Neuroinflammation and white matter alterations in occupational manganese exposure assessed by diffusion basis spectrum imaging.

OBJECTIVE: To evaluate in-vivo neuroinflammation and white matter (WM) microstructural integrity in occupational manganese (Mn) exposure. METHODS: We assessed brain inflammation using Diffusion Basis Spectrum Imaging (DBSI) in 26 Mn-exposed welders, 17 Mn-exposed workers, and 26 non-exposed participants. Cumulative Mn exposure was estimated from work histories and the Unified Parkinson's Disease Rating Scale motor subsection 3 (UPDRS3) scores were completed by a movement specialist. Tract-based Spatial Statistics allowed for whole-brain voxel-wise WM analyses to compare WM DBSI-derived measures between the Mn-exposed and non-exposed groups. Exploratory grey matter region of interest (ROI) analyses examined the presence of similar alterations in the basal ganglia. We used voxelwise general linear modeling and linear regression to evaluate the association between cumulative Mn exposure, WM or basal ganglia DBSI metrics, and UPDRS3 scores, while adjusting for age. RESULTS: Mn-exposed welders had higher DBSI-derived restricted fraction (DBSI-RF), higher DBSI-derived nonrestricted fraction (DBSI-NRF), and lower DBSI-derived fiber fraction (DBSI-FF) in multiple WM tracts (all p < 0.05) in comparison to less-exposed workers and non-exposed participants. Basal ganglia ROI analyses revealed higher average caudate DBSI-NRF and DBSI-derived radial diffusion (DBSI-RD) values in Mn-exposed welders relative to non-exposed participants (p < 0.05). Caudate DBSI-NRF was also associated with greater cumulative Mn exposure and higher UPRDS3 scores. CONCLUSIONS: Mn-exposed welders demonstrate greater DBSI-derived indicators of neuroinflammation-related cellularity (DBSI-RF), greater extracellular edema (DBSI-NRF), and lower apparent axonal density (DBSI-FF) in multiple WM tracts suggesting a neuroinflammatory component in the pathophysiology of Mn neurotoxicity. Caudate DBSI-NRF was positively associated with both cumulative Mn exposure and clinical parkinsonism, indicating a possible dose-dependent effect on extracellular edema with associated motor effects.

Well Water and Parkinson's Disease in Medicare Beneficiaries: A Nationwide Case-Control Study.

BACKGROUND: Well water frequently is considered a risk factor for Parkinson's disease (PD), but few studies were designed appropriately to test whether geographic factors affect PD risk. OBJECTIVE: To determine the risk of PD in relation to residential use of private well water. METHODS: In a nationwide, population-based case-control study, we identified all incident PD cases (N = 89,790) and all comparable controls (N = 21,549,400) age 66-90 who solely relied on Medicare coverage in the U.S. in 2009. We estimated the probability of use of private well water using zip code of residence at diagnosis/reference and U.S. Census data on household water source. We modeled this exposure linearly in logistic regression to calculate the odds ratio (OR) and 95% confidence interval (CI) of PD risk in relation to well water use. We adjusted for age, sex and race/ethnicity, and verified that smoking and use of medical care did not confound results. We repeated analyses with a 2-year exposure lag and separately within each U.S. state. RESULTS: Use of well water was inversely associated with PD risk (OR = 0.87, 95% CI 0.85-0.89). We confirmed this association in a Cox survival analysis in which we followed controls for 5 years, death or PD diagnosis. There was little evidence that well water use increased risk of PD in any individual state. CONCLUSIONS: Although it remains possible that exposures in well water in more narrow geographic regions increase PD risk, in general these results suggest that exposures more common in urban/suburban areas might also be relevant.

Transplant and risk of Parkinson disease.

INTRODUCTION: The pathophysiology of Parkinson's disease (PD) remains unclear, but growing evidence supports a role of neuroinflammation. The purpose of this study was to investigate the association between tissue transplantation and PD risk, given the importance of immunosuppressants in post-transplant management. METHODS: We performed a case-control study among Medicare beneficiaries age 66-90 using claims from 2004 to 2009. We used International Classification of Diseases, Ninth Edition (ICD-9) and Current Procedural Terminology (CPT) codes to identify PD (89,790 incident cases, 118,095 population-based controls) and history of tissue transplant (kidney, heart, liver, lung, and bone marrow). We investigated risk of PD in relation to tissue transplant in logistic regression models, adjusting for age, sex, race, smoking, and overall use of medical care. RESULTS: Beneficiaries who had received a tissue transplant at least five years prior to PD diagnosis or reference had a lower risk of PD (odds ratio [OR] 0.63, 95% confidence interval [CI] 0.53, 0.75) than those without tissue transplant. This inverse association was observed for kidney (OR 0.63, 95% CI 0.47, 0.84), heart (OR 0.58, 95% CI 0.40, 0.83), lung (OR 0.41, 95% CI 0.21, 0.77), and bone marrow (OR 0.57, 95% 0.38, 0.85) transplants. Associations were attenuated, but remained, following adjustment for indications for the respective type of transplant. Liver transplant was not associated with PD risk. CONCLUSIONS: Patients undergoing tissue transplant may have a lower risk of developing PD than the general population. Further studies are needed to determine if this association is causal and if immunosuppressants mediate this association.