Abstract
Introduction:
Progressive supranuclear palsy (PSP) is an atypical parkinsonism caused by the intracerebral aggregation of the microtubule-associated protein tau (MAPT) which is encoded by MAPT gene. Although PSP is a sporadic disease, MAPT mutations have been reported in rare cases.
Methods:
Among 190 patients with PSP who were recruited by the Neurodegenerative Research Group at Mayo Clinic during 2009–2023, we identified two patients who fulfilled diagnostic criteria for PSP-Richardson’s syndrome (PSP-RS) and harbor novel MAPT mutations. To better investigate the potential effects of these mutations, we compared the clinical, and neuroimaging characteristics of these two patients to 20 randomly selected patients with PSP-RS without a MAPT mutation.
Results:
MAPT c.1024G>A, p.Glu342Lys, and MAPT c.1217 G>A, p.Arg406Gln mutations were found in 2 men who developed PSP-RS with atypical features at the ages of 60 and 62 years, respectively. Glu342Lys mutation was associated with features resembling alpha-synucleinopathies (autonomic dysfunction, dream enactment behavior), while both mutations were associated with features suggestive of Alzheimer’s disease with poorer performance on tests of episodic memory. Comparison of 18F-flortaucipir uptake between the two MAPT mutation cases with 20 patients without a mutation revealed increased signal on flortaucipir-PET in bilateral medial temporal lobe regions (amygdala, entorhinal cortices, hippocampus, parahippocampus) but not in PSP-related regions (globus pallidum, midbrain, superior frontal cortex and dentate nucleus of the cerebellum).
Conclusion:
Glu342Lys and Arg406Gln mutations appear to modify the PSP-RS phenotype by targeting the medial temporal lobe regions resulting in more memory loss and greater flortaucipir uptake.
Introduction
Progressive supranuclear palsy (PSP) is a rare, atypical parkinsonism in which patients present with ocular motor dysfunction, postural instability, akinesia, and cognitive dysfunction [1]. PSP is a sporadic disease and belongs to a group of neurodegenerative diseases known as tauopathies that are caused by the intracerebral aggregation of the microtubule-associated protein tau (MAPT), encoded by MAPT gene. MAPT mutations have been identified in some patients with tauopathies, including patients with PSP [2]. Patients with PSP due to a MAPT mutation usually have earlier age of onset, family history of early dementia, and deviation from the most common neuroimaging and clinical features of PSP [3]. Nevertheless, the exact effect of these mutations on disease phenotype remains to be elucidated.
Herein, we report two patients with PSP-Richardson’s syndrome (PSP-RS) who were discovered to harbor novel MAPT mutations, not previously reported. We compare their clinical and neuroimaging characteristics with a group of patients with PSP-RS without a MAPT mutation to further investigate potential effects of these mutations on their disease presentation.
Materials and Methods
The Neurodegenerative Research Group (NRG) at Mayo Clinic in Rochester prospectively recruited patients with a clinical diagnosis of possible or probable PSP between 2009 and 2023 based on the most widely used criteria at the time [1]. Board-certified neurologists performed complete neurological examinations on patients and recorded their clinical characteristics. All patients underwent neuroimaging evaluations using 3.0 T brain magnetic resonance imaging (MRI), and the majority completed Positron Emission Tomography (PET) scans with 11C-Pittsburgh compound B (PiB), 18F-flortaucipir, and 18F-fluorodeoxyglucose (FDG). All patients underwent genetic screening for MAPT mutations. The Movement Disorders Society-Sponsored Revision of the Unified Parkinson’s Disease Rating Scale (UPDRS) parts I, II, and III were used to assess various aspects of parkinsonism [4]. Global disease severity was measured using the PSP-rating scale, along with its gait/midlines subscale (G/M), which specifically evaluates gait and posture impairment [5]. The PSP Saccadic Impairment Scale (PSIS) was used to assess ocular motor abnormalities [6]. To assess general cognitive function, the Montreal Cognitive Assessment (MoCA) was utilized [7]. The Frontal Assessment Battery (FAB) was used to evaluate frontal executive function and episodic memory was assessed using the Camden Memory Test – Short Recognition Memory Test for Faces and Words (Camden-F and Camden-W, respectively). Cognitive and behavioral control was evaluated using the Cambridge Behavioral Inventory (CBI), and visual confrontation naming was assessed using the Boston Naming Test (BNT) [8]. The study was approved by the Mayo Clinic Institutional Review Board, and informed consent was obtained from all patients.
