EXPRESS: Cardio‑Glymphatic Association: Left‑Heart Dysfunction in CSVD and Its Association With Glymphatic‑Related Cognitive Impairment

Cerebral small vessel disease (CSVD) is a leading cause of vascular cognitive impairment. The glymphatic system, a brain-wide waste clearance pathway, may be impaired in CSVD, but its upstream drivers and role linking systemic factors to cognitive impairment remain unclear. This study explored whether glymphatic dysfunction statistically mediates the association between left-heart dysfunction and cognitive impairment in CSVD. We enrolled 80 CSVD-VCI, 80 CSVD-NCI, and 80 normal controls aged 50-80 years. All participants underwent neuropsychological assessment, cardiac ultrasound (measuring left ventricular ejection fraction [LVEF], left ventricular end-diastolic diameter [LVEDD], and left atrial diameter [LAD]), and brain MRI to measure the DTI-ALPS index of glymphatic activity. The DTI-ALPS index was progressively reduced: NC > CSVD-NCI > CSVD-VCI. It correlated positively with LVEF and negatively with LAD, and was associated with multiple cognitive domains. Mediation analysis suggests that DTI-ALPS statistically significantly mediated the effects of LVEF and LAD on cognitive performance. These cross-sectional findings suggest that glymphatic dysfunction is a key feature of CSVD and may represent a potential correlative link connecting left-heart dysfunction to cognitive impairment, consistent with a potential cardio-glymphatic pathway in CSVD pathophysiology.