Brain atrophy staging in spinocerebellar ataxia type 3 for clinical prognosis and trial enrichment.
Authors
Affiliations (27)
Affiliations (27)
- German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany. Electronic address: [email protected].
- German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany; University of Bonn, Bonn, Germany.
- German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
- Department of Neurology, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, Brazil.
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
- Radiological Intervention Center, Department of Radiology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
- German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany; Center for Neurology, Department of Parkinson, Sleep and Movement Disorders, University Hospital Bonn, Bonn, Germany.
- Department of Neurology, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.
- Department of Neurology, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands; Department of Neurology, Rijnstate Hospital, Arnhem, Nijmegen, the Netherlands.
- Sorbonne Université, Paris Brain Institute - ICM, Inserm, CNRS, APHP, Pitié-Salpêtrière University Hospital, Paris, France.
- Division Translational Genomics of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen, Germany; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
- German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany; Department of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
- Ataxia Centre, Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK.
- Center for Magnetic Resonance Research, Department of Radiology, University of Minnesota, Minneapolis, MN, USA.
- Department of Neurology and Center for Translational Neuro- and Behavioral Sciences, University of Duisburg-Essen, Essen, Germany.
- Department of Neurology, University Hospital Heidelberg, Heidelberg, Germany.
- Department of Neurology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
- Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- Department of Radiology, Massachusetts General Hospital, Boston, MA, USA; A. A. Martinos Center for Biomedical Imaging and Harvard Medical School Charlestown, Charlestown, MA, USA.
- Ataxia Center, Laboratory for Neuroanatomy and Cerebellar Neurobiology, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
- Department of Neurology, RWTH Aachen University, Aachen, Germany; JARA-Brain Institute Molecular Neuroscience and Neuroimaging, Forschungszentrum Jülich, Jülich, Germany.
- Neurology Service, University Hospital Marqués de Valdecilla-IDIVAL, Universidad de Cantabria, Centro de Investigación en Red de Enfermedades Neurodegenerativas (CIBERNED), Santander, Spain.
- Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany; Centre for Rare Diseases, University of Tübingen, Tübingen, Germany.
- German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany; Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden; Center for Behavioral Brain Sciences (CBBS), Otto-von-Guericke University, Magdeburg, Germany.
- German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany; Center for Neurology, Department of Parkinson, Sleep and Movement Disorders, University Hospital Bonn, Bonn, Germany; Department of Neuroradiology, University Hospital Bonn, Bonn, Germany.
Abstract
Spinocerebellar ataxia type 3 (SCA3) is characterised by progressive brain atrophy, with regional volume loss detectable via MRI prior to clinical manifestation. We aimed to identify the previously unknown sequence of brain atrophy in SCA3 and evaluate whether this sequence can be translated into an atrophy staging framework to enable accurate clinical prognosis and trial enrichment. We included data from 322 SCA3 mutation carriers, enrolled in observational studies conducted across Europe, the Americas, and Asia. Participants underwent follow-up assessments up to five years after baseline. The Subtype and Stage Inference machine learning algorithm was applied to estimate the most likely atrophy sequence(s) from baseline anatomical MRI. The Scale for the Assessment and Rating of Ataxia (SARA) was used to capture ataxia severity. Atrophy stages were analysed in relation to SARA and time from disease onset. Interventional trials were simulated to estimate required sample sizes under different atrophy stage eligibility criteria. We identified a uniform sequence of brain atrophy in SCA3, characterised by earliest volumetric decline in the caudal brainstem and substantial involvement of the white matter. Atrophy stage was associated with both SARA and time from disease onset. Atrophy staging outperformed single-region volumetrics in predicting SARA over time. Applying atrophy stage cut-offs substantially reduced the sample sizes needed to adequately power hypothetical clinical trials. These findings yield mechanistic insights into the progression of neurodegeneration in SCA3 and possess immediate translational relevance, facilitating patient stratification and sample enrichment for interventional trials. National Ataxia Foundation (NAF).