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.
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