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.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
Project #
Application #
Study Section
Epidemiology and Disease Control Subcommittee 2 (EDC)
Program Officer
Wise, Bradley C
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Johns Hopkins University
Public Health & Prev Medicine
Schools of Public Health
United States
Zip Code
Fisher, Aaron; Caffo, Brian; Schwartz, Brian et al. (2016) Fast, Exact Bootstrap Principal Component Analysis for p > 1 million. J Am Stat Assoc 111:846-860
Bobb, Jennifer F; Schwartz, Brian S; Davatzikos, Christos et al. (2014) Cross-sectional and longitudinal association of body mass index and brain volume. Hum Brain Mapp 35:75-88
James, Bryan D; Glass, Thomas A; Caffo, Brian et al. (2012) Association of social engagement with brain volumes assessed by structural MRI. J Aging Res 2012:512714
James, Bryan D; Caffo, Brian; Stewart, Walter F et al. (2011) Genetic risk factors for longitudinal changes in structural MRI in former organolead workers. J Aging Res 2011:362189
Swihart, Bruce J; Caffo, Brian; James, Bryan D et al. (2010) Lasagna plots: a saucy alternative to spaghetti plots. Epidemiology 21:621-5
Schwartz, Brian S; Caffo, Brian; Stewart, Walter F et al. (2010) Evaluation of cumulative lead dose and longitudinal changes in structural magnetic resonance imaging in former organolead workers. J Occup Environ Med 52:407-14
Chen, Sining; Wang, Chi; Eberly, Lynn E et al. (2009) Adaptive control of the false discovery rate in voxel-based morphometry. Hum Brain Mapp 30:2304-11
Schwartz, Brian S; Chen, Sining; Caffo, Brian et al. (2007) Relations of brain volumes with cognitive function in males 45 years and older with past lead exposure. Neuroimage 37:633-41
Shih, Regina A; Hu, Howard; Weisskopf, Marc G et al. (2007) Cumulative lead dose and cognitive function in adults: a review of studies that measured both blood lead and bone lead. Environ Health Perspect 115:483-92
Schwartz, Brian S; Hu, Howard (2007) Adult lead exposure: time for change. Environ Health Perspect 115:451-4

Showing the most recent 10 out of 21 publications