Neuroimaging of Manganese Toxicity

锰毒性的神经影像学

• 批准号: 10553633
• 负责人: Ulrike Dydak
• 金额: $ 56.6万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-07 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10553633
• 关键词: Aluminum; Aminobutyric Acids; Animals; Antioxidants; Area; Basal Ganglia; Bayesian Analysis; Brain; Brain Mapping; Brain imaging; Brain region; Cells; Cerebellum; Chronic; Cognition; Cognitive; Data; Deposition; Diffusion; Dose; Exposure to; Glutamates; Glutathione; Health; Human; Human Characteristics; Imaging Techniques; Imaging technology; Impaired cognition; Impairment; Individual; Inhalation; Knowledge; Lead; Longitudinal Studies; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Manganese; Manufacturer; Maps; Measurement; Measures; Mediating; Mediation; Methods; Modeling; Moods; Motor; Neurologic; Neurological outcome; Neuropsychological Tests; Neurotransmitters; Occupational; Occupational Exposure; Occupations; Outcome; Oxidative Stress; Parkinson Disease; Parkinsonian Disorders; Phenotype; Protocols documentation; Reduced Glutathione; Relaxation; Reporting; Research Design; Risk; Risk Factors; Schools; Spectrum Analysis; Substantia nigra structure; Symptoms; Techniques; Technology; Testing; Thalamic structure; Time; Toxic effect; Toxicokinetics; Translating; Welding; Work; air sampling; apprenticeship; career; cognitive function; cohort; experience; frontal lobe; gamma-Aminobutyric Acid; imaging approach; imaging biomarker; imaging study; innovation; motor disorder; neurochemistry; neuroimaging; neurotoxic; neurotoxicity; novel; professional atmosphere; psychologic; recruit; response; spatiotemporal; translational impact; uptake; white matter

ABSTRACT Exposure to manganese (Mn) through inhalation of welding fumes continues to be a health risk factor, resulting in accumulation of brain Mn and neurochemical changes in welders, which further lead to changes in mood, cognitive and motor function. Yet, not much is known about the dose-response relationships of uptake and elimination of Mn in specific brain regions of the human brain. Furthermore, while animal and cell studies strongly suggest oxidative stress as one of the primary mechanisms of Mn toxicity, markers of oxidative stress and their relation to symptoms have not yet been explored in the human brain. Our novel magnetic resonance imaging (MRI) and spectroscopy (MRS) techniques allow generating whole-brain maps of Mn deposition, as well as the measurement of glutathione (GSH), a marker of oxidative stress, and g- aminobutyric acid (GABA), the main inhibitory neurotransmitter in the human brain. Using these techniques, the primary objective of the proposed work is to elucidate the spatial-temporal uptake and elimination of manganese in the human brain of welders, and the relationship of oxidative stress markers and neurotransmitter imbalances in specific brain regions to mood, cognition and motor function. Our preliminary data suggest that diffusion along white matter tracts may contribute to Mn deposition in cortical areas, and that the time of elimination of brain Mn varies across the brain. Furthermore, exposure-induced increase of thalamic GABA seems to be reversible upon reduction of Mn exposure. Making use of a longitudinal study design, our unique access to a cohort of career welders for personal air sampling and accurate exposure assessment, and our state-of-the-art neuroimaging technology, this proposal will test the central hypothesis that the dose-response relationship of Mn deposition and elimination in the human brain varies across different brain regions and leads, via oxidative stress and neurotransmitter imbalance, to brain region specific symptoms. To test whether the uptake of brain Mn accumulation occurs sequentially across the brain, leading to oxidative stress and GABA imbalance, Aim 1 will study dynamic Mn brain deposition by following 20 new welding apprentices for two years into their welding career, using personal air sampling, whole-brain quantitative MRI and the novel MRS editing technique, HERMES. In Aim 2 we will recruit 40 active experienced welders and 40 control workers to probe GSH and GABA in the thalamus, the cerebellum and the frontal cortex. A test battery for changes in mood, cognition and motor function will be used to study associations with neurochemical changes. In Aim 3 the same methods will be used to study elimination of brain Mn by following 20 welders who cease to be exposed to Mn (retire, change job) for two years. Understanding the spatio-temporal characteristics of human brain Mn deposition, neurochemical responses and their relation to symptoms will have significant translational impact on our understanding of the Mn dose-response relationship in welding and will inform safe levels of occupational Mn exposure.

摘要 通过吸入焊接烟雾接触锰（Mn）仍然是一个健康风险因素， 导致电焊工脑锰蓄积和神经化学变化，进而导致 情绪、认知和运动功能。然而，对以下物质的剂量-反应关系知之甚少： 锰在人脑特定脑区的吸收和消除。虽然动物和 细胞研究强烈表明氧化应激是锰毒性的主要机制之一， 氧化应激及其与症状的关系尚未在人脑中进行研究。我们的新型 磁共振成像（MRI）和光谱学（MRS）技术可以生成全脑地图 锰沉积，以及谷胱甘肽（GSH）的测量，氧化应激的标志物，和g- 氨基丁酸（GABA）是人脑中主要的抑制性神经递质。使用这些技术， 拟议工作的主要目标是阐明时空吸收和消除 电焊工脑中锰的含量，以及氧化应激标志物与 特定脑区的神经递质失衡对情绪、认知和运动功能的影响。我们的初步 数据表明，沿着白色物质束的扩散可能有助于锰在皮质区的沉积， 大脑Mn的消除时间在整个大脑中是不同的。此外，增加了 丘脑GABA似乎在Mn暴露减少时是可逆的。利用纵向研究 设计，我们独特的职业焊工群体的个人空气采样和准确的暴露 评估，以及我们最先进的神经成像技术，这项建议将测试中心假设 锰在人脑中的沉积和消除的剂量-反应关系在不同的环境中是不同的。 不同的大脑区域，并通过氧化应激和神经递质失衡导致大脑区域 具体症状。为了测试大脑锰累积的吸收是否在整个过程中顺序发生 大脑，导致氧化应激和GABA失衡，目的1将研究动态锰脑沉积， 在20名新的焊接学徒进入他们的焊接职业生涯两年之后，使用个人空气采样， 全脑定量MRI和新型MRS编辑技术爱马仕。在目标2中，我们将招募40名 活跃的有经验的焊工和40名对照工人，以探测丘脑中GSH和GABA， 小脑和额叶皮层一个测试电池的变化，情绪，认知和运动功能将是 用于研究神经化学变化的关联。在目标3中，将使用相同的方法来研究 通过对20名停锰（退休、转业）电焊工两年后脑锰消除情况的跟踪调查， 年了解人脑锰沉积的时空特征，神经化学 反应及其与症状的关系将对我们理解 焊接中锰的剂量-反应关系，并将告知职业锰暴露的安全水平。