Among the 190 patients in our clinical cohort of PSP, genetic screening identified two patients who had a mutation in the MAPT gene. Both patients met criteria for the PSP-RS clinical variant [1]. We compared the clinical and neuroimaging characteristics of these two patients with 20 patients with PSP-RS without MAPT mutation. We randomly selected these 20 patients, using random generated numbers, from our pool of PSP-RS patients who had an age of onset within ±5 years from the mean age of onset of the two mutant cases.
Demographics, age of onset, and duration from disease onset to first neurological evaluation by the NRG were recorded. Apolipoprotein epsilon E genotype, and the results of neuropsychological evaluations were collected. Positive family history was defined as any neurological condition in the patient’s first-degree relatives. Patterns of hypometabolism on FDG-PET were analyzed using 3D stereotactic surface projections using CortexID suite (GE Healthcare https://www.gehealthcare.co.uk/-/media/13c81ada33df479ebb5e45f450f13c1b.pdf) whereby activity at each voxel was normalized to the pons and Z-scored to an age-segmented normative database [9]. We measured regional flortaucipir uptake in medial temporal lobe regions including amygdala, entorhinal cortex, hippocampus and parahippocampal gyrus, and in PSP-related regions including globus pallidum, midbrain, motor cortex and cerebellar dentate gyrus [10]. Regional uptake values were divided by the uptake in the cerebellar crus grey matter to determine standard uptake value ratios (SUVRs).
We reported findings using median (first and third quartiles), and frequency (percent), where appropriate. All values and statistical summaries were generated using Excel version 2305.
Results
Characteristics of Case 1
A 62-year-old man presented for a second opinion regarding his diagnosis of PSP. His symptoms began two years prior with tachyphemic speech, which was unintelligible for others. He also experienced gait difficulty with dragging of his left foot, fast micrographia, sleep difficulty, impulsivity, very anxious mood, and difficulty with concentration, followed by falls occurring once a week. At the time of first visit, he had worsening of all mentioned symptoms, with the addition of new onset severe constipation, urinary incontinence, REM behavior disorder (RBD), significant neck stiffness, and absent-minimal medication effect (Levodopa Equivalent Daily Dose (LEDD mg) = 1300). On neurological examination, he had unsteady gait with a tendency to fall and drag his left foot, slowing of vertical saccades, moderate bradykinesia (left> right), axial rigidity, and marked neck stiffness without dystonia. He had moderate hypokinetic hypophonetic dysarthria and mild echolalia. His cognition was affected, and he scored 18 (out of 30) on the MoCA. Brain MRI showed severe mid-brain atrophy and hippocampal occupancy below normal limits for age (Supplementary Figure). FDG-PET scan showed hypometabolism in the midbrain, and patchy hypometabolism within the caudate, putamen and thalami (Supplementary Figure). Amyloid PET scan was negative. An autonomic reflex screen was performed which revealed only mild cardiovagal impairment. On follow up 1-year later, he had severe axial rigidity, and his attention, memory and balance had deteriorated. He reported no beneficial effect from the medications (LEDD=1700 mg). His urinary incontinence had resolved, and RBD had evolved from movements to talking.
Regarding his past medical history, he had bilateral total knee replacement 2–3 years before the onset of his parkinsonism symptoms. The left knee replacement was complicated by infection, requiring multiple revision surgeries, and was followed by pain and stiffness which may have partially contributed to his left foot dragging. Regarding his family history, his father was diagnosed with Alzheimer’s dementia and had slight tremors, falls and trouble swallowing. Genetic evaluations revealed mutation of MAPT c.1024G>A, p.Glu342Lys (E342K) in exon 12.
