Thomas, Alan

Abstract Genetic studies have significantly advanced our understanding of tauopathies, yet the genetic aetiology of Pick’s disease, a rare 3-Repeat tauopathy, remains unclear. The MAPT p.A152T variant has been identified as a risk factor for Alzheimer’s disease and progressive supranuclear palsy, but its role in Pick’s disease is unknown. In this study, we examined the prevalence of MAPT p.A152T in the largest series of neuropathologically confirmed Pick’s disease cases to date (n = 401). Through genotyping, we identified a single mutation carrier in the Pick’s disease cohort (minor allele frequency = 0.12%). We previously reported MAPT p.A152T at a 0.20% frequency in healthy controls (n = 2456), suggesting that it does not associate with 3-Repeat tauopathy risk. To further investigate the effect of the variant on MAPT transcript expression, we used bulk RNA sequencing in Alzheimer’s disease and progressive supranuclear palsy A152T mutation carriers. We did not detect significant differences in 4-Repeat tau levels, though preliminary trends may indicate more nuanced effects that need to be examined with long-read sequencing in a larger series. Overall, our study suggests that MAPT p.A152T does not increase Pick’s disease risk and may instead be linked to 4-Repeat or mixed tau pathologies, warranting further functional investigation.

AbstractIntroductionOperationalized research criteria for mild cognitive impairment with Lewy bodies (MCI‐LB) were published in 2020. The aim of this systematic review and meta‐analysis was to review the evidence for the diagnostic clinical features and biomarkers in MCI‐LB set out in the criteria.MethodsMEDLINE, PubMed, and Embase were searched on 9/28/22 for relevant articles. Articles were included if they presented original data reporting the rates of diagnostic features in MCI‐LB.ResultsFifty‐seven articles were included. The meta‐analysis supported the inclusion of the current clinical features in the diagnostic criteria. Evidence for striatal dopaminergic imaging and meta‐iodobenzylguanidine cardiac scintigraphy, though limited, supports their inclusion. Quantitative electroencephalogram (EEG) and fluorodeoxyglucose positron emission tomography (PET) show promise as diagnostic biomarkers.DiscussionThe available evidence largely supports the current diagnostic criteria for MCI‐LB. Further evidence will help refine the diagnostic criteria and understand how best to apply them in clinical practice and research.Highlights A meta‐analysis of the diagnostic features of MCI‐LB was carried out. The four core clinical features were more common in MCI‐LB than MCI‐AD/stable MCI. Neuropsychiatric and autonomic features were also more common in MCI‐LB. More evidence is needed for the proposed biomarkers. FDG‐PET and quantitative EEG show promise as diagnostic biomarkers in MCI‐LB.

