada

⁴University of Gothenburg, Wallenberg Centre for Molecular and Translational Medicine, Gothenburg, Sweden

⁵University of Gothenburg, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, Gothenburg, Sweden

⁶Sahlgrenska University Hospital, 11 Clinical Neurochemistry Laboratory, Mölndal, Sweden

Abstract

Introduction: Pathophysiological detection of Alzheimer’s disease (AD) is commonly made using cerebrospinal fluid (CSF) and positron emission tomography (PET). However, these methods are invasive and expensive, limiting their use in clinical settings. Blood-based biomarkers, mainly measuring phosphorylated tau (p-Tau) epitopes, have shown promising results to detect AD in a scalable way. However, it is still unknown whether the use of different plasma p-Tau epitopes offers overlap or complementary information. Here, we tested the hypothesis that plasma p-Tau181 and p-Tau231 markers provide complementary information to each other to identify AD pathophysiology.

Methods: Plasma p-Tau181, p-Tau231, [¹⁸F]AZD4694 amyloid-PET, [¹⁸F]MK6240 tau-PET, Magnetic resonance imaging (MRI) and cognitive assessment from 284 individuals [30 CU young adults, 155 CU, 54 MCI and 38 AD] were obtained from the McGill TRIAD cohort. The individuals with AD or MCI clinical diagnosis were classified as CI. Cut-points (p-tau181, 11.1 ng/mL; p-tau231, 11.8 ng/mL) were derived using young CU controls as reference. Individuals were group based on these two biomarkers. Then, imaging and cognition measurements were compared across groups.

Results: Plasma p-Tau231 and p-Tau p-Tau181 showed moderate correlation with each other (r = 0.64, p < 0.0001) (Figure 1). The p-Tau231+/p-Tau181+ group presented higher tau PET and amyloid PET uptake compared to groups negative for both or only one p-tau biomarker (all p < 0.01) (Figure 2(a) and (b)). Similarly, p-Tau231+/p-Tau181+ group showed worse cognitive performance and hippocampal atrophy than individuals with at least one p-tau biomarker negative (Figure 2(c) and (d)).

Conclusion: Individuals positive for both p-Tau231 and p-Tau181 showed worse cognitive performance, lower hippocampal volume, higher amyloid and tau burden than individuals with only one abnormal marker. Our findings show that both p-Tau epitopes are promising biomarkers and seem to provide complementary information and could be used to enhancing AD in vivo detection, with potential applications to trial screening and recruitment.

Acknowledgements

The authors thank all participants of the study and staff of the McGill Center for studies in Aging.

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2021-113

Disrupted association between Mu-opioid receptor levels and resting state activity in patients with schizophrenia: Multimodal imaging study with [¹¹C]-carfentanil PET and resting state fMRI (#347)

Ekaterina Shatalina¹, Abhishekh H. Ashok^{3, 4}, Matthew Wall^{5, 6}, Jim Myers⁶, Tiago Reis Marques^{2, 1}, Eugenii A. Rabiner^{5, 2} and Oliver D. Howes^{1, 2}

¹Imperial College London, MRC London Institute of Medical Sciences, London, UK

²Kings College London, Institute of Psychiatry, Psychology and Neuroscience, London, UK

³Addenbrooke’s Hospital, Cambridge University Hospital NHS Foundation Trust, Department of Radiology, Cambridge, UK

⁴University of Cambridge, Department of Radiology, Cambridge, UK

⁵Invicro LLC, London, UK

⁶Imperial College London, Faculty of Medicine, London, UK

⁷Kings College London, Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, London, UK

Abstract

Introduction: Mu opioid receptors (MOR) are involved in hedonic processing and their levels have been shown to be reduced in patients with schizophrenia, who have deficits in hedonic processing and aberrant hedonic network activity at rest. Particularly, preclinical studies have shown that activation of MOR system in amygdala can improve aversive or defensive behavioural states induced by stress or social rejection. However, precise role of MOR levels in amygdala and its association with resting neuronal activity in unknown. We set out to test whether MOR density may mediate spontaneous neural activity of the hedonic network at rest measuring by resting state functional MRI (fMRI) in patients with schizophrenia and in healthy controls.

Methods: 19 healthy controls and 18 patients with a DSM-5 confirmed diagnosis of schizophrenia underwent a [¹¹C]-carfentanil PET scan to measure MOR availability and an 8-minute resting state fMRI scan. Dynamic PET data were corrected for attenuation, scatter, and motion, and were rigid body coregistered to the structural MRI with a neuroanatomical atlas applied to the PET image by non-linear deformation parameters. [¹¹C]-carfentanil binding potential (BPND) values were quantified using the simplified reference tissue model (SRTM) with occipital lobe grey matter as the reference. FMRI data were pre-processed using standard methods followed by amplitude of low frequency fluctuations (ALFF) analyses. ALFF Z-values for regions comprising the hedonic network (striatum, amygdala, insular cortex, anterior cingulate cortex, orbitofrontal cortex) were compared between groups and correlated with [¹¹C]-carfentanil BP_ND for corresponding regions.

Results: Both [¹¹C]-carfentanil BP_ND and ALFF Z-values were comparable between patients and controls across all 5 regions (p > 0.01, adjusted for multiple comparisons). In the amygdala [¹¹C]-carfentanil BP_ND was significantly negatively associated with ALFF in healthy controls (r = −0.623, p = 0.004), but not in patients (r = –0.032, p = 0.899). No other associations were seen in any other region in either group

Conclusion: Our results show that MOR density in the amygdala is negatively associated with spontaneous neural activity in this region at rest. Given the inhibitory role of MOR, our results may indicate that reduced spontaneous firing of the amygdala may be associated with increased MOR-mediated inhibition. In patients with schizophrenia, this mechanism may be disrupted by disease pathophysiology.

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2021-114

Individual-level molecular connectivity of GABA_A receptors: assessing the similarity of [¹¹C]Ro15-4513 kinetics across brain regions (#348)

Tommaso Volpi^{1, 2}, Erica Silvestri^{1, 3}, Alexander Hammers⁴ and Alessandra Bertoldo^{1, 3}

¹University of Padova, Padova Neuroscience Center, Padova, Italy

²University of Padova, Department of Neuroscience, Padova, Italy

³University of Padova, Department of Information Engineering, Padova, Italy

⁴King’s College London & Guy’s and St Thomas’ PET Centre, School of Biomedical Engineering & Imaging Sciences, London, UK

Abstract

Introduction: Molecular connectivity (MC) is an emerging topic in neuroscience. Neurotransmitter MC is conventionally assessed as the across-subject correlation of positron emission tomography (PET) measurements, which leads to a population-level estimate^1,2. Single-subject connectivity networks can also be calculated as the similarity between PET time-activity curves (TACs), but this has only been done for [¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG) so far³. Here, we extract single-subject MC networks from [¹¹C]Ro15-4513, a PET ligand with high affinity for the α₅ subunit of the GABA_A receptor.

Methods: 4 healthy males (41.5 ± 4.4 years), who were scanned on two separate days, underwent 90-min [¹¹C]Ro15-4513 dynamic PET acquisitions (Siemens ECAT EXACT HR+, reconstruction grid: 4 × 15 s, 4 × 60 s, 2 × 150 s, 10 × 300 s, 3 × 600 s)⁴. PET data were parcellated using the grey matter-masked Hammers atlas (60 regions)⁵. The region-wise TACs were interpolated and standardized by: 1) z-scoring across regions and demeaning across time, 2) demeaning across regions and z-scoring across time, 3) dividing by mean TAC across regions³. Single-subject MC was calculated on standardized TACs as A) Pearson’s correlation, B) Euclidean distance, C) Cosine Similarity. Test-retest reproducibility of MC matrices was assessed via Pearson’s correlation.

Results: Figure 1 shows the median MC matrices for each standardization and estimation method: “networks” along the main diagonal (e.g., connections between temporal lobe regions, where there is high [¹¹C]Ro15-4513 activity), and inter-hemispheric homotopic links (secondary diagonals) are evident. Despite some similarities across methods, it emerges that the choice of the standardization strategy is clearly non-trivial. The within-subject test-retest reproducibility is very high for all methods (Pearson’s R: 0.90–0.99).

Conclusion: We extracted single-subject [¹¹C]Ro15-4513 MC, testing different standardization and estimation methods. While requiring validation to understand its functional underpinnings, this approach provides a simple way to assess a PET tracer’s kinetic structure and similarity across regions without performing kinetic modelling, and may hold promise as a biomarker of disease or drug response. Inline graphic

References

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2021-115

The pandemic brain: neuroinflammation in healthy, non-infected individuals during the COVID-19 pandemic (#349)

Ludovica Brusaferri¹, Zeynab Alshelh¹, Daniel Martins^2,
3, Minhae Kim¹, Akila Weerasekera¹, Hope Housman¹, Erin J. Morrisey¹, Paulina C. Knight¹, Kelly A. Castro-Blanco¹, Daniel Albrecht¹, Chieh-En J. Tseng¹, Nicole R. Zürcher¹, Eva-Maria Ratai¹, Oluwaseun Johnson-Akeju^1,
5, Nathaniel D. Mercaldo¹, Nouchine Hadjikhani^{1, 6}, Mattia Veronese^{2, 4}, Federico E. Turkheimer^{2, 3}, Bruce R. Rosen¹, Jacob M. Hooker¹ and Marco L. Loggia^{1, 5}

¹Harvard University, Athinoula A. Martinos Center for Biomedical Imaging, Boston Massachusetts, USA

²King’s College London, Department of Neuroimaging, London, UK

³NIHR Maudsley Biomedical Research Centre, London, UK

⁴University of Padua, Department of Information Engineering, Padua, Italy

⁵Massachusetts General Hospital, Department of Anesthesia, Boston Massachusetts, USA

⁶University of Gothenburg, Sahlgrenska Academy, Gothenburg, Sweden

Abstract

Introduction: The impact of COVID-19 on human health extends beyond the morbidity and death toll directly caused by the SARS-CoV-2 virus. In fact, accumulating evidence indicates a global increase in the incidence of fatigue, brain fog and depression, including among non-infected, since the pandemic onset.¹ Motivated by previous research linking these symptoms to neuroimmune activation in other pathological contexts,^2–5 we hypothesized that subjects examined after the enforcement of lockdown/stay-at-home measures would demonstrate increased neuroinflammation.

Methods: We performed simultaneous brain Positron Emission Tomography/Magnetic Resonance Imaging in healthy volunteers either before (n = 57) or after (n = 15) the 2020 Massachusetts lockdown, using [11C]PBR28, a radioligand for the glial marker 18 kDa translocator protein. In a subset (n = 13 pre-lockdown; n = 11 post-lockdown), we also quantified brain (thalamic) levels of myoinositol (mIns), another putative glial marker. First, we compared [11C]PBR28 and mIns signals across pre- and post-lockdown cohorts. Then, to evaluate the possible clinical significance of our findings, we collected and analyzed a retrospective pandemic-specific questionnaire from the post-lockdown subjects. Finally, we investigated multivariate associations between the spatial pattern of [11C]PBR28 post-lockdown changes and constitutive brain gene expression in post-mortem brains (Allen Human Brain Atlas).

Results: Post-lockdown subjects showed increased [11C]PBR28 and mIns signals. These neuroinflammatory markers demonstrated elevated levels in cortical and subcortical regions including sensory, motor and higher order association areas, and white matter. Post-lockdown [11C]PBR28 signal elevations were correlated with individual physical/mental fatigue indicators. Further, the regional variability of increased [11C]PBR28 signal was spatially aligned with the constitutive expression of several genes highly expressed in glial/immune cells and/or involved in neuroimmune signaling.

Conclusion: Our results of markedly increased neuroimmune response associated with COVID-19-related disruptions highlight the impacts of the pandemic and suggest that brain alterations may have occurred in response to pandemic-associated stressors in non-infected individuals. This work lays the foundations for the investigation of possible long-term effects of pandemic-induced neuroinflammation on humans’ health.

Acknowledgements

This work was funded by R01-NS094306-01A1, R01-NS095937-01A1, R01-DA047088-01 and The Landreth Family Foundation.

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References

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2021-116

Imaging nociceptive opioid peptide (NOP) receptors in alcohol use disorders (AUD) with [¹¹C]NOP-1A and PET: Findings from a second cohort (#350)

Savannah Tollefson¹, Clara Stoughton¹, Michael Himes¹, Neale S. Mason¹ and Rajesh Narendran^{1, 2}

¹University of Pittsburgh, School of Medicine, Department of Radiology, Pittsburgh Pennsylvania, USA

²University of Pittsburgh, School of Medicine, Department of Psychiatry, Pittsburgh Pennsylvania, USA

Abstract

Introduction: Nociceptin (N/OFQ), which binds to the NOP receptor, regulates anxiety, reward, and stress-resilience.¹ Recent studies showing NOP antagonists ability to block alcohol reinstatement and relapse suggest a hyperactive N/OFQ-NOP receptor system in AUD.^1,2 In a previous [¹¹C]NOP-1A study, we found no significant differences in V_T in non-treatment seeking AUD relative to controls (HC).³ Here, we used [¹¹C]NOP-1A PET to measure V_T in treatment-seeking AUD to relate to relapse.

Methods: [¹¹C]NOP-1A V_T was measured in 27 AUD and age, sex, and tobacco use matched HC. AUD were scanned following ∼10 days of abstinence confirmed with urine ethyl glucuronide (EtG). Recent heavy drinking (EtG greater than or equal to 30 pg/mg) prior to the scan was also quantified using hair samples. V_T was measured with a two tissue-compartment kinetic analysis in eleven ROIs that regulate reward and stress behaviors. To document relapse, AUD subjects were followed for 12-weeks after PET using contingency management where they were received compensation to remain abstinent.

Results: [¹¹C]NOP-1A V_T was not significantly different between AUD and HC groups.

V_T was significantly lower in hair EtG+AUD vs. EtG-AUD (Linear Mixed Model, EtG+, p = 0.049; region, p < 0.001; region X EtG, p < 0.001). Significant negative correlations between V_T and the mean number of drinking days per week and drinks consumed per drinking day before PET were also present.

AUD subjects who relapsed (n = 8) and dropped out (n = 8) had significantly lower V_T than AUD who abstained (n = 6) for 12-weeks (Linear Mixed Model, outcome, p = 0.012; region, p < 0.001; region X outcome, p < 0.001).

Conclusion: Lower NOP V_T, which is related to heavy drinking in AUD, predicted relapse to alcohol during 12-week follow-up in which subjects received money to abstain. Assuming lower V_T reflects increased N/OFQ levels, these data support the pursuit of NOP antagonists to reduce heavy drinking and promote abstinence in AUD.

Funding:

NIAAA RO1 AA025247

References

1.Ciccocioppo R, et al. NOP-related mechanisms in substance use disorders. Handb Exp Pharmacol 2019. [DOI] [PMC free article] [PubMed] [Google Scholar]
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3.Narendran R, et al. Nociceptin receptors in alcohol use disorders: a positron emission tomography study using [(11)C]NOP-1A. Biol Psychiatr 2018; 84: 708–714. [DOI] [PMC free article] [PubMed] [Google Scholar]

2021-117

In response to social acceptance, nucleus accumbens mu opioid receptor activation is associated with increased self-esteem and positive mood (#351)

Kathryn R. Hill¹, Christine DeLorenzo¹, Stephan F. Taylor², R. Todd Ogden³, Ramin V. Parsey¹ and David T. Hsu^1,2

¹Renaissance School of Medicine at Stony Brook University, Department of Psychiatry, Stony Brook New York, USA

²Michigan Medicine, University of Michigan, Department of Psychiatry, Ann Arbor Michigan, USA

³Columbia University Mailman School of Public Health, Department of Biostatistics, New York New York, USA

Abstract

Introduction: The mu opioid receptor (MOR) related biological underpinnings of rejection sensitivity (RS), a common feature of borderline personality disorder and major depressive disorder, have not yet been examined. We hypothesize that RS will be negatively associated with MOR activation during rejection and acceptance tasks. In an exploratory analysis, we assessed the relationships between MOR activation and changes in mood and self-esteem before and after the task.

Methods: RS was assessed with the Adult Rejection Sensitivity Questionnaire. Healthy participants, n = 75 (52% female), completed rejection and acceptance tasks during [¹¹C]carfentanil positron emission tomography (PET) scans, with self-reported levels of self-esteem and mood collected during and after each task. Nondisplaceable binding potential (BP_ND) was calculated from bolus plus infusion delivery of tracer with occipital lobe reference-region based Logan graphical analysis. MOR activation (BP_ND neutral – BP_ND social task) in the regions of interest (amygdala, midline thalamus, anterior insula, and nucleus accumbens) were evaluated.

Results: RS was not related to regional MOR activation during acceptance or rejection tasks. MOR activation in the nucleus accumbens was positively correlated with increase in ratings of self-esteem (r = 0.35, uncorrected p = 0.0064) and also with the feelings “happy and accepted” (r = 0.31, uncorrected p = 0.0094) during the period between acceptance task administration and 5 minutes after the task completion. MOR activation was not associated with rejection task related self-esteem and negative mood.

Conclusion: Our previous publication¹ demonstrates that this social rejection task induces MOR activation. We presently demonstrate that regional MOR activation during social rejection is not dependent on RS in healthy individuals, suggesting regional endogenous opioid response to social rejection is independent of this trait. MOR activation in the nucleus accumbens was associated with increased self-esteem and positive mood after experiencing social acceptance, warranting further investigation.

Reference

1.Hsu DT, Sanford BJ, Meyers KK, et al. Response of the µ-opioid system to social rejection and acceptance. Mol Psychiatr 2013; 18: 1211–1217. [DOI] [PMC free article] [PubMed] [Google Scholar]

2021-118

[¹⁸F]Nifene binding to α4β2* nicotinic acetylcholinergic receptors is reduced in human hippocampus of postmortem Alzheimer’s disease brains (#352)

Jogeshwar Mukherjee, Christopher Liang, Anthony-David Campoy, Rommani Mondal, Reisha M. Ladwa and Oshini V. Keerthisinghe

University of California-Irvine, Preclinical Imaging, Radiological Sciences, Irvine California, USA

Abstract

Introduction: Nicotinic acetylcholinergic receptors (nAChRs), α4β2* may be adversely affected in the hippocampus (HP) in Alzheimer’s disease (AD).¹ In our efforts to consider translational use of [¹⁸F]Nifene PET² in AD, we have carried out quantitative autoradiographic evaluation of α4β2* nAChRs using HP (CA1/subiculum plus) from postmortem AD and compared to control (CN) brains.

Methods: Human post-mortem brain tissue sections (10 µm thick) consisting of HP CA1-subiculum regions, (AD, n = 16F and 13M and CN = 16F and 16M) were obtained from Banner Health, Sun City, Arizona. Brain slices were incubated [¹⁸F]Nifene (1 µCi/cc) in Tris/pH 7.4 buffer at 25°C for 1 hr. Nonspecific binding was measured using 300 µM nicotine. Adjacent sections were tested for Tau using [¹²⁵I]IPPI (0.1 µCi/cc) in PBS pH 7.4 buffer at 25°C for 1 hr using our previously published protocols.³ Anti-tau and anti-Aβ immunostaining was carried out on adjacent slices. Using the Optiquant program, regions of interest were drawn and digital light units/mm² (DLU/mm²) were used to quantify the percentage change in binding of [¹⁸F]Nifene and [¹²⁵I]IPPI.

Results: All CN subjects exhibited significant [¹⁸F]Nifene binding (Figure 1(c)) in the HP CA1-Subiculum (SUB) regions consistent with our PET [¹⁸F]Nifene results in healthy human subjects.² Significantly lower binding in AD (Figure 1(g)) resulted in a overall 40% reduction in [¹⁸F]Nifene AD HP CA1-SUB compared to CN accross all subjects (average [¹⁸F]Nifene ratio AD/CN = 0.58). Male-female [¹⁸F]Nifene HP CA1-SUB differences in the brain sections were not significant, both in CN and AD subjects. All AD subjects had higher [¹²⁵I]IPPI Tau binding, Figure 1(f) compared to CN in Figure 1(b) (average [¹²⁵I]IPPI ratio AD/CN = 7). As expected, [¹⁸F]Nifene binding in the AD subjects was inversely correlated to [¹²⁵I]IPPI in HP CA1-SUB. Quantitative correlation of [¹⁸F]Nifene and [¹²⁵I]IPPI is underway using recently reported methods.⁴ Additional correlations with anti-Aβ (Figure 1(h)) and [¹⁸F]flotaza⁵ for Aβ plaques are also underway.

Conclusion: [¹⁸F]Nifene binding is significantly reduced in HP CA1-SUB of the postmortem AD brain. [¹⁸F]Nifene PET may potentially have a complementary role along with ongoing NFT PET studies in AD subjects. Information on the status of the α4β2* nAChRs in AD may be useful in treatment planning using acetylcholinesterase inhibitors.

Acknowledgements

Research Support: NIH/NIA RF1 AG029479, UCI UROP (ADC, RM, RML), Banner Health Research Institute

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References

1.Shimohama S, Kawamata J. Roles of nicotinic acetylcholine receptors in the pathology and treatment of Alzheimer’s and Parkinson’s diseases. In: Akaike A, Shimohama S, Misu Y. (eds). Nicotinic acetylcholine receptor signaling in neuroprotection. Singapore: Springer, 2018, pp. 137–158. [Google Scholar]
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2021-119

Imaging synaptic density in aging and frontotemporal dementia (#353)

Cécile Tissot^{1, 2}, Gleb Bezgin¹, João Pedro Ferrari-Souza^2,
3, Pâmela C. Lukasewicz Ferreira², Joseph Therriault¹, Firoza Z. Lussier¹, Mira Chamoun¹, Yi-Ting Wang¹, Jaime Fernandez-Arias¹, Jenna Stevenson¹, Nesrine Rahmouni¹, Serge Gauthier¹, Tharick A. Pascoal² and Pedro Rosa-Neto¹

¹McGill University, Montreal, QC, Canada

²University of Pittsburgh, Pittsburgh Pennsylvania, USA

³Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil

Abstract

Introduction: Tissue loss has been observed in post-mortem data in aging and neurodegenerative conditions, such as frontotemporal dementia (FTD). In dementia, we can observe specific patterns of brain damage related to symptomatology. A hypothesis is that tissue degeneration is a consequence of synaptic loss. Our goal here is to assess synaptic density in vivo using the novel radiotracer [¹⁸F]SDM8 in aging and FTD.

Methods: We included cognitively unimpaired young (CUY) [21–22 years of age (yoa)], cognitively unimpaired elderlies (CUE) [60–81 yoa], and FTD [47–72 yoa] participants from the TRIAD cohort. They underwent an MRI, a neuropsychological evaluation, and a 90-minutes dynamic [¹⁸F]SDM8 PET-scan for synaptic density. We calculated the standardized uptake value ratio from 40–90 minutes and used the centrum semiovale as the reference region. Voxel-wise analyses were conducted to assess synaptic density differences between CUY, CUE, and FTD diagnostic groups. Analyses were always corrected for sex; when including only CUE and FTD, we also corrected for age.

Results: CUY individuals present high binding of [¹⁸F]SDM8 as compared to CUE individuals, especially in the precuneus, and the frontal and temporal lobes (Figure1(a)). Moreover, when comparing CUE and FTD individuals, we observed a greater [¹⁸F]SDM8 binding in the medial frontal lobe and the frontal pole (Figure 1(b)).

Conclusion: Synaptic loss seems to increase with age, and with dementia onset. Indeed, CUE show less synaptic density as compared to CUY, in regions vulnerable to the development of neurodegenerative conditions. Moreover, we also observed a strong difference between CUE and FTD individuals, in brain regions related to the disease symptomatology, i.e. the frontal lobe. Frontal synaptic loss seems to appear in aging around the orbitofrontal cortex. Conversely, in FTD, it is more located towards the dorsomedial prefrontal cortex. We hypothesize that synaptic loss is a process appearing in aging, which seems to be potentiated in individuals diagnosed with FTD.

Acknowledgements

The authors would like to acknowledge the help of the McGill Center for Studies in Aging staff, as well as the participants in the cohort.

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Figure 1. Imaging synaptic density in aging and frontotemporal dementia.

2021-120

Associations between markers of synaptic dysfunction and tau accumulation, glial activation, and neurodegeneration in Alzheimer’s disease (#354)

Firoza Z. Lussier¹, Stijn Servaes¹, Cécile Tissot¹, Joseph Therriault¹, Min-Su Kang¹, Gleb Bezgin¹, Mira Chamoun¹, Jenna Stevenson¹, Nesrine Rahmouni¹, Andréa L. Benedet², Johanna Nilsson², Nicholas J. Ashton², Kaj Blennow², Ann Brinkmalm², Henrik Zetterberg² and Pedro Rosa-Neto¹

¹McGill University, Translational Neuroimaging Laboratory, Verdun, QC, Canada

²Sahlgrenska Academy at the University of Gothenberg, Institute of Neuroscience and Physiology, Mölndal, Sweden

Abstract

Introduction: While Alzheimer’s disease (AD) is characterized by β-amyloid and tau, growing evidence suggests that synaptic dysfunction is a key feature of AD and may be a mechanism linking these pathologies to subsequent cognitive decline. The current aim was to investigate how levels of synapse proteins selected from a novel panel of synaptic biomarkers in cerebrospinal fluid (CSF) are associated with tau accumulation, glial activation, and neurodegeneration in an AD-enriched cohort.

Methods: Participants were selected from the TRIAD cohort (N = 105; 20 young, 44 cognitively normal, 41 cognitively impaired). Mass spectrometry methods were used to quantify pre- and post-synaptic proteins in CSF, including 14–3-3 zeta/delta, gamma-synuclein, neurogranin, and syntaxin and pentraxin proteins (Nilsson, 2021).¹ Group comparisons and regression models with CSF levels of tau and glial activation markers were conducted, along with mediation analyses and correlations with AD-signature cortical thickness.

Results: Of the 12 quantified synaptic proteins, nine showed significant age effect and ten showed a significant difference in β-amyloid+/tau+ compared to β-amyloid-/tau-. Regressions with CSF p-tau231 and p-tau217 were significant for all synaptic proteins, as were regressions with CSF YKL-40 and GFAP. Mediation analysis with tau (predictor) and glial activation (mediator) showed that seven synaptic proteins’ associations with tau were significantly mediated by glial activation. These seven proteins matched those that were significantly correlated with AD-signature cortical thickness, with the exception of PEBP-1, which correlated with cortical thickness but did not have a significant mediation effect.

Conclusion: Our study of CSF synaptic dysfunction biomarkers in AD suggests that synaptic proteins whose relationship with tau is mediated by glial activation are more closely associated with reduced AD-signature neuronal degeneration assessed by cortical thickness.

graphic file with name 10.1177_0271678X211061050-img327.jpg

Figure 1. Associations between synaptic dysfunction biomarkers and AD-signature cortical thickness

Reference

1.Nilsson J. Cerebrospinal fluid biomarker panel for synaptic dysfunction in Alzheimer’s disease. Alzheimers Dement 2021; 13: e12179. [DOI] [PMC free article] [PubMed] [Google Scholar]

2021-121

Detecting two-task dopamine release via residual analysis (#355)

Connor W.J. Bevington¹, Jordan U. Hanania¹, Giovanni Ferraresso², Kevin (Ju-Chieh) Cheng^{1, 3}, Alexandra Pavel³, A. Jon Stoessl^{3, 4} and Vesna Sossi¹

¹University of British Columbia, Physics and Astronomy, Vancouver British Columbia, Canada

²University of British Columbia, Department of Mechanical Engineering, Vancouver British Columbia, Canada

³University of British Columbia, Pacific Parkinson’s Research Centre, Vancouver British Columbia, Canada

⁴University of British Columbia, Faculty of Medicine, Division of Neurology, Vancouver British Columbia, Canada

Abstract

Introduction: Dopamine (DA) release can be detected in vivo using [11C]raclopride dynamic PET imaging: a voxel-level change in dopamine concentration alters the voxel-level PET temporal signal.¹ Current detection methods suffer from low sensitivity (true positive rate), primarily due to image noise and relying on model comparison via an F-test which, at present, poorly separates true positives from true negatives.² Additionally, the current methodology has only been investigated for single-task paradigms.^3,4 Here we propose two alternative methods, one data-driven and the other task-informed, which aim to improve sensitivity and extend applicability to two-task paradigms. Sensitivity comparisons on simulated data are provided.

Methods: Denoised voxel-level signals are regressed on regional signals, producing structured residuals where DA release is present. The data-driven method then uses principal component analysis (PCA) to spatially localize the DA release, whereas the task-informed method uses known task timings to determine a predicted release timecourse, which is compared to the voxel-wise residuals via cross-correlation for spatial localization (Figure 1). We test these methods on two simulated datasets: (i) single-task: a single motor/cognitive task (∼200% basal DA increase in the L/R caudate and L putamen starting at 32 minutes); (ii) two-task: identical motor/cognitive task as above, followed by a reward task 17 minutes later (∼200% basal DA increase in the L ventral striatum). 20 noisy realizations are simulated in each case.

Results: Both methods increase true positive rate by ∼65% in the single-task simulation and ∼30% in the two-task simulation at equivalent false positive rate to the F-test method (Figure 2(a) and (b)). However, the task-informed method offers flexibility when release from multiple tasks are to be distinguished spatiotemporally, detecting the spatiotemporally distinct reward cluster with ∼2x higher sensitivity than the data-driven method (see white circles in Figure 2(c)).

Conclusion: Simulation results under varied task protocols show that our proposed data-driven and task-informed methods outperform the traditional F-test method in determining voxelwise patterns of DA release. These methods are general and can be adapted to signal detection in many domains. These methods are currently being applied to human data, comparing DA release behaviours of disease cohorts with healthy controls.

Acknowledgements

This work was supported by funding from the Natural Sciences and Engineering Research Council of Canada and the Pacific Parkinson’s Research Institute.

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References

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2021-122

Using personalized longitudinal brain models to identify neurotransmitter receptor-mediated alterations in Alzheimer’s disease (#357)

Ahmed F. Khan^{2, 3}, Quadri Adewale^{2, 3}, Tobias R. Baumeister^{2, 3}, Felix Carbonell⁴, Karl Zilles⁵, Nicola Palomero-Gallagher^{5, 6} and Yasser Iturria-Medina^{2, 3}

¹McGill University, Department of Neurology and Neurosurgery, Montreal Neurological Institute, Montreal, QC, Canada

²McGill University, McConnell Brain Imaging Center, Montreal Neurological Institute, Montreal, QC, Canada

³McGill University, Ludmer Centre for Neuroinformatics and Mental Health, Montreal, QC, Canada

⁴Biospective Inc., Montreal, QC, Canada

⁵Research Centre Jülich, Institute of Neuroscience and Medicine (INM-1), Jülich North Rhine-Westphalia, Germany

⁶Heinrich-Heine University, Cécile and Oskar Vogt Institute of Brain Research, Düsseldorf North Rhine-Westphalia, Germany

⁷RWTH Aachen, Department of Psychiatry, Psychotherapy, and Psychosomatics, Aachen North Rhine-Westphalia, Germany

⁸JARA, Translational Brain Medicine, Aachen North Rhine-Westphalia, Germany

⁹McGill University, Montreal Neurological Institute, Montreal, QC, Canada

Abstract

Introduction: Alzheimer’s disease (AD) involves degenerative alterations to several neurobiological processes,¹ with inter-subject heterogeneity.² While we do not currently understand its molecular basis, neurotransmitter receptors, as important signalling molecules affected in AD, are potential therapeutic targets. However, we currently lack integrative brain models characterizing how multiple biological processes and receptors interact to cause clinical deterioration. Here, we present a personalized, generative and whole-brain neurotransmitter receptor-enriched multifactorial causal model (re-MCM)³ of longitudinal neuroimaging changes. By interpreting model parameters as markers of receptor alterations, we are able to identify receptor-neuroimaging interactions associated with cognitive decline in AD.

Methods: We preprocessed longitudinal data from 6 neuroimaging modalities (structural, functional and arterial spin labeling MRI, and tau, amyloid-β and glucose PET) for a heterogeneous aged population from the ADNI dataset (N = 423). Using averaged (N = 3) receptor templates derived from post-mortem autoradiography for 15 neurotransmitter receptors from 6 key families (glutamatergic, GABAergic, cholinergic, adrenergic, serotonergic and dopaminergic receptors), we fit subject-specific regression models for each neuroimaging modality. Model parameters represent i) local interactions between neurobiological processes, ii) effects of local receptor densities, iii) functional alterations to receptor-based interactions, and iv) network propagation of neurobiological alterations. We then performed singular value decomposition (SVD) across AD patients with permutation testing to robustly identify parameters correlated with clinical measures of cognitive decline.

Results: Models with neuroimaging-receptor interactions were significantly more informative than neuroimaging-only models for 86.8% – 99.0% of subjects (F-test, P < 0.05), explaining 70% ( ± 20%) of the longitudinal variance in neuroimaging (across all subjects). We identified an axis of variability explaining up to 37% (P < 0.004, FWE-corrected) of inter-individual variability in AD cognitive deterioration, primarily affecting executive function, with functional alterations to glutamatergic interactions affecting tau accumulation and neural activity, GABAergic interactions concurrently affecting neural activity, amyloid and tau, and cholinergic effects on tau.

Conclusion: This project introduces the first data-driven framework for integrating neurotransmitter receptors, multi-modal neuroimaging and clinical data in an interpretable brain model. The estimation of receptor alterations despite the lack of in vivo data can allow the identification of candidate disease mechanisms and therapeutic targets, constituting a promising step towards personalized and precision neurotransmitter-based treatments.

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Figure 1. Receptor-imaging interactions affecting cognitive decline in AD.

The angle of each sector is proportional to the contribution of the corresponding mechanism to explaining the variance in the rates of cognitive decline. The inner sectors represent the 6 neuroimaging modality models that together comprise each personalized re-MCM model. Within each modality, the intermediate sectors represent the neurotransmitter system involved, while the outer sector consists of the specific two-way receptor-neuroimaging interactions or direct predictor terms in the model. Together, the mechanisms robustly explain 37% of inter-subject variance in cognitive decline.

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Figure 2. Receptor-enriched multifactorial causal modeling.

For each subject, longitudinal neuroimaging changes are decomposed into local effects from all (N_ROI = 88) brain regions due to i) the direct influence of all neuroimaging-quantified biological factors, ii) receptor density distributions, and iii) receptor-imaging interactions, and iv) global network-mediated intra-brain propagation. At a group level across AD subjects, receptor-based mechanisms robustly correlated to cognitive decline are identified using SVD.

References

1.Francis PT, María JR, Lai MK. Neurochemical basis for symptomatic treatment of Alzheimer’s disease. Neuropharmacology 2010; 59: 221–229. [DOI] [PubMed] [Google Scholar]
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2021-123

Dosimetry and biodistribution of the novel PET radioligand (R)-[¹¹C]Me-NB1 specific to the GluN2B subunit of the N-methyl-D-aspartate receptor (#358)

Lucas Rischka¹, Verena Pichler^{2, 3}, Chrysoula Vraka², Ivo Rausch², Dietmar Winkler¹, Lukas Nics², Sazan Rasul², Leo Silberbauer¹, Matej Murgaš¹, Murray B. Reed¹, Andreas Hahn¹, Simon M. Ametamey⁴, Wolfgang Wadsak^{2, 5}, Rupert Lanzenberger¹ and Marcus Hacker²

¹Medical University of Vienna, Department of Psychiatry and Psychotherapy, Vienna Wien, Austria

²Medical University of Vienna, Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Vienna Wien, Austria

³University of Vienna, Department of Pharmaceutical Sciences, Vienna Wien, Austria

⁴ETH Zurich, Centre for Radiopharmaceutical Sciences ETH-PSI-USZ, Institute of Pharmaceutical Sciences ETH, Vienna Zürich, Switzerland

⁵Center for Biomarker Research in Medicine (CBmed), Graz Wien, Austria

Abstract

Introduction: N-methyl-D-aspartate (NMDA) receptors are glutamate-gated ion channels involved in key physiological processes. However, upon activation, extrasynaptic, GluN2B-enriched NMDA receptors might cause excitotoxic processes ¹. Since these processes could be related to neuropsychiatric disorders, the GluN2B subunit has become an interesting target for mapping pathological alterations and consequently, for drug development. Thus, the GluN2B-specific radioligand (R)-[¹¹C]Me-NB1 was developed in rodents ² and further successfully translated into humans ³. Here, we investigated the clinical applicability in terms of biodistribution and dosimetry.

Methods: Four healthy subjects (2 females, 2 males, mean age 25 ± 4 years) underwent a single whole-body measurement on a fully-integrated PET/MR. PET imaging was carried out using 9 passes of increasing duration in 6 bed positions (i.e. 0.5, 0.5, 0.5, 1, 1, 2, 3, 4, 7 min per bed position, head to mid-thigh). The radioligand (R)-[¹¹C]Me-NB1 was administered via a cubital vein. The source organs for the biodistribution and dosimetry analysis are depicted in Figure 1. These organs were anatomically delineated utilizing the PET data. Time-integrated activity coefficients were computed for OLINDA/EXM 2.0 ⁴ to estimate organ absorbed doses and total effective dose (ED). For visualization purposes, activity in percentage of injected dose was plotted over time for representative source organs and each subject separately (Figure 2).

Results: Highest uptake was observed in the urinary bladder, pancreas and spleen, and the lowest in the bone marrow. The urinary bladder wall was the critical organ with a mean absorbed organ dose of 1.5 ± 1.5 µSv/MBq. The total effective dose ranged from 4.4 to 7.1 µSv/MBq with an average ED of 6.0 ± 1.1 µSv/MBq.

Conclusion: (R)-[¹¹C]Me-NB1 exhibited a similar low effective dose compared to other carbon-11 labelled radioligands ⁵. Considering a target dose of 6 MBq/kg as previously presented ³ and a person with 75 kg body weight would yield a reasonable effective dose of 2.7 mSv. In conclusion, longitudinal studies are feasible under commonly applied regulations, enabling drug development and interventional studies to further elucidate alterations in neuropsychiatric disorders.

Acknowledgements

This project was supported in part by the Swiss National Science Foundation grant numbers 310030E-160403/1 and 310030E-182872/1 to Prof. Simon M. Ametamey. Matej Murgaš is funded by the Austrian Science Fund FWF DOC 33-B27. Murray B. Reed and Leo R. Silberbauer are recipients of a DOC fellowship of the Austrian Academy of Sciences.

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References

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2021-124

Longitudinal in vivo PET imaging of human ESC-derived dopamine neurons in minipig (#359)

Thea P. Lillethorup¹, Deirdre B. Hoban², Bengt Mattsson², Dariusz Orlowski³, Jenny N. Wahlestedt², Aage O. Alstrup¹, Simone L. Bærentzen^{1, 4}, Steen Jakobsen¹, Andreas N. Glud³, Agnete Kirkeby⁵, David J. Brooks^{1, 6}, Jens Christian H. Sørensen³, Malin J. Parmar² and Anne M. Landau^{1, 4}

¹Aarhus University Hospital, Department of Nuclear Medicine and PET, Department of Clinical Medicine, Aarhus N, Denmark

²Lund University, Developmental and Regenerative Neurobiology, Wallenberg Neuroscience Center and Lund Stem Cell Centre, Department of Experimental Medical Science, Lund, Sweden

³Aarhus University Hospital, Department of Neurosurgery and Center for Experimental Neuroscience (CENSE), Department of Clinical Medicine, Aarhus N, Denmark

⁴Aarhus University, Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus N, Denmark

⁵University of Copenhagen, Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), Copenhagen, Denmark

⁶University of Newcastle upon Tyne, Newcastle, UK

Abstract

Introduction: Human embryonic stem cells (hESC) can be robustly converted into authentic ventral midbrain dopaminergic neurons (hESC-DA) and have great potential as a dopamine-replacement therapy for Parkinson’s disease (PD). As part of the ongoing work to validate these cells for clinical use, it is important to verify that the cells survive, release dopamine, and innervate their target when transplanted into the living brain. The Gottingen minipig has a highly developed central nervous system with many physiological and anatomical similarities to humans. Their limited growth permits long-term longitudinal follow up studies with positron emission tomography (PET) and their brain size allows identification of sub-regional striatal distribution of pre- and post-synaptic dopaminergic tracers traditionally used in PD patients.

Methods: To obtain direct functional proof of the grafted cells integration into circuitry in vivo, we employed longitudinal PET imaging. Minipigs were immunosuppressed and imaged 2- and 7-months post-grafting of hESC-DA with [18F]-FDOPA PET for the uptake of dopamine precursors, and [18F]-PE2I PET, targeting the dopamine transporter (DAT).

Results: PET imaging revealed ipsilateral putamen increases in dopamine uptake already 2-months post-grafting, while DAT binding was first evident at 7-months post grafting, indicating a more mature graft. This effect was confirmed by post-mortem immunohistochemical analysis showing graft survival in 2/4 minipigs and dense DAT+ fiber staining including cell bodies after 7 months. Parallel studies using the same batch of hESC-DA neurons were conducted in athymic rats to ensure quality of the cells and compare longitudinal survival, volume and fiber outgrowth of the same cells between species.

Conclusion: This study confirms the translational potential of dopamine stem cell therapy and capability of innervating a large sized striatum, which can be visualized using PET imaging, supporting its use as a clinical treatment for PD patients.

Acknowledgements

This study was supported by The Lundbeck Foundation, Parkinsonforeningen, Jascha and the Danish Innovation Fund.

2021-125

Differential associations between neocortical tau pathology and blood flow with cognitive deficits in early-onset vs late-onset Alzheimer’s disease (#360)

Denise Visser¹, Sander C.J. Verfaillie¹, Emma E. Wolters^1,
2, Emma M. Coomans¹, Tessa Timmers^{1, 2}, Hayel Tuncel¹, Ronald Boellaard¹, Sandeep S.V. Golla¹, Albert D. Windhorst¹, Philip Scheltens², Wiesje M. van der Flier^2,
4, Bart N.M. van Berckel¹ and Rik Ossenkoppele^{2, 3}

¹Department of Radiology & Nuclear Medicine, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, Netherlands

²Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, Netherlands

³Clinical Memory Research Unit, Lund University, Lund, Sweden

⁴Department of Epidemiology and Biostatistics, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, Netherlands

Abstract

Introduction: Early-onset Alzheimer’s disease (AD) and late-onset AD differ in neuropathological burden and type of cognitive deficits. Assessing tau pathology and relative cerebral blood flow (rCBF) measured with [¹⁸F]flortaucipir PET in relation to cognition may help explain these differences between early-onset and late-onset AD.

Methods: We included 79 amyloid positive individuals with MCI/AD dementia (early-onset AD: n = 35, age-at-PET = 59 ± 5, MMSE = 23 ± 4; late-onset AD: n = 44, age-at-PET = 71 ± 5, MMSE = 23 ± 4) who underwent a 130 minutes dynamic [¹⁸F]flortaucipir PET scan and extensive neuropsychological assessment. We extracted non-displaceable binding potentials (BP_ND) and R₁ (proxy of rCBF) from parametric images using receptor parametric mapping, in medial and lateral temporal, parietal, occipital and frontal regions-of-interest and used continuous scores on nine neuropsychological tests covering memory, attention, language and executive functioning. We first examined differences between early-onset AD and late-onset AD in BP_ND or R₁ using ANOVA (region-of-interests analysis) and voxel-wise contrasts. Next, we performed linear regression models to test for potential interaction effects between age-of-onset and BP_ND/R₁ (for eachregion-of-interest) on cognition.

Results: Both region-of-interest and voxel-wise contrast showed a clear pattern of greater [¹⁸F]flortaucipir BP_ND across all neocortical regions in early-onset AD, while late-onset AD patients had subtle lower R₁ values in medial temporal regions primarily (Figure 1). Furthermore, compared to late-onset AD, interaction analyses indicated that higher [¹⁸F]flortaucipir BP_ND and lower R₁ values in lateral temporal, parietal and occipital regions were more strongly associated with more severe cognitive impairment in early-onset AD (Figure 2).

Conclusion: Our results show that early-onset AD is characterized by higher levels of tau pathology and stronger associations between lateral temporal, and occipito-parietal tau pathology or lower rCBF and cognitive impairment. These findings may have important implications for clinical trials, since effects of potential tau- or blood flow targeting therapeutic interventions might exert larger effects in early-onset compared to late-onset AD patients.

Acknowledgements

We kindly thank all participants for their contribution. Research of Amsterdam Alzheimer Center is part of the Neurodegeneration program of Amsterdam Neuroscience. The Amsterdam Alzheimer Center is supported by Alzheimer Nederland and Stichting VUmc funds. [¹⁸F]Flortaucipir PET scans were made possible by Avid Radiopharmaceuticals Inc.

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2021-126

12 days of sucrose consumption reduces 3H-UCB-J binding in the caudate and prefrontal cortex of healthy Göttingen minipigs (#361)

Simone L. Bærentzen^{1, 2}, Majken B. Thomsen^{1, 2}, Aage O. Alstrup², David J. Brooks^{2, 3}, Gregers Wegener¹, Michael Winterdahl^{1, 2} and Anne M. Landau^{1, 2}

¹Aarhus University, Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus C, Denmark

²Aarhus University, Department of Nuclear Medicine and PET, Department of Clinical Medicine, Aarhus N, Denmark

³University of Newcastle upon Tyne, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle, UK

Abstract

Introduction: Over the last decades, there has been an increase in the consumption of sugar worldwide, especially in the form of sugar-sweetened beverages. This change in diet has been proven to be a contributing factor to the development of cancers, cardiovascular diseases, diabetes, obesity, metabolic syndrome and mental ill-health. Additionally, prolonged periods of high sugar intake have been linked to a reduction in cognitive performance and altered neurotransmission in humans, minipigs and rodents, and may increase the risk of Alzheimer’s disease. Here we test the hypothesis that a diet high in sucrose leads to reduced synaptic vesicle glycoprotein 2A (SV2A), an indirect measure of synaptic density, in healthy Göttingen minipigs.

Methods: Seven minipigs had either a 12-day period of access to two liters of a 25% sucrose in water solution or to tap water ad libitum followed by euthanasia and brain extraction. Tritiated UCB-J, which binds to SV2A, was applied to brain sections from prefrontal cortex, nucleus accumbens, caudate, putamen, dorsal hippocampus, ventral hippocampus and thalamus, and autoradiography was performed in the presence and absence of levetiracetam, an SV2A blocker, in order to assess specific binding.

Results: [3H]UCB-J binding was significantly lower in prefrontal cortex and caudate of minipigs drinking sucrose solution compared to the water-drinking minipigs.

Conclusion: Our data suggest that sucrose consumption can lead to reduced synaptic SV2A protein density which could contribute to cognitive deficits.

2021-127

Longitudinal tau PET using [¹⁸F]flortaucipir: Comparison of (semi)quantitative parameters (#362)

Denise Visser¹, Hayel Tuncel¹, Rik Ossenkoppele^{2, 3}, Maqsood Yaqub¹, Emma E. Wolters^{1, 2}, Tessa Timmers^{1, 2}, Emma Weltings¹, Emma M. Coomans¹, Marijke E. den Hollander¹, Wiesje M. van der Flier^{2, 4}, Bart N.M. van Berckel¹ and Sandeep S.V. Golla¹

¹Department of Radiology & Nuclear Medicine, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, Netherlands

²Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, Netherlands

³Clinical Memory Research Unit, Lund University, Lund, Sweden

⁴Department of Epidemiology and Biostatistics, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, Netherlands

Abstract

Introduction: Semi-quantitative PET measures can be affected by changes in blood flow, whereas quantitative measures are not. The aim of the study was to compare semi-quantitative (SUVr) and quantitative (R₁, BP_ND) parameters of longitudinal tau PET scans with [¹⁸F]flortaucipir, with respect to changes in blood flow.

Methods: Thirty-eight subjects with subjective cognitive decline (SCD; age 65 ± 7y, male/female 16/22, MMSE 29 ± 1, amyloid positive 12/38) and 24 Alzheimer’s disease (AD) patients (age 66 ± 7y, male/female 11/13, MMSE 24 ± 3, amyloid positive 24/24) underwent baseline (BL) and 2.1 ± 0.3 and 2.2 ± 0.3 year follow-up (FU) dynamic [¹⁸F]flortaucipir PET scans, respectively. BP_ND and R₁ were estimated using RPM and SUVr_{(80–100min)} was calculated (cerebellar gray as reference). For each region-of-interest ((trans)entorhinal, limbic and neocortical) and parameter, %change was calculated. Regional SUVrs were compared to corresponding DVR ( = BP_ND+1) using paired T-tests. Additionally, simulations were performed to model effects of flow changes on BP_ND and SUVr in different binding categories. Thereafter, %bias for SUVr with respect to underlying binding and flow were evaluated.

Results: In SCD, there was a difference between %change in the (trans)entorhinal ROI (DVR 2.56% vs SUVr 1.85%) only (Figure 1). In AD, a difference was found in the limbic ROI (DVR 6.61% vs SUVr 7.52%) only. R₁ changes were small (+0.7% in SCD and -1.6% in AD). Simulations illustrated with increasing flow a decreased %bias for SUVr in low binding conditions, whereas a slightly increased bias was observed in high binding conditions (Figure 2).

Conclusion: SUVr provided an accurate estimate of specific binding for [¹⁸F]flortaucipir over a two-year follow-up. However, simulations showed that flow changes can affect [¹⁸F]flortaucipir SUVr, hence DVR/BP_ND should be preferred in more advanced disease stages and/or conditions that could induce significant flow changes like pharmacotherapeutic interventions.

Acknowledgements

We kindly thank all participants for their contribution. We thank Ronald Boellaard for sharing his knowledge and thoughts about the project. Research of Amsterdam Alzheimer Center is part of the Neurodegeneration program of Amsterdam Neuroscience. The Amsterdam Alzheimer Center is supported by Alzheimer Nederland and Stichting VUmc funds. [¹⁸F]Flortaucipir PET scans were made possible by Avid Radiopharmaceuticals Inc. Inline graphic

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2021-128

From genes to networks: In-vivo CRISPR/Cas9-induced VMAT2 knockdown exerts functional connectome changes in the rat brain (#363)

Tudor M. Ionescu¹, Sabina Marciano¹, Ran Sing Saw¹, Rachel Cheong², Deniz Kirik², Andreas Maurer¹, Bernd J. Pichler¹ and Kristina Herfert¹

¹University of Tuebingen, Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Tuebingen, Germany

²Lund University, Brain Repair and Imaging in Neural Systems, Department of Experimental Medical Science, Lund, Sweden

Abstract

Introduction: Recent advances in CRISPR/Cas9 technology have enabled its use as a powerful tool for in-vivo gene editing. Previously, we have validated this technique in-vivo by assessing vesicular monoamine transporter 2 (VMAT2) knockdown (KD) effects using PET, behavioral and ex-vivo experiments. However, its effects on whole-brain function have not been studied to date. Here, we targeted the Slc18a2 gene, encoding the VMAT2, using Cas9 from Staphylococcus aureus (SaCas9) in rats. We performed simultaneous PET/fMRI scans to elucidate the effects of gene editing on both local molecular and network-level functional connectivity (FC) parameters.

Methods: Baseline [¹¹C]raclopride PET/fMRI scans were acquired in rats (n = 23) under medetomidine and isoflurane in air over 60min using a 7T small-animal MRI with a PET insert. AAV-SaCas9 and AAV-sgRNA-Slc18a2 were next injected into the right substantia nigra pars compacta (SNc) and DPBS into the left SNc. The rats were rescanned 8–14 weeks after using the same PET/fMRI protocol and additional PET scans were performed using [¹¹C]DTBZ and [¹⁸F]FMZ. The PET data were assessed for molecular changes and fMRI was used to evaluate effects on default-mode (DMN) and sensorimotor networks (SMN).

Results: Based on the [¹¹C]DTBZ scans we split the rats into low knockdown (KD < 20%,n = 13) and high KD (KD > 20%,n = 10) groups. Our data indicated both subtle FC increases and decreases (p < 0.05) at low KD. At high KD, strong increases were found both within the DMN and SMN, driven by the contralateral thalamus (30% change,p = 0.009), and between the two networks, indicating compensatory effects in network function following VMAT2 KD. Additionally, we found correlations between VMAT2 KD and D2R expressions (r = 0.46,p = 0.03), and robust left-right differences in regional GABA_A expressions independently of KD magnitude in several regions (p < 0.001), hinting towards neurotransmitter cross-talk effects.

Conclusion: Our study is the first to assess CRISPR/Cas9 gene editing as an in-vivo method for the investigation of both local and network-level brain function. We could robustly separate the two cohorts, thus recommending the used study design for future research of both early and advanced disease phenotypes. We demonstrated the tremendous potential combining CRISPR/Cas9 and PET/fMRI imaging has to bridge the gap between targeted gene alterations and whole-brain functional changes.

Inline graphic Assessment of FC effects

(A) Mild KD and (B) Moderate KD: Correlation matrices indicate FC at baseline and after KD. Symbols indicate alterations (white: decrease, black: increase; +: p < 0.05, uncorr.; *: p < 0.05, FDR-corr.). The brain maps show changes (p < 0.05, uncorr.) in edge and node FC, their sizes being proportional to the change. (C) Comparison of functional effects at mild and moderate KD. The matrix compares the effects of mild and moderate KD. The scatter plots show correlations between the alterations both within and between DMN and SMN (⁺ p < 0.05, * p < 0.01, ** p < 0.001).

Inline graphic Molecular alterations induced by VMAT2 knockdown

(A) A significant decrease was observed in the ipsilateral striatal [¹¹C]DTBZ confirming VMAT2 knockdown (left panel). Additionally, [¹¹C]raclopride was increased on the ipsilateral side after VMAT2 KD (middle panel). Both effects correlated significantly (R² = 0.52, p < 0.01, right panel). The analysis indicated a separation of the two groups at a knockdown above 20% based on [¹¹C]DTBZ uptake. (B) [¹¹C]Flumazenil revealed decreased ipsilateral GABA-A binding in two cortex areas in both cohorts. ⁺ p < 0.05; * p < 0.01, ** p < 0.001.

2021-129

Development of voxel-level EC₅₀ Images for use in CNS Drug Development (#364)

Jocelyn Hoye, Bart de Laat, Heather Liu and Evan D. Morris

Yale University, Radiology and Biomedical Imaging, New Haven Connecticut, USA

Abstract

Introduction: We recently introduced voxel-level images of drug occupancy from PET via our “Lassen Plot Filter”.¹ Occupancy images revealed clear dependence (locally) of ¹¹C-flumazenil displacement on dose of GABAa inhibitor, CVL-865. We hypothesized that regions requiring higher drug concentrations to achieve desired occupancy would have higher EC₅₀ values. We introduce novel “EC₅₀ images” from human data and supporting simulations.

