From Vessels to Cognition: Glymphatic Alterations Following Hemorrhage in Cerebral Amyloid Angiopathy Are Associated With Small Vessel Disease Burden

Background Cerebral amyloid angiopathy–related hemorrhage is associated with both cerebral small vessel disease (CSVD) pathology and long‐term cognitive decline. The role of glymphatic dysfunction in mediating this relationship remains unclear. Methods A total of 111 participants (64 patients with cerebral amyloid angiopathy–related hemorrhage, 47 healthy controls) underwent 7T magnetic resonance imaging at a stable postintracerebral hemorrhage stage. Imaging analyses included the Analysis Along the Perivascular Space (ALPS) index derived from diffusion tensor imaging, volumetric quantification of perivascular spaces, and choroid plexus segmentation. Hierarchical regression assessed group differences and associations with CSVD markers and cognition. Mediation analyses tested whether ALPS mediated the effect of CSVD on cognition. Results Patients with cerebral amyloid angiopathy–related hemorrhage showed significantly enlarged perivascular spaces in white matter and total brain (both P <0.001) and reduced ALPS indices ( P <0.001). Group differences in ALPS remained significant after adjusting for total intracranial volume ( P <0.001) but not after further controlling for CSVD burden ( P =0.191). In contrast, perivascular space abnormalities remained robust across all models. ALPS indices were negatively associated with white matter hyperintensity volume (contralateral side‐ALPS: β=−0.619, P <0.001; ipsilateral side‐ALPS: β=−0.443, P <0.01) and lobar cerebral microbleeds (ipsilateral side‐ALPS: β=−0.502, P =0.006), with white matter hyperintensity emerging as the strongest predictor of glymphatic dysfunction. Mean‐ALPS also correlated with deficits in global cognition, executive control, and processing speed. Mediation analyses indicated that ALPS statistically mediated the association between white matter hyperintensities and processing speed and executive function. Conclusions Noninvasively measured glymphatic dysfunction in cerebral amyloid angiopathy–related hemorrhage reflects chronic CSVD burden and contributes to cognitive decline, highlighting ALPS as a sensitive and practical functional marker.