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

BACKGROUND AND PURPOSE: 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.

MATERIALS AND METHODS: 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.

RESULTS: 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).

CONCLUSIONS: 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.

ABBREVIATIONS: 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.