Methods: Five healthy subjects were scanned with the nonselective GABAa tracer, ¹¹C-flumazenil, before and twice after administration of CVL-865. We created ten occupancy images (Figure 1) and applied an E_max model at the voxel-level to all images, combined, to create one EC₅₀ image. We performed simulations (Figure 2) to confirm our observations of regional variation in EC₅₀ and to assess the effects of plasma concentration sampling on EC₅₀ variability. EC₅₀ images were simulated using plasma concentrations from the human study (3–279 ng/mL) and a noise model consistent with observed concentration-response data. In a second simulation study the range of plasma concentrations was extended (3–1957 ng/mL), to allow all simulated EC₅₀ regions to reach a minimum of 97% occupancy.

Results: As expected, the EC₅₀ image revealed spatial variation in ‘apparent drug affinity’ (differential displacement for a given dose). High EC₅₀ was found in areas of low occupancy, for a given drug dose (Figure 1). Simulations showed that it is possible to distinguish between regional differences in EC₅₀ estimates (Figure 2). Simulations also demonstrated that sampling from a wider, more complete range of plasma drug concentrations could improve and regularize EC₅₀ precision, spatially (Figure 2).

Conclusion: Our results argue for (a) confidence in the ability of the EC₅₀ images to identify regional variation and (b) a need to tailor the range of drug doses and post-drug sampling times to ensure uniform precision of the EC₅₀. The EC₅₀ image could add value to early phase drug development by identifying regional variation in affinity that might impact therapy or safety, and by guiding dose selection for late-phase trials.

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Reference

1.de Laat B and Morris ED. A local-neighborhood Lassen plot filter for creating occupancy and non-displaceable binding images. J Cereb Blood Flow Metab 2020; 41: 1379–1389. [DOI] [PMC free article] [PubMed] [Google Scholar]

2021-130

Agonist-induced µ-opioid receptor desensitization increases radiotracer binding: A positron emission tomography study in the mice brain (#365)

Chi-Hyeon Yoo, Sarah E. Reid and Hsiao-Ying Wey

Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown Massachusetts, USA

Abstract

Introduction: µ-opioid receptor (MOR) agonists are the most effective analgesics but with detrimental side-effects. The development of tolerance, which is associated with increased risks of opioid dependent and overdose, has been reported but the underlying mechanism remain elusive. Agonist-induced receptor desensitization was proposed as a key mechanism underlies opioid tolerance. Previous findings suggested that desensitized MORs have an increased affinity for ligand binding, consistent with our preliminary findings in nonhuman primates. The goal of this study was to validate the effect of agonist-induced desensitization on MOR ligand binding in the mice brain. Specifically, positron emission tomography (PET) experiments were performed using a MOR selective radiotracer, [¹¹C]carfentanil. We measured MOR binding potential at baseline and after pretreatment of two MOR agonists (morphine and SR-17018) in wild-type (WT) mice and β-arrestin2 knockout (βarr2-KO) mice.

Methods: Bruker 4.7T MRI scanner with a PET insert were used to scan WT mice (n = 14). [¹¹C]carfentanil (∼4.72 MBq; specific activity: > 39 GBq/µmol) was intravenously given as bolus. WT mice were scanned at baseline (n = 6), after 15-min pretreatment of morphine (1.0 mg/kg, i.v.; n = 4) or SR-17018 (1.0 mg/kg, i.v.; n = 4). PET data were binned into the 36 frames, and analyzed for binding potentials (BP_ND) using a simplified reference tissue model with cerebellum as the reference tissue. For statistical analysis, a one-way analysis of variance was used.

Results: High-level of specific bindings were identified in the striatum and thalamus (Figure 1) in all groups, consistent with known distribution of MOR in the brain. Based on ANOVA analysis in the WT mice, statistically higher BP_ND was observed in the thalamus and midbrain in morphine-pretreated mice than controls and SR17018-pretreated mice (p < 0.050; Figure 2).

Conclusion: The result of this study suggests that a potential increase in ligand-target affinity due to morphine-induced MOR desensitization, while a G-protein biased MOR agonist, SR-17018, does not trigger receptor trafficking. Experiments on βarr2-KO mice are completed, and data analysis is in progress. Additional data in βarr2-KO mice will verify whether the β-arrestin2 pathway is key to regulate receptor trafficking and will confirm the accessibility of PET for measuring changes in receptor affinity.

Acknowledgements

This research is support by NIH R00DA037928 and R21DA047133 (H.-Y. W.).

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2021-131

Age and BMI associations with brain NET availability using [¹¹C]MRB (#366)

Sheida Koohsari¹, Brian Pittman¹, Nabeel Nabulsi¹, Yiyun H. Huang¹, Richard E. Carson¹, Christopher H. van Dyck², Marc N. Potenza² and David Matuskey^{1, 2}

¹Yale University, PET Center, Department of Radiology and Biomedical Imaging, New Haven Connecticut, USA

²Yale University, Department of Psychiatry, New Haven Connecticut, USA

³Yale University, Department of Neurology, New Haven Connecticut, USA

Abstract

Introduction: Understanding aging in the brain is crucial to understand disorders common in the elderly. Previous studies revealed the neuromodulatory effect of norepinephrine (NE) in conditions like dementia, Parkinson’s disease, and depression.¹ (S,S)-[¹¹C] O methylreboxetine ([¹¹C]MRB) is a selective radiotracer for norepinephrine transporter (NET), the principal regulator of NE. Here we investigate aging, along with body mass index (BMI), on brain NET availability in the largest sample to date.

Methods: Forty-three healthy controls (20 females, 23 males; age range 18–49 years; BMI range: 21–39.4) were included from previous studies. All participants underwent an MRI scan and [¹¹C]MRB PET scan. PET images of individuals were coregistered to their MRI scan. The multilinear reference tissue model 2 (MRTM2) was applied to quantify binding potential (BP_ND) values with the occipital cortex as a reference region. Norepinephrine-rich regions of the brain included the locus coeruleus (LC), pulvinar, raphe nuclei, red nucleus, thalamus, and hypothalamus. We investigated the correlations between BP_ND and age and BMI using a mixed linear model.

Results: Inverse associations between [¹¹C]MRB BP_ND and age were observed in the LC (r = −0.3615; p = 0.0172) (Figure 1), raphe nuclei (r = −0.4619; p = 0.0018), and hypothalamus (r = −0.3074; p = 0.0449), with no gender effects noted. There were no statistically significant correlations between BMI and BP_ND.

Conclusion: We observed lower NET availability with aging consistent with a previous investigation.² This work provides further evidence of NET decreases associated with aging, which could have implications in cognitive and attentional deficits of the elderly. Similar to a previous study,³ we could not replicate the correlation between BMI and NET availability reported previously.⁴ Further investigations with endocrine and behavioral measurements may provide additional insights.

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References

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2021-132

Measuring synaptic density and the dopamine transporter in Parkinson’s disease: a PET imaging study with¹¹C-UCB-J and¹⁸F-FE-PE2I (#367)

David Matuskey¹, Sule Tinaz¹, Mark Dias¹, Mika Naganawa¹, Jean-Dominique Gallezot¹, Sophie Holmes¹, Shannan Henry¹, Sheida Koohsari¹, Jim Ropchan¹, Robert A. Comley², Nabeel Nabulsi¹, Yiyun H. Huang¹, Richard E. Carson¹ and Sjoerd J. Finnema²

¹Yale University, New Haven Connecticut, USA

²Abbvie, North Chicago Illinois, USA

Abstract

Introduction: Synaptic dysfunction and loss are associated with Parkinson’s disease (PD) pathology and have been investigated using positron emission tomography (PET) with the synaptic vesicle glycoprotein 2A (SV2A) radiotracer ¹¹C‑UCB‑J.^1–3 Here we present preliminary ¹¹C‑UCB‑J and ¹⁸F-FE-PE2I data, both acquired within the same PD and healthy control (HC) subjects, to compare synaptic density with dopamine transporter (DAT) availability.

Methods: PD subjects (N = 16; 9M/7F; mean (SD) age 61(8); duration since diagnosis 7(5) years) were included along with matched HCs (N = 5; 2M/3F; mean age 56(8)). All subjects were in good physical health, with no signs of dementia (Montreal Cognitive Assessment score < 21) or severe psychiatric or medical conditions. All dopaminergic or psychotropic medications were withheld during PET imaging days to avoid potential confounds. Subjects underwent MRI, ¹¹C‑UCB‑J PET and ¹⁸F-FE-PE2I PET; PET imaging took place on a high resolution research tomograph (HRRT). As in previous work, binding potential (BP_ND), calculated using the simplified reference tissue model 2 (SRTM2), was the primary outcome measure. Reference regions were centrum semiovale (¹¹C‑UCB‑J) and cerebellum (¹⁸F-FE-PE2I). Primary regions of interest (ROI) were defined on MR and included important motor areas such as the caudate, putamen, substantia nigra (SN) and, for ¹¹C‑UCB‑J only, cortical regions.

Results: In PD subjects compared with HCs,¹¹C‑UCB‑J BP_ND was non-significantly lower in most brain regions, including the SN (-21%, p = 0.2). ¹⁸F-FE-PE2I BP_ND was significantly lower (-38% to -73%) with the greatest difference in the putamen (-73%, p < 0.001) (Figure 1).

Conclusion: In PD subjects, binding of ¹⁸F-FE-PE2I in the PD group was significantly lower, consistent with previous reports.^{3 11}C‑UCB‑J was also lower throughout all motor brain regions examined, but was nonsignificant. Further work is ongoing to investigate the temporal relationship between SV2A and DAT binding in order to increase our understanding of degeneration in PD.

Acknowledgements

We thank AbbVie for financial support of this study, the Connecticut Advocates for Parkinson’s for their help with recruitment and UCB Pharma for providing precursor for ¹¹C‑UCB‑J.

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References

1.Matuskey D, Tinaz S, Wilcox KC, et al. Synaptic changes in Parkinson Disease assessed with in vivo imaging. Ann Neurol 2020; 87: 329–338. [DOI] [PMC free article] [PubMed] [Google Scholar]
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2021-133

Longitudinal test-retest reproducibility of ¹¹C-UCB-J, a PET tracer for synaptic density imaging (#368)

Nikkita Khattar¹, Mika Naganawa², Jean-Dominique Gallezot², Jayanta Mondal², Yihuan Lu², Samantha Rossano², David Matuskey², Yiyun H. Huang², Richard E. Carson² and Takuya Toyonaga²

¹Yale University, School of Medicine, New Haven Connecticut, USA

²Yale University, PET Center, New Haven Connecticut, USA

Abstract

Introduction: ¹¹C-UCB-J, a radioligand for synaptic vesicle glycoprotein 2A (SV2A), is a potential in vivo biomarker for synaptic density.^1,2 Excellent test-retest reproducibility of ¹¹C-UCB-J was reported among same-day scans.³ To expand its applications, high longitudinal reliability is important. In this study, we evaluated same-day and longitudinal (short- to long-term) test-retest reliability of ¹¹C-UCB-J in healthy subjects.

Methods: In total, thirty HS underwent two 60-min ¹¹C-UCB-J scans. Ten subjects had two scans on the same day, while twenty subjects in the longitudinal group had scanned from 1 week to more than two years apart (median: 391 days, range: 7–1028 days). All subjects underwent arterial blood sampling and volume of distribution (V_T) was estimated by one-tissue compartment modeling. Distribution volume ratio (DVR) was calculated using centrum semiovale (CS) or cerebellum as a reference region (DVR_(CS) or DVR_(CB)). CS is defined in AAL space and the other regions of interest (ROIs) were generated by FreeSurfer (Table 1). Reproducibility was examined using test-retest variability (TRV = 100*(test-retest)/{(test+retest)/2}). To evaluate the difference of variance between groups (same-day, longitudinal) and between measures (V_T, DVR_(CS), DVR_(CB)), two-tailed F tests were applied. Longitudinal data were also analyzed with regression analysis.

Results: For V_T, DVR_(CS), and DVR_(CB), variances were consistent across ROIs, except V_T in CS (Table 1). In the same-day group, TRVs in gray matter (GM) regions (averaged over subjects) were 0.5 ± 6.7%, -1.4 ± 9.1%, and 0.3 ± 2.8% for V_T, DVR_(CS) and DVR_(CB), respectively. In the longitudinal group, TRVs for V_T, DVR_(CS) and DVR_(CB) were 0.8 ± 10.2%, 1.3 ± 15.9%, and -0.9 ± 3.8%, respectively. There was no variance difference between the same-day and longitudinal groups for any measure. BP_ND vs. DVR (same-day), BP_ND vs. DVR (longitudinal), and V_T vs. DVR (longitudinal) showed significant variance differences with Bonferroni correction (Figure 1(a)). Regression analysis on longitudinal data showed no significant inter-scan interval effect on TRV (Figure 1(b)).

Conclusion: The reproducibility of ¹¹C-UCB-J DVR (cerebellum) was excellent in both same day and longitudinal groups with BP_ND (CS) showing the poorest TRV. There was no inter-scan interval effect up to 1028 days. For appropriate cases, cerebellum could be a good pseudo reference region for future longitudinal clinical studies.

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Table 1. Test-retest variability for each region.

References

1.Nabulsi NB, Mercier J, Holden D, et al. Synthesis and preclinical evaluation of ¹¹C-UCB-J as a PET tracer for imaging the synaptic vesicle glycoprotein 2A in the brain. J Nucl Med 2016; 57: 777–784. [DOI] [PubMed] [Google Scholar]
2.Finnema SJ, Nabulsi NB, Eid T, et al. Imaging synaptic density in the living human brain. Sci Transl Med 2016; 8: 348ra396. [DOI] [PubMed] [Google Scholar]
3.Finnema SJ, Nabulsi NB, Mercier J, et al. Kinetic evaluation and test-retest reproducibility of [¹¹C]UCB-J, a novel radioligand for positron emission tomography imaging of synaptic vesicle glycoprotein 2A in humans. J Cereb Blood Flow Metab 2018; 38: 2041–2052. [DOI] [PMC free article] [PubMed] [Google Scholar]
4.Rossano S, Toyonaga T, Finnema SJ, et al. Assessment of a white matter reference region for 11C-UCB-J PET quantification. J Cereb Blood Flow Metab 2019; 271678X19879230. [DOI] [PMC free article] [PubMed] [Google Scholar]

2021-134

Simultaneous optogenetic [¹⁸F]FDG-fPET/fMRI to study brain circuits in rats (#369)

Sabrina Buss¹, Tudor M. Ionescu¹, Laura Kuebler¹, Gerald Reischl^{1, 2}, Bernd J. Pichler^{1, 2} and Kristina Herfert¹

¹Eberhard Karls University Tuebingen, Preclinical Imgaing and Radiopharmacy, Tuebingen Baden-Württemberg, Germany

²Eberhard Karls University Tuebingen, Cluster of Excellence iFIT (EXC 2180), Tuebingen Baden-Württemberg, Germany

Abstract

Introduction: Optogenetic functional magnetic resonance imaging (ofMRI) combines a precise neuronal stimulation technique, with fMRI as indirect readout of neuronal activation. This enables a cell-type specific mapping of the whole brain dynamic response to the activation or inhibition of neuronal circuits. In addition, functional positron emission tomography (fPET) enables the detection of metabolic changes with good temporal resolution on single subject level via a continuous [¹⁸F]FDG infusion. In this study, a simultaneous [¹⁸F]FDG-fPET/BOLD-fMRI protocol was applied in rats subjected to optogenetic stimulation.

Methods: Male rats were stereotactically injected with 2 µL of an adeno-associated virus vector overexpressing channelrhodopsin-2 (ChR2) (n = 17) or GFP (control) (n = 10) into the right substantia nigra compacta (rSNc). Eleven weeks post-surgery, an optical fiber connected to a 473 nm laser was implanted into the rSNc. [¹⁸F]FDG-fPET/BOLD-fMRI scans were performed on a 7T small-animal MRI equipped with an inhouse-built PET insertunder a constant infusion of α-chloralose and pancuronium bromide. [¹⁸F]FDG (142 ± 8 MBq) was infused using a bolus plus constant infusion protocol and fMRI data were simultaneously acquired using an EPI-BOLD sequence (TR: 2 s, TE: 18 ms) during a 20 Hz laser light stimulation. Data were preprocessed and analyzed using SPM12.

Results: Optogenetic stimulation of rSNc resulted in BOLD signal changes of 2.4% in the right caudate putamen (CPuR) of ChR2 injected rats, while no changes were detected on the contralateral side and in GFP control rats. BOLD signal changes highly correlated to the stimulation paradigm and mean t-scores of 4.9 ± 1.5 were observed in the dorsal, medial CPuR. A 7% higher [¹⁸F]FDG uptake in the CPuR of ChR2 injected rats was observed compared to the contralateral side and control rats in the last 10-minute time-interval of the PET acquisition (ChR2 > GFP CPuR mean t-scores: 3.6 ± 1.6). In contrast to fMRI, metabolic activation was more pronounced in the ventral, medial part of the CPuR.

Conclusion: We present for the first time simultaneous, dynamic [¹⁸F]FDG-fPET/BOLD-fMRI data during optogenetic stimulation in rats. Our data show a clear spatial and temporal mismatch between activity patterns observed with BOLD-fMRI and [¹⁸F]FDG-fPET, which may be related to the complementary readouts of both.

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Study design (a). Toxic effects on dopaminergic neurons were excluded by [¹¹C]MP PET (b,c). Confirmation of ChR2 expression in the rSTR/rSNc by fluorescence microscopy (d). [¹⁸F]FDG TACs and PET image show tracer uptake in the CPuR over time on single animal level (e, g)and group level (h) compared to the CPuL or GFP group. t-maps show CPuR activation in one ChR2 animal (f). Activation in the CPuR of ChR2 rats is confirmed by BOLD signal changes on group level (j). Overlay of fMRI and fPET reveals spatial matches and mismatches (i). Highest t -scores in ChR2 group in CPu, MB and VTA (k).

2021-135

Manifold component analysis and its use in evaluating stage-wise cortical tau propagation measured with 18F-MK-6240 PET (#370)

Gleb Bezgin¹, Tharick A. Pascoal^{2, 1}, Joseph Therriault¹, Firoza Z. Lussier¹, Min-Su Kang¹, Cécile Tissot¹, Stijn Servaes¹, Yi-Ting Wang¹, Peter Kunach¹, Jenna Stevenson¹, Serge Gauthier¹ and Pedro Rosa-Neto¹

¹McGill Centre for Studies In Aging, Translational Neuroimaging Laboratory, Montreal, QC, Canada

²University of Pittsburgh, Department of Psychiatry, Pittsburgh Pennsylvania, USA

Abstract

Introduction: In systems neuroscience, it is often necessary to represent neuroimaging data in the context of ordered regions, wherein the order signifies particular stages of sensory/cognitive processing, or progression of a disease. One prominent example is the representation of six neuropathological stages of tau protein aggregation in AD patients, first systematically investigated in the seminal Braak & Braak study in 1991.¹ With modern PET tracers, it is possible to track such progression in patients in vivo²; recent studies successfully untangled Braak stage manifestations using the whole brain tau PET/MRI representation, as well as reducing such representation into a discrete six-stage model, with six-region profiles using Braak stage regions.

Methods: We propose a novel approach called Manifold Component Analysis (MCA) for producing pseudo-continuous tau profiles, aiming to track the progression within Braak regions and across them, taking into account the uptake density and capacity. We achieve it in three steps: 1) define Braak regions anatomically on a cortical surface (Figure 1(a)); 2) use surface topology to make pseudo-continuous representation of Braak regions, ensuring gradual transition between neighbouring stage regions (Figure 1(b)); 3) sample 18F-MK-6240 PET tracer uptake across the resulting pseudo-continuous scheme (Figure 1(c)).

Results: Profiled 18F-MK-6240 accumulations across different MCA stages show an increase in follow-up compared to the baseline; such increase is predominant at the Braak region during the corresponding Braak stage, particularly prominent and significant at stages 4 and 5, and corresponding Braak regions IV and V (Figure 1(d) and (e)).

Conclusion: The Braak sub-stage profile representation using MCA helps identify changes within a given Braak stage and across the stages, both in terms of magnitude and spatial progression. It reduces surface manifold data into more interpretable spatial series, at the same time providing information on subtle between-stage transitions which represents a novel systematic way to quantify tau propagation patterns. Importantly, MCA can be used in a vast majority of other applications involving ordered regions, e.g. in the analyses of sensory processing hierarchies.

Acknowledgements

We thank Melissa Savard, Mira Chamoun, Andrea Lessa Benedet, Nesrine Rahmouni, Jaime Fernandez-Arias and Parissa Fereydouni for their help.

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a: discrete Braak regions; b: pseudo-continuous Braak regions; c: 18F-MK-6240 tracer uptake profiles for subjects averaged across their corresponding pathophysiological stages; d: average profiles for subjects assessed longitudinally, involving baseline (blue) and follow-up (red) SUVRs; e: differences between follow-up and baseline for each pathophysiological stage and each Braak region.

References

1.Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 1991; 82: 239–259. [DOI] [PubMed] [Google Scholar]
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2021-136

Evaluation of brain structure and function in currently depressed adults with a history of childhood trauma (#371)

Joshua Jones¹, Samantha J. Goldstein², Junying Wang⁵, John Gardus², Jie Yang³, Ramin V. Parsey² and Christine DeLorenzo^{2, 4}

¹University of Rochester, Rochester New York, USA

²Stony Brook University, Department of Psychiatry and Behavioral Science, Stony Brook New York, USA

³Stony Brook University, Department of Family, Population & Preventive Medicine, Stony Brook New York, USA

⁴Stony Brook University, Department of Biomedical Engineering, Stony Brook New York, USA

⁵Stony Brook University, Department of Applied Mathematics and Statistics, Stony Brook New York, USA

Abstract

Introduction: Structural differences in the dorsolateral prefrontal cortex (DLPFC), anterior cingulate cortex (ACC), hippocampus, and amygdala were reported in adults who experienced childhood trauma; however, the functional consequences are unknown. This multimodal imaging study examined structural and functional consequences of childhood trauma in adults with major depressive disorder (MDD).

Methods: Adult participants ages 18–65 with MDD completed the Childhood Trauma Questionnaire (CTQ) and simultaneous positron emission tomography (PET)/magnetic resonance imaging (MRI). Structure (volume and cortical thickness, n = 83) was quantified from MRI using Freesurfer. Function (metabolic rate of glucose uptake) was quantified from dynamic ¹⁸F-fluorodeoxyglucose (FDG)-PET images (n = 77) using Patlak graphical analysis. A linear mixed model was utilized to examine the association between structural/functional variables and discrete or continuous childhood trauma measures while controlling for confounding factors.

Results: DLPFC metabolism and cortical thickness (Figure 1(c) and (f)) and ACC metabolism (Figure 1(a)) differed significantly between some discrete childhood trauma levels. Hippocampus and amygdala volumes were significantly inversely correlated with continuous CTQ scores (Figure 2(j) and (h)). Specifically, hippocampus and amygdala volumes were lower by 12.96 (95% Confidence Interval [CI]: -23.30, -2.61) and 7.95 mm³ (95% CI: -12.72, -3.18), respectively, per point increase in CTQ.

Conclusion: Examining childhood trauma within MDD as discrete and continuous measures uncovered unique relationships with thickness/metabolism and volume, respectively. This is the first study to report functional differences and provide estimates of volume differences based on childhood trauma within MDD. While longitudinal studies are required to establish causation, this study provides insight into potential consequences of, and therefore potential therapeutic targets for, childhood trauma in the prevention of MDD.

Acknowledgements

This study was funded by R01MH104512, Brain & Behavior Foundation, The Dana Foundation, and an NYS Faculty Development Grant. We acknowledge the biostatistical consultation and support provided by the Biostatistical Consulting Core at the School of Medicine, Stony Brook University.

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2021-137

Impact of direct-4D PET image reconstruction on within- and between-subject variance of [¹¹C]UCB-J in Parkinson’s disease (#373)

Paul Gravel, Kathryn Fontaine, David Matuskey, Richard E. Carson and Jean-Dominique Gallezot

Yale University School of Medicine, Department of Radiology and Biomedical Imaging, New Haven Connecticut, USA

Abstract

Introduction: Several studies have demonstrated the benefits of direct-4D PET image reconstruction, which delivers lower-variance parametric images, over conventional indirect-3D reconstruction techniques. The goal of this work is to evaluate direct-4D reconstruction, applied on real patient PET scans, on within-subject and between-subject variance, compared to indirect-3D reconstruction.

Methods: Eight subjects diagnosed with Parkinson’s disease underwent PET imaging with [¹¹C]UCB-J, a radioligand for measuring synaptic density (SV2A)¹, on the Siemens HRRT². During each scan, continuous head motion data were acquired using the Polaris Vicra, and arterial blood was collected for measurement of the input curve. Indirect-3D reconstruction was performed using the Motion-compensation OSEM List-mode Algorithm for Resolution-recovery (MOLAR)³ followed by estimation of the voxel-wise volume of distribution (V_T = K₁/k₂) using the one-tissue compartment model. Direct-4D reconstruction was performed with Parametric-MOLAR for the one-tissue model (PMOLAR-1T)^4,5, which directly delivers parametric images of V_T. Both reconstruction methods were performed with up to 4 iterations and 30 subsets, including appropriate corrections, with event-by-event motion correction, and used 60 min. of data. In addition, each subject’s list-mode file was down-sampled to 10% of the total counts, to create a set of 10 noisy replicates. Both the voxel-level variance within-subjects (across replicates) and between-subjects were evaluated and compared between indirect-3D and direct-4D.

Results: As expected, the variability within-subject is considerably lower for direct-4D, compared to indirect-3D, (35 ± 7% reduction in SD across GM ROIs, Figures 1 and 2(a) and (c)). At the voxel level, direct‑4D also delivers lower between-subject variance albeit at a smaller degree (25 ± 6% Figure 2(b) and (d)). This is expected since the between-subject SD is composed of a biological and an intrinsic noise (within-subject) component, which direct-4D reduces.

Conclusion: These results show that direct-4D reconstruction, compared to indirect-3D, is considerably better for within-subject and between-subject studies. This approach should increase the sensitivity to detect longitudinal changes in SV2A/synaptic density due to disease progression and treatment effect.

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References

1.Finnema SJ, et al. Imaging synaptic density in the living human brain. Sci Transl Med. 2016; 8. [DOI] [PubMed] [Google Scholar]
2.Matuskey D, et al. Synaptic changes in Parkinson’s disease assessed with in-vivo imaging. Ann Neurol 2020. [DOI] [PMC free article] [PubMed]
3.Johnson CA, et al. Software architecture of the MOLAR-HRRT reconstruction engine. IEEE Nuclear Science Symp Conf Record 2004; 3956–3960. [Google Scholar]
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5.Germino M, Gallezot JD, Yan J, et al. Direct reconstruction of parametric images for brain PET with event-by-event motion correction: evaluation in two tracers across count levels. Phys Med Biol 2017; 62: 5344–5364. [DOI] [PMC free article] [PubMed] [Google Scholar]

2021-138

Initial validation of reconstruction parameters in [¹⁸F]FDG PET brain images aiming scan time reduction (#374)

Samara Pinto¹, Paulo Caribe^{1, 2}, Cristina S. Matushita³, Diego B. Pianta³, Lucas Narciso^{1, 4} and Ana Maria Marques da Silva¹

¹PUCRS, Medical Image Computing Laboratory (MEDICOM), Porto Alegre, Brazil

²Ghent University, Medical Imaging and Signal Processing (MEDISIP), Ghent, Belgium

³Brain Institute of Rio Grande do Sul, Porto Alegre, Brazil

⁴Western University, Department of Medical Biophysics, London, ON, Canada

Abstract

Introduction: Positron emission tomography (PET) imaging with [¹⁸F]FDG provides valuable information regarding the underlying pathological processes in neurodegenerative disorders, such as Alzheimer’s disease (AD)^1,2. Therefore, image reconstruction optimization strategies to reduce acquisition time are essential for this population due to involuntary motion³. This study aims to evaluate retrospective [¹⁸F]FDG PET data of healthy and AD individuals reconstructed with optimized reconstruction parameters to verify the feasibility of acquisition time reduction while ensuring satisfactory image quality and minimal impact on quantification.

Methods: PET data were obtained from 17 healthy individuals and 18 AD patients on a PET/CT scanner (GE Discovery 600) after injecting 240 ± 50 MBq of [¹⁸F]FDG. Images were reconstructed with the standard clinical settings (OSEM, 8 iterations, 16 subsets, 3 mm smoothing filter, 8 min acquisition time) and optimized reconstruction parameters⁴ (OSEM, 4 iterations, 32 subsets, 4-mm smoothing filter, 5 min acquisition time). Contrast, standardized uptake value ratio (SUVR, pons was used as reference), coefficient of variation (COV), signal-to-noise ratio (SNR), and bias were measured. Additionally, both sets of images were randomly and blindly presented to two experienced physicians. Image quality was scored (1–5; score 3 represented clinical quality) in image noise, contrast, and overall image quality. Paired t-test was used to identify differences between metrics.

Results: Metrics in Figure 1(a) from images reconstructed with optimized and standard parameters are similar for both groups. Image quality assessment (Figure 1(b)) showed no differences between clinical and optimized reconstruction parameters (Figure 2 for visual comparison). The 5 min acquisition represents a 40% reduction in imaging time compared to the standard protocol (8 min), without substantial differences in both groups’ quantitative or qualitative analyses.

Conclusion: Optimized reconstruction parameters resulted in images with similar quantification and quality compared with the standard clinical protocol, reinforcing our previous assessment in a phantom study⁴. Shortening the acquisition time is therefore possible by optimizing image reconstruction parameters without a loss in image quality. The reduced imaging time with equivalent image quality is essential for patients with neurodegenerative diseases, both by increasing patient comfort and limiting image artifacts due to head movements.

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References

1.Lowe VJ., et al. Neuroimaging correlates with neuropathologic schemes in neurodegenerative disease. Alzheimer’s Dement 2019; 15: 927–939. [DOI] [PMC free article] [PubMed] [Google Scholar]
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4.Pinto SO, Caribe PRRV, Narciso L, et al. Optimization of reconstruction parameters in [18F]FDG PET brain images aiming scan time reduction. Rev Bras Física Médica 2021; 15: 611. [Google Scholar]

2021-139

Investigating autism spectrum disorder with synaptic density PET imaging (#376)

David Matuskey, Mika Naganawa, Sheida Koohsari, Takuya Toyonaga, Kristen Torres, Lauren Pisani, Caroline Finn, Julie Wolf, Nabeel Nabulsi, Jim Ropchan, Yiyun H. Huang, Richard E. Carson, Adam Naples and James C. McPartland

Yale University, New Haven Connecticut, USA

Abstract

Introduction: The neuropathology of autism spectrum disorder (ASD) is poorly understood at the molecular level. Evidence from animal models, genetics, post-mortem studies, and single-gene disorders suggests possible involvement of synaptic changes. Here, we use positron emission tomography (PET) to assess the density of synapses with synaptic vesicle glycoprotein 2A (SV2A) in autistic adults using ¹¹C‑UCB‑J.

Methods: Eleven individuals with ASD (mean age (SD) 25 (4); six males), and eleven demographically matched healthy comparison controls (HC; 27 (4); six males) participated in an ¹¹C‑UCB‑J PET scan. Volume of distribution (V_T: ratio of activity in tissue relative to blood) was the primary outcome measure and computed with an arterial input function. Gray matter masking (GMM) and partial volume correction (PVC) with both Muller-Gartner (MG) and Iterative Yang (IY) were applied to control for possible volumetric differences. T-tests were calculated for between group differences, and p values were uncorrected for multiple comparisons given the exploratory nature.

Results: With a GMM, there were no significant findings between ASD and HCs, with brain regions varying between -4%-4%. Using MG, a significant lower V_T was found with ASD in the orbitofrontal cortex (-12%, p = 0.04) and partial lobe (-12%, p = 0.03), with trends in the ventromedial prefrontal cortex (-9%, p = 0.07), whole frontal lobe (-10%, p = 0.08) and posterior cingulate (-13%, p = 0.08). Using IY, regions varied between -4%-5% and were not significant.

Conclusion: To our knowledge, this is the first in vivo investigation with SV2A PET in ASD. Contrary to expectations, the results obtained by the two PVC methods were different. Analyses are ongoing to understand the factors that may influence the PVC methods, such as the definition of brain regions, differences in white matter and differences in volume.

2021-140

Centrum semiovale as reference region – An evaluation of methods to quantify [18F]FPEB PET binding data in man (#377)

Max Andersson, Katarina Varnäs, Christer Halldin, Jacqueline Borg, Lars Farde and Johan Lundberg

Karolinska Institutet, Center for Psychiatry Research, Department of Clinical Neuroscience, Stockholm, Sweden

Abstract

Introduction: Information have been reported on 3-[18F]Fluoro-5-[(pyridine-3-yl)ethynyl]benzonitrile ([18F]FPEB)¹ binding to the metabotropic glutamate receptor 5, based on Positron Emission Tomography (PET) data alone², or in combination with quantification of radioactivity in arterial blood.³ In the absence of arterial data, cerebellar white matter (cerWM) has been suggested as a possible reference region.⁴ However, no comparisons with other potential reference regions are published and blocking studies including cerWM are lacking.

Methods: Eight healthy male subjects (age 20–27) were recruited and examined twice (2–7 days apart at approximately the same time of day) using the High Resolution Research Tomograph (Siemens Molecular Imaging). A tracer dose of the radioligand [18F]FPEB was given as a bolus injection and dynamic PET data was collected for 93 minutes and divided into 38 time frames. Arterial blood radioactivity was measured both continuously for the first 10 minutes and with discrete samples to produce a metabolite corrected plasma radioactivity curve. Regions of interest (ROI) were automatically delineated using Freesurfer 6.0. ROIs used as reference regions were created by uniform and automated editing of the obtained cerebellar and cerebral white matter ROIs. Tracer kinetics was modeled for each region of interest using the two tissue compartment model (2TCM) as well as the multilinear reference tissue model 2 (MRTM2) to produce measures of distribution volume (V_T) and binding potential (BP_ND). Binding potentials using both cerWM and Centrum semiovale (CSO) as reference region were calculated. To investigate specific binding in proposed reference regions, autoradiography using [18F]FPEB and blocking with 10µM MPEP was performed.

Results: Including seven of the eight examined subjects, V_T was numerically lower in CSO than in cerWM. Using CSO as reference region produced higher binding potentials than cerWM as well as a lower coefficient of variation (COV) and lower absolute percentage difference (APD) between the examinations (Table 1).⁵ Results from autoradiography indicate low but existing specific binding in suggested reference regions and are consistent with the results from PET.

Conclusion: While still exhibiting specific binding, CSO could be considered as an alternative to cerWM as reference region in studies with [18F]FPEB in the absence of arterial data.

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Table 1. Mean and standard deviation (SD) of distribution volume (V_T) and binding potential (BP_ND) in frontal cortex (FC), temporal cortex (TC), anterior cingulate cortex (ACC), caudate (CAU), cerebellar white matter (cerWM) and centrum semovale (CSO). 2TCM using arterial input and MRTM2 using CSO and cerWM as reference regions. Absolute percetage difference (APD) and coefficient of variance (COV).

References

1.Wong D, Waterhouse R. ‘ 18F-FPEB, a PET radiopharmaceutical for quantifying metabotropic glutamate 5 receptors: a first-in-human study of radiochemical safety, biokinetics, and radiation dosimetry. J Nucl Med 2013; 54: 388–396. [DOI] [PMC free article] [PubMed] [Google Scholar]
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5.Further statistical comparisons will be added with the inclusion of the 8th subject.

2021-141

Comparison of a simultaneous estimation method for quantifying [¹⁸F]FEPPA uptake to standard compartmental analysis (#378)

Praveen Dassanayake^{1, 2}, Udunna Anazodo^{1, 2}, Linshan Liu², Pablo M. Rusjan^{4, 5}, Elizabeth Finger^{2, 3} and Keith St Lawrence^{1, 2}

¹University of Western Ontario, Department of Medical Biophysics, London, ON, Canada

²Lawson Health Research Institute, Imaging, London, ON, Canada

³University of Western Ontario, Department of Clinical Neurological Sciences, London, ON, Canada

⁴Douglas Research Centre, Human Neuroscience Division, Montréal, QC, Canada

⁵McGill University, Department of Psychiatry, Montréal, QC, Canada

Abstract

Introduction: The accepted method for quantifying [¹⁸F]FEPPA, a translocator protein 18 kDa (TSPO) tracer, is by two-tissue compartment modelling (2TCM) to measure the total distribution volume (V_T). However, this approach requires ≥ 2-h acquisition and arterial sampling.¹ In this work, we investigated a minimally invasive alternative that combines simultaneous estimation (SIME)^2,3 with an image-derived input function (IDIF), metabolite corrected using venous samples. The approach was evaluated on retrospective [¹⁸F]FEPPAdata to assess the feasibility of reducing the scan time to 90 min. Venous sampling was verified against arterial sampling in animal studies. The combination was used to measure the binding potential (BP_ND) in a separate set of [¹⁸F]FEPPA data.

Methods: Retrospective data from Twelve healthy volunteers (8 high affinity binders, HABs; 4 mixed affinity binders, MABs) consisting of 180 min of scanning, injection of 5 ± 0.5 mCi [¹⁸F]FEPPA, and arterial sampling.¹ SIME and 2TCM were applied to compare V_T estimates across six regions-of-interest (ROIs). Next, SIME was applied to 180, 120 and 90 min of data to determine if BP_ND was affected by duration. Animal study consisted of ten pigs in which metabolite correction was applied to simultaneously acquired arterial and venous samples. The last aim involved seven healthy volunteers, 90 min of imaging, and IDIFs extracted using caliPER.⁴

Results: SIME and 2TCM produced similar mean values for V_T and V_ND; however, SIME reduced the inter-subject variability in V_T by 45 ± 17% (Figure 1). Reducing imaging to 90 min did not significantly change BP_ND (Figure 1(c)), and BP_ND was significantly higher for HABs than for MABs (i.e. frontal lobe BP_ND = 5.4 ± 0.8 ^HABs, 3.4 ± 0.7 ^MABs). Animal experiments demonstrated good agreement between venous and arterial [¹⁸F]FEPPA fractions (Figure 2(a)). Finally, BP_ND measured using venous metabolite-corrected IDIFs were in agreement with BP_ND from the retrospective data (Figure 2(c)).

Conclusion: Regional V_T and V_ND estimates from SIME were in good agreement with 2TCM. SIME worked well with 90-min acquisition and was sensitive to the difference between HABs and MABs. Figure 2 indicates that replacing arterial with venous samples for metabolite correction and using IDIFs are both feasible, showing the potential of the minimally invasive SIME approach.

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References

1.Rusjan PM, Wilson AA. Quantitation of translocator protein binding in human brain with the novel radioligand [18F]-FEPPA and positron emission tomography. J Cereb Blood Flow Metabolism 2011; 31: 1807–1816. [DOI] [PMC free article] [PubMed] [Google Scholar]
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3.Schain M, Zanderigo F. Estimation of the binding potential BPND without a reference region or blood samples for brain PET studies. Neuroimage 2017; 146: 121–131. [DOI] [PubMed] [Google Scholar]
4.Dassanayake P, Cui L. CALIPER: a software for blood-free parametric Patlak mapping using PET/MRI input function. bioRxiv 2021;. [DOI] [PubMed]

2021-142

PET imaging of demyelination in traumatic brain injury with [¹⁸F]3F4AP in mice (#379)

Karla M. Ramos-Torres¹, Emiri Mandeville², Kazue Takahashi¹, Eng Lo² and Pedro Brugarolas¹

¹Massachusetts General Hospital, Gordon Center for Medical Imaging, Department of Radiology, Boston Massachusetts, USA

²Massachusetts General Hospital, Department of Radiology, Charlestown, USA

Abstract

Introduction: Traumatic brain injury (TBI) results from energy transmission to the brain, disrupting its normal function.¹ While clinical TBI is markedly heterogenous, the primary injury is characterized by damage to neurons, glial cells, and blood vessels. A complex secondary injury can later be observed by metabolic, cellular, and molecular changes that lead to cell death, tissue damage and white matter degeneration involving demyelination.²

Assesing myelin changes via PET imaging can shed light on the role of demyelination in TBI, providing better understanding of the disease and improvement in diagnosis and treatment monitoring. To this end we postulated that [¹⁸F]3F4AP, a novel radiotracer based on a multiple sclerosis drug that binds to potassium channels on demyelinated axons,³ could be used to image demyelination after TBI. Indeed, on a prior [¹⁸F]3F4AP imaging study in a rhesus macaque, we observed a focal hotspot at a previously injured brain area that could not be explained by changes in perfusion or inflammation.⁴ This finding motivated us to further characterize [¹⁸F]3F4AP response following brain injury using a rodent model of TBI.

Methods: Controlled cortical impact (CCI), a well-established model of TBI, was used in mice in combination with microPET studies and ex-vivo examination of the brains. [¹⁸F]3F4AP was synthesized according to previous reports.^3,5 Dynamic PET/CT imaging was performed for at least 30min after IV injection of ∼200µCi of [¹⁸F]3F4AP. Animals were imaged over a 4-week period following the injury. Postmortem analysis (gamma counting, immunoblotting and histochemical staining) was performed on a subset of animals.

Results: Longitudinal PET imaging in mice after CCI showed increased [¹⁸F]3F4AP uptake peaking at 7 days-post-injury (33 ± 8% increase in SUV_0-30min in the injury site, n = 6 mice). Gamma counting of the left vs. right side of the brain showed a 40% increase in radiotracer concentration on the injured side compared to the contralateral side (n = 3), consistent with the PET findings. Histochemical staining showed reduced myelin staining (LFB) on the injured side consistent with demyelination.

Conclusion: This study shows that [¹⁸F]3F4AP is a potential tracer for imaging TBI and a prospective noninvasive method for diagnosing and monitoring demyelinating diseases.

Acknowledgements

R00EB020075, R01NS114066, P41EB022544, S10OD018035, T32EB013180

References

1.Flygt J, Djupsjo A, Lenne F, et al. Myelin loss and oligodendrocyte pathology in white matter tracts following traumatic brain injury in the rat. Eur J Neurosci 2013; 38: 2153–2165, 12179. [DOI] [PubMed] [Google Scholar]
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4.Guehl NJ, Ramos-Torres KM, Linnman C, et al. Evaluation of the potassium channel tracer [18F]3F4AP in rhesus macaques. J Cereb Blood Flow Metab 2020; 271678X20963404. [DOI] [PMC free article] [PubMed]
5.Basuli F, Zhang X, Brugarolas P, et al. An efficient new method for the synthesis of 3-[18 F]fluoro-4-aminopyridine via Yamada-Curtius rearrangement. J Labelled Comp Radiopharm 2017; 61: 112–117. [DOI] [PMC free article] [PubMed] [Google Scholar]

2021-143

Risk and resilience in a rodent model of posttraumatic stress disorder: an in vivo [¹⁸F]FPEB and positron emission tomography imaging study examining the role of metabotropic glutamate receptor 5 (#380)

Ruth H. Asch¹, Santosh Pothula¹, Takuya Toyonaga², Krista Fowles³, Stephanie M. Groman⁴, Rolando Garcia-Milian⁵, TuKiet T. Lam^{6, 7} and Irina Esterlis^1,
8

¹Yale University School of Medicine, Department of Psychiatry, New Haven Connecticut, USA

²Yale University School of Medicine, Department of Radiology & Biomedical Imaging, New Haven Connecticut, USA

³Yale University, Yale Positron Emission Tomography Center, New Haven Connecticut, USA

⁴University of Minnesota Medical School, Department of Neuroscience, Minneapolis Minnesota, USA

⁵Yale University School of Medicine, Bioinformatics Support Program, Cushing/Whitney Medical Library, New Haven Connecticut, USA

⁶Yale University School of Medicine, Department of Molecular Biophysics and Biochemistry, New Haven Connecticut, USA

⁷Yale University School of Medicine, Keck MS & Proteomics Resource, New Haven Connecticut, USA

⁸VA Connecticut Healthcare System, US Department of Veterans Affairs National Center for Posttraumatic Stress Disorder, West Haven Connecticut, USA

Abstract

Introduction: Evidence suggests individual differences in developing posttraumatic stress disorder (PTSD). Clinical investigations implicate the metabotropic glutamate receptor 5 (mGluR5) and related signaling in PTSD. Here, we utilized a preclinical model to assess the utility of mGluR5 as a biomarker of traumatic-stress vulnerability.

Methods: Male (n = 16) and female (n = 12) rats were exposed to a stress-enhanced fear leaning (SEFL) paradigm- a model recapitulating aspects of PTSD symptomatology- and compared with control animals (n = 7 male; n = 4 female). SEFL rats were identified as vulnerable or resilient based on high vs low freezing behavior. Positron emission tomography at baseline and postSEFL was used to calculate [¹⁸F]FPEB non-displaceable binding potential (BP_ND) in four regions of interest (ROIs): amygdala, hippocampus, striatum, and prefrontal cortex (PFC). Baseline vs. postSEFL differences in BP_ND were calculated as ΔBP_ND. Additionally, we performed functional analyses of differentially expressed proteins in the PFC.

Results: There were no significant between group (control vs resilient vs vulnerable) differences in mGluR5 availability at baseline or postSEFL. However, there were significant time by sex (p = 0.021) and group by sex by time (p = 0.043) interactions across ROIs, with vulnerable rats showing trends towards increased mGluR5 availability, whereas resilient rats showed trends toward decreased mGluR5 availability postSEFL relative to baseline. Interestingly, vulnerable males exhibited greater postSEFL increases in mGluR5 availability as compared to vulnerable females. Within the SEFL groups, greater increases in mGluR5were associated with more freezing behavior on day 1 of the SEFL paradigm (fear expression/learning; r = 0.424–0.538, p = 0.039–0.007), and PFC ΔBP_ND was positively correlated with day 2 freezing behavior (contextual fear memory; r = 0.504, p = 0.012). Functional proteomic analyses revealed further sex differences, with SEFL males showing upregulation of synaptic long-term depression and glucocorticoid signaling, but vulnerable females exhibited changes in glutathione metabolism and acute phase response pathways.

Conclusion: Increased mGluR5 availability may be involved in the etiology of PTSD-related phenotypes. These results additionally highlight potentially important sex differences in responses to traumatic stress, including differential involvement of mGluR5 and related molecular networks.

2021-144

Progression of Tau and neuroinflammation PET are independently associated with structural network reorganization in Alzheimer’s disease (#381)

Julie Ottoy¹, Min-Su Kang², Jonah Isen¹, Gleb Bezgin², Jean-Paul Soucy³, Serge Gauthier², Sandra E. Black^{1, 4}, Pedro Rosa-Neto^{2, 3} and Maged Goubran^1,
5

¹University of Toronto, LC Campbell Cognitive Neurology Unit, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, ON, Canada

²McGill University, Translational Neuroimaging Laboratory, Montreal, QC, Canada

³McGill University, Montreal Neurological Institute, Montreal, QC, Canada

⁴University of Toronto, Department of Medicine (Division of Neurology), Toronto, ON, Canada

⁵University of Toronto, Department of Medical Biophysics, Toronto, ON, Canada

Abstract

Introduction: Alzheimer’s disease (AD) is characterized by alterations in the global and local topology of the brain’s structural network.¹ No studies have yet investigated how network topology in AD relates to amyloid, tau, and neuroinflammation together.

Methods: We employed diffusion-weighted MRI with probabilistic fiber tractography and graph theory approaches to investigate the topological organization of the white matter tracts in 105 cognitively normal (CN) amyloid&tau-negative, 37 CN amyloid-positive, and 72 MCI-AD amyloid-positive [TRIAD cohort]. Graph metrics were quantified globally and locally including: 1) connectivity strength; 2) efficiency²; 3) eigenvector centrality,³ reflecting nodal reinforcement of network influence; and 4) global modularity,⁴ reflecting intra-network connectivity and inter-network separation. All metrics were relative to their corresponding random-based metrics. We investigated associations of global graph metrics with amyloid-PET (¹⁸F-NAV4694) in AD-signature, and with tau-PET (¹⁸F-MK6240) and neuroinflammation-PET (¹¹C-PBR28, n = 93) in Braak-stages. All associations were corrected for age, sex, and APOE-ε4. Local associations (32 atlas-based regions) were additionally adjusted for local volume and co-pathology and multiple comparisons. Finally, each graph metric was associated with cognition (MMSE) while adjusting for global amyloid and BraakI-IV tau.

Results: Globally, we found that: 1) Increased tau was significantly associated with all graph metrics (Figure 1), which became stronger with Braak-stage progression; 2) Increased neuroinflammation in BraakIII-IV and BraakV-VI was significantly associated with reduced connectivity strength (P = 0.008 and P = 0.04), which remained significant in BraakIII-IV after tau adjustment; and 3) Increased amyloid was significantly associated with reduced connectivity strength, modularity, and centrality (all P < 0.05), which disappeared after tau adjustment. Reduced strength and centrality were associated with cognitive impairment (P = 0.001 and P = 0.026; after adjustment for all PET). Locally, tau inversely related to centrality in temporal and posterior/parietal regions (P_FDR < 0.05), suggesting reduced communication between these regions and the remaining network (Figure 2). In contrast, tau related positively to centrality in frontal and motor-sensory regions.

Conclusion: Tau pathology and neuroinflammation are associated with structural network alterations in AD with weakened and strengthened central roles for temporo-parietal and frontal regions, respectively. This may indicate a hierarchal shift of the structural network in AD where anterior/frontal networks gain importance, possibly indicating a compensatory mechanism for posterior/temporal dissociation.

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References

1.Dai Z, He Y. Disrupted structural and functional brain connectomes in mild cognitive impairment and Alzheimer’s disease. Neurosci Bull 2014; 30: 217–232. [DOI] [PMC free article] [PubMed] [Google Scholar]
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2021-145

A reference tissue forward model for improved PET accuracy using within-scan displacement studies (#382)

Joseph B. Mandeville^{1, 2}, Michael A. Levine^{1, 2}, Wim Vanduffel^{3, 1}, Bruce R. Rosen¹ and Christin Y. Sander^1,
2

¹Massachusetts General Hospital, A.A. Martinos Center for Biomedical Imaging, Boston Massachusetts, USA

²Harvard Medical School, Boston Massachusetts, USA

³KU Leuven, Laboratory for Neuro- and Psychophysiology, Leuven, Belgium

Abstract

Introduction: PET displacement experiments often use within-scan challenges as an alternative to sequential scans to decrease the temporal separation of neural states and to decrease costs or increase subjects. A one-tissue model is often used to analyze such data. In this study, we developed a novel reference region method and compared this to a 1-tissue analysis using a dataset of lateralized dopamine release in a baboon model of deep brain microstimulation, informed by simultaneous fMRI and previous literature.

Methods: A baboon was implanted with a unilateral microstimulation probe in ventral tegmentum area (VTA) to elicit dopamine release in the projection to nucleus accumbens (NAc) as performed by others.^1,2 Twelve [¹¹C]raclopride scans in eight sessions were acquired using within-scan stimulation designs. Data were analyzed by the MRTM method plus challenge method^3,4 and by a novel alternative: a forward-model full reference tissue model (fFRTM) using a single value of k₄ to stabilize results. The forward approach avoided problems associated with inverse solutions based upon noisy data regressors,^3,5 including invalid cost functions and errors from matrix inversion in the presence of noise. The optimal value of k₄ for each session was determined from goodness of fit across a series of automatically generated regions spanning binding potentials of interest. Model performance was assessed using indices of 1) test-retest reproducibility in BP_ND, 2) stability, which measures the rate of convergence of BPND versus time, and 3) sidedness of the stimulus-induced change ΔBP_ND.

Results: fFRTM identified a best value for 1/k₄ of 16.9 + 3 min. Reproducibility for fFRTM and the MRTM2 method were not statistically different within striatum. However, fFRTM offered considerably better stability (Figure 1), a critical index using within-scan designs. Mapping of stimulus-induced DBP_ND was lateralized using fFRTM with localization similar to fMRI, whereas MRTM2-based mapping was not lateralized and was consistent with simulated predictions of model bias as a function of baseline BP_ND.⁵

Conclusion: A new fFRTM implementation outperformed a 1-tissue analysis based upon MRTM for analysis of within-scan challenges by providing faster convergence of BP_ND, lateralization of DBP_ND consistent with simultaneous fMRI, and no worse test-retest reproducibility of BP_ND.

Acknowledgements

This research was supported by grants from the National Institutes Health (R01NS112295, K99DA043629, R00DA043629, P41EB015896, S10RR022976, S10RR019933, S10RR017208); Leuven (C14/17/109); Fonds Wetenschappelijk Onderzoek-Vlaanderen (FWO-Flanders; G0B8617N, G0E0520N); and the European Union’s Horizon 2020 Framework Programme for Research and Innovation under Grant Agreement No 945539 (Human Brain Project SGA3).

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References

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2021-146

First-in-human use of [¹¹C]CPPC with PET for imaging the macrophage colony stimulating factor 1 receptor in healthy brain (#383)

Jennifer M. Coughlin^{1, 2}, Yong Du², Wojciech Lesniak², Courtney Harrington¹, Mary Katherine Brosnan², Riley O’Toole¹, Adeline Zandi², Shannon Eileen Sweeney¹, Yunkou Wu², Daniel Holt², Robert Dannals², Andrew Horti², Andrew Hall² and Martin G. Pomper^{2, 1}

¹Johns Hopkins Medical Institutions, Department of Psychiatry and Behavioral Sciences, Baltimore, Maryland, USA

²Johns Hopkins Medical Institutions, Russell H. Morgan Department of Radiology and Radiological Science, Baltimore, Maryland\, USA

Abstract

Introduction: Imaging of microglia, the brain’s resident immune cells, and their contribution to brain injury and repair across neuropsychiatric conditions has been widely pursued using PET-based radiotracers. However, relevant targets such as 18 kDa translocator protein may be expressed on other cell types in human brain. [¹¹C]CPPC was developed to image the macrophage colony stimulating factor 1 receptor (CSF1R) that is essentially only expressed by microglia in the brain. We recently demonstrated high, specific uptake of [¹¹C]CPPC in murine and nonhuman primate models of neuroinflammation, and now present its pharmacokinetic behavior in the brains of healthy individuals.

