Are brain volumes based on magnetic resonance imaging mediators of the associations of cumulative lead dose with cognitive function?

The authors used cross-sectional data (2001-2003) to consider the pathway through which past occupational lead exposure impacts cognitive function. They were motivated by studies linking cumulative lead dose with brain volumes, volumes with cognitive function, and lead dose with cognitive function. It was hypothesized that the brain regions associated with lead mediate a portion of the relation between lead dose and cognitive function. Data were derived from an ongoing US study of 513 former organolead manufacturing workers. Magnetic resonance imaging was used to perform a novel analysis to investigate mediation. Volumes associated with cognitive function and lead dose were derived by using registered images and were used in a subsequent mediation analysis. Cumulative lead dose was associated with adverse function in the visuo-construction, executive function, and eye-hand coordination domains. Regarding these domains, there was strong evidence of volumetric mediation of lead's effect on cognition in the visuo-construction domain and a moderate amount for executive function and eye-hand coordination. A second path-analysis-based approach was also used. To address the possibility that chance associations explained these findings, a permuted analysis was conducted, the results of which supported the mediation inferences. The approach to evaluating volumetric mediation may have general applicability in epidemiologic neuroimaging settings.