Regional Brain Manganese Accumulation and Functional Consequences in Welders

描述（由申请人提供）：连同一些相关的遗传因素，大量数据表明环境因素，特别是神经毒性金属，可能在神经行为障碍的病因学中发挥作用。锰（Mn）是一种众所周知的神经毒性物质，在普通人群中广泛存在于汽油添加剂、化石燃料燃烧中，并在接触焊接烟雾的工人中大量积累。明显的锰神经毒性（锰中毒或锰诱发的帕金森病）引起的症状与帕金森病相似，对“无症状”焊工的研究表明，接触含锰金属烟雾与亚临床神经行为缺陷之间存在关联。人们怀疑低水平锰与神经系统疾病之间存在联系，但由于缺乏体内锰剂量对人脑的客观标记物，以及缺乏关于锰剂量与功能损害之间关系的数据，这种联系被削弱了。二价锰（Mn2+）是顺磁性的，导致T1弛豫时间的减少明显大于所有其他金属，特别是焊接烟雾中含有的金属。因此，磁共振成像（MRI） T1弛豫时间和T1对比变化可以有足够的特异性反映焊工脑组织中Mn的积累。历史上，苍白指数被用作明显的锰中毒的MRI测量。它的效用一直受到质疑，因为研究中忽略了苍白球（GP）以外的区域，而且苍白球指数可能对低水平的暴露不敏感。在人类受试者的初步数据的支持下，我们建议验证一个中心假设，即相对于匹配的对照组，“无症状”焊工在特定大脑区域（如嗅球（OB）、基底神经节（BG：即尾状核、壳核和GP）、额叶（FL））的锰积累明显更高。即额叶灰质（FGM）和白质（FWM） &前额叶皮质（包括眶额叶皮质）]，它们与空气中的锰暴露和特定区域的神经行为变化有关。我们建议对40名焊工（锅炉工/管道工）和40名匹配的对照组（电工/洒水器工）进行研究，包括回顾性和前瞻性环境暴露测量、神经心理学测试、血液金属（铁和锰）评估，以及最先进的锰（快速T1映射）和铁（敏感性加权图像（SWI））的MRI估计。通过这项研究，我们将开发一种重要的临床工具，以弥合该领域基础研究和应用研究之间的差距，从而更好地了解神经毒性金属在神经行为障碍发展中的作用。这将通过以下具体目标来实现：目标1将验证MRI T1测量为人类特定大脑区域（例如OB， BG和FL等）的Mn暴露提供可靠的生物标志物。目的2将描述脑内区域特异性锰积累的功能后果。目的3将探讨铁锰在大脑中的相互作用及其功能后果。

DESCRIPTION (provided by applicant): Along with a number of associated genetic factors, a large body of data indicates that environmental agents, especially neurotoxic metals, may play a role in the etiology of neurobehavioral disorders. Exposure to manganese (Mn), a well-known neurotoxicant, is widespread in the general population from gasoline additives, fossil fuel combustion, and accumulates at high levels in workers exposed to welding fumes. Overt Mn neurotoxicity (manganism or Mn-induced parkinsonism) causes symptoms that are similar to Parkinson's disease, and studies with "asymptomatic" welders suggest an association between exposure to Mn-containing metal fumes and subclinical neurobehavioral deficits. A link between low levels of Mn and neurological disorders is suspected, but weakened by both the lack of an in vivo objective marker of Mn dose to the human brain, and from insufficient data on how this correlates with functional impairment. Divalent Mn (Mn2+) is paramagnetic and causes a reduction in T1 relaxation time that is significantly greater than for all other metals, particularly the metals contained in welding fumes. Thus, magnetic resonance imaging (MRI) T1 relaxation time and T1 contrast changes of magnetic resonance imaging (MRI) may reflect Mn accumulation in the brain tissue of welders with adequate specificity. Historically, the pallidal index has served as an MRI measure for overt Mn poisoning. Its utility has been questioned because regions other than the globus pallidus (GP) have been neglected for study, and the pallidal index may not be sensitive to low levels of exposure. Supported by preliminary data in human subjects, we propose to test the central hypothesis that, relative to matched controls, "asymptomatic" welders will have significantly higher Mn accumulation in specific brain regions [e.g., olfactory bulbs (OB), basal ganglia (BG: i.e., caudate, putamen & GP), frontal lobe (FL: i.e., frontal gray (FGM) and white matter (FWM) & prefrontal cortex (including the orbital frontal cortex)] that correlate with airborne Mn exposure and region-specific neurobehavioral changes. We propose a study of 40 welders (boilermakers/pipefitters) and 40 matched controls (electricians/sprinkler fitters) with both retrospective and prospective environmental exposure measurements, neuropsychological tests, blood metal (Fe and Mn) assessment, and state-of-the-art MRI estimates of both Mn (with rapid T1 mapping) and Fe [with Susceptibility Weighted Images (SWI)]. Via this study, we shall develop an important clinical tool to bridge the gap between basic and applied research in this area that will lead to a better understanding of the role that neurotoxic metals play in the development of neurobehavioral disorders. This will be accomplished through the following specific aims: Aim 1 will validate that the MRI T1 measurements provide a reliable biomarker of Mn exposure in specific brain regions [e.g., OB, BG and FL, etc.] in humans. Aim 2 will delineate the functional consequences of region-specific Mn accumulation in the brain. Aim 3 will explore Fe-Mn interactions in brain and their functional consequences. PUBLIC HEALTH RELEVANCE: Manganese (Mn), a well-known neurotoxicant that is ubiquitous in the environment from gasoline additives, the combustion of fossil fuels, as well as being particularly concentrated in welding fumes, may play a role in neurodegenerative processes. The basic and epidemiological studies in this area, however, are marred by the lack of an objective marker(s) of metal deposition in the human brain and how this correlates directly with neurobehavioral impairment. The proposed study will use the improved, state-of-the-art MRI techniques to reflect regional brain Mn deposition in response to environmental exposure, delineate its functional correlations, and will lead to a better understanding of the role of environmental neurotoxicants in the development of neurobehavioral disorders.