A Severity-Agnostic Atrophy Pattern in Spinocerebellar Ataxia Type 3: Volumetrics from ENIGMA-Ataxia.
A Severity-Agnostic Atrophy Pattern in Spinocerebellar Ataxia Type 3: Volumetrics from ENIGMA-Ataxia.
Where did the research take place?
The study site has not been established. Author addresses may differ from where the research occurred.
Halifax, CA · Author affiliation
Faculty of Computer Science, Dalhousie University, Halifax, Nova Scotia, Canada.Location evidence
Minneapolis, US · Author affiliation
Department of Radiology, Center for Magnetic Resonance Research, University of Minnesota Medical School, Minneapolis, Minnesota, USA.Location evidence
US · Author affiliation · country only
Department of Applied Physiology & Kinesiology, University of Florida, Gainesville, Florida, USA.Location evidence
Houston, US · Author affiliation
Department of Neurology, Weill Cornell Medicine at Houston Methodist Research Institute, Houston, Texas, USA.Location evidence
Tübingen, DE · Author affiliation
Department of Diagnostic and Interventional Neuroradiology, University Hospital Tübingen, Tübingen, Germany.Location evidence
BR · Author affiliation · country only
Department of Neurology, School of Medical Sciences, University of Campinas, Campinas, Brazil.Location evidence
Chongqing, CN · Author affiliation
7T Magnetic Resonance Imaging Translational Medical Center, Department of Radiology, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, China.Location evidence
Paris, FR · Author affiliation
Sorbonne Université, Paris Brain Institute (ICM), Pitié-Salpêtrière Hospital, AP-HP, INSERM, CNRS, University Hospital Pitié-Salpêtrière, Paris, France.Location evidence
Curitiba, BR · Author affiliation
Post-Graduate Program of Internal Medicine, Internal Medicine Department, Hospital de Clínicas, Federal University of Paraná, Curitiba, Brazil.Location evidence
Halle, DE · Author affiliation
Department for Radiation Medicine, University Clinic and Outpatient Clinic for Radiology, University Hospital Halle (Saale), University Medicine Halle, Halle (Saale), Germany.Location evidence
Aachen, DE · Author affiliation
Department of Neurology, RWTH Aachen University, Aachen, Germany.Location evidence
Jülich, DE · Author affiliation
JARA-BRAIN Institute Molecular Neuroscience and Neuroimaging, Research Center Jülich GmbH, Jülich, Germany.Location evidence
Bonn, DE · Author affiliation
German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.Location evidence
Mexico City, MX · Author affiliation
Neuropsychology Laboratory, Department of Physiology, Faculty of Medicine, National Autonomous University of Mexico, Mexico City, Mexico.Location evidence
Essen, DE · Author affiliation
Center for Translational Neuro- and Behavioral Sciences (C-TNBS), Essen University Hospital, University of Duisburg-Essen, Essen, Germany.Location evidence
Hopkins, US · Author affiliation
Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, USA.Location evidence
Baltimore, US · Author affiliation
Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, USA.Location evidence
Ann Arbor, US · Author affiliation
Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA.Location evidence
Marina, US · Author affiliation
Imaging Genetics Center, Mark and Mary Stevens Institute for Neuroimaging and Informatics, Keck School of Medicine, University of Southern California, Marina del Rey, California, USA.Location evidence
Norman, US · Author affiliation
Norman Fixel Institute for Neurological Diseases, University of Florida, Gainesville, Florida, USA.Location evidence
Nijmegen, NL · Author affiliation
Department of Neurology, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.Location evidence
Arnhem, NL · Author affiliation
Department of Neurology, Rijnstate Hospital, Arnhem, The Netherlands.Location evidence
Brisbane, AU · Author affiliation
QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.Location evidence
Melbourne, AU · Author affiliation
School of Translational Medicine, Monash University, Melbourne, Victoria, Australia.Location evidence
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Original 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.