Progression of biological markers in spinocerebellar ataxia type 3: longitudinal analysis of prospective data from the ESMI cohort

Moritz Berger^{1

2}, Hector Garcia-Moreno^{3

4}, Mónica Ferreira^{5

6}, Jeannette Hubener-Schmid⁷, Tamara Schaprian⁵, Philipp Wegner^{5

6}, Tim Elter⁴, Kennet M Teichmann⁵, Magda M Santana^{8

9

10}, Marcus Grobe-Einsler^{5

11}, Demet Oender^{5

11}, Berkan S C Koyak^{5

11}, Sarah Bernsen^{5

11}, Luís Pereira de Almeida^{8

9

10}, Patrick Silva^{8

9

10}, Joana Afonso Ribeiro¹², Inês Cunha¹³, Cristina Gonzalez-Robles³, Shamsher Khan³, Amanda Heslegrave^{14

15}, Henrik Zetterberg^{14

15

16}, Manuela Lima^{17

18}, Mafalda Raposo^{19

17}, Ana F Ferreira^{17

18}, João Vasconcelos²⁰, Bart P van de Warrenburg²¹, Judith van Gaalen^{21

22}, Teije H van Prooije²¹, Jeroen de Vries²³, Ludger Schols^{24

25}, Olaf Riess⁷, Matthis Synofzik^{25

26}, Dagmar Timmann²⁷, Andreas Thieme²⁷, Friedrich Erdlenbruch²⁷, Jon Infante^{28

29}, Ana L Pelayo-Negro^{28

29}, Leire Manrique³⁰, Kathrin Reetz^{31

32}, Imis Dogan^{31

32}, Gulin Oz³³, James M Joers³³, Khalafalla Bushara³⁴, Chiadikaobi Onyike³⁵, Michal Povazan³⁶, Heike Jacobi³⁷, Jeremy D Schmahmann³⁸, Eva-Maria Ratai³⁹, Matthias Schmid^{1

5}, Paola Giunti^{3

4}, Thomas Klockgether⁵, Jennifer Faber^{5

11

40}

Affiliations

¹ Medical Faculty, Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany.
² Core Facility Biostatistics, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
³ Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Ataxia Centre, University College London, London WC1N 3BG, UK.
⁴ Department of Neurogenetics, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London WC1N 3BG, UK.
⁵ German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
⁶ University of Bonn, Bonn, Germany.
⁷ Institute for Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany.
⁸ Center for Neuroscience and Cell Biology, University of Coimbra (CNC-UC), Coimbra, Portugal.
⁹ Center for Innovative in Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal.
¹⁰ Gene Therapy Center of Excellence (GeneT), Coimbra, Portugal.
¹¹ Department of Parkinson's Disease, Sleep and Movement Disorders, Center for Neurology, University Hospital Bonn, Bonn, Germany.
¹² Department of Neurology, Child Development Centre, Coimbra University Hospital Center (CHUC), Coimbra, Portugal.
¹³ Department of Neurology, Coimbra University Hospital Center (CHUC), Coimbra, Portugal.
¹⁴ Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK.
¹⁵ UK Dementia Research Institute at UCL, London, UK.
¹⁶ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, S-431 80, Mölndal, Sweden.
¹⁷ Faculdade de Ciências e Tecnologia, Universidade dos Açores, Ponta Delgada, Portugal.
¹⁸ UMIB - Unit for Multidisciplinary Research in Biomedicine, ICBAS - School of Medicine and Biomedical Sciences, University of Porto, Porto, Portugal.
¹⁹ Instituto de Biologia Molecular e Celular (IBMC), Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal.
²⁰ Hospital CUF Açores, Lagoa, Portugal.
²¹ Department of Neurology, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.
²² Department of Neurology, Rijnstate Hospital, Arnhem, the Netherlands.
²³ Department of Neurology, University Medical Center Groningen, Groningen, the Netherlands.
²⁴ Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research & Center of Neurology, University of Tuebingen, Tuebingen, Germany.
²⁵ German Center for Neurodegenerative Diseases (DZNE), Tuebingen, Germany.
²⁶ Division Translational Genomics of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research & Center of Neurology, University of Tuebingen, Germany.
²⁷ Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
²⁸ University Hospital Marqués de Valdecilla-IDIVAL, Santander, Spain.
²⁹ Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Universidad de Cantabria, Santander, Spain.
³⁰ University Hospital of Navarra, Pamplona, Spain.
³¹ Department of Neurology, RWTH Aachen University, Pauwelsstr. 30, Aachen 52074, Germany.
³² JARA-BRAIN Institute Molecular Neuroscience and Neuroimaging, Research Centre Juelich GmbH and RWTH Aachen University, Aachen 52074, Germany.
³³ Department of Radiology, Center for Magnetic Resonance Research, University of Minnesota, Minneapolis, MN, USA.
³⁴ Department of Neurology, University of Minnesota Medical School, Minneapolis, MN, USA.
³⁵ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
³⁶ Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
³⁷ Department of Neurology, University Hospital of Heidelberg, Heidelberg, Germany.
³⁸ Laboratory for Neuroanatomy and Cerebellar Neurobiology, Ataxia Center, Massachusetts General Hospital and Harvard Medical School, MA, USA.
³⁹ Department of Radiology, A. A. Martinos Center for Biomedical Imaging and Harvard Medical School, Massachusetts General Hospital, Charlestown, MA, USA.
⁴⁰ Department of Neuroradiology, University Hospital Bonn, Bonn, Germany.

