Imaging Biomarkers of Neurotoxicity in Welders

摘要 锰是一种公认的神经毒物，影响相同的运动和认知大脑通路。 受帕金森病(PD)影响，特别是黑质纹状体系统。大量的研究，主要来自我们的 合作小组，证明接触锰的工人具有重叠的临床表型 基本上与帕金森病有关，包括锰剂量依赖的进行性帕金森综合症和黑质纹状体功能障碍。 正电子发射断层扫描(PET)脑成像。在目前的PET成像项目的头五年， 我们使用大脑中多巴胺系统的PET生物标志物来确定接触锰的工人有 PET放射性配体6-[18F]-氟-L-多巴(FDOPA)与未暴露的相比尾酸结合量降低 工人们。这些差异在五年的跟踪调查中仍然存在。我们还发现了锰的剂量依赖性。 放射性配基[11C](N-)测定多巴胺2型受体(D2R)结合的上调 (甲基)苯哌利多(NMB)，在黑质中，大脑中受影响最大的同一区域。 警察。此外，我们还发现，丘脑(即纹状体外)与锰的剂量反应成反比。 [11C]二氢四苯肼(DTBZ)结合，以及尾核、壳核和 随着时间的推移，黑质。最近，我们的实验室发现了锰引起神经炎症(小胶质细胞)的证据 在死亡的锰矿工的大脑中的激活)为我们的体内发现提供了一种潜在的机制 焊工队伍。这一更新建立在我们之前的研究基础上，通过探索神经炎症在锰中毒中的作用。 诱发的多巴胺能神经毒性。我们的假设是，锰诱导的进行性帕金森症是一种 神经退行性疾病是由于锰剂量依赖的多巴胺能变性所致。我们将表演 来自我们的纵向锰暴露工人队列的研究参与者重复DTBZ和NMB PET成像 已接受基线DTBZ和NMB扫描以调查寿命之间的关联 累积的锰暴露，由最先进的中子激活的骨锰定量提供信息，以及年率 DTBZ和NMB结合的变化。我们还将执行N-acetyl-N-(2-[(11)C]methoxybenzyl)-2-phenoxy-5- 在这些工人中进行吡啶胺[(11)C]PBR28(PBR28)PET成像以表征小胶质细胞的模式 相同脑区的激活，并研究终生累积锰暴露与 PBR28结合可作为神经炎症的标志物。然后，我们将探索神经炎症作为一种 锰致纹状体变性的中介物。最后，我们扩大了我们的队列，以丰富活跃的工人和 将进行纵向正电子发射计算机断层扫描，以表征终身累积锰暴露与 这些放射性配基的纹状体和纹状体外结合/摄取的年变化率 以及退休的接触锰的工人。成功实现这些目标将提供一个独特的机会 了解一种重要的环境黑质纹状体神经毒物的机制，并可能为 对帕金森病的环境发病机制的认识。

Abstract Manganese (Mn) is an established neurotoxicant that affects the same motor and cognitive brain pathways affected in Parkinson disease (PD), notably the nigrostriatal system. A large body of research, largely from our collaborative team, demonstrates that Mn-exposed workers have a clinical phenotype which overlaps substantially with PD, including Mn-dose-dependent progressive parkinsonism and nigrostriatal dysfunction on positron emission tomography (PET) brain imaging. In the first five years of the present PET imaging project, we used PET biomarkers of the dopaminergic system in the brain to establish that Mn-exposed workers had lower caudate binding of the PET radioligand 6-[18F]fluoro-L-dopa (FDOPA), as compared to non-exposed workers. These differences remained over five years of follow-up. We also found Mn-dose-dependent upregulation of dopamine type 2 receptor (D2R) binding, as measured by the radioligand [11C](N- methyl)benperidol (NMB), in the substantia nigra, the same region of the brain most dramatically affected in PD. In addition, we found an inverse Mn-dose-response association with thalamic (i.e., extrastriatal) [11C]dihydrotetrabenazine (DTBZ) binding, as well as a decline in DTBZ binding in caudate, putamen, and substantia nigra over time. More recently, our lab found evidence of Mn-induced neuroinflammation (microglial activation) in the brains of deceased Mn miners providing a potential mechanism for the in vivo findings in our welder cohort. This renewal builds on our previous studies by exploring the role of neuroinflammation in Mn- induced dopaminergic neurotoxicity. Our hypothesis is that Mn-induced progressive parkinsonism is a neurodegenerative disorder and is due to Mn-dose-dependent dopaminergic degeneration. We will perform repeat DTBZ and NMB PET imaging in research participants from our longitudinal Mn-exposed worker cohort who have already undergone baseline DTBZ and NMB scans to investigate the association between lifetime cumulative Mn exposure, informed by state-of-the-art neutron activated bone Mn quantication, and annual rate of change in DTBZ and NMB binding. We will also perform N-acetyl-N-(2-[(11)C]methoxybenzyl)-2-phenoxy-5- pyridinamine [(11)C]PBR28 (PBR28) PET imaging in these workers to characterize patterns of microglial activation in the same brain regions, and investigate the relationship between lifetime cumulative Mn exposure and PBR28 binding as a marker of neuroinflammation. We then will explore the role of neuroinflammation as a mediator of Mn-induced striatal degeneration. Finally, we enlarge our cohort to enrich for active workers and will perform longitudinal PET imaging to characterize the relation between lifetime cumulative Mn exposure and the annual rate of change in both striatal and extrastriatal binding/uptake of these radioligands between active and retired Mn-exposed workers. Successful completion of these aims will provide a unique opportunity to understand the mechanism of an important environmental nigrostriatal neurotoxicant and potentially inform the understanding of the environmental pathogenesis of PD.