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Abstract

Background and Objectives

Neurofilament light (NfL) appears to be a promising fluid biomarker in repeat-expansion spinocerebellar ataxias (SCAs), with piloting studies in mixed SCA cohorts suggesting that NfL might be increased at the ataxic stage of SCA type 1 (SCA1). We here hypothesized that NfL is increased not only at the ataxic stage of SCA1, but also at its (likely most treatment-relevant) preataxic stage.

Methods

We assessed serum NfL (sNfL) and CSF NfL (cNfL) levels in both preataxic and ataxic SCA1, leveraging a multicentric cohort recruited at 6 European university centers, and clinical follow-up data, including actually observed (rather than only predicted) conversion to the ataxic stage. Levels of sNfL and cNfL were assessed by single-molecule array and ELISA technique, respectively.

Results

Forty individuals with SCA1 (23 preataxic, 17 ataxic) and 89 controls were enrolled, including 11 preataxic individuals converting to the ataxic stage. sNfL levels were increased at the preataxic (median 15.5 pg/mL [interquartile range 10.5–21.1 pg/mL]) and ataxic stage (31.6 pg/mL [26.2–37.7 pg/mL]) compared to controls (6.0 pg/mL [4.7–8.6 pg/mL]), yielding high age-corrected effect sizes (preataxic: r = 0.62, ataxic: r = 0.63). sNfL increases were paralleled by increases of cNfL at both the preataxic and ataxic stage. In preataxic individuals, sNfL levels increased with proximity to predicted ataxia onset, with significant sNfL elevations already 5 years before onset, and confirmed in preataxic individuals with actually observed ataxia onset. sNfL increases were detected already in preataxic individuals with SCA1 without volumetric atrophy of cerebellum or pons, suggesting that sNfL might be more sensitive to early preataxic neurodegeneration than the currently known most change-sensitive regions in volumetric MRI. Using longitudinal sNfL measurements, we estimated sample sizes for clinical trials with the reduction of sNfL as the endpoint.

Discussion

sNfL levels might provide easily accessible peripheral biomarkers in both preataxic and ataxic SCA1, allowing stratification of preataxic individuals regarding proximity to onset, early detection of neurodegeneration even before volumetric MRI alterations, and potentially capture of treatment response in clinical trials.

Trial Registration Information

ClinicalTrials.gov Identifier: NCT01037777.

Classification of Evidence

This study provides Class III evidence that NfL levels are increased in both ataxic and preataxic SCA1 and are associated with ataxia onset.