PMID: 40678042
PMCID: PMC12270660
DOI: 10.1016/j.lanepe.2025.101339

Progression of biological markers in spinocerebellar ataxia type 3: longitudinal analysis of prospective data from the ESMI cohort

Moritz Berger et al. Lancet Reg Health Eur. 2025.

. 2025 Jul 3:55:101339.

doi: 10.1016/j.lanepe.2025.101339. eCollection 2025 Aug.

Authors

Affiliations

¹ Medical Faculty, Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany.
² Core Facility Biostatistics, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
³ Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Ataxia Centre, University College London, London WC1N 3BG, UK.
⁴ Department of Neurogenetics, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London WC1N 3BG, UK.
⁵ German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
⁶ University of Bonn, Bonn, Germany.
⁷ Institute for Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany.
⁸ Center for Neuroscience and Cell Biology, University of Coimbra (CNC-UC), Coimbra, Portugal.
⁹ Center for Innovative in Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal.
¹⁰ Gene Therapy Center of Excellence (GeneT), Coimbra, Portugal.
¹¹ Department of Parkinson's Disease, Sleep and Movement Disorders, Center for Neurology, University Hospital Bonn, Bonn, Germany.
¹² Department of Neurology, Child Development Centre, Coimbra University Hospital Center (CHUC), Coimbra, Portugal.
¹³ Department of Neurology, Coimbra University Hospital Center (CHUC), Coimbra, Portugal.
¹⁴ Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK.
¹⁵ UK Dementia Research Institute at UCL, London, UK.
¹⁶ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, S-431 80, Mölndal, Sweden.
¹⁷ Faculdade de Ciências e Tecnologia, Universidade dos Açores, Ponta Delgada, Portugal.
¹⁸ UMIB - Unit for Multidisciplinary Research in Biomedicine, ICBAS - School of Medicine and Biomedical Sciences, University of Porto, Porto, Portugal.
¹⁹ Instituto de Biologia Molecular e Celular (IBMC), Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal.
²⁰ Hospital CUF Açores, Lagoa, Portugal.
²¹ Department of Neurology, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.
²² Department of Neurology, Rijnstate Hospital, Arnhem, the Netherlands.
²³ Department of Neurology, University Medical Center Groningen, Groningen, the Netherlands.
²⁴ Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research & Center of Neurology, University of Tuebingen, Tuebingen, Germany.
²⁵ German Center for Neurodegenerative Diseases (DZNE), Tuebingen, Germany.
²⁶ Division Translational Genomics of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research & Center of Neurology, University of Tuebingen, Germany.
²⁷ Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
²⁸ University Hospital Marqués de Valdecilla-IDIVAL, Santander, Spain.
²⁹ Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Universidad de Cantabria, Santander, Spain.
³⁰ University Hospital of Navarra, Pamplona, Spain.
³¹ Department of Neurology, RWTH Aachen University, Pauwelsstr. 30, Aachen 52074, Germany.
³² JARA-BRAIN Institute Molecular Neuroscience and Neuroimaging, Research Centre Juelich GmbH and RWTH Aachen University, Aachen 52074, Germany.
³³ Department of Radiology, Center for Magnetic Resonance Research, University of Minnesota, Minneapolis, MN, USA.
³⁴ Department of Neurology, University of Minnesota Medical School, Minneapolis, MN, USA.
³⁵ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
³⁶ Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
³⁷ Department of Neurology, University Hospital of Heidelberg, Heidelberg, Germany.
³⁸ Laboratory for Neuroanatomy and Cerebellar Neurobiology, Ataxia Center, Massachusetts General Hospital and Harvard Medical School, MA, USA.
³⁹ Department of Radiology, A. A. Martinos Center for Biomedical Imaging and Harvard Medical School, Massachusetts General Hospital, Charlestown, MA, USA.
⁴⁰ Department of Neuroradiology, University Hospital Bonn, Bonn, Germany.

