Ross, Owen A

Background: Early-onset Parkinson’s disease (EOPD), occurring between ages 40 and 55, carries social, societal, and personal consequences and may progress, with fewer comorbidities than typical, later-onset disease. Objective: To examine the incidence and survival of EOPD and other Parkinsonism occurring before age 55 in the population-based cohort of residents in seven Minnesota counties. Methods: A movement-disorder specialist reviewed all the medical records in a 2010–2015 Parkinsonism-incident cohort to confirm diagnosis and subtypes. Results: We identified 27 patients diagnosed at ≤ 50 years with incident Parkinsonism 2010–15:11 (41%) cases of EOPD, 13 (48%) drug-induced Parkinsonism, and 3 (11%) other Parkinsonism; we also identified 69 incident cases of Parkinsonism ≤ 55 years, of which 28 (41%) were EOPD, 28 (41%) DIP, and 13 (19%) other Parkinsonism. Overall incidence for Parkinsonism ≤ 50 years was 1.98/100,000 person-years, and for EOPD was 0.81/100,000 person-years. In patients ≤ 55 years, Parkinsonism incidence was 5.05/100,000 person-years: in EOPD, 2.05/100,000 person-years. Levodopa-induced dyskinesia was present in 45%of EOPD (both ≤ 50 years and ≤ 55 years). Onset of cardinal motor symptoms was proximate to the diagnosis of EOPD, except for impaired postural reflexes, which occurred later in the course of EOPD. Among the 69 Parkinsonism cases ≤ 55 years, 9 (13%; all male) were deceased (only 1 case of EOPD). Men had a higher mortality risk compared to women (p = 0.049). Conclusion: The incidence of EOPD ≤ 50 years was 0.81/100,000 person-years (1.98 in Parkinsonism all type); prior to ≤ 55 years was 2.05/100,000 person-years (5.05 in Parkinsonism all type) with higher incidence in men than women. Men with Parkinsonism, all type, had higher mortality compared to women.

ObjectiveThe objective of this study was to describe clinical features, [18F]‐fluorodeoxyglucose (FDG)‐positron emission tomography (PET) metabolism and digital pathology in patients with logopenic progressive aphasia (LPA) and pathologic diagnosis of diffuse Lewy body disease (DLBD) and compare to patients with LPA with other pathologies, as well as patients with classical features of probable dementia with Lewy bodies (pDLB).MethodsThis is a clinicopathologic case‐control study of 45 patients, including 20 prospectively recruited patients with LPA among whom 6 were diagnosed with LPA‐DLBD. We analyzed clinical features and compared FDG‐PET metabolism in LPA‐DLBD to an independent group of patients with clinical pDLB and regional α‐synuclein burden on digital pathology to a second independent group of autopsied patients with DLBD pathology and antemortem pDLB (DLB‐DLBD).ResultsAll patients with LPA‐DLBD were men. Neurological, speech, and neuropsychological characteristics were similar across LPA‐DLBD, LPA‐Alzheimer's disease (LPA‐AD), and LPA‐frontotemporal lobar degeneration (LPA‐FTLD). Genetic screening of AD, DLBD, and FTLD linked genes were negative with the exception of APOE ε4 allele present in 83% of LPA‐DLBD patients. Seventy‐five percent of the patients with LPA‐DLBD showed a parietal‐dominant pattern of hy pometabolism; LPA‐FTLD – temporal‐dominant pattern, whereas LPA‐AD showed heterogeneous patterns of hypometabolism. LPA‐DLBD had more asymmetrical hypometabolism affecting frontal lobes, with relatively spared occipital lobe in the nondominantly affected hemisphere, compared to pDLB. LPA‐DLBD had minimal atrophy on gross brain examination, higher cortical Lewy body counts, and higher α‐synuclein burden in the middle frontal and inferior parietal cortices compared to DLB‐DLBD.InterpretationWhereas AD is the most frequent underlying pathology of LPA, DLBD can also be present and may contribute to the LPA phenotype possibly due to α‐synuclein‐associated functional impairment of the dominant parietal lobe. ANN NEUROL 2021;89:520–533

Plasma neurofilament light is a reliable, uniform marker to estimate neuroaxonal injury and forecast all-cause mortality across major stroke types.