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References

1.
Robitaille Y, Schut L, Kish SJ. Structural and immunocytochemical features of olivopontocerebellar atrophy caused by the spinocerebellar ataxia type 1 (SCA-1) mutation define a unique phenotype. Acta Neuropathol. 1995;90(6):572-581.
2.
Rüb U, Schöls L, Paulson H, et al. Clinical features, neurogenetics and neuropathology of the polyglutamine spinocerebellar ataxias type 1, 2, 3, 6 and 7. Prog Neurobiol. 2013;104:38-66.
3.
Paulson HL, Shakkottai VG, Clark HB, Orr HT. Polyglutamine spinocerebellar ataxias: from genes to potential treatments. Nat Rev Neurosci. 2017;18(10):613-626.
4.
Friedrich J, Kordasiewicz HB, O'Callaghan B, et al. Antisense oligonucleotide-mediated ataxin-1 reduction prolongs survival in SCA1 mice and reveals disease-associated transcriptome profiles. JCI Insight. 2018;3(21):e123193.
5.
Kourkouta E, Weij R, González-Barriga A, et al. Suppression of mutant protein expression in SCA3 and SCA1 mice using a CAG repeat-targeting antisense oligonucleotide. Mol Ther Nucleic Acids. 2019;17:601-614.
6.
Winter B, Guenther R, Ludolph AC, Hermann A, Otto M, Wurster CD. Neurofilaments and tau in CSF in an infant with SMA type 1 treated with nusinersen. J Neurol Neurosurg Psychiatry. 2019;90(9):1068-1069.
7.
Finkel RS, Mercuri E, Darras BT, et al. Nusinersen versus sham control in infantile-onset spinal muscular atrophy. N Engl J Med. 2017;377(18):1723-1732.
8.
Khalil M, Teunissen CE, Otto M, et al. Neurofilaments as biomarkers in neurological disorders. Nat Rev Neurol. 2018;14(10):577-589.
9.
Kuhle J, Barro C, Andreasson U, et al. Comparison of three analytical platforms for quantification of the neurofilament light chain in blood samples: ELISA, electrochemiluminescence immunoassay and Simoa. Clin Chem Lab Med. 2016;54(10):1655-1661.
10.
Barro C, Chitnis T, Weiner HL. Blood neurofilament light: a critical review of its application to neurologic disease. Ann Clin Transl Neurol. 2020;7(12):2508-2523.
11.
Coarelli G, Darios F, Petit E, et al. Plasma neurofilament light chain predicts cerebellar atrophy and clinical progression in spinocerebellar ataxia. Neurobiol Dis. 2021;153:105311.
12.
Wilke C, Bender F, Hayer SN, et al. Serum neurofilament light is increased in multiple system atrophy of cerebellar type and in repeat-expansion spinocerebellar ataxias: a pilot study. J Neurol. 2018;265(7):1618-1624.
13.
Jacobi H, Reetz K, du Montcel ST, et al. Biological and clinical characteristics of individuals at risk for spinocerebellar ataxia types 1, 2, 3, and 6 in the longitudinal RISCA study: analysis of baseline data. Lancet Neurol. 2013;12(7):650-658.
14.
Jacobi H, du Montcel ST, Bauer P, et al. Long-term disease progression in spinocerebellar ataxia types 1, 2, 3, and 6: a longitudinal cohort study. Lancet Neurol. 2015;14(11):1101-1108.
15.
Jacobi H, du Montcel ST, Romanzetti S, et al. Conversion of individuals at risk for spinocerebellar ataxia types 1, 2, 3, and 6 to manifest ataxia (RISCA): a longitudinal cohort study. Lancet Neurol. 2020;19:738-747.
16.
Schmitz-Hubsch T, du Montcel ST, Baliko L, et al. Scale for the assessment and rating of ataxia: development of a new clinical scale. Neurology. 2006;66(11):1717-1720.
17.
Norgren N, Karlsson JE, Rosengren L, Stigbrand T. Monoclonal antibodies selective for low molecular weight neurofilaments. Hybrid Hybridomics. 2002;21(1):53-59.
18.
Reetz K, Costa AS, Mirzazade S, et al. Genotype-specific patterns of atrophy progression are more sensitive than clinical decline in SCA1, SCA3 and SCA6. Brain. 2013;136(pt 3):905-917.
19.
Adanyeguh IM, Perlbarg V, Henry PG, et al. Autosomal dominant cerebellar ataxias: imaging biomarkers with high effect sizes. Neuroimage Clin. 2018;19:858-867.
20.
Wilke C, Preische O, Deuschle C, et al. Neurofilament light chain in FTD is elevated not only in cerebrospinal fluid, but also in serum. J Neurol Neurosurg Psychiatry. 2016;87(11):1270-1272.
21.
Khalil M, Pirpamer L, Hofer E, et al. Serum neurofilament light levels in normal aging and their association with morphologic brain changes. Nat Commun. 2020;11(1):812.
22.
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.
23.
Byrne LM, Rodrigues FB, Blennow K, et al. Neurofilament light protein in blood as a potential biomarker of neurodegeneration in Huntington's disease: a retrospective cohort analysis. Lancet Neurol. 2017;16(8):601-609.
24.
Tezenas du Montcel S, Durr A, Rakowicz M, et al. Prediction of the age at onset in spinocerebellar ataxia type 1, 2, 3 and 6. J Med Genet. 2014;51:479-486.
25.
Byrne LM, Rodrigues FB, Johnson EB, et al. Evaluation of mutant huntingtin and neurofilament proteins as potential markers in Huntington's disease. Sci Transl Med. 2018;10(458):eaat7108.
26.
Alagaratnam J, von Widekind S, De Francesco D, et al. Correlation between CSF and blood neurofilament light chain protein: a systematic review and meta-analysis. BMJ Neurol Open. 2021;3(1):e000143.
27.
Ashton NJ, Janelidze S, Al Khleifat A, et al. A multicentre validation study of the diagnostic value of plasma neurofilament light. Nat Commun. 2021;12(1):3400.
28.
Weydt P, Oeckl P, Huss A, et al. Neurofilament levels as biomarkers in asymptomatic and symptomatic familial amyotrophic lateral sclerosis. Ann Neurol. 2016;79(1):152-158.
29.
van der Ende EL, Meeter LH, Poos JM, et al. Serum neurofilament light chain in genetic frontotemporal dementia: a longitudinal, multicentre cohort study. Lancet Neurol. 2019;18(12):1103-1111.
30.
Kim DH, Kim R, Lee JY, Lee KM. Clinical, imaging, and laboratory markers of premanifest spinocerebellar ataxia 1, 2, 3, and 6: a systematic review. J Clin Neurol. 2021;17(2):187-199.
31.
Lin CC, Ashizawa T, Kuo SH. Collaborative efforts for spinocerebellar ataxia research in the United States: CRC-SCA and READISCA. Front Neurol. 2020;11:902.

