Progression of biological markers in spinocerebellar ataxia type 3: longitudinal analysis of prospective data from the ESMI cohortResearch in context
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...
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2025-08-01
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| author | 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 |
| author_facet | 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 |
| author_sort | Moritz Berger |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-8b6f2d34f33147bd850f9afffb77d54c |
| institution | Kabale University |
| issn | 2666-7762 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | The Lancet Regional Health. Europe |
| spelling | doaj-art-8b6f2d34f33147bd850f9afffb77d54c2025-08-20T03:29:35ZengElsevierThe Lancet Regional Health. Europe2666-77622025-08-015510133910.1016/j.lanepe.2025.101339Progression of biological markers in spinocerebellar ataxia type 3: longitudinal analysis of prospective data from the ESMI cohortResearch in contextMoritz Berger0Hector Garcia-Moreno1Mónica Ferreira2Jeannette Hubener-Schmid3Tamara Schaprian4Philipp Wegner5Tim Elter6Kennet M. Teichmann7Magda M. Santana8Marcus Grobe-Einsler9Demet Oender10Berkan S.C. Koyak11Sarah Bernsen12Luís Pereira de Almeida13Patrick Silva14Joana Afonso Ribeiro15Inês Cunha16Cristina Gonzalez-Robles17Shamsher Khan18Amanda Heslegrave19Henrik Zetterberg20Manuela Lima21Mafalda Raposo22Ana F. Ferreira23João Vasconcelos24Bart P. van de Warrenburg25Judith van Gaalen26Teije H. van Prooije27Jeroen de Vries28Ludger Schols29Olaf Riess30Matthis Synofzik31Dagmar Timmann32Andreas Thieme33Friedrich Erdlenbruch34Jon Infante35Ana L. Pelayo-Negro36Leire Manrique37Kathrin Reetz38Imis Dogan39Gulin Oz40James M. Joers41Khalafalla Bushara42Chiadikaobi Onyike43Michal Povazan44Heike Jacobi45Jeremy D. Schmahmann46Eva-Maria Ratai47Matthias Schmid48Paola Giunti49Thomas Klockgether50Jennifer Faber51Medical 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, GermanyDepartment 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, UKGerman Center for Neurodegenerative Diseases (DZNE), Bonn, Germany; University of Bonn, Bonn, GermanyInstitute for Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, GermanyGerman Center for Neurodegenerative Diseases (DZNE), Bonn, GermanyGerman Center for Neurodegenerative Diseases (DZNE), Bonn, Germany; University of Bonn, Bonn, GermanyDepartment of Neurogenetics, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London WC1N 3BG, UKGerman Center for Neurodegenerative Diseases (DZNE), Bonn, GermanyCenter 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, PortugalGerman Center for Neurodegenerative Diseases (DZNE), Bonn, Germany; Department of Parkinson’s Disease, Sleep and Movement Disorders, Center for Neurology, University Hospital Bonn, Bonn, GermanyGerman Center for Neurodegenerative Diseases (DZNE), Bonn, Germany; Department of Parkinson’s Disease, Sleep and Movement Disorders, Center for Neurology, University Hospital Bonn, Bonn, GermanyGerman Center for Neurodegenerative Diseases (DZNE), Bonn, Germany; Department of Parkinson’s Disease, Sleep and Movement Disorders, Center for Neurology, University Hospital Bonn, Bonn, GermanyGerman Center for Neurodegenerative Diseases (DZNE), Bonn, Germany; Department of Parkinson’s Disease, Sleep and Movement Disorders, Center for Neurology, University Hospital Bonn, Bonn, GermanyCenter 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, PortugalCenter 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, PortugalDepartment of Neurology, Child Development Centre, Coimbra University Hospital Center (CHUC), Coimbra, PortugalDepartment of Neurology, Coimbra University Hospital Center (CHUC), Coimbra, PortugalDepartment of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Ataxia Centre, University College London, London WC1N 3BG, UKDepartment of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Ataxia Centre, University College London, London WC1N 3BG, UKDepartment of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK; UK Dementia Research Institute at UCL, London, UKDepartment 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, SwedenFaculdade 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, PortugalInstituto 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, PortugalFaculdade 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, PortugalHospital CUF Açores, Lagoa, PortugalDepartment of Neurology, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, the