The Lancet Regional Health. Europe (Aug 2025)
Progression of biological markers in spinocerebellar ataxia type 3: longitudinal analysis of prospective data from the ESMI cohortResearch in context
- Moritz Berger,
- Hector Garcia-Moreno,
- Mónica Ferreira,
- Jeannette Hubener-Schmid,
- Tamara Schaprian,
- Philipp Wegner,
- Tim Elter,
- Kennet M. Teichmann,
- Magda M. Santana,
- Marcus Grobe-Einsler,
- Demet Oender,
- Berkan S.C. Koyak,
- Sarah Bernsen,
- Luís Pereira de Almeida,
- Patrick Silva,
- Joana Afonso Ribeiro,
- Inês Cunha,
- Cristina Gonzalez-Robles,
- Shamsher Khan,
- Amanda Heslegrave,
- Henrik Zetterberg,
- Manuela Lima,
- Mafalda Raposo,
- Ana F. Ferreira,
- João Vasconcelos,
- Bart P. van de Warrenburg,
- Judith van Gaalen,
- Teije H. van Prooije,
- Jeroen de Vries,
- Ludger Schols,
- Olaf Riess,
- Matthis Synofzik,
- Dagmar Timmann,
- Andreas Thieme,
- Friedrich Erdlenbruch,
- Jon Infante,
- Ana L. Pelayo-Negro,
- Leire Manrique,
- Kathrin Reetz,
- Imis Dogan,
- Gulin Oz,
- James M. Joers,
- Khalafalla Bushara,
- Chiadikaobi Onyike,
- Michal Povazan,
- Heike Jacobi,
- Jeremy D. Schmahmann,
- Eva-Maria Ratai,
- Matthias Schmid,
- Paola Giunti,
- Thomas Klockgether,
- Jennifer Faber
Affiliations
- Moritz Berger
- Medical Faculty, Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany; Core Facility Biostatistics, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Hector Garcia-Moreno
- Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Ataxia Centre, University College London, London WC1N 3BG, UK; Department of Neurogenetics, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London WC1N 3BG, UK
- Mónica Ferreira
- German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany; University of Bonn, Bonn, Germany
- Jeannette Hubener-Schmid
- Institute for Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany
- Tamara Schaprian
- German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
- Philipp Wegner
- German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany; University of Bonn, Bonn, Germany
- Tim Elter
- Department of Neurogenetics, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London WC1N 3BG, UK
- Kennet M. Teichmann
- German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
- Magda M. Santana
- Center for Neuroscience and Cell Biology, University of Coimbra (CNC-UC), Coimbra, Portugal; Center for Innovative in Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal; Gene Therapy Center of Excellence (GeneT), Coimbra, Portugal
- Marcus Grobe-Einsler
- German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany; Department of Parkinson’s Disease, Sleep and Movement Disorders, Center for Neurology, University Hospital Bonn, Bonn, Germany
- Demet Oender
- German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany; Department of Parkinson’s Disease, Sleep and Movement Disorders, Center for Neurology, University Hospital Bonn, Bonn, Germany
- Berkan S.C. Koyak
- German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany; Department of Parkinson’s Disease, Sleep and Movement Disorders, Center for Neurology, University Hospital Bonn, Bonn, Germany
- Sarah Bernsen
- German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany; Department of Parkinson’s Disease, Sleep and Movement Disorders, Center for Neurology, University Hospital Bonn, Bonn, Germany
- Luís Pereira de Almeida
- Center for Neuroscience and Cell Biology, University of Coimbra (CNC-UC), Coimbra, Portugal; Center for Innovative in Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal; Gene Therapy Center of Excellence (GeneT), Coimbra, Portugal
- Patrick Silva
- Center for Neuroscience and Cell Biology, University of Coimbra (CNC-UC), Coimbra, Portugal; Center for Innovative in Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal; Gene Therapy Center of Excellence (GeneT), Coimbra, Portugal
- Joana Afonso Ribeiro
- Department of Neurology, Child Development Centre, Coimbra University Hospital Center (CHUC), Coimbra, Portugal
- Inês Cunha
- Department of Neurology, Coimbra University Hospital Center (CHUC), Coimbra, Portugal
- Cristina Gonzalez-Robles
- Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Ataxia Centre, University College London, London WC1N 3BG, UK
- Shamsher Khan
- Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Ataxia Centre, University College London, London WC1N 3BG, UK
- Amanda Heslegrave
- Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK; UK Dementia Research Institute at UCL, London, UK
