Manganese-related neurotoxicity in asymptomatic welders

项目摘要/摘要 毫无疑问，高水平的锰暴露会导致神经毒性。这种相互竞争的更新， 然而，重点是慢性、低水平锰暴露的后果(即更相关的是 职业和公共卫生)。在本项目期间，我们招募和研究了一批 慢性焊接暴露的无症状焊工的平均水平低于大多数先前的研究。在……里面 在这些焊工中，我们证明了1)T1映射(R1)比 传统的苍白球指数(PI)，大脑中的锰积累在基底节(BG)最高 结构，非线性，与短期暴露指标相关，具有特定的、明显的拐点； 2)标准神经心理测试(NPT)检测到与焊接相关的几个认知功能显著下降 功能任务；以及3)R2*[据称测量组织铁(Fe)含量]在BG和 执行功能的音素流利性表现与语音流利性显著相关。 然而，与基于他人工作的原始假设相反，BG和BG都是 对电机系统至关重要，在传统焊工和精细焊工中具有最高的锰和铁积累量 运动任务没有显示出焊工的显著缺陷。我们假设传统的和精细的运动任务 可能没有足够的敏感度来检测我们的焊工的细微变化，但在功能上很重要 接触水平相对较低。因此，我们开始对多指协同的指标进行量化，a 最新的基于理论的方法，量化手运动功能的稳定性。另一个意想不到的发现是 在我们的焊工中，接触锰的指标(即，r1或pI)与NPT的结果都没有相关性，也 与我们最初的假设相反。我们推测，大脑中MN-NPT相关性的缺乏可能是由于 至少部分归因于锰积累的暂时性，这不一定反映长期的、累积的 神经病变或后果，特别是当锰暴露相对较低时。因此，我们 应用扩散张量成像(DTI)评估大脑微结构变化，以捕捉潜在的锰- 相关的神经病理学。总而言之，这些努力导致了我们目前的核心假设 应用：焊接暴露，即使在低水平，也会导致不可逆的微结构变化，如 DTI(目标1)表明，磁化率图(目标2)表明较高的铁积累，以及 神经行为后果，可以通过创新的协同指标敏感地捕获，并在- 深度神经心理测验(目标3)。拟议的研究将严格检验中心假设 通过研究100名焊工(包括在职和退休)和60名对照，在基线和18个月的随访中。 最后，我们将探讨焊接暴露、锰积累(R_1和P_i)、铁积累(R_2~*和QSM)、 微结构变化(DTI)在导致协同和/或神经行为变化的因果链条上， 并探索可能改变或中断这条道路的因素(目标4)。

PROJECT SUMMARY/ABSTRACT There is little doubt that high level Mn exposure can cause neurotoxicity. This competing renewal, however, is focused on the consequences of chronic, low level Mn exposure (i.e., more relevant to occupational and public health). During the current project period, we recruited and studied a cohort of asymptomatic welders with chronic welding exposure at an average level lower than most previous studies. In these welders, we demonstrated that 1) T1 mapping (R1) reflected Mn exposure levels more sensitively than the traditional pallidal index (PI), with Mn accumulation in the brain being highest in basal ganglia (BG) structures, non-linear, and having a specific, marked inflection point in relation to short term exposure metrics; 2) standard neuropsychological tests (NPTs) detected significant welding-related declines in several cognitive function tasks; and 3) R2* [purported measurement for tissue iron (Fe) content] also was higher in BG and correlated significantly with phonemic fluency performance of executive functions. Yet contrary to the original hypothesis based on the work of others, and the fact that the BG both are critical for the motor system and have the highest Mn and Fe accumulation in welders, traditional and fine motor tasks failed to show significant deficits in welders. We postulated that traditional and fine motor tasks may have inadequate sensitivity for detecting subtle, but functionally important, changes in our welders who have relatively lower levels of exposure. Thus, we have begun to quantify indices of multi-finger synergy, a recent theory-based method that quantifies stability of hand motor function. Another unexpected finding was that neither measure of Mn exposure (i.e., R1 nor PI) correlated with the results of NPTs in our welders, also contrary to our original hypotheses. We postulated that the lack of brain Mn-NPT correlations may be due, at least in part, to the transient nature of Mn accumulation that does not necessarily reflect long-term, cumulative neuropathological changes or consequences, especially when Mn exposure is relatively low. Thus, we implemented diffusion tensor imaging (DTI) to assess brain microstructural changes to capture potential Mn- related neuropathology. Together, these efforts have led to our central hypotheses for the current application: welding exposure, even at low levels, leads to irreversible microstructural changes as indicated by DTI (Aim 1), higher Fe accumulation as indicated by susceptibility mapping (Aim 2), and neurobehavioral consequences that can be captured sensitively by innovative synergy metrics and in- depth neuropsychological testing (Aim 3). The proposed study shall rigorously test the central hypotheses by studying 100 welders (both active and retired) and 60 controls at baseline and at an 18-month follow-up. Lastly, we shall explore that welding exposure, Mn accumulation (R1 & PI), Fe accumulations (R2* & QSM), and microstructural changes (DTI) are on the causal chain leading to synergy and/or neurobehavioral changes, and explore the factors that may modify or interrupt this path (Aim 4).