Characteristics of Case 2
A 66-year-old man presented to for enrolment in a study on PSP. His symptoms started at age 62 with dysphagia, followed by shuffling gait, imbalance without falls, difficulty arising from a seated position, soft speech, micrographia, pseudobulbar affect, and coughing and chocking episodes with ingestion. At the time of neurological evaluation, he had vertical supranuclear gaze palsy, and axial >appendicular rigidity. Right side-predominant postural tremor, and moderate bradykinesia were noted. He reported a partial response to medication (LEDD=900 mg). Brain MRI showed moderately severe chronic ischemic/degenerative changes within the deep and subcortical white matter of both cerebral hemispheres and generalized cerebral atrophy including the hippocampal structures (Supplementary Figure). He was followed up for 2 years and showed moderate progression in his parkinsonism symptoms, associated with significant sialorrhea and epiphora. At the time of his last follow-up (age 68), FDG-PET scan revealed hypometabolism of the right medial temporal lobe (Supplementary Figure), and MRI showed moderate to advanced leukoaraiosis, moderate cerebral and cerebellar volume loss, and asymmetric hippocampal volume loss (R>L). Amyloid PET scan was negative. Regarding his family history, he reported seizures in his daughter.
Genetic evaluations revealed mutation of MAPT c.1217 G>A, p.Arg406Gln (R406W) in exon 13.
Characteristics of PSP-RS patients without MAPT mutations & comparison with mutant cases
Demographic and clinical characteristics of the two PSP-RS patients with MAPT mutation, and the 20 PSP-RS patients without MAPT mutation are shown in Table. The two cases with a mutation had worse scores on the Camden-F compared to the 20 patients without a mutation. Case 1 scored much lower on the MoCA and Camden-F than Case 2. Case 2 was impaired on the BNT compared to Case 1 and patients without a mutation and scored much lower on the CBI and UPDRS 1.
Table.
Demographics and clinical characteristics of 2 cases with PSP-RS with MAPT mutation, and patients with PSP-RS who did not have MAPT mutation.
| Variables | Case 1 | Case 2 | Patients with PSP-RS without MAPT mutation* |
|---|---|---|---|
| Gender [M] | M | M | 10 (50 %) |
| Education | 12 | 12 | 14 (12–16) |
| Family history [Yes] | Y | Y | 3 (17.64 %) |
| Age of onset | 60 | 62 | 63 (59.75–65) |
| Time from onset to first neurological evaluation (y) | 2.2 | 3.4 | 4.05 (3.25–5-37) |
| Apo E genotype | 33 | 34 | 5 (25 %)¥ |
| MoCA | 18 | 25 | 23.5 (21.25–26) |
| UPDRS I | 15 | 2 | 13 (10–19) |
| UPDRS II | 22 | 13 | 24 (14–27) |
| UPDRS III | 39 | 50 | 38.5 (34–48.25) |
| PSPRS | 37 | 43 | 41.5 (32–49.25) |
| PSPRS-G/M | 15 | 13 | 13 (9.75–14.5) |
| PSIS | 2 | 3 | 3.5 (3–4) |
| CBI | 40 | 14 | 37.5 (21.5–43.5) |
| FAB | 15 | 15 | 14 (13–16) |
| BNT | 13 | 6 | 14 (13–14) |
| Camden-F | 18 | 19 | 23 (21–24) |
| Camden-W | 18 | 23 | 24 (20–25) |
| PiB PET-SUVR† | 1.41 | 1.39 | 1.42 (1.36–1.5) |
Values are reported as median (first and third quartile) and number (percent) where appropriate.
Number (percent) of patients with PSP-RS without MAPT mutation who had an ApoE ε4 for the second allele.
SUVR>1.48 was considered as positive.
