White Matter Microstructure and Cognitive Decline in Subacute Ischemic Stroke: Insights from Free Water Imaging and Glymphatic Dysfunction

This study aimed to investigate white matter microstructural changes and their relationship with cognitive function in patients with subacute ischemic stroke (IS) using free water diffusion tensor imaging (FW-DTI) and tract-based spatial statistics (TBSS). Thirty-nine patients with subacute IS (31 males, age 59.2±11.2 years) and 39 well-matched healthy controls (HC, 30 males, age 58.5±7.7 years) underwent diffusion spectrum imaging. FW, fractional anisotropy (FA), mean diffusivity (MD), and FW-corrected DTI metrics (FA T and MD T ) were analyzed using TBSS. Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA). Group differences and correlations in these metrics, as well as their correlations with cognitive performance and clinical variables, were examined. Compared with the HCs, IS patients showed significantly higher FW in both the whole-brain ( t = –3.03, p = 0.003) and white matter skeleton ( t = –3.20, p = 0.002), and reduced white matter skeleton FA ( t = 3.81, p < 0.001) and FA T ( t = 3.60, p = 0.006). After adjusting for alcohol and smoking, MoCA scores were negatively correlated with whole-brain ( ρ = –0.49, p = 0.032) and white matter skeleton FW ( ρ = –0.48, p = 0.039) in the IS group. White matter skeleton FW was positively associated with time since stroke onset ( ρ = 0.48, p = 0.039). Age was negatively correlated with white matter skeleton FA ( r = –0.35, p = 0.030) and FA T ( r = –0.38, p = 0.018), but positively with whole-brain FW ( r = 0.59, p < 0.001) and white matter skeleton MD ( r = 0.38, p = 0.018). FW-DTI reveals widespread microstructural disruption in patients with subacute IS, which may reflect glymphatic dysfunction and vasogenic edema. Elevated FW is associated with cognitive decline, highlighting its potential as a biomarker for post-stroke cognitive impairment. • The study applies free water imaging to investigate white matter changes and cognitive function in subacute ischemic stroke. • The use of multi-shell diffusion imaging, FW-DTI modeling, and TBSS provide a technically sound and methodologically advanced framework. • FW provides a novel metric for assessing white matter damage in the subacute phase and may serve as a potential imaging biomarker of poststroke cognitive health.