Glymphatic Dysfunction is Associated with Cognitive Impairment in White Matter Hyperintensities: A DTI-Based Study

Background: The underlying mechanisms of cognitive impairment in patients with white matter hyperintensities (WMHs) remain largely elusive. Glymphatic dysfunction, as measured by the diffusion tensor imaging along the perivascular space (DTI-ALPS) index, has been associated with cognitive decline across various neurological and psychiatric disorders. Objective: This study aims to examine the potential association between glymphatic dysfunction, as measured by the DTI-ALPS index, and cognitive impairment in patients with WMHs. Methods: A total of 88 patients with varying degrees of WMHs (Mild = 25, Moderate = 34, Severe = 29) and 32 matched healthy controls were recruited. Comprehensive neuropsychological assessments and MRI scans were performed on all participants. We compared demographic information, cognitive function, and DTI-ALPS indices between patients with WMHs and controls, and evaluated the correlation between cognitive impairment and the DTI-ALPS index. Results: Apart from hypertension, demographic characteristics were comparable across the four groups. Patients with WMHs showed significant impairments in emotional status, global function, language function, memory function, processing speed and cognitive flexibility. A reduction in LeftALPS, RightALPS, and MeanALPS was observed in patients with WMHs, with these decreases significantly and negatively correlated with the WMHs volume (LeftALPS, R = -0. 381, PFDR < 0. 001; RightALPS, R = -0. 423, PFDR < 0. 001; and MeanALPS, R = -0. 476, PFDR < 0. 001). After FDR correction, MeanALPS remained significantly correlated with language function (S-VFT: R = 0. 338, PFDR = 0. 030), while trends were observed between MeanALPS and emotional status, global function, memory function, and processing speed. Conclusion: Cognitive impairment in patients with WMHs is closely linked to decreased DTI-ALPS index, especially as white matter lesions worsen. Glymphatic dysfunction may play a critical role in this cognitive impairment, positioning the DTI-ALPS index may serve as a potential biomarker for cognitive impairment in patients with WMHs.