Age, Lead, Exposure, and Neurobehavioral Decline

描述（由申请人提供）：本竞争性更新申请（第三阶段）旨在解决有关神经毒物，衰老以及大脑结构和功能关系的新的基本问题。在过去的十年里，一致的证据表明，铅会导致成人大脑的重要变化。本研究旨在了解神经毒物如何导致CNS持续或进行性结构变化，结构变化与进行性功能丧失的关系，以及对介导因素（遗传多态性，血管健康）的了解。在第二阶段，获得了656个脑部MRI，获得了96个感兴趣区域（ROI）的体积，并使用标准方法对白色物质（WM）病变的图像进行分级。在横断面分析中，进行了以下观察：胫骨电极导线与CNS体积之间的负相关;胫骨电极导线与WM病变的患病率和严重程度之间的直接相关; CNS体积与神经行为测试评分之间的直接相关（体积较小，表现较差）。现在的数据表明，铅导致成年人中枢神经系统进行性功能下降，结构变化，至少是持久的，都超出了由于正常老化单独。为了了解进行性功能丧失，研究必须调查结构性病变是持续性的还是进行性的，WM和GM效应是否相关，以及这些效应是否存在遗传或血管调节剂。现在正在寻求资金，以完成对500名受试者的第二次MRI，另一次神经行为评估和血管健康评估。目标是确定胫骨电极导线是否会导致大脑中的持续性或进行性结构病变;是否是老化对CNS结构和功能影响的调节剂;使用更好的WM成像方法时，铅如何导致WM病变; WM病变、GM体积变化和功能变化如何相关;以及血管健康是否是铅和中枢神经系统损伤以及结构和功能关系的介导者或调节者。

DESCRIPTION (provided by applicant): This competitive renewal application (Phase III) aims to address new fundamental questions regarding neurotoxicants, aging, and structure and function relations in the brain. Over the past ten years, a consistent body of evidence suggests that lead causes important changes in the adult brain. This research aims to understand how a neurotoxicant causes persistent or progressive structural change in the CNS, the relation of structural change to progressive functional loss, and insight on mediating factors (genetic polymorphisms, vascular health). In Phase II, 656 MRIs of the brain were obtained, volumes of 96 regions of interest (ROIs) were derived, and images were graded for white matter (WM) lesions using a standard method. In cross-sectional analysis, these observations were made: inverse associations between tibia lead and CNS volumes; direct associations between tibia lead and prevalence and severity of WM lesions; and direct associations between CNS volumes and neurobehavioral test scores (smaller volume, worse performance). The data now suggest that lead causes progressive functional decline in the adult CNS, and structural changes that are at least persistent, both beyond what is due to normal aging alone. To understand the progressive functional loss, research must investigate whether the structural lesion is persistent or progressive, whether WM and GM effects are linked, and whether there are genetic or vascular moderators of these effects. Funding is now sought to complete a second MRI on 500 subjects, another neurobehavioral assessment, and an evaluation of vascular health. The goals are to determine if tibia lead causes a persistent or a progressive structural lesion in the brain; if lead is a moderator of the effect of aging on CNS structure and function; how lead causes WM lesions using better WM imaging methods; how WM lesions, changes in GM volumes, and changes in function are related; and if vascular health is a mediator or moderator of lead and CNS injury and of structure and function relations.