Stage-Dependent Biomarker Changes in Spinocerebellar Ataxia Type 3

Jennifer Faber^{1

2}, Moritz Berger³, Carlo Wilke⁴, Jeannette Hubener-Schmid⁵, Tamara Schaprian¹, Magda M Santana^{6

7}, Marcus Grobe-Einsler^{1

2}, Demet Onder^{1

2}, Berkan Koyak^{1

2}, Paola Giunti^{8

9}, Hector Garcia-Moreno^{8

9}, Cristina Gonzalez-Robles^{8

9}, Manuela Lima¹⁰, Mafalda Raposo^{10

11}, Ana Rosa Vieira Melo¹⁰, Luís Pereira de Almeida^{6

7}, Patrick Silva^{6

7

12}, Maria M Pinto^{7

8

12}, Bart P van de Warrenburg¹³, Judith van Gaalen^{13

14}, Jeroen de Vries¹⁵, Gulin Oz¹⁶, James M Joers¹⁶, Matthis Synofzik^{4

17}, Ludger Schols^{4

17}, Olaf Riess⁵, Jon Infante^{18

19}, Leire Manrique¹⁸, Dagmar Timmann²⁰, Andreas Thieme²⁰, Heike Jacobi²¹, Kathrin Reetz^{22

23}, Imis Dogan^{22

23}, Chiadikaobi Onyike²⁴, Michal Povazan²⁵, Jeremy Schmahmann²⁶, Eva-Maria Ratai²⁷, Matthias Schmid^{1

3}, Thomas Klockgether^{1

2}

Affiliations

¹ German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
² Department of Neurology, University Hospital Bonn, Bonn, Germany.
³ University of Bonn, Medical Faculty, Institute for Medical Biometry, Informatics, and Epidemiology, Bonn, Germany.
⁴ German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
⁵ Institute for Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany.
⁶ Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal.
⁷ Center for Innovative in Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal.
⁸ Ataxia Centre, Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, UK.
⁹ Department of Neurogenetics, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, UK.
¹⁰ Faculdade de Ciências e Tecnologia, Universidade dos Açores, Ponta Delgada, Portugal.
¹¹ Instituto de Biologia Molecular e Celular (IBMC), Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal.
¹² Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal.
¹³ Department of Neurology, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.
¹⁴ Department of Neurology, Rijnstate Hospital, Arnhem, the Netherlands.
¹⁵ University Medical Center Groningen, Neurology, Groningen, the Netherlands.
¹⁶ Center for Magnetic Resonance Research, Department of Radiology, University of Minnesota, Minneapolis, MN, USA.
¹⁷ Division Translational Genomics of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research & Center of Neurology, University of Tübingen, Tübingen, Germany.
¹⁸ University Hospital Marqués de Valdecilla-IDIVAL, Santander, Spain.
¹⁹ Centro de investigación biomédica en red de enfermedades neurodegenerativas (CIBERNED), Universidad de Cantabria, Santander, Spain.
²⁰ Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Hospital Essen, University of Duisburg-Essen, Duisburg, Germany.
²¹ Department of Neurology, University Hospital of Heidelberg, Heidelberg, Germany.
²² Department of Neurology, RWTH Aachen University, Aachen, Germany.
²³ JARA-BRAIN Institute Molecular Neuroscience and Neuroimaging, Research Centre Juelich GmbH and RWTH Aachen University, Aachen, Germany.
²⁴ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
²⁵ Johns Hopkins University School of Medicine, Baltimore, MD, USA.
²⁶ Ataxia Center, Laboratory for Neuroanatomy and Cerebellar Neurobiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
²⁷ Massachusetts General Hospital, Department of Radiology, A. A. Martinos Center for Biomedical Imaging and Harvard Medical School, Charlestown, MA, USA.

PMID: 37962377
DOI: 10.1002/ana.26824

Stage-Dependent Biomarker Changes in Spinocerebellar Ataxia Type 3

Jennifer Faber et al. Ann Neurol. 2024 Feb.

. 2024 Feb;95(2):400-406.

doi: 10.1002/ana.26824. Epub 2023 Dec 5.