M= Male; Y= Years; Apo E= Apolipoprotein E (for patients with PSP-RS without MAPT mutation, the number of patients with a ε4 allele was included); MoCA= Montreal Cognitive Assessment; UPDRS= Movement Disorders Society- sponsored revision of the Unified Parkinson’s Disease Rating Scale; PSPRS= Progressive Supranuclear Palsy- Rating Scale; PSPRS-G/M= Progressive Supranuclear Palsy- Rating Scale-gait/midlines; Journal Pre-proof PSIS= PSP Saccadic Impairment Scale; FAB= Frontal Assessment Battery; CBI= Cambridge Behavioral Inventory; BNT= Boston Naming Test; Camden-F and Camden-W = Camden Memory Test –Short Recognition Memory Test for faces and words, respectively; PiB PET= Positron Emission Tomography scans with 11C-Pittsburgh compound B; SUVR= Standard Uptake Value Ratios; NA= Not Available.
Data regarding CBI and BNT was available in 18 patients, and data regarding Camden-F and W, UPDRS I and II, and family history was available in 17 patients. Rest of the variables were available in all 20 cases.
Comparison of flortaucipir-PET SUVRs between patients with and without a mutation is shown in Figure. When compared to patients without MAPT mutation, both cases with a MAPT mutation had higher uptake in medial temporal regions including bilateral amygdala, hippocampi, parahippocampi and especially entorhinal cortices; however, similar uptake was observed in the globus pallidum, midbrain, superior frontal cortex and dentate gyrus of the cerebellum.
Figure.
Histogram of the flortaucipir-PET SUVRs for Cases 1 and 2 and PSP-RS patients who did not have MAPT mutation.
Entorhinal Cx= Entorhinal cortex; Para Hippo= Parahippocampus; Dentate Nuc Cbl= Dentate Nucleus of Cerebellum.
Discussion
We report two patients with PSP-RS who had atypical clinical and neuroimaging characteristics and were found to harbor two novel MAPT mutations. Based on the flortaucipir-PET and neuropsychologic evaluations, they exhibited higher degrees of tau accumulation in medial temporal lobe regions and poor performance on a measure of episodic memory compared to patients without a MAPT mutation.
Some of the suggested mechanisms by which MAPT mutations can cause neurodegenerative diseases include neuronal dysfunction and morphological changes similar to aging, alterations in microtubule dynamics, and potentiating tau aggregation [3]. Previous studies have reported MAPT mutation in 0.6–13.3% of patients with PSP with a mean age of onset of 46.3 years [3]. In our clinical cohort of PSP, a MAPT mutation was present in 1% of patients, and both of our cases developed symptoms in their 60s similar to those without a MAPT mutation.
In the first case, the presence of urinary incontinence and RBD was slightly unusual for PSP and raised an initial suspicion of an underlying alpha-synucleinopathy, such as multiple system atrophy. Furthermore, he showed greater degrees of cognitive and gait impairment compared to the PSP-RS patients without a MAPT mutation. In the second case, although his non-motor and motor experiences of daily living (according to UPDRS I and II) and cognitive and behavioral control (according to CBI) was largely preserved, his visual confrontation naming ability on the BNT was severely impaired which differed from PSP-RS patients without a MAPT mutation. Additionally, case 1 had impaired episodic memory for both faces and words while case 2 had impaired memory for faces only.
Medial temporal regions, and especially hippocampus, are crucial for episodic memory, memory formation and consolidation [11]. We believe that higher tau accumulation in these regions, as evidenced by flortaucipir-PET, along with hippocampal atrophy and hypometabolism seen on MRI and FDG-PET, underlie the observed episodic memory impairment in our cases, and possibly the poor performance on confrontation naming in case 2. A previous study reported that patients with MAPT mutations outside of exon 10 have high flortaucipir-PET SUVRs with values within the range of what is observed in patients with Alzheimer’s Disease (AD), while patients with MAPT mutations in exon 10 did not show this pattern [12]. Moreover, a study showed that MAPT mutation are correlated with symmetric atrophy of frontotemporal lobes on brain MRI [3]. Our findings are somewhat inconsistent with previous studies, as the MAPT mutations in both of our patients were outside exon 10 (exons 12 and 13) yet the increased uptake in the medial temporal lobe was not near the level typically observed in AD.
