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Author(s): Xue-Bing Ding [sup.1] [sup.2] , Xin-Xin Wang [sup.1] [sup.2] , Dan-Hao Xia [sup.1] [sup.2] , Han Liu [sup.1] [sup.2] , Hai-Yan Tian [sup.1] [sup.2] , Yu Fu [sup.1] [sup.2] [...], Animal studies implicate meningeal lymphatic dysfunction in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease (PD). However, there is no direct evidence in humans to support this role.sup.1-5. In this study, we used dynamic contrast-enhanced magnetic resonance imaging to assess meningeal lymphatic flow in cognitively normal controls and patients with idiopathic PD (iPD) or atypical Parkinsonian (AP) disorders. We found that patients with iPD exhibited significantly reduced flow through the meningeal lymphatic vessels (mLVs) along the superior sagittal sinus and sigmoid sinus, as well as a notable delay in deep cervical lymph node perfusion, compared to patients with AP. There was no significant difference in the size (cross-sectional area) of mLVs in patients with iPD or AP versus controls. In mice injected with [alpha]-synuclein ([alpha]-syn) preformed fibrils, we showed that the emergence of [alpha]-syn pathology was followed by delayed meningeal lymphatic drainage, loss of tight junctions among meningeal lymphatic endothelial cells and increased inflammation of the meninges. Finally, blocking flow through the mLVs in mice treated with [alpha]-syn preformed fibrils increased [alpha]-syn pathology and exacerbated motor and memory deficits. These results suggest that meningeal lymphatic drainage dysfunction aggravates [alpha]-syn pathology and contributes to the progression of PD. Reduced meningeal lymphatic flow detected in patients with idiopathic Parkinson's disease compared to patients with atypical Parkinsonian disorders and cognitively normal controls.

Author(s): Diana Matheoud [sup.1] [sup.2] , Tyler Cannon [sup.3] , Aurore Voisin [sup.4] , Anna-Maija Penttinen [sup.4] , Lauriane Ramet [sup.4] , Ahmed M. Fahmy [sup.1] , Charles Ducrot [sup.4] [...], Parkinson's disease is a neurodegenerative disorder with motor symptoms linked to the loss of dopaminergic neurons in the substantia nigra compacta. Although the mechanisms that trigger the loss of dopaminergic neurons are unclear, mitochondrial dysfunction and inflammation are thought to have key roles.sup.1,2. An early-onset form of Parkinson's disease is associated with mutations in the PINK1 kinase and PRKN ubiquitin ligase genes.sup.3. PINK1 and Parkin (encoded by PRKN) are involved in the clearance of damaged mitochondria in cultured cells.sup.4, but recent evidence obtained using knockout and knockin mouse models have led to contradictory results regarding the contributions of PINK1 and Parkin to mitophagy in vivo.sup.5-8. It has previously been shown that PINK1 and Parkin have a key role in adaptive immunity by repressing presentation of mitochondrial antigens.sup.9, which suggests that autoimmune mechanisms participate in the aetiology of Parkinson's disease. Here we show that intestinal infection with Gram-negative bacteria in Pink1.sup.-/- mice engages mitochondrial antigen presentation and autoimmune mechanisms that elicit the establishment of cytotoxic mitochondria-specific CD8.sup.+ T cells in the periphery and in the brain. Notably, these mice show a sharp decrease in the density of dopaminergic axonal varicosities in the striatum and are affected by motor impairment that is reversed after treatment with l-DOPA. These data support the idea that PINK1 is a repressor of the immune system, and provide a pathophysiological model in which intestinal infection acts as a triggering event in Parkinson's disease, which highlights the relevance of the gut-brain axis in the disease.sup.10. In mice lacking PINK1, bacterial infection in the intestine results in mitochondrial antigen presentation and generation of CD8.sup.+ T cells, and infected mice develop motor impairments, suggesting that PINK1 suppresses autoimmunity.