PMID: 40678042
PMCID: PMC12270660
DOI: 10.1016/j.lanepe.2025.101339

Abstract

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: ATXN3; Biomarker; Disease modelling; MRI; NfL; Spinocerebellar ataxia; Staging model.

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Conflict of interest statement

JF received consultancy honoraria from Vico therapeutics, unrelated to the present manuscript. GO has consulted for IXICO Technologies Limited, Servier and UCB Biopharma SRL/Lacerta Therapeutics Inc, serves on the Scientific Advisory Board of BrainSpec Inc. and received research support from Biogen, each unrelated to the current manuscript. JS is site PI for Biohaven Pharmaceuticals clinical trials NCT03701399 and NCT02960893; received consults for Biohaven Pharmaceuticals; and royalties from Oxford University Press, Elsevier, MacKeith Press, and Springer; and is the inventor of the Brief Ataxia Rating Scale, Cerebellar Cognitive Affective/Schmahmann Syndrome Scale, the Patient Reported Outcome Measure of Ataxia, and the Cerebellar Neuropsychiatry Rating Scale which are licenced to the General Hospital Corporation; all unrelated to the current manuscript. MGE received consultancy honoraria from Biogen and Healthcare Manufaktur Germany, both unrelated to the present manuscript. HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZpath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Enigma, LabCorp, Merck Sharp & Dohme, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Quanterix, Red Abbey Labs, reMYND, Roche, Samumed, ScandiBio Therapeutics AB, Siemens Healthineers, Triplet Therapeutics, and Wave. HZ is chair of the Alzheimer’s Association Global Biomarker Standardization Consortium and chair of the IFCC WG-BND. HZ is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, and a shareholder of MicThera (outside submitted work). PG has received grants and honoraria for advisory board from Vico Therapeutics, honoraria for advisory board from Triplet Therapeutics, grants and personal fees from Reata Pharmaceutical, grants from Wave. LS has received consultancy honoraria from Vico, Alexion and Novartis, unrelated to the present manuscript. MSy has received consultancy honoraria from Ionis, UCB, Prevail, Orphazyme, Biogen, Servier, Reata, GenOrph, AviadoBio, Biohaven, Zevra, Lilly, Quince, and Solaxa, all unrelated to the present manuscript. TK received consultancy honoraria from Arrowhead, Bristol Myers Squibb and UCB, unrelated to the present manuscript. KR received consultancy honoraria from Roche and Lilly unrelated to the present manuscript. BvdW would like to thank Heidi van den Boogaard and Janneke Rigter-Schimmel for their help in the ESMI logistics and assessments. JAR received honoraria for participation in advisory boards and speaking fees for Roche, Novartis Gene therapy and Biogen, all in the field of paediatric neuromuscular disorders. IC has received honoraria for participation in advisory boards and speaking fees for Bial, in the field of Epilepsy. AT holds stocks of Viatris Inc. is a pharmaceutical company. EMR received consulting fees from Aletheia and is part of the advisory board of Brain Spec without financial support. We would like to thank Anne Boehlen for her support in the administration of ESMI.

