White matter structural network alterations in spinocerebellar ataxia type 3: A graph theory analysis

Spinocerebellar ataxia type 3 (SCA3) is an inherited neurodegenerative disorder characterized by progressive motor impairment and cerebellar atrophy. While previous studies have reported white matter (WM) microstructural damage in SCA3, the topological organization of WM structural networks and its relationship with genetic load and clinical severity remain poorly understood. Here, we applied graph theory to diffusion tensor imaging (DTI) data to investigate WM structural network alterations in 42 SCA3 patients and 41 age- and sex-matched healthy controls. We reconstructed WM structural networks and performed graph-theoretical analysis to evaluate network segregation and integration patterns. Compared to controls, SCA3 patients showed extensive microstructural damage in cerebral WM tracts, predominantly affecting the cerebello-thalamo-cortical pathway. Network topology was significantly disrupted, with reduced global efficiency (p < 0.001), decreased local efficiency (p < 0.001), and increased characteristic path length (p < 0.001). Node-level abnormalities were observed in the precentral gyrus, cerebellum, hippocampus, and thalamus (p < 0.05, FDR corrected). Crucially, nodal efficiency in vermis VI exhibited negative correlations with CAG repeat length (r = -0.62, p < 0.001), disease severity (r = -0.58, p < 0.001), and motor impairment scores (r = -0.65, p < 0.001). These results indicate that SCA3 involves a breakdown in both network segregation and integration. Nodal efficiency in the vermis VI represents a promising neuroimaging biomarker that bridges genetic load and motor decline, providing a potential tool for tracking disease progression.