In Vivo N-Methyl-d-Aspartate Receptor (NMDAR) Density as Assessed Using Positron Emission Tomography During Recovery From NMDAR-Antibody Encephalitis

Marian Galovic; Adam Al-Diwani; Umesh Vivekananda; Matthew C Walker; Sarosh R Irani; Matthias J Koepp

doi:10.1001/jamaneurol.2022.4352

. 2022 Dec 5;80(2):211–213. doi: 10.1001/jamaneurol.2022.4352

In Vivo N-Methyl-d-Aspartate Receptor (NMDAR) Density as Assessed Using Positron Emission Tomography During Recovery From NMDAR-Antibody Encephalitis

Marian Galovic ¹, Adam Al-Diwani ², Umesh Vivekananda ³, Matthew C Walker ³, Sarosh R Irani ², Matthias J Koepp ^3,^✉, for the NEST Investigators

¹Department of Neurology, Clinical Neuroscience Center, University Hospital Zurich, Zurich, Switzerland

²Oxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom

³Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom

Accepted for Publication: September 9, 2022.

Published Online: December 5, 2022. doi:10.1001/jamaneurol.2022.4352

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Corresponding Author: Matthias J. Koepp, MD, PhD, Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, 33 Queen Sq, London WC1N 3BG, United Kingdom (m.koepp@ucl.ac.uk).

Author Contributions: Prof Koepp had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Galovic, Al-Diwani, Irani, Koepp.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Galovic, Al-Diwani, Irani, Koepp.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Galovic.

Obtained funding: Irani, Koepp.

Administrative, technical, or material support: Al-Diwani, Vivekananda, Koepp.

Supervision: Irani, Koepp.

Conflict of Interest Disclosures: Dr Galovic reported receiving personal fees from Advisis, Arvelle, Bial, Eisai, Nestlé Health Science, and UCB outside the submitted work. Dr Irani reported receiving personal fees from UCB and Immunovant and grants from UCB, ONO Pharma, CSL Behring, and Janssen Pharmaceuticals outside the submitted work. Dr Irani also reports a patent for PCT/GB2009/051441 with royalties paid from Ei AG, a PCT/G82019/051257 licensed patent application, and a patent for diagnostic testing of immunoglobulins pending. Prof Koepp reported receiving nonfinancial support from GE Healthcare for the tracer ([¹⁸F]GE-179) used during the conduct of the study. No other disclosures were reported.

Funding/Support: This work was funded by Training and Novel Probes Programme in PET Neurochemistry grant MR/K02308X/1 from the Medical Research Council (MRC) PET Neuroscience Programme and by grant MR/L013215/1 from the MRC Developmental Pathway Funding Scheme (Dr Galovic). This work was undertaken in part at University College London (UCL)/UCL Hospital, which receives support from the National Institute for Health Research (NIHR) UCL Hospitals Biomedical Research Centre. This study was also supported by clinical research training fellowship 205126/Z/16/Z (Dr Al-Diwani) and fellowship 104079/Z/14/Z (Dr Irani) from the Wellcome Trust, a 2017 Margaret Temple grant (Drs Al-Diwani and Irani) and 2013 Vera Down grant (Dr Irani) from the British Medical Association, NIHR Oxford and NIHR Oxford Health Biomedical Research Centres (Drs Al-Diwani and Irani), senior clinical fellowship MR/V007173/1 from MRC (Dr Irani), grant P1201 from Epilepsy Research UK (Dr Irani), and a Multiple Sclerosis Society research award from the Fulbright UK-US Commission (Dr Irani).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

