Neuropathologic basis of frontotemporal dementia in progressive supranuclear palsy.

BackgroundProgressive supranuclear palsy (PSP) is a neurodegenerative disorder characterized by neuronal loss in the extrapyramidal system with pathologic accumulation of tau in neurons and glia. The most common clinical presentation of PSP, referred to as Richardson syndrome, is that of atypical parkinsonism with vertical gaze palsy, axial rigidity, and frequent falls. Although cognitive deficits in PSP are often ascribed to subcortical dysfunction, a subset of patients has dementia with behavioral features similar to the behavioral variant of frontotemporal dementia. In this study we aimed to identify the clinical and pathological characteristics of PSP presenting with frontotemporal dementia.MethodsIn this study, we compared clinical and pathologic characteristics of 31 patients with PSP with Richardson syndrome with 15 patients with PSP with frontotemporal dementia. For pathological analysis, we used semiquantitative methods to assess neuronal and glial lesions with tau immunohistochemistry, as well image analysis of tau burden using digital microscopic methods.ResultsWe found greater frontal and temporal neocortical neuronal tau pathology in PSP with frontotemporal dementia compared with PSP with Richardson syndrome. White matter tau pathology was also greater in PSP with frontotemporal dementia than PSP with Richardson syndrome. Genetic and demographic factors were not associated with atypical distribution of tau pathology in PSP with frontotemporal dementia.ConclusionsThe results confirm the subset of cognitive-predominant PSP mimicking frontotemporal dementia in PSP. PSP with frontotemporal dementia has distinct clinical features that differ from PSP with Richardson syndrome, as well as differences in distribution and density of tau pathology. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society

Occupational risk factors for Parkinson's disease: a case-control study in Japan

<p>Abstract</p> <p>Background</p> <p>The evidence for associations between occupational factors and the risk of Parkinson's disease (PD) is inconsistent. We assessed the risk of PD associated with various occupational factors in Japan.</p> <p>Methods</p> <p>We examined 249 cases within 6 years of onset of PD. Control subjects were 369 inpatients and outpatients without neurodegenerative disease. Information on occupational factors was obtained from a self-administered questionnaire. Relative risks of PD were estimated using odds ratios (ORs) and 95% confidence intervals (CIs) based on logistic regression. Adjustments were made for gender, age, region of residence, educational level, and pack-years of smoking.</p> <p>Results</p> <p>Working in a professional or technical occupation tended to be inversely related to the risk of PD: adjusted OR was 0.59 (95% CI: 0.32-1.06, <it>P </it>= 0.08). According to a stratified analysis by gender, the decreased risk of PD for persons in professional or technical occupations was statistically significant only for men. Adjusted ORs for a professional or technical occupation among men and women were 0.22 (95% CI: 0.06-0.67) and 0.99 (0.47-2.07), respectively, and significant interaction was observed (<it>P </it>= 0.048 for homogeneity of OR). In contrast, risk estimates for protective service occupations and transport or communications were increased, although the results were not statistically significant: adjusted ORs were 2.73 (95% CI: 0.56-14.86) and 1.74 (95% CI: 0.65-4.74), respectively. No statistical significance was seen in data concerning exposure to occupational agents and the risk of PD, although roughly a 2-fold increase in OR was observed for workers exposed to stone or sand.</p> <p>Conclusion</p> <p>The results of our study suggest that occupational factors do not play a substantial etiologic role in this population. However, among men, professional or technical occupations may decrease the risk of PD.</p

