Manganese-related neurotoxicity in asymptomatic welders

项目总结/摘要 毫无疑问，高水平的锰暴露会导致神经毒性。这种竞争性的更新， 然而，集中在慢性，低水平锰暴露的后果（即，更切合 职业和公共卫生）。在当前的项目期间，我们招募并研究了一组 慢性焊接暴露的无症状焊工的平均水平低于大多数以前的研究。在 这些焊工，我们证明，1）T1映射（R1）反映锰暴露水平更敏感， 传统的苍白球指数（PI），Mn在脑中的蓄积在基底节（BG）中最高 结构，非线性的，并且具有与短期暴露度量相关的特定的、显著的拐点; 2)标准神经心理学测试（NPTs）检测到焊接相关的几个认知功能的显著下降， 功能任务;和3）R2* [组织铁（Fe）含量的预期测量]也高于BG和 与执行功能的音位流畅性表现显著相关。 然而，与基于其他人工作的原始假设相反，BG两者都是 关键的电机系统，并有最高的锰和铁积累焊工，传统和精细 运动任务未能显示出显着的赤字焊工。我们假设传统和精细运动任务 可能没有足够的灵敏度来检测细微的，但功能上重要的变化，我们的焊工， 暴露程度相对较低。因此，我们已经开始量化多指协同的指数， 最近的理论为基础的方法，量化稳定的手运动功能。另一个意想不到的发现是 Mn暴露的测量（即，R1或PI）与我们焊工的NPT结果相关， 与我们最初的假设相反我们推测，大脑Mn-NPT相关性的缺乏可能是由于， 至少部分是由于锰积累的瞬时性质，其不一定反映长期的累积性。 神经病理学变化或后果，特别是当锰暴露相对较低时。因此我们 实施扩散张量成像（DTI），以评估脑微结构变化，以捕获潜在的Mn- 相关神经病理学总之，这些努力导致了我们对当前的核心假设 应用：焊接暴露，即使在低水平下，也会导致不可逆的微观结构变化， 如DTI所示（目标1），如磁化率图所示（目标2）， 神经行为的后果，可以捕捉灵敏的创新协同指标和在- 深度神经心理学测试（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（在职和退休）和60名对照组的基线和18个月的随访。 最后，我们将探讨焊接暴露，锰积累（R1和PI），铁积累（R2* 和QSM）， 和微结构变化（DTI）在因果链上导致协同作用和/或神经行为变化， 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).