Imaging Biomarkers of Neurotoxicity in Welders

说明(申请人提供)：锰是一种神经毒物，存在于土壤、空气和水中。对电焊工等职业暴露人群的调查，为表征与锰有关的剂量相关的多巴胺能系统损害提供了一个理想的机会。我们合作机构最近的研究表明，长期暴露于含锰焊接烟雾和[18F]氟多巴(FDOPA)PET多巴胺能障碍的工人中，帕金森病的患病率很高。这项研究利用了通过NIEHS资助的研究项目开发的、具有良好特征的焊工队列，他们具有详细的暴露和临床评估。根据这一建议，40名接受FDOPA PET基线扫描的职业焊工将使用FDOPA对黑质纹状体多巴胺系统进行重复的PET成像，并首次使用突触前多巴胺能放射性配体[11C]二氢四苯并嗪(DTBZ)和突触后多巴胺D2受体选择性放射性配体[11C]N-甲基苯丙啶(NMB)进行首次成像。这些工人将与第二组非焊工参考对象进行比较，后者将在基线和四年内进行成像。本项目的具体目标是：1)研究焊接工人多巴胺能功能障碍的进展情况，作为进行性神经毒性的证据；2)利用放射性配体DTBZ研究焊接烟雾暴露的剂量-反应关系，作为锰与突触前多巴胺系统损伤之间潜在病因关系的指标；以及3)使用放射性配体NMB调查焊接烟雾暴露的剂量-反应关系，作为锰与突触后多巴胺系统损伤之间潜在病因关系的指标。这项建议使用最先进的成像方法来调查常见的环境和职业健康危害对健康的影响。这项研究的结果将对世界各地的公众和工人的健康产生广泛的影响，并将为未来基于社区的金属神经毒性研究提供信息。此外，这项研究结合我们之前发表的数据，将提供收敛 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尖端的分子和核磁共振技术，机构和研究人员非常适合这一独特的流行病学和成像建议。

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.