Disrupted cerebellar structural connectome in spinocerebellar ataxia type 3 and its association with transcriptional profiles

Abstract

AbstractSpinocerebellar ataxia type 3 (SCA3) is primarily characterized by progressive cerebellar degeneration, including gray matter atrophy and disrupted anatomical and functional connectivity of the cerebellum. The alterations of topological organization of cerebellar white matter structural network in SCA3 and the underlying neurobiological mechanism remain unknown. Using a cohort of 20 patients with SCA3 and 20 healthy controls, we constructed cerebellar structural networks from diffusion magnetic resonance imaging and investigated alterations of topological organization. Then we mapped the alterations with transcriptome data from the Allen Human Brain Atlas to identify possible biological mechanisms for regional selective vulnerability to white matter damage. Compared with healthy controls, decreased global and nodal efficiency, and widely distributed decreased edge strength were observed in SCA3 patients. The regions with decreased nodal global efficiency were mainly located in cerebellar anterior lobe, and the genes express higher in these regions were significantly enriched in synapse-related biological processes. The regions with decreased nodal local efficiency were mainly located in cerebellar posterior lobe, and the higher gene expression in these regions were significantly enriched in metabolic biological processes. Similar hub distributions were found in two groups of subjects, whereas the strengths of rich-club and feeder connections were lower in SCA3 patients. Moreover, strength of the inter-module connections was lower in SCA3 group and negatively correlated with SARA score, ICARS score, and CAG repeat number. These findings suggest a mechanism of white matter vulnerability and a potential image biomarker for the disease severity, providing insights into neurodegeneration and pathogenesis in this disease.