Vascular drivers of cerebrospinal fluid movement and enlarged perivascular spaces

Perivascular spaces (PVSs) facilitate cerebrospinal fluid flow and waste clearance, which are critical for maintaining brain homeostasis. Enlarged PVSs (ePVSs) are an emerging marker of cerebral small vessel disease and are implicated in protein accumulation, neurodegeneration, and cognitive decline. While prior reviews have described the anatomy and correlates of ePVSs, the vascular mechanisms that drive perivascular fluid dynamics, and how their dysfunction might lead to ePVSs, have not been reviewed. This review examines how vascular mechanisms drive perivascular fluid dynamics and discusses how their impairment may contribute to ePVS formation and their impact on cognition. We propose an integrated vascular-ePVS hypothesis in which early vascular dysfunction may contribute to impaired waste clearance and ePVS burden, potentially linking early-life vascular health with later proteinopathy and cognitive decline. Elucidating the vascular contributions to ePVSs is imperative to identify therapeutic targets to preserve cognition in Alzheimer's disease and related dementias.