NEST Investigators: Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK: Prof Franklin I. Aigbirhio, DPhil; Roberto Canales, PhD; Martin Fisher, PhD; Tim D. Fryer, BSc, MSc, PhD; Abigail Hancock-Scott; Young T. Hong, PhD; Joseph J. Russell, PhD; Selena Sephton, PhD; Lindsay McMurray, MSc, PhD. Department of Statistical Science, University College London, London, UK: Gareth Ambler, PhD; Centre for Radiopharmaceutical Chemistry, University College London, London, UK: Prof Erik Årstad, PhD; Thibault Gendron, PhD; Kerstin Sander, PhD. Institute of Nuclear Medicine, University College London Hospitals, London, UK: Anna Barnes, PhD; John C. Dickson, PhD; Kjell Erlandsson, BSc, PhD; Prof Ashley Groves, MD; Brian Hutton, PhD; Sarah McQuaid, PhD; Alaleh Rashidnasab, PhD; Hasan Sari, PhD; Prof Kris Thielemans, PhD; Benjamin A. Thomas, PhD. Department of Computer Science, University of Verona, Verona, Italy: Ilaria Boscolo Galazzo, PhD. Division of Anaesthesia, Department of Medicine, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK: Sarah Chetcuti, FFICM, FRCA; Jonathan P. Coles, PhD. Department of Medical Physics and Bioengineering, University College London, London, UK: Bianca De Blasi, PhD; Francisco Torrealdea, PhD. Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK: John S. Duncan, FRCP; Daichi Sone, MD, PhD. Translational Research Office, University College London, London, UK: Simon Eaglestone, PhD. Physiological Neuroimaging Group, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom: Evan Edmond, MA, BMBCh, MRCP; Charlotte J. Stagg, MRCP, DPhil. King’s College London and Guy’s and St Thomas’ PET Centre, Division of Imaging Sciences & Biomedical Engineering, King’s College London, London, UK: Alexander Hammers, MD, PhD; Colm J. McGinnity, MD, PhD. Department of Neurology, Clinical Neuroscience Center, University Hospital Zurich, Zurich, Switzerland: Ilijas Jelcic, MD. Department of Radiology, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK: Roido Manavaki, PhD.

Disclaimer: The views expressed are those of the authors and not necessarily those of the National Health Service, NIHR, or Department of Health and Social Care.

Additional Contributions: The authors thank the staff at GE Healthcare, in particular William Trigg, PhD, Sajinder Kaur Luthra, PhD, and Jo Stevens, MSc, for their help and support during this study. They were not compensated for their contributions beyond their established salaries.

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Corresponding author.

PMCID: PMC9857588 PMID: 36469313

Abstract

This case-control study uses a radiotracer and positron emission tomography to assess N-methyl-d-aspartate receptor (NMDAR) density changes during recovery from NMDAR-antibody encephalitis.

N-methyl-d-aspartate receptor (NMDAR) autoantibodies are a common cause of autoimmune encephalitis.¹ In vitro and animal studies indicated that NMDAR internalization is a major mechanism underlying NMDAR-antibody encephalitis,² but direct support in humans is limited to a reduction of NMDAR staining in postmortem hippocampi.^2,3

Methods

In this case-control study, we performed cross-sectional resting-state positron emission tomography (PET) of NMDARs in vivo using radioligand [¹⁸F]GE-179, which binds within the ion channel of open, activated NMDARs. We included 5 patients recovering from definite NMDAR-antibody encephalitis¹ (eTable in the Supplement) and 29 healthy volunteers (HVs) who took no medications that interfere with NMDARs and underwent PET–magnetic resonance scanning. Four patients with NMDAR-antibody encephalitis had persistent GluN1 autoantibodies in serum and mild symptoms, were scanned 2 to 8 months after discharge, and were classified as persistently seropositive. One patient had undetectable serum GluN1 antibodies, was scanned 16 months after discharge, and was classified as seroreverted. The study was reviewed and approved by the local ethical committees, and all participants gave written informed consent. The study followed the STROBE reporting guideline.

From preprocessed data,⁴ we used [¹⁸F]GE-179 total volume of distribution (V_T) to quantify open, activated NMDAR density. We assessed gray matter atrophy using magnetic resonance voxel-based morphometry and compared regional and voxelwise data using a general linear model adjusting for age, sex, and site. A cluster-level voxelwise P < .05 corrected for multiple comparisons (p_FWE) was considered significant. SPM, version 12 (UCL Queen Square Institute of Neurology) and SPSS, version 27 (IBM) were used for statistical analyses.

