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. Trial registration ClinicalTrial ID: ChiCTR2100045857 ( http://www.chictr.org.cn/edit.aspx?pid=55652&htm=4 ) Key Points • Pre- SCA3 showed WM damage mainly in cerebellar peduncles. Continuous brain damage was characterized by brainstem, widespread, and relatively symmetric cerebellar and basal ganglia atrophy. • Volumetric abnormalities were most evident in the bilateral pallidum, brainstem, and cerebellar peduncles in SCA3. • The volume of pons might identify the disease progression longitudinally.