Age, Lead, Exposure, and Neurobehavioral Decline

描述(由申请人提供)：这项竞争性续签申请(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，铅会导致成年人大脑的重要变化。这项研究旨在了解神经毒物如何导致中枢神经系统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，以及对中介因素(遗传多态、血管健康)的洞察。在第二阶段，获得了656个大脑的磁共振成像，得出了96个感兴趣区域(ROI)的体积，并使用标准方法对白质(WM)病变的图像进行了分级。在横断面分析中，观察到了以下几点：胫骨导联与中枢神经系统体积呈负相关；胫骨导联与西医损害的患病率和严重程度呈正相关；中枢神经导联与神经行为测试分数呈正相关(体积越小，表现越差)。现在的数据表明，铅会导致成人中枢神经系统功能的进行性下降，以及至少是持续的结构变化，这两种变化都超出了正常衰老的范围。为了了解进行性功能丧失，研究必须调查结构损害是持续性的还是进行性的，西医和GM的影响是否有联系，以及这些影响是否有遗传或血管调节因素。目前正在寻求资金，以完成对500名受试者的第二次核磁共振检查，另一次神经行为评估，以及血管健康评估。我们的目标是确定胫骨铅是导致脑部持续性还是进行性结构损害；铅是否是衰老对中枢神经系统结构和功能影响的调节因子；使用更好的西医成像方法，铅是如何引起WM损害的；WM损害、GM体积的变化和功能变化是如何关联的；以及血管健康是铅和中枢神经系统损伤以及结构和功能关系的调解者还是调节者。

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.