- Henrik Zetterberg
- Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK; UK Dementia Research Institute at UCL, London, UK; Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, S-431 80, Mölndal, Sweden
- Manuela Lima
- Faculdade de Ciências e Tecnologia, Universidade dos Açores, Ponta Delgada, Portugal; UMIB - Unit for Multidisciplinary Research in Biomedicine, ICBAS - School of Medicine and Biomedical Sciences, University of Porto, Porto, Portugal
- Mafalda Raposo
- Instituto de Biologia Molecular e Celular (IBMC), Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal; Faculdade de Ciências e Tecnologia, Universidade dos Açores, Ponta Delgada, Portugal
- Ana F. Ferreira
- Faculdade de Ciências e Tecnologia, Universidade dos Açores, Ponta Delgada, Portugal; UMIB - Unit for Multidisciplinary Research in Biomedicine, ICBAS - School of Medicine and Biomedical Sciences, University of Porto, Porto, Portugal
- João Vasconcelos
- Hospital CUF Açores, Lagoa, Portugal
- Bart P. van de Warrenburg
- Department of Neurology, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands
- Judith van Gaalen
- Department of Neurology, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands; Department of Neurology, Rijnstate Hospital, Arnhem, the Netherlands
- Teije H. van Prooije
- Department of Neurology, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands
- Jeroen de Vries
- Department of Neurology, University Medical Center Groningen, Groningen, the Netherlands
- Ludger Schols
- Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research & Center of Neurology, University of Tuebingen, Tuebingen, Germany; German Center for Neurodegenerative Diseases (DZNE), Tuebingen, Germany
- Olaf Riess
- Institute for Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany
- Matthis Synofzik
- German Center for Neurodegenerative Diseases (DZNE), Tuebingen, Germany; Division Translational Genomics of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research & Center of Neurology, University of Tuebingen, Germany
- Dagmar Timmann
- Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- Andreas Thieme
- Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- Friedrich Erdlenbruch
- Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- Jon Infante
- University Hospital Marqués de Valdecilla-IDIVAL, Santander, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Universidad de Cantabria, Santander, Spain
- Ana L. Pelayo-Negro
- University Hospital Marqués de Valdecilla-IDIVAL, Santander, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Universidad de Cantabria, Santander, Spain
- Leire Manrique
- University Hospital of Navarra, Pamplona, Spain
- Kathrin Reetz
- Department of Neurology, RWTH Aachen University, Pauwelsstr. 30, Aachen 52074, Germany; JARA-BRAIN Institute Molecular Neuroscience and Neuroimaging, Research Centre Juelich GmbH and RWTH Aachen University, Aachen 52074, Germany
- Imis Dogan
- Department of Neurology, RWTH Aachen University, Pauwelsstr. 30, Aachen 52074, Germany; JARA-BRAIN Institute Molecular Neuroscience and Neuroimaging, Research Centre Juelich GmbH and RWTH Aachen University, Aachen 52074, Germany
- Gulin Oz
- Department of Radiology, Center for Magnetic Resonance Research, University of Minnesota, Minneapolis, MN, USA
- James M. Joers
- Department of Radiology, Center for Magnetic Resonance Research, University of Minnesota, Minneapolis, MN, USA
- Khalafalla Bushara
- Department of Neurology, University of Minnesota Medical School, Minneapolis, MN, USA
- Chiadikaobi Onyike
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Michal Povazan
- Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Heike Jacobi
- Department of Neurology, University Hospital of Heidelberg, Heidelberg, Germany
- Jeremy D. Schmahmann
- Laboratory for Neuroanatomy and Cerebellar Neurobiology, Ataxia Center, Massachusetts General Hospital and Harvard Medical School, MA, USA
- Eva-Maria Ratai
- Department of Radiology, A. A. Martinos Center for Biomedical Imaging and Harvard Medical School, Massachusetts General Hospital, Charlestown, MA, USA
- Matthias Schmid
- Medical Faculty, Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
- Paola Giunti
- Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Ataxia Centre, University College London, London WC1N 3BG, UK; Department of Neurogenetics, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London WC1N 3BG, UK; Corresponding author. Institute of Neurology Queen Square, UCL Queen Square, London WC1N 3BG, UK.
