Differential effects of aging on regional corpus callosum microstructure and the modifying influence of pulse pressure

Abstract

The corpus callosum is composed of several subregions, distinct in cellular and functional organization. This organization scheme may render these subregions differentially vulnerable to the aging process. Callosal integrity may be further compromised by cardiovascular risk factors, which negatively influence white matter health. Here, we test for heterochronicity of aging, hypothesizing an anterior-to-posterior gradient of vulnerability to aging that may be altered by effects of cardiovascular health. In 174 healthy adults across the adult lifespan (mean age=53.56 ± 18.90, range=20-94 years old, 58.62% women), pulse pressure (calculated as participant's systolic minus diastolic blood pressure) was assessed to determine cardiovascular risk. A deterministic tractography approach via diffusion weighted imaging was utilized to extract fractional anisotropy (FA), radial diffusivity (RD) and axial diffusivity (AD) from each of five callosal subregions, serving as estimates of microstructural health. General linear models tested effects of age, hypertension, and pulse pressure on these cross-sectional metrics. We observed no significant effect of hypertensive diagnosis on callosal microstructure. We found a significant main effect of age and an age x pulse pressure interaction whereby older age and elevated pulse pressure were associated with poorer FA, AD, and RD. Age effects revealed non-linear components and occurred along an anterior-posterior gradient of severity in the callosum. This gradient disappeared when pulse pressure was considered. These results indicate that age-related deterioration across the callosum is regionally variable, and that pulse pressure, a proxy of arterial stiffness, exacerbates this aging pattern in a large lifespan cohort.

Significance Statement Aging is associated with microstructural changes in the corpus callosum, the largest white matter tract in the brain. Additionally, cardiovascular factors, such as hypertension and pulse pressure, affect corpus callosum microstructure. However, it is unclear whether these factors uniformly impact the corpus callosum throughout aging. The current study aimed to characterize patterns of corpus callosum aging and assess the influence of hypertension and pulse pressure across subregions of callosal white matter. We found an age-related gradient on corpus callosum microstructure, with the most pronounced impact on anterior regions. However, this gradient was absent when pulse pressure was considered. These findings suggest that callosal subregions are differentially sensitive to age-related decline, and pulse pressure modifies and exacerbates these declines.