Regional Brain Manganese Accumulation and Functional Consequences in Welders

描述（由申请人提供）：沿着许多相关遗传因素，大量数据表明环境因子，尤其是神经毒性金属，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物，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积累高水平。明显的锰神经毒性（锰中毒或锰诱导的帕金森病）引起的症状与帕金森病相似，对“无症状”焊工的研究表明，暴露于含锰金属烟雾和亚临床神经行为缺陷之间存在关联。低水平的锰和神经系统疾病之间的联系被怀疑，但削弱了锰剂量的人体大脑的体内客观标志物的缺乏，并从不足的数据，这是如何与功能障碍。二价Mn（Mn 2+）是顺磁性的，并导致T1弛豫时间的减少，其显著大于所有其他金属，特别是焊接烟雾中所含的金属。因此，磁共振成像（MRI）的T1弛豫时间和T1对比度变化的磁共振成像（MRI）可以反映锰积累在脑组织中的焊工具有足够的特异性。从历史上看，苍白球指数已被用作明显锰中毒的MRI测量。其效用受到质疑，因为苍白球（GP）以外的区域已被忽略的研究，苍白球指数可能不敏感的低水平的曝光。在人类受试者的初步数据的支持下，我们提出测试中心假设，即相对于匹配的对照，“无症状”焊工在特定的大脑区域中具有显著更高的Mn积累[例如，嗅球（OB），基底神经节（BG：即，尾状核、壳核和GP），额叶（FL：即，额叶灰质（FGM）和白色物质（FWM）和前额叶皮层（包括眶额叶皮层）]，与空气中锰暴露和区域特异性神经行为变化相关。我们提出了一项研究，40名焊工（锅炉制造商/管道安装工）和40名匹配的对照（电工/洒水器安装工），回顾性和前瞻性的环境暴露测量，神经心理学测试，血液金属（铁和锰）评估，以及最先进的MRI估计锰（快速T1映射）和铁[敏感性加权图像（SWI）]。通过这项研究，我们将开发一个重要的临床工具，以弥合这一领域的基础和应用研究之间的差距，这将导致更好地了解神经毒性金属在神经行为障碍的发展中发挥的作用。这将通过以下具体目标来实现：目标1将验证MRI T1测量值提供特定脑区域中Mn暴露的可靠生物标志物[例如，OB、BG和FL等]在人类身上。目的2将描绘特定区域的锰在大脑中积累的功能后果。目的3探讨脑内铁锰相互作用及其功能后果。 公共卫生相关性：锰（Mn）是一种众所周知的神经毒物，在环境中无处不在，来自汽油添加剂，化石燃料的燃烧，以及特别集中在焊接烟雾中，可能在神经退行性过程中发挥作用。然而，这一领域的基础和流行病学研究由于缺乏人类大脑中金属沉积的客观标志物以及这与神经行为障碍的直接相关性而受到损害。拟议的研究将使用改进的，最先进的MRI技术来反映区域脑锰沉积对环境暴露的反应，描绘其功能相关性，并将导致更好地了解环境神经毒物在神经行为障碍发展中的作用。

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.