Subcortical brain volumetric differences related to white matter lesion volume and cognition in healthy aging.

White matter hyperintensity (WMH) lesions associated with small vessel cerebrovascular disease (CVD) are common structural neuroimaging findings in older adults. Greater global brain WMH burden related to aging has been implicated in dementia but has also been linked to brain atrophy and cognitive dysfunction in old age. We sought to investigate the regionally distributed association of global WMH lesion load with subcortical gray matter (SGM) volumes using a multivariate network analysis method in 178 community-dwelling, healthy older adults (mean age = 69.77 ± 10.22 years). We additionally applied mediation models with WMH-related subcortical volumetric differences as a mediator to evaluate a potential global WMH-related vascular risk pathway leading to cognitive aging. Global WMH burden was associated with a regionally distributed pattern of SGM atrophy involving bilateral putamen and left nucleus accumbens, with relative volume increases in bilateral caudate nucleus. Mediation analyses revealed that increasing age predicted greater WMH-SGM pattern expression, which then predicted slowed processing speed that was, in turn, associated with decrements in other age-sensitive cognitive domains of memory, executive functioning, and fine motor function. These results suggest that the multivariate WMH-SGM pattern and its association with processing speed may provide an important early indicator of age-related decrements in higher-order cognitive processes, reflecting a potential link between CVD and broader cognitive dysfunction across multiple domains in healthy aging.