Post-stroke brain functional reorganization is associated with glymphatic dysfunction during stroke recovery

Ischemic stroke may impair glymphatic clearance, but whether this is associated with post-stroke brain functional reorganization in humans remains unclear. We prospectively enrolled 48 capsular stroke (CS) patients, 28 pontine stroke (PS) patients, and 50 healthy controls. All participants underwent MRI examinations at baseline (< 7 days) and 90 days post-stroke. Cerebrovascular reactivity (CVR) and the diffusion tensor imaging along the perivascular space (DTI-ALPS) index were measured to assess functional reorganization and glymphatic function. Regions with significant intergroup CVR differences were identified as regions-of-interest (ROIs) reflecting focal functional reorganization. Correlations between ROI-based CVR and DTI-ALPS indices were analyzed to determine which ROIs related to functional reorganization were associated with glymphatic function in CS and PS patients. Cross-lagged panel models (CLPMs) were constructed to analyze the temporal sequence of functional reorganization and glymphatic dysfunction. Both CS and PS patients exhibited focal CVR reorganization and reduced DTI-ALPS indices. Significant associations between CVR and DTI-ALPS indices were found in the putamen and thalamus in both groups. In the putamen, among CS patients, baseline CVR was negatively correlated with both baseline and 90-day ipsilesional hemispheric DTI-ALPS indices (IL.DTI-ALPS) (r = -0.479, p = 0.001; r = -0.493, p < 0.001). In PS patients, baseline contralesional hemispheric DTI-ALPS indices (CL.DTI-ALPS) was negatively correlated with both baseline and 90-day CVR (r = -0.510, p = 0.006; r = -0.532, p = 0.004). Similar patterns of association were observed in the thalamus. Additionally, CLPMs revealed that in CS patients, CVR changes were temporally associated with subsequently reduced DTI-ALPS, while in PS patients, reduced DTI-ALPS were temporally associated with subsequent CVR changes. Focal CVR reorganization in the putamen and thalamus was associated with post-stroke glymphatic dysfunction in a bidirectional, lesion-location-specific manner. These findings enhance our understanding of post-stroke glymphatic impairment and may help inform strategies to mitigate post-stroke cognitive decline.