The Role of White Matter Hyperintensity Volume in Brain and Cognitive Aging

Abstract

White matter hyperintensity (WMH) volume is a neuroimaging marker of white matter lesion load and may be an important risk factor for Alzheimer’s disease (AD). Even within healthy aging, decreases in cognitive functions including in processing speed, executive functions, and memory, as well as reductions in gray matter, primarily in frontal and temporoparietal brain regions, have been associated with greater WMH volume. Although many studies have investigated the effects of total WMH volume, fewer have examined how the regional distribution of WMH volumes may differentially impact brain and cognitive aging. Therefore, the overarching goal of my research was to investigate the role of regional WMH lesion volume on brain structure and cognition, and to evaluate how important demographic, health, and genetic risk factors relate to differences in the regional accumulation of WMH volumes in a cohort of community-dwelling, healthy older adults, ages 50-89. First, I evaluated the interaction between apolipoprotein E (APOE) ε4 status, a genetic risk factor for AD, and age group, on regional WMH volumes, and found significant interactive effects for age group and APOE ε4 status for left temporal and right parietal WMH volumes. Further, I performed follow-up moderated mediation analyses to examine whether observed significant differences in regional WMH volumes (related to APOE ε4 status and age group interactive effects) were, in turn, associated with cognitive performance differences. The moderated mediation analyses revealed that, in the young-old (ages 50-69), but not the old-old (ages 70-89) group, there were significant indirect effects of ε4 status on memory and executive functions, but not processing speed, through left temporal WMH volume. Second, I assessed the relation between age and the regional distribution of WMH volume and subsequently evaluated associations with vascular and dementia-related risk factors, as well as cognition. Using a multivariate regional covariance model, the Scaled Subprofile Model (SSM), I identified an age-related regional WMH volume pattern, and found greater expression of the pattern was significantly associated with higher Cardiovascular Risk Factors, Aging and Dementia (CAIDE) scores, a vascular-related risk score that was developed to predict the risk of dementia, as well as first-degree family history of dementia. Additionally, I found the age-related pattern significantly related to motor processing speed. Third, I examined the relation between hippocampal volume and the regional distribution of WMH volume and subsequently assessed associations with subjective and objective memory. Using the SSM, I established left and right hippocampal-related regional WMH volume patterns and found lower expression of these patterns were significantly associated with increasing age and greater subjective memory complaints, but not objective memory performance. Together, these findings demonstrate the importance of examining the effects of regional distribution of WMH volumes to better characterize the role of white matter hyperintensities in brain and cognitive aging.