Large-vessel hemodynamics are associated with glymphatic dysfunction and cognitive impairment in cerebral small vessel disease

Abstract Background Disruption of cerebral hemodynamics may impair perivascular and glymphatic clearance, contributing to aging-related brain pathology. This study aimed to explore the interaction between large-vessel hemodynamics and glymphatic neuroimaging markers in cerebral small vessel disease (CSVD), a common age-related condition. Methods Using 4D flow MRI, we quantified flow/area pulsatility index (PIflow/PIarea) and wall shear stress (WSS) in carotid arteries and superior sagittal sinus (SSS) among 66 CSVD patients and 34 healthy controls (HCs). Free water (FW) fraction and diffusivity along the perivascular space (ALPS) were measured as glymphatic markers via diffusion-weighted imaging. Multivariate regressions and mediation analyses were conducted to assess the relationships between vascular metrics and glymphatic markers, as well as disease burden, adjusting for age, sex, white matter hyperintensity (WMH) volume, and vascular risk factors. Results CSVD patients exhibited increased arterial and venous PIs and WSS alongside elevated FW in multiple brain regions. PIarea of common carotid artery (CCA) and higher WSS of internal carotid artery (ICA)-C1 correlated with increased FW of basal ganglia (FW-BG); PIflow of SSS linked to FW in the hippocampus; and PIarea of ICA-C4 correlated with ALPS (β = 0.188-0.267, p < .05). Contrastingly, HCs exhibited inverse associations between PIs/WSS and glymphatic markers (β = −0.517 to −0.317, p < .05). Interestingly, FW-BG mediated 42.1% of the effect between PIarea-CCA and CSVD burden (BootCI:0.015-0.956, p < .05). Elevated WSS of SSS predicted worse global cognition (β = −0.32, p = .005). Conclusions Altered large-vessel hemodynamics correlated to glymphatic dysfunction and cognitive function in CSVD, highlighting the critical role of vascular health in preserving brain clearance and cognitive aging.