Abstract Introduction The cytoprotective PTEN‐induced kinase 1 (PINK1)‐parkin RBR E3 ubiquitin protein ligase (PRKN) pathway selectively labels damaged mitochondria with phosphorylated ubiquitin (pS65‐Ub) for their autophagic removal (mitophagy). Because dysfunctions of mitochondria and degradation pathways are early features of Alzheimer's disease (AD), mitophagy impairments may contribute to the pathogenesis. Methods Morphology, levels, and distribution of the mitophagy tag pS65‐Ub were evaluated by biochemical analyses combined with tissue and single cell imaging in AD autopsy brain and in transgenic mouse models. Results Analyses revealed significant increases of pS65‐Ub levels in AD brain, which strongly correlated with granulovacuolar degeneration (GVD) and early phospho‐tau deposits, but were independent of amyloid beta pathology. Single cell analyses revealed predominant co‐localization of pS65‐Ub with mitochondria, GVD bodies, and/or lysosomes depending on the brain region analyzed. Discussion Our study highlights mitophagy alterations in AD that are associated with early tau pathology, and suggests that distinct mitochondrial, autophagic, and/or lysosomal failure may contribute to the selective vulnerability in disease.

AbstractTau deposition is a key biological feature of Alzheimer’s disease that is closely related to cognitive impairment. However, it remains poorly understood why certain individuals may be more susceptible to tau deposition while others are more resistant. The recent availability of in vivo assessment of tau burden through positron emission tomography provides an opportunity to test the hypothesis that common genetic variants may influence tau deposition. We performed a genome-wide association study of tau-positron emission tomography on a sample of 754 individuals over age 50 (mean age 72.4 years, 54.6% men, 87.6% cognitively unimpaired) from the population-based Mayo Clinic Study of Aging. Linear regression was performed to test nucleotide polymorphism associations with AV-1451 (18F-flortaucipir) tau-positron emission tomography burden in an Alzheimer’s-signature composite region of interest, using an additive genetic model and covarying for age, sex and genetic principal components. Genome-wide significant associations with higher tau were identified for rs76752255 (P = 9.91 × 10−9, β = 0.20) in the tau phosphorylation regulatory gene PPP2R2B (protein phosphatase 2 regulatory subunit B) and for rs117402302 (P = 4.00 × 10−8, β = 0.19) near IGF2BP3 (insulin-like growth factor 2 mRNA-binding protein 3). The PPP2R2B association remained genome-wide significant after additionally covarying for global amyloid burden and cerebrovascular disease risk, while the IGF2BP3 association was partially attenuated after accounting for amyloid load. In addition to these discoveries, three single nucleotide polymorphisms within MAPT (microtubule-associated protein tau) displayed nominal associations with tau-positron emission tomography burden, and the association of the APOE (apolipoprotein E) ɛ4 allele with tau-positron emission tomography was marginally nonsignificant (P = 0.06, β = 0.07). No associations with tau-positron emission tomography burden were identified for other single nucleotide polymorphisms associated with Alzheimer’s disease clinical diagnosis in prior large case–control studies. Our findings nominate PPP2R2B and IGF2BP3 as novel potential influences on tau pathology which warrant further functional characterization. Our data are also supportive of previous literature on the associations of MAPT genetic variation with tau, and more broadly supports the inference that tau accumulation may have a genetic architecture distinct from known Alzheimer’s susceptibility genes, which may have implications for improved risk stratification and therapeutic targeting.

Abstract Objective To determine whether distinct microtubule‐associated protein tau MAPT H1 subhaplotypes are associated with clinical and demographic features in Parkinson’s disease. Methods A retrospective cohort study included 855 unrelated Caucasian patients with Parkinson’s disease who were seen by Movement Disorder specialists at the Mayo Clinic Florida between 1998 and 2016. The primary outcome measures were specific demographic and clinical features of Parkinson’s disease, including age at onset, disease progression, survival, motor signs, dementia, dystonia, dyskinesia, autonomic dysfunction, impulse control disorder, psychiatric features, REM sleep behavior disorder, restless legs syndrome, and Parkinson’s disease subtype. Specific clinical features were measured at the initial visit and most recent visit. These outcomes were assessed for association with MAPT H1 subhaplotypes, which were defined by six haplotype tagging variants. Results Median onset age was 64 years (range: 22‐94 years); 548 (64%) of patients were male. Significant associations ( P < 0.0029) were observed between MAPT H1b and orthostatic hypotension (OR = 1.72, P = 0.001); between H1j and rest tremor (OR = 0.15; P < 0.001) as well as REM sleep behavior disorder (OR = 3.87, P < 0.001); between H1r and bradykinesia (OR = 0.11; P < 0.001); and between H1v and restless legs syndrome (OR = 4.02, P = 0.002). Interpretation Four MAPT H1 subhaplotypes, but not the H2 haplotype, were significantly associated with specific clinical features in Parkinson’s disease. MAPT haplotypic structure may explain some of the phenotypic variability in disease. Replication of our findings will be critical to fully resolve the Parkinson’s disease risk association signal at Chr17q21.