Glymphatic system impairment in Wilson's disease: An overlooked mechanism for neurological dysfunction?

Mounting evidence highlights the critical role of the brain's glymphatic system in cerebral waste clearance, yet its alterations in Wilson's disease (WD) remain unclear. This study aimed to systematically evaluate structural and functional alterations of the glymphatic system across WD clinical phenotypes and their associations with neurological impairment.

Nineteen patients with neurological WD (neuro-WD), 13 with hepatic WD (hep-WD), and 25 healthy controls (HCs) were enrolled. Quantitative MRI metrics included choroid plexus (ChP) volume and diffusion parameters, basal ganglia perivascular space (PVS_BG) volume, and free water-eliminated diffusion tensor imaging analysis along the perivascular space (FWE-DTI-ALPS) index. Group differences were analyzed using ANCOVA, post hoc t-tests, and receiver operating characteristic analyses. Partial correlation analyses were performed to examine associations between MRI and clinical parameters.

ChP and PVS_BG volumes increased progressively across HC, hep-WD, and neuro-WD groups, whereas the FWE-DTI-ALPS index decreased (all p < 0.01), accompanied by elevated free water content and altered diffusion properties in the ChP. The combination of ChP and PVS markers distinguished WD from HC (AUC = 0.939), while ChP volume alone effectively differentiated neuro-WD from hep-WD (AUC = 0.799). ChP volume correlated negatively with the FWE-DTI-ALPS index (r = -0.619), and PVS_BG volume was inversely associated with FWE-DTI-ALPS (r = -0.320). Clinically, ChP enlargement correlated with higher urinary copper levels, whereas fractional anisotropy values, both before and after free water correction, were negatively correlated with serum iron.

These findings provide preliminary imaging evidence of alterations in glymphatic-related MRI markers in WD and suggest that these markers may help differentiate neurological from hepatic phenotypes in research settings. In addition, we emphasize that the observed ALPS changes should be interpreted cautiously, and future longitudinal and multi-shell studies are required before clinical translation can be considered.