Abstract
Peak width of skeletonized mean diffusivity (PSMD) is a reliable marker of white matter (WM) integrity in cerebral small vessel disease (CSVD). However, the mediating role of WM damage (as measured by PSMD) in the association between CSVD and cognitive impairment remains unclear. This research applied multivariate regression analysis to explore correlations among CSVD markers, PSMD and cognitive function in older community residents. Additionally, we analysed associations between PSMD and cognitive performance across different CSVD burden levels. Simple and chain mediation analyses were employed to evaluate PSMD's mediating role in the relationship among cerebrovascular risk factors, CSVD and cognitive decline. The cohort consisted of 273 participants categorized by CSVD severity into mild, moderate and severe groups. Each CSVD marker, along with PSMD, was significantly correlated with cognitive performance when controlling for demographic factors (age, sex and education) and apolipoprotein E (APOE) genotype. PSMD fully mediated the relationship between enlarged perivascular spaces and both the Mini-Mental State Examination and Modified Common Objects Sorting Test scores, while it partially mediated the relationships involving the CSVD burden, white matter hyperintensity volume, lacunes and cerebral microbleeds (indirect effect P < 0.05). Exploratory chain analysis revealed that hypertension and coronary heart disease indirectly influenced cognition through CSVD and PSMD pathways (P < 0.05). CSVD may impact cognitive function in older adults through the aggravated WM injury measured by PSMD. Vascular risk factors may serve as upstream determinants in the pathway linking CSVD, PSMD and cognitive dysfunction.