Regarding FDG-PET, patients with PSP-RS without MAPT mutation show hypometabolism in midbrain, basal ganglia, thalamus, premotor, precentral, and prefrontal regions, as well as in the anterior cingulate [6]. Bilateral temporal hypometabolism is the most common neuroimaging finding in patients with a MAPT mutation, similar to what is observed in patients with typical AD who present with early prominent memory impairments [3, 11]. It is reported that MAPT mutations in the splicing region primarily result in the involvement of the medial temporal lobe, whereas mutations in the coding region mainly affect the lateral temporal lobes [3]. This aligns with our observation; however, in the case 2, the hypometabolism was asymmetric and predominantly on the right side.
The primary limitation of our study is that neither patient underwent pathological examination to confirm the presence of underlying PSP pathology. However, the absence of amyloid on the PiB PET scans also indicates no evidence for AD in them. There are case reports on the presence of concomitant corticobasal degeneration (CBD) in patients with PSP, and pathological examinations are required to determine whether the increased medial temporal lobe uptake in the two patients that we reported is due to greater burden of PSP pathology or CBD (4R) tau.
Conclusion:
We present two novel MAPT mutations, MAPT c.1024G>A, p. Glu342Lys, and MAPT c.1217 G>A, p. Arg406Gln, that were associated with atypical features in PSP. Both mutations were associated with increased memory loss and medial temporal lobe neurodegeneration and flortaucipir uptake. Further studies to dissect the functional consequences of these mutations and their pathogenic effects are needed.
Supplementary Material
Study highlights:
MAPT mutations have been reported in rare cases of progressive supranuclear palsy.
We found novel MAPT mutations: c.1024G>A, p.Glu342Lys, and c.1217 G>A, p.Arg406Gln.
Both mutations were associated with greater memory loss and flortaucipir uptake.
Patients showed medial temporal lobe neurodegeneration.
These mutations modify PSP-RS phenotype by targeting medial temporal lobe regions.
Acknowledgements:
This work was supported by the National Institute of Neurological Disorders and Stroke (R01-NS89757 and RF1-NS112153).
Footnotes
Declaration of interests
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
References
- [1].Höglinger GU, Respondek G, Stamelou M, Kurz C, Josephs KA, Lang AE, Mollenhauer B, Müller U, Nilsson C, Whitwell JL, Arzberger T, Englund E, Gelpi E, Giese A, Irwin DJ, Meissner WG, Pantelyat A, Rajput A, van Swieten JC, Troakes C, Antonini A, Bhatia KP, Bordelon Y, Compta Y, Corvol JC, Colosimo C, Dickson DW, Dodel R, Ferguson L, Grossman M, Kassubek J, Krismer F, Levin J, Lorenzl S, Morris HR, Nestor P, Oertel WH, Poewe W, Rabinovici G, Rowe JB, Schellenberg GD, Seppi K, van Eimeren T, Wenning GK, Boxer AL, Golbe LI, Litvan I, Clinical diagnosis of progressive supranuclear palsy: The movement disorder society criteria, Mov Disord 32(6) (2017) 853–864. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [2].Coppola G, Chinnathambi S, Lee JJ, Dombroski BA, Baker MC, Soto-Ortolaza AI, Lee SE, Klein E, Huang AY, Sears R, Lane JR, Karydas AM, Kenet RO, Biernat J, Wang LS, Cotman CW, Decarli CS, Levey AI, Ringman JM, Mendez MF, Chui HC, Le Ber I, Brice A, Lupton MK, Preza E, Lovestone S, Powell J, Graff-Radford N, Petersen RC, Boeve BF, Lippa CF, Bigio EH, Mackenzie I, Finger E, Kertesz A, Caselli RJ, Gearing M, Juncos JL, Ghetti B, Spina S, Bordelon YM, Tourtellotte WW, Frosch MP, Vonsattel JP, Zarow C, Beach TG, Albin RL, Lieberman AP, Lee VM, Trojanowski JQ, Van Deerlin VM, Bird TD, Galasko DR, Masliah E, White CL, Troncoso JC, Hannequin D, Boxer AL, Geschwind MD, Kumar S, Mandelkow EM, Wszolek ZK, Uitti RJ, Dickson DW, Haines JL, Mayeux R, Pericak-Vance MA, Farrer LA, Ross OA, Rademakers R, Schellenberg GD, Miller BL, Mandelkow E, Geschwind DH, Evidence for a role of the rare p.A152T variant in MAPT in increasing the risk for FTD-spectrum and Alzheimer’s diseases, Hum Mol Genet 21(15) (2012) 3500–12. