Brain Structure Mediates Impact of Pulmonary Dysfunction on Cognition in Spinocerebellar Ataxia Type 3

Background Spinocerebellar ataxia type 3 (SCA3) is a common autosomal dominant disorder marked by both cognitive and pulmonary dysfunction. Although a connection between these impairments exists, the mechanisms underlying this relationship are not well understood. In this study, we aim to explore the neural and physiological pathways linking pulmonary and cognitive deficits in SCA3 through multimodal integration. Methods Seventy-six SCA3 patients from the OSCCAR cohort underwent assessments including pulmonary function testing (classified as normal [NPF] or impaired [IPF]), cognitive evaluations (MoCA, MMSE, CVLT-II), and multimodal MRI (3T Siemens). Structural brain volumes were analyzed using CAT12/SPM12, and resting-state functional connectivity was assessed with the CONN toolbox. Mediation analysis was employed to determine whether gray matter volume mediated the relationship between pulmonary and cognitive impairments. Results SCA3 patients with IPF exhibited global cognition and verbal memory that is significantly worse compared to those with NPF. For example, recall-discrimination decreases, intrusions increase, and forget quickly ( p  < 0.05). IPF patients also had significant gray matter atrophy, predominantly in temporal regions (β = −0.16 to − 0.91, p  < 0.05), extending to the frontal, parietal, insular, and cerebellar areas (β = −0.03 to − 0.34, p  < 0.05). Additionally, the connectivity between rITG-medial temporal and intra-cerebellar was impaired (β ≤ −0.21, p  < 0.05). Conclusion Pulmonary dysfunction in SCA3 is associated with greater cognitive impairment and cortical gray matter atrophy. Our findings suggest that gray matter volume may serve as a mediator in the pathway linking pulmonary and cognitive dysfunction.