Imaging Biomarkers of Neurotoxicity in Welders

焊工神经毒性的成像生物标志物

基本信息

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.
摘要 锰(Mn)是一种公认的神经毒物,影响相同的运动和认知脑通路 帕金森病(PD),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,表明锰暴露工人有一个临床表型重叠, 基本上与PD,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, 我们使用脑中多巴胺能系统的PET生物标志物来确定锰暴露工人 PET放射性配体6-[18F]氟-L-多巴(FDOPA)的尾状结合较低,与未暴露的相比 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[11 C](N-)测量,多巴胺2型受体(D2 R)结合上调 甲基)苯哌利多(NMB),在黑质,同一地区的大脑最显着影响, 警局此外,我们发现了与丘脑(即,纹状体外) [11 C]二氢丁苯那嗪(DTBZ)结合,以及尾状核、壳核和 随着时间的推移黑质。最近,我们的实验室发现了锰诱导的神经炎症(小胶质细胞)的证据。 激活)的死亡锰矿工的大脑中提供了一个潜在的机制,在我们的体内发现, 焊工队列。这一更新建立在我们以前的研究基础上,通过探索神经炎症在Mn中的作用, 诱发多巴胺能神经毒性。我们的假设是,锰诱导的进行性帕金森病是一种 在某些实施方案中,Mn是神经变性病症的一种,并且是由于Mn剂量依赖性多巴胺能变性。我们将执行 在我们纵向锰暴露工人队列的研究参与者中重复DTBZ和NMB PET成像 已经接受过基线DTBZ和NMB扫描的患者, 累积锰暴露量,由最先进的中子活化骨锰定量提供信息,以及年暴露率 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-甲基-N-(2-[(11)C]甲氧基苄基)-2-苯氧基-N-(2-[(11)C]甲氧基苄基)-N-苯氧基-N-(2-甲氧基苄基)- 吡啶胺[(11)C] PBR 28(PBR 28)PET成像在这些工人中表征小胶质细胞的模式 激活在相同的大脑区域,并探讨终身累积锰暴露之间的关系 和PBR 28结合作为神经炎症的标志物。然后,我们将探讨神经炎症的作用, 介导锰诱导的纹状体变性。最后,我们扩大了我们的队列,以丰富活跃的工人, 将进行纵向PET成像,以表征寿命累积Mn暴露与 这些放射性配体的纹状体和纹状体外结合/摄取的年变化率 和退休的锰暴露工人。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 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)
Neuromythology of Manganism.
  • DOI:
    10.1007/s40471-015-0040-x
  • 发表时间:
    2015-06
  • 期刊:
  • 影响因子:
    3.3
  • 作者:
    Andruska KM;Racette AB
  • 通讯作者:
    Racette AB
Inflammatory bowel disease and risk of Parkinson's disease in Medicare beneficiaries.
  • DOI:
    10.1016/j.parkreldis.2018.02.008
  • 发表时间:
    2018-05
  • 期刊:
  • 影响因子:
    4.1
  • 作者:
    Camacho-Soto A;Gross A;Searles Nielsen S;Dey N;Racette BA
  • 通讯作者:
    Racette BA
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Brad A Racette其他文献

Pregnancy in multiple system atrophy: a case report
  • DOI:
    10.1186/1752-1947-5-599
  • 发表时间:
    2011-12-30
  • 期刊:
  • 影响因子:
    0.800
  • 作者:
    Lirong Zhu;Nigel J Cairns;Samer D Tabbal;Brad A Racette
  • 通讯作者:
    Brad A Racette

Brad A Racette的其他文献

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{{ truncateString('Brad A Racette', 18)}}的其他基金

Imaging Biomarkers of Neurotoxicity in Welders
焊工神经毒性的成像生物标志物
  • 批准号:
    10747199
  • 财政年份:
    2023
  • 资助金额:
    $ 50.72万
  • 项目类别:
Manganese-Induced Neurotoxic Effects Research in South Africa
南非锰诱发的神经毒性作用研究
  • 批准号:
    10805968
  • 财政年份:
    2023
  • 资助金额:
    $ 50.72万
  • 项目类别:
Manganese-Induced Neurotoxic Effects Research in South Africa (MINERS)
南非锰诱发的神经毒性效应研究 (MINERS)
  • 批准号:
    10242754
  • 财政年份:
    2017
  • 资助金额:
    $ 50.72万
  • 项目类别:
Manganese-Induced Neurotoxic Effects Research in South Africa (MINERS)
南非锰诱发的神经毒性效应研究 (MINERS)
  • 批准号:
    9768467
  • 财政年份:
    2017
  • 资助金额:
    $ 50.72万
  • 项目类别:
Motor and Cognitive Health Outcomes in a Mn-Exposed African Community
接触锰的非洲社区的运动和认知健康结果
  • 批准号:
    8975835
  • 财政年份:
    2015
  • 资助金额:
    $ 50.72万
  • 项目类别:
Motor and Cognitive Health Outcomes in a Mn-Exposed African Community
接触锰的非洲社区的运动和认知健康结果
  • 批准号:
    9115153
  • 财政年份:
    2015
  • 资助金额:
    $ 50.72万
  • 项目类别:
Motor and Cognitive Health Outcomes in a Mn-Exposed African Community
接触锰的非洲社区的运动和认知健康结果
  • 批准号:
    9236970
  • 财政年份:
    2015
  • 资助金额:
    $ 50.72万
  • 项目类别:
Risk of Parkinson Disease Associated with Solvent Exposures in Finland
芬兰与溶剂接触相关的帕金森病风险
  • 批准号:
    8752056
  • 财政年份:
    2014
  • 资助金额:
    $ 50.72万
  • 项目类别:
Risk of Parkinson Disease Associated with Solvent Exposures in Finland
芬兰与溶剂接触相关的帕金森病风险
  • 批准号:
    8916722
  • 财政年份:
    2014
  • 资助金额:
    $ 50.72万
  • 项目类别:
Imaging Biomarkers of Neurotoxicity in Welders
焊工神经毒性的成像生物标志物
  • 批准号:
    8593295
  • 财政年份:
    2012
  • 资助金额:
    $ 50.72万
  • 项目类别:

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