Abstract
BACKGROUND: Accumulating evidences indicate regional gray matter (GM) morphology atrophy in spinocerebellar ataxia type 3 (SCA3); however, whether large-scale morphological brain networks (MBNs) undergo widespread reorganization in these patients remains unclear. OBJECTIVE: To investigate the topological organization of large-scale individual-based MBNs in SCA3 patients. METHODS: The individual-based MBNs were constructed based on the inter-regional morphological similarity of GM regions. Graph theoretical analysis was taken to assess GM structural connectivity in 76 symptomatic SCA3, 24 pre-symptomatic SCA3, and 54 healthy normal controls (NCs). Topological parameters of the resulting graphs and network-based statistics analysis were compared among symptomatic SCA3, pre-symptomatic SCA3, and NCs groups. The inner association between network properties and clinical variables was further analyzed. RESULTS: Compared to NCs and pre-symptomatic SCA3 patients, symptomatic SCA3 indicated significantly decreased integration and segregation, a shift to "weaker small-worldness", characterized by decreased C(p) , lower E(loc,) and E(glob) (all p < 0.005). Regarding nodal properties, symptomatic SCA3 exhibited significantly decreased nodal profiles in the central executive network (CEN)-related left inferior frontal gyrus, limbic regions involving the bilateral amygdala, left hippocampus, and bilateral pallidum, thalamus; and increased nodal degree, efficiency in bilateral caudate (all p(FDR) <0.05). Meanwhile, clinical variables were correlated with altered nodal profiles (p(FDR) ≤0.029). SCA3-related subnetwork was closely interrelated with dorsolateral cortico-striatal circuitry extending to orbitofrontal-striatal circuits and dorsal visual systems (lingual gyrus-striatal). CONCLUSION: Symptomatic SCA3 patients undergo an extensive and significant reorganization in large-scale individual-based MBNs, probably due to disrupted prefrontal cortico-striato-thalamo-cortical loops, limbic-striatum circuitry, and enhanced connectivity in the neostriatum. This study highlights the crucial role of abnormal morphological connectivity alterations beyond the pattern of brain atrophy, which might pave the way for therapeutic development in the future.