Imaging Biomarkers of Neurotoxicity in Welders

焊工神经毒性的成像生物标志物

基本信息

批准号：
10659057
负责人：
Brad A Racette
金额：
$ 50.72万
依托单位：
ST. JOSEPH'S HOSPITAL AND MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/10659057
关键词：
Affect Basal Ganglia Binding Biological Markers Brain Brain imaging Brain region Clinical Cognitive Corpus striatum structure Data Dopamine Dose Exhibits Functional disorder Globus Pallidus Image Laboratory Finding Levodopa Manganese Measures Mediating Mediation Mediator Motor Neurodegenerative Disorders Neurotoxins Neutrons Occupational Outcome Parkinson Disease Parkinsonian Disorders Participant Pathogenesis Pathway interactions Pattern Policies Positron-Emission Tomography Research Role Sample Size Scanning Substantia nigra structure System Thalamic structure Time Up-Regulation Work Workplace bone brain pathway clinical phenotype clinically relevant cohort dihydrotetrabenazine follow-up glial activation imaging biomarker improved in vivo insight longitudinal positron emission tomography neuroinflammation neurotoxicity nigrostriatal degeneration nigrostriatal system putamen radioligand rate of change receptor receptor binding response uptake vesicular monoamine transporter 2 worker safety

项目摘要

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) 是一种已知的神经毒物，会影响相同的运动和认知大脑通路帕金森病 (PD) 受影响，尤其是黑质纹状体系统。大量的研究，大部分来自我们协作团队证明，接触锰的工人具有重叠的临床表型实质上与帕金森病有关，包括锰剂量依赖性进行性帕金森病和黑质纹状体功能障碍正电子发射断层扫描（PET）脑成像。在当前 PET 成像项目的前五年中，我们使用大脑中多巴胺能系统的 PET 生物标志物来确定接触锰的工人与未暴露的相比，PET 放射性配体 6-[18F]氟-L-多巴 (FDOPA) 的尾状核结合较低工人。这些差异在五年的随访中仍然存在。我们还发现锰剂量依赖性通过放射性配体 [11C](N- 测量) 2 型多巴胺受体 (D2R) 结合的上调甲基）苯哌啶醇（NMB），位于黑质，该区域是大脑中受影响最严重的区域。 PD。此外，我们发现锰剂量反应与丘脑（即纹状体外）呈负相关 [11C]二氢丁苯那嗪 (DTBZ) 结合，以及尾状核、壳核和核中 DTBZ 结合的下降随着时间的推移黑质。最近，我们的实验室发现了锰诱导的神经炎症（小胶质细胞）的证据已故锰矿矿工大脑中的激活）为我们的体内发现提供了潜在机制焊工队列。这项更新建立在我们之前的研究的基础上，通过探索神经炎症在锰- 诱导多巴胺能神经毒性。我们的假设是，锰诱发的进行性帕金森病是一种神经退行性疾病，是由于锰剂量依赖性多巴胺能变性所致。我们将表演对来自我们纵向锰暴露工人队列的研究参与者重复 DTBZ 和 NMB PET 成像已经接受基线 DTBZ 和 NMB 扫描以调查寿命之间的关联的人累积锰暴露量，由最先进的中子激活骨锰定量和年率提供 DTBZ 和 NMB 结合的变化。我们还将进行 N-乙酰基-N-(2-[(11)C]甲氧基苄基)-2-苯氧基-5- 对这些工作人员进行吡啶胺 [(11)C]PBR28 (PBR28) PET 成像，以表征小胶质细胞的模式相同大脑区域的激活，并研究终生累积锰暴露之间的关系和 PBR28 结合作为神经炎症的标志物。然后我们将探讨神经炎症作为锰诱导的纹状体变性的介质。最后，我们扩大了我们的队伍，以丰富活跃的工人和将进行纵向 PET 成像，以表征终生累积锰暴露与这些放射性配体之间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。成功完成这些目标将为了解重要的环境黑质纹状体神经毒物的机制，并可能为了解 PD 的环境发病机制。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A predictive model to identify Parkinson disease from administrative claims data.

从行政索赔数据中识别帕金森病的预测模型。

DOI：
发表时间：
2017-10-03
期刊：
影响因子：
9.9
作者：
Searles Nielsen, Susan;Warden, Mark N;Camacho;Willis, Allison W;Wright, Brenton A;Racette, Brad A
通讯作者：
Racette, Brad A

Neuromythology of Manganism.

锰的神经神话学。