Methods: Eight individuals within 18–65 years of age and in stable health participated. [¹¹C]CPPC was injected via bolus intravenous injection at the initiation of dynamic PET neuroimaging on a High Resolution Research Tomograph scanner. Ninety minutes of dynamic emission data were collected after bolus injection of [¹¹C]CPPC, with collection of arterial blood samples for generation of a metabolite-corrected arterial input function. PET images were reconstructed into 30 frames using the iterative ordinary-Poisson ordered-subset expectation-maximization algorithm. Time-activity curves (TACs) were generated for regions of interest using the co-registered magnetic resonance imaging data from each participant. One- and two-tissue compartmental models (1TCM and 2TCM), as well as Logan graphical analysis were then compared.

Results: Plasma activity peaked within 60 seconds post injection and decreased to < 5% of the peak by 10 minutes. HPLC isolated [¹¹C]CPPC from its radiometabolites, which were more polar and well resolved from the parent compound. [¹¹C]CPPC represented ∼80% of total plasma activity by 30 minutes and ∼45% by 90 minutes. [¹¹C]CPPC rapidly entered the brain, and cortical and subcortical tissue TACs peaked by 30–35 minutes post injection and then declined. The 1TCM was preferred. Total distribution volume values computed from 1TCM aligned well with those from Logan graphical analysis (t* = 30), with V_T values listed highest to lowest in thalamus > cortical regions > hippocampus.

Conclusion: For all healthy subjects, [¹¹C]CPPC PET data yielded a pattern of brain uptake in vivo that fits well a 1TCM in key regions of interest, and supports study further of [¹¹C]CPPC for imaging the CSF1R in the healthy human brain.

2021-147

Interaction between vascular risk and Alzheimer’s disease pathology boosts neurodegeneration and cognitive decline in cognitively unimpaired individuals (#384)

João Pedro Ferrari-Souza^{1, 2}, Wagner S. Brum³, Lucas A. Hauschild¹, Lucas U. Da Ros¹, Pâmela C. Lukasewicz Ferreira^1,
2, Bruna Bellaver^{1, 2}, Douglas T. Leffa⁴, Andrei Bieger¹, Cécile Tissot^{5, 2}, Marco Antônio De Bastiani¹, Andréa L. Benedet^{3, 5}, Joseph Therriault⁵, Diogo O. Souza¹, Pedro Rosa-Neto⁵, Thomas Karikari^{3, 2}, Tharick A. Pascoal^{2, 5} and Eduardo R. Zimmer^{1, 6}

¹Universidade Federal do Rio Grande do Sul, Department of Biochemistry, Porto Alegre, Brazil

²University of Pittsburgh, Department of Psychiatry, Pittsburgh Pennsylvania, USA

³Sahlgrenska University Hospital, Clinical Neurochemistry Laboratory, Gothenburg, Sweden

⁴Hospital de Clínicas de Porto Alegre, ADHD Outpatient Program & Development Psychiatry Program, Porto Alegre, Brazil

⁵McGill University, McGill Centre for Studies in Aging, Montreal, QC, Canada

⁶Universidade Federal do Rio Grande do Sul, Department of Pharmacology, Porto Alegre, Brazil

⁷The Sahlgrenska Academy at the University of Gothenburg, Department of Psychiatry and Neurochemistry, Mölndal, Sweden

⁸McGill University, Department of Neurology and Neurosurgery, Montreal, QC, Canada

Abstract

Introduction: Vascular risk factors (VRFs) play an important role in the development of Alzheimer’s disease (AD). However, it is not fully understood how VRFs are associated with AD pathology to promote neurodegeneration and cognitive decline. In the present retrospective cohort study, our primary objective was to test whether VRF burden synergistically interacts with AD pathology to accelerate neurodegeneration and cognitive decline in cognitively unimpaired (CU) individuals. Secondarily, we aimed to assess whether VRF burden is related to changes in cerebrospinal fluid (CSF) AD biomarkers.

Methods: We assessed CU participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. Baseline VRF burden was calculated considering the history for cardiovascular disease, hypertension, diabetes mellitus, hyperlipidemia, stroke or transient ischemic attack, smoking, atrial fibrillation, and left ventricular hypertrophy. AD pathology was evaluated using CSF amyloid-β_1-42 (Aβ_1-42) and CSF tau phosphorylated at threonine 181 (p-tau₁₈₁). Individuals were dichotomized as having an elevated VRF burden if ≥ 2 VRFs (V+) and as presenting biological AD if CSF p-tau₁₈₁ ≥ 24 pg/mL and CSF Aβ_1-42 ≤ 976.6 pg/mL [(AT)+]. Linear mixed-effects (LME) models were performed to evaluate the longitudinal trajectory of (i) plasma neurofilament light (NfL; n = 269), (ii) cognition indexed by modified version of Preclinical Alzheimer’s Cognitive Composite (mPACC; n = 503), and (iii) CSF AD biomarkers (Aβ_1-42 and p-tau₁₈₁; n = 284). Additionally, time-to-event analysis was carried to evaluate the risk of clinical progression to cognitive impairment (n = 503).

Results: LME models demonstrated that an elevated VRF burden interacted with AD pathology to promote higher rates of neurodegeneration (β = 5.68, p = .005; Figure 1(a)) and cognitive decline (β = −0.43, p = .019; Figure 1(b)). Nonetheless, VRF burden was not associated with CSF Aβ_1-42 or p-tau₁₈₁ changes over time. Survival analysis demonstrated that only individuals with the presence of both biological AD and elevated VRF burden [(AT)+V+] had a significantly greater risk of clinical progression to cognitive impairment (adjusted Hazard Ratio = 3.5, p < .001).

Conclusion: Our results suggest that VRF burden and Alzheimer’s disease pathology are independent processes, however, they synergistically lead to neurodegeneration and cognitive decline, favoring the onset of cognitive impairment. These findings support that the clinical evaluation of vascular risk factor burden might improve the clinical assessment especially of subjects at higher risk for developing cognitive impairment.

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2021-148

APOE isoforms differentially modulate the associations between regional tau deposition and neuroinflammation in Alzheimer’s disease (#385)

Yi-Ting Wang^{1, 3}, Andréa L. Benedet⁴, Cécile Tissot^1,
3, Firoza Z. Lussier^{1, 3}, Gleb Bezgin^{1, 3}, Stijn Servaes^{1, 3}, Joseph Therriault^{1, 3}, Min-Su Kang^{1, 2}, Jaime Fernandez Arias^{1, 3}, Sulantha Mathotaarachchi¹ and Pedro Rosa-Neto^{1, 2}

¹McGill University, The McGill University Research Centre for Studies in Aging, Montreal, QC, Canada

²McGill University, Department of Neurology and Neurosurgery, Montreal, QC, Canada

³McGill University, Douglas Research Centre, Montreal, QC, Canada

⁴University of Gothenburg, Institute of Neuroscience and Physiology, Gothenburg, Sweden

Abstract

Introduction: Apolipoprotein E (APOE) is a 34-kDa glycoprotein highly expressed in the CNS, primarily by astrocytes and microglia. Three allelic variants: APOE ε2, APOE ε3 and APOE ε4 exist, with this APOE polymorphisms being recognised as the most important risk factors for sporadic Alzheimer disease (AD). One hallmark of AD is the presence of neuroinflammation, which manifests as the presence of both reactive astrocytes and microglia. Mounting evidence suggests that APOE has immunomodulatory effects and it seems to modulate brain inflammatory responses in an isoform-dependent manner. The role of APOE ε4 in neuroinflammation was interrogated in previous studies. Experiments in APOE targeted-replacement mice showed that APOE ε4 mice had a greater inflammatory response to LPS injection than APOE ε3 mice. However, the relevance of these mechanisms to other isoform-dependent disease-relevant observations, such as differential tau deposition still warrants further investigation.

Methods: This was a cross-sectional study examining a total number of 162 subjects from the TRIAD cohort at McGill University Research Centre for Studies in Aging, Canada. Cerebral tau neurofibrillary tangles were assessed using positron emission tomography (PET) radiopharmaceuticals [¹⁸F]MK6240. Cerebrospinal fluid (CSF) neuroinflammation biomarkers including soluble triggering receptor expressed on myeloid cells 2 (sTREM2), YKL40 and glial fibrillary acidic protein (GFAP) were also measured. Voxelwise analyses were performed to evaluate the relationships between regional tau burden and neuroinflammation biomarkers.

Results: Voxelwise analyses revealed that subjects with different APOE variants showed different relationships between neuroinflammation biomarkers and tau burden. Noteworthy, in APOE ε4 carriers, a significant correlation between neuroinflammation biomarkers and tau burden was found in medial temporal regions, after corrected for age, sex and pathological status. These associations were absent in APOE ε2 or ε3 subjects, suggested APOE exerts immunomodulatory effects in an isoform-dependent way.

Conclusion: APOE isoforms differentially modulate the associations between regional tau deposition and neuroinflammation.

Inline graphic APOE modulates the relationships between neuroinflammation biomarkers and tau burden

The models were corrected for age, sex, pathological status and educational attainment. T-statistical parametric maps were corrected for multiple comparisons using a random field theory cluster threshold of P < 0.001, overlaid on the ADNI reference template.

2021-149

Employing simultaneous (EEG-)PET-MRI to map arousal-induced hemodynamic and metabolic dynamics (#387)

Jingyuan Chen^{1, 2}, Ciprian Catana^{1, 2}, Jonathan Polimeni^1,
2, Kyle Droppa¹, Nina Fultz¹, Hsiao-Ying Wey^{1, 2}, Julie C. Price^{1, 2}, Bruce R. Rosen^{1, 2}, Laura Lewis³ and Christin Y. Sander^{1, 2}

¹Massachusetts General Hospital, Radiology, Boston Massachusetts, USA

²Harvard Medical School, Radiology, Boston Massachusetts, USA

³Boston University, Biomedical Engineering, Boston Massachusetts, USA

Abstract

Introduction: Arousal-induced metabolic dynamics have previously been characterized by quantifying differential metabolism between two separate PET scans.^1,2 In this study, we show that a recently developed technique functional PET (fPET)-FDG^3,4 can track metabolic dynamics accompanying sleep-wake transitions within a single scan; and that by integrating fPET-FDG with simultaneous EEG-fMRI, one can jointly map global and local physiological and metabolic changes regulated by arousal.

Methods: Each subject underwent one night of partial sleep deprivation and took part in a 60∼120 min PET-MRI scan the next afternoon. Subjects’ arousal states were delineated according to concurrent EEG or behavioral measures. Data were collected on a 3T MR scanner with a BrainPET insert. FDG was administered using a 20% bolus plus constant infusion paradigm (injected activity up to 8 mCi).⁴ Reconstruction and attenuation correction of PET images (2.5 mm iso., 30-s temporal resolution) followed.³ BOLD-weighted EPI data (3 mm iso., TR = 2/2.4 s) were collected to track ongoing hemodynamic changes. Sleep-induced changes in hemodynamic signals vs. glucose metabolism: standard deviations of fMRI percent signal changes in each arousal state were computed and compared; the slopes of fPET signals (approximately proportional to glucose metabolism³) were fitted separately for each arousal state and compared.

Results: Our results demonstrated that fPET-FDG can track metabolic dynamics coupled to arousal (Figure 1), with decreased slopes (reduced glucose uptakes) at the transitions from wake to sleep. In line with previous studies, during sleep, the strongest changes in hemodynamic fluctuation amplitudes occurred in the sensory regions⁵; and the metabolic reductions were most salient in the association cortices and thalamus.². We additionally noticed that the spatial distributions of sleep-induced hemodynamic increases and metabolic decreases were highly complementary to each other (Figure 2).

Conclusion: We have implemented a multi-modal framework that enables us to jointly map and link transient changes of hemodynamic and metabolic signals accompanying brain arousal state transitions, thus opening up the opportunity to model the interactions among various dynamic processes and achieve a holistic view on the mechanisms underlying arousal regulation in ensuing investigations.

Acknowledgements

This work was supported in part by the NIH (grants K99-NS118120, R01-MH111438, P41-EB015896), by the MGH/HST Athinoula A. Martinos Center for Biomedical Imaging; and was made possible by the resources provided by NIH Shared Instrumentation Grants S10OD010759, S10RR022976, S10RR019933 and S10RR017208.

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References

1.Nofzinger E, et al. Human regional cerebral glucose metabolism during non‐rapid eye movement sleep in relation to waking. Brain 2002; 125: 1105–1115. [DOI] [PubMed] [Google Scholar]
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2021-150

Biomarker modeling of Alzheimer’s disease using PET-based in vivo Braak staging (#388)

Joseph Therriault, Tharick A. Pascoal, Firoza Z. Lussier, Cécile Tissot, Mira Chamoun, Gleb Bezgin, Stijn Servaes, Andréa L. Benedet, Nicholas J. Ashton, Thomas Karikari, Juan Lantero-Rodriguez, Yi-Ting Wang, Jaime Fernazdez-Arias, Gassan Massarweh, Paolo Vitali, Jean-Paul Soucy, Paramita Saha-Chaudhuri, Kaj Blennow, Henrik Zetterberg, Serge Gauthier and Pedro Rosa-Neto

McGill University, Montreal, QC, Canada

Abstract

Introduction: Alzheimer’s disease (AD) is the leading cause of dementia worldwide and can be detected in vivo using biomarkers of amyloid-b and tau. Gold standard diagnostic methods for AD rely on staging systems to measure disease severity, which have not yet been incorporated into the in vivo biological research framework for AD. The topographical information conferred by tau-PET offers the potential to translate the gold standard histopathological Braak staging system to living individuals.

Methods: Using [¹⁸F]MK6240 tau-PET, we applied the Braak staging model to 345 individuals. We measured amyloid-PET, cerebrospinal fluid (CSF) and plasma phosphorylated tau (pTau) epitopes, neurodegeneration and neuropsychological function in relation to in vivo Braak stage. ANOVA assessed relationships between Braak stage with biomarker and clinical changes. Progression of in vivo Braak stage was assessed in 163 individuals with follow-up [¹⁸F]MK6240 scans.

Results: Advancing in vivo Braak stage was associated rising plasma pTau species, as well as rise and plateau of amyloid-PET & CSF pTau species. Early Braak stages were associated with isolated memory impairment, while later Braak stages were closely associated with the severity of dementia. Follow up tau-PET scans indicated sequential progression of in vivo Braak stages over time, with substantially higher rates of progression in amyloid-b+ individuals.

Conclusion: In vivo Braak stages had stage-specific associations with the severity of amyloid-b deposition, CSF measures of pTau and clinical function. In vivo Braak staging contributes to the understanding of the natural history of biological AD and provides a framework to measure AD severity in living humans.

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2021-151

Neuro-immune signatures in chronic low back pain subtypes (#389)

Zeynab Alshelh¹, Ludovica Brusaferri¹, Atreyi Saha¹, Erin J. Morrissey¹, Paulina C. Knight¹, Minhae Kim¹, Yi Zhang², Jacob M. Hooker¹, Daniel Albrecht¹, Angel Torrado-Carvajal^{1, 3}, Michael S. Placzek¹, Oluwaseun J. Akeju², Julie C. Price¹, Robert Edwards⁴, Jeungchan Lee¹, Roberta Sclocco^{1, 5}, Ciprian Catana¹, Vitaly Napadow^{1, 4} and Marco L. Loggia¹

¹Massachusetts General Hospital/Harvard Medical School, Radiology, Boston Massachusetts, USA

²Massachusetts General Hospital/Harvard Medical School, Anaesthesia, Critical Care and Pain Medicine, Boston Massachusetts, USA

³Universidad Rey Juan Carlos, Medical Image Analysis an Biometry Laboratory, Madrid, Spain

⁴righam and Women’s Hospital/Harvard Medical School, Department of Anaesthesiology, Perioperative and Pain Medicine, Boston Massachusetts, USA

⁵Logan University, Radiology, Chesterfield Missouri, USA

Abstract

Introduction: We recently showed that patients with different chronic pain conditions demonstrated elevated brain levels of the glial marker 18kDa translocator protein, which suggests that neuroinflammation might be a pervasive phenomenon observable across multiple etiologically heterogeneous pain disorders. Interestingly, the spatial distribution of this neuroinflammatory signal appears to exhibit a degree of disease specificity, suggesting that different pain conditions may exhibit distinct “neuroinflammatory signatures”. To further explore this hypothesis, we tested whether neuroinflammatory signal can characterize putative etiological subtypes of chronic low back pain patients based on clinical presentation. Specifically, we explored neuroinflammation in patients whose chronic low back pain either did or did not radiate to the leg (i.e., “radicular” vs. “axial” back pain).

Methods: Fifty-four chronic low back pain patients, twenty-six with axial back pain (43.7 ± 16.6 y.o. [mean ± SD]) and twenty-eight with radicular back pain (48.3 ± 13.2 y.o.), underwent PET/MRI with [¹¹C]PBR28, a second-generation radioligand for the 18kDa translocator protein. [¹¹C]PBR28 signal was quantified using standardized uptake values ratio. Functional MRI data were collected simultaneously to the [¹¹C]PBR28 data 1) to functionally localize the primary somatosensory cortex back and leg subregions and 2) to perform functional connectivity analyses (in order to investigate possible neurophysiological correlations of the neuroinflammatory signal). PET and functional MRI measures were compared across groups, cross-correlated with one another and with the severity of “fibromyalgianess”. Furthermore, statistical mediation models were employed to explore possible causal relationships between these three variables.

Results: For the primary somatosensory cortex representation of back/leg, [¹¹C]PBR28 PET signal and functional connectivity to the thalamus were: 1) higher in radicular compared to axial back pain patients, 2) positively correlated with each other and 3) positively correlated with fibromyalgianess scores, across groups. Finally, 4) fibromyalgianess mediated the association between [¹¹C]PBR28 PET signal and primary somatosensory cortex-thalamus connectivity across groups.

Conclusion: Our findings support the existence of “neuroinflammatory signatures” that are accompanied by neurophysiological changes, and correlate with clinical presentation in chronic pain patients. These signatures may contribute to the subtyping of distinct pain syndromes and also provide information about inter-individual variability in neuro-immune brain signals, within diagnostic groups, that could eventually serve as targets for mechanism-based precision medicine approaches. Inline graphic

Figure 1. [11C]PBR28 signal in S1 and S1-thalamus connectivity correlations with Fibromyalgia Survey Scores.

Top panel: Average SUVR was extracted from S1 (see Figure 4 caption) and plotted against Fibromyalgia Survey Scores (data have been adjusted for scanner and genotype). Bottom panel: S1 – thalamus connectivity values were extracted (see Figure 4 caption) and plotted against Fibromyalgia Survey Scores (data have been adjusted for scanner). Triangle denotes data from Protocol 1, circle denotes data from Protocol 2.

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Figure 2. Voxel-wise group differences in [11C]PBR28 signal

a. Maps displaying areas with significantly elevated [¹¹C]PBR28 SUVR in cLBP_RAD compared to cLBP_AX in a voxelwise analysis, adjusted for Protocol and genotype. b. Average ± standard deviation SUVR extracted from several clusters identified as statistically significant in the voxelwise SUVR analysis from A(adjusted for scanner and genotype). c. BOLD fMRI localizing the somatotopic representation of S1 area for the Back+Leg and the overlap between Back+Leg e-stim and [¹¹C]PBR28 SUVR signal in cLBP_RAD > cLBP_AX.

2021-152

Tau accumulation using [18F]MK6240 PET is associated with increase in executive dysfunction in prodromal AD (#390)

Vanessa Pallen¹, Firoza Z. Lussier², Nina M. Poltronetti¹, Joseph Therriault², Cécile Tissot², Gleb Bezgin², Jaime F. Arias^{1, 5}, Nesrine Rahmouni¹, Jenna Stevenson¹, Alyssa Stevenson¹, Sulantha Mathotaarachchi², Andréa L. Benedet³, Min-Su Kang², Yi-Ting Wang², Mira Chamoun¹, Pedro Rosa-Neto^{1, 5}, Serge Gauthier^{6, 4} and Tharick A. Pascoal^{2, 1}

¹McGill University Research Center for Studies in Aging, Verdun, QC, Canada

²McGill University, Translational Neuroimaging Laboratory, Verdun, QC, Canada

³University of Gothenburg, Gothenburg, Sweden

⁴McGill University, Neurology & Neurosurgery, Montreal, QC, Canada

⁵Montreal Neurological Institute, Montreal, QC, Canada

⁶Douglas Hospital, Mental Health University Institute, Verdun, QC, Canada

Abstract

Introduction: Decline in executive function has been noted to precede other forms of cognitive decline in the prodromal stage of Alzheimer’s disease (Clark et al., 2011). The D-KEFS Color-Word Interference test (CWIT) is a cognitive test measuring executive function across several conditions. Few studies have explored the relationship between tau deposition and executive dysfunction. However, to date, no study has explored this relationship in prodromal AD. This study aimed at exploring such associations

Methods: We looked at cognitively unimpaired and impaired elderly individuals from the TRIAD cohort in Montreal, QC who underwent neuropsychological evaluations across 2 time points. In vivo tau accumulation was assessed at baseline with [18F]-MK6240 PET. Standardized uptake value ratio was calculated 90–110 minutes post-injection using cerebellar grey matter as the reference region. Voxel-wise linear regression models were applied with the rate of change of CWIT condition 3 and 4 completion times as predictor variables with tau tracer binding being the response variable. Age, sex, education, Geriatric Depression Scale score, APOEε4, diagnostic group, and amyloid-β status were included as covariates in regression models. Results were corrected for multiple comparisons using random field theory with a cluster threshold of p < .001.

Results: A total of 105 (CN = 65;MCI = 36;AD = 4) individuals were included in this analysis, with mean follow-up time of neuropsychological evaluation being 15.9 months. We found that brain [18F]-MK6240 uptake was correlated with change in D-KEFS CWIT condition 3 and 4 completion times, with a greater pattern of association in condition 3 (inhibition). For condition 3, associations were strongest in the precuneus, posterior cingulate, and primarily right dorsal frontal and parietal regions. For condition 4 (flexibility), we found a strong association in the left temporal pole and left dorsal frontal regions.

Conclusion: These results support previous claims that tau follows a distinct regional distribution similar to that of the dorsal attention network which is related to higher order cognitive function such an inhibition and switching (Hansson et al., 2017). Additionally, given that most individuals in this study were CN or MCI, our findings suggest that tau pathology is associated with a decrease in executive function even in prodromal stages of AD.

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Figure 1. Tau & alternating task.

[18F]-MK6240 SUVR ∼ rate of change in inhibition/switching task completion time + age + education + GDS score + APOE4 + Dx group + amyloid-β status

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Figure 2. Tau & inhibition task.

[18F]-MK6240 SUVR ∼ rate of change in inhibition task completion time + age + education + GDS score + APOE4 + Dx group + amyloid-β status

References

1.Clark LR, Schiehser DM, Weissberger GH, et al. Specific measures of executive function predict cognitive decline in older adults. J Int Neuropsychol Soc 2011; 18: 118–127. [DOI] [PMC free article] [PubMed] [Google Scholar]
2.Hansson O, Grothe MJ, Strandberg TO, et al. Tau pathology distribution in Alzheimer’s disease corresponds differentially to cognition-relevant functional brain networks. Front Neurosci 2017; 11. 10.3389/fnins.2017.00167 [DOI] [PMC free article] [PubMed] [Google Scholar]

2021-153

Neuroimaging VMAT2 in Parkinson’s disease with rapid eye movement sleep behaviour disorder (#391)

Mikaeel Valli^{1, 2}, Sang Soo Cho³, Carme Uribe¹, Mario Masellis^{4, 2}, Robert Chen^{5, 2}, Alexander Mihaescu^{1, 2} and Antonio P. Strafella^{1, 5}

¹CAMH, Brain Health Imaging Centre, Toronto, ON, Canada

²University of Toronto, Institute of Medical Science, Toronto, ON, Canada

³Seoul National University, Seoul, South Korea

⁴Sunnybrook Health Sciences Centre, Toronto, ON, Canada

⁵Toronto Western Hospital, Toronto, ON, Canada

Abstract

Introduction: REM sleep behaviour disorder (RBD) is a common condition found in 50% of Parkinson’s disease (PD) patients. Molecular imaging evidence shows that PD with RBD (PD-RBD+) show lower dopamine transporter activity within the caudate and putamen compared to PD without RBD (PD-RBD–). However, the characterization of the vesicular monoamine transporter 2 (VMAT2), an index of nigrostriatal dopamine innervation, has been rarely explored in PD patients with RBD.

Methods: We enrolled 15 PD-RBD+, 15 PD-RBD– and 15 age matched healthy controls (HC) for the [¹¹C]DTBZ PET imaging study. This technique measures VMAT2 availability within striatal regions of interest (ROI). Mixed effect model was used to compare the radioligand binding of VMAT2 between the three groups for each striatal ROI, while co-varying for sex, cognitive and depression scores. Multiple regressions were also computed to predict clinical measures from group condition and VMAT2 binding within all ROIs explored. Significant level was set at p < 0.05 (Bonferroni corrected).

Results: We observed significant main effect of group condition on VMAT2 availability within the caudate, putamen, ventral striatum, globus pallidus, substantia nigra, and subthalamus. Specifically, we observed that both PD-RBD+ and PD-RBD– group had lower VMAT2 availability compared to HC. PD-RBD– showed a negative relationship between motor severity and VMAT2 availability within the left caudate. This relationship was not found in the PD-RBD+ group.

Conclusion: Our findings reveal that both PD patient subgroups had reduced VMAT2 levels relative to HC—which reflects denervation within the nigrostriatal pathway. No significant interactions were detected between radioligand binding and clinical scores in PD-RBD+. Taken together, we found limited evidence that VMAT2 may contribute differently in PD-RBD+ relative to PD-RBD–. Future studies are encouraged to explore other underlying neural chemistry mechanisms contributing to RBD in PD patients.

Acknowledgements

The authors thank Alvina Ng, Laura Nguyen and Anusha Ravichandran for their technical assistance. The authors also thank Marcos Sanches for his invaluable assistance with the statistical analyses.

This work was supported by Canadian Institutes of Health Research (CIHR) (MOP 136778). APS was supported by the Canada Research Chair program. MV was supported by the CIHR’s Doctoral Award program.

2021-154

Olfactory impairment is related to tau pathology and neuroinflammation in Alzheimer’s disease (#392)

Julia I. Klein^{1, 3}, Xinyu Yan², Aubrey Johnson¹, Zeljko Tomljanovic¹, James Zou¹, Krista Polly¹, Lawrence S. Honig¹, Adam M. Brickman¹, Yaakov Stern^{1, 4}, Davangere P. Devanand⁴, Seonjoo Lee^{2, 5} and William C. Kreisl¹

¹Columbia University Irving Medical Center, Taub Institute, New York New York, USA

²Columbia University Irving Medical Center, Mailman School of Public Health, New York New York, USA

³Weill Cornell Medicine, New York New York, USA

⁴Columbia University Irving Medical Center, Gertrude H. Sergievsky Center, New York New York, USA

⁵The Research Foundation for Mental Hygiene, Inc, New York New York, USA

Abstract

Introduction: Olfactory impairment is evident in Alzheimer’s disease (AD), however, its precise relationships with clinical biomarker measures of tau pathology and neuroinflammation are not well understood. To determine if odor identification performance measured with the University of Pennsylvania Smell Identification Test (UPSIT) is related to in vivo measures of tau pathology and neuroinflammation.

Methods: Cognitively normal and cognitively impaired participants were selected from an established research cohort of adults aged 50 and older who underwent neuropsychological testing, brain MRI, and amyloid PET. Fifty-four participants were administered the UPSIT. Forty-one underwent ¹⁸F-MK-6240 PET (measuring tau pathology) and fifty-three underwent ¹¹C-PBR28 PET (measuring TSPO, present in activated microglia). Twenty-three participants had lumbar puncture to measure CSF concentrations of total tau (t-tau), phosphorylated tau (p-tau) and β-amyloid (Aβ₄₂).

Results: Low UPSIT performance was associated with greater¹⁸F-MK-6240 binding in medial temporal cortex, hippocampus, middle/inferior temporal gyri, inferior parietal cortex and posterior cingulate cortex (p < 0.05). Similar relationships were seen for ¹¹C-PBR28. These relationships were primarily driven by amyloid-positive participants. Lower UPSIT performance was associated with greater CSF concentrations of t-tau and p-tau (p < 0.05). Amyloid status and cognitive status exhibited independent effects on UPSIT performance (p < 0.01).

Conclusion: Olfactory identification deficits are related to extent of tau pathology and neuroinflammation, particularly in those with amyloid pathophysiology. The independent association of amyloid-positivity and cognitive impairment with odor identification suggests that low UPSIT performance may be a marker for AD pathophysiology in cognitive normal individuals, although impaired odor identification is associated with both AD and non-AD related neurodegeneration.

2021-155

Associations between neutrophils and amyloid deposition in the Alzheimer’s disease spectrum (#393)

Nesrine Rahmouni^{1, 2}, Cecile Tissot^{1, 2}, Gleb Bezgin^1,
2, Jenna Stevenson^{1, 2}, Alyssa Stevenson^{1, 2}, Firoza Z. Lussier^{1, 2}, Joseph Therriault^{1, 2}, Mira Chamoun^{1, 2}, Min-Su Kang^{1, 2}, Dayna Baldo^{1, 2}, Tharick A. Pascoal^{2, 3}, Andréa L. Benedet^{2, 4} and Pedro Rosa-Neto^{1, 2}

¹McGill University Research Center for Studies in Aging, McGill, Montreal, QC, Canada

²Translational Neuroimaging Laboratory, McGill, Montreal, QC, Canada

³University of Pittsburgh, Psychiatry, Pittsburgh Pennsylvania, USA

⁴University of Gothenburg, Gothenburg, Sweden

Abstract

Introduction: Neutrophils are key components of early innate immunity and contribute to uncontrolled systemic inflammation. Several studies have highlighted the link between systemic inflammation and the Alzheimer’s disease (AD) pathophysiology. In fact, experiments with animal models and studies with AD patients demonstrated the hyperactivation of neutrophils associated with AD pathology and cognitive decline. However, the comprehension of the inflammatory component in the AD spectrum is still uncomplete. We thus investigated whether the amount of systemic neutrophils is correlated with brain amyloid-β in the AD spectrum.

Methods: The present study was conducted in a population of 213 individuals (138 cognitively unimpaired (CU) and 75 cognitively impaired (CI; 35 MCI and 20 AD) from the Translational Biomarkers in Aging and Dementia TRIAD cohort. The neutrophil relative values were assessed using the Automated Beckman DXH hematology Analyzer. Amyloid (Aβ) deposition was assessed with [18F]AZD4694 PET and standardized uptake value ratio (SUVRs) were calculated between 40 to 70 min post-injection, using cerebellum grey matter as the reference region. A voxel-based regression model evaluated the relationship between neutrophil count and Aβ PET, adjusted for age, sex, years of education and diagnosis. RFT was used to account for multiple comparisons.

Results: In the present study, a positive association was found between systemic neutrophil counts and brain Aβ load, where the associated regions were the anterior cingulate, cuneus, and occipital pole areas (Figure 1). Also, CI individuals showed significantly higher neutrophil counts as compared to the CU group (Figure 2).

Conclusion: Our findings review the link between the peripheral immune system and the central nervous system amyloid deposition. Further studies should investigate the use of neutrophil counts as biomarkers of AD.

graphic file with name 10.1177_0271678X211061050-img216.jpg

Figure 1. Correlation between neutrophil counts and AB global SUVR.

CI individuals showed significantly higher neutrophil counts as compared to the CU group.

graphic file with name 10.1177_0271678X211061050-img217.jpg

Figure 2. Association between systemic neutrophil count and amyloid load assessed with [18F]AZD4694 PET.

A positive association was found between systemic neutrophil counts and brain Aβ load, where the associated regions were the anterior cingulate, cuneus, and occipital pole areas.

2021-156

Verbal Fluency associated with tau accumulation and not amyloid deposition in the Alzheimer’s disease spectrum (#395)

Nesrine Rahmouni^{1, 2}, Alyssa Stevenson^{1, 2}, Jenna Stevenson^{1, 2}, Cecile Tissot^{1, 2}, Firoza Z. Lussier^1,
2, Gleb Bezgin^{1, 2}, Joseph Therriault^{1, 2}, Mira Chamoun^1,
2, Nina M. Poltronetti^{1, 2}, Vanessa Pallen^{1, 2}, Min-Su Kang^{1, 2}, Tharick A. Pascoal^{2, 3}, Paolo Vitali^{1, 2}, Andréa L. Benedet^{2, 4} and Pedro Rosa-Neto^{1, 2}

¹McGill University Research Center for Studies in Aging, McGill, Montreal, QC, Canada

²Translational Neuroimaging Laboratory, McGill, Montreal, QC, Canada

³University of Pittsburgh, Department of Psychiatry, Pittsburgh Pennsylvania, USA

⁴University of Gothenburg, Gothenburg, Sweden

Abstract

Introduction: Recent studies have shown that pathological amyloid deposition and tau accumulation, hallmarks of the Alzheimer’s disease, are closely related to cognitive deficits in older individuals. The present study evaluates the associations between the Alzheimer’s disease hallmarks and verbal fluency and lexical speed access impairment.

Methods: The present study was conducted in a population of 262 individuals (162 cognitively unimpaired individuals (CU), 100 cognitively impaired individuals (CI; 61 MCI and 39 AD). The verbal Letter Fluency test was used to assess the vocabulary size and lexical speed access. Individuals underwent an MRI, a [18F]AZD4694 amyloid-PET scan and a [18F]MK6240 tau-PET scan. [18F]AZD4694 and [18F]MK6240 standardized uptake value ratio (SUVRs) were calculated between 40 to 70 min and 90 to 110 min post-injection, respectively, using cerebellum grey matter as the reference region. A voxel-based regression model evaluated the relationship between the cognitive scoring and the PET markers [18F]AZD4694 and [18F]MK6240, correcting for age, sex, education, APOE, diagnosis and RFT was used to account for multiple comparisons.

Results: In the present study, negative correlations were found between Letter Fluency scores and tau accumulation via PET-imaging in individuals where the associated regions were prefrontal cortex, which plays an important role in this neuropsychological task, as well as in the medial frontal, superior temporal, medial occipital lobes and precuneus area. No associations were found between the Letter Fluency scoring and amyloid deposition.

Conclusion: Our results suggest that tau accumulation is associated with lower vocabulary size and lexical speed access, whereas amyloid deposition does not influence this neuropsychological field.

graphic file with name 10.1177_0271678X211061050-img218.jpg

Figure 1. Correlation between Letter Fluency scores and [18F]MK6240 Braak 3 SUVR.

Pearson’s correlation, p < 0.001, correlating Letter Fluency scores with the PET marker [18F]MK6240 in braak stage 3.

graphic file with name 10.1177_0271678X211061050-img219.jpg

Figure 2. Association between Verbal Fluency scores and tau accumulation assessed with [18F]MK6240 PET.

A voxel-based regression model evaluated the relationship between the Letter Fluency score and the PET marker [18F]MK6240

2021-157

Reducing Model Bias in Measurement of Dopamine Response to Behavioral Challenge (#396)

Michael A. Levine¹, Joseph B. Mandeville¹, Finnegan Calabro², Julie C. Price¹, Beatriz Luna² and Ciprian Catana¹

¹Massachusetts General Hospital, A. A. Martinos Center for Biomedical Imaging, Boston Massachusetts, USA

²University of Pittsburgh Medical Center, Psychiatry, Pittsburgh Pennsylvania, USA

Abstract

Introduction: [¹¹C]Raclopride Positron Emission Tomography (PET) can be used to probe dopamine release in response to behavioral challenge, applying compartmental kinetic modeling and extracting macroparameters, including binding potential (BP_ND). However, behavioral challenges produce small changes in neurotransmitter release, and detection may be conflated with model-based sources of bias. Voxel maps of absolute change in binding potential (ΔBP_ND, i.e. BP_ND-POST – BP_ND-PRE) in humans were compared to simulated maps which describe the bias induced by the Multilinear Reference Tissue Model (MRTM2).¹

Methods: 69 healthy adult participants underwent bolus plus constant infusion [¹¹C]raclopride PET over 90 min with simultaneous functional Magnetic Resonance Imaging and a reward learning task (avg. start, end time: 40, 70 min).² Bias was estimated from a forward simulation of the two-tissue compartment model (2TCM), using an analytic arterial input function,³ global K₁’ and k₄,⁴ a single k₂’ (0.30/min), participant-averaged voxel maps of R1 and BP_ND, and no challenge. The acquired and simulated PET data were fit with an E xtension of MRTM2 that includes a challenge term (unit step at 40 minutes), producing parametric maps of ΔBP_ND (E-MRTM2). D ebiasing was performed by eliminating the contribution of the uptake period (0–27.5 min) to BP_ND estimation (DE-MRTM2).⁵

Results: In simulations, E-MRTM2 estimates of ΔBP_ND bias were -0.4% in striatum, 19.5% in white matter, and 16.1% in gray matter. DE-MRTM2 reduced ΔBP_ND bias to -0.3% in striatum, 4.1% in white matter, and 5.7% in gray matter. In human participants, E-MRTM2 estimated ΔBP_ND of -2.7% in striatum, 6.1% in white matter, and -4.3% in gray matter, while DE-MRTM2 estimated ΔBP_ND of -2.2% in striatum, 2.5% in white matter, and -6.6% in gray matter. Voxel maps of ΔBP_ND show that DE-MRTM2 decreases bias globally in simulations. In parametric human data, DE-MRTM2 reduces the ‘halo’ effect around the edges of the striatum and eliminates the spatial correlation of ΔBP_ND with gray and white matter (Figure 1).

Conclusion: The results suggest that model bias from fitting a single compartment model (E-MRTM2) to two-tissue data can be reduced by fitting a model that excludes the contribution of the uptake period to the estimation of BP_ND (DE-MRTM2).

Acknowledgements

This work was partly supported by National Institute of Biomedical Imaging and Bioengineering Grant 5R01EB014894-02, National Institute of Mental Health Grant Number R01MH080243, National Institute of Neurological Disorders and Stroke Grant Number R01NS112295, National Institute of General Medical Sciences Grant T32 GM008313, NIH Blueprint for Research Science Grant T90DA022759/R90DA023427, and NIH Shared Instrumentation Grant S10RR023043.

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References

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2021-158

Single dose of cocaine alters synaptic vesicle glycoprotein 2A density in adolescent rats (#397)

Rachele Rossi¹, Simone Larsen Bærentzen^{1, 2}, Majken Borup Thomsen^{1, 2}, Caroline Cristiano Real¹, Gregers Wegener¹, Albert Gjedde^{1, 3} and Anne M. Landau^{1, 2}

¹University of Aarhus, Translational Neuropsychiatric Unit (TNU), Department of Clinical Medicine, Aarhus, Denmark

²University of Aarhus, Department of Nuclear Medicine and PET, Department of Clinical Medicine, Aarhus, Denmark

³McGill University, Department of Neurology and Neurosurgery, Montreal, QC, Canada

Abstract

Introduction: Synaptic vesicle glycoprotein 2A (SV2A) serves as a marker of synaptic density. As an anti-epileptic drug that binds to the SV2A protein, Levetiracetam is the source of radiolabelled tracers of SV2A. By binding to dopamine transporters, cocaine affects the function of synapses. Here, we tested the temporal and spatial properties of neuroimaging of SV2A after a single dose of cocaine by autoradiography of the specific binding of [³H]UCB-J to SV2A.

Methods: We injected male adolescent rats with cocaine (20 mg/kg; n = 16) or saline (n = 12). We tested the animals in open field trials for 30 minutes immediately after administration. We collected, froze, and sectioned the brains at 1 hour or at 7 days after injection, and generated autoradiograms of the binding of [³H]UCB-J to medial prefrontal cortex, striatum, nucleus accumbens, amygdala, and dorsal and ventral hippocampus in the presence or absence of Levetiracetam.

Results: Cocaine-injected rats had increased activity in the open field trials, unlike controls. [³H]UCB-J binding was slightly lower in the medial prefrontal cortex in cocaine vs. saline rats 1 hour after injection. In contrast, binding was higher in amygdala and hippocampus in cocaine vs. saline rats 7 days after injection. We detected no statistically significant differences in striatum or nucleus accumbens.

Conclusion: Changes of synaptic density in limbic brain regions indicate that effects of cocaine may regulate neurotransmission with differential effects in different areas over time. The findings add to the understanding of SV2A expression in physiological and pathological conditions that would improve the interpretation of imaging outcomes.

Acknowledgements

Rachele Rossi thanks the Erasmus+ Traineeship Program for the opportunity to do the research.

2021-159

Protective role of β-amyloid revealed by PET of [¹¹C]PiB and [¹⁸F]FDG in Alzheimer’s disease (#398)

Elise Rischel¹, Michael Gejl², Birgitte Brock³, Jørgen Rungby⁴ and Albert Gjedde^{1, 2}

¹University of Copenhagen, Department of Neuroscience, Copenhagen N, Denmark

²Aarhus University, Department of Clinical Medicine, Aarhus C, Denmark

³Steno Diabetes Center Copenhagen (SDCC); Gentofte, Denmark, Gentofte, Denmark

⁴University of Copenhagen, Department of Endocrinology, Bispebjerg Hospital, Copenhagen N, Denmark

Abstract

Introduction: In Alzheimer’s disease (AD), evidence suggests that beta-amyloid accumulates in regions with the highest cerebral metabolic rate of glucose (CMRglc). However, in individual regions, the accumulation appears to be inversely related to the magnitude of CMRglc. This difference suggests a generally protective role of beta-amyloid in the maintenance of glucose metabolism that ultimately fails in AD. We tested the hypothesis by comparing the binding potentials (BP_ND) of tracer Pittsburgh Compound B ([11C]PiB), representing the beta-amyloid accumulation, and estimates of CMRglc in separate regions and individual subjects with AD.

Methods: We used positron emission tomography (PET) to examine the correlation between regionally averaged and individual regional values of the BP_ND of [11C]PiB, and regionally averaged and individual regional values of CMRglc measured with tracer [18F]fluorodeoxyglucose ([18 F]FDG) in specific brain regions of 29 patients with AD.

Results: We found significant direct correlation between the average values of the BP_ND of [11C]PiB and CMRglc of dfferent regions, and significant inverse correlations between individual values of PIB BP_ND and CMRglc values in precuneus, temporal lobe, occipital lobe, parietal lobe and whole cerebral cortex. Inverse correlations were not significant in frontal lobe, cingulate cortex, or cerebellum.

Conclusion: We found significant positive correlation between the two tracers in regions on average, but inverse correlations for individual subjects in separate regions. The results are consistent with β-amyloid acting as a protective mechanism that ultimately fails. The observation implies that the β-amyloid accumulates in separate regions in proportion to glucose metabolism, while in each separate region the metabolism declines in inverse proportion to the accumulation of the β-amyloid, suggesting a protective role of amyloid accumulation that ultimately fails.

References

1.Gejl M, Brock B, Egefjord L, et al. Blood-brain glucose transfer in Alzheimer’s disease: effect of GLP-1 analog treatment. Scient Rep 2017; 7: 1–10. [DOI] [PMC free article] [PubMed] [Google Scholar]
2.Rodell A, Aanerud J, Braendgaard H, et al. Washout allometric reference method (WARM) for parametric analysis of [11C]PiB in human brains. Front Aging Neurosci 2013; 5: 1–14. [DOI] [PMC free article] [PubMed] [Google Scholar]
3.Rodell AB, O’Keefe G, Rowe CC, et al. Cerebral blood flow and Abeta-amyloid estimates by WARM analysis of [11C]PiB uptake distinguish among and between neurodegenerative disorders and aging. Front Aging Neurosci 2017; 8: 1–11. [DOI] [PMC free article] [PubMed] [Google Scholar]

2021-160

Using a support vector machine to identify signatures of different p-tau CSF species in incipient Alzheimer’s disease (#399)

Stijn Servaes¹, Firoza Z. Lussier¹, Joseph Therriault¹, Gleb Bezgin¹, Min-Su Kang¹, Yi-Ting Wang¹, Jenna Stevenson¹, Cécile Tissot¹, Jaime F. Arias¹, Andréa L. Benedet^{1, 4}, Mira Chamoun¹, Tharick A. Pascoal^{1, 5}, Serge Gauthier^{1, 2} and Pedro Rosa-Neto^1,
2

¹Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, Douglas Hospital, McGill University, Montreal, QC, Canada

²Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada

³Montreal Neurological Institute, Montreal, QC, Canada

⁴Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

⁵Department of Psychiatry, University of Pittsburgh, Pittsburgh Pennsylvania, USA

Abstract

Introduction: The presence of p-tau in biofluids has previously been proposed to be a response to neurofibrillary tangle pathology.¹ However, the increase of p-tau in cerebrospinal fluid (CSF) precedes detectable neurofibrillary tangle pathology, as indexed by tau PET, by up to a decade,² suggesting that soluble tau could be an indication of early tau pathology. As Alzheimer’s disease (AD) is the only disorder that consistently shows an increase in CSF p-tau, whereas this biomarker is normal in other neurodegenerative disorders,³ research has focused on the potential of several p-tau species for early clinical diagnosis. With this study, we investigated the heterogeneity of p-tau species in CSF in order to assess the clinical status of participants of the TRIAD cohort.

Methods: Support vector machines were used to identify cutoff values of p-tau181, p-tau217, p-tau231 and p-tau235 in CSF, both individually and combined, to separate a group of AD patients (n = 25) and young controls (n = 28). Using these cutoff values, signatures were calculated on an individual level in a group of individuals with cognitive impairment (n = 62) and age-matched controls (n = 75). Additionally, [18F]MK6240 SUVR maps and memory composite scores were calculated and evaluated using the Logical Memory test, the Rey Auditory Verbal Learning Test, the Face Name Association Test and the Free and Cued Selective Reminding Test.

Results: When combining different CSF p-tau species, the largest contribution in order of importance came from p-tau181, followed by p-tau217, p-tau235 and p-tau231. Achieving the cutoff for multiple p-tau species was associated with higher Braak stages (Figure 1) and lower memory composite scores (Figure 2). In particular, achieving the cutoff value for p-tau217 was associated with later Braak stages.

Conclusion: Our findings suggest that heterogeneity in p-tau species carries predictive power in the identification of incipient Alzheimer’s Disease.

graphic file with name 10.1177_0271678X211061050-img221.jpg

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References

1.Ashton NJ, Pascoal TA, Karikari TK, et al. Plasma p-tau231: a new biomarker for incipient Alzheimer’s disease pathology. Acta Neuropathol 2021; 141: 709–724. [DOI] [PMC free article] [PubMed] [Google Scholar]
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3.Jack CR, Jr, Bennett DA, Blennow K, et al. NIA-AA research framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement 2018; 14: 535–562. [DOI] [PMC free article] [PubMed] [Google Scholar]

2021-161

Ex-vivo analysis of metabotropic glutamate receptor type 5 hippocampal abnormalities in epileptogenic foci (#400)

Maria Zimmermann^{1, 2}, Luciano Minuzzi^{2, 3}, Arturo Aliaga^2,
4, Marie-Christine Guiot⁵, Jeffrey A. Hall¹, Jean-Paul Soucy^{1, 4}, Gassan Massarweh⁴, Pedro Rosa-Neto^{1, 2} and Eliane Kobayashi¹

¹McGill University, Department of Neurology and Neurosurgery, Montréal Neurological Institute, Montréal, QC, Canada

²McGill University, Translational Neuroimaging Laboratory, Douglas Research Institute, Montréal, QC, Canada

³McMaster University, Department of Psychiatry and Behavioural Neurosciences, Hamilton, ON, Canada

⁴McGill University, PET Unit, McConnell Brain Imaging Centre, Montréal, QC, Canada

⁵McGill University, Department of Pathology, Montréal Neurological Institute, Montréal, QC, Canada

Abstract

Introduction: Hippocampal metabotropic glutamate receptor 5 (mGluR5) abnormalities in patients with intractable mesial temporal lobe epilepsy (MTLE) have been characterized ex-vivo via immunoreactivity studies of surgically-extracted specimens, and in-vivo via Positron Emission Tomography with [¹¹C]ABP688, a negative allosteric modulator of mGluR5. Reduced [¹¹C]ABP688 binding potentials (BPs) have been found within the involved hippocampus of refractory MTLE patients,¹ contrasting with mGluR5 upregulation observed in MTLE immunohistochemistry studies.^2,3 These reduced BPs may signify hyperexcitability-induced receptor conformation changes, the presence of excess glutamate, or decreased cell surface-expressed mGluR5. To further investigate mGluR5 alterations in MTLE, we performed [³H]ABP688 autoradiography on hippocampi surgically-extracted from MTLE patients compared to post-mortem healthy controls to evaluate ex-vivo receptor densities (B_max) and dissociation constants (K_D) in the absence of endogenous glutamate.

Methods: We assessed B_max and K_D in frozen hippocampal specimens (16 MTLE, 5 controls) using saturation autoradiography with six different concentrations of [³H]ABP688 (0.25–8nM). Non-specific binding was determined using 10mM 2-Methyl-6-(phenylethynyl)pyridine. Differences in B_max and K_D were evaluated using a two-tailed Welsh’s t-test and a two-tailed Mann-Whitney U Test, respectively. A linear regression model was used to assess B_max changes with K_D, age and sex as predictors.

Results: MTLE specimens showed a 46.8% reduction in B_max compared to control hippocampi (p = 0.0046). There was no significant change in K_D between the groups. A linear regression model revealed that the decrease in B_max in the MTLE group was independent of age, sex, and K_D.

Conclusion: The observed reductions in [³H]ABP688 binding and the nonsignificant difference in K_D suggest that the decreased BPs found in vivo cannot be explained by the presence of excess glutamate or by reduced affinity of ABP688 for mGluR5. Our results are consistent with mGluR5 downregulation/internalization, or a conformational change resulting in complete occlusion of ABP688’s binding site in a proportion of mGluR5 receptors.

Acknowledgements

This study was supported by operating funds from the Savoy Foundation (www.savoy-foundation.ca;

pilot project grant to E.K. and P.R.-N and MSc studentship to M.Z.).

graphic file with name 10.1177_0271678X211061050-img223.jpg

Figure 1. [3H]ABP688 binding in Hippocampus.

Autoradiographic saturation binding curves constructed from total and non-specific binding data using the one-site binding model (GraphPad Prism). Displayed are the mean curves for specific binding of mGluR5 by [³H]ABP688 in the resected hippocampus of mesial temporal lobe epilepsy patients and in healthy control hippocampal specimens. Error bars are SEM.

graphic file with name 10.1177_0271678X211061050-img224.jpg

Figure 2. [3H]ABP688 Bmax and Kd values in the Hippocampus.

Receptor density (B_max) and dissociation constant (K_D) values in the surgically-extracted hippocampus of patients with intractable mesial temporal lobe epilepsy, and in hippocampal specimens from healthy controls. (A) Receptor density was reduced in patients compared to controls. B_max values are represented as mean ± std. deviation. (B) Dissociation constants were unchanged in patients compared to controls. K_D values are represented as median with interquartile range. ** indicates p < 0.005; ns indicates a non-significant comparison.

References

1.Lam J, DuBois JM, Rowley J, et al. In vivo metabotropic glutamate receptor type 5 abnormalities localize the epileptogenic zone in mesial temporal lobe epilepsy. Ann Neurol 2019; 85: 218–228. [DOI] [PubMed] [Google Scholar]
2.Kandratavicius L, Rosa-Neto P, Monteiro MR, et al. Distinct increased metabotropic glutamate receptor type 5 (mGluR5) in temporal lobe epilepsy with and without hippocampal sclerosis. Hippocampus 2013; 23: 1212–1230. [DOI] [PMC free article] [PubMed] [Google Scholar]
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2021-162

Covid-19 pandemic: Quantifying the effects of the first lockdown on behavioral and cognitive measures using TASIC (#401)

Jenna Stevenson¹, Firoza Z. Lussier^{1, 2}, Stijn Servaes^1,
2, Mira Chamoun^{1, 2}, Nesrine Rahmouni¹, Cécile Tissot^1,
2, Nina M. Poltronetti¹, Tharick A. Pascoal^{2, 3}, Andréa L. Benedet^{2, 4}, Gleb Bezgin^{1, 2}, Suzanne King⁵, Serge Gauthier^{1, 6} and Pedro Rosa-Neto^{1, 2}

¹The McGill University Research Centre for Studies in Aging, Montreal, Canada

²Translational Neuroimaging Laboratory, Montreal, Canada

³University of Pittsburgh, Department of Psychiatry, Pittsburgh, USA

⁴University of Gothenburg, Gothenburg, Sweden

⁵McGill University, Department of Psychiatry, Montreal, Canada

⁶Douglas Mental Health University Institute, Montreal, Canada

Abstract

Introduction: Following the rapid spread of the COVID-19 virus throughout Quebec, the TRIAD cohort, a longitudinal observational study, evaluated the effects of COVID-19 on it’s aging and vulnerable population and their caregivers. This study aims at investigating the behavioural and psychological effects of COVID-19 and social isolation on the aging population. The TRIAD Assessment of Social Isolation and Cognition (TASIC) was developed to assess these effects on participants of observational trials.

Methods: Pre-pandemic data including, demographical information, Clinical Dementia Rating (CDR), Mini-Mental State Examination (MMSE), Geriatric Depression Scale (GDS), Montreal Cognitive Assessment (MoCA) and a Social Support Questionnaire, were collected during in-person visits and take-home questionnaires. Following the onset of COVID-19, TASIC was created to include additional COVID-19 specific scales developed by Dr. Rosa-Neto and Dr. King that include Knowledge of COVID-19 scale, the Montreal Assessment of Stress related to COVID-19 (MASC), as well as the Impact of Events Scale (IESR), the Peritraumatic Distress Inventory (PDI), the Peritraumatic Dissociative Experiences Questionnaire (PDEQ) for COVID-19. Assessments were conducted via telephone interviews with TRIAD participants (n = 292) and their informants (n = 243) by eight trained research assistants from April through June 2020. All participants enrolled in previous TRIAD studies, deemed eligible through detailed screening criteria were contacted.

Results: As a result of this study, and previous work done by the cohort, a culmination of information is available, with 90% of TRIAD participants having completed the COVID-19 study also having plasma collected. 80% of participants from the COVID-19 study have PET imaging using [¹⁸F]AZD4694 and [18F]MK6240 and MRI sequencing.

Conclusion: The COVID-19 study conducted by TRIAD provides a unique opportunity to understand the effects of a global pandemic on our aging population as well as caregiver burden. This data, in conjunction with other measures available in the cohort, can make important strides in finding ways to help, and better understand those most impacted by the crisis.