Alcohol drinking and risk of Parkinson's disease: a case-control study in Japan

<p>Abstract</p> <p>Background</p> <p>Although some epidemiologic studies found inverse associations between alcohol drinking and Parkinson's disease (PD), the majority of studies found no such significant associations. Additionally, there is only limited research into the possible interactions of alcohol intake with aldehyde dehydrogenase (ALDH) 2 activity with respect to PD risk. We examined the relationship between alcohol intake and PD among Japanese subjects using data from a case-control study.</p> <p>Methods</p> <p>From 214 cases within 6 years of PD onset and 327 controls without neurodegenerative disease, we collected information on "peak", as opposed to average, alcohol drinking frequency and peak drinking amounts during a subject's lifetime. Alcohol flushing status was evaluated via questions, as a means of detecting inactive ALHD2. The multivariate model included adjustments for sex, age, region of residence, smoking, years of education, body mass index, alcohol flushing status, presence of selected medication histories, and several dietary factors.</p> <p>Results</p> <p>Alcohol intake during peak drinking periods, regardless of frequency or amount, was not associated with PD. However, when we assessed daily ethanol intake separately for each type of alcohol, only Japanese sake (rice wine) was significantly associated with PD (adjusted odds ratio of ≥66.0 g ethanol per day: 3.39, 95% confidence interval: 1.10-11.0, <it>P </it>for trend = 0.001). There was no significant interaction of alcohol intake with flushing status in relation to PD risk.</p> <p>Conclusions</p> <p>We did not find significant associations between alcohol intake and PD, except for the daily amount of Japanese sake. Effect modifications by alcohol flushing status were not observed.</p

Poly-GR dipeptide repeat polymers correlate with neurodegeneration and Clinicopathological subtypes in C9ORF72-related brain disease

Abstract Frontotemporal lobar degeneration (FTLD) is heterogeneous in clinical presentation, neuropathological characteristics and genetics. An expanded GGGGCC hexanucleotide repeat in C9ORF72 is the most common genetic cause of both FTLD and motor neuron disease (MND). Dipeptide repeat polymers (DPR) are generated through repeat-associated non-ATG translation, and they aggregate in neuronal inclusions with a distribution distinct from that of TDP-43 pathology. Recent studies from animal and cell culture models suggest that DPR might be toxic, but that toxicity may differ for specific DPR. Arginine containing DPR (poly-GR and poly-PR) have the greatest toxicity and are less frequent than other DPR (poly-GP, poly-GA). A unique feature of arginine-containing DPR is their potential for post-translational modification by methyl-transferases, which produces methylarginine DPR. In this report, we explored the relationship of DPR and methylarginine to markers of neurodegeneration using quantitative digital microscopic methods in 40 patients with C9ORF72 mutations and one of three different clinicopathologic phenotypes, FTLD, FTLD-MND or MND. We find that density and distribution of poly-GR inclusions are different from poly-GA and poly-GP inclusions. We also demonstrate colocalization of poly-GR with asymmetrical dimethylarginine (aDMA) immunoreactivity in regions with neurodegeneration. Differences in aDMA were also noted by clinical phenotype. FTLD-MND had the highest burden of poly-GR pathology compared to FTLD and MND, while FTLD-MND had higher burden of aDMA than FTLD. The results suggest that poly-GR pathology is associated with toxicity and neurodegeneration. It remains to be determined if dimethylarginine modification of poly-GR could contribute to its toxicity

Neuropathologic basis of frontotemporal dementia in progressive supranuclear palsy.

BackgroundProgressive supranuclear palsy (PSP) is a neurodegenerative disorder characterized by neuronal loss in the extrapyramidal system with pathologic accumulation of tau in neurons and glia. The most common clinical presentation of PSP, referred to as Richardson syndrome, is that of atypical parkinsonism with vertical gaze palsy, axial rigidity, and frequent falls. Although cognitive deficits in PSP are often ascribed to subcortical dysfunction, a subset of patients has dementia with behavioral features similar to the behavioral variant of frontotemporal dementia. In this study we aimed to identify the clinical and pathological characteristics of PSP presenting with frontotemporal dementia.MethodsIn this study, we compared clinical and pathologic characteristics of 31 patients with PSP with Richardson syndrome with 15 patients with PSP with frontotemporal dementia. For pathological analysis, we used semiquantitative methods to assess neuronal and glial lesions with tau immunohistochemistry, as well image analysis of tau burden using digital microscopic methods.ResultsWe found greater frontal and temporal neocortical neuronal tau pathology in PSP with frontotemporal dementia compared with PSP with Richardson syndrome. White matter tau pathology was also greater in PSP with frontotemporal dementia than PSP with Richardson syndrome. Genetic and demographic factors were not associated with atypical distribution of tau pathology in PSP with frontotemporal dementia.ConclusionsThe results confirm the subset of cognitive-predominant PSP mimicking frontotemporal dementia in PSP. PSP with frontotemporal dementia has distinct clinical features that differ from PSP with Richardson syndrome, as well as differences in distribution and density of tau pathology. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society