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Association of Childhood Lead Exposure With MRI Measurements of Structural Brain Integrity in Midlife

Reuben A, Elliott M, Abraham W, Broadbent J, Houts R, Ireland D, Knodt A, Poulton R, Ramrakha S, Hariri A, Caspi A, Moffitt T (2020) JAMA 2020;324(19):1970-1979  doi:10.1001/jama.2020.19998 

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Importance  Childhood lead exposure has been linked to disrupted brain development, but long-term consequences for structural brain integrity are unknown.

Objective  To test the hypothesis that childhood lead exposure is associated with magnetic resonance imaging (MRI) measurements of lower structural integrity of the brain in midlife.

Design, Setting, and Participants  The Dunedin Study followed a population-representative 1972-1973 birth cohort in New Zealand (N = 564 analytic sample) to age 45 years (until April 2019).

Exposures  Childhood blood lead levels measured at age 11 years.

Main Outcomes and Measures  Structural brain integrity at age 45 years assessed via MRI (primary outcomes): gray matter (cortical thickness, surface area, hippocampal volume), white matter (white matter hyperintensities, fractional anisotropy [theoretical range, 0 {diffusion is perfectly isotropic} to 100 {diffusion is perfectly anisotropic}]), and the Brain Age Gap Estimation (BrainAGE), a composite index of the gap between chronological age and a machine learning algorithm–estimated brain age (0 indicates a brain age equivalent to chronological age; positive and negative values represent an older and younger brain age, respectively). Cognitive function at age 45 years was assessed objectively via the Wechsler Adult Intelligence Scale IV (IQ range, 40-160, standardized to a mean of 100 [SD, 15]) and subjectively via informant and self-reports (z-score units; scale mean, 0 [SD, 1]).

Results  Of 1037 original participants, 997 were alive at age 45 years, of whom 564 (57%) had received lead testing at age 11 years (302 [54%] male) (median follow-up, 34 [interquartile range, 33.7-34.7] years). Mean blood lead level at age 11 years was 10.99 (SD, 4.63) μg/dL. After adjusting for covariates, each 5-μg/dL higher childhood blood lead level was significantly associated with 1.19-cm2 smaller cortical surface area (95% CI, −2.35 to −0.02 cm2P = .05), 0.10-cm3 smaller hippocampal volume (95% CI, −0.17 to −0.03 cm3P = .006), lower global fractional anisotropy (b = −0.12; 95% CI, −0.24 to −0.01; P = .04), and a BrainAGE index 0.77 years older (95% CI, 0.02-1.51 years; P = .05) at age 45 years. There were no statistically significant associations between blood lead level and log-transformed white matter hyperintensity volume (b = 0.05 log mm3; 95% CI, −0.02 to 0.13 log mm3P = .17) or mean cortical thickness (b = −0.004 mm; 95% CI, −0.012 to 0.004 mm; P = .39). Each 5-μg/dL higher childhood blood lead level was significantly associated with a 2.07-point lower IQ score at age 45 years (95% CI, −3.39 to −0.74; P = .002) and a 0.12-point higher score on informant-rated cognitive problems (95% CI, 0.01-0.23; P = .03). There was no statistically significant association between childhood blood lead levels and self-reported cognitive problems (b = −0.02 points; 95% CI, −0.10 to 0.07; P = .68).

Conclusions and Relevance  In this longitudinal cohort study with a median 34-year follow-up, higher childhood blood lead level was associated with differences in some MRI measures of brain structure that suggested lower structural brain integrity in midlife. Because of the large number of statistical comparisons, some findings may represent type I error.