The Impact of Vascular Health Risk Factors on Brain and Cognitive Aging

Abstract

Even among generally healthy older adults, aging can adversely affect vascular health. Age-related changes associated with vascular health risk factors contribute to decrements in cognitive functions that are preferentially affected by aging in cognitively unimpaired older adults. These effects may partly be attributable to structural brain alterations in subcortical and cortical gray matter volumes, as well as white matter hyperintensity (WMH) lesion load. In this research study, I sought to investigate the impact of different vascular health risk factors—homocysteine (Hcy), WMH burden, and cardiorespiratory fitness (CRF)—and their interrelationships on brain structure in aging. I additionally evaluated potential contributions of the differences in structural brain measures associated with each vascular health risk factor to performance in age-sensitive cognitive domains in a cohort of healthy older adults. First, I investigated the association of cortical lobar brain volumes with WMH lesions and a previously established multivariate network pattern associated with plasma Hcy levels showing reduced subcortical gray matter (SGM) volumes of hippocampus and nucleus accumbens (Song et al., 2023). I additionally evaluated the potential mediating roles of these brain imaging markers in a vascular brain pathway leading to age-associated cognitive dysfunction. I found smaller parietal lobar gray matter associated with greater expression of the Hcy-related SGM network pattern, which was further related to greater WMH volume. Additionally, greater volumes of WMH lesions, greater Hcy-SGM pattern expression, and smaller parietal lobe volume sequentially mediated slowed processing speed, but not executive functioning or memory. Second, I investigated the regionally distributed association of global WMH burden with SGM volumes using a multivariate network analysis method. I additionally evaluated a potential WMH-related vascular risk pathway leading to cognitive aging by applying mediation models. I identified a regionally distributed pattern of SGM atrophy associated with global WMH burden, which involved bilateral putamen and left nucleus accumbens, as well as relative bilateral volumetric increases in the caudate nucleus. Furthermore, greater WMH-SGM pattern expression related to aging predicted slowed processing speed, which, in turn, predicted poorer performance in other age-sensitive cognitive domains of executive functioning, memory, and fine motor function/speed. Third, I investigated the regional distribution of WMH lesions associated with CRF and evaluated the potential role of CRF-related regional WMH volumetric differences as a modifier of cognitive aging. Multivariate regional network analysis revealed a distributed pattern of WMH volume reductions in bilateral frontal and right parietal lobes and relative volume increases in bilateral occipital lobes associated with CRF, distinctly from self-reported habitual physical activity. Younger age and male sex were associated with greater CRF-WMH pattern expression. Additionally, a significant age-by-CRF-WMH network pattern interaction was observed for memory, but not for processing speed and executive functions, such that the negative association between age and memory performance was attenuated as the pattern expression increased. These findings, taken together, point to the importance of investigating how differences in vascular health contribute to structural brain aging, which can advance our current understanding of the underlying neural mechanisms associated with age-related cognitive dysfunction and help identify the contributing factors to its inter-individual variability.