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[Preprint]. 2025 Jan 31:2025.01.30.25321426.

doi: 10.1101/2025.01.30.25321426.

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

Moritz Berger¹, Hector Garcia-Moreno^{2

3}, Monica Ferreira^{4

5}, Jeannette Hubener-Schmid⁶, Tamara Schaprian⁴, Philipp Wegner^{4

5}, Tim Elter⁴, Kennet Teichmann⁴, Magda M Santana^{7

8

9}, Marcus Grobe-Einsler^{4

10}, Demet Onder^{4

10}, Berkan Koyak^{4

10}, Sarah Bernsen^{4

10}, Luís Pereira de Almeida^{7

8

9}, Patrick Silva^{7

8

9}, Joana Afonso Ribeiro¹¹, Inês Cunha¹², Cristina Gonzalez-Robles², Shamsher Khan², Amanda Heslegrave^{13

14}, Henrik Zetterberg^{13

14

15}, Manuela Lima^{16

17}, Mafalda Raposo^{18

16}, Ana F Ferreira^{16

17}, João Vasconcelos¹⁹, Bart P van de Warrenburg²⁰, Judith van Gaalen^{20

21}, Teije H van Prooije²⁰, Jeroen de Vries²², Ludger Schols^{23

24}, Olaf Riess⁶, Matthis Synofzik^{25

24}, Dagmar Timmann²⁶, Andreas Thieme²⁶, Friedrich Erdlenbruch²⁶, Jon Infante^{27

28}, Ana Lara Pelayo^{27

28}, Leire Manrique²⁹, Kathrin Reetz^{30

31}, Imis Dogan^{30

31}, Gulin Oz³², James M Joers³², Khalaf Bushara³³, Chiadikaobi Onyike³⁴, Michal Povazan³⁵, Heike Jacobi³⁶, Jeremy D Schmahmann³⁷, Eva-Maria Ratai³⁸, Matthias Schmid¹, Paola Giunti^{2

3}, Thomas Klockgether⁴, Jennifer Faber^{4

10

39}

Affiliations

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

PMID: 39974031
PMCID: PMC11838669
DOI: 10.1101/2025.01.30.25321426

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

Moritz Berger et al. medRxiv. 2025.

[Preprint]. 2025 Jan 31:2025.01.30.25321426.

doi: 10.1101/2025.01.30.25321426.

Authors

Affiliations

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

PMID: 39974031
PMCID: PMC11838669
DOI: 10.1101/2025.01.30.25321426

Update in

Progression of biological markers in spinocerebellar ataxia type 3: longitudinal analysis of prospective data from the ESMI cohort.
Berger M, Garcia-Moreno H, Ferreira M, Hubener-Schmid J, Schaprian T, Wegner P, Elter T, Teichmann KM, Santana MM, Grobe-Einsler M, Oender D, Koyak BSC, Bernsen S, Pereira de Almeida L, 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-Negro 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. Lancet Reg Health Eur. 2025 Jul 3;55:101339. doi: 10.1016/j.lanepe.2025.101339. eCollection 2025 Aug. Lancet Reg Health Eur. 2025. PMID: 40678042 Free PMC article.

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).

Results: Data from 291 SCA3 mutation carriers before and after clinical onset and 121 healthy controls were included. NfL levels became abnormal 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]). Lower age (p=0.0459) and lower medulla oblongata volume (p<0.0001) were predictors of SARA progression.

Conclusion: 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.

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Conflict of interest statement

Conflicts of interest JF received consultancy honoraria from Vico therapeutics, unrelated to the present manuscript. GO has consulted for IXICO Technologies Limited, uniQure biopharma B.V., VICO Therapeutics, Servier, Sanofi 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 licensed 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 for Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics and CogRx; has given lectures in symposia sponsored by Fujirebio, Alzecure and Biogen, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. 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. MS 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 BvdW would like to thank Heidi van den Boogaard and Janneke Rigter-Schimmel for their help in the ESMI logistics and assessments. We would like to thank Anne Boehlen for her support in the administration of ESMI.

Figures

**Appendix Figure 1:. Flow chart of study participants**
In total, 523 participants were enrolled in the European Spinocerebellar ataxia type 3/Machado-Joseph Disease Initiative (ESMI) from Nov 9,2016 to July 18, 2023. For 104 participants no fluid or imaging biomarker was available. From the remaining 419 participants, 412 were included in the present analysis.

**Appendix Figure 2:. Individual trajectories of SARA and biological markers in SCA3**
Data are shown as individual trajectories of SARA, fluid biological markers, and MRI markers in SCA3 on a timescale defined by onset of gait disturbances. For illustration, the modelled curves shown in figure 1 of the main text are superimposed. NfL and MRI data were z-transformed in relation to healthy controls. Z-scores of MRI volumes and FA values were inverted. The normal distribution in healthy controls defined by the range of z-scores between ± 2 is indicated by the horizontal ribbon shaded in grey. For the SARA sum score the cut-off value of 3^, is indicated by a dotted horizontal line. CGM=cerebellar grey matter. CWM=cerebellar white matter. FA ICP=fractional anisotropy of inferior cerebellar peduncle. FA SCP=fractional anisotropy of superior cerebellar peduncle. NfL=neurofilament light chain. RD ICP=radial diffusivity inferior cerebellar peduncle. SARA=Scale for the Assessment and Rating of Ataxia. SCP= superior cerebellar peduncle.

**Figure 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 visualization. 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.

**Figure 2.. Partial dependence plots of the multivariable model for SARA progression.**
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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References

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This is a preprint.

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

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

Authors

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Update in

Abstract

Conflict of interest statement

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