Authors

Affiliations

¹ German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
² Department of Neurology, University Hospital Bonn, Bonn, Germany.
³ University of Bonn, Medical Faculty, Institute for Medical Biometry, Informatics, and Epidemiology, Bonn, Germany.
⁴ German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
⁵ Institute for Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany.
⁶ Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal.
⁷ Center for Innovative in Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal.
⁸ Ataxia Centre, Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, UK.
⁹ Department of Neurogenetics, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, UK.
¹⁰ Faculdade de Ciências e Tecnologia, Universidade dos Açores, Ponta Delgada, Portugal.
¹¹ Instituto de Biologia Molecular e Celular (IBMC), Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal.
¹² Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal.
¹³ Department of Neurology, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.
¹⁴ Department of Neurology, Rijnstate Hospital, Arnhem, the Netherlands.
¹⁵ University Medical Center Groningen, Neurology, Groningen, the Netherlands.
¹⁶ Center for Magnetic Resonance Research, Department of Radiology, University of Minnesota, Minneapolis, MN, USA.
¹⁷ Division Translational Genomics of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research & Center of Neurology, University of Tübingen, Tübingen, Germany.
¹⁸ University Hospital Marqués de Valdecilla-IDIVAL, Santander, Spain.
¹⁹ Centro de investigación biomédica en red de enfermedades neurodegenerativas (CIBERNED), Universidad de Cantabria, Santander, Spain.
²⁰ Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Hospital Essen, University of Duisburg-Essen, Duisburg, Germany.
²¹ Department of Neurology, University Hospital of Heidelberg, Heidelberg, Germany.
²² Department of Neurology, RWTH Aachen University, Aachen, Germany.
²³ JARA-BRAIN Institute Molecular Neuroscience and Neuroimaging, Research Centre Juelich GmbH and RWTH Aachen University, Aachen, Germany.
²⁴ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
²⁵ Johns Hopkins University School of Medicine, Baltimore, MD, USA.
²⁶ Ataxia Center, Laboratory for Neuroanatomy and Cerebellar Neurobiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
²⁷ Massachusetts General Hospital, Department of Radiology, A. A. Martinos Center for Biomedical Imaging and Harvard Medical School, Charlestown, MA, USA.

PMID: 37962377
DOI: 10.1002/ana.26824

Abstract

Spinocerebellar ataxia type 3/Machado-Joseph disease is the most common autosomal dominant ataxia. In view of the development of targeted therapies, knowledge of early biomarker changes is needed. We analyzed cross-sectional data of 292 spinocerebellar ataxia type 3/Machado-Joseph disease mutation carriers. Blood concentrations of mutant ATXN3 were high before and after ataxia onset, whereas neurofilament light deviated from normal 13.3 years before onset. Pons and cerebellar white matter volumes decreased and deviated from normal 2.2 years and 0.6 years before ataxia onset. We propose a staging model of spinocerebellar ataxia type 3/Machado-Joseph disease that includes a biomarker stage characterized by objective indicators of neurodegeneration before ataxia onset. ANN NEUROL 2024;95:400-406.

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Update of

Stage-dependent biomarker changes in spinocerebellar ataxia type 3.
Faber J, Berger M, Carlo W, Hübener-Schmid J, Schaprian T, Santana MM, Grobe-Einsler M, Onder D, Koyak B, Giunti P, Garcia-Moreno H, Gonzalez-Robles C, Lima M, Raposo M, Melo ARV, de Almeida LP, Silva P, Pinto MM, van de Warrenburg BP, van Gaalen J, de Vries J, Jeroen, Oz G, Joers JM, Synofzik M, Schöls L, Riess O, Infante J, Manrique L, Timmann D, Thieme A, Jacobi H, Reetz K, Dogan I, Onyike C, Povazan M, Schmahmann J, Ratai EM, Schmid M, Klockgether T. Faber J, et al. medRxiv [Preprint]. 2023 Apr 25:2023.04.21.23287817. doi: 10.1101/2023.04.21.23287817. medRxiv. 2023. Update in: Ann Neurol. 2024 Feb;95(2):400-406. doi: 10.1002/ana.26824. PMID: 37163081 Free PMC article. Updated. Preprint.

References

1. Paulson H. Machado-Joseph disease/spinocerebellar ataxia type 3. Handb Clin Neurol 2012;103:437-449.
1. Garcia-Moreno H, Prudencio M, Thomas-Black G, et al. Tau and neurofilament light-chain as fluid biomarkers in spinocerebellar ataxia type 3. Eur J Neurol 2022;29:2439-2452.
1. Hubener-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.
1. Li QF, Dong Y, Yang L, et al. Neurofilament light chain is a promising serum biomarker in spinocerebellar ataxia type 3. Mol Neurodegener 2019;14:39.
1. Wilke C, Haas E, Reetz K, et al. Neurofilaments in spinocerebellar ataxia type 3: blood biomarkers at the preataxic and ataxic stage in humans and mice. EMBO Mol Med 2020;12:e11803.

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Stage-Dependent Biomarker Changes in Spinocerebellar Ataxia Type 3

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Stage-Dependent Biomarker Changes in Spinocerebellar Ataxia Type 3

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