Glymphatic System Dysfunction and its Associated Factors in Wilson's Disease: A DTI-ALPS Study

Wilson's disease (WD) is a genetic disorder of copper (Cu) metabolism that causes Cu accumulation in multiple organs, particularly the liver and brain, resulting in progressive multisystem damage. This study investigated glymphatic system function and its associated factors in patients with WD.

Seventy-one patients with WD (19 hepatic, 52 neurological) and 15 healthy controls (HCs) were enrolled. The analysis along the perivascular space (ALPS) index was quantified using diffusion tensor imaging (DTI-ALPS). Comparisons were performed between patients and than HCs, and across WD phenotypes, and correlations with clinical characteristics were analyzed.

Compared with HCs, patients with WD exhibited significantly reduced ALPS index (p < 0.001). Patients with neurological WD had a significantly lower ALPS index than those with hepatic WD (p = 0.018) and HCs (p < 0.001). No significant difference was observed between patients with hepatic WD and HCs (p = 0.077). In neurological WD, the ALPS index was significantly higher on the left side than that on the right (p < 0.001), whereas no significant interhemispheric differences were found in hepatic WD or HCs (p > 0.05). In neurological WD, the ALPS index correlated positively with albumin, fasting blood glucose, and the white matter volume-to-total intracranial volume ratio (V_WM/TIV ratio), and negatively with age, alanine aminotransferase, aspartate aminotransferase (AST), and the unified WD rating scale-part I (UWDRS-I) score. Multiple regression identified age, AST, and the UWDRS-I score as independent predictors of reduced ALPS index.

Neurological WD was associated with impaired glymphatic system function and altered lateralization. Age, AST, and the UWDRS-I score were independently associated with dysfunction.Glymphatic function, assessed by DTI-ALPS index, was impaired in neurological WD compared with the hepatic phenotype and controls. Age, AST, and UWDRS-I score independently predicted dysfunction, linking neurodegeneration, liver injury, and altered glymphatic activity.