Results

The sample comprised 4 seropositive cases (all women; mean [SD] age, 28 [6] years), 1 seroreverted case (female aged 25-30 years), and 29 HVs (21 [72%] men; 8 [28%] women; mean [SD] age, 41 [13] years). Seropositive cases 1 to 4 had lower gray matter V_T (estimated marginal mean, 6.2; 95% CI, 4.4-8.0) compared with HVs (mean, 8.8; 95% CI, 8.1-9.4; F = 6.5; P = .02) and the seroreverted case 5 (9.7) (Figure). Voxel-based analysis showed reduced V_T in seropositive cases within bilateral anterior temporal lobes (left: t = 4.5, p_FWE = 0.02; right: t = 4.9, p_FWE = 0.05) and a large cluster involving bilateral superior parietal lobes, paracentral lobules, left posterior cingulate gyrus, and left precuneus (t = 5.8; p_FWE < .001). Volume-of-interest analyses corroborated regional V_T reductions in seropositive temporal (34% reduction; F = 8.3; P = .008) and parietal (31% reduction; F = 7.3; P = .01) lobes and mesial temporal region (40% reduction; F = 8.9; P = .006).

Figure. — The figure shows the spatial distributions of [¹⁸F]GE-179 total volume of distribution (V_T) on brain slices and surface projections.

Gray matter V_T was not associated with higher serum GluN1 antibody levels, shorter time since discharge and episode onset, cognition at the time of scanning, or symptom severity at discharge. Areas of decreased gray matter volume in cerebellar hemispheres and regions with significantly reduced V_T did not overlap.

Discussion

We found a mean 30% regional reduction in the density of open, active NMDARs, most prominently in anterior temporal and superior parietal cortices, in patients with persisting serum GluN1 autoantibodies recovering from NMDAR-antibody encephalitis. Patients had mild cognitive symptoms, indicating the considerable compensatory capacity of the brain. In contrast, a recovered, seroreverted patient had slightly elevated NMDAR density, indicating a rebound of NMDAR function.

NMDAR hypofunction has been observed in patients with depression⁵ or first-episode psychosis.⁶ Our results are not explained by brain atrophy or perfusion.⁴ The potential of [¹⁸F]GE-179 PET as a biomarker for NMDAR-antibody encephalitis severity and recovery should be further evaluated.

Limitations include the small sample size; different age and sex distributions among participants; and lack of intrathecal GluN1 autoantibody titers on scanning day, detailed cognitive testing, and a comparison group with other inflammatory or encephalopathic central nervous system diseases. Findings may be more prominent during the acute phase vs recovery, but logistical barriers exist to scanning patients with severe disease. Our study supports the hypothesis of NMDAR internalization and indicates involvement of large cortical areas beyond the limbic system.

Supplement.

eTable. Characteristics of Patients With N-Methyl-d-Aspartate Receptor-Antibody Encephalitis

Click here for additional data file.^{(131.7KB, pdf)}

References

1.Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016;15(4):391-404. doi: 10.1016/S1474-4422(15)00401-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
2.Hughes EG, Peng X, Gleichman AJ, et al. Cellular and synaptic mechanisms of anti-NMDA receptor encephalitis. J Neurosci. 2010;30(17):5866-5875. doi: 10.1523/JNEUROSCI.0167-10.2010 [DOI] [PMC free article] [PubMed] [Google Scholar]
3.Zrzavy T, Endmayr V, Bauer J, et al. Neuropathological variability within a spectrum of NMDAR-encephalitis. Ann Neurol. 2021;90(5):725-737. doi: 10.1002/ana.26223 [DOI] [PubMed] [Google Scholar]
4.Galovic M, Erlandsson K, Fryer TD, et al. ; NEST investigators . Validation of a combined image derived input function and venous sampling approach for the quantification of [¹⁸F]GE-179 PET binding in the brain. Neuroimage. 2021;237:118194. doi: 10.1016/j.neuroimage.2021.118194 [DOI] [PubMed] [Google Scholar]
5.McGinnity CJ, Koepp MJ, Hammers A, et al. NMDA receptor binding in focal epilepsies. J Neurol Neurosurg Psychiatry. 2015;86(10):1150-1157. doi: 10.1136/jnnp-2014-309897 [DOI] [PMC free article] [PubMed] [Google Scholar]
6.Beck K, Arumuham A, Veronese M, et al. N-methyl-D-aspartate receptor availability in first-episode psychosis: a PET-MR brain imaging study. Transl Psychiatry. 2021;11(1):425. doi: 10.1038/s41398-021-01540-2 [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement.

