Glymphatic Function as a Moderator in White Matter Injury and Cognitive Impairment: A Community-Dwelling Cohort Study

White matter injury (WMI) is associated with cognitive dysfunction in aging population; however, a clinicoradiological discrepancy often arises between WMI and cognition function in clinical practice. Emerging evidence suggests that the glymphatic system plays a crucial role in clearing metabolic waste and maintaining cognitive function. We hypothesize that glymphatic dysfunction may contribute to this discrepancy by moderating the impact of WMI on cognition. We conducted a retrospective review of community-dwelling residents in our center who underwent multimodal MRI scan and neuropsychological testing from April 2017 to December 2021. WMI, as indicated by white matter hyperintensities (WMHs) and normal-appearing white matter (NAWM) microstructural injury, along with cerebral blood flow (CBF), were quantified by multimodal MRI. Cognition was assessed by mini-mental state examination (MMSE). Glymphatic function was evaluated using diffusion tensor imaging along the perivascular space (DTI-ALPS). Moderation analyses were performed to explore the potential role of glymphatic function. A total of 947 participants were included in the final analysis. A higher WMHs burden was found to be associated with lower MMSE scores in the low DTI-ALPS group (r = -0.261, p <0.001), but the correlation was not significant in the high DTI-ALPS group (r = -0.082, p = 0.07). After adjusting for confounding factors, DTI-ALPS moderated the relationship between WMHs burden and MMSE score (β = 1.792, p = 0.02), and the moderating effect was significant in participants aged ≤60 years old (β = 2.573, p = 0.04), without lacunes (β = 2.576, p = 0.01) or without cerebral microbleeds (β = 3.008, p = 0.004). Longitudinal analysis demonstrated that DTIALPS also moderated the relationship between WMHs burden and cognitive decline (β = -3.771, p =0.001). Furthermore, DTI-ALPS moderated the relationship between NAWM microstructural injury and MMSE score (β = -20.201, p =0.01), but no moderating effect was detected between CBF and MMSE score (p > 0.05). Glymphatic system plays a moderate role in the association between WMI and cognitive impairment, highlighting its potential importance in WMI-related cognitive impairment. Further studies are needed to explore the relative mechanisms. ASL = Arterial spin labeling; CMBs = Cerebral microbleeds; DTI-ALPS = Diffusion tensor imaging along the perivascular space; ESWAN = Enhanced T2 star weighted angiography; FA = Fractional anisotropy; ICV = Intracranial volume; MMSE = Mini-mental state examination; NAWM = Normal-appearing white matter; WMHs = White matter hyperintensities; WMI = White matter injury.