CAG repeat length shapes bidirectional functional connectome alterations in spinocerebellar ataxia type 3: a...

The ATXN3 gene is the primary driver of brain damage in spinocerebellar ataxia type 3 (SCA3). We aimed to elucidate the patterns of connectome alterations shaped by cytosine-adenine-guanine (CAG) repeat length in SCA3. Eighty-nine genetically confirmed patients with SCA3 and 89 age-, sex-, education-matched healthy controls underwent multimodal MRI and comprehensive clinical assessments. Connectome-based predictive modeling (CPM) was used to identify functional connectivity patterns associated with CAG repeat length. Structural brain damage was assessed using voxel-based morphometry. Mediation analysis was performed to examine the role of structural impairment in connectivity changes. CPM identified a positive and a negative network, whose connectivity strength increased or decreased with CAG repeat length. The positive network (r = 0.397, P < 0.001) was mainly localized within the cerebello-motor circuit and was positively associated with ataxia severity and functional disability. The negative network (r = 0.243, P = 0.022) was distributed across large-scale networks, with selective vulnerability of interhemispheric connectivity, and was associated with motor dysfunction. Besides the canonical motor pathways, limbic-related connectivity was related to motor impairment. Structural analyses revealed widespread gray matter atrophy centered on the cerebellum. Cerebellar atrophy statistically mediated the association between CAG repeat length and connectivity decreases. CAG repeat length is associated with a bidirectional connectopathy in SCA3. Cerebellar atrophy may mediate the connectivity decreases. Future longitudinal studies are required to examine the underlying causal pathway.