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2021-163

Amyloid-PET and free-water diffusion MRI of the white matter: a multi-center mixed cohort of small vessel disease and Alzheimer’s disease pathology (#402)

Julie Ottoy¹, Miracle Ozzoude¹, Katherine Zukotynski^1,
2, Min-Su Kang³, Sabrina Adamo¹, Christopher Scott¹, Joel Ramirez¹, Walter Swardfager⁴, Benjamin Lam⁵, Aparna Bhan¹, Parisa Mojiri¹, Alex Kiss⁶, Stephen Strother^{7, 8}, Christian Bocti⁹, Michael Borrie¹⁰, Howard Chertkow¹¹, Richard Frayne¹², Robin Hsiung¹³, Robert J. Laforce¹⁴, Michael D. Noseworthy¹⁵, Frank S. Prato¹⁰, Demetrios J. Sahlas¹⁶, Eric E. Smith¹⁷, Philip H. Kuo¹⁸, Vesna Sossi¹³, Alexander Thiel¹¹, Jean-Paul Soucy³, Jean-Claude Tardif¹⁹, Sandra E. Black^1,
5 and Maged Goubran^{1, 7}

¹University of Toronto, LC Campbell Cognitive Neurology Unit, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, ON, Canada

²McMaster University, Departments of Medicine and Radiology, Hamilton, ON, Canada

³McGill University, Montreal Neurological Institute, Montreal, QC, Canada

⁴University of Toronto, Department of Pharmacology & Toxicology, Toronto, ON, Canada

⁵University of Toronto, Department of Medicine (Division of Neurology), Toronto, ON, Canada

⁶University of Toronto, Department of Research Design and Biostatistics, Sunnybrook Research Institute, Toronto, ON, Canada

⁷University of Toronto, Department of Medical Biophysics, Toronto, ON, Canada

⁸University of Toronto, The Rotman Research Institute Baycrest, Toronto, ON, Canada

⁹Université de Sherbrooke, Département de Médecine, Sherbrooke, QC, Canada

¹⁰Western University, Lawson Health Research Institute, London, ON, Canada

¹¹McGill University, Jewish General Hospital and Department of Neurology and Neurosurgery, Montreal, QC, Canada

¹²University of Calgary, Departments of Radiology and Clinical Neuroscience, Calgary Alberta, Canada

¹³University of British Columbia, Physics and Astronomy Department and DM Center for Brain Health, Vancouver British Columbia, Canada

¹⁴Université Laval, Clinique Interdisciplinaire de Mémoire, Département des Sciences Neurologiques, Quebec, QC, Canada

¹⁵McMaster University, Department of Electrical and Computer Engineering, Hamilton, ON, Canada

¹⁶McMaster University, Department of Medicine, Hamilton, ON, Canada

¹⁷University of Calgary, Hotchkiss Brain Institute, Calgary Alberta, Canada

¹⁸University of Arizona, Department of Medical Imaging, Medicine, and Biomedical Engineering, Tucson Arizona, USA

¹⁹Université de Montréal, Montreal Heart Institute, Montreal, QC, Canada

Abstract

Introduction: To investigate the neurobiological underpinnings of amyloid-PET binding in the white matter (WM) using free-water diffusion MRI in a multi-centre mixed cohort of small vessel disease (SVD) and Alzheimer’s disease (AD) pathology.

Methods: We included sixty participants with moderate-to-severe white matter hyperintensity burden (WMH; median (IQR): 30.51(22.14)cm³) from dementia/stroke-prevention clinics (48% amyloid-positive) as part of the MITNEC-C6 project across seven sites in Canada. Additionally, we included sixty cognitively normal or early MCI with mild-to-moderate WMH burden (median (IQR): 5.82(9.29)cm³) from the ADNI-2 database (22% amyloid-positive). We applied a bi-tensor diffusion MRI model that differentiates between extracellular (free-water fraction) and tract-specific WM compartments (free-water adjusted fractional anisotropy or FA_adjusted) (Figure 1). We tested associations of these diffusion metrics with amyloid standardized uptake value ratio (SUVR) in both WMH and normal-appearing WM, and with cognition. To further investigate how the diffusion metrics and the demographical variables including age, sex, education, WMH volume, and cortical amyloid SUVR covary with WM amyloid SUVR, we performed partial-least-square analysis using ten-fold cross-validation with five repeats.

Results: In WMH, amyloid SUVR was significantly lower compared to normal-appearing WM and associated strongly with higher free-water (β = −0.36 ± 0.13, P = 0.005). Partial-least-square analysis in the moderate-to-severe burden group showed that free-water as well as WMH volume were most strongly associated with amyloid SUVR in WMH (Figure 2-left; component-1 explaining 24% variance), while FA_adjusted as well as cortical amyloid were most strongly associated with amyloid SUVR in normal-appearing WM (Figure 2-right; component-1 explaining 31% variance). Higher level of free-water was more closely related to cognitive impairment (MMSE: β_WMH = −0.40 ± 0.13, P = 0.003; βnormal-appearing = −0.30 ± 0.11, P = 0.01) than FA_adjusted (MMSE: β_{normal-appearing} = 0.21 ± 0.09, P = 0.02).

Conclusion: In mixed AD and SVD, representative of the more common AD population, amyloid-PET changes in WM lesions may largely reflect extracellular free-water. In contrast, normal-appearing WM changes may reflect tract-specific microstructural injury (possibly demyelination). Our study supports free-water as a potential [early] WM-related biomarker in AD.

Acknowledgements

For the Medical Imaging Trials Network of Canada (MITNEC) and the Alzheimer’s Disease Neuroimaging Initiative.

graphic file with name 10.1177_0271678X211061050-img227.jpg

Figure 1. Bi-tensor model of the white matter.

Schematic representation of the two-compartment model per brain voxel (red color), including an extracellular (free-water; purple color) and tract-specific (FA_{adjusted
for free-water}; yellow color) compartment. Abbreviations: NAWM, normal-appearing white matter; WMH, white matter hyperintensities; FA, fractional anisotropy; FW, free water. Inline graphic

Figure 2. Amyloid SUVR in relation to diffusion MRI metrics and demographics.

PLS analysis showing the relationship of amyloid SUVR with DTI and demographical variables in WMH (left) and NAWM (right). Error bars represent 95%CI based on bootstrapping with 5,000 repetitions. Abbreviations: NAWM, normal-appearing white matter; WMH, white matter hyperintensities; FA, fractional anisotropy; FW, free water; MD, mean diffusivity.

2021-164

Evaluation of [¹⁸F]FR – a potential PET tracer for the diagnosis of cerebral amyloid angiopathy (#403)

Daniel Bleher¹, Marilena Poxleitner¹, Gregory D. Bowden^1,
2, Sabrina Buss¹, Ann-Kathrin Grotegerd¹, Sonja Schembecker¹, Bernd J. Pichler^{1, 2}, Andreas Maurer^{1, 2} and Kristina Herfert¹

¹Eberhard Karls Universität, Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Tübingen Baden-Württemberg, Germany

²Eberhard Karls Universität, Cluster of Excellence iFIT (EXC 2180), Tübingen Baden-Württemberg, Germany

Abstract

Introduction: The β-amyloid peptide Aβ_1-40 is the main component in cerebral amyloid angiopathy (CAA), a degenerative disorder of the brain vasculature with a prevalence of 50% in elderly people, but its diagnosis is still not possible without brain biopsy. A selective radiotracer would aid the clinical delineation of vascular from parenchymal amyloid depositions (PEA) present in Alzheimer’s Disease (AD) mainly composed of Aβ_1-42. Herein, we evaluate the benzoxazinole derivative [¹⁸F]FR as PET tracer targeting CAA.

Methods: Specificity and selectivity of [³H]FR was tested in invitro binding assays using recombinant Aβ_1-40 and Aβ_1-42 fibrils. Two different AD mouse models, the APP23 model with, and the APPPS1 model without CAA pathology in the brain were used for further evaluation. In vitro autoradiography (AR) and immunofluorescence staining was performed on brain sections. ICTAD-1, a fluorescent dye able to distinguish between Aβ_1-40 and Aβ_1-42, was used as reference. After automated radiolabeling, purification, and formulation of [¹⁸F]FR, the pharmacokinetic profile was determined in mice. In vivo PET with [¹⁸F]FR was performed in wild type and transgenic mice.

Results: [³H]FR shows specific binding to both fibril entities with a selectivity towards Aβ_1-40 (K_d = 5.7 nM) over Aβ_1-42 (K_d = 122 nM)_. AR with [¹⁸F]FR demonstrated specific binding of the radiotracer towards CAA in mice brain sections and only moderate binding to PEA. Metabolite analysis revealed one radio-metabolite in plasma and brain with 91% of the parent compound remaining in the brain at 5 min. Preliminary in vivo PET data analysis revealed a high binding potential (BP_nd) of [¹⁸F]FR in the cortex of APP23 mice with CAA (BP_nd = 0.23 ± 0.04; n = 5) with negligible binding in APPPS1 mice (BP_nd = 0.04 ± 0.04; n = 4) and wild type mice (BP_nd = 0.02 ± 0.04; n = 9).

Conclusion: FR demonstrated selectivity towards CAAover PEAin vitro and in vivo. After completed invivo evaluation of FR, future studies will evaluate the compound in the CAA mouse model APPDutch and in pigs to investigate metabolite formation in higher species.

Acknowledgements

The authors want to thank Johannes Kinzler, Ramona Stremme, Linda Schramm and Christian Köder for support on radiosynthesis and animal handling.

2021-165

Cognitive reserve: Evaluating the relationship between WASI-II matrix reasoning and tau accumulation using [18F]MK6240 in monolingual and bilingual individuals (#404)

Alyssa Stevenson^{1, 2}, Nesrine Rahmouni^{1, 2}, Jenna Stevenson^{1, 2}, Cécile Tissot^{1, 2}, Joseph Therriault^1,
2, Firoza Z. Lussier^{1, 2}, Gleb Bezgin^{1, 2}, Mira Chamoun^1,
2, Nina M. Poltronetti^{1, 2}, Vanessa Pallen^{1, 2}, Min-Su Kang^{1, 2}, Tharick A. Pascoal^{2, 3}, Andréa L. Benedet^{2, 4} and Pedro Rosa-Neto^{1, 2}

¹McGill University Research Centre for Studies in Aging, McGill, Montreal, QC, Canada

²Translational Neuroimaging Laboratory, McGill, Montreal, QC, Canada

³University of Pittsburgh, Department of Psychiatry, Pitsburgh Pennsylvania, USA

⁴University of Gothenburg, Gothenburg, Sweden

Abstract

Introduction: Cognitive reserve (CR), a protective mechanism, allows for sustained cognitive functioning in older adults with greater experiential resources. Bilingualism, an indicator of greater cognitive reserve, has been found to preserve cognitive performance in older adults despite significant disease pathology. While the association with amyloid has been well acknowledged, the effect of tau is still under investigation. In the present study, we aim to evaluate the effect of bilingualism on individuals’ cognition and tau load.

Methods: This study was conducted in 310 individuals (193 cognitively unimpaired (CU)) and 117 cognitively impaired (CI; 70 MCI and 47 AD) from the TRIAD cohort. 49.7% of the study participants were monolingual. Wechsler Abbreviated Scale of Intelligence – Second Edition (WASI-II) was used to measure cognitive ability and reasoning in individuals. Accumulation of tau was assessed with [18F]MK6240 PET and standardized uptake value ratio (SUVRs) were calculated between 90 to 110 min post-injection, using cerebellum grey matter as the reference region. A voxel-based regression model evaluated the relationship between the WASI-II score and the PET marker [18F]MK6240, correcting for age, sex, education, APOE, diagnosis and RFT was used to account for multiple comparisons.

Results: Our data showed a negative association between the cognitive score and tau accumulation in both monolingual and bilingual groupings. In the bilingual individuals, the associated regions were the anterior cingulate cortex and lateral frontal cortex. In the monolingual group, the associated regions were medial occipital, medial parietal and medial prefrontal cortex. In addition, bilingual individuals demonstrated significantly higher scores on the WASI-II test in comparison to monolingual individuals.

Conclusion: Our results demonstrate that bilingual individuals have fewer regions affected than their monolingual counterparts. This suggests that bilingual individuals are more resilient to the accumulation of tau; shown in higher scores in cognitive ability and reasoning.

graphic file with name 10.1177_0271678X211061050-img229.jpg

graphic file with name 10.1177_0271678X211061050-img230.jpg

References

1.Costumero V, Marin-Marin L, Calabria M, et al. A cross-sectional and longitudinal study on the protective effect of bilingualism against dementia using brain atrophy and cognitive measures. Alz Res Therapy 2020; 12: 11. [DOI] [PMC free article] [PubMed] [Google Scholar]
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2021-166

Amyloid beta deposition and cognitive decline in Parkinson’s disease: a study of the PPMI cohort (#405)

Alexander Mihaescu^{1, 3}, Mario Masellis^{3, 5}, Ariel Graff-Guerrero^{1, 3}, Mikaeel Valli¹, Carme Uribe^{1, 2}, Maria Diez-Cirarda^{1, 7} and Antonio P. Strafella^{2, 3}

¹Centre for Addiction and Mental Health, Research Imaging Centre, Toronto, ON, Canada

²University Health Network, Krembil Research Institute, Toronto, ON, Canada

³University of Toronto, Institute of Medical Science, Toronto, ON, Canada

⁴Toronto Western Hospital, Morton and Gloria Shulman Movement Disorder Unit, Toronto, ON, Canada

⁵Sunnybrook Hospital, LC Campbell Cognitive Neurology Research Unit, Toronto, ON, Canada

⁶Sunnybrook Research Institute, Hurvitz Brain Sciences Program, Toronto, ON, Canada

⁷Biocruces Bizkaia Health Research Institute, Neurodegenerative Diseases Group, Barcelona, Spain

Abstract

Introduction: The accumulation of amyloid beta (Aβ) in the brain has a complex and poorly understood impact on the progression of Parkinson’s disease (PD) pathology.^1,2 Increased Aβ burden has been associated with cognitive decline in PD, especially in PD with dementia.³ Some studies however have found no association between high Aβ burden and cognitive decline in PD patients,^4,5 instead suggesting normal aging may be responsible for both Aβ accumulation and cognitive decline. To better understand the relationship between PD cognitive decline and Aβ deposition, our study focused on a homogenous group of idiopathic PD patients whose cognitive abilities were measured longitudinally for 2 years after their Aβ scan.

Methods: Our study used PD patient and healthy control (HC) data from the Parkinson’s Progression Marker Initiative (PPMI) cohort. 25 de novo idiopathic PD patients and 31 HC underwent a [¹⁸F]florbetaben (FBB) positron emission tomography (PET) scan which can measure the density of Aβ in vivo in the brain. [¹⁸F] FBB density was expressed as a standardized uptake value ratio (SUVR) of 20 bilateral cortical regions of interest (ROI) parcellated using an MNI-modified AAL template. Demographic information, clinical characteristics, and cognitive test scores were also collected. The data was analyzed using IBM SPSS version 27 software with linear regression modeling, Pearson correlations, and hierarchical cluster analysis.

Results: A stepwise linear regression of the PD group revealed a strong adjusted R² of 0.495 in a model explaining their Montreal Cognitive Assessment (MoCA) score 1-year post-scan using the SUVR from 20 cortical ROIs as independent variables. The ROIs found in this stepwise model were the left rectus, the left anterior cingulate cortex, and the right parietal cortex. We found the PD group’s brain regions formed two clusters, with increased Aβ in cluster two correlating more strongly with a lower MoCA score.

Conclusion: The results suggest Aβ has a moderate association with cognitive decline in PD. We found Aβ accumulation in the brain had a patchwork effect on PD cognition depending on which ROIs are affected. More Aβ accumulation preferentially in cluster 2 ROIs may be involved in PD patients’ cognitive dysfunction.

Acknowledgements

PPMI – a public-private partnership – is funded in part by the Michael J. Fox Foundation for Parkinson’s Research.

References

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2021-167

[¹²⁴I]IAZA: Development of a new radioiodinated PET imaging agent for human Alzheimer’s disease brain (#406)

Thrisha T. Reddy, Christopher Liang and Jogeshwar Mukherjee

UCI School of Medicine, Radiological Sciences, Irvine California, USA

Abstract

Introduction: Amyloid b (Ab) and Tau (neurofibrillary tangles) imaging Alzheimer’s disease (AD) is currently underway using various radiotracers. Using “azo” derivatives, we have reported Ab plaque binding properties of [¹¹C]TAZA [1] and [¹⁸F]Flotaza² in postmortem human brain AD. Here we report development and evaluation of a new iodine-124 “azo” analog, [¹²⁴I]IAZA (4-[¹²⁴I]iodo-4’-N,N-dimethylaminoazobenzene), as a potential PET imaging agent for AD.

Methods: The radiosynthesis of [¹²⁴I]IAZA used electrophilic substitution of tributyltin by [¹²⁴I]iodide (Figure 1) and purified on HPLC.³ Human AD post-mortem brain slices (10 µm) consisting of anterior cingulate (AC) and corpus callosum CC and temporal cortex were used for in vitro binding studies. Brain slices incubated with [¹²⁴I]IAZA⁴ in 50% ethanol PBS buffer pH 7.4 (60 mL;0.5 µCi/mL) at 25°C for 1.25 hr. Drug effects of 10 mM 5-OH-BTA-0, curcumin, IAZA, IPPI and MK-6240 were measured. The slices were washed with PBS buffer, 50% and 90% ethanolic PBS buffer and cold water. Brain sections were dried, exposed on phosphor film and analyzed using Optiquant software and binding of [¹²⁴/¹²⁵I]IAZA was measured in DLU/mm².

Results: The single step radiosynthesis of [¹²⁴I]IAZA was very efficient. Slices from subjects were positively immunostained with anti-Ab and Anti-Tau. Selective binding of [¹²⁴I]IAZA was observed in grey matter regions (Figure 2). The ratio of AC to CC was > 10. Similarly, temporal cortex exhibited significant binding of [¹²⁴I]IAZA. Very little white matter binding was seen when 90% alcohol was used in the washing of the slices. IAZA displaced > 90% of [¹²⁴I]IAZA, displacement by Ab drugs, 5-OH-BTA-0 and curcumin was low, similar to [¹²⁵I]IAZA⁴ and Tau drugs, IPPI and MK-6240 displaced ∼40%. These findings suggest that [^124/125I]IAZA may have unique binding sites in the AD brain.

Conclusion: [¹²⁴I]IAZA exhibited high binding in postmortem human AD brains. Although it is a close analog of [¹¹C]TAZA [1] and [¹⁸F]Flotaza,² [^124/125I]IAZA appears to be dissimilar. Along with our recently developed [¹²⁵I]IPPI for Tau,⁵ it offers a useful tool for the study of postmortem AD brains. Studies are underway to evaluate the utility of [¹²⁴I]IAZA in transgenic AD mice models, P301S for Tau and 5XFAD for Ab.

Acknowledgements

NIH/NIA RF1 AG029479 (JM), UCI UROP (TTR). Banner Health Research Institute for tissue samples and UCI Pathology for immunostaining. Inline graphic

graphic file with name 10.1177_0271678X211061050-img232.jpg

References

1.Pan ML, Mukherjee MT, Patel HH, et al. Evaluation of [¹¹C]TAZA for amyloid Ab plaque imaging in postmortem Alzheimer’s disease brain region and whole body distribution in rodent PET/CT. Synapse 2016; 70: 163–176. [DOI] [PMC free article] [PubMed] [Google Scholar]
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2021-168

Mapping the multivariate effects of amyloid, tau, and neuroinflammation on cortical thickness in AD (#408)

Min-Su Kang¹, Julie Ottoy², Gleb Bezgin⁴, Gassan Massarweh⁴, Jean-Paul Soucy⁴, Serge Gauthier³ and Pedro Rosa-Neto³

¹McGill University, IPN, Montreal, QC, Canada

²Toronto University, Sunnybrook Research Institute, Toronto, ON, Canada

³McGill University, Neurology and Neurosurgery, Montreal, QC, Canada

⁴McGill University, Montreal Neurological Institute, Montreal, QC, Canada

Abstract

Introduction: Understanding the effects of amyloid, tau, and neuroinflammation on neurodegeneration is important for identifying an effective therapeutic target and combination therapy for AD. Here, we aimed to elucidate the amyloid, tau, and neuroinflammation effects on neurodegeneration and cognition using multimodal imaging biomarkers.

Methods: A total of 111 participants (57 A-T-, 12 A+T-, 42 A+T+) from the TRIAD cohort underwent T1, 3 PET, and MMSE procedures. Cortical thickness measurement was generated using the Freesurfer pipeline while static [¹⁸F]AZD4694, [¹¹C]PBR28, and [¹⁸F]MK6240 SUVR images were generated using the PETsurfer pipeline. A multivariate PLS regression model was conducted to evaluate the effect of [¹⁸F]AZD4694, [¹¹C]PBR28, and [¹⁸F]MK6240 on cortical thickness. Then, the significant latent variables (LVs) were evaluated to understand the pathologic effect on cognition based on a multiple regression between the MMSE and latent variable scores with age, sex, education, and APOEε4 as covariates.

Results: Our study revealed two significant LVs that explained 28% and 21.2% of the cortical thickness, respectively. Here, the first LV score showed a significant negative effect on MMSE and a significant increase in A+T+ compared to A-T- and A+T- and in A+T+ compared to A-T-. Upon further examination of the first LV, [¹¹C]PBR28 in bilateral transverse temporal, hippocampal, and insular regions showed positive effects while all [¹⁸F]AZD4694 and [¹⁸F]MK6240 regions showed negative effects on cortical thickness.

Conclusion: This study highlights a complex pathologic mechanism, in which activated glial neuroinflammation showed protective effects while amyloid and tau showed degenerative effects on cortical thickness, leading to cognitive impairment in AD.

graphic file with name 10.1177_0271678X211061050-img233.jpg

Figure 1. LV1 bootstrap ratio.

graphic file with name 10.1177_0271678X211061050-img234.jpg

Figure 2. LV1 loadings.

2020 Abstract

2020-01

Anti-correlations between ¹⁸F-FDG PET and resting state dynamic functional connectivity: Insights into brain network variability (#3)

Tommaso Volpi¹, Marco Aiello², Valentin Riedl³, Maurizio Corbetta^{1, 4} and Alessandra Bertoldo^{1, 5}

¹Padova Neuroscience Center, University of Padova, Padova, Italy

²IRCCS SDN, Napoli, Italy

³TUM-Neuroimaging Center, Department of Neuroradiology, Technical University of Munich, Munich, Germany

⁴Department of Neurosciences, University of Padova, Padova, Italy

⁵Department of Information Engineering, University of Padova, Padova, Italy

Abstract

Introduction: There is increasing interest in understanding the relationship between the brain’s metabolic consumption, imaged by ¹⁸F-FDG PET, and its functional connectivity (FC) architecture emerging from resting-state fMRI studies, which is assumed to partly rely on local glucose metabolism. Correlations between ¹⁸F-FDG PET measures and FC in simultaneous recordings have been reported,^1,2 but without investigating FC temporal variability.

Methods: Simultaneous ¹⁸F-FDG PET and resting state fMRI data were acquired in 28 healthy subjects (59.8 ± 10.8 yrs, 14 F) on a Siemens mMR Biograph 3T.^1,2 Standard uptake value ratio (SUVR) to whole-brain average was computed from ¹⁸F-FDG data; rs-fMRI was acquired for 10¹ and 7² minutes (TE/TR = 30/2000 ms). Both PET and fMRI scans were registered to T1w images and sampled over the Gordon-Laumann functional atlas.³ Time-varying FC (Pearson’s correlation) was computed with a sliding windows approach (window size: 30 TRs, step: 1 TR). FC graph metrics were computed for each sliding window: degree (DEG), strength (STR), participation coefficient (PAR), clustering coefficient (CC), betweenness centrality (BC). Coefficients of variation CV% (graph metrics’ standard deviation across sliding windows divided by their mean) were computed for each node and averaged across subjects; Pearson correlation with SUVR was computed considering: all ROIs; only network hubs, identified on the average static FC matrix as 15% highest DEG nodes.

Results: We identified statistically significant anti-correlations between nodes’ SUVR and CVs% of DEG, STR, CC, BC (ranging from r = −0.30 to -0.50, p < 0.01), but not with CV% of PAR (Figure 1). Anti-correlations were stronger when considering only between-network links (r = −0.44 vs. -0.33). Network hubs, defined according to DEG, had CVs% that were less significantly anti-correlated with SUVR (around r = −0.10).

Conclusion: An unexpected pattern of anti-correlations between ¹⁸F-FDG SUVR and FC variability was identified, which was consistent across most graph metrics, implying that the least variable connections are the ones that require more energy. These results need further investigation, e.g. employing absolute quantification of PET data and alternative dynamic FC methods, as well as validation from a biological and/or computational standpoint.

graphic file with name 10.1177_0271678X211061050-img235.jpg

References

1.Riedl V, Bienkowska K. Local activity determines functional connectivity in the resting human brain: a simultaneous FDG-PET/fMRI study. J Neurosci 2014; 34: 6260–6266. [DOI] [PMC free article] [PubMed] [Google Scholar]
2.Aiello M, Salvatore E. Relationship between simultaneously acquired resting-state regional cerebral glucose metabolism and functional MRI: a PET/MR hybrid scanner study. Neuroimage 2015; 113: 111–121. [DOI] [PubMed] [Google Scholar]
3.Gordon EM, Laumann TO. Generation and evaluation of a cortical area parcellation from resting-state correlations. Cereb Cortex 2016; 26: 288–303. [DOI] [PMC free article] [PubMed] [Google Scholar]

2020-02

Does ebselen: A potential new lithium mimetic, decrease synaptic glutamate availability? (#9)

Nisha Singh^{1, 2}, Filipa Mota¹, Teresa Sementa¹, Natasha Moses², Carlotta Taddei¹, Jayanta Borlodoi¹, Stefan Hader¹, Thomas Eykyn¹, Diana Cash², Mattia Veronese² and Federico E Turkheimer²

¹School of Biomedical Engineering & Imaging Sciences, King’s College London, London, UK

²Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK

Abstract

Introduction: In bipolar disorder, magnetic resonance spectroscopy has shown elevations in brain glutamate. We recently showed that ebselen, a potential new lithium mimetic, decreased brain glutamate in healthy volunteers.¹ However, if this change is reflected in glutamatergic neurotransmission, or is a consequence of metabolism, remains unknown. In this study, we used in vivo positron emission tomography to determine if ebselen reduced glutamate transmission using [¹⁸F]FPEB, an mGluR5 radiotracer. We hypothesised that ebselen, by virtue of inhibiting glutaminase,² should decrease brain glutamate, and we would observe increased brain uptake of [¹⁸F]FPEB with ebselen treatment, compared to controls. Less glutamate at the receptor level implies more available sites for the tracer to bind to and consequently increased [¹⁸F]FPEB uptake.

Methods: Rats were divided into four groups (n = 4/group); ‘ebselen acute’, ‘vehicle acute’, ‘ebselen chronic’ (two weeks) and, ‘vehicle chronic’ groups. The acute treatment groups were administered 5 mg/kg ebselen or vehicle intravenously (IV) followed by an IV injection of [¹⁸F]FPEB 15 minutes later, and scanned for 45 minutes. The chronic treatment groups were at baseline, after one week, and two weeks of ebselen treatment (3 µg/mL in drinking water). The data was analysed using Logan graphical analysis with cerebellum as normative region and distribution volume ratio as the main parameter of interest.

Results: In the acute treatment group, there was an overall increase in [¹⁸F]FPEB brain uptake (p = 0.028), as hypothesized. In the chronic treatment group, there was an increased [¹⁸F]FPEB uptake (p = 0.004), however, the vehicle group also showed an increase (p < 0.001). On looking closer, there was a significant correlation between weight of the rat and brain uptake of [¹⁸F]FPEB (p = 0.03) and so the results were co-varied for weight. After corrected for weight, there was a significant increase in [¹⁸F]FPEB after 1 week of treatment, (p = 0.004) but not after two weeks.

Conclusion: Acute administration of ebselen decreased synaptic availability of glutamate. However, chronic dosing offered a more complicated picture, where synaptic glutamate levels decreased after one week of treatment but then normalised after two weeks.

Acknowledgements

BAP In Vivo training award, MRC.

graphic file with name 10.1177_0271678X211061050-img236.jpg

Ebselen acutely reduces glutamate transmission

References

1.Masaki C, Sharpley AL, Godlewska BR, et al. Effects of the potential lithium-mimetic, ebselen, on brain neurochemistry: a magnetic resonance spectroscopy study at 7 tesla. Psychopharmacology (Berl) 2016; 233: 1097–1104. [DOI] [PMC free article] [PubMed] [Google Scholar]
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2020-03

Examining the underpinnings of loudness dependence of auditory evoked potentials with positron emission tomography (#17)

Rajapillai LI Pillai¹, Elizabeth A Bartlett², Mala R Ananth¹, Chencan Zhu³, Jie Yang⁴, Greg Hajcak⁵, Ramin V Parsey¹ and Christine DeLorenzo^1,
6

¹Psychiatry, Stony Brook University, Stony Brook, NY, USA

²Molecular Imaging and Neuropathology, New York State Psychiatric Institute, New York, NY, USA

³Applied Mathematics and Statistics, Stony Brook University, Stony Brook, NY, USA

⁴Family, Population, and Preventive Medicine, Stony Brook University, Stony Brook, NY, USA

⁵Biomedical Sciences and Psychology, Florida State University, Tallahassee, FL, USA

⁶Biomedical Engineering, Stony Brook University, Stony Brook, NY, USA

Abstract

Introduction: Loudness dependence of auditory evoked potentials (LDAEP) has long been considered to reflect central basal serotonin transmission. However, the relationship between LDAEP and individual serotonin receptors and transporters has not been fully explored in humans, which limits its use as a potential biomarker. Establishing the correlation between LDAEP and PET-based estimates of the serotonin 1A receptor and serotonin transporter binding could increase the utility of this non-invasive modality.

Methods: To examine LDAEP’s relationship with the serotonin system, we performed PET using serotonin-1A (5-HT_1A) imaging via [¹¹C]CUMI-101 and serotonin transporter (5-HTT) imaging via [¹¹C]DASB on a mixed sample of healthy controls (n = 4: 4 females, 0 males), patients with unipolar (MDD, n = 11: 4 females, 7 males) and bipolar depression (BD, n = 8: 4 females, 4 males). Full quantification was performed including arterial sampling or simultaneous estimation (SIME).¹ On these same participants, we also performed electroencephalography (EEG) within a week of PET scanning, using 1000 Hz tones of varying intensity to evoke LDAEP. We then evaluated the relationship between LDAEP and 5-HT_1Aor 5-HTT binding potential (BP_Ffor [¹¹C]CUMI-101 and V_T/f_Pfor [¹¹C]DASB) in both the raphe² (5-HT_1A)/midbrain (5-HTT) areas and in the temporal cortex. In an exploratory analysis, we examined the relationship between LDAEP and 5-HT_1A/5-HTT across 25 regions of the brain, as well as the effects of age and sex, as previous studies have found differences in PET and EEG measures for both.

Results: LDAEP was significantly correlated with 5-HT_1ABP_Fpositively and with 5-HTT V_T/f_Pnegatively in the temporal cortex (p < 0.05), but did not correlate with either in midbrain or raphe (Figure 1). In males only, exploratory analysis showed LDAEP significantly correlated with 5-HT_1ABP_Fin temporal cortex, anterior cingulate cortex, medial prefrontal cortex, occipital cortex, orbitofrontal cortex, and parietal cortex; these correlations were not observed with 5-HTT (see Figure 2 for sample regions).

Conclusion: This multimodal study partially validates preclinical models of a serotonergic influence on LDAEP. Replication in larger samples is necessary to further clarify our understanding of the role of serotonin in perception of auditory tones.

Acknowledgements

We acknowledge the biostatistical computation and support provided by the Biostatistical Consulting Core at School of Medicine, Stony Brook University, and in particular Dr. Mengru Zhang, who provided key support for this study. This work was funded by NIMH grants F30MH109412 (PI: Pillai) and R01MH090276 (PI: Parsey). We would like to thank Emily Hale-Rude for EEG setup assistance and Dr. Craig Tenke for assistance in experimental design and for auditory stimuli.

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References

1.Bartlett EA, et al. Quantification of positron emission tomography data using simultaneous estimation of the input function: validation with venous blood and replication of clinical studies. Mol Imaging Biol 2018; 21: 926–934. [DOI] [PMC free article] [PubMed] [Google Scholar]
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2020-04

Physiological brain activation by visual stimulation does not alter binding of the synaptic density tracer [¹¹C]UCB-J (#26)

Kelly Smart, Heather Liu, David Matuskey, Ming-Kai Chen, Kristen Torres, Nabeel Nabulsi, David Labaree, Yiyun H Huang, Evan D Morris, Ansel T Hillmer and Richard E Carson.

Yale PET Center, Yale School of Medicine, New Haven, CT, USA

Abstract

Introduction: The radiotracer [¹¹C]UCB-J provides a measure of synaptic vesicle density in vivo with clinical applications in neurological and psychiatric disorders. [¹¹C]UCB-J binds to the synaptic vesicle glycoprotein 2A (SV2A), a ubiquitously expressed protein involved in regulation of neurotransmitter release through vesicle exocytosis. Changes in brain activity could potentially affect tracer binding if binding site availability is altered during the process of vesicle transport, fusion, or recycling. The objective of this study was to determine whether physiological brain activation induces measurable changes in [¹¹C]UCB-J binding.

Methods: Seven subjects (four women) completed two 60-minute [¹¹C]UCB-J PET scans (654 ± 99.0 MBq) on a high-resolution research tomograph (HRRT). In the baseline scan, a static black screen was displayed on video glasses worn by the subject. During the visual activation scan, an 8-Hz flashing radial checkerboard was presented in 3-minute intervals separated by 2-minute rest periods throughout the scan. Scans were performed on the same day with order counter-balanced across subjects. Tissue influx constant, K₁, and volume of distribution, V_T, were determined using a metabolite-corrected arterial input function and the 1-tissue compartment model. Regional values were determined in primary visual cortex (V1; Brodmann area 17), in temporal cortex as negative control, and in centrum semiovale (white matter) to assess nonspecific binding. Parametric whole-brain images of V_T and K₁ were compared using SPM.

Results: In V1, [¹¹C]UCB-J K₁ increased 25 ± 8.3% (p = 0.009; 95% CI 18–35%) during activation (Figure 1). No change was observed in temporal cortex (-3.1 ± 6.1%, p = 0.77) or centrum semiovale (-4.0 ± 6.1%, p = 0.64). There was no change in V_T from baseline to activation in V1 (mean change -3.9 ± 8.8%, p = 0.34; 95% CI -12 to 4%), temporal cortex (-3.1 ± 9.1%, p = 0.61), or centrum semiovale (-1.1 ± 10%, p = 0.83). Representative parametric images during baseline and activation are shown in Figure 2. Whole-brain analyses confirmed an increase in K₁ specific to visual cortex (cluster-level p_FWE = 0.031), with no significant changes in V_T across the brain.

Conclusion: Despite a robust increase in tracer influx to V1, [¹¹C]UCB-J V_T did not change during visual stimulation. [¹¹C]UCB-J V_T is therefore likely to be a stable measure of synaptic vesicle density regardless of brain state at the time of scan.

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2020-05

Reliability assessment of neuronal activation using fPET, BOLD and ASL obtained with simultaneous PET/MR imaging (#38)

Lucas Rischka¹, Godber M Godbersen¹, Verena Pichler², Paul Michenthaler¹, Sebastian Klug¹, Manfred Klöbl¹, Vera Ritter¹, Wolfgang Wadsak^{2, 3}, Marcus Hacker², Siegfried Kasper¹, Rupert Lanzenberger¹ and Andreas Hahn¹

¹Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria

²Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria

³Center for Biomarker Research in Medicine (CBmed), Graz Steiermark, Austria

Abstract

Introduction: Mapping of cognitive tasks on a neuronal level represents a crucial factor for our understanding of human brain function. Recently, the novel approach of functional PET (fPET) was introduced, enabling quantification of task-specific activation within a single measurement.^1,2 Besides task-sensitivity, a valuable neuroimaging method also provides high reliability of activation. We therefore investigated the test-retest performance of task-specific glucose metabolism with fPET and [¹⁸F]FDG. Using simultaneous PET/MR imaging enabled an unbiased direct comparison to well-established fMRI methods measuring BOLD-derived activation (BOLD) and cerebral blood flow (CBF) with ASL.

Methods: Twenty healthy subjects underwent two measurements on a hybrid PET/MRI scanner. During the scan, subjects completed an adapted version of the video game Tetris® representing a complex visuo-spatial coordination task with varying task load (i.e. easy/hard condition). In order to track task-specific changes on a multimodal level, functional PET was acquired simultaneously with ASL and within the same session as BOLD (Figure 1). Data processing of CBF and BOLD was performed with standard procedures.^2,3 Glucose metabolism (influx constant K_i) was quantified with a general linear model, including regressors for each task load, and the Gjedde-Patlak plot.² Functional ROIs were defined across all three modalities by a conjunction analysis of significant activations during the hard condition (p < 0.05 FWE-corrected, Figure 2). Test-retest reliability was assessed for both task conditions using the within-subject Coefficient of Variation (CoV) and Intra-Class Correlation (ICC_3,1).

Results: Regions active during the task are depicted in Figure 2. The median CoV of the hard/easy condition was 0.20/0.33 (glucose metabolism), 0.17/0.30 (CBF) and 0.21/0.27 (BOLD). The ICC showed moderate consistency for glucose metabolism (0.64/0.41) and CBF (0.60/0.56) but poor for BOLD (0.23/0.38).

Conclusion: We demonstrated matching activation across the three complementary imaging modalities. However, glucose metabolism and cerebral blood flow exhibited a higher consistency between the measurements than BOLD-derived activation. Hence, fPET shows at least similar reliability compared to well-established methods. Since fPET is still novel it has great potential for optimization, such as innovative task modeling or radioligand administration strategies. We propose to consider fPET as a complementary, reliable imaging approach to map task-specific changes in future studies.

Acknowledgements

This research was supported by a grant from the Austrian Science Fund to A. Hahn (FWF KLI 610). L. Rischka and M. Klöbl are recipients of DOC Fellowships of the Austrian Academy of Sciences at the Department of Psychiatry and Psychotherapy, Medical University of Vienna.

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References

1.Hahn, et al. Quantification of task-specific glucose metabolism with constant infusion of 18F-FDG. J Nucl Med 2016; 57: 1933–1940. [DOI] [PubMed] [Google Scholar]
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2020-06

Assessment of model bias upon detection of dopamine response to challenge (#50)

Michael A Levine^{1, 2}, Joseph B Mandeville¹, Finnegan Calabro³, Julie C Price¹, Beatriz Luna³ and Ciprian Catana¹

¹A.A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston, MA, USA

²Biophysics, Harvard University, Boston, MA, USA

³Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA

Abstract

Introduction: [¹¹C]Raclopride Positron Emission Tomography (PET) is used to probe dopamine release in response to a behavioral challenge by applying compartmental kinetic modeling, extracting macroparameters including binding potential (BP_ND). However, behavioral challenges produce small changes in neurotransmitter release, whose detection may be conflated with sources of systematic bias such as model selection. To investigate this effect, voxel maps of absolute change in binding potential (ΔBP_ND, i.e. BP_ND-POST – BP_ND-PRE) in humans were compared to simulated maps which describe the bias induced by the Multilinear Reference Tissue Model (MRTM,MRTM2).¹

Methods: 69 healthy young adult participants underwent bolus plus constant infusion [¹¹C]raclopride PET over 90 min with simultaneous functional Magnetic Resonance Imaging and a reward learning task (avg. start, end time: 40,70 min).² A two-tissue compartment model (2TCM) was forward simulated using an analytic arterial input function,³ global K₁’ and k₄,⁴ a single k₂’ (0.30/min), voxel maps of R1 and BP_ND created by averaging fit maps acquired across participants, and no challenge. The acquired and simulated PET data were fit voxel-wise with an extension of MRTM2 that includes a challenge term (unit step at 40 minutes) to produce parametric maps of ΔBP_ND. Real and simulated ΔBP_ND maps were compared for both MRTM and MRTM2 to evaluate the potential for bias.

Results: In human participants, MRTM and MRTM2 estimated average putamen BP_ND to be 3.3 ± SD 1.2 and 3.4 ± SD 0.3, respectively. In response to the behavioral challenge, an average change in putamen BP_ND of -0.17 ± SD 0.17 (-5.4% ± SD 5.1%) and -0.17 ± SD 0.09 (-5.2% ± SD 2.5%) were observed across participants for MRTM (Figure 1(a)) and MRTM2 (Figure 1(c)) respectively. Simulating a 2TCM without challenge and fitting the models produced a change in putamen BP_ND of 0.03 (0.9%) for MRTM (Figure 1(b)) and -0.04 (-1.2%) for MRTM2 (Figure 1(d)).

Conclusion: The results suggest a significant behavioral reward challenge response (ΔBP_ND), exceeding the level of model-induced bias observed in simulations. MRTM2 could lead to overestimation of dopamine responses to behavioral challenge. We are currently investigating approaches to overcome this bias including de-weighting the delivery period and regularizing the Full Reference Tissue Model.⁵

Acknowledgements

This work was supported by National Institute of Mental Health Grant Number 5R01MH080243-07 and National Institute of Neurological Disorders and Stroke Grant Number R01NS112295.

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References

1.Ichise M, et al. Linearized reference tissue parametric imaging methods: application to [11C]DASB positron emission tomography studies of the serotonin transporter in human brain. J Cereb Blood Flow Metab 2003; 23: 1096–1112. [DOI] [PubMed] [Google Scholar]
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2020-07

Non-displacable binding is a potential confounding factor in [¹¹C]PBR28 PET studies (#53)

Gjertrud L Laurell¹, Pontus Plavén-Sigray^{1, 2}, Aurelija Jucaite^{2, 3}, Andrea Varrone², Kelly P Cosgrove^{4, 5}, Claus Svarer¹, Gitte M Knudsen^{1, 6}, R Todd Ogden⁷, Francesca Zanderigo^{8, 9}, Simon Cervenka², Ansel T Hillmer^4,
10 and Martin Schain¹

¹Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark

²Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet & Stockholm Health Care Services, Stockholm, Sweden

³Precision Medicine and Genomics, PET Science Centre, AstraZeneca, Stockholm, Sweden

⁴PET Center, Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, USA

⁵Department of Psychiatry, Yale University, New Haven, CT, USA

⁶Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

⁷Department of Biostatistics, Columbia University, New York, NY, USA

⁸Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York NY, USA

⁹Molecular Imaging and Neuropathology Area, New York State Psychiatric Institute, New York, NY, USA

¹⁰Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT, USA

Abstract

Introduction: [¹¹C]PBR28 is a frequently used PET radioligand that binds to the 18kDa translocator protein (TSPO), a biomarker sensitive to glial cell activation. In clinical TSPO PET studies, the radioligand total distribution volume, V_T, is typically regarded as the preferred outcome measure. V_T is the sum of the ligand specific (V_S) and non-displaceable binding (V_ND). Thus, differences in brain-wide V_ND across groups are potentially a confounding factor because group differences in regional V_T could be attributable to differences in V_ND, rather than differences in actual TSPO densities.

Methods: Here, we used a recently developed method for estimation of V_ND (simultaneous estimation, SIME¹) to disentangle the components V_ND and V_S in data from four previously published [¹¹C]PBR28 PET studies: (i) before and after a lipopolysaccharide challenge² (8 subjects); (ii) in alcohol use disorder³ (14 patients, 15 controls); (iii) in first-episode psychosis⁴ (16 patients, 16 controls); and (iv) in Parkinson’s disease⁵ (16 patients, 16 controls). In each dataset, regional V_T estimates were obtained with a two-tissue compartment model, and brain-wide V_ND was estimated with SIME. Regional V_S was calculated as V_T – V_ND. Regional V_T and V_S, and brain-wide V_ND were then compared across groups.

Results: Lower V_ND values were found for individuals with alcohol use disorder (34%, p = 0.00084, Figure 1) and Parkinson’s disease (34%, p = 0.0032, Figure 2), when compared to their corresponding controls. We found no difference in V_ND between first-episode psychosis patients and their controls (p = 0.30), and the administration of lipopolysaccharide did not change V_ND (p = 0.38). We also observed a clear effect of genotype on V_ND; when pooling all controls, we observed that high-affinity binders not only displayed higher specific binding, but also had markedly higher V_ND than mixed affinity binders (p = 0.00016).

Conclusion: Our findings suggest that in TSPO PET studies, levels of non-displaceable binding may differ both between patient groups and between conditions, and should therefore be taken into account.

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References

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2020-08

Transcriptome-based human cerebral cortex parcellation (#55)

Matej Murgaš, Gregor Gryglewski, Manfred Klöbl, Murray B Reed and Rupert Lanzenberger.

Department of Psychiatry and Psychotherapy, Medical University of Vienna, Wien, Austria

Abstract

Introduction: Compartmentalization of the human cerebral cortex, in the terms of structural organization, e.g. Desikan-Killiany,¹ cytoarchitecture, Brodmann areas,² or functional specialization, Glasser atlas³ is an essential part of neuroimaging. However, mappings based on proteomic and transcriptomic data are still largely missing. Hence, the aim of this work was to find a specific delineation to the functionally specific areas using molecular information from the mRNA transcriptome.

Methods: The dataset of 18686 mRNA expression patterns mapped to the fsaverage space (FreeSurfer common space) consisting of 163842 vertices per hemisphere were used. mRNA maps were interpolated from 3702 microarray samples of six left hemispheres taken from the Allan Human Brain atlas.⁴ Using agglomerative hierarchical cluster analysis with average linkage and Pearson correlation as the distance metric, a structural representation of the data was created. The Bayesian Information Criterion (BIC) was used to optimize the number of clusters. Subsequently, the similarities with already existing atlases were quantified using the Dice coefficient, demonstrating the goodness of overlap between the parcellations.

Results: The hierarchical structure of the data is presented in Figure 1(a) as dendrogram. Based on the BIC, the dendrogram was cut so that the cerebral cortex was split into 33 regions (Figure 1(b) – middle). The transcriptome-based compartmentalization was compared to the Brodmann areas (10 of 42 regions with Dice > 0.5, mean 0.37), the Desikan-Killiany atlas (6 of 34 regions with Dice > 0.5 mean 0.35) and the Glasser atlas (42 of 180 regions with Dice > 0.5, mean 0.4). Although some regions show a certain overlap with all three parcellations, mostly low dice coefficients emphasize the difference of the atlases under comparison.

Conclusion: The presented work introduces a parcellation of the human cerebral cortex based on the whole-brain transcriptome. In future work, molecular-based mapping of the cortex could be used in the prediction of the activation and structural patterns associated with psychopharmacological challenges. Prospectively, molecular-based approach could help us to understand the interspecies homology on the level of functional organization comparing brains of various non-human primates.

Acknowledgements

M.M. is funded by the Austrian Science Fund FWF DOC 33-B27. M.K. and M.B.R. are recipients of a DOC-fellowship of the Austrian Academy of Sciences at the Department of Psychiatry and Psychotherapy, MUV.

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2020-09

Neuroinflammation in autism spectrum disorder: A [¹⁸F]FEPPA PET Study. (#57)

Dominic Simpson¹, Stephanie H Ameis^{2, 3}, Avideh Gharehgazlou⁴, Romina Mizrahi^{2, 3} and Pablo M Rusjan^1,
3

¹Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON, Canada

²Department of Psychiatry, University of Toronto, Toronto, ON, Canada

³Centre for Addiction and Mental Health, Toronto, ON, Canada

⁴Institute of Medical Science, University of Toronto, Toronto, ON, Canada

Abstract

Introduction: Converging evidence points to the significant involvement of the immune system and neuroinflammation in Autism Spectrum Disorders (ASD). For example, people diagnosed with ASD present with elevated levels of cytokines in peripheral blood and CSF. Monocytes derived from individuals on the autism spectrum show aberrant innate immune responses upon stimulation with lipopolysaccharide, with excessive production of proinflammatory cytokines. Translocator protein 18 kDa (TSPO) is a mitochondrial protein mostly localized in microglia, which can be quantified with PET, providing an in-vivo marker of neuroinflammation/microglial activation. This preliminary analysis aimed to explore whether markers of brain inflammation/microglial activation were altered in participants with ASD in-vivo using [¹⁸F]FEPPA PET imaging.

Methods: ASD participants were scanned for 2 hours with an HRRT following an injection of [18F]FEPPA. Clinical diagnosis of ASD was confirmed using the Autism Diagnostic Observation Schedule-2. All subjects had an IQ≥70. Subjects were classified based on their rs6971 TSPO polymorphism to high, medium, or low affinity binders (HAB, MAB, and LAB, respectively), and LABs were excluded. The 2-TCM was used to determine the total volume of distribution (V_T) of 4 previously identified regions of interest (ROI): the prefrontal, temporal, cerebellar and anterior cingulate cortices. Data for typically developing volunteers (Controls) from previous studies were used for comparison. Linear mixed models were used with group and genotype as fixed factors, ROIs as a repeated within-subject factor, participants as a random effect (including intercept), and V_T as the dependent variable. Posthoc testing was adjusted using Bonferroni.

Results: We scanned 13 individuals with ASD (5F, age 25 ± 5, 5 MAB). 13 Controls (9F, age 24 ± 5, 5 MAB) were chosen from previous studies to match age and genotype. The V_T for the ACC of an ASD subject did not present identifiability. There were no significant differences in V_T in participants with ASD versus controls (F = 1.7,p = 0.2), though V_T was 15% lower in MABs, and 23% in HABs in ASD (Figure 1). Of note, a single subject (ASD, HAB) had V_T > 2 SD of the mean.

Conclusion: While no clear evidence of altered inflammation/microglia activation was found in participants with ASD, this preliminary analysis was limited by a small sample size.

Acknowledgements

CIHR MOP-142376.

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2020-10

Development of a carbon-11 positron emission tomography pro-radiotracer for imaging the astrocyte glutamate transporter 1 (#64)

Igor C Fontana^{1, 2}, Salvatore Bongarzone¹, Eduardo R Zimmer², Diogo O Souza² and Antony Gee¹

¹Division of Imaging Sciences and Biomedical Engineering, King’s College London, St Thomas’ Hospital, London, UK

²Graduation Program in Biological Sciences: Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil

Abstract

Introduction: The astrocyte glutamate transporter 1 (GLT-1) is essential for the clearance and recycling of glutamate in the brain. In fact, GLT-1 dysfunction is associated with neuronal death and linked to multiple brain disorders.¹ Synthesizing inhibitors with high selectivity to GLT-1 may help understanding glutamatergic dysfunction in these conditions. Greenfield et al.² described a GLT-1-selective inhibitor (Figure 1(a) – IC₅₀in vitro = 0.7 µM), with suitable molecular structure for carbon-11 radiolabelling, but with low brain penetrance profile (typical for carboxylic acids). To overcome this limitation, developing an analogous ester to be hydrolysed to the active form inside the brain, seems a promising approach. Here, we aim to develop a carbon-11 labelled pro-radiotracer ([¹¹C]IF1), which we hypothesize will be hydrolysed to the GLT-1-targeting radiotracer ([¹¹C]IF2 – Figure 1(b)) after crossing the blood-brain barrier (BBB) (Figure 1(c)).

Methods: The [¹¹C]IF1 radiosynthesis was performed using an Eckert & Ziegler Modular-Lab system. [¹¹C]CO₂ was converted to [¹¹C]CO as previously reported by Taddei et al.³ The [¹¹C]CO afforded [¹¹C]IF0 via a palladium-mediated [¹¹C]carbonylation reaction. [¹¹C]IF1 was obtained after removal of the BOC protecting group with trifluoroacetic acid (Figure 1(d)). Positron emission tomography (PET) imaging experiments were conducted as shown in Figure 2(a).

Results: [¹¹C]IF1 was obtained within 18 min after the end of bombardment with radiochemical yield of 79% (based on radio‐HPLC analysis of the crude product) and radiochemical purity of 99%. Preliminary results from PET imaging analysis were depicted in Figure 2(b). In brief, standardize uptake values (SUVs) were high in the intestine (SUV = 17) and liver (SUV = 6), but low in the brain (SUV = 0.8).

Conclusion: [¹¹C]IF1, a potential GLT-1 pro-radiotracer, was successfully synthesized from [¹¹C]CO. The low in vivo [¹¹C]IF1 brain uptake suggests that the methyl ester is too rapidly metabolised to enable BBB penetration. Interestingly, astrocyte-like cells are highly abundant in the intestine and liver. Thus, it is likely that [¹¹C]IF1 also binds to peripheral GLT-1. Work is in progress to further characterize [¹¹C]IF1 peripheral binding and also to optimize this reaction, furnishing the pharmacophore with a more metabolically resistant ester function to allow greater BBB penetration.

Acknowledgements

[1] Universidade Federal do Rio Grande do Sul (UFRGS); [2] Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES); [3] King’s College London; [4] Wellcome EPSRC Centre For Medical Engineering.

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Figure 1. [11C]IF1 PET imaging in healthy mice. a. [¹¹C]IF1 and [¹¹C]IF2 PET biodistribution scheme. Female mice were anesthetised with isoflurane 2.5% and 100 µL of [¹¹C]IF1 or [¹¹C]IF2 (saline with 10% ethanol) were administered into mouse tail vein. After a 60 min dynamic PET scan, CT was acquired and animals were culled. b. The pro-radiotracer [¹¹C]IF1 was mostly taken up in the intestine, liver, kidneys and bladder. [¹¹C]IF1 dynamic SUV. [¹¹C]IF1 brain uptake was very low (SUV = 0.8), with highest accumulation in the liver (SUV = 6) and intestine (SUV = 17).

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Figure 2. Development of a carbon-11 GLT-1 specific pro-radiotracer.

a. GLT-1 specific inhibitor developed by Greenfield et al. (2005). b. GLT-1-specific radiotracer – [¹¹C]IF2. c. Hypothesis of work: the pro-radiotracer [¹¹C]IF1 is hydrolysed, releasing inside the brain the EAAT2-specific radiotracer [¹¹C]IF2. d. Radiosynthesis scheme to obtain the pro-radiotracer [¹¹C]IF1

References

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2020-11

Amyloid (A), tau (T) and voxel-based morphometry (N) correlates of visual memory performance (#86)

Tharick A Pascoal^{1, 2}, Andréa L Benedet^{1, 2}, Joseph Therriault^{1, 2}, Min-Su Kang^{1, 2}, Melissa Savard^{1, 2}, Sulantha Mathotaarachchi^{2, 3}, Firoza Z Lussier^{1, 2}, Cécile Tissot^{1, 2}, Serge Gauthier^{1, 2}, Pedro Rosa-Neto^{1, 2} and Jaime Fernandez Arias^{1, 2}

¹McGill University Research Center for Studies in Aging, McGill University, Montreal, Québec, Canada

²Translational Neuroimaging Laboratory, Montreal, Québec, Canada

³Cerveau Technologies, Knoxville, TN, USA

Abstract

Introduction: The Aggie Figures Learning Test (AFLT) is a memory test that was designed to be a visual analogue of the Rey Auditory Verbal Learning Test (RAVLT). Previous studies have found associations between tau and amyloid PET and brain volume and RAVLT scores. However, to date, no study has explored the associations between these markers and AFLT scores. We aimed at exploring such associations.

