Manganese (Mn) is a neurotoxicant that is present in soil, air, and water. Investigations of occupationally- exposed groups, such as welders, provide an ideal opportunity to characterize dose-related dopaminergic system damage associated with Mn. Recent studies from our collaborating institutions demonstrate a high prevalence of Parkinsonism in workers with chronic exposure to Mn containing welding fumes and dopaminergic dysfunction on [18F] fluorodopa (FDOPA) PET. This study utilizes an established, well characterized cohort of welders with detailed exposure and clinical assessments, developed through NIEHS funded research projects. For this proposal, a cohort of 40 career welders with baseline FDOPA PET scans will undergo repeat PET imaging of the nigrostriatal dopamine system using FDOPA and first time imaging with the presynaptic dopaminergic radioligand [11C]dihydrotetrabenazine (DTBZ) and the post-synaptic dopamine D2 receptor selective radioligand [11C]N-methylbenperidol (NMB). These workers will be compared to a second group of non-welder reference subjects who will be imaged at baseline and four years. The specific goals of this project are: 1) to investigate progression of dopaminergic dysfunction in welding exposed workers as evidence of progressive neurotoxicity, 2) to use the radioligand DTBZ to investigate the dose-response relationship with welding fume exposure as an indicator of the underlying etiologic relationship between Mn and damage to the presynaptic dopaminergic system, and 3) to use the radioligand NMB to investigate the dose-response relationship with welding fume exposure as an indicator of the underlying etiologic relationship between Mn and damage to the postsynaptic dopamine system. This proposal uses state-of-the-art imaging methods to investigate the health effects of a common environmental and occupational health hazard. The results of this study will have broad implications for public and worker health worldwide and will inform future community based studies of metal neurotoxicity. In addition, this study, in conjunction with our previously published data, will provide converging evidence of the role of Mn as a nigrostriatal neurotoxin. The methods described in this application represent cutting edge molecular and MRI techniques and the institutions and investigators are ideally suited for this unique epidemiology and imaging proposal.
Manganese is a widespread neurotoxicant that is associated with damage to some of the same brain regions as in Parkinson disease. We have shown recently that manganese exposed welders frequently have damage to the nigrostriatal brain system and a high prevalence of Parkinsonism. This proposal employs state of the art molecular imaging to investigate progression of dopaminergic dysfunction and dose dependent pre- and post- synaptic dopaminergic neurotoxicity in a cohort of well characterized manganese exposed welders.
|Costa-Mallen, Paola; Zabetian, Cyrus P; Agarwal, Pinky et al. (2015) Haptoglobin phenotype modifies serum iron levels and the effect of smoking on Parkinson disease risk. Parkinsonism Relat Disord 21:1087-92|
|Criswell, Susan R; Nelson, Gill; Gonzalez-Cuyar, Luis F et al. (2015) Ex vivo magnetic resonance imaging in South African manganese mine workers. Neurotoxicology 49:8-14|
|Andruska, Kristin M; Racette, And Brad A (2015) Neuromythology of Manganism. Curr Epidemiol Rep 2:143-148|
|Morris, Marie; Willis, Allison W; Searles Nielsen, Susan et al. (2015) Physician response to a medication alert system in inpatients with levodopa-treated diseases. Neurology 85:420-4|
|Racette, Brad A; Willis, Allison W (2015) Time to change the blind men and the elephant approach to Parkinson disease? Neurology 85:190-6|
|Searles Nielsen, Susan; Checkoway, Harvey; Criswell, Susan R et al. (2015) Inducible nitric oxide synthase gene methylation and parkinsonism in manganese-exposed welders. Parkinsonism Relat Disord 21:355-60|
|Racette, Brad A (2014) Manganism in the 21st century: the Hanninen lecture. Neurotoxicology 45:201-7|