Imaging Biomarkers of Neurotoxicity in Welders

焊工神经毒性的成像生物标志物

• 批准号: 8451796
• 负责人: Brad A Racette
• 金额: $ 61.26万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-12-06 至 2017-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8451796
• 关键词: Adult; Affect; Age; Air; Basal Ganglia; Binding; Biological Markers; Brain; Brain region; Carboxy-Lyases; Child; Chronic; Clinical assessments; Communities; Corpus striatum structure; Data; Dopa; Dopamine; Dopamine D2 Receptor; Dose; Environment; Environmental Health; Epidemiology; Exposure to; Financial compensation; Functional disorder; Funding; Future; Gender; Goals; Grant; Hazardous Substances; Health; Health Hazards; High Prevalence; Human; Image; Institution; Investigation; Ligands; Magnetic Resonance Imaging; Manganese; Measures; Mediating; Metals; Methods; Molecular; National Institute of Environmental Health Sciences; Neuraxis; Neurologic; Neurologic Effect; Neurons; Neurotoxins; Occupational Health; Parkinson Disease; Parkinsonian Disorders; Positron-Emission Tomography; Publishing; Research Personnel; Research Project Grants; Role; Scanning; Soil; Synapses; System; Techniques; Time; Water; Welding; base; career; cohort; dihydrotetrabenazine; dopamine system; dopaminergic neuron; imaging modality; in vivo; molecular imaging; neurotoxicity; pet animal; postsynaptic; presynaptic; public health relevance; putamen; radioligand; receptor; response; uptake; vesicular monoamine transporter

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：锰 (Mn) 是一种存在于土壤、空气和水中的神经毒物。对职业暴露群体（例如焊工）的调查提供了一个理想的机会来表征与锰相关的剂量相关的多巴胺能系统损伤。我们合作机构的最新研究表明，长期接触含锰焊接烟雾和 [18F] 氟多巴 (FDOPA) PET 多巴胺能功能障碍的工人帕金森病患病率较高。这项研究利用了经过 NIEHS 资助的研究项目开发的、经过详细暴露和临床评估的已建立的、特征明确的焊工队列。对于该提案，由 40 名接受过基线 FDOPA PET 扫描的职业焊工组成的队列将使用 FDOPA 对黑质纹状体多巴胺系统进行重复 PET 成像，并使用突触前多巴胺能放射性配体 [11C]二氢丁苯那嗪 (DTBZ) 和突触后多巴胺 D2 进行首次成像受体选择性放射性配体[11C]N-甲基苯哌啶醇(NMB)。这些工人将与第二组非焊工参考对象进行比较，这些参考对象将在基线和四年内进行成像。该项目的具体目标是：1) 研究焊接烟雾暴露工人中多巴胺能功能障碍的进展，作为进行性神经毒性的证据，2) 使用放射性配体 DTBZ 来研究与焊接烟雾暴露的剂量反应关系，作为潜在的神经毒性的指标Mn 与突触前多巴胺能系统损伤之间的病因关系，以及 3) 使用放射性配体 NMB 来研究与焊接烟雾暴露的剂量反应关系锰与突触后多巴胺系统损伤之间潜在病因关系的指标。该提案使用最先进的成像方法来研究常见环境和职业健康危害对健康的影响。这项研究的结果将对全球公众和工人健康产生广泛影响，并将为未来基于社区的金属神经毒性研究提供信息。此外，这项研究与我们之前发布的数据相结合，将提供收敛的结果 锰作为黑质纹状体神经毒素作用的证据。本申请中描述的方法代表了最先进的分子和 MRI 技术，机构和研究人员非常适合这种独特的流行病学和影像学建议。