Methods: Structural MRI, amyloid PET ([18F]-NAV4694) and tau PET ([18F]-MK6240) were acquired for 161 individuals. We conducted analyses on two sub-samples. Demographic data is shown on Table 1. MRI were segmented into probabilistic grey (GM) and white (WM) maps, non-linearly registered to the ADNI template using Dartel and smoothed with an 8 mm FWHM gaussian kernel. Voxel-wise linear regression models were applied, using VoxelStats, with AFLT sub-scores as dependent variables and either tau and amyloid binding or Voxel-Based Morphometry as predictors. We corrected for sex, Apoe genotype, age and years of education.

Results: We found negative associations between tau binding and AFLT total (trials 1–5) and AFLT delayed recall (DR) scores in the MTL and temporo-occipital cortices, as well as in some of their WM tracts. These associations were stronger for the total scores and, in both cases, in the right hemisphere. For the amyloid biomarker, associations with AFLT total and AFLT DR scores were negative in right ventromedial PFC, right posterior thalamus and basal ganglia. In this case, strongest associations are reported between amyloid burden and AFLT DR scores. Finally, we found positive associations between AFLT total and DR scores and VBM in the fusiform gyrus bilaterally.^1–3

Conclusion: Results resemble previously reported findings on associations between RAVLT and tau, amyloid and brain volume estimates. Our findings are also in line with initial reporting of patients with left hemisphere damage having more difficulties with RAVLT and patients with right hemisphere damage finding more trouble with AFLT tasks.⁴ In addition, relationships with tau tend to be more posterior, while relationships with amyloid were shown to be more anterior. Further analyses based on diagnostic categories are needed to explore how these associations change with pathology.⁵

Acknowledgements

Many thanks to the Translational Biomarkers of Aging and Dementia (TRIAD) cohort, the Weston Brain Institute, the Douglas Mental Health University Institute, Canadian Institutes of Health Research, and the Fundación San Rafael.

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Demographic data

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Imaging results

On the left, amyloid and tau correlates for AFLT Delayed Recall Scores; in the middle, amyloid and tau correlates for total AFLT scores; on the right, VBM correlates for both DR and total AFLT scores.

References

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2020-12

Neuroinflammation as a predictor of total knee arthroplasty recovery (#88)

Zeynab Alshelh¹, Erin J Morrissey¹, Angel Torrado-Carvajal^{1, 2}, Atreyi Saha¹, Minhae Kim¹, Samantha Rotman¹, Daniel Albrecht¹, Oluwaseun J Akeju³, Yang Lin¹, Kayla Florio³, Young-Min Kwon⁴, Hany Bedair⁴, Antonia Chen⁵, Zhongcong Xie³, Vitaly Napadow¹, Robert Edwards³ and Marco L Loggia¹

¹Radiology, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA

²Medical Image Analysis and Biometry Laboratory, Universidad Rey Juan Carlos, Madrid, Spain

³Anesthesia, Massachusetts General Hospital, Boston, MA, USA

⁴Orthopaedics, Massachusetts General Hospital, Boston, MA, USA

⁵Orthopaedics, Brigham and Women’s Hospital, Boston, MA, USA

Abstract

Introduction: Knee-osteoarthritis (KOA) is one of the most prevalent causes of pain and disability. Identifying whether a patient will experience persistent post-surgical pain (PPSP) can be extremely useful in the clinical decision-making process. While the mechanisms underlying PPSP remain elusive, the decoupling between pain and peripheral pathology, suggests that alterations in the central nervous system might have a role^1-2. A growing body of literature implicates a dysregulation in the activation of glial cells in preclinical pain models^3-4. Here, we tested the hypothesis that neuroinflammation predicts PPSP in KOA patients scheduled to undergo primary-TKA. To this end, we used an integrated PET/MR imaging paired with [¹¹C]PBR28, a radioligand that binds to the 18 kDa translocator protein, which is upregulated in activated glia⁵.

Methods: Eight subjects with KOA were recruited for the study. At the pre-TKA visit patients were assessed for pain, stiffness, functional limitation, physical function and pain interference, then were subsequently scanned. One-year post-TKA, patients were assessed again to determine changes from the pre-TKA visit. Correlation analyses were performed between the pain change scores and pre-TKA PET signal, in a voxel-wise analysis. [¹¹C]PBR28 signal extracted from the regions significant in this analysis were assessed for correlations with change in stiffness, functional limitation, physical function and pain interference.

Results: In the voxel-wise analysis, subjects showed a negative correlation between [¹¹C]PBR28 and change in pain intensity in regions encompassing parts of the anterior cingulate cortex, the dorsomedial prefrontal cortex and ventromedial prefrontal cortex, indicating that in these regions, higher pre-surgical [¹¹C]PBR28 signal predicts poorer recovery one-year post-TKA. Within these regions, there was a negative correlation between [¹¹C]PBR28 signal and change in functional limitation (r = −0.95, p = 0.004), physical function (r = −0.96, p = 0.003) and pain interference (r = −0.88, p = 0.021) and no significant correlation between [¹¹C]PBR28 signal and change in stiffness (r = −0.70, p = 0.123).

Conclusion: Our results indicate that higher inflammatory signal in the brain of patients with KOA before undergoing primary TKA might be predictive of a poorer recovery 1-year post surgery. If these results are reproduced in a larger sample, then these findings could better inform our decision-making process on whether primary TKA should be performed in specific patients and also to individualize pre- and post-surgical treatment accordingly.

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2020-13

Reduced metabotropic glutamate receptor subtype 5 in fragile X syndrome (#92)

James R Brasic¹, Anil K Mathur¹, Ayon Nandi¹, Keith Slifer^{2, 3}, Zabecca Brinson¹, Matthew Ryan⁴, Rebecca Landa^{3, 5}, Ebony Holliday⁵, Thomas W Sedlak^{1, 3}, Emily Dillon⁵, Samuel D Martin¹, Pankhuri Vyas⁶, Rohan Panaparambil¹, Omar KAE El Mandouh¹, Elizabeth M Berry-Kravis⁷, Ernest M Mahone^{3, 4}, Dean F Wong^{1, 8} and Dejan B Budimirovic^{3, 9}

¹Russell H. Morgan Department of Radiology and Radiological Science, Division of Nuclear Medicine and Molecular Imaging, Section of High Resolution Brain Positron Emission Tomography Imaging, Johns Hopkins University, Baltimore, MD, USA

²Behavioral Psychology Department, Kennedy Krieger Institute, Johns Hopkins University, Baltimore, MD, USA

³Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, USA

⁴Neuropsychology Department, Kennedy Krieger Institute, Johns Hopkins University, Baltimore, MD, USA

⁵Center for Autism and Related Disorders, Kennedy Krieger Institute, Johns Hopkins University, Baltimore, MD, USA

⁶Otolaryngology-Head and Neck Surgery, Johns Hopkins University, Baltimore, MD, USA

⁷Rush University Medical Center, Departments of Pediatrics, Neurological Sciences, Biochemistry, Chicago, IL, USA

⁸Department of Radiology, Laboratory of Central Nervous System (CNS) Neuropsychopharmacology and Multimodal Imaging (CNAMI), Mallinckrodt Institute of Radiology, Washington University in Saint Louis, Saint Louis, MO, USA

⁹Psychiatry Department, Fragile X Clinic, Kennedy Krieger Institute, Johns Hopkins University, Baltimore, MD, USA

Abstract

Introduction: Fragile X Mental Retardation Protein (FMRP) deficits lead to fragile X syndrome (FXS), the leading known single-gene cause of intellectual disability and autism spectrum disorder (ASD). Converging evidence in animal models of FXS demonstrated reversal of overly active metabotropic glutamate receptor subtype 5 (mGluR₅) by pharmacological interventions. Yet clinical trials of the mGluR₅ antagonists have failed in adult or adolescent humans with FXS. While studies using positron emission tomography (PET) have shown that these drugs do engage mGluR₅, their expression has not been measured in FXS.¹ Here, we aim to show a feasibility to measure an expression of the mGluR₅ receptors in humans with FXS.²

Methods: Positron emission tomography (PET) with a high resolution research tomograph (HRRT) was conducted for 90 minutes after the intravenous bolus injection of 185 megabequerels (MBq) (5 millicuries [mCi] 3-[¹⁸F]fluoro-5-(2-pyridinylethynyl)benzonitrile ([¹⁸F]FPEB), a potent, selective mGluR₅ inhibitor³ to two men with the full mutation for fragile X syndrome (FXS) aged 24–27 (25.5 ± 2.12) years, six men with idiopahtic autism spectrum disoder (IASD) aged 18–23 (20 ± 2.10) years, and three men with typical development (TD) aged 26–31 (27 ± 3.61) years.⁴ The nondisplaceable binding potential (BP_ND) was calculated for relevant volumes of interest (VOIs) (Figure 1) on PET images coregistered with magnetic resonance imagery (MRI).³

Results: In contrast to both the IASD and TD groups, BP_NDs for the men with FXS were reduced in all VOIs (Figure 2). Reductions in the men with FXS were particularly marked in the limbic system and the striatum (Figure 2).

Conclusion: This study supports the viability of PET to measure mGluR₅ density in FXS. The marked reductions of mGluR₅ density in the cortices and the limbic system support the finding that two distinct but interrelated social behavior abnormalities, one linked to impaired cognitive processes (delayed socialization) and the second one to disturbance in limbic circuits (avoidance), play a role in the development of ASD in boys with FXS.⁵ The protocol suggests that PET may be used to quantify a mGluR₅ binding to confirm target engagement for clinical trials of novel glutamatergic agents for FXS and other subtypes of ASD.

Acknowledgements

This research is funded by a Radiology Bridge Funding Initiative to Stimulate and Advance Research (RAD BriteStar Bridge) Award, Johns Hopkins University, Baltimore, Maryland (JRB) and the Intellectual & Developmental Disabilities Research Center (U54 HD079123) at the Kennedy Krieger Institute of Johns Hopkins Medical Institutions in Baltimore, Maryland (JRB). Hiroto Kuwabara, MD, PhD, provided image analysis. The Positron Emission Tomography (PET) Radiotracer Service Center and the Research MRI Service Center at Johns Hopkins Medicine provided excellent performance of the scans of this study.

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Figure 2. Nondisplaceable binding potentials for [18F]FPEB of men with FXS, ASD, and TD. Nondisplaceable binding potentials (BP_NDs) after the intravenous bolus inject of approximately 185 megabequerels (MBq) (5 millicuries [mCi] 3-[¹⁸F]fluoro-5-(2-pyridinylethynyl)benzonitrile ([¹⁸F]FPEB), a radiotracer for metabotropic glutamate receptor subtype 5 (mGluR₅) (3) were calculated for volumes of interests (Figure 1) of two men with fragile X syndrome (FXS), six men with autism spectrum disorder (ASD), and three men with typical development (TD) (4).

The densities of mGluR₅s were markedly lower in the men with FXS than the men with ASD and TD.

References

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2020-14

Clinical validation of [¹⁸F]EKZ-001: A novel positron emission tomography ligand for quantifying HDAC6 in the human brain (#104)

Michel Koole¹, Donatienne Van Weehaeghe^{1, 2}, Guy Bormans³, Sofie Celen³, Kim Serdons², Jan de Hoon⁴, Marissa Herbots⁴, Christopher Cawthorne¹, Frederick A Schroeder⁵, Jacob M Hooker⁶, Janice E Kranz⁵, Koen Van Laere^{1, 2} and Tonya M Gilbert⁵

¹Nuclear Medicine and Molecular Imaging, KU Leuven, Leuven, Belgium

²Nuclear Medicine and Molecular Imaging, University Hospitals Leuven, Leuven, Belgium

³Laboratory for Radiopharmaceutical Research, KU Leuven, Leuven, Belgium

⁴Center for Clinical Pharmacology, University Hospitals Leuven, Leuven, Belgium

⁵Eikonizo Therapeutics, Inc., Cambridge, MA, USA

⁶Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA

Abstract

Introduction: Histone deacetylase 6 (HDAC6) is a cytoplasmic enzyme that modulates intracellular transport¹ and protein quality control.² Inhibition of HDAC6 deacetylase activity has shown beneficial effects in disease models,^3,4 including Alzheimer’s disease, amyotrophic lateral sclerosis and major depressive disorder. This first-in-human positron emission tomography (PET) study evaluated [¹⁸F]EKZ-001 ([¹⁸F]Bavarostat⁵), a radioligand selective for HDAC6, in healthy adult subjects.

Methods: [¹⁸F]EKZ-001 was administered by intravenous bolus injection (142 ± 32 MBq). Biodistribution and radiation dosimetry studies were performed in four healthy subjects (2M/2F, 23.5 ± 2.4 years) using sequential whole-body PET/CT (Figure 1). The most appropriate kinetic model to quantify brain uptake was determined in 12 healthy subjects (6M/6F, 57.6 ± 3.7 years) from 120-minute dynamic PET/MR using a metabolite-corrected arterial plasma input function. Four subjects underwent retest scans (2M/2F, 57.3 ± 5.6 years) with a one-day interscan interval to determine test-retest variability (TRV). Fittings of a one-tissue and two-tissue compartment model (1–2TCM) were compared using the Akaike information criterion (AIC) while regional distribution volumes (V_T) were also calculated with Logan graphical analysis (LGA) and time stability of V_T was assessed. V_T differences between males and females were evaluated using a whole brain voxel-wise analysis.

Results: The effective dose was 39.1 ± 7.0 µSv/MBq. Based on AIC, 2TCM was the preferred model compared to 1TCM. Regional LGA V_T were in line with 2TCM values, however with a lower absolute TRV of 7.7 ± 4.9%. Regional V_T values were relatively homogeneous with highest values in hippocampus, entorhinal cortex, anterior cingulate, insula and cerebellum (Figure 2). Reduction of acquisition time was achieved by a coffee-break protocol with a 0- to 60-minute scan followed by a 90- to 120-minute scan resulting in regional LGA V_T with TRV of 4.5 ± 7.9% and average bias < 1%. Males demonstrated significantly higher LGA V_T than females in a majority of cortical and subcortical brain regions (P_height < 0.001, k_extent = 50). No relevant tracer related adverse events were reported.

Conclusion: [¹⁸F]EKZ-001 is safe and appropriate for quantifying HDAC6 expression in the human brain with the Logan plot as the preferred quantitative approach. Sex differences should be considered in future studies.

Acknowledgements

This study was supported by funding from the Alzheimer’s Drug Discovery Foundation, Inc. (ADDF) to Eikonizo (J.E.K.).

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2020-15

Fetal imaging of synaptic vesicle glycoprotein 2A using ¹⁸F-SynVesT-1 PET on the primate miniEXPLORER (#105)

Samantha Rossano^{1, 2}, Takuya Toyonaga¹, Stephanie M Groman³, Songye Li¹, Eric Berg⁴, Yiyun H Huang¹, Alice F Tarantal⁵ and Richard E Carson^1,
2

¹Yale PET Center, Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, USA

²Department of Biomedical Engineering, Yale University, New Haven, CT, USA

³Department of Psychiatry, Yale University, New Haven, CT, USA

⁴Department of Biomedical Engineering, University of California, Davis, CA, USA

⁵Departments of Pediatrics and Cell Biology and Human Anatomy and California National Primate Research Center, University of California, Davis, CA, USA

Abstract

Introduction: The formation of synapses between neurons, or synaptogenesis, begins mid-gestation in primates and continues following birth into the neonatal period.¹ Synaptic vesicle glycoprotein 2A (SV2A) PET imaging of gravid rhesus monkeys allows for longitudinal studies of synaptic density across gestation (term = 165 ± 10 days). The current study investigated changes in SV2A density in the fetal brain during the 2^nd and 3^rd trimester by collecting longitudinal SV2A PET images in four gravid rhesus monkeys using the primate miniEXPLORER.²

Methods: Four gravid rhesus were administered ¹⁸F-SynVesT-1 (SDM-8) twice between gestational days 100–140 (2^nd and 3^rd trimesters). PET images were acquired on the primate miniEXPLORER and reconstructed using TOF-OSEM (2 iterations/20 subsets). CT images were acquired for attenuation correction and anatomical delineation. Fetal brain uptake was quantified by distribution volume ratio (DVR) using the simplified reference tissue model (T_MAX = 30mins) using the maternal brain as a reference region. Fetal brain images collected at gestation day 140 were registered to a 2-week-old neonatal rhesus template³ and DVRs were reported in ten regions: Frontal, parietal, temporal, occipital lobes; cerebellum, hippocampus, amygdala, caudate, putamen, thalamus/midbrain. Near term, tissues were harvested and samples from one animal were evaluated for SV2A using Western blots.⁴

Results: PET/CT images and corresponding time activity curves are shown for a representative subject in Figure 1. Across gestation, fetal brain volume and DVR increased such that the average ( ± SD, N = 4) fetal brain volume was 68 ± 9 mL (Figure 2(a)) and the average DVR was 0.32 ± 0.05 (Figure 2(b)) two weeks before tissue collection. The regional distribution of ¹⁸F-SynVesT-1 was heterogeneous at 140 days, with high uptake in subcortical regions compared to cortical regions (Figure 2(c) and (d)). Ex vivo SV2A measures significantly correlated with DVR (Figure 2(e)).

Conclusion: Using the primate miniEXPLORER to image synaptic density (SV2A), fetal/maternal brain DVR increased during the last two months of gestation, a pattern consistent with previous literature. However, the in vivo relative synaptic density substantially underestimates ex vivo data, which shows a fetal/adult ratio ³1.0 in the days before birth in cortical regions. These in vivo data are consistent with previous pilot data (Yale) using ¹¹C‑UCB‑J. Ongoing work includes ex vivo validation of SV2A expression.

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2020-16

Simultaneous multi-parameter multi-tracer estimation with dynamic neuro-PET data (#106)

Ayla Mansur^{1, 2}, Gaia Rizzo¹, Eugenii A Rabiner^{1, 3}, Roger N Gunn^{1, 2} and for the MIND-MAPS Consortium.

¹Invicro LLC, Boston, MA, USA

²Division of Brain Sciences, Imperial College London, London, UK

³Centre for Neuroimaging Sciences, King’s College London, London, UK

Abstract

Introduction: The MIND-MAPS program (https://lp.invicro.com/mind-maps) studies the mitochondria/endoplasmic reticulum/synaptic axis with 18F-BCPP-EF, 11C-SA-4503 and 11C-UCB-J scans acquired in each subject. This work takes advantage of this unique multi-tracer dataset to investigate whether simultaneous model fitting across tracers could provide further insight into the underlying physiology and improve the robustness of outcome measure estimation.

Methods: For each subject (n = 12), three sets (one per tracer) of arterial input functions and time-activity data from 13 grey matter regions were used. The one tissue compartment model is suitable for quantifying 11C-UCB-J,¹ while the two tissue compartment model can be used to quantify 18F-BCPP-EF, 11C-SA-4503.² For these models, the delivery K₁ can be expanded as f(1-e^-PS/f)^3,4 where f is flow, PS is the permeability surface product and (1-e^-PS/f) is extraction. f was shared across tracers and PS and the non-displaceable distribution volume (K₁/K₂) was shared across regions for each subject. Microparameters were estimated from a simultaneous nonlinear least squares estimation using the Levenberg-Marquardt optimisation algorithm which fitted all data together and enabled calculation of K₁ and V_T. Akaike information criteria⁵ were used to compare simultaneous and independent fitting methods. The inter-subject variability of parameters derived using the two methods was compared.

Results: The simultaneous and independent estimation approaches performed similarly with each providing good fits to the data (Figure 1). Mean flow was 73 ± 46 ml/100g/min (values with COV > 100% excluded). The average extraction for 11C-UCB-J, 18F-BCPP-EF and 11C-SA-4503 was 0.50 ± 0.17, 0.63 ± 0.17 and 0.53 ± 0.17, respectively. Simultaneous estimation was the most parsimonious model in 12/13 regions for 11C-UCB-J but only in 1/13 and 2/13 of the regions for 18F-BCPP-EF and 11C-SA-4503 respectively. The inter-subject variability of V_T and K₁ was not significantly different across methods (Figure 2). Outcome measures derived using the two methods were well correlated for all three tracers (18F-BCPP-EF R²_VT = 0.99, R²_K1 = 0.99; 11C-SA-4503 R²_VT = 0.92, R²_K1 = 0.90; 11C-UCB-J R²_VT = 1.00, R²_K1 = 0.97).

Conclusion: The simultaneous approach had little impact on improving the numerical identifiability of the main outcome measures. We showed that it is possible to derive the otherwise unidentifiable physiological parameters flow and extraction by taking advantage of multi-tracer data in the same subject

Acknowledgements

The authors thank the MIND-MAPS consortium members for their continued support.

graphic file with name 10.1177_0271678X211061050-img258.jpg

Figure 2. Box plots showing distribution of (a) independtantly and simulatenoulsy derived V_T estimates, and (b) independtantly and simulatenoulsy derived K₁ estimates for three representative regions.

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2020-17

Thalamic distributions of α4β2* subtype nicotinic acetylcholine receptors in two independently collected positron emission tomography datasets (#107)

Evan Gallagher¹, Robert K Doot², Kelly P Cosgrove^3,
4, Ansel T Hillmer³ and Jacob G Dubroff²

¹Neuroscience Graduate Group, University of Pennsylvania, Philadelphia, PA, USA

²Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA

³Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT, USA

⁴Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA

Abstract

Introduction: Positron emission tomography (PET) brain imaging of the α4β2* subtype nicotinic acetylcholine receptor (nAChR) has improved our understanding of both nicotine dependence and neurodegeneration. These studies consistently show greatest receptor availability in the thalamus.^1,2 Although postmortem studies reveal heterogeneous distribution of nAChRs within the thalamus,^3,4 PET studies have not rigorously examined these thalamic substructures. This study seeks to compare thalamic nAChR distributions in two independently collected PET datasets using two different nAChR-targeting radiotracers, 2[¹⁸F]A and [¹⁸F]Flubatine.

Methods: T1-weighted magnetic resonance images and dynamic PET images with venous metabolite sampling were collected (1) from 24 smokers scanned with 2[¹⁸F]A,¹ and (2) from 5 non-smokers scanned with [18F]Flubatine.² For each subject, 17 thalamic volumes of interest (VOIs) were generated using a Freesurfer-based segmentation pipeline.⁵ These VOIs underwent erosion to < 50% of their original volume and were then overlaid onto the co-registered PET images (Figure 1). Normalized distribution volumes (V_T) were then collected from all VOIs to establish an average α4β2* nAChR distribution for each dataset.

Results: The mediodorsal lateral nucleus and the anterior pulvinar demonstrated the highest nAChR availability, while the medial pulvinar and anteroventral nucleus showed lower availability. Results from other VOIs were less consistent; see Figure 2.

Conclusion: In agreement with postmortem studies, thalamic segmentation of both 2[¹⁸F]A and [¹⁸F]Flubatine PET imaging data revealed greatest α4β2* nAChR availability in the mediodorsal lateral and anterior pulvinar nuclei of the thalamus. Discrepancies between the two datasets could reflect differences in radiotracer specificity, characteristics of the study populations (smokers vs non-smokers), or PET instrumentation. These differences warrant further exploration. Furthermore, this analysis pipeline can readily be applied to other PET brain imaging studies using other radiotracers with substantial thalamic binding.

Acknowledgements

Sources of funding: R01 DA038832; K23 DA038726; K01 DA040023; K01 AA024788.

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References

1.Dubroff JG, Doot RK, Falcone M, et al. Decreased nicotinic receptor availability in smokers with slow rates of nicotine metabolism. J Nucl Med   2015; 56: 1724–1729. [DOI] [PMC free article] [PubMed] [Google Scholar]
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2020-18

Quantification and kinetic analysis of [¹¹C]deschloroclozapine positron emission tomography imaging for designer receptors exclusively activated by designer drugs in monkey brain (#108)

Xuefeng Yan¹, Rachel Dick¹, Sanjay Telu¹, Mark Eldridge², Jeih-San Liow¹, Paolo Zanotti-Fregonara¹, Cheryl Morse¹, Lester Manly¹, Robert Gladding¹, Yuji Nagai³, Takafumi Minamimoto³, Sami S Zoghbi¹, Barry J Richmond², Victor W Pike¹ and Robert B Innis¹

¹Molecular Imaging Branch, National Institute of Mental Health, Magnuson Clinical Center, National Institutes of Health, Bethesda, MD, USA

²Laboratory of Neuropsychology, National Institute of Mental Health, Magnuson Clinical Center, National Institutes of Health, Bethesda, MD, USA

³Department of Functional Brain Imaging, National Institutes for Quantum and Radiological Science and Technology, National Institute of Radiological Sciences, Chiba, Japan

Abstract

Introduction: Designer Receptors Exclusively Activated by Designer Drugs (DREADD) is a powerful chemogenetic tool for manipulation of neuronal activity. Positron emission tomography (PET) imaging with a selective radioligand allows non-invasive visualization of DREADD. Although studies have shown that [¹¹C]deschloroclozapine ([¹¹C]DCZ) is a novel high-potency ligand for DREADD, no full quantitative analysis has been reported. Here we aimed to establish the gold standard for [¹¹C]DCZ kinetic analysis and explore the suitability of reference tissue-based quantification methods.

Methods: Dynamic [¹¹C]DCZ PET scans with arterial input function were acquired for 120 minutes at baseline and after intravenous administration of either clozapine-N-oxide (CNO, 10 mg/kg) or DCZ (1 or 10 mg/kg) in one monkey that received injection of virus expressing human M4 muscarinic DREADD (hM₄Di) into the right amygdala. Goodness-of-fit for 1TCM and 2TCM were compared with F-tests, Akaike and MSC values. Regional binding potentials (BP_ND) derived from the total distribution volume (V_T) were compared with those obtained from reference tissue models, with the cerebellum as the reference region.

Results: The baseline scans showed a high [¹¹C]DCZ uptake in the hM₄Di-DREADD region, which could be blocked by CNO and DCZ. Cerebellum uptake was lowest, but still almost 10% of the activity could be displaced by the blockers. 2TCM fitted the data better than 1TCM. Compared to 2TCM, BP_ND-hM4Di estimated with reference tissue models was about 50% lower, while the underestimation was only about 20% in all the other regions.

Conclusion: [¹¹C]DCZ PET images can be quantified with a 2TCM. However, reference tissue methods show underestimation, which is more important in the regions with high BP_ND, such as the hM₄Di region.

Acknowledgements

We would like to thank NIH veterinary staff for all of their help with this project.

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Figure 1. Regional plot of BPND difference between reference tissue models and 2TCM.

Compared to 2TCM, BP_ND-hM4Di estimated with reference tissue models was about 50% lower, while the underestimation was only about 20% in all the other regions.

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Representative Logan-derived VT parametric images

2020-19

Pretreatment brain metabolism imaging for prediction of major depressive disorder outcome (#109)

Kathryn R Hill, John Gardus, Ramin V Parsey and Christine DeLorenzo.

Department of Psychiatry, Stony Brook University, Stony Brook, NY, USA

Abstract

Introduction: Prediction of antidepressant treatment outcome could reduce burden of depression. Following our proposal (R01MH104512), we evaluated pretreatment metabolic rate of glucose uptake (MRGlu) in three regions, raphe nucleus (RN),¹ right insula,² and left ventral prefrontal cortex (vPFC), for prediction of major depressive disorder (MDD) treatment outcome in a placebo controlled randomized trial of selective serotonin reuptake inhibitors (SSRI).

Methods: All participants (n = 73) were diagnosed with MDD and scored > 21 on the Montgomery–Åsberg Depression Rating Scale. Participants were either medication naïve (n = 42) or medication free 3 weeks before study initiation (n = 31). The outcome measure was the Hamilton Rating Scale for Depression (HRDS17) after 8 weeks of escitalopram (SSRI) or placebo. Pretreatment MRGlu was calculated using 2-[¹⁸F]-fluorodeoxyglucose (FDG) acquired for 60 minutes on a Siemens Biograph mMR. Simultaneous Estimation (SimE)³ was used to estimate the arterial input function and MRGlu from a venous sample acquired 39–43.7 minutes post injection (4 subjects: 63–75 minutes, 2 subjects: arterial sample at 40 minutes). Subject motion was corrected for by rigid body registration to a reference frame⁴ with subsequent coregistration of MRI to average PET image. The RN, insula and vPFC were automatically delineated using atlases as previously described⁴ (RN atlas: https://renaissance.stonybrookmedicine.edu/psychiatry/research/cubit/data). Patlak modeling, correcting for blood glucose and lumped constant, was applied to the regional time activity curves for MRGlu estimation. Linear regression was used to examine the association between week-8 HRDS17 and pretreatment MRGlu of the 3 regions. Pretreatment HRDS17 (1 subject: week-1), treatment type (SSRI or placebo) and age were covariates (alpha = 0.05).

Results: Covariates of treatment type and age (average = 29.3 ± 13.4 years) were not significantly associated with week-8 HRDS17. However, pretreatment HRDS17 was significantly associated with week-8 HRDS17. Pretreatment MRGlu(mg/(min*100mL)) in all regions was not significantly associated with outcome (Figure 1).

Conclusion: In our cohort, regional pretreatment metabolism in the RN, right insula, and left vPFC does not predict antidepressant treatment outcome. Further, treatment group did not influence this relationship. Voxel-based analysis may reveal findings outside these regions. However, given the heterogeneity of MDD, prediction from pretreatment metabolism may be symptom dimension dependent, providing a future direction for investigation.

Acknowledgements

Funding source: R01MH104512. Inline graphic

References

1.Kaufman J, Sullivan GM, Yang J, et al. Quantification of the serotonin 1A receptor using PET: identification of a potential biomarker of major depression in males. Neuropsychopharmacology 2015; 40: 1692–1699. [DOI] [PMC free article] [PubMed] [Google Scholar]
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2020-20

Parametric mapping of [11C]PBR28 brain PET imaging using spectral analysis (#112)

Marcello Tuosto¹, Tiago R Marques², Oliver D Howes², Paolo Zanotti-Fregonara³, Federico E Turkheimer⁴, Alessandra Bertoldo¹ and Mattia Veronese⁴

¹Department of information Engineering, Padova University, Padova, Italy

²Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK

³Houston Methodist Hospital, Houston, TX, USA

⁴Department of Neuroimaging, King’s College London, London, UK

Abstract

Introduction: The aim of this study was to investigate the use of Spectral Analysis (SA) for voxelwise analysis of [11C]PBR28 brain PET imaging studies. As any other TSPO PET imaging ligand, [11C]PBR28 quantification is methodologically complicated by the heterogeneity of TSPO expression and its cell-dependent modulation during neuroinflammatory response.¹ Compartmental models to account for this complexity exist, but they are inapplicable at the high noise of voxel data. On the contrary SA is noise-robust and provides useful information about tracer kinetics with a free-compartmental structure.

Methods: SA impulse response function calculated at 90 minutes after tracer injection (IRF90) was used as proxy of distribution volume (VT) [Fan et al, EJNMMI 2018]. To test IRF90-VT consistency, 21 dynamic [11C]PBR28 brain PET scans (age:38 ± 16 years, 16/5 males/females, 17/4 HABS/MABS, all healthy controls) from a previous study² were reanalysed with SA and compartmental modelling (both standard 2TCM and 2TCM-1K with endothelial modelling). A second group of 8 patients with psychosis from a [11C]PBR28 PET blocking study with XBD173 [Veronese et al, JCBFM 2017] was reanalysed to test IRF90 specificity to TSPO availability.

Results: Regional averages of voxelwise IRF90 estimates were strongly associated with region of interest VT estimates provided by 2TCM-1K (r = 0.86 ± 0.11) but less with those obtained with standard 2TCM (r = 0.76 ± 0.32) (Figure 1). Distribution of spectral components were also more consistent with endothelial TSPO modelling in 89% of the ROIs as compared to 2TCM. SA-IRF90 parametric mapping proved to have great spatial quality and to be sensitive to both TSPO genotype (HABs vs MABs mean relative differences = 25%) and TSPO availability (mean signal displacement after 90 mg oral administration of XBD173 = 39%) (Figure 2).

Conclusion: SA-IRF90 can be used for voxelwise quantification of [11C]PBR28 PET data as it provides high quality parametric maps, is sensitive to TSPO availability and individual TSPO genotype, and returns information of tissue tracer kinetics comparable to compartmental modelling analysis. Specifically, the inclusion of a slow irreversible component seems to be a frequent solution (both at ROI and voxel level), in agreement with the modelling provided by 2TCM-1K.

Acknowledgements

NIHR Maudsley BRC. Inline graphic

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References

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2.Bloomfield PS, Selvaraj S, Veronese M, et al, Microglial Activity in People at Ultra High Risk of Psychosis and in Schizophrenia: An [(11)C]PBR28 PET Brain Imaging Study. Am J Psychiatry 2016; 173(1): 44–52. [DOI] [PMC free article] [PubMed] [Google Scholar]

2020-21

Test-retest and α2-receptor challenge with [¹¹C]yohimbine with search for a suitable reference region (#113)

Bénédicte Ballanger¹, Chloé Laurencin^{1, 2}, Sophie Lancelot^{1, 3}, Florent Gobert², Thibault Iecker³, François Liger³, Frédéric Bonnefoi³, Zacharie Irace3⁴, Inés Mérida³, Jérôme Redouté³, Justine Debatisse^{4, 5}, Didier Le Bars³ and Nicolas Costes³

¹Lyon Neuroscience Research Center, CRNL, INSERM, CNRS, Université Claude Bernard, Lyon, France

²Hospices Civils de Lyon, Lyon University Hospital, Lyon, France

³CERMEP – Life Imaging, Lyon, France

⁴Siemens-Healthcare, SAS, Saint-Denis, France

⁵CarMeN Laboratory, INSERM, INRA, INSA Lyon, Université Claude Bernard, Lyon, France

Abstract

Introduction: Previous work¹ introduced the [¹¹C]yohimbine as a suitable ligand for positron emission tomography (PET) of central a2-adrenoreceptors (a2-Ars). The corpus callosum (CC) was an acceptable reference region. However, reproducibility of non-displaceable binding potential (BPnd) in healthy humans estimated with a simplified modelling method with reference region, as well as displaceability with an a2-ARs agonist was not evaluated. In this work, we performed a human investigation with dynamic PET including test-retest reliability study, a a2-ARs challenge, and search for a convenient reference regions.

Methods: Twelve healthy humans underwent two [¹¹C]yohimbine investigations in a 90-minute dynamic acquisition performed on a PET-MRI scanner. Seven had arterial blood sampling with metabolite assessment and plasmatic Yohimbine free fraction evaluation at the first scan. The second scan was a simple retest for 5 subjects, and for 7 subjects, a scan performed 30-min after oral administration of clonidine for occupancy evaluation.² With the arterial input function (AIF), distribution volumes (DV) were estimated with 1TC, 2TC direct fitting, and with Logan plot (LP) and SRTM methods in various cortical and subcortical brain regions, and in white matter (WM) area. Several regions: cerebellum (CER), vermis, cerebellum WM (CERWM), frontal WM (FLWM), caudate nucleus and CC) were considered as reference region for DV ratio (DVR) and BPnd estimation with LP and SRTM. Test-retest reliability parameters (bias and ICC) and occupancy parameters were evaluated.

Results: Bias of DVR estimation with LP and SRTM, relative to reference AIF-1TC modeling, showed that CERWM had the lowest biais (<7%). Test-retest showed that the LP with CC is highly reproducible (mean ICC > 0.87) but with a slight bias (11%), whereas CERWM has lower bias (7%), and an acceptable ICC (O.6) in cortical and subcortical regions. Similar conclusion but with lower performance were found with SRTM. 61% occupancy was found in cortical regions with CERWM as reference, whereas CC showed less accurate.

Conclusion: Test-retest reliability study confirmed that the CC is an good reference region, reproducible and able to evidence moderate occupancy with concurrent drug on a2-ARs. Alternatively, cerebellum white matter is a convenient reference region when measurements in the CC would not be reliable for structural or lesional reasons.

Acknowledgements

This work was supported by the french national ‘invest for the futur’ programs (LILI – Lyon Integrated Life Imaging: hybrid MR-PET ANR-11-EQPX-0026) and funded by the French "Agence Nationale pour la Recherche" (ANR -JCJC-2017-2021). ZI and JD are partially supported by Siemens-Heathcare SAS.

References

1.Nahimi A, Jakobsen S, Munk OL, et al. Mapping α2 adrenoceptors of the human brain with 11C-yohimbine. J Nucl Med 2015; 56: 392–398. [DOI] [PubMed] [Google Scholar]
2.Takano A, Varrone A, Gulyás B, et al. Guidelines to PET measurements of the target occupancy in the brain for drug development. Eur J Nucl Med Mol Imaging 2016; 43: 2255–2262. [DOI] [PMC free article] [PubMed] [Google Scholar]

2020-22

Design of a clinically applicable bolus-plus-constant-infusion PET imaging scheme for gold standard quantification of amyloid-beta in Alzheimer’s disease (#133)

Julie Ottoy¹, Min-Su Kang², Jeroen Verhaeghe¹, Sigrid Stroobants¹, Jenna Stevenson², Nesrine Rahmouni², Jean-Paul Soucy³, Serge Gauthier^{2, 3}, Daniel Chartrand³, Pedro Rosa-Neto^{2, 3} and Steven Staelens¹

¹Molecular Imaging Center Antwerp, University of Antwerp, Antwerpen, Belgium

²The McGill University Research Centre for Studies in Aging, McGill University, Montréal, Québec, Canada

³MNI, McGill University, Montréal, Québec, Canada

Abstract

Introduction: The standardized uptake value ratio (SUVR) has been widely applied in anti-Aβ trials of Alzheimer’s disease. However, the method is prone to bias from variation in plasma clearance and cerebral blood flow. For more accurate Aβ quantification, the distribution volume ratio (DVR) could be applied, but requires long dynamic scanning. In addition, both SUVR and DVR require selection of a reference region. Here, we suggest an alternative tissue-to-plasma ratio method based on bolus-plus-constant-infusion (B/I) PET.

Methods: Five PSEN1 carriers (MMSE 26.4 ± 3) underwent dynamic 90-min [¹⁸F]-AV45-PET with bolus followed by continuous tracer infusion. 90-min continuous sampling as well as 10 arterial and 6 venous samples were taken to determine individual metabolite-corrected plasma inputs and calculation of the ‘gold standard’ V_T,2TCM and graphical V_T,Logan. Plasma free fraction (Fp) was determind in arterial and venous blood. Additionally, V_T,B/I was determined as the equilibrium ratio (55–75min) of tracer concentration in tissue to the average of 3 metabolite-corrected arterial or venous plasma samples (C_tissue/C_plasma = V_T,B/I). Last, DVR was calculated using cerebellar grey (CB-DVR_B/I), subcortical white matter (WM-DVR_B/I), or pons (pons-DVR_B/I) as the reference and compared to DVR_2TCM.

Results: After 55min, the B/I method demonstrated true equilibrium with low rate of [¹⁸F]-AV45 concentration change (e.g., C_parietal 2.0 ± 1.4%, C_CB 3.1 ± 3.4%, and C_plasma 5.6 ± 3.5% change/20min). The arterial parent fraction stabilized at 31 ± 2% and V_{T,B/I_arterial} corresponded well to the full-kinetic V_T,2TCM and V_T,Logan (average cortical difference: 2.9 ± 0.8 and 3.3 ± 0.7%, respectively) (Figure 1). Tracer concentractions remained 32 ± 10% lower in venous compared to arterial plasma. Fp (9 ± 2%) did not differ between arterial and venous blood. When using tissue reference, CB-DVR_B/I underestimated true Aβ load possibly due to the presence of cerebellar Aβ (Figure 2). In contrast, WM-DVR and pons-DVR were positively correlated to the full-kinetic V_T (Figure 2). The WM-DVR_B/I showed +6.2 ± 1.3 and the pons-DVR_B/I +6.9 ± 1.2% difference compared to their DVR_2TCM.

Conclusion: 20-min static B/I-PET in combination with few arterial samples is sufficient to reproduce the full-kinetic V_T. Further investigation is needed to understand arterial-venous [¹⁸F]-AV45 concentration differences to replace arterial by venous samples. Additionally, in the presence of a suitable reference region, B/I-PET can be applied to calculate DVR using a static scan and without the need for blood data.

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2020-23

Validation of longitudinal [¹⁸F]FEPPA-PET in rat subcortical stroke revealed that TSPO misses chronic remote white matter inflammation (#134)

Nassir Al-Khishman^{1, 2}, Austyn Roseborough³, Matthew S Fox², Qi Qi^{1, 2}, Alexander Levit³, Vladimir Hachinski⁴, Whitehead N Shawn² and Jonathan D Thiessen^1,
2

¹Medical Biophysics, University of Western Ontario, London, ON, Canada

²Lawson Health Research Institute, London, ON, Canada

³Anatomy and Cell Biology, University of Western Ontario, London, ON, Canada

⁴Clinical Neurological Sciences, University of Western Ontario, London, ON, Canada

Abstract

Introduction: Soon after their first stroke, 1 in 10 people will develop dementia.¹ Cognitive deficits develop alongside inflammation that subsides in the infarct but persists in remote white matter after ischemic subcortical stroke according to [¹¹C]PK11195.² Our group showed that in rats, ischemic subcortical stroke leads to proinflammatory microglia in remote white matter by day-28 and cognitive decline by month-3.^3,4 In this study, our objectives were to (i) spatiotemporally quantify remote WM inflammation using [¹⁸F]FEPPA TSPO-PET and MRI and (ii) validate the cerebellum as a reference region for quantifying [¹⁸F]FEPPA uptake.

Methods: To induce ischemic subcortical stroke, the right dorsal striatum was injected with the vasoconstrictor endothelin-1 (n = 10) or saline (n = 13). Out of these, 5 stroke and 6 saline rats underwent in vivo imaging at baseline then post-stroke at day-7 and day-28. Dynamic [¹⁸F]FEPPA PET was acquired to quantify inflammation (Siemens Inveon). Rats were transferred to a 3T MRI (Siemens Biograph mMR) with a dedicated rat brain RF coil (Cubresa) to acquire anatomical MRI. T₂-weighted MRI was used to delineate the infarct, corpus collosum (CC), and reference regions used to calculate uptake ratios (UR): cerebellum, contralateral region to the infarct, and periaqueductal gray. The in vivo imaging rats were sacrificed at day-28 and the remaining rats at day-7 for immunohistochemistry to quantify TSPO, activated astrocytes using GFAP, and proinflammatory microglia using iNOS and OX6.

Results: UR trends were similar between reference regions, but using the cerebellum correlated best with TSPO immunohistochemistry analysis. Infarct [¹⁸F]FEPPA UR in the stroke group peaked at day-7 and slightly dropped by day-28 (Figure 1). OX6, iNOS, and GFAP increased from day-7 to day-28. As for remote WM, the contralateral CC showed day-28 stroke-induced inflammation only in terms of OX6 (Figure 2).

Conclusion: We validated the cerebellum as a reference region for [¹⁸F]FEPPA PET. The opposing trends of activated astrocytes and proinflammatory microglia suggest that their contribution to stroke-induced TSPO is small. Interestingly, OX6 detected a unique type of chronic microglial activation in remote white matter. Overall, this study suggests that a whole-brain spatiotemporal quantification of inflammation requires the development of in vivo protocols that can quantify multiple inflammatory markers.

Acknowledgements

We would like to thank Lynn Wang, Lise Desjardins, Jennifer Hadway, Kevin Nishimura, and Alec Pencz for their technical help.

graphic file with name 10.1177_0271678X211061050-img268.jpg

Immunohistochemistry of TSPO shows only an increase in TSPO at day-7 post stroke of the ipsilateral corpus collosum (CC). Another protein, OX6, detects day-28 inflammation in remote regions such as the contralateral CC.

graphic file with name 10.1177_0271678X211061050-img269.jpg

Uptake ratio maps (to cerebellum) of [¹⁸F]FEPPA show a response in stroke rats only. The response is focal to the infarct, peaking post-stroke at day-7 then slightly dropping by day-28.

References

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2020-24

Strength in numbers: Multilevel modelling of time activity curves (#140)

Granville J Matheson^{1, 2}, Yakuan Chen^{3, 4}, Francesca Zanderigo^{1, 5} and R Todd Ogden^{1, 3}

¹Molecular Imaging and Neuropathology Division, New York State Psychiatric Department, Columbia University, New York, NY, USA

²Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden

³Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, NY, USA

⁴AT&T Services, Inc., Middletown, NJ, USA

⁵Department of Psychiatry, Columbia University, New York, NY, USA

Abstract

Introduction: The predominant approach for quantifying PET radiotracer influx or binding involves application of pharmacokinetic models to time activity curve (TAC) data from each subject separately, to derive estimates of binding that are subsequently compared between individuals or groups. However, this approach is both inefficient and imprecise, as all insights learned by the model when applied to a TAC from one subject are effectively “forgotten” when presented with the next. Multilevel modelling, in contrast, exploits similarities between data from different individuals, leading to improved estimates and predictions.¹

Methods: We have developed and applied a multilevel two-tissue compartmental model, in which both estimation of kinetic parameters and group-level statistical comparisons are performed simultaneously within one large model. This approach leverages similarities between individuals to adaptively regularise parameter fitting and thereby improve individual estimates. Simulations were performed by generating model data and adding noise.² We have also extended the work of Chen et al.,² which used maximum likelihood estimation, to a Bayesian model using Hamiltonian Markov Chain Monte Carlo. We demonstrate the performance of this approach using a [¹¹C]WAY100635 dataset of 97 individuals, using TACs derived from the midbrain.

Results: Based on our simulations, we found that a multilevel approach was more accurate than the conventional approach, providing equal statistical power for effect sizes of as little as a quarter.² All approaches produced virtually identical fits; however the variance of estimated parameters was greatly reduced using multilevel approaches (Figure 1), and standardised effect sizes for patient-control comparisons were increased by between 1.7 and 4.3 times for different outcome measures (Figure 2).

Conclusion: Multilevel modelling improves the accuracy and statistical sensitivity of PET studies for investigating clinical questions. By making use of existing compartmental models, this approach should theoretically be applicable, and provide more accurate analysis, for any tracer for which compartmental modelling is possible. While a Bayesian approach to fitting these models is more computationally intensive, it allows us, in ongoing work, to flexibly extend this framework to additionally model multiple regions across multiple individuals simultaneously, to allow fitting of more complex compartmental models, and to incorporate prior knowledge effectively to improve estimation further.

Acknowledgements

This research was supported by Grant 1R01EB024526 from the National Institute of Biomedical Imaging and Bioengineering, by Karolinska Institutet Travel Grant, by Psykiatrifonden (4–498/2019) and by the Paul Janssen Fellowship in Translational Neuroscience.

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References

1.Gelman A, Hill J. Data analysis using regression and multilevel hierarchical models. New York, NY, USA: Cambridge University Press, 2007. [Google Scholar]
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2020-25

Decreased binding of [C-11]UCB-J PET in cognitively impaired (#142)

Alexandra DiFilippo¹, Tyler Tullis¹, Matthew Zammit¹, Todd Barnhart², Jonathan Engle², Dhanabalan Murali^{1, 2}, Grace McKinney², Nancy Davenport², Tobey Betthauser², Sterling Johnson², Barbara Bendlin² and Bradley Christian^1,
2

¹Waisman Center, University of Wisconsin-Madison, Madison, WI, USA

²School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA

Abstract

Introduction: [¹¹C]UCB-J is a PET radioligand which specifically binds to synaptic vesicle protein SV2A. As synaptic loss is a hallmark of neurodegenerative diseases, PET imaging can provide for an in vivo analysis of synaptic changes and the corresponding cognitive decline in Alzheimer’s Disease (AD). The purpose of this work is to investigate changes in [¹¹C]UCB-J uptake in subjects presenting with cognitive impairment.

Methods: [¹¹C]UCB-J dynamic PET imaging was conducted over 70 minutes in fifteen participants recruited from the UW ADRC. Amyloid (A+/-) status was determined using [¹¹C]PiB PET scans. The participants included eleven cognitively unimpaired (CU) (A-), one CU A+ subject, three cognitively impaired (CI) (one MCI, two AD-dementia) A- subjects. [¹¹C]UCB-J binding was quantified using DVR values calculated using SRTM2. ROIs were taken using FreeSurfer templates acquired using individual T1w MR images.

Results: Relative to the CU (A-) subjects, decreased [¹¹C]UCB-J DVR measures were present in all four non-control subjects. However, the CI (A-) subjects exhibited less binding than the CU (A+) subject. The largest decreases were seen in the hippocampus, where the CI (A-) and CU (A+) cases had DVRs of 0.48 ± 0.10 and 0.71, respectively compared to 0.88 ± 0.13 for the control CU (A-) subjects. The parahippocampus showed decreases in the CI (A-) cases (0.59 ± 0.14 vs 0.90 ± 0.14) but not in the CU (A+) subject (0.74).

Conclusion: For all three subjects in cognitive decline [¹¹C]UCB-J binding shows the most reduction in the hippocampus and parahippocampus when compared to the cognitively unimpaired A- subjects. Less significant decreases in binding were also seen in these regions in the CU (A+) subject. Ongoing, longitudinal studies with larger sample sizes will investigate associations between cognitive, amyloid, and tau status with [¹¹C]UCB-J measured synaptic density.

2020-26

Evaluation of [¹⁸F]MNI-1188: A reversible monoacylglycerol lipase (MAGL) PET radiotracer in non-human primates (#143)

Cristian Constantinescu¹, Alexandra Gouasmat¹, Cedric Tresse¹, Roger N Gunn², Jan Passchier² and Vincent Carroll¹

¹Invicro, New Haven, CT, USA

²Invicro, London, UK

Abstract

Introduction: MAGL is a key enzyme regulating the level of 2-arachidonoylglycerol (2-AG), an endocannabinoid ligand. Inhibition of this enzyme mobilizes 2-AG and induces non-opioid stress-induced analgesia. Furthermore, inhibition of MAGL leads to selective activation of presynaptic CB1 receptors, which play a role in inhibition of epileptic seizures. A reversible MAGL PET tracer could support development of new drug candidates against this target in vivo. Herein, we report the evaluation of [¹⁸F]MNI-1188, as the first reversible MAGL-specific radioligand.

Methods: Two 180 min scans, at baseline and following homologous competition (1.0 mg/kg, 5 min iv bolus at 10 min before tracer) were conducted with the active enantiomer, [¹⁸F]MNI-1188, in rhesus monkey. The same subject received an additional scan with the inactive enantiomer, [¹⁸F]MNI-1190. All scans were performed on a microPET Focus 220 scanner with associated arterial blood and metabolite assays. Data were modeled with 1 and 2-tissue compartmental models (1TC and 2TC), and multilinear analysis (MA1) to estimate total distribution volume, V_T. Occupancy and the non-displaceable volume of distribution (V_ND) were estimated from Lassen plot analysis.

Results: [¹⁸F]MNI-1188 entered the brain with a peak uptake of ∼3% ID at ∼ 7 min post injection (p.i.) accompanied by a clear washout and a heterogenous signal consistent with the known distribution of MAGL (Figure 1). V_T ranged from ∼10 ml.cm⁻³ in brainstem to ∼20 ml.cm⁻³ in cortex. Tracer kinetics were best described with 2TC and MA1 models. Time stability analysis showed that a scan as short as 40 min produced good parameter estimates (V_T within 5% of the value at 180 min). [¹⁸F]MNI-1188 underwent fast declining metabolism with ∼20% parent remaining at 30 min p.i. Plasma free fraction was ∼26%. Plasma-to-blood partition is initially low (∼0.4) and monotonically increases towards 1.0 between 0 and 90 min p.i., suggesting peripheral binding to blood cells. Homologous competition yielded ∼92% occupancy in the brain (V_ND∼1.2) and blocked the peripheral binding sites. The inactive enantiomer [¹⁸F]MNI-1190 quickly entered the brain and washed out rapidly with no regional selectivity (V_T∼1.5).

Conclusion: [¹⁸F]MNI-1188 is a promising reversible PET radiotracer with favorable properties for imaging and quantitation of MAGL enzyme in the brain.

Acknowledgements

Authors would like to acknowledge Amy Amenta (Invicro) and the staff at Yale University PET Center, in particular Daniel Holden and Krista Fowles for their support of imaging operations.

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2020-27

Early stopping in clinical PET studies: Save money and mSv! (#147)

Jonas E Svensson¹, Martin Schain², Gitte M Knudsen^2,
3, R Todd Ogden^{4, 5} and Pontus Plavén-Sigray^{1, 2}

¹Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden

²Neurobiology Research Unit, Copenhagen University Hospital, Copenhagen, Denmark

³Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark

⁴Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, USA

⁵Molecular Imaging and Neuropathology Area, New York State Psychiatric Institute, New York, USA

Abstract

Introduction: Two major issues in clinical PET studies are the high costs of the examinations, and the radiation exposure to people. Clearly, it is in the interest of the PET researcher to keep the number of included subjects to a minimum, while still being able to collect enough data to make sound scientific inference. Here we evaluated a statistical framework with the aim to stop the recruitment of subjects in a clinical PET study as soon as enough data have been collected to make a conclusion, so called sequential testing.

Methods: The Bayes Factor (BF) metric, which captures the relative likelihood of one hypothesis over another, was calculated after the collection of every data point in a paired-sample design (e.g., pre- and post-scan). When the BF reached three times more support for the null-hypothesis (H0) over the alternative (H1), or vice versa, the study was stopped. Using simulations over a range of effects based on data from real clinical PET studies, we evaluated the 1) average sample size needed to reach an early stopping decision and 2) the long-running error rates of false negative and false positive evidence, i.e. declaring support for the wrong hypothesis.

Results: Compared to employing the classical null-hypothesis significance testing (NHST) procedure, i.e., the use of a fixed sample size and p-value, BF sequential testing allowed for stopping a study early (Table 1). By using “default” specifications of the one-sided BF t-test, the procedure can save on average one third of subjects and resources compared a fixed sample size design. For most effects, the false positive and negative evidence rates were both kept below 10%. However, at true small effects, the method showed a high rate of false negative evidence.

