Perivascular pathology, not macrovascular complexity, governs glymphatic-related dysfunction in preclinical cerebral small vessel disease

The glymphatic system facilitates brain waste clearance, and its dysfunction has been linked to aging, neurodegeneration, and cerebral small vessel disease (CSVD). Enlarged perivascular spaces (ePVS) are established imaging markers of impaired clearance, while the role of macrovascular architecture, particularly the complexity of the circle of Willis (CoW), remains uncertain. In this cross-sectional study of 60 asymptomatic adults with low-to-moderate vascular risk, CoW complexity was quantified using fractal dimension (D_f) analysis, and perivascular diffusivity, an indirect proxy of glymphatic-related activity, was estimated using diffusion tensor image analysis along perivascular space (DTI-ALPS) index, and ePVS burden was stratified as a CSVD marker. CoW complexity was correlated with higher DTI-ALPS and lower ePVS burden, but these relationships did not remain significant after adjusting for age, sex, and vascular risk. In contrast, the presence of ePVS was the strongest and most consistent predictor of reduced DTI-ALPS values, highlighting its central role in impaired fluid dynamics. Thus, ePVS remains the dominant and clinically relevant imaging biomarker of glymphatic-related activity in asymptomatic adults with low-to-moderate vascular risk, providing a potential mechanistic link to early cerebrovascular aging. These findings underscore the importance of microvascular health in maintaining glymphatic function and may guide early biomarkers and preventive strategies in preclinical CSVD.