Date Published: May 27, 2008
Publisher: Public Library of Science
Author(s): Kim M Cecil, Christopher J Brubaker, Caleb M Adler, Kim N Dietrich, Mekibib Altaye, John C Egelhoff, Stephanie Wessel, Ilayaraja Elangovan, Richard Hornung, Kelly Jarvis, Bruce P Lanphear, John Balmes
Abstract: BackgroundAlthough environmental lead exposure is associated with significant deficits in cognition, executive functions, social behaviors, and motor abilities, the neuroanatomical basis for these impairments remains poorly understood. In this study, we examined the relationship between childhood lead exposure and adult brain volume using magnetic resonance imaging (MRI). We also explored how volume changes correlate with historic neuropsychological assessments.Methods and FindingsVolumetric analyses of whole brain MRI data revealed significant decreases in brain volume associated with childhood blood lead concentrations. Using conservative, minimum contiguous cluster size and statistical criteria (700 voxels, unadjusted p < 0.001), approximately 1.2% of the total gray matter was significantly and inversely associated with mean childhood blood lead concentration. The most affected regions included frontal gray matter, specifically the anterior cingulate cortex (ACC). Areas of lead-associated gray matter volume loss were much larger and more significant in men than women. We found that fine motor factor scores positively correlated with gray matter volume in the cerebellar hemispheres; adding blood lead concentrations as a variable to the model attenuated this correlation.ConclusionsChildhood lead exposure is associated with region-specific reductions in adult gray matter volume. Affected regions include the portions of the prefrontal cortex and ACC responsible for executive functions, mood regulation, and decision-making. These neuroanatomical findings were more pronounced for males, suggesting that lead-related atrophic changes have a disparate impact across sexes. This analysis suggests that adverse cognitive and behavioral outcomes may be related to lead's effect on brain development producing persistent alterations in structure. Using a simple model, we found that blood lead concentration mediates brain volume and fine motor function.
Partial Text: Lead is widely recognized as a potent neurotoxicant, yet debate continues as to what levels of exposure result in irreversible brain injury. Evidence of lead “poisoning” is typically observed only at blood lead concentrations greater than 40 μg/dl (1.93 μmol/l) . Encephalopathy is typically associated with blood lead concentrations greater than 100 μg/dl (4.83 μmol/l), but may occur at blood lead concentrations as low as 70 μg/dl (3.38 μmol/l), manifesting with focal lesions in the basal ganglia, thalami, cerebellum, cortical gray matter, and subcortical white matter [2–5]. Clinical neuroimaging studies in children with low to moderate (5 to 40 μg/dl [0.24 to 1.93 μmol/l]) blood lead concentrations tend to have few specific findings characteristic of lead exposure. However, such blood lead levels increase the individual likelihood of impaired cognition and executive function, impulsiveness, aggression, and delinquent behavior [6–11].
Higher mean childhood blood lead concentrations were associated with significant decrements in gray matter volume for several cortical regions (Figure 1; Table 2). The volumetric-based analysis revealed an inverse, linear dose-effect relationship between mean childhood blood lead concentration and brain volume in specific regions. (Figure 2). Prefrontal cortical areas of lead-related volumetric decline involved the medial and the superior frontal gyri comprising the ventrolateral prefrontal cortex (VLPFC) as well as the anterior cingulate cortex (ACC). Other areas of lead-related volume loss were located in postcentral gyri, the inferior parietal lobule, and the cerebellar hemispheres. Using conservative, minimum contiguous cluster size and statistical criteria (700 voxels, unadjusted p < 0.001), approximately 1.2% of the total gray matter was significantly and inversely associated with mean childhood blood lead concentration. No significant volume changes were observed within white matter or CSF volume. Our study showed that higher mean childhood blood lead concentration is associated with region-specific reductions in adult gray matter volume. The findings suggest that childhood lead exposure is associated with volume loss in considerable portions of the prefrontal cortex, including the ACC and the VLPFC. The ACC, a component of the brain's limbic system positioned about the rostrum of the corpus callosum, processes cognitive and emotional information separately with distinguishable territories (reviewed in ). The functions attributed to the cognitive subdivision, located in the dorsal aspects of the ACC, include modulating attention and executive functions via sensory and/or response selection . Additional attributed functions include anticipation of cognitively demanding tasks, error detection, monitoring completion, assessing potential conflicts, complex motor control, performing new behaviors, motivation and reward-based decision making [30–32]. The affective and emotional division, which is located ventrally, is associated with regulation of personal and social behavior, decision-making, and emotional responses. VLPFC has also been suggested as being similarly associated with mood regulation [33,34]. Source: http://doi.org/10.1371/journal.pmed.0050112