Conclusion: BF sequential testing allows researcher to save money and injected radioactivity, while still keeping error rates at acceptable levels at a range of effect sizes relevant for PET research. Importantly, studies can also be stopped early when the effect is zero or negligible. The method shows potential for saving resources that can then be spend on examining other neurobiological effects of interest instead.

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Table 1. Simulation results of a pre-intervention-post study using [11C]Raclopride BP_ND in striatum as example. A set of Planned N was defined in order detect a range of changes in BP_ND, using an alpha = 0.05 and 80% power. 1000 simulations were then run for each setting, in which samples were drawn from a population having the specified effect sizes. We also used the same Planned N but simulated data where there was no change in BP_ND. The BF was calculated sequentially after the collection of each data point. At a BF > 3 in favour of either an effect or no effect, the study was stopped (Actual N).

2020-28

Meta-analysis of the glial marker TSPO in psychosis revisited: Reconciling inconclusive findings of patient-control differences (#148)

Pontus Plavén-Sigray^{1, 2}, Granville J Matheson¹, Jennifer M Coughlin^{3, 4}, Sina Hafizi⁵, Heikki Laurikainen⁶, Julie Ottoy⁷, Livia de’Picker⁸, Pablo M Rusjan⁵, Jarmo Hietala⁶, Oliver D Howes^{9, 10}, Romina Mizrahi⁵, Manuel Morrens⁸, Martin G Pomper^{3, 4} and Simon Cervenka¹

¹Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden

²Neurobiology Research Unit, Copenhagen University Hospital, Copenhagen, Denmark

³Department of Psychiatry and Behavioral Sciences, Johns Hopkins Medical Institutions, Baltimore, MD, USA

⁴Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical Institutions, Baltimore, MD, USA

⁵Department of Psychiatry, University of Toronto, Toronto, Canada

⁶Department of Psychiatry, University of Turku and Neuropsychiatric Imaging group, Turku University Hospital, Turku, Finland

⁷Molecular Imaging Center Antwerp, University of Antwerp, Antwerp, Belgium

⁸Collaborative Antwerpen Psychiatric Research Institute (CAPRI), University of Antwerp, Antwerp, Belgium

⁹IoPPN, King’s College London, London, UK

¹⁰MRC London Institute of Medical Sciences, Hammersmith Hospital, London, UK

Abstract

Introduction: Positron emission tomography (PET) studies examining the glial marker translocator protein (TSPO) in schizophrenia have been inconclusive. We previously demonstrated lower TSPO in psychosis patients in an individual participant data (IPD) meta-analysis of studies using second generation TSPO radioligands.¹ Subsequently, a summary-statistics meta-analysis, including one newly published study, showed no difference.² Here, the aim was to repeat the IPD analysis including two new samples unavailable at the time of our previous analysis to reevaluate the conclusions. The primary objective was to examine the hypotheses of 1) higher or 2) lower or 3) no difference in radioligand binding between patients and healthy control subjects.

Methods: Individual participant data were obtained from PET studies that used a second generation TSPO radioligand, reported distribution volume (V_T) values in brain in patients with psychosis as compared to healthy controls, and reported TSPO affinity type of all participants. The outcome measure was V_T in frontal cortex (FC), temporal cortex (TC) and hippocampus (HIP). We applied linear mixed modelling and Bayes factors (BF) to examine the relative support for higher, lower, or no-change of TSPO levels in patients compared to healthy controls.

Results: Individual participant data from seven studies were included, amounting to 99 patients with first-episode psychosis or schizophrenia and 109 healthy control subjects. In all regions investigated, BF showed moderate to strong support (BF > 5) for lower V_T in patients as compared to no difference, and strong support (BF > 10) for lower V_T compared to higher V_T in patients. Mean patient-control differences in standardized V_T values are shown in Figure 1.

Conclusion: In this updated meta-analysis, we found moderate to strong support for lower TSPO in psychosis patients compared to control subjects. In vitro data has shown a lack of correspondence between TSPO and pro-inflammatory activation, also recently confirmed in a post-mortem study in schizophrenia. Hence, based on the present results no firm conclusions can be made regarding the pro-inflammatory versus anti-inflammatory status of glial cells in psychosis patients. Additional work is needed to understand the biological relevance of the observed lower TSPO in patients.

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References

1.Plavén-Sigray P, Matheson GJ, Collste K, et al. Positron emission tomography studies of the glial cell marker translocator protein in patients with psychosis: a meta-analysis using individual participant data. Biol Psychiatry 2018; 84: 433–442. [DOI] [PMC free article] [PubMed] [Google Scholar]
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2020-29

Bayesian partial volume correction for image derived input function (#153)

Zacharie Irace^{1, 2}, Inés Merida¹, Florent Gobert^{3, 4}, Frédéric Dailler⁴ and Nicolas Costes¹

¹CERMEP-Life Imaging, Lyon, France

²Siemens Healthcare SAS, Saint Denis, France

³Lyon Neuroscience Research Center, Lyon, France

⁴Hospices Civils de Lyon, Lyon, France

Abstract

Introduction: In PET kinetic modeling, the collection of the input function is necessary for absolute quantification. The growing popularity of hybrid PET-MR devices offers new expectations towards Image Derived Input Function (IDIF) methods, to avoid invasive arterial sampling. Direct quantification with IDIF extracted from MRI-mask is impractical because of strong Partial Volume Effects (PVE). To correct for PVE, Geometric Transfer Matrix (GTM)-based methods¹ consider the observed Time Activity Curves (TACs) as a weighted mixture of the unknown true TACs. The GTM method requires the inversion of a low rank matrix, which makes the method sensitive to noise and biased on small regions such as carotids. We propose a Bayesian approach for a more robust resolution of the GTM model, with the aim of estimating an IDIF.

Methods: A mask of the carotids was defined by applying an adaptive threshold to a smoothed arterial MR-angiography with connexity constraints. The volume defined by 5 mm around the carotids was considered as the background mask. The IDIF was parametrized as the first three coordinates of a Principal Components Analysis, and the background TAC with 3 parameters of an irreversible 2-tissue compartment model. The probability distribution of these 6 parameters was jointly estimated with Markov Chain Monte Carlo (MCMC) in a Bayesian context.² The Maximum-A-Posteriori of these densities lead to an estimate of IDIF. The method was applied to 22 patients with lesioned brain that had 90-min dynamic PET [¹⁸F]FDG scan. Their Cerebral Metabolic Rate of Glucose (CMRGlu) values were obtained in 78 regions from the estimated IDIF, and from arterial sampling for comparison.

Results: Better fits of IDIF with the arterial curve were obtained with the proposed Bayesian GTM method compared to the original GTM. The average bias on CMRGlu was 25.9 ( ± 103)% for GTM and 0.5( ± 47)% for Bayesian GTM. Regression on CMRGlu also showed slope and determination coefficients closer to 1, and intercept closer to zero.

Conclusion: Bayesian framework allowed to integrate prior knowledge from kinetics modeling to guide the GTM resolution. This, combined with a MCMC sampling approach, lead to more robust and accurate IDIF estimates than with the original GTM method.

Acknowledgements

This work was supported by the french national ‘invest for the futur’ programs (LILI – Lyon Integrated Life Imaging: hybrid MR-PET ANR-11-EQPX-0026) and the Hospital University Institut CESAME (Brain and Mental Health ANR-10-IBHU-0003). ZI is partially supported by Siemens-Heathcare SAS.

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Example for a specific subject

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Results on all subjects

References

1.Rousset OG, Ma Y, Evans AC. Correction for partial volume effects in PET: principle and validation. J Nucl Med 1998; 39: 904–911. [PubMed] [Google Scholar]
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2020-30

In vivo relationship between brain arachidonic acid incorporation and cerebral metabolic rate of glucose in the healthy brain and in bipolar disorder: A pilot study (#164)

Francesca Zanderigo^{1, 2}, R Todd Ogden^{2, 3}, Shankar Vallabhajosula⁴, Paresh Kothari⁴, Anastasia Nikolopoulou⁴, Dileep Kumar², Stanley Rapoport⁵, Maria Oquendo⁶, John Mann^{1, 7} and Elizabeth Sublette^1,
2

¹Psychiatry, Columbia University, New York, NY, USA

²Molecular Imaging and Neuropathology Area, New York State Psychiatric Institute, New York, NY, USA

³Biostatistics, Mailman School of Public Health, Columbia University, New York, NY, USA

⁴Radiology, Weill Cornell Medicine, New York, NY, USA

⁵National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA

⁶Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

⁷Radiology, Columbia University, New York, NY, USA

Abstract

Introduction: Polyunsaturated fatty acids (PUFA) are major determinants of brain development and functioning, with roles in balancing pro- and anti-inflammatory cascades, regulation of cell-cell signaling, and binding to peroxisome proliferator-activated receptors (PPARs), which affect genes involved in lipid storage, beta-oxidation and glucose metabolism. We performed a pilot PET study using 1-[¹¹C]arachidonic acid ([¹¹C]AA), an omega-6 PUFA, and [¹⁸F]FDG to directly assess how brain arachidonic acid (AA) incorporation coefficient (K*) relates to cerebral metabolic rate of glucose (CMR_glu) in vivo.

Methods: Six healthy volunteers (HVs) and 2 participants with bipolar disorder (BD) were imaged using [¹¹C]AA and then [¹⁸F]FDG three hours later. K* and CMR_glu were quantified in 26 bilateral regions of interest (ROIs). Pearson’s linear correlation coefficient (r) between CMR_glu and corresponding K* values was calculated in each ROI.

Results: Representative within-subject maps of CMR_glu and K* are shown (Figure 1). In HVs, CMR_glu correlated inversely with K* across all ROIs, with r values ranging from -0.068 to -0.643 (in medial prefrontal cortex, mPFC). CMR_glu values in the 2 BD participants were within the range observed in HVs, although their values were in the lower end of the range, and K* values were higher. Considering all subjects together, CMR_glu correlated inversely with K* across all ROIs, with r values ranging from -0.445 to -0.752 (mPFC). Figure 2 shows the scatter plots in 7 ROIs where we previously observed a significant positive correlation between brain [¹⁸F]FDG activity and plasma levels of AA (esterified to the phosphotriglycerides),¹ considering the HVs together with the 2 BD participants.

Conclusion: Consistent with previous animal studies concerning PUFAs and bioenergetics,^2,3 our preliminary findings indicate an inverse correlation between K* and CMR_glu. Possible mediators of this relationship are PPARs, which regulate genes involved in metabolic adaptation between glucose and fatty acid utilization.^4,5 Although sample size is small, this is the first report of direct brain measurement of both K* and CMR_glu within the same subjects. Larger studies are needed to confirm the relationship and compare bipolar and healthy groups.

Acknowledgements

The National Institute of Mental Health provided funding for this study (MH096255, PI: M. Elizabeth Sublette MD, PhD).

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References

1.Sublette ME, et al. Plasma polyunsaturated fatty acids and regional cerebral glucose metabolism in major depression. Prostaglandins Leukot Essent Fatty Acids 2009; 80: 57–64. [DOI] [PMC free article] [PubMed] [Google Scholar]
2.Pifferi F, et al. Long-chain n-3 PUFAs from fish oil enhance resting state brain glucose utilization and reduce anxiety in an adult nonhuman primate, the grey mouse lemur. J Lipid Res 2015; 56: 1511–1518. [DOI] [PMC free article] [PubMed] [Google Scholar]
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2020-31

Quantification of vesicular monoamine transporter type 2 (VMAT2) occupancy with [¹⁸F]AV‑133 in non-human primate (#170)

Christine Sandiego¹, Eugenii A. Rabiner², Roger N Gunn², Richard Wong³, Gordon Loewen³, Dietrich Haubenberger³ and Ryan Terry-Lorenzo³

¹Invicro, New Haven, CT, USA

²Invicro, London, UK

³Neurocrine Biosciences, San Diego, CA, USA

Abstract

Introduction: Vesicular monoamine transporter 2 (VMAT2) has been implicated in a broad range of CNS disorders. [¹⁸F]AV-133 (aka [¹⁸F]FP-DTBZ) is widely used to study VMAT2 in humans, with a suitable imaging range between 90–120 min post injection for analysis with SUVr.¹ NBI compound (DD-139) is a selective VMAT2 inhibitor. The aim of this study was to examine the relationship of DD-139 plasma concentration with VMAT2 occupancy, measured with [¹⁸F]AV‑133, and to compare dynamic with static quantification in non-human primate (NHP) brain.

Methods: Three cynomolgus macaques were imaged over 120 min with [¹⁸F]AV-133 (3.3 ± 0.5 mCi) in a Focus-220 PET camera at baseline and 60 min post intravenous infusion of DD-139 (0.026, 0.084, 0.26, 0.52 or 0.78 mg/kg) that continued throughout the scan. During each DD-139 scan, blood samples were collected to measure plasma concentration. [¹⁸F]AV-133 images were normalized into cynomolgus MR atlas space and time-activity curves were generated for brain regions: caudate, putamen, and cerebellum (reference region). Binding potential (BP_ND) was estimated with non-invasive Logan graphical analysis (t* = 35 min) using the full kinetic data. Using 90–120 min, target to reference tissue activity concentration, C_T/C_REF-1, was computed. Occupancy of DD-139 was calculated in the caudate and putamen (i.e., striatum) using BP_ND and C_T/C_REF-1. The relationship between DD-139 occupancy (averaged between caudate and putamen) and plasma concentration (averaged between 0–120 min), EC₅₀, was determined with the E_max model (E_max = 100, slope = 1).

Results: DD-139 demonstrated dose-dependent occupancy of the VMAT2 in the striatum, as measured with [¹⁸F]AV-133 (Figure 1). BP_ND and C_T/C_REF-1 were related by BP_ND = 1.12*(C_T/C_REF-1) – 0.23, R² = 0.97. Occupancy using BP_ND and C_T/C_REF-1 predicted a similar EC₅₀, 11.0 ng/mL and 12.6 ng/mL, respectively (Figure 2).

Conclusion: The relationship of VMAT2 occupancy and DD-139 plasma concentration were measured with [¹⁸F]AV-133 in NHP brain. Estimation of occupancy and EC₅₀ were very similar between dynamic or static quantification. This may be useful for studying therapeutic agents in patients who cannot withstand 120 min of imaging.

Acknowledgements

We would like to thank the staff at the Yale PET Center for carrying out the NHP studies and the Discovery Team at Invicro, New Haven, for providing radiochemistry and study coordination.

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Reference

1.Lin KJ, Lin WY, Hsieh CJ, et al. Optimal scanning time window for 18F-FP-(+)-DTBZ (18F-AV-133) summed uptake measurements. Nucl Med Biol 2011; 38: 1149–1155. [DOI] [PubMed] [Google Scholar]

2020-32

Full quantification of brain glucose metabolism using a portable positron emission tomography (PET) camera: A preliminary report (#171)

Elizabeth A Bartlett^{1, 2}, Mohammad Lesanpezeshki¹, Ragy Girgis², David Beylin³, Morgan Cambareri¹, R Todd Ogden^{1, 4}, John Mann^{1, 5}, Jeffrey Miller^{1, 2} and Francesca Zanderigo^{1, 2}

¹Molecular Imaging and Neuropathology Area, New York State Psychiatric Institute, New York, NY, USA

²Department of Psychiatry, Columbia University Medical Center, New York, NY, USA

³Brain Biosciencies, Inc., Rockville, MD, USA

⁴Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, NY, USA

⁵Department of Radiology, Columbia University Medical Center, New York, NY, USA

Abstract

Introduction: PET quantifies components of neurotransmitter systems, and incorporation and metabolism of specific compounds, in the living brain. Current PET scanners, however, are expensive and non-portable.¹ New portable, less expensive PET cameras,^2,3 including CerePET™ by Brain Biosciences, Inc. (Rockville, MD),^4,5 can radically expand the realm of possible PET applications. We are in Year 2 of an NIH-funded study that is gathering PET and arterial blood data in 20 healthy controls (HCs) imaged with [¹⁸F]FDG using both the standard Siemens Biograph™ and portable CerePET™ devices. The data will allow for the first within-subject comparison of images acquired both with a traditional and a portable scanner. Here we report a preliminary comparison.

Methods: Thus far, 8 HCs have undergone dynamic [¹⁸F]FDG imaging with both scanners on 2 separate days (range of days between imaging sessions: 1 to 154) and concurrent arterial blood sampling. The net influx rate (K_i) and corresponding cerebral metabolic rate of glucose (CMR_glu) were quantified in 24 bilateral regions of interest (ROIs) across the brain and at the voxel level, using the two-tissue irreversible compartment model (2TCIRR) and Patlak approach. Within-subject ROI-level estimates of K_iand CMR_glu were compared across scanners using Pearson’s linear correlation coefficient (r) and regression analysis. Results are summarized across ROIs for each subject.

Results: Within-subject correlation of CerePET™ estimates with corresponding Biograph™ estimates is high regardless of outcome measure (CMR_glu or K_i) and quantification approach (r range: 0.781 to 0.983). Regression slopes between scanners range from 0.337 to 0.781 (CMR_glu, 2TCIRR), 0.301 to 0.802 (CMR_glu, Patlak; Figure 1), 0.310 to 0.651 (K_i, 2TCIRR) and 0.278 to 0.665 (K_i, Patlak). The largest subject-level between-scanner bias is observed in the individual with the highest number of days between imaging sessions. CMR_glu maps for a representative subject are reported in Figure 2.

Conclusion: Our preliminary comparison indicates good correspondence between brain glucose metabolism measurements obtained via portable CerePET™ and traditional Biograph™ scanning. We anticipate the agreement will increase as we harmonize reconstruction, pre-processing (e.g., motion correction), and attenuation-correction across scanners. The data will also be used for validation of approaches for noninvasive quantification of the K_iof tracers with irreversible kinetics.

Acknowledgements

The National Institute of Biomedical Imaging and Bioengineering provided funding for this study (R01-EB026481, PI: Francesca Zanderigo, PhD).

graphic file with name 10.1177_0271678X211061050-img281.jpg

Comparison of cerebral metabolic rate of glucose (CMRglu) maps across the CerePET and Biograph

Voxel-wise glucose cerebral metabolic rate (CMR_glu) maps shown in Montreal Neurological Institute (MNI) space for a representative subject for the non-portable, Biograph™ scanner (TOP) and the portable, CerePET™ scanner (BOTTOM).

graphic file with name 10.1177_0271678X211061050-img282.jpg

Comparison of [18F]FDG glucose cerebral metabolic rate across the CerePET and Biograph

Glucose cerebral metabolic rate (CMR_glu) is plotted for the portable CerePET™ scanner (y-axis) and for the non-portable Biograph™ scanner (x-axis). CMR_glu was estimated via the Patlak approach. The regression lines are plotted for each subject with dotted lines and identity is shown with a solid black line.

References

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2020-33

Simultaneous assessment of α4β2 nicotinic acetylcholine receptor (nAChR) availability and neuronal response to rewarding food-cues in human obesity using PET-MRI (#172)

Swen Hesse^{1, 2}, Michael Rullmann^{1, 2}, Georg A Becker¹, Julia Luthardt¹, Eva Schweickert-de Palma², Tilman Guennewig², Franziska Zientek^{1, 2}, Thies Jochimsen¹, Matthias Blüher^{3, 4}, Anja Landsmann², Sarah Martin², Philipp M Meyer¹, Marianne Patt¹, Anja Hilbert^{2, 5}, Jane Neumann^{6, 7}, Peter Brust⁸ and Osama Sabri¹

¹Department of Nuclear Medicine, University of Leipzig, Leipzig, Saxony, Germany

²Integrated Research and Treatment Center (IFB) Adiposity Diseases, University of Leipzig, Leipzig, Saxony, Germany

³Helmholtz Zentrum München, Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG), Leipzig, Germany

⁴Department of Internal Medicine, University of Leipzig, Leipzig, Saxony, Germany

⁵Department of Psychosomatic Medicine and Psychotherapy, University of Leipzig, Leipzig, Saxony, Germany

⁶Department of Medical Engineering and Biotechnology, Ernst-Abbe-Hochschule, University of Applied Sciences, Jena Thuringia, Germany

⁷Department of Neurology, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Saxony, Germany

⁸Department of Neuroradiopharmaceuticals, Helmholtz-Zentrum Dresden-Rossendorf, Leipzig, Saxony, Germany

Abstract

Introduction: Cholinergic modulation of brain reward and attentional networks appears to play a crucial role in information processing about salience as a key biological mechanism in obesity (OB). We investigated the α4β2-nAChRs availability and neuronal network activity applying PET-MRI and (-)-[¹⁸F]flubatine in individuals with OB and normal-weight controls (NW) at rest and in response to salient food cues with focus on the ventral tegmental area (VTA) and the thalamus (THAL).

Methods: Twenty-six individuals with OB (n = 11; 7♀; age 42 ± 15 yrs; BMI 37 ± 3 kg/m²) and NW (n = 15; 12♀; 28 ± 7 yrs; BMI 22 ± 2 kg/m²) underwent PET-MRI with (-)-[¹⁸F]flubatine twice on separate days (rest and stim) using a bolus-infusion protocol (298 ± 6 MBq) with list-mode acquisition 0–60 min and 120–165 min p.i. paralleled by MPRAGE and EPI sequence. Total distribution volumes V_T (mL/cm³) were estimated as the ratio between mean (−)-[¹⁸F]flubatine activity in tissue between 120 and 165 min and free parent (−)-[¹⁸F]flubatine in plasma obtained from venous blood. Food pictures (stim) were shown 120–135 min p.i.

Results: Under rest, V_T VTA tend lower in OB vs NW (16.1 ± 2.1 vs. 17.5 ± 2.2; p = 0.1). During stim, V_T VTA as well as V_T THAL tend higher in OB (17.0 ± 1.7, p = 0.3; 28.3 ± 3.5 vs. rest 25.9 ± 3.2, p = 0.2) but not in NW (17.7 ± 2.6, p = 0.9; 26.3 ± 3.4 vs. 26.2 ± 2.5, p = 0.9). Eigenvector centrality mapping revealed higher centrality (p_uncorr < 0.001) of the insula as a core node of the salience network and the nucleus accumbens in NW but not in OB, in fronto-parietal attentional/executive networks in both (NW > OB) under stim vs rest. Applying V_T VTA as covariate in functional connectivity analyses using VTA as a seed markedly weakened the strong connectivity between VTA and the orbito-frontal cortex (OFC) (see Figure 1). Using V_T THAL as seed, strongest connectivity was found with visual input areas of the temporal cortex.

Conclusion: Compared with NW, individuals with OB displayed different neuronal presentation in the control over attention to high-incentive, salient cues apparently modulated by changes of the mesolimbic and cortico-thalamic cholinergic system. Most interestingly, the number of available α4β2-nAChR binding sites in the VTA has an impact on the function of the OFC which is the most important region for providing a value judgement of food.

Acknowledgements

The work was supported by the Federal Ministry of Education and Research, Germany, FKZ: 01E01001.

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Figure 1. Functional connectivity analysis. Seed-based (SPM) analysis indicating the effect of V_T VTA on functional connectivity between rest and stim (food cues) study (OFC, orbito-frontal cortex; VTA, ventral tegmental area).

2020-34

Determination of the 5-HT_2C receptor fraction in the human hippocampus in vivo: A [¹¹C]Cimbi-36 PET study (#173)

Gaia Rizzo^{1, 2}, Graham E Searle¹, Jan Passchier¹, Yvonne Lewis¹, David Erritzoe², Roger N Gunn^{1, 2}, Gitte M Knudsen³, John D Beaver⁴ and Eugenii A Rabiner^1,
5

¹Invicro LLC, London, UK

²Imperial College London, London, UK

³University of Copenhagen, Copenhagen, Denmark

⁴Biogen, Cambridge, MA, USA

⁵King’s College London, London, UK

Abstract

Introduction: Evaluation of drug binding at the brain 5HT_2C receptors (5HT_2CR) in vivo has been hampered by the lack of suitably selective PET ligands. [¹¹C]CIMBI-36 has similar affinity for the 5HT_2A receptor and 5HT_2CR in vitro.¹ Non-human primate PET studies estimated that 5HT_2CR represents 30% to 70% of [¹¹C]Cimbi-36 specific binding in the hippocampus.² In the human brain 5-HT_2C mRNA expression is high in the choroid plexus and hippocampus.³ We evaluated the 5HT_2CR fraction in the human hippocampus, by quantifying the 5-HT_2A and 5-HT_2C components of the [¹¹C]Cimbi-36 PET signal after the administration of risperidone, an antipsychotic with 50–100 fold higher affinity for the 5-HT_2A than for the 5HT_2CR in vitro.

Methods: Two 90-min dynamic [¹¹C]Cimbi-36 PET scans, at baseline and 2 hours post-administration of a single oral dose of risperidone (0.5, 1 or 2 mg), were administered to seven healthy males. All image analysis was performed using MIAKAT™. Regional volumes of distribution were derived using MA1 (t* = 20 min) and binding potential was calculated using the grey-masked ventrolateral cerebellum as a reference region.

Under the assumption that the specific binding in the cortex constitutes almost entirely of 5-HT_2A binding and that risperidone does not bind to 5HT_2CR, cortical occupancy (including frontal, parietal and occipital cortices, Occ_CORT) and risperidone concentration in plasma (C^RISP) were used to estimate E_50-HT2A^RISP (risperidone concentration that leads to 50% occupancy of the 5-HT_2A) as:

OCC_CORT = C^RISP/(C^RISP+E_50-5HT2A^RISP)

Occupancy values in the hippocampus (Occ_HIPP) were used to estimate the f_{2C_HIPP} (fraction of [¹¹C]Cimbi-36 signal in the hippocampus attributable to the 5-HT_2C) as:

OCC_HIPP = (1-f_{2C_HIPP}) C^RISP/(C^RISP+E_50-5HT2A^RISP)Amygdala (Occ_AMY) was used as a control region, similar in size and anatomical location to the hippocampus, but with low expected 5-HT_2C expression.

Results: Occ_CORT was significantly higher than Occ_HIPP (p < 0.01, paired Student’s t-test, Figure 1), but not Occ_AMY. The estimated f_{2C_HIPP} was 0.50 (95% CI, 0.24–0.76), while the estimated E_50-HT2A^RISP was 2.51 ng/ml (95% CI, 1.40–3.63 ng/ml) (Figure 2).

Conclusion: 1. The 5HT_2CR represents between 25% and 75% of the total [¹¹C]Cimbi-36 hippocampus BP_ND

2. [¹¹C]Cimbi-36 may be useful in evaluating drug interaction with the 5HT_2CR in the human brain.

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References

1.Ettrup A, Hansen M, Santini MA, et al. Radiosynthesis and in vivo evaluation of a series of substituted 11C-phenethylamines as 5-HT (2A) agonist PET tracers. Eur J Nucl Med Mol Imaging 2011; 38: 681–693. [DOI] [PubMed] [Google Scholar]
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2020-35

Magnitude of translocator protein binding and its association with C-reactive protein in depression: An ¹¹C-PK11195 PET study (#174)

Julia J Schubert¹, Mattia Veronese¹, Tim D Fryer^{2, 3}, Roido Manavaki⁴, Manfred G Kitzbichler⁵, Edward T Bullmore^5,
6, Federico E Turkheimer¹ and NIMA Consortium (https://www.neuroimmunology.org.uk/)

¹Neuroimaging, King’s College London, London, UK

²Clinical Neuroscience, University of Cambridge, Cambridge, UK

³Wolfson Brain Imaging Centre, University of Cambridge, Cambridge, UK

⁴Radiology, University of Cambridge, Cambridge, UK

⁵Psychiatry, University of Cambridge, Cambridge, UK

⁶Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge, UK

Abstract

Introduction: Inflammation has previously been implicated in the pathophysiology of major depressive disorder.^1,2 A relationship between peripheral and central inflammation has been proposed, in which peripheral cytokines directly induce central immune activation.^3,4 The aims of the current work are to use ¹¹C-PK11195 positron emission tomography (PET) to investigate whether translocator protein (TSPO) binding, as a measure for neuroinflammation, in anterior cingulate (ACC), prefrontal (PFC) and insular (INS) cortical regions is 1) significantly increased in depression and 2) associated with C-reactive protein (CRP), as a biomarker for peripheral inflammation.

Methods: 51 depressed cases (DCs) and 25 healthy controls (HCs) underwent 60-minute dynamic ¹¹C-PK11195 PET. A venous blood sample was collected to assess CRP. DC was stratified into high CRP (>3mg/L; N = 20) and low CRP (<3mg/L; N = 31) subgroups. Binding potentials (BP_ND) for ACC, PFC, and INS regions of interest (ROIs) were calculated using a simplified reference tissue model with a supervised clustering reference region approach.⁵

Results: Analysis of variance revealed significant BP_ND case-control differences across ACC, PFC, and INS ROIs (F(1,72) = 5.59, P = 0.02). Significantly higher BP_ND was observed in ACC of DC compared to HC (d = 0.49; t(74) = 2.00, P = 0.03), which remained significant when corrected for age and sex (F(1,72) = 6.60, P = 0.01) (Figure 1(a)). Significantly higher BP_ND was observed in ACC of low CRP DC compared to HC (d = 0.53; t(54) = 1.96, P = 0.03) (Figure 1(b)). No other significant case-control differences were observed. No significant correlations were observed between BP_ND and CRP in ACC, PFC, or INS ROIs.

Conclusion: We successfully replicated previous results of increased TSPO binding in DC compared to HC and provide further support for a relationship between neuroinflammation and depression, although the effect size of case-control differences in the TSPO PET signal is small (Figure 2). TSPO PET signal is not correlated with peripheral CRP concentrations in this cohort. These results encourage future, more mechanistic studies that will require novel PET radioligands with specific brain immune targets.

Acknowledgements

We acknowledge the Cambridgeshire and Peterborough NHS Foundation Trust, University of Cambridge, Wellcome Trust, National Institute of Health Research (NIHR) Clinical Research Network: Kent, Surrey and Sussex & Eastern, NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London, and NIHR Cambridge Biomedical Research Centre. We gratefully thank all study participants, research teams and laboratory staff.

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References

1.Holmes SE, Hinz R, Conen S, et al. Elevated translocator protein in anterior cingulate in major depression and a role for inflammation in suicidal thinking: a positron emission tomography study. Biol Psychiatry 2017; 83: 61–69. [DOI] [PubMed] [Google Scholar]
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2020-36

Novel software for computer-aided differential diagnosis of Parkinsonism using positron emission tomography (#175)

Elin Lindström^{1, 2}, Charles Widström², Torsten Danfors², Mark Lubberink^{1, 2} and My Jonasson^{1, 2}

¹Uppsala University, Uppsala, Sweden

²Uppsala University Hospital, Uppsala, Sweden

Abstract

Introduction: The PET tracer [¹¹C]PE2I (N-(3-iodoprop-2E-enyl)-2β-carbomethoxy-3β-(4-methylphenyl)nortropane) is a selective dopamine transporter (DAT) compound that has been successfully introduced for differential diagnosis of Parkinsonism.¹ Using tracer kinetic analysis of a dynamic [¹¹C]PE2I-PET scan, DAT availability and relative cerebral blood flow (rCBF) can be measured at the voxel level. The aim was to develop an automated workflow from dynamic PET-data to statistical comparison of the patient’s regional rCBF and DAT availability values to a normal control database, allowing for computer-aided differential diagnosis of Parkinsonism.

Methods: The automated workflow was based on previously validated and published methodology.^2,3 In brief, the dynamic PET images were realigned to correct for inter-frame patient motion. A volume of interest (VOI) template in MNI space was projected onto an early sum image. rCBF images were generated from 40-min dynamic PET-data using a basis function implementation of the simplified reference tissue model and SUVR-1 was estimated for the 30–40 min interval, with cerebellar gray matter as reference region. Regionally average voxel values were extracted in conjunction with z-scores from comparison to a normal database (n = 30). Surface projection maps of rCBF and rCBF z-score were computed after translation to MNI space. The software was written in Qt and C++ and implemented within the Hermes environment. Results in 22 subjects were compared to a previous analysis using in-house written software in Matlab.

Results: Quantitative results of the automated software agreed well with previous analysis (R² correlation of SUVR-1 in putamen of 0.83 and rCBF in the limbic area of 0.77) (Figure 1). So far, the software has been used for differential diagnosis of about 300 patients at Uppsala University Hospital. Total processing time of approximately 5 min/patient.

Conclusion: [¹¹C]PE2I enables a differential diagnosis of Parkinsonism based on both DAT availability and general brain function (rCBF) using a single scan, replacing a dual scan approach using DATscan-SPECT and FDG-PET. The software-aided approach improves logistics and may be helpful for experienced [¹¹C]PE2I-PET readers analyzing challenging cases. The single scan approach and software have been successfully introduced as a routine clinical application at Uppsala University Hospital and the software is freely available for other interested centers.

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References

1.Appel L, Jonasson M, Danfors T, et al. Use of 11C-PE2I PET in differential diagnosis of Parkinsonian disorders. J Nucl Med 2015; 56: 234–242. [DOI] [PubMed] [Google Scholar]
2.Jonasson M, Appel L, Engman J, et al. Validation of parametric methods for [11C]PE2I positron emission tomography. NeuroImage 2013; 74: 172–178. [DOI] [PubMed] [Google Scholar]
3.Jonasson M, Appel L, Danfors T, et al. Development of a clinically feasible [11C]PE2I PET method for differential diagnosis of parkinsonism using reduced scan duration and automated reference region extraction. Am J Nucl Med Mol Imaging 2017; 7: 263–274. [PMC free article] [PubMed] [Google Scholar]

2020-37

Comparison of centiloids and amyloid load for evaluation of amyloid change in Down syndrome (#176)

Matthew Zammit¹, Charles Laymon², Dana Tudorascu², Ann Cohen², Davneet Minhas², Shahid Zaman³, Beau Ances⁴, Chester A Mathis², Sterling Johnson¹, William E Klunk², Benjamin Handen² and Bradley Christian¹

¹University of Wisconsin-Madison, Madison, WI, USA

²University of Pittsburgh, Pittsburgh, PA, USA

³University of Cambridge, Cambridge, UK

⁴Washington University in St. Louis, St. Louis, MO, USA

Abstract

Introduction: Individuals with Down syndrome (DS) carry a triplicate copy of the gene encoding APP production, leading to an early presence of Aβ plaques in the brain. As a population, a majority of DS adults will develop clinical dementia by their late 60’s. The recent development of both Centiloids and Amyloid Load provide methodologies for standardizing the quantification of Aβ using PET. This work aims to compare these two measures in the DS population.

Methods: N = 169 adults with DS (age = 39.3 ± 8.4 years) were evaluated for Aβ using [C-11]PiB PET. A subset (n = 68) underwent longitudinal evaluation (3.0 ± 0.7 scans; 2.4 ± 0.6 years apart). All images were spatially normalized to MNI152 space, and 50–70 minute SUVr images were generated using a cerebellum reference region. Mean SUVr values were extracted from a global composite ROI and converted to units of Centiloids (CL).¹ The Amyloid Load index (Aβ_L) was calculated from each SUVr image, given inputs of DS-specific image templates of specific and nonspecific PiB binding.^2,3 Aβ(+) was defined as having Aβ_L > 20.0.³ Change scores between baseline and follow-up scans were evaluated for both CL and Aβ_L across Aβ(-), Aβ converter (converted from Aβ(-) to Aβ(+)), and Aβ(+) groups. Effect sizes (Cohen’s d) were determined for CL and Aβ_L change scores across each group.

Results: Change scores (presented as change/year) for CL (Aβ(-): 1.37 ± 2.36; Aβ converter: 6.25 ± 3.00; Aβ(+): 7.59 ± 4.10) and Aβ_L (Aβ(-): 0.60 ± 1.07; Aβ converter: 3.20 ± 0.77; Aβ(+): 3.35 ± 1.69) reveal a lower variance in the Aβ_L measure (Figure 1). Effect sizes for each measure are displayed in Table 1. For the Aβ(-) and Aβ(+) groups, CL and Aβ_L show similar effect sizes. For the Aβ converter group, the lower variance of Aβ_L results in a greater effect size compared to CL.

Conclusion: These results show that both Centiloids and Amyloid Load have similar performance to detect longitudinal increases in Aβ. Compared to Centiloids, the larger effect size for Amyloid Load in the Aβ converter group suggests this measure provides lower variability when evaluating Aβ change during the earliest stages of Aβ accumulation.

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Table 1. Effect sizes (Cohen’s d with 95% CI’s) between baseline and follow-up scans for Centiloids (CL) and Amyloid Load (Aβ_L) in Down syndrome.

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References

1.Klunk WE, Koeppe RA, Price JC, et al. The Centiloid Project: standardizing quantitative amyloid plaque estimation by PET. Alzheimer’s Dementia 2015; 11: 1–15. [DOI] [PMC free article] [PubMed] [Google Scholar]
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2020-38

First-in-human evaluations of [¹¹C]PS13 for imaging cyclooxygenase-1 and [¹¹C]MC1 for imaging cyclooxygenase-2 (#180)

Min-Jeong Kim¹, Fernanda Juarez Anaya¹, Jae-Hoon Lee¹, Jinsoo Hong¹, William Miller¹, Sanjay Telu¹, Cheryl Morse¹, Prachi Singh¹, Michelle Y Cortes-Salva¹, Katharine Henry¹, Yanira Ruiz-Perdomo², Jose A Montero Santamaria¹, Jeih-San Liow¹, Sami S Zoghbi¹, Masahiro Fujita¹, James D Katz², Victor W Pike¹ and Robert B Innis¹

¹Molecular Imaging Branch, National Institute of Mental Health, Bethesda, MD, USA

²National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD, USA

Abstract

Introduction: The cyclooxygenase (COX) system comprises two isoforms—COX-1 and COX-2—that are important targets for neuroinflammatory biomarkers.¹ We developed two PET radioligands: [¹¹C]PS13 for COX-1 and [¹¹C]MC1 for COX-2.^2–4 Previous monkey and human whole blood assays as well as PET imaging studies in monkey demonstrated the excellent in vitro and in vivo selectivity of these ligands,⁵ justifying the extension of studies into human individuals. This study sought to assess the distribution of binding and in vivo selectivity of [¹¹C]PS13 in healthy individuals and those of [¹¹C]MC1 in patients with rheumatoid arthritis.

Methods: Injection of radioligand was followed by dynamic PET scans. For [¹¹C]PS13, test-retest brain scans in 10 healthy individuals and whole-body scans in 24 healthy individuals were obtained. For [¹¹C]MC1, whole-body scans were obtained in two patients with rheumatoid arthritis and two healthy controls. Whole-body scans were repeated after administration of blocking drugs that preferentially target COX-1 (aspirin and ketoprofen) or COX-2 (celecoxib). Concurrent blood samples were obtained to measure concentrations of parent radioligand and radiometabolites.

Results: In baseline, substantial uptake of [¹¹C]PS13 was observed in most major organs, including the spleen, gastrointestinal tract, kidneys, and brain. This uptake was blocked by aspirin or ketoprofen but minimally blocked by celecoxib. In brain, [¹¹C]PS13 showed high uptake in the hippocampus and occipital cortices as well as pericentral cortices. When total distribution volume of [¹¹C]PS13 was calculated in brain, the overall test-retest variability was 6.0–8.5%. With [¹¹C]MC1, significantly higher uptake was observed in arthritic joints of the patients with rheumatoid arthritis compared to the corresponding joints of healthy controls. The increased uptake was partially blocked by celecoxib.

Conclusion: Our results suggest that COX-1 is constitutively expressed in major organs and that COX-2 is expressed in inflamed joints with rheumatoid arthritis. The in vivo selectivity of [¹¹C]PS13 and [¹¹C]MC1 was well demonstrated by pharmacological blockade. The test-retest reliability of brain [¹¹C]PS13 binding was also validated. Both [¹¹C]PS13 and [¹¹C]MC1 are potential probes for measuring brain and systemic inflammation in various conditions as well as target engagement by therapeutic drugs.

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References

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2020-39

Using hybrid PET/MRI to determine if perfusion MRI has comparable sensitivity to ¹⁵O-water PET for detecting dementia-related hypoperfusion (#181)

Tracy Ssali^{1, 2}, Lucas Narciso^{1, 2}, Justin W Hicks^1,
2, Matthais Günther³, Frank S Prato^{1, 2}, Udunna Anazodo^{1, 2}, Elizabeth Finger⁴ and Keith St Lawrence^1,
2

¹Medical Imaging, Lawson Health Research Institute, London, Canada

²Medical Biophysics, Western University, London, Canada

³Fraunhofer Institute for Medical Image Computing MEVIS, Bremen, Germany

⁴Department of Clinical Neurological Sciences, Western University, London, Canada

Abstract

Introduction: The ability of arterial spin labeling (ASL) MRI to detect perfusion abnormalities in clinical populations can be limited by poor signal to noise and transit-time artifacts. This has been evident in studies involving frontotemporal dementia (FTD) patients, where reports on the diagnostic value of ASL have been inconsistent.^1,2 Recent advances in ASL protocols including optimized labeling parameters should enable detection of more subtle perfusion abnormalities.³ This study presents a head-to-head comparison of regional hypoperfusion detected by ASL and PET with radiolabeled water (¹⁵O-water) – the gold standard for measuring cerebral blood flow (CBF) in humans.

Methods: Data were acquired from 9 controls (age: 63 ± 10, sex: 3 female/6 male) and 7 FTD patients across FTD subtypes (age: 69 ± 9, sex: 4 female/3 male) on the Siemens biograph mMR. Five minutes of list mode data were acquired after a bolus injection of approximately 800Mbq of ¹⁵O-water. Perfusion was quantified using a double-integration method.⁴ ASL data were collected immediately following PET acquisition and CBF images generated using a one compartment model.³ Statistical maps of regional hypoperfusion were determined using a case-control design using absolute and relative CBF (normalized to whole-brain blood flow).

Results: Global CBF measured by ASL was: 55.9 ± 9.6 and 49.9 ± 11.4 ml/100g/min (ns) and by ¹⁵O-water was: 51.1 ± 8.2 and 45 ± 9.9 ml/100g/min (ns) in controls and patients, respectively. Control CBF maps are shown in Figure 1. Both ASL MRI and ¹⁵O-water PET images showed hypoperfusion in regions commonly associated with each FTD subtype (Figure 2).

Conclusion: This work highlights the potential of ASL for identifying regional hypoperfusion in participants with FTD. Preliminary data showed that ASL was capable of detecting disease-specific perfusion abnormalities and the pattern were very similar to those detected by ¹⁵O-water PET. However, the hypoperfusion regions identified by PET were typically greater in number and larger in area than those identified by ASL. Further work is required to determine the impact of these differences on the diagnostic accuracy of ASL.

Acknowledgements

This work is supported by: Frederick Banting and Charles Best Canada Graduate Doctoral Award, Canadian Institutes of Health Research Grant and Alzheimer’s Drug Discovery Foundation Grant.

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Regional hypoperfusion detected by ASL and 15O-water

T-maps generated using absolute (top) and relative (bottom) CBF measured by ASL (red) and ¹⁵O-water (blue) in 4 representative frontotemporal dementia FTD subtypes. Areas in red/blue indicate regions of significant hypoperfusion in the patient participant compared to the control group.

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Normalized perfusion maps

Perfusion maps measured by ¹⁵O-water and ASL. Data shown has been averaged across healthy controls (n = 9) and normalized to mean global flow.

References

1.Anazodo UC, et al. Using simultaneous PET/MRI to compare the accuracy of diagnosing frontotemporal dementia by arterial spin labelling MRI and FDG-PET. NeuroImage Clin 2018; 17: 405–414. [DOI] [PMC free article] [PubMed] [Google Scholar]
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2020-40

Olfactory impairment is related to tau pathology and neuroinflammation in Alzheimer’s disease (#187)

Julia I Klein^{1, 2}, Xinyu Yan³, Aubrey Johnson¹, Zeljko Tomljanovic¹, James Zou¹, Krista Polly¹, Estrella Morenas-Rodriguez^{4, 5}, Christian Haass^{4, 6}, Lawrence S Honig¹, Adam M Brickman¹, Yaakov Stern¹, Seonjoo Lee^{3, 7} and William C Kreisl¹

¹Columbia University Irving Medical Center, Taub Institute, New York, NY, USA

²Weill Cornell Medical College, New York, NY, USA

³Mailman School of Public Health, Columbia University Irving Medical Center, New York, NY, USA

⁴German Center for Neuroegenerative Disease, Munich, Germany

⁵Institut d’Investigacion Biomèdiques, Universitat Autònoma de Barcelona, Barcelona, Spain

⁶Metabolic Biochemistry Biomedical Center, Ludwig-Maximilians-Universität München, Munich, Germany

⁷The Research Foundation for Mental Hygiene, New York, NY, USA

Abstract

Introduction: Olfactory impairment is observed early in Alzheimer’s disease (AD).^1–4 and can be quantified using the University of Pennsylvania Smell Identification Test (UPSIT). The relationships between odor identification and in vivo measures of known pathological features of Alzheimer’s disease, including tau pathology and neuroinflammation, are less established. We sought to determine if low UPSIT performance was associated with increased neuroinflammation, measured by ¹¹C-PBR28 PET and CSF sTREM2 and YKL-40. We further evaluated the relationship between odor identification and tau pathology using PET imaging with ¹⁸F-MK-6240, an improved tau radioligand, and CSF concentrations of total tau and phosphorylated tau.

Methods: Participants were selected from an established research cohort of adults aged 50 and older who underwent neuropsychological testing, brain MRI, and amyloid PET. Fifty-four participants were administered the UPSIT. Forty-one of these underwent ¹⁸F-MK-6240 PET to measure tau pathology and fifty-three underwent ¹¹C-PBR28 PET to measure the 18 kDa translocator protein (a biomarker of inflammation). Twenty-three participants had lumbar puncture to measure CSF concentrations of total tau (t-tau), phosphorylated tau (p-tau), and inflammatory biomarkers sTREM2 and YKL-40.

Results: Negative correlations between UPSIT performance and ¹⁸F-MK-6240 binding were seen in medial temporal cortex, hippocampus, middle/inferior temporal gyri, inferior parietal cortex and posterior cingulate cortex (p < 0.05). Similar inverse relationships were seen for ¹¹C-PBR28. UPSIT performance negatively correlated with CSF concentrations of t-tau, p-tau, and YKL-40 (p < .05). Moreover, UPSIT scores correlated with hippocampal volume and cognitive performance. Analysis of variance, controlling for age and sex showed that amyloid status and cognitive status exhibit independent effects on UPSIT performance (p < 0.01).

Conclusion: Olfactory identification declines with increasing tau pathology and neuroinflammation along the Alzheimer’s continuum. Amyloid-positivity and cognitive impairment exhibit independent effects on odor identification, suggesting that 1) low UPSIT performance may signify risk of AD in cognitively normal individuals, and 2) impaired odor identification is associated with both AD- and non-AD-related neurodegeneration.

Acknowledgements

¹⁸F-Florbetaben was supplied by Life Molecular Imaging. ¹⁸F-MK-6240 was supplied by Cerveau Technologies. TSPO genotyping was performed by Regina Santella, PhD and the Columbia University Biomarkers Shared Resource. We wish to acknowledge the contributions of the staff and faculty of the Irving Institute for Clinical Research, the MRI Center and the David A. Gardner PET Imaging Center at the Columbia University Irving Medical Center.

References

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2020-41

Automated data quality control in [18F]FDOPA brain PET imaging using deep learning (#190)

Antonella D Pontoriero¹, Barbara Santangelo^{1, 2}, Sameer Jahuar², Ilaria Bonoldi², Maria Rogdaki², Federico E Turkheimer¹, Oliver D Howes² and Mattia Veronese¹

¹Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK

²Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK

Abstract

Introduction: With biomedical imaging research racing for larger datasets, it becomes critical to find new methods to guarantee that the quality of data collected is not compromised before using them for further analysis or clinical assessment. Some attempts to use Artificial Intelligence have already been applied to Magnetic Resonance Imaging (MRI), to perform automated quality control (QC) both for single-site and multi-site datasets.^1–3 No automated QC methods for PET imaging exist today. The aim of this study is to develop and validate an automated QC pipeline for brain [18F]FDOPA PET imaging as biomarker for dopamine system in mental health applications.

Methods: This project uses Convolutional Neural Networks (CNNs), a deep-learning approach which provides better outcomes when compared to other learning models aimed at classification of images.⁴ Here, 3 different CNNs are combined to assess 1) the spatial alignment to standard MNI brain template, 2) the spatial distribution of [18F]FDOPA tracer uptake and 3) signal-to-noise ratio (SNR) of the image. A dataset of 200 manually QC [18F]FDOPA PET images (injected dose: 150 ± 12MBq) from three different PET/CT scanners is combined with 200 scans in which misalignment, altered tracer uptake and/or low SNR are simulated. A cross-validation is performed; 80% of the data is used for training and 20% for validation while training. Categorical cross-entropy (target value 0) and categorical accuracy (target value 1) are used performances indexes. The same models are trained on the original 3D images, 2D images of a representative single slice of the 3D image and on 1D data obtained by tracing a representative line of the 2D image (Figure 1).

Results: With 3D datasets, the best performances are obtained for the spatial distribution of [18F]FDOPA tracer uptake (accuracy = 0.76, cross-entropy = 0.53) while the SNR network is the poorest. When training on low-dimensional datasets, the time required for training is extremely reduced while the performances remain comparable (Table 1).

Conclusion: This feasibility study shows that it is possible to perform QC of [18F]FDOPA imaging with CNNs. However, it must be investigated how generalisable the approach is when using a completely new dataset not included in the training.

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Table 1. Performance and training time for [18F]FDOPA CNNs for 1D, 2D and 3D datasets.

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References

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2020-42

Human blocking study to assess selectivity of [¹⁸F]FTP PET for dopamine D3 receptors (#193)

Robert K Doot¹, Anthony J Young¹, Tiffany L Dominguez¹, Christopher G Ward², Shihong Li¹, Zeinab Helili¹, Regan Sheffer¹, Hsiaoju Lee¹, Erin K Schubert¹, Robert H Mach¹ and Jacob G Dubroff¹

¹Dept. of Radiology, Perelman School of Medicine, Univ. of Pennsylvania, Philadelphia, PA, USA

²Dept. of Anesthesiology and Critical Care Medicine, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

Abstract

Introduction: Dopamine D3 receptors (D3R) in the D2 family of receptors are thought to be important to neurobiological reward pathways and implicated in drug addiction, Parkinson’s disease, and schizophrenia. [¹⁸F]Fluortriopride ([¹⁸F]FTP) was developed as a D3R-selective radiotracer¹ and based on nonhuman primate imaging¹ was anticipated to be more selective for D3R than current human D2 family radiotracers.² First-in-human [¹⁸F]FTP images revealed unexpected uptake outside of the dopamine system. This distribution may be due to [¹⁸F]FTP binding to serotonin 5-HT_1A receptors (HT_1AR), which have high affinity for N-phenyl piperazine analogs like [¹⁸F]FTP.³ The goal of this blocking study goal was to assess whether the unexpected [¹⁸F]FTP uptake was due to nonselective binding or selective binding to HT_1AR.

Methods: Search of the NIMH Psychoactive Drug Screening Program (PDSP) Ki database for drugs that could selectively block [¹⁸F]FTP from either HT_1AR or D3R suggested using either HT_1AR-blocking Lysergic acid diethylamide (LSD) or D3R-blocking perphenazine. LSD was not safe to use at levels required for blocking. 8-mg PO of perphenazine was selected based on a safe record in over 45,000 humans⁴ and a report estimating a maximum D2-family receptor occupancy of 98% in a [¹¹C]raclopride human study.⁵ Five healthy volunteers (3 female, 2 male) underwent two 60-minute dynamic brain scans with arterial blood sampling following bolus injection of [¹⁸F]FTP (230 ± 29MBq (mean ± SD, n = 10) both without perphenazine and starting 1-hr following perphenazine administration. Total distribution volumes (V_T) were estimated (Pmod v3.7) in D3R-rich (caudate nucleus, globus pallidus, putamen, and thalamus) and HT_1AR-rich regions (frontal lobe, insula, parahippocampus, hippocampus, temporal lobe, and entorhinal area). Two-tailed paired t-tests were performed to test for significant differences (SPSS 25, p < 0.05).

Results: Representative [¹⁸F]FTP brain images of a healthy control before and after perphenazine challenge are in Figure 1. V_T results are shown in Figure 2 with no significant differences observed for D3R-rich regions (p = 0.38) or for HT_1AR-rich regions (p = 0.33).

Conclusion: [¹⁸F]FTP uptake in D3R-rich regions was not significantly changed following perphenazine challenge (p = 0.38) suggesting nonselective binding of [¹⁸F]FTP throughout human brains and future efforts to image D3R should focus on alternative D3R radiotracers including those under development in preclinical studies.

Acknowledgements

Authors appreciate research support provided by the United States of America’s National Institute on Drug Abuse of the National Institutes of Health under Award Numbers K01DA040023 (RD), K23DA038726 (JD) and R01DA029840-06A1 (RM).

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2020-43

ApoE4 packs a punch in women: Sex-specific vulnerability for tau (#194)

Yi-Ting Wang^{1, 2}, Min-Su Kang^{1, 2}, Joseph Therriault^1,
2, Tharick A Pascoal^{1, 2}, Melissa Savard^{1, 2}, Firoza Z Lussier^{1, 2}, Andréa L Benedet^{1, 2}, Cécile Tissot^{1, 2}, Jaime Fernandez Arias^{1, 2}, Serge Gauthier^{1, 2} and Pedro Rosa-Neto^{1, 2}

¹Research Centre for Studies in Aging, McGill University, Montreal, Québec, Canada

²Translational Neuroimaging Laboratory, McGill University, Montreal, Québec, Canada

Abstract

Introduction: Apolipoprotein E (APOE) is the strongest genetic risk factor for sporadic Alzheimer’s disease (AD), with the ε4 allele conferring increased risk. APOE has been implicated in various neuropathological cascades relevant to AD, including amyloidosis, tau tangle pathology,¹ microglial activation and neurodegeneration. Research leveraging in vivo tau biomarkers indicates that APOEε4 is associated with higher levels of tau in the cerebrospinal fluid² (CSF). A meta-analysis published in 2017 states that the effect of APOEε4 is more robust among women compared with men, indicating the presence of a sex difference.³ The role that sex plays in AD has long been the subject of intense investigation. Previous works reported mixed results about the sex-specific effect of APOEε4 on tau pathology. Some studies suggest that women show a more robust association between APOEε4 and tau, while other works reveal no sex difference. The overarching goal of this study is to investigate the APOE effect on tau pathology in a sex-specific manner.

