A Severity‐Agnostic Atrophy Pattern in Spinocerebellar Ataxia Type 3: Volumetrics from <scp>ENIGMA</scp> ‐Ataxia

BACKGROUND: Spinocerebellar ataxia type 3 (SCA3) is a rare, inherited neurodegenerative disease characterized by progressive loss of motor coordination. OBJECTIVES: We undertook a multisite magnetic resonance imaging study to profile the spatial spread of atrophy across the brain, determine whether atrophy preferentially maps onto specific functional networks, and investigate the relationship between cerebellar and cerebral atrophy. METHODS: Whole-brain grey and white matter (GM and WM) voxel-based morphometry was performed on 408 individuals with SCA3 (82 pre-ataxic) and 293 controls. The SCA3 cohort was stratified by ataxia severity to study progression. Cerebellar GM atrophy was mapped onto a task-based functional atlas. Cerebrocerebellar volumetric covariance was assessed to determine whether cerebral and cerebellar atrophy were coupled. RESULTS: The atrophy pattern is spatially consistent but progressive in magnitude across the disease course. The greatest atrophy (Cohen's d > 1.5) occurred in the pons, cerebellar WM, and cerebellar peduncles; correlations with ataxia severity and duration were also strongest (-0.4 > r > -0.65) in those regions. Cerebellar GM atrophy was greatest (d ≅ 0.7) in functional regions associated with motor planning/execution, attention, and emotional processing. Sparse cerebral cortical atrophy appears only in the most severe disease subgroup, while striatal atrophy begins in the earliest stages but does not worsen with increasing clinical severity. Reduced cerebrocerebellar volumetric covariance is observed in SCA3 participants versus controls. CONCLUSIONS: Cerebellar and brainstem atrophy underlies greater ataxia severity in SCA3, but the spatial pattern of structural changes remains relatively consistent across the course of the disease. Cerebellar GM atrophy is spatially non-uniform, and occurs maximally in regions consistent with the motor and cognitive clinical presentation of SCA3. Cerebellar atrophy is not mirrored by corresponding cerebral structural changes. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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Journal
Movement Disorders
Published
2026-05-10
DOI
https://doi.org/10.1002/mds.70349
Primary Topic
Genetic Neurodegenerative Diseases
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article

A Severity‐Agnostic Atrophy Pattern in Spinocerebellar Ataxia Type 3: Volumetrics from ENIGMA ‐Ataxia

Judith van Gaalen, Sophia I. Thomopoulos, David J. Arpin, Gülin Öz et al.
Movement Disorders
Genetic Neurodegenerative Diseases
article

A Severity‐Agnostic Atrophy Pattern in Spinocerebellar Ataxia Type 3: Volumetrics from ENIGMA ‐Ataxia

Judith van Gaalen, Sophia I. Thomopoulos, David J. Arpin, Gülin Öz, D Timmann, Jerry L. Prince, Shuo Han, Juan Fernández-Ruíz, Andreas Deistung, Jun Luo, Sarah H. Ying, Carlos R. Hernandez-Castillo, Hélio A. Ghizoni Teive, Alberto R. M. Martinez, Henry Paulson, Isaac Adanyeguh, Matthis Synofzik, Sophia L. Göricke, Marcondes C. França, Chiadi U. Onyike, Alexandra Durr, Jennifer Faber, Xingang Wang, Sergio E. Ono, Xi Chen, David Vaillancourt, Giulia Coarelli, Philipp Wegner, Thomas Klockgether, Mónica Ferreira, for the EUROSCA MR Study Group, Tetsuo Ashizawa, for the ESMI MR Study Group, Imis Dogan, Ian H. Harding, Kathrin Reetz, Fernando Cendes, Jason W. Robertson, Thiago J.R. Rezende, Léo Coutinho, Bart van de Warrenburg, Chen Liu, Benjamin Bender, Paul M. Thompson
article en

Abstract

BACKGROUND: Spinocerebellar ataxia type 3 (SCA3) is a rare, inherited neurodegenerative disease characterized by progressive loss of motor coordination. OBJECTIVES: We undertook a multisite magnetic resonance imaging study to profile the spatial spread of atrophy across the brain, determine whether atrophy preferentially maps onto specific functional networks, and investigate the relationship between cerebellar and cerebral atrophy. METHODS: Whole-brain grey and white matter (GM and WM) voxel-based morphometry was performed on 408 individuals with SCA3 (82 pre-ataxic) and 293 controls. The SCA3 cohort was stratified by ataxia severity to study progression. Cerebellar GM atrophy was mapped onto a task-based functional atlas. Cerebrocerebellar volumetric covariance was assessed to determine whether cerebral and cerebellar atrophy were coupled. RESULTS: The atrophy pattern is spatially consistent but progressive in magnitude across the disease course. The greatest atrophy (Cohen's d > 1.5) occurred in the pons, cerebellar WM, and cerebellar peduncles; correlations with ataxia severity and duration were also strongest (-0.4 > r > -0.65) in those regions. Cerebellar GM atrophy was greatest (d ≅ 0.7) in functional regions associated with motor planning/execution, attention, and emotional processing. Sparse cerebral cortical atrophy appears only in the most severe disease subgroup, while striatal atrophy begins in the earliest stages but does not worsen with increasing clinical severity. Reduced cerebrocerebellar volumetric covariance is observed in SCA3 participants versus controls. CONCLUSIONS: Cerebellar and brainstem atrophy underlies greater ataxia severity in SCA3, but the spatial pattern of structural changes remains relatively consistent across the course of the disease. Cerebellar GM atrophy is spatially non-uniform, and occurs maximally in regions consistent with the motor and cognitive clinical presentation of SCA3. Cerebellar atrophy is not mirrored by corresponding cerebral structural changes. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Movement Disorders
University of Southern California (US), Centre National de la Recherche Scientifique (FR), Dalhousie University (CA), University of Bonn (DE), Johns Hopkins University (US), Radboud University Nijmegen (NL), Army Medical University (CN), Inserm (FR), Universidade Estadual de Campinas (UNICAMP) (BR), Cornell University (US), QIMR Berghofer Medical Research Institute (AU), University of Michigan (US), University Hospital Bonn (DE), German Center for Neurodegenerative Diseases (DE), Radboud University Medical Center (NL), University of Florida (US), Sorbonne Université (FR), Centrus Diagnósticos por Imagem (BR), Methodist Hospital (US), Essen University Hospital (DE), Pitié-Salpêtrière Hospital (FR), Southwest Hospital (CN), Jülich Aachen Research Alliance (DE), Hospital de Clínicas Universidade Federal do Paraná (BR), Hertie Institute for Clinical Brain Research (DE), Brazilian Institute of Neuroscience and Neurotechnology (BR), Rijnstate Hospital (NL), University Hospital in Halle (DE), Resonance Research (United States) (US), Universidade Federal do Paraná (BR), Monash University (AU), University of Duisburg-Essen (DE), RWTH Aachen University (DE), Universidad Nacional Autónoma de México (MX)
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Genetic Neurodegenerative Diseases
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