eTable. Characteristics of Patients With N-Methyl-d-Aspartate Receptor-Antibody Encephalitis

Click here for additional data file.^{(131.7KB, pdf)}

[nld220006r1] 1.Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016;15(4):391-404. doi: 10.1016/S1474-4422(15)00401-9 [DOI] [PMC free article] [PubMed] [Google Scholar]

[nld220006r2] 2.Hughes EG, Peng X, Gleichman AJ, et al. Cellular and synaptic mechanisms of anti-NMDA receptor encephalitis. J Neurosci. 2010;30(17):5866-5875. doi: 10.1523/JNEUROSCI.0167-10.2010 [DOI] [PMC free article] [PubMed] [Google Scholar]

[nld220006r3] 3.Zrzavy T, Endmayr V, Bauer J, et al. Neuropathological variability within a spectrum of NMDAR-encephalitis. Ann Neurol. 2021;90(5):725-737. doi: 10.1002/ana.26223 [DOI] [PubMed] [Google Scholar]

[nld220006r4] 4.Galovic M, Erlandsson K, Fryer TD, et al. ; NEST investigators . Validation of a combined image derived input function and venous sampling approach for the quantification of [¹⁸F]GE-179 PET binding in the brain. Neuroimage. 2021;237:118194. doi: 10.1016/j.neuroimage.2021.118194 [DOI] [PubMed] [Google Scholar]

[nld220006r5] 5.McGinnity CJ, Koepp MJ, Hammers A, et al. NMDA receptor binding in focal epilepsies. J Neurol Neurosurg Psychiatry. 2015;86(10):1150-1157. doi: 10.1136/jnnp-2014-309897 [DOI] [PMC free article] [PubMed] [Google Scholar]

[nld220006r6] 6.Beck K, Arumuham A, Veronese M, et al. N-methyl-D-aspartate receptor availability in first-episode psychosis: a PET-MR brain imaging study. Transl Psychiatry. 2021;11(1):425. doi: 10.1038/s41398-021-01540-2 [DOI] [PMC free article] [PubMed] [Google Scholar]

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In Vivo N-Methyl-d-Aspartate Receptor (NMDAR) Density as Assessed Using Positron Emission Tomography During Recovery From NMDAR-Antibody Encephalitis

Marian Galovic, MD, PhD

Adam Al-Diwani, BMBCh, DPhil

Umesh Vivekananda, MD, PhD

Matthew C Walker, PhD

Sarosh R Irani, MD, DPhil

Matthias J Koepp, MD, PhD

Abstract

Methods

Results

Figure. Radioligand [¹⁸F]GE-179 Uptake in Autoantibody Seropositive or Seroreverted Patients With N-Methyl-d-Aspartate Receptor (NMDAR)-Antibody Encephalitis and Healthy Volunteers (HVs).

Discussion

References

Associated Data

Supplementary Materials

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PERMALINK

In Vivo N-Methyl-d-Aspartate Receptor (NMDAR) Density as Assessed Using Positron Emission Tomography During Recovery From NMDAR-Antibody Encephalitis

Marian Galovic, MD, PhD

Adam Al-Diwani, BMBCh, DPhil

Umesh Vivekananda, MD, PhD

Matthew C Walker, PhD

Sarosh R Irani, MD, DPhil

Matthias J Koepp, MD, PhD

Abstract

Methods

Results

Figure. Radioligand [18F]GE-179 Uptake in Autoantibody Seropositive or Seroreverted Patients With N-Methyl-d-Aspartate Receptor (NMDAR)-Antibody Encephalitis and Healthy Volunteers (HVs).

Discussion

References

Associated Data

Supplementary Materials

ACTIONS

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RESOURCES

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Figure. Radioligand [¹⁸F]GE-179 Uptake in Autoantibody Seropositive or Seroreverted Patients With N-Methyl-d-Aspartate Receptor (NMDAR)-Antibody Encephalitis and Healthy Volunteers (HVs).