Imaging Biomarkers of Neurotoxicity in Welders

焊工神经毒性的成像生物标志物

• 批准号: 10747199
• 负责人: Brad A Racette
• 金额: $ 52.61万
• 依托单位: ST. JOSEPH'S HOSPITAL AND MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-11 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10747199
• 关键词: Imaging; Biomarkers; Neurotoxicity; Welders

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.

抽象的 锰（MN）是一种已建立的神经毒性，影响相同的电动机和认知脑途径 受到帕金森氏病（PD）的影响，尤其是黑质体系。大量研究，主要来自我们 协作团队表明，暴露于MN的工人具有重叠的临床表型 基本上具有PD，包括Mn剂量依赖性的进行性帕金森氏症和骨纹状体功能障碍 正电子发射断层扫描（PET）脑成像。在本宠物成像项目的头五年中， 我们使用大脑中多巴胺能系统的PET生物标志物来确定MN暴露的工人 与非暴露 工人。这些差异在五年的随访中仍然存在。我们还发现Mn剂量依赖性 通过辐射仪[11C]（n-）测量的多巴胺2受体（D2R）结合的上调 甲基）苯哌啶（NMB），在黑质中，大脑的同一区域受到最大影响 PD。此外，我们发现了与丘脑的逆MN剂量反应缔合（即层次外） [11C]二氢苯甲嗪（DTBZ）结合，以及尾状，鬼核桃和dtbz结合的下降 随着时间的流逝，黑质。最近，我们的实验室发现了MN诱导的神经炎症的证据（小胶质细胞 激活）在已故MN矿工的大脑中，为我们的体内发现提供了潜在的机制 焊工队列。这种更新是基于我们以前的研究，探索神经炎症在Mn-中的作用 诱导的多巴胺能神经毒性。我们的假设是Mn引起的渐进式帕金森主义是一种 神经退行性疾病，是由于Mn剂量依赖性多巴胺能变性引起的。我们将表演 在我们纵向MN暴露的工人队列的研究参与者中重复DTBZ和NMB PET成像 他们已经进行了基线DTBZ和NMB扫描以调查寿命之间的关联 累积MN暴露，通过最新的中子激活骨MN量化和年率告知 DTBZ和NMB结合的变化。我们还将执行N-乙酰基-N-（2 - [（11）C]甲氧基苯基）-2-苯氧-5-- 吡啶胺[（11）C] PBR28（PBR28）这些工人的PET成像以表征小胶质细胞的模式 在同一大脑区域激活，并研究寿命累积MN暴露之间的关系 和PBR28结合为神经炎症的标记。然后，我们将探索神经炎症的作用 MN诱导的纹状体变性的介体。最后，我们扩大了同伙，以丰富活跃的工人和 将执行纵向PET成像以表征寿命累积MN暴露与 这些放射线的纹状体和层外结合/摄取的年度变化率 和退休的MN暴露工人。这些目标的成功完成将为您提供独特的机会 了解重要的环境黑质神经毒性的机制，并有可能告知 了解PD的环境发病机理。