# Progressive subcortical involvement as spinocerebellar ataxia type 3 advances

## TL;DR

This study shows how brain structures change as spinocerebellar ataxia type 3 progresses, linking these changes to clinical symptoms and genetic factors.

## Contribution

The study reveals progressive subcortical shape changes and their bidirectional correlation with clinical and genetic markers in SCA3.

## Key findings

- White matter microstructural abnormalities expand from the cerebellar peduncle as SCA3 progresses.
- Subcortical structures show inward atrophy and outward inflation, correlating with clinical measurements and CAG repeat length.
- Localized shape changes in subcortical structures are linked to clinical heterogeneity in SCA3.

## Abstract

Spinocerebellar ataxia type 3 (SCA3) is a progressive neurodegenerative disease characterized by heterogeneous motor and nonmotor manifestations. The progressive pattern of subcortical shape abnormalities and their associations with the clinical phenotypes in SCA3 remain unknown.

Tract-based spatial statistics (TBSS) and FSL-FIRST were used to characterize the progressive patterns of the abnormalities in white matter microstructure and subcortical shape in four subgroups of SCA3 patients stratified based on disease duration (n = 56). These were compared to matched healthy control groups (n = 59).

TBSS analyses revealed a clear progressive pattern of white matter microstructural abnormalities throughout the course of SCA3, as indicated by an expanding topographic distribution of fractional anisotropy (FA) reductions that originated from the cerebellar peduncle. Vertex-based shape analyses uncovered an increasing number of affected subcortical structures in symptomatic patients as the disease progressed with concurrent inward atrophy and outward inflation in subcortical structures including the bilateral thalamus, caudate, putamen, pallidum, hippocampus and brainstem. Moreover, the localized shape changes of subcortical structures correlated bidirectionally with clinical measurements including the length of CAG repeats within the ATXN3 gene, the scores on the scale of the assessment, the rating of ataxia, the instrumental activities of daily living scale, and the mini-mental state examination.

We demonstrated progressive, localized, and bidirectional changes in the shape of subcortical structures that related to diverse clinical manifestations in SCA3, highlighting the pivotal role of localized shape abnormalities in contributing to the clinical heterogeneity of this disorder.

Imaging genetics study the relationship between MJD1 gene and cognitive impairment with Spinocerebellar Ataxia type 3, ChiCTR1800019901. Registered 8 December 2018 and ChiCTR2000039434. Registered 28 October 2020, http://chictr.org.cn.

The online version contains supplementary material available at 10.1186/s13023-025-03803-3.