Accelerated brain aging and anterior white matter hyperintensity burden in chronic post-stroke aphasia: a lesion-aware MRI analysis

BACKGROUND AND PURPOSE: Chronic post-stroke aphasia is heterogeneous, and focal lesion models do not fully explain persistent language impairment. We tested whether accelerated brain aging and regional white matter hyperintensity (WMH) burden provide complementary MRI markers of residual brain vulnerability in chronic post-stroke aphasia. MATERIALS AND METHODS: We analyzed Western Aphasia Battery Aphasia Quotient (WAB-AQ), brain-predicted age difference (Brain-PAD), aphasia subtype, fluency phenotype, regional WMH burden, and lesion-volume/site measures in 137 participants from the Aphasia Recovery Cohort using covariate-adjusted regression, mixed-effects modeling, lesion-aware sensitivity analyses, and internal validation. RESULTS: Higher Brain-PAD was associated with lower WAB-AQ in the full cohort (β = -3.38, p < 0.001) and remained significant after accounting for subtype and fluency structure. Non-fluent participants had higher Brain-PAD than fluent participants (β = 2.19, p < 0.001). Among candidate WMH measures, anterior WMH was the most consistently supported vascular feature. In the final WMH-complete model, Brain-PAD (β = -3.11, p < 0.001) and anterior WMH burden (β = -8.20, p = 0.001) were independently associated with lower WAB-AQ and improved model fit beyond Brain-PAD alone (ΔR² = 0.077). In lesion-aware sensitivity analyses, total lesion volume was strongly associated with WAB-AQ, but Brain-PAD and anterior WMH remained associated with WAB-AQ after lesion-volume adjustment. CONCLUSIONS: Chronic post-stroke aphasia severity was better characterized by a lesion-aware dual-vulnerability model in which accelerated brain aging indexed global structural vulnerability and anterior WMH burden captured complementary lobar vascular white matter injury beyond total lesion volume.