Cortical gyrification abnormalities are coupled with white matter microstructural disruption in dentatorubral-pallidoluysian atrophy

Abstract Background Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare polyglutamine neurodegenerative disorder characterized by progressive gray matter and white matter (WM) degeneration. Cortical gyrification may reflect coordinated cortical-WM organization. However, whether DRPLA exhibits abnormal gyrification and how such changes relate to cortical-WM structural disruption remain unclear. Methods Twenty-nine patients with adult-onset DRPLA, 11 prodromal mutation carriers, and 30 healthy controls were included. Surface-based local gyrification index (LGI) analysis was performed to identify gyrification abnormalities. Cortical morphometric and diffusion-derived measures were extracted from LGI-significant clusters. Tractography and tract-based spatial statistics were used to assess microstructural abnormalities in anatomically connected WM tracts. Associations between LGI and corresponding imaging and clinical measures were examined, and mediation analysis tested whether LGI-associated imaging measures mediated the association between disease status and LGI reduction. Results Patients with adult-onset DRPLA showed widespread bilateral LGI reductions, whereas prodromal mutation carriers showed no detectable LGI abnormalities. LGI reductions were accompanied by cortical morphometric and microstructural alterations and by widespread microstructural abnormalities in connected WM tracts. Lower LGI was associated with smaller cortical surface area, lower fractional anisotropy and higher orientation dispersion index (ODI) in corresponding WM tracts; increased ODI further mediated the association between disease status and reduced LGI. Lower LGI values were associated with greater motor disease severity and genetic burden. Conclusions Adult-onset DRPLA is characterized by widespread LGI reductions coupled with cortical tissue alterations and connected WM tract disruption. These findings suggest that LGI reductions reflect disrupted cortical-WM structural coordination and may serve as imaging markers of disease burden in adult-onset DRPLA.