Information & Authors

Information

Published In

Neurology®
Volume 98Number 20May 17, 2022
Pages: e1985-e1996
PubMed: 35264424

Publication History

Received: September 14, 2021
Accepted: February 4, 2022
Published online: March 9, 2022
Published in print: May 17, 2022

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Disclosure

C. Wilke has nothing to disclose. D. Mengel has served as consultant for Biogen. L. Schöls, H. Hengel, and M. Rakowicz have nothing to disclose. T. Klockgether received consulting fees from Biohaven, Roche, UCB, Uniqure, and Vico Therapeutics. A. Durr is currently receiving grants from the NIH (RO1), French National Hospital Clinical Research Program, Agence nationale de la recherche, Triplet Therapeutics, Biogen, and Verum; serves on the advisory boards of Roche, Triplet Therapeutics, and Biogen; and holds partly a patent on anaplerotic therapy of Huntington disease and other polyglutamine diseases (B 06291873.5). A. Filla, B. Melegh, and . Schüle have nothing to disclose. K. Reetz has received grants from the German Federal Ministry of Education and Research (01GQ1402, 01DN18022), the German Research Foundation (IRTG 2150), Alzheimer Forschung Initiative eV (NL-18002CB), and Friedreich's Ataxia Research Alliance and honoraria for presentations or advisory boards from Biogen and Roche. H. Jacobi has nothing to disclose. M. Synofzik received consultancy honoraria from Orphazyme Pharmaceuticals and Janssen Pharmaceuticals, both unrelated to the current project and manuscript. He received consultancy honoraria from Ionis Pharmaceuticals on trial planning in SCA1, also unrelated to the current project and manuscript. Go to Neurology.org/N for full disclosures.

Study Funding

The authors report no targeted funding.