Figures

**Fig. 1**
Progression of (a) SARA, (b) ATXN3, (c) NfL, (d) MRI brainstem volumes, (e) MRI cerebellar volumes, and (f) MRI diffusion measures in SCA3. Data were analysed by additive mixed regression models with participant-specific random intercepts on a timescale defined by onset of gait disturbances (vertical dashed line in red) using a cubic P-spline with six B-spline basis functions. The estimated 95% CIs are shown by the shaded areas around the curves. NfL and MRI data were z-transformed in relation to healthy controls. Z-scores of MRI volumes and FA values were inverted for a better visualisation. The horizontal ribbon shaded in grey indicates the normal range (±2) of the z-transformed measures (NfL, MRI measures) of healthy controls. For SARA the applied cut-off of 3 is indicated by a dotted horizontal line. CGM = cerebellar grey matter. CWM = cerebellar white matter. FA ICP = fractional anisotropy of the inferior cerebellar peduncle. FA SCP = fractional anisotropy of the superior cerebellar peduncle. NfL = neurofilament light chain. RD ICP = radial diffusivity of the inferior cerebellar peduncle. SCP = superior cerebellar peduncle.

**Fig. 2**
Partial dependence plots of the multivariable model for SARA progression, including variables with p < 0.05 in univariable models. Predicted values of SARA as a function of the time from onset and age (a) and the time from onset and medulla oblongata volume given as z-score (b). In both panels, the value of the other predictor was set to the observed mean (medulla oblongata volume: −2.6; age: 46.4 years), respectively. The closer the white lines, which represent identical SARA values, are together, the faster is the predicted progression.

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Update of

Progression of biological markers in spinocerebellar ataxia type 3: analysis of longitudinal data from the ESMI cohort.
Berger M, Garcia-Moreno H, Ferreira M, Hubener-Schmid J, Schaprian T, Wegner P, Elter T, Teichmann K, Santana MM, Grobe-Einsler M, Onder D, Koyak B, Bernsen S, de Almeida LP, Silva P, Ribeiro JA, Cunha I, Gonzalez-Robles C, Khan S, Heslegrave A, Zetterberg H, Lima M, Raposo M, Ferreira AF, Vasconcelos J, van de Warrenburg BP, van Gaalen J, van Prooije TH, de Vries J, Schols L, Riess O, Synofzik M, Timmann D, Thieme A, Erdlenbruch F, Infante J, Pelayo AL, Manrique L, Reetz K, Dogan I, Oz G, Joers JM, Bushara K, Onyike C, Povazan M, Jacobi H, Schmahmann JD, Ratai EM, Schmid M, Giunti P, Klockgether T, Faber J. Berger M, et al. medRxiv [Preprint]. 2025 Jan 31:2025.01.30.25321426. doi: 10.1101/2025.01.30.25321426. medRxiv. 2025. Update in: Lancet Reg Health Eur. 2025 Jul 03;55:101339. doi: 10.1016/j.lanepe.2025.101339. PMID: 39974031 Free PMC article. Updated. Preprint.

References

1. Paulson H. Machado-Joseph disease/spinocerebellar ataxia type 3. Handb Clin Neurol. 2012;103:437–449. - PMC - PubMed
1. Klockgether T., Ashizawa T., Brais B., et al. Paving the way toward meaningful trials in ataxias: an ataxia global initiative perspective. Mov Disord. 2022;37:1125–1130. doi: 10.1002/mds.29032. - DOI - PubMed
1. Hübener-Schmid J., Kuhlbrodt K., Peladan J., et al. Polyglutamine-expanded ataxin-3: a target engagement marker for spinocerebellar ataxia type 3 in peripheral blood. Mov Disord. 2021;36:2675–2681. doi: 10.1002/mds.28749. - DOI - PubMed
1. Prudencio M., Garcia-Moreno H., Jansen-West K.R., et al. Toward allele-specific targeting therapy and pharmacodynamic marker for spinocerebellar ataxia type 3. Sci Transl Med. 2020;12 doi: 10.1126/scitranslmed.abb7086. - DOI - PMC - PubMed
1. Gaetani L., Blennow K., Calabresi P., Di Filippo M., Parnetti L., Zetterberg H. Neurofilament light chain as a biomarker in neurological disorders. J Neurol Neurosurg Psychiatry. 2019;90:870–881. doi: 10.1136/jnnp-2018-320106. - DOI - PubMed

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Progression of biological markers in spinocerebellar ataxia type 3: longitudinal analysis of prospective data from the ESMI cohort

Affiliations

Progression of biological markers in spinocerebellar ataxia type 3: longitudinal analysis of prospective data from the ESMI cohort

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

Update of

References

Grants and funding

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