Neuroimaging of Manganese Toxicity

锰毒性的神经影像学

• 批准号: 10385692
• 负责人: Ulrike Dydak
• 金额: $ 55.08万
• 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/10385692
• 关键词: Aluminum; Animals; Antioxidants; Area; Basal Ganglia; Bayesian Analysis; Brain; 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 Name; 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; Relaxation; Reporting; Research Design; Risk; Risk Factors; Schools; Spectrum Analysis; Substantia nigra structure; Symptoms; Techniques; Technology; Testing; Thalamic structure; Time; Toxic effect; Toxicokinetics; Translating; Ursidae Family; 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; spectroscopic imaging; 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.

抽象的 通过吸入焊接烟雾而接触锰（MN）仍然是健康危险因素， 导致脑MN的积累和焊工的神经化学变化，这进一步导致了变化 情绪，认知和运动功能。然而，关于 在人脑的特定大脑区域的吸收和消除MN。此外，动物和 细胞研究强烈认为氧化应激是Mn毒性的主要机制之一，即 在人脑中尚未探索氧化应激及其与症状的关系。我们的小说 磁共振成像（MRI）和光谱（MRS）技术允许生成全脑图 Mn沉积以及谷胱甘肽（GSH）的测量，氧化应激和G-的标志 氨基丁酸（GABA），人脑中的主要抑制性神经递质。使用这些技术， 拟议工作的主要目的是阐明时空吸收和消除 焊接人类大脑中的锰，以及氧化应激标志物的关系 特定大脑区域的神经递质失衡对情绪，认知和运动功能。我们的初步 数据表明，沿着白质区的扩散可能有助于皮质区域的MN沉积，以及 消除大脑MN的时间在整个大脑中各不相同。此外，暴露引起的增加 丘脑GABA在减少MN暴露后似乎是可逆的。利用纵向研究 设计，我们独特地进入个人空气抽样和准确曝光的职业焊工队列 评估以及我们最先进的神经影像学技术，该提案将检验中心假设 Mn沉积与消除人脑的剂量反应关系在跨 通过氧化应激和神经递质的不平衡导致不同的大脑区域和导致大脑区域 具体症状。测试脑MN积累的摄取是否依次发生 大脑导致氧化应激和GABA失衡，AIM 1将通过 在使用个人空气抽样的两年后，在焊接职业两年后，经过20个新的焊接学徒， 全脑定量MRI和小说夫人编辑技术Hermes。在AIM 2中，我们将招募40 活跃的经验丰富的焊工和40名控制工人在丘脑中探测GSH和GABA， 小脑和额叶皮层。测试电池，以改变情绪，认知和运动功能的变化 用于研究与神经化学变化的关联。在AIM 3中，将使用相同的方法来学习 通过以下20个焊工不再暴露于MN（退休，更改工作）来消除大脑MN 年。了解人脑MN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对我们的理解产生重大的翻译影响 MN焊接中的MN剂量反应关系，将为安全水平的职业MN暴露提供信息。