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [3].Ruiz-Barrio I, Horta-Barba A, Illán-Gala I, Kulisevsky J, Pagonabarraga J, Genotype-Phenotype Correlation in Progressive Supranuclear Palsy Syndromes: Clinical and Radiological Similarities and Specificities, Front Neurol 13 (2022) 861585. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [4].Goetz CG, Fahn S, Martinez-Martin P, Poewe W, Sampaio C, Stebbins GT, Stern MB, Tilley BC, Dodel R, Dubois B, Holloway R, Jankovic J, Kulisevsky J, Lang AE, Lees A, Leurgans S, LeWitt PA, Nyenhuis D, Olanow CW, Rascol O, Schrag A, Teresi JA, Van Hilten JJ, LaPelle N, Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS): Process, format, and clinimetric testing plan, Mov Disord 22(1) (2007) 41–7. [DOI] [PubMed] [Google Scholar]
- [5].Golbe LI, Ohman-Strickland PA, A clinical rating scale for progressive supranuclear palsy, Brain 130(Pt 6) (2007) 1552–65. [DOI] [PubMed] [Google Scholar]
- [6].Whitwell JL, Master AV, Avula R, Kantarci K, Eggers SD, Edmonson HA, Jack CR, Jr KA Josephs, Clinical Correlates of White Matter Tract Degeneration in Progressive Supranuclear Palsy, Archives of Neurology 68(6) (2011) 753–760. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [7].Nasreddine ZS, Phillips NA, Bédirian V, Charbonneau S, Whitehead V, Collin I, Cummings JL, Chertkow H, The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment, Journal of the American Geriatrics Society 53(4) (2005) 695–699. [DOI] [PubMed] [Google Scholar]
- [8].Lezak MD, Neuropsychological Assessment, Oxford University Press; 2004. [Google Scholar]
- [9].Minoshima S, Frey KA, Koeppe RA, Foster NL, Kuhl DE, A diagnostic approach in Alzheimer’s disease using three-dimensional stereotactic surface projections of fluorine-18-FDG PET, J Nucl Med 36(7) (1995) 1238–48. [PubMed] [Google Scholar]
- [10].Ghirelli A, Tosakulwong N, Weigand SD, Clark HM, Ali F, Botha H, Duffy JR, Utianski RL, Buciuc M, Murray ME, Labuzan SA, Spychalla AJ, Pham NTT, Schwarz CG, Senjem ML, Machulda MM, Baker M, Rademakers R, Filippi M, Jack CR Jr., Lowe VJ, Parisi JE, Dickson DW, Josephs KA, Whitwell JL, Sensitivity-Specificity of Tau and Amyloid β Positron Emission Tomography in Frontotemporal Lobar Degeneration, Ann Neurol 88(5) (2020) 1009–1022. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [11].Whitwell JL, Graff-Radford J, Tosakulwong N, Weigand SD, Machulda MM, Senjem ML, Spychalla AJ, Vemuri P, Jones DT, Drubach DA, Knopman DS, Boeve BF, Ertekin-Taner N, Petersen RC, Lowe VJ, Jack CR Jr., Josephs KA, Imaging correlations of tau, amyloid, metabolism, and atrophy in typical and atypical Alzheimer’s disease, Alzheimers Dement 14(8) (2018) 1005–1014. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [12].Jones DT, Knopman DS, Graff-Radford J, Syrjanen JA, Senjem ML, Schwarz CG, Dheel C, Wszolek Z, Rademakers R, Kantarci K, Petersen RC, Jack CR Jr., Lowe VJ, Boeve BF, In vivo (18)F-AV-1451 tau PET signal in MAPT mutation carriers varies by expected tau isoforms, Neurology 90(11) (2018) e947–e954. [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.