ABSTRACT Background Multiple System Atrophy is a rare neurodegenerative disease with alpha‐synuclein aggregation in glial cytoplasmic inclusions and either predominant olivopontocerebellar atrophy or striatonigral degeneration, leading to dysautonomia, parkinsonism, and cerebellar ataxia. One prior genome‐wide association study in mainly clinically diagnosed patients with Multiple System Atrophy failed to identify genetic variants predisposing for the disease. Objective Since the clinical diagnosis of Multiple System Atrophy yields a high rate of misdiagnosis when compared to the neuropathological gold standard, we studied only autopsy‐confirmed cases. Methods We studied common genetic variations in Multiple System Atrophy cases (N = 731) and controls (N = 2898). Results The most strongly disease‐associated markers were rs16859966 on chromosome 3, rs7013955 on chromosome 8, and rs116607983 on chromosome 4 with P ‐values below 5 × 10 −6 , all of which were supported by at least one additional genotyped and several imputed single nucleotide polymorphisms. The genes closest to the chromosome 3 locus are ZIC1 and ZIC4 encoding the zinc finger proteins of cerebellum 1 and 4 (ZIC1 and ZIC4). Interpretation Since mutations of ZIC1 and ZIC4 and paraneoplastic autoantibodies directed against ZIC4 are associated with severe cerebellar dysfunction, we conducted immunohistochemical analyses in brain tissue of the frontal cortex and the cerebellum from 24 Multiple System Atrophy patients. Strong immunohistochemical expression of ZIC4 was detected in a subset of neurons of the dentate nucleus in all healthy controls and in patients with striatonigral degeneration, whereas ZIC4‐immunoreactive neurons were significantly reduced inpatients with olivopontocerebellar atrophy. These findings point to a potential ZIC4‐mediated vulnerability of neurons in Multiple System Atrophy. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Abstract Dementia with Lewy bodies (DLB) is neuropathologically defined by the presence of α-synuclein aggregates, but many DLB cases show concurrent Alzheimer’s disease pathology in the form of amyloid-β plaques and tau neurofibrillary tangles. The first objective of this study was to investigate the effect of Alzheimer’s disease co-pathology on functional network changes within the default mode network (DMN) in DLB. Second, we studied how the distribution of tau pathology measured with PET relates to functional connectivity in DLB. Twenty-seven DLB, 26 Alzheimer’s disease and 99 cognitively unimpaired participants (balanced on age and sex to the DLB group) underwent tau-PET with AV-1451 (flortaucipir), amyloid-β-PET with Pittsburgh compound-B (PiB) and resting-state functional MRI scans. The resing-state functional MRI data were used to assess functional connectivity within the posterior DMN. This was then correlated with overall cortical flortaucipir PET and PiB PET standardized uptake value ratio (SUVr). The strength of interregional functional connectivity was assessed using the Schaefer atlas. Tau-PET covariance was measured as the correlation in flortaucipir SUVr between any two regions across participants. The association between region-to-region functional connectivity and tau-PET covariance was assessed using linear regression. Additionally, we identified the region with highest and the region with lowest tau SUVrs (tau hot- and cold spots) and tested whether tau SUVr in all other brain regions was associated with the strength of functional connectivity to these tau hot and cold spots. A reduction in posterior DMN connectivity correlated with overall higher cortical tau- (r = −0.39, P = 0.04) and amyloid-PET uptake (r = −0.41, P = 0.03) in the DLB group, i.e. patients with DLB who have more concurrent Alzheimer’s disease pathology showed a more severe loss of DMN connectivity. Higher functional connectivity between regions was associated with higher tau covariance in cognitively unimpaired, Alzheimer’s disease and DLB. Furthermore, higher functional connectivity of a target region to the tau hotspot (i.e. inferior/medial temporal cortex) was related to higher flortaucipir SUVrs in the target region, whereas higher functional connectivity to the tau cold spot (i.e. sensory-motor cortex) was related to lower flortaucipir SUVr in the target region. Our findings suggest that a higher burden of Alzheimer’s disease co-pathology in patients with DLB is associated with more Alzheimer’s disease-like changes in functional connectivity. Furthermore, we found an association between the brain’s functional network architecture and the distribution of tau pathology that has recently been described in Alzheimer’s disease. We show that this relationship also exists in patients with DLB, indicating that similar mechanisms of connectivity-dependent occurrence of tau pathology might be at work in both diseases.

AbstractBackgroundDementia with Lewy bodies (DLB) is neuropathologically defined by the presence of α‐synuclein aggregations, but many DLB cases show significant Alzheimer’s disease (AD) pathology in the form of β‐amyloid and tau. Our first objective was to investigate the effect of AD co‐pathology on functional network failure in DLB. Secondly, we studied how the distribution of tau relates to functional connectivity in DLB.MethodTwenty‐three DLB, 23 age‐ and sex‐matched AD, and 90 cognitively unimpaired (CU) participants underwent AV1451 tau‐PET, Pittsburgh compound‐B (PiB) PET, and resting state (rs)‐fMRI scans. The rs‐fMRI data were used to calculate the Network Failure Quotient (NFQ), a marker of functional network failure within the default mode network. The NFQ was then correlated with overall cortical tau standardized uptake value ratio (SUVr). The strength of inter‐regional functional connectivity was assessed using the Schaefer100 atlas. Tau‐PET covariance was measured as the correlation in AV1451 SUVr between any two regions across participants. The association between region‐to‐region functional connectivity and tau‐PET covariance was assessed using linear regression. Additionally, we identified the region with highest and the region with lowest tau SUVrs (tau hot‐ and coldspot) and tested whether tau SUVr in all other brain regions was associated with the strength of functional connectivity to these tau hot‐ and coldspots.ResultOverall higher cortical tau‐PET uptake correlated with higher NFQ (i.e. greater functional network failure) in DLB who were PiB+ (N=14, ρ=0.60, p=0.02), but not in DLB who were PiB‐ (N=9, ρ=‐0.06, p=0.87). Higher functional connectivity between regions was associated with higher tau covariance in CU, AD, and DLB, independent of PiB status. Higher functional connectivity of a target region to the tau hotspot (i.e. inferior/medial temporal cortex) was related to higher AV1451 SUVRs in the target region whereas higher functional connectivity to the tau coldspot (i.e. sensory‐motor cortex) was related to lower AV1451 SUVr in the target region.ConclusionGreater tau burden in DLB patients with β‐amyloid co‐pathology is associated with an AD‐like functional network failure. As previously demonstrated within the AD spectrum, functional connectivity may contribute to the spreading of tau across the brain also in DLB.