A growing brain disease Parkinson disease (PD) is the world's fastest growing brain disease, eclipsing the growth of Alzheimer disease (1). From 1990 to 2015, the number of individuals with [...], Parkinson disease (PD) is now the world's fastest growing brain disease; however, the factors underlying this rise are unclear. The past 25 years has witnessed a vast expansion in our understanding of the genetics of PD, but few individuals with PD carry one of the major known genetic risk factors. Environmental factors, including individual (e.g., medications) and ambient (e.g., pollutants), may contribute to this rise. In this issue of the JCI, Sasane et al. examined the risk of PD associated with medications commonly used to treat benign prostatic hypertrophy. In contrast with previous studies, certain [[alpha].sub.1] receptor antagonists failed to lower PD risk. Rather, the commonly used comparator drug, tamsulosin, increased PD risk. This finding highlights the importance of selecting comparator groups to correctly identify risk factors. Future studies to address the rise of PD with emphasis on both individual as well as the understudied ambient environmental factors are warranted.

INTRODUCTION Cardiovascular risk factors are implicated as risk factors for neuronal damage in healthy elderly persons and in persons with dementia. (1,2) Parkinson's disease (PD), the second most common neurodegenerative [...], BACKGROUND/OBJECTIVES: The objective of this study was to investigate whether serum triglycerides (S-TG), cholesterol, blood pressure and waist/height ratio are risk factors for Parkinson's disease (PD). SUBJECTS AND METHODS: A population -based sample within the Northern Sweden Health and Disease Study (NSHDS) was used in this study (n = 101 790 subjects). Cases with PD were identified prospectively in a community-based study of idiopathic Parkinsonism in the period 2004-2009 in the county of Vasterbotten in northern Sweden. The case database obtained was crosslinked to the NSHDS. Eighty-four of 147 patients with PD had visited the primary health care 2-8 years before diagnosis for participation in the NSHDS. For each case, four referents from the NSHDS population were selected, matched for sex, age, year of health survey, subcohort and geographic area. RESULTS: Cases had lower mean S-TG levels (P =0.007). After stratification for sex, the lower S-TG remained significant for men (P = 0.006) but not for women (P = 0.450), and these were confirmed by the conditional logistic regression for all cases, none adjusted (hazard ratio (HR): 0.65; 95% confidence interval (CI): 0.42, 0.99) and after adjusting for age, body mass index (BMI) and physical activity (HR: 0.61; 95% CI: 0.39, 0.96). Systolic blood pressure (SBP) was negatively associated with PD risk after adjustments for age, BMI and physical activity (HR: 0.98; 95% CI: 0.97-0.99). Smoking and former smoking were associated with a reduced risk for PD. CONCLUSIONS: We found lower S-TG and SBP 2-8 years before a diagnosis of PD. Smoking was confirmed to be negatively associated with PD, whereas recreational activity indicates a risk for women. European Journal of Clinical Nutrition (2015) 69, 729-733; doi: 10.1038/ejcn.2014.259; published online 17 December 2014

Author(s): Ga Eun Nam 1, Seon Mee Kim 2,*, Kyungdo Han 3, Nan Hee Kim 4, Hye Soo Chung 4, Jin Wook Kim 2, Byoungduck Han 1, Sung Jung Cho [...], Background The association of metabolic syndrome (MetS) with the development of Parkinson disease (PD) is currently unclear. We sought to determine whether MetS and its components are associated with the risk of incident PD using large-scale cohort data for the whole South Korean population. Methods and findings Health checkup data of 17,163,560 individuals aged [greater than or equal to]40 years provided by the National Health Insurance Service (NHIS) of South Korea between January 1, 2009, and December 31, 2012, were included, and participants were followed up until December 31, 2015. The mean follow-up duration was 5.3 years. The hazard ratio (HR) and 95% confidence interval (CI) of PD were estimated using a Cox proportional hazards model adjusted for potential confounders. We identified 44,205 incident PD cases during follow-up. Individuals with MetS (n = 5,848,508) showed an increased risk of PD development compared with individuals without MetS (n = 11,315,052), even after adjusting for potential confounders including age, sex, smoking, alcohol consumption, physical activity, income, body mass index, estimated glomerular filtration rate, and history of stroke (model 3; HR, 95% CI: 1.24, 1.21-1.27). Each MetS component was positively associated with PD risk (HR, 95% CI: 1.13, 1.10-1.16 for abdominal obesity; 1.13, 1.10-1.15 for hypertriglyceridemia; 1.23, 1.20-1.25 for low high-density lipoprotein cholesterol; 1.05, 1.03-1.08 for high blood pressure; 1.21, 1.18-1.23 for hyperglycemia). PD incidence positively correlated with the number of MetS components (log-rank p < 0.001), and we observed a gradual increase in the HR for incident PD with increasing number of components (p < 0.001). A significant interaction between age and MetS on the risk of incident PD was observed (p for interaction < 0.001), and people aged [greater than or equal to]65 years old with MetS showed the highest HR of incident PD of all subgroups compared to those Conclusions Our population-based large-scale cohort study suggests that MetS and its components may be risk factors of PD development.