NetherlandsDepartment of Neurology, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands; Department of Neurology, Rijnstate Hospital, Arnhem, the NetherlandsDepartment of Neurology, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, the NetherlandsDepartment of Neurology, University Medical Center Groningen, Groningen, the NetherlandsDepartment of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research & Center of Neurology, University of Tuebingen, Tuebingen, Germany; German Center for Neurodegenerative Diseases (DZNE), Tuebingen, GermanyInstitute for Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, GermanyGerman 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, GermanyDepartment of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Hospital Essen, University of Duisburg-Essen, Essen, GermanyDepartment of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Hospital Essen, University of Duisburg-Essen, Essen, GermanyDepartment of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Hospital Essen, University of Duisburg-Essen, Essen, GermanyUniversity Hospital Marqués de Valdecilla-IDIVAL, Santander, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Universidad de Cantabria, Santander, SpainUniversity Hospital Marqués de Valdecilla-IDIVAL, Santander, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Universidad de Cantabria, Santander, SpainUniversity Hospital of Navarra, Pamplona, SpainDepartment 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, GermanyDepartment 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, GermanyDepartment of Radiology, Center for Magnetic Resonance Research, University of Minnesota, Minneapolis, MN, USADepartment of Radiology, Center for Magnetic Resonance Research, University of Minnesota, Minneapolis, MN, USADepartment of Neurology, University of Minnesota Medical School, Minneapolis, MN, USADepartment of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USAJohns Hopkins University School of Medicine, Baltimore, MD 21205, USADepartment of Neurology, University Hospital of Heidelberg, Heidelberg, GermanyLaboratory for Neuroanatomy and Cerebellar Neurobiology, Ataxia Center, Massachusetts General Hospital and Harvard Medical School, MA, USADepartment of Radiology, A. A. Martinos Center for Biomedical Imaging and Harvard Medical School, Massachusetts General Hospital, Charlestown, MA, USAMedical Faculty, Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany; German Center for Neurodegenerative Diseases (DZNE), Bonn, GermanyDepartment 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.German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany; Corresponding author. Venusberg-Campus 1/99, Bonn 53127, Germany.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.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.http://www.sciencedirect.com/science/article/pii/S2666776225001310Spinocerebellar ataxiaMRINfLATXN3Disease modellingStaging model |
| spellingShingle | 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 Progression of biological markers in spinocerebellar ataxia type 3: longitudinal analysis of prospective data from the ESMI cohortResearch in context The Lancet Regional Health. Europe Spinocerebellar ataxia MRI NfL ATXN3 Disease modelling Staging model |
| title | Progression of biological markers in spinocerebellar ataxia type 3: longitudinal analysis of prospective data from the ESMI cohortResearch in context |
| title_full | Progression of biological markers in spinocerebellar ataxia type 3: longitudinal analysis of prospective data from the ESMI cohortResearch in context |
| title_fullStr | Progression of biological markers in spinocerebellar ataxia type 3: longitudinal analysis of prospective data from the ESMI cohortResearch in context |
| title_full_unstemmed | Progression of biological markers in spinocerebellar ataxia type 3: longitudinal analysis of prospective data from the ESMI cohortResearch in context |
| title_short | Progression of biological markers in spinocerebellar ataxia type 3: longitudinal analysis of prospective data from the ESMI cohortResearch in context |
| title_sort | progression of biological markers in spinocerebellar ataxia type 3 longitudinal analysis of prospective data from the esmi cohortresearch in context |
| topic | Spinocerebellar ataxia MRI NfL ATXN3 Disease modelling Staging model |
| url | http://www.sciencedirect.com/science/article/pii/S2666776225001310 |
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