Structural alterations of spinocerebellar ataxias type 3: from pre-symptomatic to symptomatic stage

Objectives To investigate and characterize the structural alterations of the brain in SCA3, and their correlations with the scale for the assessment and rating of ataxia (SARA) and normal brain ATXN3 expression. Methods We performed multimodal analyses in 52 SCA3 (15 pre-symptomatic) and healthy controls (HCs) (n = 35) to assess the abnormalities of gray and white matter (WM) of the cerebrum, brainstem, and cerebellum via FreeSurfer, SUIT, and TBSS, and their associations with disease severity. Twenty SCA3 patients (5 pre- and 15 symptomatic) were followed for at least a year. Besides, we uncovered the normal pattern of brain ATXN3 spatial distribution. Results Pre-symptomatic patients showed only WM damage, mainly in the cerebellar peduncles, compared to HCs. In the advanced stage, the WM damage followed a caudal-rostral pattern. Meanwhile, continuous nonlinear structure damage was characterized by brainstem volumetric reduction and relatively symmetric cerebellar and basal ganglia atrophy but spared the cerebral cortex, partially explained by the ATXN3 overexpression. The bilateral pallidum, brainstem, and cerebellar peduncles demonstrated a very large effect size. Besides, all these alterations were significantly correlated with SARA; the pons (r = -0.65) and superior cerebellar peduncle (r = -0.68) volume demonstrated a higher correlation than the cerebellum with SARA. The longitudinal study further uncovered progressive atrophy of pons in symptomatic SCA3. Conclusions Significant WM damage starts before the ataxia onset. The bilateral pallidum, brainstem, and cerebellar peduncles are the most vulnerable targets. The volume of pons appears to be the most promising imaging biomarker for a longitudinal study.

Automated summary

This study aims to investigate the structural alterations in the brain of SCA3 patients and their correlations with ATXN3 expression and disease severity. The findings suggest that white matter damage occurs before the onset of ataxia in pre-symptomatic patients, mainly in the cerebellar peduncles. In the advanced stage, the damage follows a caudal-rostral pattern. The study also reveals brainstem volumetric reduction and cerebellar and basal ganglia atrophy, which are partially explained by ATXN3 overexpression. The bilateral pallidum, brainstem, and cerebellar peduncles show significant effect sizes. These alterations are correlated with the severity of the disease and the volume of the pons appears to be a promising imaging biomarker for longitudinal study.