AGE, LEAD EXPOSURE, AND NEUROBEHAVIORAL DECLINE

描述(摘自申请者的摘要)：这是第二次 重新提交竞争性续期申请，以继续研究 过去接触有机和无机铅对中枢神经系统的长期影响。这个 最初研究的主要目标是确定过去接触一种 推定的神经毒物与认知功能下降有关。 我们研究的队列的一个独特特征是，没有一个参与者 在注册时职业暴露于铅。平均时间 因为上次接触是16年了。我们发现，过去累积吸收的 铅，以胫骨铅衡量，与神经行为的下降有关 测试分数，在语言和视觉记忆测试中明显下降。 许多效果在涉及陈述性新学习的测试中可以看到， 众所周知，这需要海马体和相关结构。这些 渐进性变化，可与学习和记忆相关的变化相媲美 随着年龄的增长，上一次长期接触铅的职业不太可能 仅用中枢神经化学的变化来解释。此外，我们的发现是 与动物证据一致表明有机和无机铅可以 导致细胞死亡和选择性地靶向边缘系统的区域 表明视觉和言语记忆受损的流行病学证据 暴露在无机铅中。作为合乎逻辑的下一步，我们建议 确定是否存在结构性(即，基于MRI的体积测量) 与我们观察到的认知功能的变化有关。这些数据 将帮助确定是否有特定的CNS目标站点可供引入，并将 为理解调节的机制提供基础 成人铅暴露对中枢神经系统功能的影响，为人类 观察性研究和动物实验研究。为此，我们建议： 1.确定胫骨铅是否与中枢神经系统结构的改变有关 (即较小的脑体积)被怀疑为铅的目标。2.确定是否 中枢神经系统结构的变化要么是在原因通路中，要么是改变了 胫骨铅与认知功能指标变化的关系。 这些目标将在一项为期三年的550项当前研究中得到解决 过去曾接触过铅的参与者，100名参与者 控制组，以及另外100名新招募的有过去线索的受试者 曝光。

DESCRIPTION (Adapted from applicant's abstract): This is the second resubmission of a competitive renewal application to continue studying the long-term CNS effects of past exposure to organic and inorganic lead. The primary goal of the original study was to determine if past exposure to a putative neurotoxicant was associated with a decline in cognitive function. A unique feature of the cohort we have studied is that none of the participants were occupationally exposed to lead at the time of enrollment. The average time since last exposure was 16 years. We found that past cumulative absorption of lead, measured as tibial lead, was associated with a decline in neurobehavioral test scores, with pronounced declines in tests of verbal and visual memory. Many of the effects were seen in tests that involved declarative new learning, which is known to require the hippocampus and related structures. These progressive changes, comparable to changes in learning and memory associated with aging, long after last occupational exposure to lead are unlikely to be explained by changes in CNS neurochemistry alone. Moreover, our findings are consistent with animal evidence suggesting that organic and inorganic lead can lead to cell death and selectively target areas of the limbic system and epidemiologic evidence that indicates impairment of visual and verbal memory from exposure to inorganic lead. As a logical next step, we propose to determine if there are structural (i.e., MRI based volumetric measures) correlates to the changes in cognitive function we have observed. These data will help determine if there are specific CNS target sites for lead in and will provide the foundation for understanding mechanisms that mediate the effect of adult lead exposure on CNS function, providing an important link between human observational studies and animal experimental studies. To this end we propose: 1. To determine if tibial lead is associated with changes in CNS structures (i.e., smaller brain volumes) suspected as targets of lead. 2. To determine if changes in CNS structures are either in the causal pathway of, or modify the relation between, tibial lead and changes in measures of cognitive function. These aims will be addressed in a three year study of 550 current study participants with past exposure to lead, 100 individuals who participated as controls, and an additional 100 newly recruited subjects with past lead exposure.