Authors

Affiliations & Disclosures

From the Division Translational Genomics of Neurodegenerative Diseases (C.W., D.M., M.S.) and Department of Neurodegenerative Diseases (L.S., H.H., R.S.), Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen; German Center for Neurodegenerative Diseases (DZNE) (C.W., D.M., L.S., H.H., R.S., M.S.), Tübingen, Germany; First Department of Neurology (M.R.), Institute of Psychiatry and Neurology, Warsaw, Poland; Department of Neurology (T.K.), University Hospital Bonn; German Center for Neurodegenerative Diseases (DZNE) (T.K., H.J.), Bonn, Germany; Sorbonne Université (A.D.), Paris Brain Institute, APHP, INSERM, CNRS, France; Department of Neuroscience and Reproductive and Odontostomatological Sciences (A.F.), Federico II University Naples, Italy; Department of Medical Genetics and Szentagothai Research Center (B.M.), University of Pécs Medical School, Hungary; Department of Neurology (K.R.), RWTH Aachen University; JARA-BRAIN Institute Molecular Neuroscience and Neuroimaging (K.R.), Forschungszentrum Jülich, RWTH Aachen; and Department of Neurology (H.J.), University Hospital of Heidelberg, Germany.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
(1) National Ataxia Foundation, (2) Wilhelm Vaillant Stiftung
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
David Mengel, MD*
From the Division Translational Genomics of Neurodegenerative Diseases (C.W., D.M., M.S.) and Department of Neurodegenerative Diseases (L.S., H.H., R.S.), Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen; German Center for Neurodegenerative Diseases (DZNE) (C.W., D.M., L.S., H.H., R.S., M.S.), Tübingen, Germany; First Department of Neurology (M.R.), Institute of Psychiatry and Neurology, Warsaw, Poland; Department of Neurology (T.K.), University Hospital Bonn; German Center for Neurodegenerative Diseases (DZNE) (T.K., H.J.), Bonn, Germany; Sorbonne Université (A.D.), Paris Brain Institute, APHP, INSERM, CNRS, France; Department of Neuroscience and Reproductive and Odontostomatological Sciences (A.F.), Federico II University Naples, Italy; Department of Medical Genetics and Szentagothai Research Center (B.M.), University of Pécs Medical School, Hungary; Department of Neurology (K.R.), RWTH Aachen University; JARA-BRAIN Institute Molecular Neuroscience and Neuroimaging (K.R.), Forschungszentrum Jülich, RWTH Aachen; and Department of Neurology (H.J.), University Hospital of Heidelberg, Germany.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
Altoida Inc.
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
Baden-Württemberg Stiftung (1.16101.21)
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Ludger Schöls, MD
From the Division Translational Genomics of Neurodegenerative Diseases (C.W., D.M., M.S.) and Department of Neurodegenerative Diseases (L.S., H.H., R.S.), Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen; German Center for Neurodegenerative Diseases (DZNE) (C.W., D.M., L.S., H.H., R.S., M.S.), Tübingen, Germany; First Department of Neurology (M.R.), Institute of Psychiatry and Neurology, Warsaw, Poland; Department of Neurology (T.K.), University Hospital Bonn; German Center for Neurodegenerative Diseases (DZNE) (T.K., H.J.), Bonn, Germany; Sorbonne Université (A.D.), Paris Brain Institute, APHP, INSERM, CNRS, France; Department of Neuroscience and Reproductive and Odontostomatological Sciences (A.F.), Federico II University Naples, Italy; Department of Medical Genetics and Szentagothai Research Center (B.M.), University of Pécs Medical School, Hungary; Department of Neurology (K.R.), RWTH Aachen University; JARA-BRAIN Institute Molecular Neuroscience and Neuroimaging (K.R.), Forschungszentrum Jülich, RWTH Aachen; and Department of Neurology (H.J.), University Hospital of Heidelberg, Germany.
Disclosure
Scientific Advisory Boards:
1.
(1) VICO Therapeutics
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
I received the following grants:PI: Genetic disorders in Arab Societies (grantSCHO754/5-2), DFG: 2014-2019PI: ESMI (01ED1602B), BMBF: 2016-2019PI: Treat-HSP (01GM1905A), BMBF: 2019-2022PI: Treat-ION (01GM1907A), BMBF: 2019-2022
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