Introduction Previous studies have shown an association between Parkinson's disease (PD) and exposure to pesticides. A recent meta-analysis of 39 studies reported a 60% increased risk of PD associated with [...], BACKGROUND: Pesticides have been associated with Parkinson&apos;s disease (PD), but there are few data on important exposure characteristics such as dose-effect relations. It is unknown whether associations depend on clinical PD subtypes. OBJECTIVES: We examined quantitative aspects of occupational pesticide exposure associated with PD and investigated whether associations were similar across PD subtypes. METHODS: As part of a French population-based case-control study including men enrolled in the health insurance plan for farmers and agricultural workers, cases with clinically confirmed PD were identified through antiparkinsonian drug claims. Two controls were matched to each case. Using a comprehensive occupational questionnaire, we computed indicators for different dimensions of exposure (duration, cumulative exposure, intensity). We used conditional logistic regression to compute odds ratios (ORs) and 95% confidence intervals (CIs) among exposed male farmers (133 cases, 298 controls). We examined the relation between pesticides and PD subtypes (tremor dominant/non-tremor dominant) using polytomous logistic regression. RESULTS: There appeared to be a stronger association with intensity than duration of pesticide exposure based on separate models, as well as a synergistic interaction between duration and intensity (p-interaction = 0.04). High-intensity exposure to insecticides was positively associated with PD among those with low-intensity exposure to fungicides and vice versa, suggesting independent effects. Pesticide exposure in farms that specialized in vineyards was associated with PD (OR = 2.56; 95% CI: 1.31, 4.98). The association with intensity of pesticide use was stronger, although not significantly (^-heterogeneity = 0.60), for tremor-dominant (p-trend < 0.01) than for non-tremor-dominant PD (p-trend = 0.24). CONCLUSIONS: This study helps to better characterize different aspects of pesticide exposure associated with PD, and shows a significant association of pesticides with tremor-dominant PD in men, the most typical PD presentation. http://dx.doi.org/10.1289/ehp.1307970

J Neurol Neurosurg Psychiatry 2004;75:637-639. doi: 10.1136/jnnp.2003.020982 Parkinson's disease seems to occur more commonly in men than women based primarily on studies of death rates and prevalence. In recent years, [...]

Introduction Parkinson disease (PD) is the second most prevalent neurodegenerative disorder, after Alzheimer disease (Lang and Lozano 1998). Exposure to metals has been implicated in the pathogenesis of PD. Manganese [...], Background: Exposure to metals has been implicated in the pathogenesis of Parkinson disease (PD). OBJECTIVES: We sought to examine in a large prospective study of female nurses whether exposure to airborne metals was associated with risk of PD. METHODS: We linked the U.S. Environmental Protection Agency (EPA)&apos;s Air Toxics tract-level data with the Nurses&apos; Health Study, a prospective cohort of female nurses. Over the course of 18 years of follow-up from 1990 through 2008, we identified 425 incident cases of PD. We examined the association of risk of PD with the following metals that were part of the first U.S. EPA collections in 1990, 1996, and 1999: arsenic, antimony, cadmium, chromium, lead, manganese, mercury, and nickel. To estimate hazard ratios (HRs) and 95% CIs, we used the Cox proportional hazards model, adjusting for age, smoking, and population density. RESULTS: In adjusted models, the HR for the highest compared with the lowest quartile of each metal ranged from 0.78 (95% CI: 0.59, 1.04) for chromium to 1.33 (95% CI: 0.98, 1.79) for mercury. CONCLUSIONS: Overall, we found limited evidence for the association between adulthood ambient exposure to metals and risk of PD. The results for mercury need to be confirmed in future studies. http://dx.doi.org/10.1289/ehp.1307218