Phenotype-specific white matter microstructural alterations and their clinical correlates in Wilson disease

Abstract

Abstract Wilson disease (WD) is a genetic disorder of copper metabolism that leads to progressive brain damage, yet the microstructural mechanisms underlying white matter alterations remain insufficiently understood. Diffusion tensor imaging provides limited biological specificity and is sensitive to free water contamination. Therefore, we applied neurite orientation dispersion and density imaging to characterize white matter microstructure and its clinical relevance in 30 patients with WD, including neurological and hepatic phenotypes, and 30 matched healthy controls. We demonstrate widespread, phenotype-specific microstructural alterations, with reductions in neurite density and orientation dispersion accompanied by increased extracellular volume fraction and diffusivity metrics (mean, axial, and radial diffusivity) in neurological WD and isolated increased isotropic volume fraction without abnormalities in conventional diffusion metrics in hepatic WD across major white matter tracts. These patterns provide a coherent explanation for previously inconsistent fractional anisotropy findings. Reduced neurite density was associated with greater neurological impairment and lower cognitive performance, particularly in processing speed and visual attention. Together, these findings highlight neurite density as a potential marker of clinically relevant white matter disruption and reveal distinct microstructural signatures across WD phenotypes, consistent with differential underlying mechanisms and a potential progression from free water-related alterations to axonal degeneration. Advanced diffusion imaging thus enables a more specific characterization of white matter pathology and supports linking microstructural alterations to clinical outcomes in neurological disorders.