- Thomas Klockgether
- German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany; Corresponding author. Venusberg-Campus 1/99, Bonn 53127, Germany.
- Jennifer Faber
- German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany; Department of Parkinson’s Disease, Sleep and Movement Disorders, Center for Neurology, University Hospital Bonn, Bonn, Germany; Department of Neuroradiology, University Hospital Bonn, Bonn, Germany; Corresponding author. Venusberg-Campus 1/99, Bonn 53127, Germany.
- DOI
- https://doi.org/10.1016/j.lanepe.2025.101339
- Journal volume & issue
-
Vol. 55
p. 101339
Abstract
Summary: Background: Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominantly inherited adult-onset disease. We aimed to describe longitudinal changes in clinical and biological findings and to identify predictors for clinical progression. Methods: We used data from participants enrolled in the ESMI cohort collected between Nov 09, 2016 and July 18, 2023. The data freeze included data from 14 sites in five European countries and the United States. We assessed ataxia with the Scale for the Assessment and Rating of Ataxia (SARA). We measured disease-specific mutant ataxin-3 protein (ATXN3) and neurofilament light chain (NfL) in plasma and performed MRIs. Data were analysed by regression modelling on a timescale defined by onset. The onset of abnormality of a marker was defined as the time at which its value, as determined by modelling, exceeded the mean ± 2 SD of healthy controls. To study responsiveness of markers, we determined the sensitivity to change ratios (SCSs). Findings: Data from 291 SCA3 mutation carriers before and after clinical onset and 121 healthy controls were included. NfL levels became abnormal in SCA3 mutation carriers more than 20 years (−21.5 years [95% CI n.d.–9.5]) before onset. The earliest MRI abnormality was volume loss of medulla oblongata (−4.7 years [95% CI n.d.–3.3]). The responsiveness of markers depended on the disease stage. Across all stages, pons volume had the highest responsiveness with an SCS of 1.35 [95% CI 1.11–1.78] exceeding that of SARA (0.99 [95% CI 0.88–1.11]). In SCA3, lower age (p = 0.0459 [95% CI of slope change −0.0018 to 0.0000]) and lower medulla oblongata volume (p < 0.0001 [95% CI of slope change −0.0298 to −0.0115]) were predictors of SARA progression. Interpretation: Our study provides quantitative information on the progression of biological markers in SCA3 mutation carriers before and after onset of ataxia, and allowed the identification of predictors for clinical progression. Our data could prove useful for the design of future clinical trials. Funding: HEU Joint Programme – Neurodegenerative Disease Research (JPND) (Federal Ministry of Education and Research, Germany; The Netherlands Organisation for Health Research and Development; Foundation for Science and Technology, Portugal; Medical Research Council, Regional Fund for Science and Technology, Azores), and Servier. At the US sites this work was in part supported by the National Ataxia Foundation and the National Institute of Neurological Disorders and Stroke (NINDS) grant R01NS080816.
Keywords
