Diffusion along Perivascular Spaces as a Marker for Glymphatic System Impairment in Huntington's Disease

Abstract Background The aim was to investigate if glymphatic function is impaired in patients with Huntington's disease (HD) and its clinical relevance. Methods Forty‐nine subjects carrying mutant Huntingtin (m HTT ), comprising 35 manifest (mHD) and 14 pre‐manifest (PreHD), and 35 healthy controls (HC) were recruited in this study. The diffusion along perivascular spaces (ALPS) index and the percentage of perivascular space in the basal ganglia (pPVS_BG) were obtained in different groups. The discrimination effects of ALPS index were detected using receiver operating characteristic (ROC) analysis, and the correlations of ALPS index with clinical features of HD were further analyzed. Results ALPS index was decreased in m HTT carriers compared to HCs, and it was lower in mHD compared to PreHD patients. ROC analysis showed that the ALPS index could discriminate m HTT from HC (AUC [area under the curve] = 0.903), mHD from PreHD (AUC = 0.886), and PreHD from controls (AUC = 0.755). Lower ALPS index correlated with greater disease burden, severity of the disease, lager pPVS_BG, and lower brain volume and thickness of cortices. Regression analysis showed that ALPS index could predict the performance of motor and cognitive functions. Mediation analysis revealed that ALPS partially mediated the effects of CAG repeat and age on the cognitive decline in HD. Conclusions This study demonstrated that the impairment of the glymphatic system, especially in the paraventricular white matter and BG, was correlated with the clinical manifestations, disease burden, and brain structural changes in m HTT carriers. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.