Methods: This was a cross-sectional study in subjects with AD (n = 44), MCI (n = 54), cognitively normal controls (n = 154) and young healthy controls (n = 35) from the TRIAD study at McGill University Research Centre for Studies in Aging, Canada. A total of 287 subjects were studied, among which 108 were APOEε4 carriers and 179 were non-APOEε4 carriers. Cerebral amyloid load and tau level were assessed using positron emission tomography (PET) radiopharmaceuticals [¹⁸F]AZD4694 ([¹⁸F]NAV4694) and [¹⁸F]MK6240 respectively.

Results: Male and female APOE ε4/ε4carriers showed a 13.2% and 65.1% higher [¹⁸F]MK6240 SUVR repectively when compared with their ε3/ε3counterparts. Female APOEε4 carriers showed significant higher tau burden in hippocampus (P < 0.01), entorhinal cortex (P < 0.05) and parahippocampal cortex (P < 0.05) compared to male ε4 carriers. A sex-specific vulnerability for tau was observed. More specifically, in amyloid-positive female APOEε4carriers, higher tau burden was found to be strongly associated with worse cognitive function assessed by Mini-Mental State Examination (MMSE).

Conclusion: We provide strong evidence that women are more vulnerable for the effects of APOEε4 on tau, suggesting APOE may modulate AD pathology in a sex-specific manner, particularly in the presence of amyloidosis. Inline graphic

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References

1.Farfel JM, Yu L, De Jager PL, et al. Association of APOE with tau-tangle pathology with and without β-amyloid. Neurobiol Aging 2016; 37: 19–25. [DOI] [PMC free article] [PubMed] [Google Scholar]
2.Hohman TJ, Dumitrescu L, Barnes LL, et al. Sex-specific association of apolipoprotein E with cerebrospinal fluid levels of tau. JAMA Neurol 2018; 75: 989–998. doi:10.1001/jamaneurol.2018.0821. [DOI] [PMC free article] [PubMed] [Google Scholar]
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2020-44

Measurement of HDAC6 target occupancy in macaque using [¹⁸F]EKZ-001 positron emission tomography (#201)

Tonya M Gilbert¹, Sofie Celen², Michel Koole³, Isabeau Vermeulen², Kim Serdons⁴, Frederick A Schroeder¹, Florence Wagner⁵, Tom Bleeser⁶, Wim Vanduffel⁷, Koen Van Laere^{3, 4}, Janice E Kranz¹, Jacob M Hooker⁸, Guy Bormans² and Christopher Cawthorne³

¹Eikonizo Therapeutics, Inc., Cambridge, MA, USA

²Laboratory for Radiopharmaceutical Research, KU Leuven, Leuven, Belgium

³Nuclear Medicine and Molecular Imaging, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium

⁴Nuclear Medicine and Molecular Imaging, University Hospitals Leuven, Leuven, Belgium

⁵Center for the Development of Therapeutics, Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA

⁶Anesthesiology and Algology, KU Leuven, Leuven, Belgium

⁷Laboratory for Neuro- and Psychophysiology, KU Leuven, Leuven, Belgium

⁸Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA

Abstract

Introduction: Histone deacetylase 6 (HDAC6) is a multifunctional enzyme involved in diverse cellular processes such as intracellular transport¹ and protein quality control.² Inhibition of HDAC6 can alleviate defects in cell and rodent models of neurodegenerative disorders, including Alzheimer’s disease³ and amyotrophic lateral sclerosis.⁴ However, while HDAC6 represents a potentially powerful therapeutic target, development of effective brain-penetrant HDAC6 inhibitors remains challenging. Here [¹⁸F]EKZ-001 ([¹⁸F]Bavarostat⁵) positron emission tomography (PET) was applied to measure dose-occupancy relationships of HDAC6 inhibitors in the non-human primate brain.

Methods: [¹⁸F]EKZ-001 was administered by intravenous bolus injection (∼185 MBq). The most appropriate kinetic model for brain imaging was determined in rhesus macaque (N = 3 males) from 120-minute dynamic PET/MR using radiometabolite-corrected arterial plasma as an input function. The total volume of distribution (V_T) was calculated using one-tissue and two-tissue compartment models (1TCM and 2TCM) and fits were evaluated using the Akaike information criterion (AIC). V_T was also calculated with Logan graphical analysis (LGA) using a starting time of 40 minutes post-injection. Heterologous-blocking studies were performed in rhesus macaque (N = 1 male) with the novel candidate HDAC6 inhibitor, EKZ-317, and an existing HDAC6 inhibitor tool compound, ACY-775, at 0.1 and 2 mg/kg, using an intravenous pre-treatment paradigm 5 minutes before [¹⁸F]EKZ-001 injection. Target occupancy was estimated using the Lassen plot.

Results: Based on AIC, 2TCM was the preferred model compared to 1TCM. Regional LGA V_Tsignificantly correlated with 2TCM valuesin baseline and blocking conditions. Lassen plots using V_Tderived from either 2TCM or LGA gave comparable target occupancy estimates. Non-displaceable distribution volume (V_ND) was consistent between blocking conditions and quantitation methods (approximately 10%), indicating a high degree of specific binding. EKZ-317 achieved full HDAC6 occupancy at 2 mg/kg, and greater than 90% occupancy at 0.1 mg/kg, demonstrating a higher level of HDAC6 target engagement than ACY-775 in brain (Figure 1).

Conclusion: [¹⁸F]EKZ-001 PET showed favorable kinetic properties in non-human primate for calculation of V_T in brain. This work supports the translation of [¹⁸F]EKZ-001 PET for HDAC6 target occupancy studies in humans and may facilitate the development of brain penetrant HDAC6 inhibitor therapeutics.

Acknowledgements

This study was supported by funding from Eikonizo Therapeutics, Inc.

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References

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2020-45

Extra-striatal D_2/3 receptor availability in youth at risk for addiction (#202)

Natalia Jaworska¹, Sylvia Cox², Maria Tippler², Natalie Castellanos-Ryan³, Chawki Benkelfat², Sophie Parent³, Alain Dagher⁴, Frank Vitaro³, Michel Boivin⁵, Robert Pihl⁶, Sylvana Côté⁷, Richard Tremblay⁸, Jean Séguin⁸ and Marco Leyton²

¹Institute of Mental Health Research, University of Ottawa, Ottawa, ON, Canada

²Department of Psychiatry, McGill University, Montreal, Québec, Canada

³School of Psychoeducation, Université de Montréal, Montreal, Québec, Canada

⁴Montreal Neurological Institute, McGill University, Montreal, Québec, Canada

⁵Department of Psychology, Université Laval, Quebec, Canada

⁶Department of Psychology, McGill University, Montreal, Québec, Canada

⁷Department of Social and Preventative Medicine, Université de Montréal, Montreal, Québec, Canada

⁸Department of Pediatrics & Psychology, Université de Montréal, Montreal, Québec, Canada

⁹CHU Ste-Justine Research Centre, Université de Montréal, Montreal, Québec, Canada

Abstract

Introduction: The neurobiological traits that confer risk for addictions remain poorly understood. However, dopaminergic function throughout the prefrontal cortex, limbic system, and upper brainstem has been implicated in behavioral features that influence addiction vulnerability, including poor impulse control and altered sensitivity to rewards and punishments; i.e., externalizing features. To test these associations in humans, we measured type-2/3 dopamine receptor (DA_2/3R) availability in youth at high vs. low risk for substance use disorders.

Methods: Fifty-eight participants (18.5 ± 0.6yr) were recruited from cohorts that have been followed since birth: half had high (high EXT, N = 27, 16F/11M) and half had low externalizing traits (low EXT, N = 31, 20F/11M). All underwent a 90-min positron emission tomography [¹⁸F]fallypride scan and completed the Barratt Impulsiveness Scale (BIS-11), Substance Use Risk Profile Scale (SURPS), and Sensitivity to Punishment (SP) & Sensitivity to Reward (SR) Questionnaire.

Results: The high vs. low EXT participants reported elevated substance use, BIS-11, SR and SURPS Impulsivity scores, had a greater prevalence of psychiatric disorders, and exhibited higher [¹⁸F]fallypride binding potential (BP_ND) values in prefrontal, limbic and paralimbic regions, even when controlling for substance use. Group differences were not evident in the midbrain dopamine cell body region, but, across all participants, low midbrain BP_ND values were associated with low SP scores.

Conclusion: Altered DA_2/3R availability in extra-striatal terminal and dopamine cell body regions might constitute biological vulnerability traits, generating an EXT trajectory for addictions with and without co-occurring alterations in punishment sensitivity; i.e., an internalizing feature.

2020-46

Evaluation of [¹⁸F]APN-1607 to image tau protein in patients with Alzheimer’s disease and progressive supranuclear palsy: Test-retest and cross-sectional analysis (#204)

Christine Sandiego¹, Roger N Gunn², David S Russell^2,
3, Ken Marek³, Richard Margolin^{4, 5}, PJ Chen⁴, Paul Tempest⁴ and Ming-Kuei Jang⁴

¹Invicro, New Haven, CT, USA

²Invicro, London, UK

³Institute for Neurodegenerative Disorders, New Haven, CT, USA

⁴Aprinoia Therapeutics, Taipei, Taiwan

⁵CNS Research Solutions LLC, Cambridge, MA, USA

Abstract

Introduction: [¹⁸F]APN-1607 is a novel PET tracer for imaging fibrillar tau, a key characteristic of several neurodegenerative diseases known as tauopathies. These conditions include Alzheimer’s disease (AD) and progressive supranuclear palsy (PSP). This study aimed to assess [¹⁸F]APN-1607 binding in patients with AD and PSP, compared with healthy volunteers (HV) and to evaluate test-retest variability (TRTV) of blood- and reference region-based outcome measures.

Methods: [¹⁸F]APN-1607 PET was conducted over 180 min in 5 HV, 7 AD and 8 PSP subjects; 2 HV, 4 AD and 3 PSP subjects returned for a retest scan. In 7 subjects who completed test and retest scans, arterial blood samples were collected throughout the imaging sessions, as required for quantitative analysis. Distribution volume ratio (DVR) was estimated with invasive and non-invasive Logan graphical analysis (LGA). SUVr was averaged between 60–90 and 120–150 min, using the cerebellar cortex as reference region. TRTV of DVR and SUVr were evaluated across cortical (temporal, parietal and frontal lobes) and subcortical (thalamus, pallidum, and substantia nigra) regions. DVR(invasive) was considered the gold standard and was compared via linear regression analysis with DVR(non-invasive) and SUVr. SUVr was compared between HV, PSP and AD subjects.

Results: TRTV of [¹⁸F]APN-1607 in HV, PSP and AD subjects was less than 10% for DVR and SUVr, averaged across regions. SUVr(120–150 min) was in best agreement (R² = 0.97, slope = 1.04) with invasive DVR, compared with non-invasive DVR(R² = 0.97, slope = 0.85) and SUVr(60–90 min)(R² = 0.90, slope = 0.87). Images of [¹⁸F]APN-1607 SUVr(120–150 min) in representative HV, PSP and AD subjects are shown in Figure 1. Regional cross-sectional analysis of [¹⁸F]APN-1607 SUVr(120–150) is shown in Figure 2. In cortical regions SUVr(120–150 min) (mean ± SD) was 0.97 ± 0.13 in HV, 0.99 ± 0.24 in PSP and 1.76 ± 0.53 in AD subjects. In subcortical regions, SUVr(120–150 min) was 1.19 ± 0.17 in HV, 1.37 ± 0.21 in PSP and 1.20 ± 0.23 in AD subjects.

Conclusion: [¹⁸F]APN-1607 showed excellent test-retest reliability across outcome measures and is a promising PET radioligand for imaging tau in specific neurodegenerative diseases. Cross-sectional analysis demonstrated substantially higher binding in cortical regions for AD compared to HV and PSP, and moderately higher binding in subcortical regions for PSP, compared to HV and AD.

Acknowledgements

For this work, would like to acknowledge the chemistry and clinic teams at Invicro, New Haven.

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2020-47

Validation of a non-invasive hybrid PET/MRI method for imaging the cerebral metabolic rate of oxygen (#209)

Lucas Narciso^{1, 2}, Tracy Ssali^{1, 2}, Linshan Liu¹, Heather Biernaski¹, John Butler¹, Laura Morrison¹, Jennifer Hadway¹, Justin W Hicks^{1, 2}, Michael C Langham³, Felix W Wehrli³, Hidehiro Iida⁴ and Keith St Lawrence^1,
2

¹Lawson Health Research Institute, London, ON, Canada

²Department of Medical Biophysics, Western University, London, ON, Canada

³Department of Radiology, University of Pennsylvania Medical Centre, Philadelphia, PA, USA

⁴Turku PET Centre, University of Turku, Turku, Finland

Abstract

Introduction: PET is the gold standard for imaging the cerebral metabolic rate of oxygen (CMRO₂) in humans; however, the procedure requires multiple ¹⁵O-tracers and arterial blood sampling. Hybrid PET/MR offers a means of simplifying the procedure by using MRI-based measurements of whole-brain (WB) CMRO₂ as a reference to calibrate dynamic ¹⁵O-oxygen-PET data.¹ This hybrid approach eliminates the need for invasive arterial sampling, only requires PET images of ¹⁵O-oxygen, and reduces the total duration to 5 min. It is also predicted to be insensitive to errors related to blood-borne activity and recirculating water because they do not affect MRI CMRO₂ measurements.² In this study, we present initial validation of the approach conducted in a large animal model that enabled arterial sampling for measurement of CMRO₂ by a previously validated PET method.

Methods: PET and MRI data were obtained from juvenile pigs (n = 9, 18.9 ± 2.1 kg) under two metabolic conditions on a 3T Siemens Biograph mMR system. MR imaging included arterial spin labelling (ASL) and Oxflow to measure regional cerebral blood flow (CBF) and WB CMRO₂, respectively.³ Concurrent PET imaging involved 5-min list-mode acquisitions after injecting 500 MBq of ¹⁵O-water, followed by inhaling 2200 MBq of ¹⁵O-oxygen. Arterial sampling was obtained using an MR-compatible system (Swisstrace). CT images were acquired post-mortem for attenuation correction. Dynamic PET images were reconstructed into 48 time-frames (30 × 3s, 6 × 5s, 6 × 10s and 6 × 20s). CMRO₂ images were generated from the PET data alone⁴ and by the hybrid PET/MR procedure.

Results: Results from the hybrid PET/MR approach (n = 6, Figure 1) presented mean CMRO₂ within the expected range, for both baseline (1.88 ± 0.24 mL/100 g/min) and lower metabolic conditions (1.20 ± 0.33 mL/100 g/min; 36% reduction, p < 0.01).

Conclusion: Initial WB CMRO₂ results obtained with the hybrid PET/MR approach were within the expected range, further reinforcing our previous assessments.¹ These results suggest that quantitative measurements of CMRO₂ can be obtained without the need for arterial blood sampling. The complete analysis of our experiments can be found in Narciso et al.²

Acknowledgements

This work is supported by the Canadian Institutes of Health Research.

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2020-48

Non-invasive quantification of [¹¹C]PBR28 binding in non-human primates (#211)

Lucero G Aceves-Serrano¹, Jacob Goddard², Vesna Sossi² and Doris J Doudet¹

¹Department of Medicine/Neurology, University of British Columbia, Vancouver, BC, Canada

²Department of Physics and Astronomy, University of British Columbia, Vancouver, BC, Canada

Abstract

Introduction: Quantification of neuroinflammation tracers (i.e. TSPO tracers) can be troublesome as it requires arterial cannulation. We assessed the usefulness of four different quantitative and semi-quantitative blood-free measurements of [¹¹C]-PBR28 binding and compared them to the standard blood dependent measurements.

Methods: Thirteen [¹¹C]-PBR28 scans from non-human primates (NHP) were acquired along with metabolite and plasma activity to create arterial input functions (AIFs). BP_ND was quantified with AIF (BP_ND^AIF)¹ using activity in white matter as V_ND. Additionally, four alternate measurements were computed: BP_ND with a population-derived input function (BP_ND^PBIF), standard uptake value (SUV), SUV ratio to white matter (SUVr) and BP_ND‐‐‐ using white matter as non-specific input (BP_ND^WM).² Four animals were scanned twice providing test-retest reproducibility data.

Results: Free fraction was stable across animals (0.093 ± 0.012). Parent and metabolite fractions were similar in arterial (N = 9) and venous samples (N = 3) (Figure 1(a)). There was good reproducibility between the test and retest scans for BP_ND^AIF (ICC = 0.721) BP_ND^PBIF (ICC = 0.699) SUVr (ICC = 0.855) and BP_ND^WM (ICC = 0.868) but not for SUV(ICC = 0.225). There was a good correlation between the BP_ND^AIF and BP_ND^PBIF within scans (mean r across animals = 0.944 ± 0.15) but only moderate correlation for SUV, SUVr and BP_ND^WM (mean r across animals ranging between 0.64 ± 0.09 and 0.71 ± 0.09). The shape of the late portion of the non-corrected plasma curve greatly resembled that of the white matter activity confirming that at least some [¹¹C]-PBR28 metabolite(s) cross the blood-brain barrier (Figure 1(b)).

Conclusion: In NHP, the stability of peripheral metabolism permits the use of a PBIF to measure BP_ND. The high correlation between BP_ND^AIF and BP_ND^PBIF and the good test-retest value suggest that a population curve may be a good alternative to individual sampling to study the effect of intervention within subjects. Additionally, arterial and venous plasma appears to be equally useful to provide an estimate of peripheral metabolism. Further work on this data set will test the performance of SIME.

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Activity curves

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Parent and metabolite fraction

References

1.Logan J, Fowler JS, Volkow ND, et al. Graphical analysis of reversible radioligand binding from time-activity measurements applied to [N-11C-methyl]-cocaine PET studies in human subjects. J Cereb Blood Flow Metab 1990; 10: 740–747. [DOI] [PubMed] [Google Scholar]
2.Logan J, Fowler JS, Volkow D, et al. Distribution volume ratios without blood sampling from graphical analysis of PET data. J Cereb Blood Flow Metab 1996; 16: 843–840. [DOI] [PubMed] [Google Scholar]

2020-49

Type 5 metabotropic glutamate receptor availability in youth at risk for addictions: Effects of vulnerability traits and cannabis use (#217)

Sylvia Cox¹, Maria Tippler¹, Natalia Jaworska², Kelly Smart³, Natalie Castellanos-Ryan⁴, France Durand¹, Dominique Allard¹, Chawki Benkelfat¹, Sophie Parent⁴, Alain Dagher⁵, Frank Vitaro⁴, Michel Boivin⁶, Robert Pihl⁷, Sylvana Côté⁸, Richard Tremblay⁹, Jean Séguin¹⁰ and Marco Leyton^{1, 5}

¹Department of Psychiatry, McGill University, Montreal, Québec, Canada

²Institute of Mental Health Research, University of Ottawa, Ottawa, ON, Canada

³Yale PET Center, Yale University, New Haven, CT, USA

⁴School of Psychoeductation, Université de Montréal, Montreal, Québec, Canada

⁵Department of Neurology and Neurosurgery, McGill University, Montreal, Québec, Canada

⁶Department of Psychology, Université Laval, Québec, Canada

⁷Department of Psychology, McGill University, Montreal, Québec, Canada

⁸Department of Social and Preventative Medicine, Université de Montréal, Montreal, Québec, Canada

⁹Department of Pediatrics and Psychology, Université de Montréal, Montreal, Québec, Canada

¹⁰Department of Psychiatry and Addictology, Université de Montréal, Montreal, Québec, Canada

Abstract

Introduction: The excitatory neurotransmitter glutamate has been implicated in experience-dependent neuroplasticity and drug-seeking behaviors. Type 5 metabotropic glutamate (mGlu5) receptors might be particularly important. In humans, mGlu5 receptor availability has been reported to be lower in people with alcohol, tobacco, and cocaine use disorders. Since the reductions could reflect effects of drug use or pre-existing traits, we used positron emission tomography (PET) to measure mGlu5 receptor availability in young adults at elevated risk for addictions.

Methods: Fifty-nine participants (18–20 y.o.) were recruited from a longitudinal study that has been followed since birth. Based on diverse externalizing behaviors that predict future substance use problems, half of the participants were at low risk, half were at high risk. Cannabis use histories varied markedly, and participants were divided into three groups: zero, low and high use. Participants were scanned using high-resolution research tomograph PET with tracer 3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone-O-¹¹C-methyl-oxime ([¹¹C]ABP688) and 3T magnetic resonance imaging for anatomical co-registration.

Results: Compared to low risk volunteers, those at elevated risk for substance use disorders had lower [¹¹C]ABP688 binding potential (BP_ND) values in cortico-limbic regions including the striatum, amygdala, insula, and orbitofrontal cortex (OFC). Cannabis use by risk group interactions were observed in the striatum and OFC. In these regions, high cannabis use was associated with low [¹¹C]ABP688 binding in the high risk group only. When the high risk, high cannabis using individuals (n = 9) were compared to all other participants (n = 50), [¹¹C]ABP688 BP_ND values were significantly lower in the striatum, OFC, and insula. These effects were evident when controlling for the use of other substances (Figure 1).

Conclusion: The results indicate that mGlu5 receptor availability is low in youth at elevated risk for addictions, particularly those who are frequently using cannabis.

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2020-50

Morphine administration increases translocator protein availability in humans (#218)

Eric A Woodcock¹, Gustavo A Angarita¹, David Matuskey^1,
2, Yiyun H Huang², Ansel T Hillmer^{1, 2}, Richard E Carson^{2, 3} and Kelly P Cosgrove^{1, 2}

¹Psychiatry, Yale University, New Haven, CT, USA

²PET Center, Yale University, New Haven, CT, USA

³Radiology and Biomedical Imaging, Yale University, New Haven, CT, USA

Abstract

Introduction: There is tremendous need to investigate novel treatment targets for opioid use disorder, such as the neuroimmune system. In preclinical studies, opioid administration reliably evokes pro-inflammatory responses in the periphery and brain. These pro-inflammatory responses have been shown to influence appetitive (e.g., opioid-seeking) and dysphoric (e.g., pain and withdrawal) addiction processes which perpetuate opioid use. In this paradigm development study, we investigated the neuroimmune effects of acute opioid administration using Positron Emission Tomography (PET) imaging with [¹¹C]PBR28, a radiotracer that binds to the 18kDa translocator protein (TSPO), a marker of microglia.

Methods: Healthy individuals with prior medical opioid exposure (n = 4; 3M; 2 ‘high-affinity’ binders; Age = 30 years; BMI = 26.5 [range = 24-30]) completed two 120-minute [¹¹C]PBR28 PET scans in one day: before and 2-hours after intramuscular morphine (0.07mg/kg). Arterial blood was acquired to measure the metabolite-corrected input function. Volumes of distribution (V_T), i.e., TSPO availability, were calculated in 10 regions of interest (ROIs) using multilinear analysis–1 (t* = 30). Regional [¹¹C]PBR28 V_T values were evaluated using a repeated-measures analysis of variance with rs6971 genotype as a fixed factor (‘high’ vs. ‘mixed affinity’ TSPO binders). Subjective and behavioral effects were also assayed before and after morphine.

Results: Morphine increased TSPO availability by 28%-39% across ROIs, F(1,2) = 9.56, p = .09, partial η² = 0.83, ‘very large’ effect (Figure 1). Morphine increased withdrawal latency on the Cold Pressor Task, i.e., pain tolerance, F(1,2) = 3.98, p = .18, partial η² = 0.66, ‘very large’ effect. Morphine decreased systolic and diastolic blood pressure by 11 mmHg and 7 mmHg, respectively (ps < .09; Figure 2(a)). Subjective drug effects were modest (Figure 2(b)).

Conclusion: These preliminary findings suggest that morphine evokes a neuroimmune response in people. The magnitude of TSPO increase observed herein is comparable to prior research in non-human primates. Notably, TSPO availability increased in all brain regions, which suggests that morphine’s neuroimmune effects are not limited to regions with µ opioid receptor binding, consistent with non-human primate findings. The morphine dose administered (<6mg) is comparable to a standard-of-care post-operative analgesic dose. Indeed, preliminary data suggest morphine enhanced thermal pain tolerance. Future studies could use this paradigm to investigate the role of neuroimmune signaling in addiction processes among individuals with opioid use disorder.

Acknowledgements

The authors acknowledge the staff at the Yale University PET center, Jon Mikael Anderson, Aleksandra Rusowicz, Brittany LeVasseur, Stephen Baldassarri, Olivia Wilson, Nicole DellaGioia, Ryan Cool, Sarah DeBonee, and Elizabeth Yanac.

Funding was generously provided by the National Institute on Drug Abuse (K99 DA048125; EAW), the National Institute of Mental Health (R01 MH110674; KPC), and the Veterans Affairs National Center for PTSD (KPC).

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2020-51

Evaluation of PET quantitation methods using a 3D-printed anatomically accurate brain phantom (#234)

Davneet Minhas¹, Anish Ghodadra¹, Zheming Yu¹, Sarah K Royse¹, Howard Aizenstein², Ann Cohen², Dana Tudorascu³, Brian Lopresti¹, Chester A Mathis¹, William E Klunk² and Charles Laymon¹

¹Department of Radiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

²Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA

³Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

Abstract

Introduction: A variety of reconstruction- and image-based methods have been developed to improve the resolution of PET. However, there remains a lack of consensus on their use due to a lack of ground truth-based evaluation. In this work, we assess techniques using a human-based PET phantom with physiologically relevant radiotracer distributions.

Methods: A lateral temporal phantom with six fillable, thin-walled (1.0 mm) chambers corresponding to inferior, middle, and superior temporal gray matter (GM) and white matter (WM) was constructed via 3D-printing (Formlabs Form 3) using the FreeSurfer v5.3 segmented sample subject “bert” as a pattern. Inferior and superior temporal GM regions were filled with a 2.2 kBq/cc concentration of F-18 solution and WM regions with 1.2 kBq/cc at time of scan, simulating a high amyloid-burden subject with a GM-to-WM [¹¹C]PiB radioactivity ratio of 1.8. The phantom was scanned (Siemens Biograph mCT) for 180 minutes. Data were reconstructed using three techniques – FBP; OSEM (4 and 5 iterations); and TrueX (4 and 5 iterations), an iterative method incorporating a spatially variant point-spread function – into 7 frames with each containing the counts expected in a 20-minute [¹¹C]PiB scan. Image-based geometric transfer matrix (GTM) partial-volume correction (PVC) was applied to the FBP and OSEM images. Average regional radioactivity concentrations across frames, uncorrected and PVC, were compared to known ground truth. Method-associated variability was assessed using coefficients of variation (CoV) across frames.

Results: CT (empty phantom), FBP, OSEM, and TrueX images are presented in Figure 1. Average regional radioactivity for each of the reconstruction methods, uncorrected and PVC, are presented in Figure 2.

Conclusion: GTM PVC resulted in overestimated but more accurate regional quantification relative to uncorrected data, regardless of reconstruction method. GTM PVC also resulted in increased variability with CoVs 1.2-to-1.9 times that of uncorrected CoVs across methods and regions. TrueX improved apparent image quality but not quantitative accuracy relative to uncorrected FBP and OSEM. This study adhered to one fundamental assumption of the GTM technique: radioactivity uniformity within a region. This assumption may be violated in human imaging. Future studies will address this and will examine the effect of varying levels of cortical atrophy.

Acknowledgements

This study was funded by United States National Institutes of Health (NIH) grant number P01 AG025204-13S.

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2020-52

Alterations in cerebral blood flow in patients with secondary progressive and stem cells treated multiple sclerosis – A perfusion study with ¹⁵O-water-PET (#237)

Lieuwe Appel^{1, 2}, Andreas Tolf^{3, 4}, Torsten Danfors^1,
2, Elna-Marie Larsson^{1, 2}, Anne-Marie Landtblom^{3, 4}, Gunnar Antoni^{2, 5}, Jens Sörensen^{1, 2}, Joachim Burman^{3, 4} and Mark Lubberink^{1, 6}

¹Surgical Sciences, Uppsala University, Uppsala, Sweden

²Medical Imaging Centre, Uppsala University Hospital, Uppsala, Sweden

³Neuroscience, Uppsala University, Uppsala, Sweden

⁴Neurology, Uppsala University Hospital, Uppsala, Sweden

⁵Medicinal Chemistry, Uppsala University, Uppsala, Sweden

⁶Medical Physics, Uppsala University Hospital, Uppsala, Sweden

Abstract

Introduction: Multiple sclerosis (MS) is an autoimmune and degenerative disorder where the immune system malfunctions attack the central nervous system, leading to demyelination and neuronal/axonal loss. Impaired cerebral blood flow (CBF) has been associated with disease progression in neurodegenerative disorders. Chemotherapy combined with haematopoietic stem cell transplantation (HSCT) was introduced as an alternative treatment in 2004 at our hospital. Nowadays there is a growing evidence that HSCT is a successful treatment, but the question remains whether it is an ultimate cure for MS. This study aimed to investigate differences in CBF between three cohorts: patients with secondary progressive MS (SPMS), treated patients (HSCT) and healthy controls (HC).

Methods: ¹⁵O-water-PET scans with arterial blood sampling were acquired at rest for 10 SPMS, 9 HSCT (10 years after treatment), and 10 HC (age and gender matched). Arterial input functions were corrected for delay and dispersion. Hence, CBF and distribution volume (V_T) values were generated using a standard single-tissue compartment model including a fitted blood volume parameter. T1-weighted MR images were used for segmentation and automated definition of volumes of interest. Nonparametric tests were used to detect significant differences between cohorts (p < 0.05).

Results: Global CBF, including gray and white matter, was significantly lower in SPMS compared to HSCT, whereas no significant differences were found between HSCT and HC. Regional CBF revealed similar patterns for SPMS, and significant differences with HC and HSCT were especially found in subcortical regions – Figure 1. Further, V_T was significantly higher in HSCT compared to SPMS, both global and regional – Figure 2.

Conclusion: These preliminary results revealed an impaired CBF and decreased V_T in SPMS. Similar levels of CBF and V_T for HSCT and HC indicates that HSCT treatment might restore overall brain functionality. In part, the current findings also confirm the outcome of clinical investigations/observations.^1,2 Specific CBF and V_T alterations in gray matter suggest a relationship with various disabilities in MS patients.

Acknowledgements

Thanks to the MS-patients and healthy volunteers for their study participation, anesthetists for a careful setup of arterial lines and the imaging staff for a skillfull data acquisition.

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References

1.Burman J, et al. Autologous haematopoietic stem cell transplantation for aggressive multiple sclerosis: the Swedish experience. J Neurol Neurosurg Psychiatry 2014; 85: 1116. [DOI] [PubMed] [Google Scholar]
2.Tolf A, et al. Sustained remission in multiple sclerosis after hematopoietic stem cell transplantation. Acta Neurol Scand 2019; 40: 320–327. [DOI] [PubMed] [Google Scholar]

2020-53

Development of novel PET imaging agents for neurodegeneration (#239)

Christopher Liang, Rommani Mondal, Krystal Patel and Jogeshwar Mukherjee

Preclinical Imaging, Radiological Sciences, University of California, Irvine, CA, USA

Abstract

Introduction: Proteinopathies, including α-synuclein aggregates, a hallmark Parkinson’s disease (PD) and tau aggregates in Alzheimer’s disease related disorders (ADRD) are a target for PET radiotracer development. Coexistence of these aggregates in neurodegeneration has been suggested,^1,2 but recent flortaucipir PET findings suggest lack of tau aggregates in PD patients.³ In an effort to develop PET agents for ADRD and PD, we examined molecules containing overlapping Aβ-amyloid, dopamine receptor or tau binding structures. Here we report a new fluoroalkylazaindole ([¹⁸F]FAZIN3) as a potential PET imaging agent for neurodegeneration.

Methods: AZIN3-Tosyl was radiolabeled with 10–20 mCi of [¹⁸F]fluoride in acetonitrile containing Kryptofix/K₂CO₃. [¹⁸F]FAZIN3 (0.5–1 mCi) was purified by HPLC. Male C57BL/6 mice were used for in vivo Inveon PET/CT studies. Human post-mortem brain tissues consisting of anterior cingulate (AC) and corpus callosum (CC) were used (controls (CN), n = 6; PD, n = 6; AD, n = 6). Brain slices were incubated [¹⁸F]FAZIN3 (1 µCi/cc) in PBS (pH 7.4) buffer at 25°C for 60 min. Competition with clorgyline, deprenyl and MK-6240 were also carried out.

Results: PET/CT scans showed clearance of [¹⁸F]FAZIN3 from the brain with low retention in any brain region (Figure 1). No radioactivity was observed in the bones suggesting that [¹⁸F]FAZIN3 was resistant to defluorination (Figure 1). All CN subjects exhibited lower [¹⁸F]FAZIN3 binding in the AC compared to the PD and AD subjects (Figure 2). In the case of PD subjects, AC exhibited a more than 2-fold increase in binding of [¹⁸F]FAZIN3 (PD/CN = 2.12) for AC. Similarly, AD subjects showed a two-fold increase in [¹⁸F]FAZIN3 binding (AD/CN = 2.04). Binding of [¹⁸F]FAZIN3 was reduced > 90% in both AD and PD brain slices using clorgyline, a monoamine oxidase A (MAO-A) inhibitor. Deprenyl (MAO-B inhibitor) and MK-6240 had little effect on [¹⁸F]FAZIN3 binding.

Conclusion: We have developed a novel PET imaging agent, [¹⁸F]FAZIN3. The exquisite binding of [¹⁸F]FAZIN3 in the PD and AD brain suggests unique upregulation of MAO-A. Thus, PET imaging studies using [¹⁸F]FAZIN will be complimentary to studies reported with flortaucipir³ and [¹⁸F]MK-6240^4,5 in understanding the role of MAO-A in neurotransmitter depletion, neuronal damage from reactive oxygen species and inflammation in AD and PD.

Acknowledgements

NIH/NIA RF1 AG029479 (JM).

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[18F]FAZIN3 Mouse PET/CT Images

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Postmortem Human Brain Autoradiographs

References

1.Castillo-Carranza DL, et al. a-Synuclein oligomers induce a unique toxic tau strain. Biol Psychiatry 2018; 84: 499–508. [DOI] [PMC free article] [PubMed] [Google Scholar]
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4.Aguero C, et al. Autoradiography validation of novel tau PET tracer [F-18]-MK-6240 on human postmortem brain tissue. Acta Neuropathologica Comm 2019; 7:37, 1-15. [DOI] [PMC free article] [PubMed] [Google Scholar]
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2020-54

Evaluation of neuroinflammation in HIV patients and “elite controllers” using [¹¹C]-PBR28 PET (#241)

Hasan Sari¹, Yang Lin¹, Andrew Salvatore¹, Zeynab Alshelh¹, Angel Torrado-Carvajal^{1, 2}, Shibani Mukerji³, Eva-Maria Ratai¹, Jacqueline Chu⁴, Rajesh Gandhi⁴, Oluwaseun J Akeju⁵, Atreyi Saha¹, Vitaly Napadow¹, Robert Edwards⁵, Julie C Price¹, Marco L Loggia¹ and Cristina Granziera⁶

¹MGH/HST Martinos Center for Biomedical Imaging, Charlestown, MA, USA

²Laboratory of Medical Image Analysis, Universidad Rey Juan Carlos, Madrid, Spain

³Department of Neurology, Massachusetts General Hospital, Boston, MA, USA

⁴Department of Infectious Diseases, Massachusetts General Hospital, Boston, MA, USA

⁵Department of Anaesthesia, Massachusetts General Hospital, Boston, MA, USA

⁶Department of Biomedical Engineering, University of Basel, Allschwil Basel-Land, Switzerland

Abstract

Introduction: [¹¹C]-PBR28 is a PET radioligand with a high affinity for the translocator protein (TSPO), which can mark the presence of neuroinflammation. In recent studies, an increase in TSPO expression was shown in people with HIV (PWH) compared to controls.^1,2 In this work, we evaluate [¹¹C]-PBR28 PET standardized-uptake value ratios (SUVR) in PWH including a group of “elite controllers (EC)”, a group of participants who are able to maintain low viral loads without treatment.

Methods: Thirteen PWHs (age: 55 ± 5.9 years, sex:12M/1F, genotype: 10HAB/3MAB), 18 healthy controls (HC) (age: 48 ± 13.5 years, sex:10M/8F, genotype: 11HAB/5MAB) and 6 ECs (age: 59 ± 7.3 years, sex 5M/1F, genotype: 4HAB/2MAB) were scanned using an integrated PET/MR scanner. All PWHs were aviremic. Standardized-uptake value (SUV) images were generated (60–90min post-injection) and transformed to Montreal Neurological Institute (MNI) space using FSL.³ To generate a pseudo-reference region, an unpaired t-test was performed to identify voxels with no statistically difference between HCs and PWHs. Given the large preponderance of males in our sample, only datasets from male participants were used in this comparison. The resultant z-maps were thresholded to include voxels between -0.2 and 0.2 (p > 0.84).⁴ The resulting region was used to normalize the region-of-interests (ROIs) and compute SUVRs. Regions with significant difference between PWH and HCs were identified and Dunnett’s test was used to test if ECs were different from remaining groups.

Results: Regional SUVR values for each group are shown in Table 1. After Bonferroni correction, statistically significant group differences in [¹¹C]PBR28 SUVRs were observed between HCs and PWHs in 4 of the 9 ROIs. The most significant differences were seen in thalamus, putamen and parietal operculum cortex (p < 0.01, corrected). Figure 1 shows box-plots of SUVRs in these regions. ECs demonstrated significantly less inflammation (p < 0.05) compared to the PWHs in thalamus, putamen, and parietal operculum cortex.

Conclusion: The results of this work demonstrate significantly greater [¹¹C]-PBR28 signal in PWHs compared to HCs, suggestive of neuroinflammation. ECs demonstrated lower [¹¹C]PBR28 signal than PWHs with higher viral loads, suggesting that these patients’ ability to naturally control their viral load might be also accompanied by lower levels of neuroinflammation.

Acknowledgements

This work was supported NIH grant R01DA047088-01 (ML and EMR).

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Table 1. Regional ¹¹C-PBR28 SUVR values for healthy control and HIV positive patients, grouped for each genotype. 2-way ANOVA test was used to compute p-values using genotypes as the fixed factor. Regions with significant group differences after Bonferroni correction are marked with *.

References

1.Vera JH, Guo Q. Neuroinflammation in treated HIV-positive individuals: a TSPO PET study. Neurology 2016; 86: 1425–1432. [DOI] [PMC free article] [PubMed] [Google Scholar]
2.Coughlin JM, Wang Y. Regional brain distribution of translocator protein using [11C]DPA-713 PET in individuals infected with HIV. J NeuroVirol 2014; 20: 219–232. [DOI] [PMC free article] [PubMed] [Google Scholar]
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2020-55

Extension of pseudo-CT method for attenuation correction of simultaneous PET/MR brain imaging in rhesus macaques (#244)

Jonathan M DuBois¹, Lu Wang², William Zhou¹, Steven Liang³, David Izquierdo-Garcia¹ and Hsiao-Ying Wey¹

¹Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Harvard Medical School, Massachusetts General Hospital, Charlestown, MA, USA

²Department of Nuclear Medicine and PET/CT-MRI Center, The First Affiliated Hospital of Jinan University & Institute of Molecular and Functional Imaging, Jinan University, Guangzhou, China

³Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

Abstract

Introduction: Non-human primates (NHP) are a valuable model for neuroimaging research, allowing neurobiological investigation of brain function as well as facilitating the development and translation of new biomarkers and therapeutics. Unfortunately, many of the methodological advances of human brain imaging have not yet been applied to NHPs. While MR-based attenuation correction (AC) methods have been developed for human imaging, AC remains a major challenge to accurate quantification of PET data acquired on a PET/MR scanner for NHPs. To address this, we have extended our well validated human pseudo-CT method^1,2 to develop MR and CT population templates for the rhesus macaque. This method combines a 6 tissue-class segmentation and diffeomorphic non-rigid deformation from a single MRI to generate a pseudo-CT image.¹ The pseudo-CT attenuation (µ) maps from MR data can be used in PET/MR scanners to improve PET quantification for NHP studies.

Methods: Ten NHPs (rhesus macaque) were imaged on a PET/CT (GE Discovery 690) and on a 3T MRI (GE Discovery 750). The T1-weigthed MR images and CT images were segmented to obtain 6 tissue-classes: WM, GM, CSF, bone, soft-tissue, and air. The tissue classes from all animals were non-rigidly co-registered using a diffeomorphic approach to generate tissue class templates and a CT template (using SPM8). CT-like (pseudo-CT) images can be obtained by applying the inverse transformation, which were converted to linear attenuation coefficients to be used for AC of PET data.³ Bland-Altmant plots were calculated to test accuracy using a leave-one-out cross-validation (LOOCV) analysis across all 10 subjects.

Results: Qualitatively, the pseudo-CT template closely resembles the real CT image in individual subjects (Figure 1), which is consistent with previous results shown in the human brain. Voxel-wise LOOCV of the 10 NHPs showed only small errors in the brain, with an absolute relative change of 1.6% when comparing the pseudo-CT to the real CT.

Conclusion: We present an approach for deriving the head pseudo-CT µ map for rhesus macaques, which will allow for robust AC in integrated PET/MR scanners. We are currently working on comparing the accuracy of this technique against PET-based AC methods in NHPs to evaluate the impact on PET quantification.

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References

1.Izquierdo-Garcia D, et al. An SPM8-based approach for attenuation correction combining segmentation and nonrigid template formation: application to simultaneous PET/MR brain imaging. J Nucl Med 2014; 55: 1825–1830. [DOI] [PMC free article] [PubMed] [Google Scholar]
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2020-56

Validation of kinfitr: An open-source tool for reproducible PET kinetic modelling (#246)

Jonathan Tjerkaski, Simon Cervenka, Lars Farde and Granville J Matheson

Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden

Abstract

Introduction: In PET imaging, binding is typically assessed by fitting pharmacokinetic models to time-activity curves (TACs). However, there are wide variety of different models, and a multitude of other analytical decisions which must be made before these models can be applied. As such, there is a need for both analytical flexibility and transparency. The recently developed kinfitr¹ is an open-source tool designed to provide this functionality, allowing reproducible PET modelling using the R programming language. Here, we validate the performance of kinfitr against the widely-used PMOD software.²

Methods: We used previously-collected TAC data from test-retest studies of four different radioligands, using six kinetic models. Two of these tracers ([¹¹C]SCH23390, n = 15, and [¹¹C]AZ10419369, n = 8) were modelled using non-invasive models, and two ([¹¹C]PBR28, n = 12, and (R)- [¹¹C]PK11195, n = 6) were modelled using invasive models with metabolite-corrected arterial input function. We assessed the agreement of estimated binding outcomes and microparameters, as well as test-retest performance for each tool, and agreement between models within each tool.

Results: We obtained high correlations between kinfitr and PMOD for both non-invasive and invasive models (median Pearson’s r = 0.99, range: 0.95–1.00). Linearised methods exhibited lower agreement due to differences in the selection of t* values between tools. No substantial differences were observed in between- or within-individual variation. We obtained high correlations between the microparameters of the simplified reference tissue model (mean r > 0.99) and of the two-tissue compartment model (mean r: K₁ > 0.99, k₂ 0.81, k₃ 0.80, k₄ 0.88). Strong agreement was also observed between different models using each tool independently, for both non-invasive (median r: kinfitr 0.99, PMOD 0.99) and invasive models (median r: kinfitr 0.99, PMOD 0.79).

Conclusion: There was excellent agreement between kinfitr and PMOD. We therefore conclude that kinfitr is a valid and reliable tool for kinetic modelling of PET data. kinfitr is operated using R code, thereby ensuring computational reproducibility³: all analysis steps are transparently recorded and can be reproduced by re-running the code. In this way, re-analysis using different parameters or models only requires modification of the relevant lines of code, rather than repeating all steps of the analysis anew.

Acknowledgements

This research was supported by the Swedish Society of Medicine (Svenska Läkaresällskapet).

graphic file with name 10.1177_0271678X211061050-img319.jpg

graphic file with name 10.1177_0271678X211061050-img320.jpg

References

1.Matheson GJ. kinfitr: reproducible PET pharmacokinetic modelling in R. bioRxiv 2019; 755751
2.Mikolajczyk K, Szabatin M, Rudnicki P, et al. A JAVA environment for medical image data analysis: initial application for brain PET quantitation. Med Inform (Lond) 1998; 23: 207–214 [DOI] [PubMed] [Google Scholar]
3.Sandve GK, Nekrutenko A, Taylor J, et al. Ten simple rules for reproducible computational research. PLoS Comput Biol 2013; 9: e1003285.. [DOI] [PMC free article] [PubMed] [Google Scholar]

2020-57

Lower thalamic dopamine D2-receptor binding and connectivity in drug-naive patients with psychosis – A combined [11C]FLB 457 PET and DTI study (#248)

Pauliina Victorsson¹, Pontus Plavén-Sigray^{1, 2}, Alexander Santillo^{1, 3}, Granville J Matheson¹, Maria Lee¹, Karin Collste¹, Helena Fatouros-Bergman¹, Ingrid Agartz^{1, 4}, Christer Halldin¹, Lars Farde¹ and Simon Cervenka¹

¹Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden

²Neurobiology Research Unit, Copenhagen University Hospital, Copenhagen, Denmark

³Clinical Memory Research Unit, Lund University, Lund, Sweden

⁴Norwegian Centre for Mental Disorders Research (NORMENT), Institute of Clinical Medicine, University of Oslo, Oslo, Norway

⁵Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway

Abstract

Introduction: Previous PET studies have demonstrated lower levels of the dopamine D2-receptor (D2-R) in thalamus in patients with schizophrenia.¹ However, some studies were performed using radioligands with suboptimal affinity or included patients on antipsychotic treatment. Moreover, the relationship to cortical connectivity has not been investigated. Here we examined antipsychotic-naïve first-episode psychosis patients using PET and the high-affinity D2-R radioligand [11C]FLB457, aiming to a) replicate findings of lower D2-R in whole thalamus in patients, and b) investigate D2-R differences in connectivity-based thalamic subregions. Moreover, thalamocortical connectivity was examined using diffusion tensor imaging (DTI) in a subset of individuals.

Methods: Nineteen patients and 19 age- and sex matched healthy comparison subjects were examined using a High Resolution Research Tomograph (HRRT). Whole thalamus was defined using the Harvard Oxford Subcortical Atlas, whereas thalamic subregions were based on the Oxford Thalamic Connectivity Atlas. Binding potential (BPND) was calculated using the Logan graphical analysis with cerebellum as reference region. Statistical analyses (pre-registered at https://osf.io/nhr3w/) were performed using frequentist and Bayesian paired-samples t-tests. In 11 patients and 15 healthy subjects the anterior and inferior thalamic radiation were manually extracted using DTI whole brain tractography.

Results: Patients had significantly lower binding than control subjects in whole thalamus (Cohen’s D = −0.479, p = 0.026). The Bayes Factor indicated approximately 5 times more support for the hypothesis of lower BPND in patients, compared to the null hypothesis. Among subregions, the ROI corresponding to frontal thalamic connectivity showed the largest effect (Cohen’s D = −0.527, p = 0.017, Bayes Factor > 6). Patients showed significantly lower fractional anisotropy values compared with controls (Cohen’s D = −0.692, p = 0.036) in the inferior thalamic radiation, which predominantly projects to and from the orbitofrontal, temporal and insular cortex.

Conclusion: This study replicates previous findings of lower thalamic D2-R availability in patients. The strongest effect was observed in the subregion dominated by connections to prefrontal cortex, and aberrations in thalamocortical connectivity was confirmed in a subsample. The findings may reflect a dysregulation of the thalamic dopamine system in schizophrenia, which in turn could affect functional thalamocortical connectivity.

Acknowledgements

The contributions from the staff at the Karolinska PET Centre, the staff at the participating psychiatric units in Stockholm (Prima Vuxenpsykiatri, Psykiatri Nordväst and Norra Stockholms Psykiatri), as well as the members of Karolinska Schizophrenia Project are gratefully acknowledged.

graphic file with name 10.1177_0271678X211061050-img321.jpg

graphic file with name 10.1177_0271678X211061050-img322.jpg

Reference

1.Kambeitz J, Abi-Dargham A, Kapur S, et al. Alterations in cortical and extrastriatal subcortical dopamine function in schizophrenia: systematic review and meta-analysis of imaging studies. Br J Psychiatry 2014; 204: 420–429. [DOI] [PubMed] [Google Scholar]

2020-58

Tau deposition assessed by [¹⁸F]MK6240 PET is associated with longitudinal decrease in grey matter density across the spectrum of Alzheimer’s disease (#250)

Firoza Z Lussier¹, Tharick A Pascoal¹, Joseph Therriault¹, Andréa L Benedet¹, Cécile Tissot¹, Yi-Ting Wang¹, Jaime F Arias¹, Melissa Savard¹, Serge Gauthier² and Pedro Rosa-Neto¹

¹Translational Neuroimaging Laboratory, McGill Research Centre for Studies in Aging, Verdun Québec, Canada

²Alzheimer’s Disease Research Unit, McGill Research Centre for Studies in Aging, Verdun Québec, Canada

Abstract

Introduction: Reduction in grey matter (GM) is a well-established neuroimaging finding in Alzheimer’s disease (AD). Here, we sought to determine whether baseline tau-PET using the high-affinity tracer [¹⁸F]MK6240 is predictive of longitudinal changes in GM across the AD spectrum.

Methods: Baseline [¹⁸F]MK6240 PET data and longitudinal structural MRI was acquired for 79 participants in the TRIAD cohort (47 CN, 20 MCI, 12 AD). [¹⁸F]MK6240 standardized uptake value ratio (SUVR) were calculated 90–110 minutes post-injection using cerebellar GM as the reference region. T1-weighted MR images were segmented into probabilistic GM and WM maps, which were non-linearly registered to the ADNI template using DARTEL and smoothed with an 8 mm FWHM Gaussian kernel. Voxel-based morphometry (VBM) was run on GM and WM maps. Longitudinal changes in GM density were indexed by voxel-wise percentage change in GM VBM. Voxel-based regression analyses were conducted to examine associations between baseline [¹⁸F]MK6240 SUVR and change in GM density, with age, gender, years of education, diagnosis, and time interval between MRI acquisitions employed as covariates.

Results: Baseline [¹⁸F]MK6240 SUVRs in Braak I/II, III/IV, and V/VI were significantly correlated with longitudinal decrease in GM density in the lateral and medial temporal lobe, including hippocampal regions. All results survived correction for multiple comparisons using random field theory at p < 0.001.

Conclusion: Our results suggest that tau pathology at baseline is associated with the progression of GM atrophy over time in brain regions vulnerable to AD pathological changes, providing evidence that tau-PET may identify individuals who are more susceptible to atrophy.

graphic file with name 10.1177_0271678X211061050-img323.jpg

Tau assessed by [18F]MK6240 is associated longitudinal decreases in grey matter density

Results from voxel-based linear regression analyses between [18F]MK6240 SUVR in (A) Braak I/II, (B) Braak III/IV, (C) Braak V/VI and longitudinal change in GM density. Positive associations were found bilaterally in the lateral and medial temporal lobe. (Greater change in GM density represented decrease in density). Analyses have been corrected for multiple comparisons using random field theory at p < 0.001.

2020-59

Pre-clinical evaluation of novel COX-2 PET radiotracers for imaging neuroimmune dysregulation (#255)

Michael S Placzek^{1, 2}, Michel Weiwer³, Misha M Riley¹, Daniel K Wilton^{2, 4}, Florence Wagner³, Beth Stevens^{2, 4} and Jacob M Hooker^{1, 2}

¹Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, USA

²Harvard Medical School, Boston, MA, USA

³Broad Institute of MIT and Harvard, Stanley Center for Psychiatric Research, Cambridge, MA, USA

⁴Department of Neurology, F. M. Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA, USA

Abstract

Introduction: In the brain, COX-2 is specifically upregulated in response to inflammatory events, including those that occur in neurodegenerative diseases.¹ COX-2-targeting radiotracers have been pursued by several groups, but translation to human imaging has yet to succeed.² With a focus on high COX-2 binding affinity and fast on-rate, we discovered BRD1158, with improved potency and faster on-rate for COX-2 compared to rofecoxib, celecoxib, and MC1. In vitro and in vivo evaluation in rodents and nonhuman primates demonstrated [¹¹C]BRD1158 has high brain uptake and specific binding for COX-2, warranting further evaluation.

Methods: [¹¹C]BRD1158 was radiolabeled at the methylsulfone by treating the corresponding thioester precursor with [¹¹C]CH₃I. [¹¹C]BRD1158 in vitro autoradiography with slide-mounted brain tissue slices (rat and human) was performed by incubating tissue with either radioligand+vehicle or radioligand+blocking (10 µM self-block). Huntington’s Disease post-mortem brain tissue (globus pallidus) and age matched healthy control was used for autoradiography. To evaluate [¹¹C]BRD1158 brain uptake we measured whole brain SUV in rats and baboons with PET-MR. Regional brain time activity curves for both rat and baboon were generated with PMOD using PxRat atlas and b2k baboon atlas.

Results: Using a COX-2 enzymatic assay (2 min pre-incubation), BRD1158 was a potent COX-2 inhibitor (IC₅₀ = 20 nM), compared to rofecoxib (600 nM), and MC1 (43 nM). In vitro autoradiography (Figure 1) with rat brain slices demonstrated appreciable specific binding (22 ± 11%; n = 6 slices). In a pilot experiment with human HD tissue (1 subject), we observed robust [¹¹C]BRD1158 specific binding in globus pallidus tissue (23 ± 5%, n = 6 slices). In vivo, [¹¹C]BRD1158 had high brain uptake in rat (whole brain SUV C_max = 1.9) and baboon (whole brain SUV C_max = 3.3), and favorable washout kinetics for a brain PET radiotracer (rat t_1/2 = 7.8 min; baboon t_1/2 = 17.2 min) (Figure 2).

Conclusion: We have identified BRD1158 as a potent and selective COX-2 inhibitor that has high brain uptake in both rodent and baboon. [¹¹C]BRD1158 also showed moderate specific binding in both rat and human tissue, and further evaluation is underway to prepare for eIND and first-in-human COX-2 imaging.

Acknowledgements

The authors would like to acknowledge support from the Stanley Center for Psychiatric Research at Broad Institute, Huntington’s Disease Society of America, and NIH-NINDS 1R01NS111168-01A1.

graphic file with name 10.1177_0271678X211061050-img324.jpg

graphic file with name 10.1177_0271678X211061050-img325.jpg

References

1.Bartels A, Leenders K. Cyclooxygenase and neuroinflammation in Parkinson’s disease neurodegeneration. Curr Neuropharmacol 2010; 8: 62–68. [DOI] [PMC free article] [PubMed] [Google Scholar]
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Author Index

A

Abe, J.

