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

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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