Regional Brain Manganese Accumulation and Functional Consequences in Welders

描述(由申请人提供)：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。接触锰(Mn)是一种众所周知的神经毒物，在普通人群中普遍存在，主要原因是汽油添加剂、化石燃料燃烧，以及接触焊接烟雾的工人体内累积水平较高。明显的锰神经毒性(锰中毒或锰致帕金森症)会引起类似帕金森氏症的症状，而对“无症状”焊工的研究表明，暴露在含锰金属烟雾中与亚临床神经行为缺陷之间存在关联。低水平的锰与神经疾病之间的联系被怀疑，但由于缺乏人体内锰剂量的客观标记物，以及关于这种联系如何与功能损害相关的数据不足，这种联系被削弱了。二价锰(Mn2)是顺磁性的，导致T1弛豫时间的缩短明显大于所有其他金属，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MRI的T1对比度变化可以较好地反映电焊工脑组织中锰的积聚，具有足够的特异性。从历史上看，苍白球指数一直是一种公开的锰中毒的磁共振成像指标。它的实用性受到了质疑，因为苍白球(GP)以外的区域在研究中被忽略了，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支持下，我们建议检验中心假设，与匹配的对照组相比，“无症状”焊工在特定大脑区域[例如，嗅球(OB)、基底节(BG：尾状核、壳核和GP)、额叶(FL：额叶灰质(FGM)和白质(FWM)和前额皮质(包括眼眶额叶皮质)]中的锰积累将显著增加，这些区域与空气中锰暴露和区域特定的神经行为变化相关。我们建议对40名焊工(锅炉制造商/管道工)和40名匹配的对照组(电工/喷水配件工)进行一项研究，包括回顾和预期的环境暴露测量、神经心理测试、血液金属(Fe和Mn)评估以及最新的MRI评估，包括Mn(使用快速T1标测)和Fe[使用磁化率加权图像(SWI)]。通过这项研究，我们将开发一种重要的临床工具，弥合这一领域基础研究和应用研究之间的差距，从而更好地理解神经毒性金属在神经行为障碍发展中所起的作用。这将通过以下具体目标来实现：目标1将验证MRI T1测量提供了特定脑区[例如，OB、BG和FL等]中锰暴露的可靠生物标记物。在人类身上。目标2将描述大脑中特定区域的锰积累的功能后果。目标3将探索大脑中铁-锰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.