2021-18 39

2021-21 42

2021-92 119

Abrahamsson, N.

2021-24 45

Aceves-Serrano, L.G.

2020-48 250

2021-110 139

Adamo, S.

2021-163 193

Adewale, Q.

2021-122 151

Aeschbach, D.

2021-28 49

2021-30 50

Agalliu, D.

2021-77 102

Agartz, I.

2020-57 260

Aguirre-Aranda, I.

2021-33 53

Ahmed, H.

2021-22 43

Aiello, M.

2020 Abstract 199

2021-65 89

Aizenstein, H.

2020-51 253

Akeju, O.J.

2020-12 211

2020-54 256

2021-151 181

Albrecht, D.

2020-12 211

2021-115 144

2021-151 181

Alfaifi, B.Q.

2021-85 110

Aliaga, A.

2021-11 31

2021-161 190

2021-70 94

Al-Khishman, N.

2020-23 223

Allard, D.

2020-49 251

Almby, K.

2021-24 45

Alotaibi, M.

2021-82 106

Alshelh, Z.

2020-12 211

2020-54 256

2021-115 144

2021-151 181

Alstrup, A.O.

2021-124 154

2021-126 155

2021-47 67

2021-49 70

2021-51 72

Althubaity, N.S.

2021-62 86

Alves, I.L.

2021-86 111

Ameis, S.H.

2020-09 207

Ametamey, S.M.

2021-123 152

2021-22 43

Ananth, M.R.

2020-03 201

Anazodo, U.

2020-39 240

2021-105 133

2021-141 170

2021-89 115

Ances, B.

2020-37 238

Anderson, J.M.

2021-79 103

Andersson, M.

2021-140 169

Angarita, G.A.

2020-50 252

2021-39 59

2021-57 81

Antoni, G.

2020-52 254

Antonov, A.

2021-84 109

Appel, L.

2020-52 254

Appelhoff, S.

2021-91 117

Arakawa, R.

2021-81 105

Araneta, M.F.

2021-111 140

Arcego, D.M.

2021-96 123

Arias, J.F.

2020-11 210

2020-43 245

2020-58 261

2021-107 135

2021-148 177

2021-152 182

2021-160 189

Arias, J.Fernández.

2021-75 99

Asch, R.H.

2021-143 172

Ashok, A.H.

2021-113 142

2021-40 60

Ashton, N.J.

2021-112 141

2021-120 149

2021-150 180

Asselin, M.-C.

2021-82 106

Atassi, N.

2021-17 38

Audrain, H.

2021-47 67

2021-51 72

Aumont, E.

2021-55 78

Auvity, S.

2021-66 90

Avendaño-Estrada, A.

2021-33 53

Ávila-Rodríguez, M.Á.

2021-33 53

Åhs, F.

2021-25 46

B

Bærentzen, S.L.

2021-124 154

2021-126 155

2021-158 188

Babu, S.

2021-17 38

Baldo, D.

2021-155 185

Ballanger, B.

2020-21 221

Bard, J.

2021-01 21

Barkhof, F.

2021-101 129

2021-102 130

2021-27 47

2021-86 111

Barletta, V.

2021-06 26

Barnhart, T.

2020-25 225

Barret, O.

2021-10 30

2021-29 49

2021-56 79

Bars, D.L.

2020-21 221

Barth, B.

2021-96 123

Bartlett, E.A.

2020-03 201

2020-32 232

2021-02 22

Bastiani, M.A.D.

2021-147 176

Bauer, A.

2021-28 49

2021-30 50

Baumann, M.

2021-52 74

Baumeister, T.R.

2021-122 151

Baur, D.M.

2021-28 49

2021-30 50

Bdair, H.

2021-11 31

Beaver, J.D.

2020-34 234

Becker, A.

2021-59 83

Becker, G.A.

2020-33 233

2021-84 109

Bedair, H.

2020-12 211

Bedard, M.-A.

2021-55 78

Beer, S.

2021-28 49

2021-30 50

Beliveau, V.

2021-04 24

Bellaver, B.

2021-112 141

2021-147 176

Belov, V.

2021-109 138

Bendlin, B.

2020-25 225

Benedet, A.L.

2020-11 210

2020-43 245

2020-58 261

2021-107 135

2021-112 141

2021-120 149

2021-147 176

2021-148 177

2021-150 180

2021-152 182

2021-155 185

2021-156 186

2021-160 189

2021-162 192

2021-165 195

Benkelfat, C.

2020-45 247

2020-49 251

2021-11 31

Berg, E.

2020-15 215

Bernard-Gauthier, V.

2021-70 94

Berry-Kravis, E.M.

2020-13 212

2021-56 79

Bertoglio, D.

2021-01 21

Bertoldo, A.

2020 Abstract 199

2020-20 220

2021-105 133

2021-114 143

2021-38 58

2021-65 89

Best, L.M.

2021-95 122

Betthauser, T.

2020-25 225

2021-74 98

2021-91 117

Bevington, C.W.J.

2021-121 149

Beylin, D.

2020-32 232

Bezgin, G.

2021-107 135

2021-119 148

2021-120 149

2021-135 164

2021-144 173

2021-148 177

2021-150 180

2021-152 182

2021-155 185

2021-156 186

2021-160 189

2021-162 192

2021-165 195

2021-168 198

2021-55 78

2021-75 99

Bhan, A.

2021-163 193

Bieger, A.

2021-147 176

Biernaski, H.

2020-47 249

Björkstrand, J.

2021-25 46

Blüher, M.

2020-33 233

Black, S.E.

2021-144 173

2021-163 193

Blair, R.W.

2021-91 117

Bleeser, T.

2020-44 246

Bleher, D.

2021-164 194

2021-93 120

Blennow, K.

2021-112 141

2021-120 149

2021-150 180

Bloomfield, P.

2021-16 37

Bocti, C.

2021-163 193

Boctor, E.M.

2021-52 74

Boehm, M.

2021-23 44

Boellaard, R.

2021-101 129

2021-125 154

2021-27 47

Boileau, I.

2021-36 56

2021-76 101

2021-95 122

Boivin, M.

2020-45 247

2020-49 251

2021-99 127

Bonanno, F.

2021-93 120

Bonaventura, J.

2021-23 44

Bongarzone, S.

2020-10 208

Boniface, H.

2021-91 117

Bonnefoi, F.

2020-21 221

Bonoldi, I.

2020-41 243

Borg, J.

2021-140 169

Borlodoi, J.

2020-02 200

Bormans, G.

2020-14 213

2020-44 246

Borrie, M.

2021-163 193

Bowden, G.D.

2021-164 194

2021-93 120

Boyle, A.J.

2021-09 29

2021-16 37

Bradberry, C.

2021-23 44

Brasic, J.R.

2020-13 212

2021-56 79

Brendgen, M.

2021-99 127

Breuil, L.

2021-100 127

2021-66 90

2021-78 103

Brickman, A.M.

2020-40 242

2021-154 184

Brinkmalm, A.

2021-120 149

Brinson, Z.

2020-13 212

Brock, B.

2021-159 188

Brooks, A.F.

2021-11 31

Brooks, D.J.

2021-124 154

2021-126 155

Brosnan, M.K.

2021-146 176

Brouillette, K.N.

2021-95 122

Brown, T.

2021-10 30

Brugarolas, P.

2021-142 171

Brum, W.S.

2021-112 141

2021-147 176

Brusaferri, L.

2021-115 144

2021-151 181

Brust, P.

2020-33 233

2021-104 132

2021-84 109

Budimirovic, D.B.

2020-13 212

2021-56 79

Bullmore, E.T.

2020-35 236

2021-62 86

Burman, J.

2020-52 254

Buskirk, M.V.

2021-111 140

Buss, S.

2021-134 163

2021-164 194

2021-93 120

Butler, J.

2020-47 249

C

Côté, S.

2020-45 247

2020-49 251

Cai, L.

2021-37 57

Caillé, F.

2021-66 90

2021-78 103

Calabro, F.

2020-06 204

2021-157 187

Cambareri, M.

2020-32 232

Campoy, A.-D.

2021-118 146

Carbonell, F.

2021-122 151

Caribe, P.

2021-138 168

Carlin, A.R.

2021-82 106

Carroll, V.

2020-26 226

2021-10 30

Carson., R.E.

2020-04 202

Carson, R.E.

2020-15 215

2020-50 252

2021-131 160

2021-132 161

2021-133 162

2021-137 167

2021-139 169

2021-22 43

2021-35 55

2021-39 59

2021-55 78

2021-57 81

2021-91 117

Cash, D.

2020-02 200

Castellanos-Ryan, N.

2020-45 247

2020-49 251

2021-99 127

Castro-Blanco, K.A.

2021-115 144

Catana, C.

2020-06 204

2021-149 178

2021-151 181

2021-157 187

Catanese, M.C.

2021-06 26

Cawthorne, C.

2020-14 213

2020-44 246

Celen, S.

2020-14 213

2020-44 246

Cernasov, P.M.

2021-17 38

Cervenka, S.

2020-07 205

2020-28 228

2020-56 258

2020-57 260

Chamoun, M.

2021-112 141

2021-119 148

2021-120 149

2021-150 180

2021-152 182

2021-155 185

2021-156 186

2021-160 189

2021-162 192

2021-165 195

2021-75 99

Chan, J.

2021-17 38

Chan, P.

2021-29 49

Chappie, T.A.

2021-81 105

Chartrand, D.

2020-22 222

Chen, A.

2020-12 211

Chen, D.Y.-T.

2021-44 64

Chen, J.

2021-149 178

Chen, M.-K.

2020-04 202

Chen, P.

2020-46 248

Chen, R.

2021-153 183

Chen, Y.

2020-24 224

2021-82 106

Cheng, K.(Ju-Chieh).

2021-121 149

Cheong, R.

2021-128 157

Chertkow, H.

2021-163 193

Chew, S.

2021-17 38

Cho, S.S.

2021-153 183

Christian, B.

2020-25 225

2020-37 238

2021-74 98

Chu, J.

2020-54 256

Cohen, A.

2020-37 238

2020-51 253

Collij, L.E.

2021-102 130

2021-86 111

Collste, K.

2020-57 260

Comley, R.A.

2021-132 161

2021-67 92

Constantinescu, C.

2020-26 226

2021-10 30

Coomans, E.M.

2021-102 130

2021-125 154

2021-127 156

2021-27 47

Coope, D.

2021-82 106

2021-85 110

Corbetta, M.

2020 Abstract 199

2021-65 89

Cortes-Salva, M.Y.

2020-38 239

Cosgrove, K.P.

2020-07 205

2020-17 217

2020-50 252

2021-12 32

2021-57 81

2021-79 103

Costes, N.

2020-21 221

2020-29 229

Cote, S.

2021-99 127

Coughlin, J.M.

2020-28 228

2021-146 176

Cousins, O.

2021-63 87

Cox, S.

2020-45 247

2020-49 251

2021-55 78

2021-99 127

Cutforth, T.

2021-77 102

Cybulska, K.

2021-01 21

D

Díaz-Ruíz, A.

2021-33 53

d’Ambrosio, E.

2021-31 51

Dagher, A.

2020-45 247

2020-49 251

2021-54 76

2021-55 78

2021-99 127

Dahoun, T.

2021-38 58

Dailler, F.

2020-29 229

Dalenberg, J.R.

2021-91 117

Danfors, T.

2020-36 237

2020-52 254

Dannals, R.

2021-146 176

Dassanayake, P.

2021-105 133

2021-141 170

Dauba, A.

2021-100 127

Davenport, N.

2020-25 225

Davies, R.

2021-37 57

Davis, M.T.

2021-39 59

de Geus5, E.J.C.

2021-102 130

de’Picker, L.

2020-28 228

Debatisse, J.

2020-21 221

Debonee, S.

2021-39 59

DeLorenzo., C.

2020-19 219

DeLorenzo, C.

2020-03 201

2021-117 146

2021-136 165

Demjaha, A.

2021-31 51

den Braber, A.

2021-102 130

den Hollander, M.E.

2021-102 130

Deng, H.P.

2021-34 54

Deuther-Conrad, W.

2021-104 132

2021-84 109

Devanand, D.P.

2021-154 184

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2021-125 154

2021-127 156

Tinaz, S.

2021-132 161

2021-42 62

Tippler, M.

2020-45 247

2020-49 251

2021-99 127

Tissot, C.

2020-11 210

2020-43 245

2020-58 261

2021-107 135

2021-112 141

2021-119 148

2021-120 149

2021-135 164

2021-147 176

2021-148 177

2021-150 180

2021-152 182

2021-155 185

2021-156 186

2021-160 189

2021-162 192

2021-165 195

2021-75 99

Tjerkaski, J.

2020-56 258

Tolf, A.

2020-52 254

Tollefson, S.

2021-116 145

2021-61 85

Tomassen, J.

2021-102 130

Tomljanovic, Z.

2020-40 242

2021-154 184

2021-77 102

Tong, J.

2021-09 29

2021-16 37

2021-36 56

Tonietto, M.

2021-91 117

Torrado-Carvajal, A.

2020-12 211

2020-54 256

2021-151 181

Torres, K.

2020-04 202

2021-139 169

Tournier, N.

2021-100 127

2021-66 90

2021-78 103

Toussaint, M.

2021-104 132

Toussaint, P.-J.

2021-108 136

2021-48 69

Toyonaga, T.

2020-15 215

2021-133 162

2021-139 169

2021-143 172

2021-35 55

2021-73 97

Treaba, C.A.

2021-06 26

Tremblay, R.

2020-45 247

2020-49 251

2021-99 127

Tremblay, S.

2021-43 63

Tresse, C.

2020-26 226

Truillet, C.

2021-66 90

Tseng, C.-E.J.

2021-06 26

2021-115 144

2021-17 38

2021-69 93

Tsujikawa, T.

2021-20 41

Tsukada, H.

2021-67 92

Tudorascu, D.

2020-37 238

2020-51 253

Tullis, T.

2020-25 225

Tuncel, H.

2021-125 154

2021-127 156

2021-27 47

Tuominen, L.

2021-41 61

2021-43 63

2021-55 78

Tuosto, M.

2020-20 220

Turkheimer, F.E.

2020-02 200

2020-20 220

2020-35 236

2020-41 243

2021-115 144

2021-31 51

2021-38 58

2021-62 86

2021-63 87

Tyndale, R.

2021-95 122

U

Uribe, C.

2021-153 183

2021-166 196

V

Valentine, H.

2021-52 74

Vallabhajosula, S.

2020-30 230

Vallee, I.

2021-76 101

Valli, M.

2021-153 183

2021-166 196

van Berckel, B.N.M.

2021-101 129

2021-102 130

2021-125 154

2021-127 156

2021-27 47

2021-86 111

van der Flier, W.M.

2021-101 129

2021-125 154

2021-127 156

van der Landen, S.

2021-102 130

van Dyck, C.H.

2021-131 160

Van Laere, K.

2020-14 213

2020-44 246

van Leeuwenstijn, M.

2021-101 129

Van Weehaeghe, D.

2020-14 213

Vanduffel, W.

2020-44 246

2021-145 174

Vanmechelen, E.

2021-112 141

Varlow, C.

2021-07 27

Varnäs, K.

2021-140 169

Varrone, A.

2020-07 205

2021-81 105

Vartananian, O.

2021-76 101

Vasdev, N.

2021-07 27

2021-09 29

2021-16 37

2021-36 56

2021-70 94

2021-76 101

2021-95 122

Verfaillie, S.C.J.

2021-101 129

2021-125 154

2021-27 47

Vergie, I.

2021-76 101

Verhaeghe, J.

2020-22 222

2021-01 21

Vermeulen, I.

2020-44 246

Veronese, M.

2020-02 200

2020-20 220

2020-35 236

2020-41 243

2021-115 144

2021-31 51

2021-38 58

2021-60 84

2021-62 86

2021-63 87

2021-91 117

Victorsson, P.

2020-57 260

Videbech, P.

2021-47 67

Visser, D.

2021-101 129

2021-125 154

2021-127 156

Visser, P.J.

2021-102 130

Vitali, P.

2021-150 180

2021-156 186

Vitaro, F.

2020-45 247

2020-49 251

2021-99 127

Volpi, T.

2020 Abstract 199

2021-105 133

2021-114 143

2021-65 89

Vraka, C.

2021-123 152

Vyas, P.

2020-13 212

W

Wadhwa, P.

2021-83 108

Wadsak, W.

2020-05 203

2021-123 152

2021-72 96

Wagner, F.

2020-44 246

2020-59 262

Wagstyl, K.

2021-108 136

Wahlestedt, J.N.

2021-124 154

Wainstein, G.

2021-55 78

Wakabayashi, Y.

2021-81 105

Wall, M.

2021-113 142

2021-67 92

Wang, C.

2021-06 26

Wang, J.

2021-136 165

Wang, L.

2020-55 257

Wang, Y.-T.

2020-43 245

2020-58 261

2021-107 135

2021-119 148

2021-135 164

2021-148 177

2021-150 180

2021-152 182

2021-160 189

2021-75 99

Wang, Z.

2021-96 123

Ward, C.G.

2020-42 244

Warsh, J.

2021-36 56

2021-76 101

2021-95 122

Watling, S.E.

2021-36 56

2021-76 101

2021-95 122

Wayne, C.

2021-77 102

Weerasekera, A.

2021-115 144

Wegener, G.

2021-126 155

2021-158 188

2021-47 67

2021-51 72

Wegener, T.

2021-03 23

2021-13 33

2021-88 114

Wehrli, F.W.

2020-47 249

Weiwer, M.

2020-59 262

Weltings, E.

2021-102 130

2021-127 156

Wenzel, B.

2021-104 132

2021-84 109

Wey, H.-Y.

2020-55 257

2021-130 159

2021-149 178

2021-41 61

Widström, C.

2020-36 237

Wikström, J.

2021-24 45

Wilson, O.

2021-39 59

Wilton, D.K.

2020-59 262

Wimberley, C.

2021-86 111

Wimmer, N.R.Z.

2021-06 26

2021-69 93

Windhorst, A.D.

2021-101 129

2021-102 130

2021-125 154

2021-27 47

Winkeler, A.

2021-100 127

Winkler, D.

2021-123 152

Winterdahl, M.

2021-126 155

2021-47 67

2021-49 70

2021-51 72

Wolf, J.

2021-139 169

Wolters, E.E.

2021-102 130

2021-125 154

2021-127 156

2021-27 47

Wolz, R.

2021-86 111

Wong, C.Y.W.

2021-82 106

Wong, D.F.

2020-13 212

2021-52 74

2021-56 79

Wong, R.

2020-31 231

Woodcock, E.A.

2020-50 252

2021-57 81

Wu, Y.

2021-146 176

Wyffels, L.

2021-01 21

X

Xie, Z.

2020-12 211

Xin, Y.

2021-74 98

Xiong, M.

2021-90 116

Xu, Y.

2021-22 43

Y

Yamada, T.

2021-18 39

2021-21 42

2021-92 119

Yan, X.

2020-18 218

2020-40 242

2021-111 140

2021-154 184

2021-83 108

Yang, J.

2020-03 201

2021-136 165

Yaqub, M.

2021-127 156

2021-86 111

2021-91 117

Yokell, D.L.

2021-109 138

Yoo, C.-H.

2021-130 159

Young, A.J.

2020-42 244

2021-19 40

Yous, S.

2021-11 31

Yousaf, T.

2021-62 86

Yu, Z.

2020-51 253

Z

Zürcher, N.R.

2021-115 144

2021-17 38

Zaharchuk, G.

2021-44 64

Zakiniaeiz, Y.

2021-12 32

2021-73 97

Zaman, S.

2020-37 238

Zammit, M.

2020-25 225

2020-37 238

Zanderigo, F.

2020-07 205

2020-24 224

2020-30 230

2020-32 232

2021-02 22

Zandi, A.

2021-146 176

Zanotti-Fregonara, P.

2020-18 218

2020-20 220

2021-111 140

2021-83 108

Zetterberg, H.

2021-112 141

2021-120 149

2021-150 180

Zhang, A.

2021-111 140

Zhang, L.

2021-22 43

2021-81 105

Zhang, Y.

2021-151 181

Zhao, M.Y.

2021-44 64

Zheng, M.-Q.

2021-22 43

Zhou, W.

2020-55 257

Zhou, Y.

2021-42 62

Zhu, C.

2020-03 201

Zhu, Y.

2021-106 134

Zientek, F.

2020-33 233

Zilles, K.

2021-108 136

2021-122 151

Zimmer, E.R.

2020-10 208

2021-112 141

2021-147 176

Zimmermann, M.

2021-161 190

Zoghbi, S.S.

2020-18 218

2020-38 239

2021-111 140

2021-81 105

2021-83 108

Zou, J.

2020-40 242

2021-154 184

Zukotynski, K.

2021-163 193

Keyword Index

[¹¹C]-(R)-PK11195

2021-85 110

[¹¹C]carfentanil

2021-130 159

[¹¹C]-carfentanil

2021-79 103

[¹¹C]carfentanil positron emission tomography

2021-117 146

[¹¹C]Cimbi-36

2020-34 234

2021-14 170

[¹¹C]colchicine

2021-70 94

[¹¹C]CPPC

2021-146 176

[¹¹C]DTBZ

2021-153 183

[¹¹C]HD-800

2021-70 94

[¹¹C]Martinostat

2021-06 26

[¹¹C]MK-6884

2021-109 138

[¹¹C]NOP-1A

2021-116 145

[¹¹C]PBR2

2021-110 139

[¹¹C]PBR28

2020-07 205

2021-61 85

[¹¹C]-PBR28

2020-40 242

[¹¹C]PE2I

2020-36 237

[¹¹C]Raclopride

2021-34 54

[¹¹C]Ro15-4513

2021-114 143

[¹¹C]-UCB-J

2020-04 202

2021-133 162

2021-67 92

[¹¹C]UCM1014

2021-11 31

[¹¹C]UCM765

2021-11 31

[¹¹C]verubulin

2021-70 94

[¹²⁴I]IBETA

2021-87 112

[¹²⁵I]IAZA

2021-167 197

[¹²⁵I]-IPPI

2021-80 104

[¹⁵O]

2020-39 240

[¹⁵O]-oxygen

2020-47 249

[¹⁵O]water

2021-82 106

[¹⁵O]-water

2021-89 115

[¹⁸F]Bavarostat

2020-14 213

2020-44 246

[¹⁸F]-BCCP-EF

2021-67 92

[¹⁸F]EKZ-001

2020-14 213

2020-44 246

[¹⁸F]FDG brain PET

2021-138 168

[¹⁸F]FDG PET

2021-105 133

[¹⁸F]-FDG PET

2020-01 199

[¹⁸F]FDG SUVR

2021-65 89

[¹⁸F]FDOPA PET

2020-41 243

[¹⁸F]FDS PET imaging

2021-100 127

[¹⁸F]FEPPA

2021-141 170

[¹⁸F]flortaucipir

2021-125 154

[¹⁸F]Flotaza

2021-87 112

[¹⁸F]fluoroagomelatine

2021-11 31

[¹⁸F]FPEB

2021-140 169

[¹⁸F]-MK-6240

2020-40 242

[¹⁸F]NOS

2021-19 40

[¹⁸F]SynVesT-1

2021-90 116

[³H]ABP688

2021-161 190

[³H]UCB-J

2021-158 188

5

5-HT2A receptor

2021-14 170

5HT2A receptors

2021-47 67

5HT2C

2020-34 234

5XFAD

2021-58 82

A

A2A receptor

2021-104 132

acetylcholine receptors

2021-84 109

AD

2020-40 242

addiction

2020-50 252

2021-49 70

adenosine A1 receptor

2021-30 50

adenosine receptor

2021-104 132

Adenosine receptor

2021-28 49

adrenergic receptor

2020-21 221

aging

2021-119 148

2021-50 71

Aging

2021-131 160

alcohol-use disorder

2021-116 145

alpha2 adrenoceptors

2021-46 66

alpha7

2021-84 109

alpha-synuclein

2021-106 134

2021-15 184

2021-93 120

Alzheimer’s disease

2020-22 222

2020-46 248

2020-53 255

2021-07 27

2021-101 129

2021-102 130

2021-112 141

2021-118 146

2021-122 151

2021-125 154

2021-127 156

2021-135 164

2021-144 173

2021-147 176

2021-148 177

2021-150 180

2021-154 184

2021-155 185

2021-156 186

2021-159 188

2021-160 189

2021-162 192

2021-163 193

2021-167 197

2021-168 198

2021-18 39

2021-21 42

2021-27 47

2021-45 66

2021-48 69

2021-53 75

2021-58 82

2021-59 83

2021-74 98

2021-80 104

2021-86 111

2021-87 112

2021-92 119

2021-97 124

2021-98 125

amnestic MCI

2021-48 69

Amphetamine

2021-34 54

amplitude of low frequency fluctutations

2021-67 92

Amyloid

2020-11 210

2020-37 238

2021-101 129

2021-155 185

2021-156 186

2021-159 188

2021-162 192

2021-164 194

2021-166 196

2021-167 197

2021-168 198

2021-20 41

2021-32 52

2021-45 66

2021-53 75

2021-58 82

2021-86 111

2021-87 112

2021-98 125

Amyotrophic Lateral Sclerosis

2021-17 38

Anesthetics

2021-51 72

Animal model

2021-01 21

anosmia

2021-154 184

Antidepressant treatment response prediction

2020-19 219

APOE

2020-43 245

2021-148 177

arachidonic acid

2020-30 230

Arterial Spin Labeling

2020-05 203

2020-39 240

Astrocytes

2020-10 208

2021-45 66

asymmetry

2021-85 110

aterial input function

2020-52 254

atlas

2021-41 61

Atlas

2021-04 24

ATP-binding cassette

2021-66 90

Attenuation Correction

2020-55 257

autism

2021-139 169

autism spectrum disorder

2021-69 93

Autism spectrum disorder

2020-13 212

Autism spectrum disorder (ASD)

2021-56 79

Autism Spectrum Disorders

2020-09 207

autoradiography

2021-108 136

2021-140 169

2021-158 188

2021-54 76

2021-93 120

Autoradiography

2021-04 24

2021-118 146

2021-161 190

AV-133

2020-31 231

B

basal ganglia encephalitis

2021-77 102

bayes factor

2020-27 227

Bayesian

2020-29 229

2021-94 121

Bayesian modeling

2021-42 62

Behavioral Challenge

2020-06 204

2021-157 187

Behavioral psychology

2021-56 79

between-subject variance

2021-137 167

binding

2021-85 110

binding potential

2021-96 123

Binding Potential

2021-73 97

binding potential (BPND)

2021-141 170

biodistribution

2021-123 152

Biograph

2020-32 232

biomarker

2021-01 21

2021-147 176

biomarkers

2021-98 125

Biomarkers

2021-155 185

bipolar disorder

2020-02 200

2020-30 230

blood biomarker

2021-112 141

Blood Brain Barrier

2021-100 127

2021-62 86

blood-free PET quantification

2021-02 22

BMI

2021-131 160

Bolus-infusion

2021-14 170

BP quantification

2020-48 250

Braak stages

2021-135 164

Brain

2020-54 256

2021-30 50

brain activation

2020-04 202

brain development

2020-15 215

Brain imaging

2021-22 43

brain mapping

2021-103 131

Brain PET

2020-16 216

2021-129 158

2021-73 97

C

caffeine

2021-28 49

cAMP

2021-81 105

cannabis

2021-79 103

Carbon-11

2020-10 208

2021-78 103

carfentanil

2021-41 61

CBD

2021-97 124

CBF water PET

2020-52 254

Centiloids

2020-37 238

Cerebral Amyloid Angiopathy

2021-164 194

cerebral blood flow

2021-101 129

2021-125 154

2021-20 41

2021-24 45

2021-86 111

2021-89 115

cerebral cortex

2021-135 164

Cerebral cortex parcellation

2020-08 206

cerebral metabolic rate of glucose

2020-32 232

Cerebral metabolism

2020-47 249

Cerebrovascular disease

2021-44 64

cerebrovascular reactivity

2021-44 64

CerePET

2020-32 232

Chemogenetics

2021-23 44

Childhood Trauma

2021-136 165

choroid plexus

2021-63 87

Choroid Plexus

2021-62 86

chronic pain

2021-151 181

chronic traumatic encephalopathy

2021-76 101

Clearing agent

2021-32 52

click-reaction

2021-32 52

clinical assessment

2021-107 135

Clinical trials

2021-56 79

CMRGlu

2021-105 133

CMRO2

2020-47 249

cocaine

2021-158 188

cognition

2021-125 154

2021-55 78

cognitive decline

2021-147 176

2021-166 196

cognitive reserve

2021-165 195

Compartmental

2020-24 224

compartmental modeling

2020-29 229

compartmental modelling

2020-21 221

computer-aided diagnosis

2020-36 237

connectivity

2021-144 173

Connectivity

2021-53 75

constant infusion

2020-22 222

cortical thickness

2021-168 198

Covid

2021-162 192

COVID-19

2021-115 144

cox-2

2020-59 262

Crispr/Cas9

2021-128 157

cross-sectional

2020-46 248

CRP

2020-35 236

csf

2021-160 189

CSF

2021-120 149

CSF1R

2021-21 42

cyclooxygenase 1

2020-38 239

cyclooxygenase 2

2020-38 239

cyclooxygenase-1 and -2

2021-09 29

cyclooxygenase-2

2021-111 140

D

D3 receptors

2020-42 244

Data Harmonization

2021-73 97

data-driven Methods:2021-121 149

DaTscans

2021-42 62

Deep Learning

2020-41 243

Dementia

2020-39 240

2021-150 180

demyelination

2021-142 171

denoising

2021-121 149

depression

2020-35 236

Depression

2021-35 55

2021-43 63

2021-62 86

Deschloroclozapine (DCZ)

2020-18 218

designer receptor exclusively activated by designer drugs (DREADD)

2020-18 218

diprenorphine

2021-41 61

Direct-4D reconstruction

2021-137 167

disease progression

2021-122 151

Disease progression models

2021-42 62

Displacement

2021-14 35

docosahexaenoic acid

2021-61 85

Dopamine

2020-06 204

2020-42 244

2020-45 247

2021-05 25

2021-12 32

2021-145 174

2021-157 187

2021-25 46

2021-34 54

2021-49 70

2021-99 127

Dopamine D2-receptor

2020-57 260

Dopamine release

2021-121 149

2021-60 84

Dopamine synthesis

2021-60 84

2021-71 95

Dopamine transporter

2021-132 161

Dopaminergic degeneration

2021-15 36

Dopaminergic system

2021-03 23

2021-13 33

dorsal attention network

2021-152 182

dosimetry

2021-123 152

Down syndrome

2020-37 238

DREADDs

2021-23 44

drug-drug interaction

2021-66 90

DTBZ

2021-29 49

DTI

2020-57 260

2021-17 38

dynamic (DVR/BPND)

2021-127 156

Dynamic functional connectivity

2020-01 199

dynamic PET

2021-114 143

Dynamic PET

2020-35 236

dynamics

2021-55 78

E

Early Detection

2021-74 98

early life stress

2021-99 127

early stopping

2020-27 227

ebselen

2020-02 200

EC50

2021-129 158

EEG

2021-33 53

electroconvulsive stimulation

2021-47 67

electroencephalography

2020-03 201

2021-46 66

Endocannabinoid System

2021-95 122

enzyme

2020-26 226

2021-10 30

epigenetics

2021-69 93

epilepsy

2021-40 60

epilepsy.

2021-33 53

ER176

2021-77 102

executive function

2021-152 182

externalizing traits

2020-49 251

2021-99 127

extracerebral signal

2021-59 83

F

F18-CPFPX

2021-30 50

Fatty Acid Hydrolase

2021-95 122

FAZIN3

2020-53 255

FDG

2020-19 219

2021-159 188

2021-24 45

2021-43 63

FDG-PET

2021-33 53

2021-48 69

fear

2021-25 46

first-in-human

2020-14 213

2021-146 176

florbetapir

2020-22 222

fluorine-18

2021-07 27

2021-104 132

fMRI

2021-67 92

Focused Ultrasound

2021-100 127

FPEB

2020-02 200

2021-35 55

Free water

2021-163 193

frontal cortex

2021-96 123

frontotemporal dementia

2021-119 148

FTC146

2021-37 57

Fully quantitative

2020-19 219

function

2021-55 78

functional connectivity

2021-72 96

Functional connectivity

2021-128 157

functional MRI

2020-05 203

2021-20 41

functional PET

2020-05 203

2021-149 178

2021-71 95

G

GABA

2021-04 24

gender

2021-30 50

Gene editing

2021-128 157

gene expression

2021-54 76

Genes

2021-128 157

genetics

2021-102 130

Geometric Transfer Matrix

2020-29 229

Glia

2020-12 211

glial activation

2021-120 149

glial cells

2021-151 181

glioma

2021-82 106

GLT-1

2020-10 208

glucose metabolism

2020-30 230

glucose metabolism

2021-72 96

Glucose metabolism

2021-24 45

GluN2B

2021-22 43

GluN2B subunit

2021-123 152

glutamate

2020-02 200

2020-45 247

2021-52 74

2021-60 84

glycogen synthase kinase-3

2021-09 29

Graph theory

2020-01 199

gray matter volume

2021-96 123

grey matter volume

2021-60 84

H

HDAC

2021-69 93

HDAC6

2020-14 213

2020-44 246

Healthy

2021-115 144

healthy ageing

2021-90 116

healthy brain

2020-30 230

heterogeneity

2021-82 106

Hierarchical clusering

2020-08 206

Hippocampus

2021-161 190

histone deacetylases

2021-06 26

HIV

2020-54 256

HSCT

2020-52 254

HT1A receptors

2020-42 244

human

2021-10 30

2021-39 59

Human embryonic stem cells

2021-124 154

Human hippocampus

2021-118 146

Huntington’s Disease

2021-01 21

I

I-124

2021-58 82

IDIF

2021-105 133

2021-110 139

image analysis

2021-80 104

Image Analysis

2021-64 88

Image Derived Input Function

2020-29 229

image quality

2021-138 168

image-derived input function

2021-89 115

image-derived input function (IDIF)

2021-141 170

imaging biomarker

2021-112 141

Immune activation

2020-09 207

2020-28 228

Immune system

2021-155 185

independent component analysis

2021-48 69

inflammation

2020-38 239

2021-151 181

Inflammation

2020-12 211

injected radioactivity

2020-27 227

Internalization

2021-34 54

Inter-Scanner

2021-73 97

IPPI Tau

2021-118 146

irreversible

2021-10 30

irreversible kinetics

2021-02 22

isoflurane

2021-51 72

K

kainic acid

2021-33 53

kinetic modeling

2021-02 22

2021-08 28

2021-140 169

Kinetic Modeling

2020-06 204

2021-145 174

2021-157 187

kinetic modelling

2020-07 205

2020-52 254

2021-90 116

Kinetic modelling

2020-16 216

kinetic models

2020-18 218

Knee osteoarthritis

2020-12 211

L

Lassen Plot

2021-129 158

lateral ventricles

2021-63 87

Lateralization

2021-75 99

LDAEP

2020-03 201

learning and memory

2021-50 71

lesions

2021-06 26

Lewy Bodies

2021-64 88

limbic system

2020-13 212

linear-parametric neurotransmitter PET

2021-05 25

Lipopolysaccharide

2021-16 37

longitudinal

2021-133 162

longitudinal [¹⁸F]flortaucipir PET

2021-127 156

LSD1

2021-10 30

lysine-specific histone demethylase

2021-10 30

M

M4 mAChR

2021-109 138

macrophage colony stimulating factor 1 receptor

2021-146 176

MAGL

2020-26 226

Major Depressive Disorder

2020-19 219

2021-136 165

MAO-A

2021-98 125

mapping

2021-152 182

MDD

2021-81 105

MDL100907

2021-47 67

medial temporal lobe

2021-75 99

Melatonin receptors

2021-11 31

membrane transporter

2021-66 90

mental health

2021-99 127

Mesial Temporal Lobe Epilepsy

2021-161 190

metabolic connectivity mapping

2021-72 96

metabolism

2021-149 178

Metabolism

2021-136 165

Metabotropic glutamate receptor 5 (mGluR5)

2021-143 172

mGlu5

2020-49 251

mglur5

2021-35 55

mGluR5

2021-07 27

2021-161 190

mGuR5

2021-39 59

mHTT

2021-01 21

mice

2021-90 116

microdialysis

2021-52 74

microglia

2020-59 262

2021-146 176

2021-154 184

2021-18 39

2021-21 42

2021-77 102

Microparameters

2021-105 133

MicroPET imaging

2021-33 53

Microstructure

2021-163 193

Microtubules

2021-70 94

mild cognitive impairment

2021-45 66

mild traumatic brain injury

2021-76 101

Mild Traumatic Brain Injury

2021-95 122

minipigs

2021-51 72

Minipigs

2021-124 154

2021-126 155

mitochondrial dysfunction

2021-50 71

mk2640

2021-160 189

MK-6240

2021-59 83

modeling

2020-26 226

modelling

2021-38 58

Modelling

2020-24 224

2020-56 258

Molecular connectivity

2021-114 143

Molecular Imaging

2021-83 108

money

2020-27 227

Monkey

2021-23 44

Monoamine Oxidase

2021-64 88

Monoamine Oxidase A

2020-53 255

Monoamine oxidase B

2021-16 37

morphine

2020-50 252

Morphine

2021-57 81

mouse imaging

2021-09 29

MRI

2020-17 217

2020-39 240

2021-136 165

mRNA

2020-08 206

2021-04 24

2021-68 92

MRS

2021-115 144

mu opioid receptor

2021-79 103

Mu opioid receptor

2021-117 146

Multicenter collaboration

2020-28 228

Multilevel

2020-24 224

multi-modal

2021-122 151

multimodal analysis

2021-20 41

Multimodal imaging

2021-68 92

multimodal neuroimaging

2021-113 142

2021-67 92

Multiple regression modelling

2021-65 89

Multiple sclerosis

2021-06 26

multiple system atrophy

2021-93 120

multi-site PET

2021-08 28

Multi-tracer

2020-16 216

multi-tracer PET

2021-88 114

mu-opioid receptor

2021-130 159

myelin

2021-103 131

N

net influx rate

2021-02 22

Network

2021-53 75

neurobiology

2021-103 131

neurodegeneration

2021-104 132

2021-122 151

2021-147 176

2021-63 87

Neurodevelopmental disabilities

2021-56 79

neuroepigenetics

2021-06 26

neuroimaging

2021-109 138

2021-52 74

Neuroimaging

2021-74 98

2021-83 108

neuroimmune signaling

2020-50 252

Neuroimmune System

2021-57 81

Neuroinflamation

2021-17 38

neuroinflammation

2020-35 236

2020-59 262

2021-111 140

2021-144 173

2021-168 198

2021-92 119

Neuroinflammation

2020-54 256

2021-115 144

2021-148 177

2021-16 37

2021-162 192

2021-19 40

2021-62 86

neuronal plasticity-related proteins

2021-26 46

neuropathic

2021-151 181

neuropharmacology

2021-66 90

neuroplasticity

2021-72 96

neuropsychiatric disorders

2021-123 152

neuropsychology

2020-11 210

neuropsychologytau

2021-107 135

neuroreceptor template

2021-38 58

neurotransmitter release

2021-25 46

neurotransmitters

2021-108 136

Neutrophils

2021-155 185

next-generation

2021-05 25

NHP

2020-55 257

2021-109 138

Nicotine

2020-17 217

2021-50 71

Nicotine patch

2021-12 151

Nicotinic receptors

2020-17 217

Nicotinic Receptors

2020-33 233

Nifene

2021-118 146

NMDA receptor

2021-123 152

2021-22 43

N-methyl-D-aspartate

2021-52 74

nondisplaceable binding potential

2020-13 212

non-human primate

2020-31 231

nonverbal memory

2021-75 99

Norepinephrine

2021-131 160

norepinephrine transporter

2021-26 46

novel pattern analysis

2021-13 164

Novel pattern analysis

2021-03 23

NR2B/NMDA receptor

2021-37 57

NR2B-SMe

2021-37 57

Nucleus accumbens

2021-117 146

O

Obesity

2020-33 233

2021-24 45

Occupancy

2020-31 231

2021-129 158

olfaction

2021-154 184

oncology

2021-09 29

opioid

2021-49 70

2021-79 103

opioid receptor

2021-41 61

Opioid use disorder

2020-50 252

2021-57 81

optimization

2021-138 168

optogenetics

2021-134 163

oxidative stress

2021-106 134

2021-50 71

oxygenation

2021-44 64

P

Pain

2020-12 211

PAM

2021-109 138

PANDAS

2021-77 102

parametric images

2020-36 237

parametric imaging

2021-05 25

parametric mapping

2020-20 220

Parametric-MOLAR

2021-137 167

Parkinson’s disease

2020-36 237

2020-53 255

2021-13 164

2021-153 183

2021-166 196

2021-19 40

2021-29 49

2021-42 62

2021-46 66

2021-64 88

2021-88 114

2021-93 120

Parkinson’s disease

2021-03 23

2021-106 134

2021-124 154

2021-132 161

Partial volume correction

2021-08 28

Partial Volume Correction

2020-29 229

PBIF

2021-110 139

PD rodent model

2021-15 181

PDE4B

2021-81 105

perfusion

2021-44 64

2021-82 106

PET

2020-21 221

2020-51 253

2021-26 46

PET [¹⁸F]flortaucipir

2021-76 101

PET imaging

2020-02 200

2021-01 21

2021-07 27

2021-09 29

2021-124 154

2021-131 160

2021-15 151

2021-164 194

PET reporter systems

2021-83 108

PET tracer evaluation

2021-93 120

PET/CT

2021-19 10

2021-58 82

PET/CT studies

2021-87 112

PET/fMRI

2021-128 157

PET/MR

2020-05 203

2021-24 45

PET/MRI

2020-06 204

2020-47 249

2021-145 174

2021-157 187

2021-20 41

2021-34 54

2021-44 64

2021-89 115

PET-BIDS

2021-91 117

PET-fMRI

2020-33 233

PET-imaging

2021-156 186

PET-MR

2021-17 38

PET-MRI

2021-149 178

2021-69 93

PF-06445974

2021-81 105

phantom

2020-51 253

Pharmacokinetic

2020-22 222

2020-24 224

2020-56 258

2021-100 127

2021-103 131

2021-66 90

2021-94 121

Photoacoustic

2021-52 74

PiB

2020-51 253

2021-159 188

Pick’s Disease

2021-97 124

piglets

2021-84 109

polygenic score

2021-96 123

population variability

2021-38 58

portable PET device

2020-32 232

Positron emission tomography (PET)

2021-56 79

positron-emission tomography

2021-111 140

Posttraumatic stress disorder

2021-143 172

2021-95 122

Post-traumatic Stress Disorder

2021-36 56

Precision medicine

2021-31 51

Preclinical

2020-23 223

2021-126 155

preclinical alzheimer’s

2021-152 182

pre-clinical imaging

2020-15 215

2020-59 262

pre-targeting

2021-32 52

principal component analysis

2021-121 149

Progressive Supranuclear Palsy

2020-46 248

propagation

2021-135 164

propofol

2021-51 72

Pro-radiotracer

2020-10 208

Proteome

2021-68 92

Proteomics

2021-143 172

PSAMs

2021-23 44

pseudo-CT

2020-55 257

psychiatry

2021-99 127

Psychosis

2020-28 228

2021-31 51

p-tau

2021-160 189

p-Tau biomarkers

2021-112 141

PVC

2020-51 253

Q

Quality Control

2020-41 243

quantification

2021-127 156

2021-138 168

2021-86 111

quantification Methods:

2020-31 231

QuPath

2021-64 88

2021-80 104

R

2020-56 258

R1

2021-101 129

raclopride

2021-25 46

radiochemistry

2021-78 103

Radiotracer

2021-22 43

reactive oxygen species

2021-106 134

receptor desensitization

2021-130 159

receptor trafficking

2021-130 159

receptors

2021-108 136

reconstruction

2020-51 253

2021-108 136

2021-138 168

reference region

2021-140 169

refractory

2021-40 60

Rejection sensitivity

2021-117 146

relationship

2020-30 230

reliability

2020-21 221

REM Sleep Behaviour Disorder

2021-153 183

Reproducible

2020-56 258

Resting state

2021-65 59

Resting state brain networks

2020-01 199

Reward Circuitry

2021-57 81

reward processing

2021-71 95

rheumatoid arthritis

2020-38 29

RIPK1

2021-18 39

2021-92 119

Rodent models

2021-143 172

ROStrace

2021-106 134

S

scanning window

2021-29 49

schizophrenia

2021-113 142

Schizophrenia

2020-28 228

2020-57 260

sequential testning

2020-27 227

serotonin

2021-47 67

Serotonin

2020-34 234

serotonin 1A

2020-03 201

serotonin receptor

2021-96 123

serotonin transporter

2020-03 201

Sex difference

2020-43 245

sigma receptor

2021-37 57

signal classification

2021-05 25

signal standardization

2021-114 143

Simulations

2021-129 158

simultaneous estimation

2020-07 205

simultaneous estimation (SIME)

2021-141 170

Simultaneous Estimation (SimE) of the arterial input function

2020-19 219

simultaneous fPET/fMRI

2021-134 163

Simultaneous PET/fMRI

2020-01 199

2021-65 89

Simultaneous PET/MR

2020-55 257

sleep

2021-149 178

small vessel disease

2021-163 193

social isolation

2021-26 46

source-to-target modeling

2021-02 22

spatial patterns

2021-88 114

spatio-temporal patterns

2021-13 164

Spatio-temporal patterns

2021-03 23

spectral analysis

2021-59 83

Spectral Analysis

2020-20 220

SPMS

2020-52 254

static (SUVr)

2021-127 156

statistics

2021-94 121

Stimulation Study

2020-33 233

Stress-enhanced fear learning (SEFL)

2021-143 172

striatum

2021-12 151

structure

2021-55 78

Subcortical Stroke

2020-23 223

subjective cognitive decline

2021-101 129

substance use disorders

2020-45 247

2020-49 251

sucrose

2021-49 70

Sucrose-consumption

2021-126 155

suicide

2021-39 59

sulfonylurea receptor 1

2021-78 103

support vector machine

2021-160 189

SUVR bias

2021-86 111

sv2a

2020-25 225

2021-35 55

SV2A

2021-126 155

2021-133 162

2021-137 167

2021-158 188

synapses

2020-25 225

Synaptic activity

2021-27 47

synaptic density

2020-04 202

2020-15 215

2021-119 148

2021-132 161

2021-133 162

2021-139 169

2021-158 188

2021-27 47

synaptic dysfunction

2021-120 149

T

target engagement

2020-13 212

target occupancy

2020-44 246

Tau

2020-11 210

2020-40 242

2020-43 245

2020-46 248

2020-58 261

2021-102 130

2021-107 135

2021-120 149

2021-125 154

2021-135 164

2021-144 173

2021-148 177

2021-150 180

2021-152 182

2021-156 186

2021-162 192

2021-167 197

2021-168 198

2021-27 47

2021-53 75

2021-76 101

2021-80 104

2021-98 125

Tau PET

2021-59 83

2021-75 99

Tau proteins

2021-154 184

Tauopathies

2021-97 124

Tauopathy

2021-74 98

test-retest

2020-46 248

2021-133 162

Test-Retest

2021-73 97

Test-retest reliability

2020-05 203

thalamic segmentation

2020-17 217

Thalamus

2020-57 260

THC

2020-49 251

2021-79 103

TMS

2021-43 63

tobacco smoking

2021-12 151

Tracer Development

2021-164 194

Transcriptome

2021-68 92

translocator protein

2020-07 205

trauma

2021-39 59

traumatic brain injury

2021-142 171

2021-63 87

Treatment response

2021-31 51

TSPO

2020-09 207

2020-20 220

2020-23 223

2020-28 228

2020-35 236

2020-48 250

2020-50 252

2021-16 193

2021-36 56

2021-57 81

2021-61 85

2021-85 110

twins

2021-102 130

two-tissue compartment modelling

2021-141 170

U

ucb-j

2020-25 225

UCB-J

2021-126 155

2021-139 169

2021-35 55

Upper Motor Neuron

2021-17 38

UPSIT

2020-40 242

V

vagus nerve stimulation

2021-84 109

Validation

2020-56 258

Variational Bayesian

2021-105 133

vascular risk factor

2021-147 176

vasculature

2021-103 131

vbm

2020-11 210

VBM

2021-60 84

Verbal Fluency

2021-156 186

verbal memory

2021-107 135

visual memory

2020-11 210

2021-107 135

VMAT2

2020-31 231

2021-153 183

voxel-based analysis

2021-48 69

voxelwise analysis

2021-121 149

vulnerability

2020-45 247

W

white matter

2021-163 193

White Matter Inflammation

2020-23 223

within-scan challenges

2021-14 170

within-subject scanning

2020-32 232

within-subject variance

2021-137 167

Y

yohimbine

2020-21 221

2021-46 66

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PERMALINK

NRM 2021 Abstract Booklet

Contents

2021-01

In vivo PET imaging of mutant huntingtin using [11C]CHDI-180R as candidate marker in a mouse model of Huntington’s Disease (#4)

Abstract

2021-02

Data-driven, blood-free quantification of positron emission tomography radiotracers with irreversible kinetics using the publicly-available Source-to-Target Automatic Rotating Estimation (STARE): Validation with [18F]FDG data and simulations (#10)

Abstract

2021-03

Novel data-driven method captures spatio-temporal patterns of neurodegeneration in Parkinson’s disease (#12)

Abstract

References

2021-04

A high-resolution in vivo atlas of the human brain’s benzodiazepine binding site of GABAA receptors (#13)

Abstract

References

2021-05

An algorithm for classifying neurotransmitter signals from future ultra-high sensitivity dynamic PET (#22)

Abstract

References

2021-06

In vivo neuroimaging of histone deacetylases in multiple sclerosis using [11C]Martinostat (#24)

Abstract

References

2021-07

Optimized synthesis of [18F]FPEB and preliminary neuroimaging of mGlur5 in transgenic mouse models (#25)

Abstract

2021-08

Estimating PET partial volume full-width-half-maximum directly from human data (#30)

Abstract

References

2021-09

Repurposing novel PET neuroimaging radioligands in xenograft mouse models of cancer (#32)

Abstract

References

2021-10

[18F]MNI-1054, a novel PET ligand for lysine-specific histone demethylase 1A (LSD1): First-in-human validation including radiation dosimetry, kinetic modeling and test-retest variability (#39)

Abstract

2021-11

Towards the development of PET tracers for the imaging of melatonin receptors (#43)

Abstract

References

2021-12

Nicotine patch reduces striatal smoking-induced dopamine release compared to placebo patch (#46)

Abstract

References

2021-13

Distinct spatio-temporal patterns of putuminal dopamine processing in Parkinson’s disease: A multi-tracer positron emission tomography study (#47)

Abstract

References

2021-14

Ketanserin can block but not displace [11C]Cimbi-36 binding in the pig brain (#68)

Abstract

References

2021-15

Alpha-synuclein preformed fibril (PFF)-triggered synucleinopathy recapitulates neurochemical features of human PD: a PET study in rats (#71)

Abstract

References

2021-16

Evaluation of MAO-B and TSPO PET radiotracers in a lipopolysaccharide rat model of neuroinflammation (#72)

Abstract

Reference

2021-17

Clinical measures of upper motor neuron burden strongly associate with neuroimaging in amyotrophic lateral sclerosis (#73)

Abstract

References

2021-18

Development of novel PET ligands to image the receptor interacting protein kinase 1 (#77)

Abstract

Reference

2021-19

[18F]NOS PET measurement of in vivo neuroinflammation in Parkinson’s disease and healthy humans (#93)

Abstract

References

2021-20

Functional changes in Alzheimer’s disease evaluated by multimodality PET/MRI imaging (#96)

Abstract

References

2021-21

In vivo PET imaging of mutant huntingtin using [¹¹C]CHDI-180R as candidate marker in a mouse model of Huntington’s Disease (#4)

Data-driven, blood-free quantification of positron emission tomography radiotracers with irreversible kinetics using the publicly-available Source-to-Target Automatic Rotating Estimation (STARE): Validation with [¹⁸F]FDG data and simulations (#10)

A high-resolution in vivo atlas of the human brain’s benzodiazepine binding site of GABA_A receptors (#13)

In vivo neuroimaging of histone deacetylases in multiple sclerosis using [¹¹C]Martinostat (#24)

Optimized synthesis of [¹⁸F]FPEB and preliminary neuroimaging of mGlur5 in transgenic mouse models (#25)

[¹⁸F]MNI-1054, a novel PET ligand for lysine-specific histone demethylase 1A (LSD1): First-in-human validation including radiation dosimetry, kinetic modeling and test-retest variability (#39)

Ketanserin can block but not displace [¹¹C]Cimbi-36 binding in the pig brain (#68)

[¹⁸F]NOS PET measurement of in vivo neuroinflammation in Parkinson’s disease and healthy humans (#93)

PET imaging of [¹¹C]NCGG401 for colony stimulating factor 1 receptor (#111)

Development of ¹⁸F-labeled radioligands for the GluN2B subunits of NMDA receptors: Synthesis and evaluation in non-human primates (#123)

Increased cerebral glucose consumption during hypoglycemia in obese patients measured using dynamic bolus-injection ¹⁸F-FDG PET/MR during hyperinsulinemic euglycemic and hypoglycemic clamp (#138)

Dopamine release after fear conditioning as measured using bolus-infusion¹¹C-raclopride PET-MRI (#139)

Tau pathology is associated with synaptic loss and altered synaptic function: a combined [¹⁸F]flortaucipir, [¹¹C]UCB-J and magnetoencephalography study (#145)

Effect of 5-day regular coffee consumption and subsequent abstention on A₁ adenosine receptor occupancy and availability (#156)

Sex-related differences in cerebral A₁ adenosine receptor availability in the human brain (#160)

Measure of metabolic and electric rat brain changes induced by kainic acid, an EEG and ¹⁸FDG-PET studio (#184)

In vivo evidence for disrupted association between synaptic and glutamatergic markers in depression – A combined [¹¹C]UCB-J and [¹⁸F]FPEB study (#188)

Translocator protein in occupational post-traumatic stress disorder: Preliminary findings using the [¹⁸F]FEPPA PET radioligand (#189)

The PET radioligands ([¹¹C]NR2B-X; X = Me, R or S; X = SMe, S) are selective for binding to the NR2B subunit of NMDA over the s1 receptor in rat in vivo (#191)