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

Spinocerebellar 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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by the STI2030-Major Projects (2022ZD021330, 2021ZD0200500), National Natural Science Foundation of China (32271145, 81871425), Fundamental Research Funds for the Central Universities (2017XTCX04), Open Research Fund of the State Key Laboratory of Cognitive Neuroscience and Learning (CNLZD2101, CNLYB2001). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics Committee of China-Japan Friendship Hospital gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors * dMRI : diffusion magnetic resonance imaging ICARS : International Cooperative Ataxia Rating Scale GO : Gene Ontology polyQ : polyglutamine SARA : Scale for the Assessment and Rating of Ataxia SCA3 : spinocerebellar ataxia type 3 SUIT : spatially unbiased atlas template of the cerebellum and brainstem WM : white matter