Age-Related Brain Atrophy Mediates a Composite Outcome of One-Year Ischemic Stroke Recurrence and All-Cause Mortality Through YKL-40–Related Inflammatory Pathways: A Structural Equation Model

Chronological age is a strong predictor of poor outcomes after ischemic stroke but may not fully capture underlying biological vulnerability. This study investigated whether age-related brain atrophy and plasma YKL-40, a marker of astroglial inflammation, mediate the association between age and the one-year risk of ischemic stroke recurrence or all-cause mortality. Data were obtained from 4,305 participants enrolled in the Third China National Stroke Registry. Baseline brain atrophy was quantified from structural T1-weighted MRI using an automated deep learning–based pipeline (FastSurfer), yielding hemispheric cortical and white matter volumes that were modeled as indicators of a latent atrophy construct. Structural equation modeling was applied to estimate direct and indirect pathways linking age, brain atrophy, YKL-40, and one-year composite outcomes, adjusting for sex, atrial fibrillation or flutter, hypertension, and diabetes, with indirect effects evaluated using 5,000 bootstrap resamples. The total effect of age on one-year outcomes was not significant (β = −0.011; 95