Glymphatic system impairment in cerebral small vessel disease: associations with perivascular space volume and cognition.

Objective: While emerging evidence links glymphatic dysfunction to cerebral small vessel disease (CSVD), its clinical relevance remains poorly defined. This study aimed to investigate the relationships among glymphatic function, perivascular space (PVS), and cognitive performance in CSVD. Methods: We enrolled 120 CSVD patients [52 with no cognitive impairment (CSVD-NCI) and 68 with mild cognitive impairment (CSVD-MCI)] and 40 healthy controls (HCs). Glymphatic function was assessed using the left ALPS index derived from diffusion tensor imaging analysis along the perivascular space (DTI-ALPS). Group comparisons in the ALPS index and PVS volume fraction (VF), and correlations among glymphatic function, PVS burden, and cognition were analyzed. Results: Compared to HCs, CSVD patients showed decreased ALPS index and increased PVS VF in basal ganglia (BG), caudate, putamen, and hippocampus, with more pronounced alterations in the left hemisphere. The ALPS index was inversely correlated with PVS VF in the BG (r = -0.232, p = 0.014), thalamus (r = -0.213, p = 0.024), caudate (r = -0.221, p = 0.019), and putamen (r = -0.210, p = 0.026) in CSVD. Furthermore, a lower ALPS index was associated with poorer performance in global cognition (r = 0.312, p = 0.001), executive function (r = 0.242, p = 0.012), processing speed (r = 0.264, p = 0.006), and visuospatial function (r = 0.272, p = 0.004). Finally, the ALPS index partially mediated the association between putamen-PVS VF and global cognitive function, especially in the left hemisphere. Conclusion: Our findings demonstrate that impaired glymphatic function was associated with enlarged BG-PVS, especially in the putamen, and worse cognitive performance, highlighting its potential role in disease progression and cognitive decline in CSVD.