Associations between CAG repeat size, brain and spinal cord volume loss, and motor symptoms in spinocerebellar ataxia type 3: a cohort study

Background: Spinocerebellar ataxia type 3 (SCA3) is a hereditary polyglutamine disease, caused by abnormally expanded cytosine–adenine–guanine (CAG) repeats in ATXN3 gene. It is classically characterized by cerebellar and spinal cord atrophy and presents with progressive ataxia. we here investigated the associations between expanded CAG repeat size, brain and spinal cord volume loss, and motor functions in SCA3. Methods: In this prospective cross-observational study, we analyzed 3D T1-weighted MRIs from 92 patients with SCA3 and 42 healthy controls using voxel-based morphometry and region of interest approaches. Associations between CAG repeat size, brain and spinal cord volume loss, and International Cooperative Ataxia Rating Scale (ICARS) score were investigated using partial correlation and mediation analyses. Sample sizes of potential markers were calculated. Results: Compared with healthy controls, SCA3 patients had lower cerebellar volume and cervical spinal cord area. SCA3 patients evolved along a stage-independent decline that began in the cerebellum, progressed to spinal cord, brainstem, thalami, and basal ganglia, and extensive subcortex. CAG repeat size was associated with right cerebellar lobule IV volume ( r = -0.423, P < 0.001) and cervical spinal cord area ( r = -0.405, P < 0.001), and higher ICARS ( r = 0.416, P < 0.001). Mediation analysis revealed an indirect effect of CAG repeat size on ICARS through spinal cord. Sample sizes estimation revealed that a minimum sample size was achieved with spinal cordmeasures. Conclusions: CAG repeat size influenced cerebellar lobule IV and cervical spinal cord volume loss. Our results indicated the potential of cervical spinal cord area as a marker for disease progression and sample size estimations in future SCA3 clinical studies.