Role of Cerebral White Matter Differences in Cognitive Aging

Abstract

Extensive research has evaluated factors associated with healthy brain and cognitive aging, with recent studies focusing on age-related differences in microstructural (i.e., diffusion tensor imaging metrics) and macrostructural (i.e., white matter hyperintensity volume; WMH) white matter assessed by magnetic resonance imaging (MRI). It has been suggested that disruptions to white matter tract integrity, which may be attributable to reductions in myelin and axonal integrity, affect connectivity within and between brain regions. These disrupted connections may in turn, adversely impact cognitive functioning, preferentially affecting executive function, processing speed, and memory performance. Thus, I sought to further investigate the role of white matter differences in cognition in 196 healthy older adults, ages 50-89 years, using multiple global and regional diffusivity metrics (fractional anisotropy (FA); mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD)), global white matter lesion load, individual cognitive tests, and a combination of univariate and multivariate statistical methods. First, I assessed the relation between age and regional white matter integrity and subsequently evaluated effects of vascular risk factors. I identified distinct age-related regional white matter covariance patterns for each diffusivity metric and found additive effects of WMH volume on the white matter patterns. Second, I investigated individual differences in the associations between regional white matter diffusivity metrics and performance on tests assessing executive functions, processing speed, and memory, while accounting for effects of age and other demographic characteristics as well as vascular risk factors. Lower FA and higher RD were associated with poorer executive function performance. Robust effects for higher RD were related to reductions in executive function and processing speed tasks. Third, to establish directional associations between age, white matter integrity, and cognition, I initially derived cognitive-related regional white matter integrity network patterns for each diffusivity metric and then evaluated their mediating role on the relation between age and cognition. Age moderated the effect of cognitive-related white matter pattern expression on memory performance, with old-old adults showing poorer memory abilities through lower pattern expressions. In addition, the cognitive-related patterns for FA, RD, and AD mediated the effects of age on executive function and processing speed performance. Lastly, I created global white matter indices combining WMH volume and each diffusivity metric to assess their mediating impact on the relation between age and cognition. Age moderated the effect of the global WMH-integrity indices for all diffusivity measures, with middle-old and old-old ages showing poorer executive function and processing speed performance through higher expression of the WMH-integrity indices. Together, these findings demonstrate the importance of evaluating regional tract and global differences in diffusion metrics and WMH volume to better characterize the role of white matter in brain aging, advancing our understanding of how white matter differentially impacts specific cognitive processes in older adults.