The role of glymphatic dysfunction in cerebral small vessel disease and vascular cognitive impairment, and therapeutic implications.

Abstract

BACKGROUND: The glymphatic system is a brain-wide perivascular clearance pathway that facilitates cerebrospinal fluid-interstitial fluid (CSF-ISF) exchange and the removal of metabolic waste from the brain parenchyma. Increasing evidence indicates that glymphatic transport is critically dependent on the integrity and function of cerebral small vessels, suggesting a close link with cerebral small vessel disease (cSVD). Structural and functional alterations of small vessels may disrupt glymphatic flow, while impaired glymphatic clearance may in turn exacerbate small vessel-related brain injury, indicating a bidirectional interaction between these two processes. METHODS: In this review, we synthesize current evidence on the relationship between cSVD and glymphatic dysfunction, integrating findings from experimental models and in vivo human studies. We discuss shared pathophysiological mechanisms linking small vessel pathology to impaired perivascular fluid transport, summarize associations between glymphatic dysfunction and established cSVD imaging markers, and evaluate emerging therapeutic strategies aimed at restoring or enhancing glymphatic function. We highlight areas of convergence and inconsistency in the existing literature and identify key knowledge gaps that warrant further investigation. We also review potential therapeutic approaches, both behavioral and pharmacological to improve glymphatic function. CONCLUSION: Current evidence supports a close but incompletely understood bidirectional relationship between cSVD and glymphatic dysfunction. Targeting glymphatic function may represent a possible therapeutic strategy for cSVD and vascular cognitive impairment.