MAPT‐Associated Familial Progressive Supranuclear Palsy with Typical Corticobasal Degeneration Neuropathology: A Clinicopathological Report

Corticobasal degeneration (CBD) is a rare, 4-repeat (4R) tauopathy characterized by astrocytic plaque neuropathology. Although ~25% of sporadic CBD cases present with progressive supranuclear palsy-Richardson's syndrome (PSP-RS),1 only one other case of microtubule-associated protein tau gene (MAPT)- related CBD with a PSP-like phenotype has been reported.2 We aim to highlight important issues regarding the classification of MAPT-associated tauopathies and the implications for clinical research. This left-handed man presented age 42 with a 9 month history of difficulty focusing on near objects and unsteadiness causing one fall. He had been treated with sertraline for depression 6 months earlier. There was an autosomal dominant family history of young-onset PSP-RS with associated behavioral symptoms and a L284R MAPT mutation was identified in his mother (Fig. 1).3 Limb rigidity was detected 1 year later and a DaTscan showed severe bilateral nigrostriatal dopaminergic deficiency. He did not benefit from ropinirole and within 2 years of onset, he was having recurrent falls, trouble with manual dexterity and behavioral change characterized by apathy, irritability, obsessive behavior and disinhibition manifesting as blunt jokes. He also developed difficulty with multitasking suggestive of executive dysfunction. On examination, there was frontalis overactivity, a supranuclear gaze palsy, mild dysarthria, symmetric upper limb hypokinesia and increased tone, and positive palmomental reflexes. There was no limb ataxia, dyspraxia or dystonia. His gait was slow and rigid (Video 1). There were executive function deficits on neuropsychometry (Table S1) with mainly midbrain and very mild frontal and parietal atrophy on neuroimaging (Fig. 1). The phenotype was consistent with the movement disorder society criteria for probable PSP-RS4 and he was confirmed to have the same MAPT mutation as his mother. He participated in the PROgressive Supranuclear Palsy CorTico-Basal (PROSPECT) and GENetic Frontotemporal Dementia Initiative (GENFI) studies and completed 52 weeks of placebo on the Gosuranemab tau antibody trial (Biogen). Over the final year of his illness he developed severe dysarthria, dysphagia and neck rigidity that was unresponsive to levodopa. He died age 45 following a disease duration of 4 years. A neuropathological examination was undertaken including an evaluation by a second neuropathologist blinded to the clinical history (TR). Macroscopic examination demonstrated marked atrophy of the subthalamic nucleus, pallor of the substantia nigra and locus coeruleus and reduction in size of the dentate nucleus (Fig. 2). Histological examination revealed neuronal and glial 4R tau pathology, with frequent astrocytic plaques typical of CBD (Fig. 2). CBD pathology was most prominent in the posterior frontal lobe, deep gray nuclei and tegmental regions of the brainstem. In addition, there were rare grain-like inclusions in the hippocampus, deep gray nuclei, and midbrain and pontine tegmentum. Notably, histological examination showed no evidence of tufted astrocytes—PSP hallmark pathology. Alzheimer's type neurofibrillary tangle tau pathology in the medial temporal lobe corresponded to Braak and Braak stage II at most. There was no amyloid-β pathology, indicating no evidence of Alzheimer's disease neuropathological change. There was no limbic TDP43 proteinopathy or α-synuclein pathology in the brainstem or limbic regions examined. This case highlights the controversial issue of whether the histological features of MAPT-associated familial tauopathies are the same, similar or distinct from their sporadic counterparts.5-7 The glial and neuronal tau pathology seen in this case was indistinguishable from sporadic CBD, even though the clinical phenotype and pattern of regional brain atrophy were typical of PSP-RS. Although most MAPT-associated tauopathy cases can be shoehorned into a specific frontotemporal lobar degeneration-tau subtype, these cases often, albeit not always as reported here, have atypical histological characteristics in terms of the morphology or 3R/4R tau isoform composition of cellular inclusions.8, 9 Moreover, neuropathological findings can differ between and within families with the same mutation.5 As previously suggested,5, 7 using the term frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) to describe MAPT-associated tauopathies should be avoided because the progranulin gene, which is associated with TDP43 proteinopathy, is also located on chromosome 17. However, categorizing MAPT cases based on the sporadic tau inclusion morphology they resemble may also fail to highlight atypical histological features in some cases. In terms of structure-based classification, the tau filament structures identified from one intron 10 + 16 and two intron 10 + 3 MAPT cases were all identical to that of sporadic argyrophilic grain disease, consistent with the presence of argyrophilic grains in the +3 cases but not the astrocytic plaque-like pathology in the +16 case.10 Whilst phenotypic variability is determined by regional involvement of neuropathology, the molecular basis for cellular tau inclusion heterogeneity is unclear. It may, amongst other reasons, be influenced by the variable involvement of tau produced by the non-mutant allele in the misfolding process and as yet unidentified or poorly characterized genetic and epigenetic factors.8 These issues underline several challenges to the field including the use of transgenic animal models for studying sporadic tauopathies and identifying homogeneous patient cohorts for clinical trials as exemplified here. We thank the patient and their family without whose generous donation this report would not have been possible. We thank QSBB staff for their assistance with material preparation. (1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the first draft, B. Review and Critique. P.W.C.: 1A, 1C, 3A. R.F.: 1C, 3B. M.T.J.: 1C, 3B. E.J.: 1C, 3B. T.T.W.: 1A, 3B. T.R.: 1C, 3B. H.R.M.: 1A, 3B. J.D.M.: 1A, 3B. Z.J.: 1A, 1C, 3B. Ethical Compliance Statement: Queen Square Brain Bank protocols have been approved by the NHS Health Research Authority, Ethics Committee London-Central (REC reference 18/LO/0721) and informed consent was obtained for publication. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Funding Sources and Conflicts of Interest: No specific funding was received for this work and the authors declare that there are no conflicts of interest relevant to this work. Financial Disclosures for the Previous 12 Months: P.W. Cullinane is supported by funding from the Reta Lila Weston Trust for Medical Research. R. Fumi reports no disclosures relevant to the manuscript. M. Theilmann Jensen reports no disclosures relevant to the manuscript. E. Jabbari reports no disclosures relevant to the manuscript. T.T. Warner receives grant support from the Medical Research Council, the Reta Lila Weston Trust for Medical Research, Corticobasal Degeneration Solutions Inc., the UCL Biomedical Research Centre, the Association of British Neurologists, and the Rosetrees Trust, and honoraria from Britannia Pharmaceuticals. T. Revesz is supported by the National Institute for Health Research (NIHR) Queen Square Biomedical Research Unit in Dementia based at University College London Hospitals (UCLH), University College London (UCL) and the Reta Lila Weston Institute of Neurological Studies, UCL Institute of Neurology. H.R. Morris is employed by UCL. In the last 12 months he reports paid consultancy from Roche and Amylyx; lecture fees/honoraria—BMJ, Kyowa Kirin, Movement Disorders Society. Research Grants from Parkinson's UK, Cure Parkinson's Trust, PSP Association, Medical Research Council, Michael J. Fox Foundation. Dr. Morris is a co-applicant on a patent application related to C9ORF72—Method for diagnosing a neurodegenerative disease (PCT/GB2012/052140). J.D. Rohrer is supported by the Miriam Marks Brain Research UK Senior Fellowship and has received funding from an MRC Clinician Scientist Fellowship (MR/M008525/1) and the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH). Z. Jaunmuktane received support from the Department of Health's NIHR Biomedical Research Centre's funding scheme to UCLH. Table S1. Neuropsychometric testing. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.