I received additional funding from theHSP-Selbsthilfegruppe Deutschland eV and the Fördervereinfuer HSP-Forschung
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Holger Hengel, MD
From the Division Translational Genomics of Neurodegenerative Diseases (C.W., D.M., M.S.) and Department of Neurodegenerative Diseases (L.S., H.H., R.S.), Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen; German Center for Neurodegenerative Diseases (DZNE) (C.W., D.M., L.S., H.H., R.S., M.S.), Tübingen, Germany; First Department of Neurology (M.R.), Institute of Psychiatry and Neurology, Warsaw, Poland; Department of Neurology (T.K.), University Hospital Bonn; German Center for Neurodegenerative Diseases (DZNE) (T.K., H.J.), Bonn, Germany; Sorbonne Université (A.D.), Paris Brain Institute, APHP, INSERM, CNRS, France; Department of Neuroscience and Reproductive and Odontostomatological Sciences (A.F.), Federico II University Naples, Italy; Department of Medical Genetics and Szentagothai Research Center (B.M.), University of Pécs Medical School, Hungary; Department of Neurology (K.R.), RWTH Aachen University; JARA-BRAIN Institute Molecular Neuroscience and Neuroimaging (K.R.), Forschungszentrum Jülich, RWTH Aachen; and Department of Neurology (H.J.), University Hospital of Heidelberg, Germany.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
(1) Deutsche Forschungsgemeinschaft (DFG), HE 8803/1-1, PI, 2021-2024
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Maria Rakowicz, MD
From the Division Translational Genomics of Neurodegenerative Diseases (C.W., D.M., M.S.) and Department of Neurodegenerative Diseases (L.S., H.H., R.S.), Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen; German Center for Neurodegenerative Diseases (DZNE) (C.W., D.M., L.S., H.H., R.S., M.S.), Tübingen, Germany; First Department of Neurology (M.R.), Institute of Psychiatry and Neurology, Warsaw, Poland; Department of Neurology (T.K.), University Hospital Bonn; German Center for Neurodegenerative Diseases (DZNE) (T.K., H.J.), Bonn, Germany; Sorbonne Université (A.D.), Paris Brain Institute, APHP, INSERM, CNRS, France; Department of Neuroscience and Reproductive and Odontostomatological Sciences (A.F.), Federico II University Naples, Italy; Department of Medical Genetics and Szentagothai Research Center (B.M.), University of Pécs Medical School, Hungary; Department of Neurology (K.R.), RWTH Aachen University; JARA-BRAIN Institute Molecular Neuroscience and Neuroimaging (K.R.), Forschungszentrum Jülich, RWTH Aachen; and Department of Neurology (H.J.), University Hospital of Heidelberg, Germany.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
Polish Ministry of Science and Higher Education: 674/N-RISCA/ - principal investigator in Poland, 2010-2014.
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Thomas Klockgether, MD
From the Division Translational Genomics of Neurodegenerative Diseases (C.W., D.M., M.S.) and Department of Neurodegenerative Diseases (L.S., H.H., R.S.), Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen; German Center for Neurodegenerative Diseases (DZNE) (C.W., D.M., L.S., H.H., R.S., M.S.), Tübingen, Germany; First Department of Neurology (M.R.), Institute of Psychiatry and Neurology, Warsaw, Poland; Department of Neurology (T.K.), University Hospital Bonn; German Center for Neurodegenerative Diseases (DZNE) (T.K., H.J.), Bonn, Germany; Sorbonne Université (A.D.), Paris Brain Institute, APHP, INSERM, CNRS, France; Department of Neuroscience and Reproductive and Odontostomatological Sciences (A.F.), Federico II University Naples, Italy; Department of Medical Genetics and Szentagothai Research Center (B.M.), University of Pécs Medical School, Hungary; Department of Neurology (K.R.), RWTH Aachen University; JARA-BRAIN Institute Molecular Neuroscience and Neuroimaging (K.R.), Forschungszentrum Jülich, RWTH Aachen; and Department of Neurology (H.J.), University Hospital of Heidelberg, Germany.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
Novartis(commercial)speaker honorariumBayer (commercial)speaker honorarium
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
Biohaven (commercial) consulting feesRoche(commercial) consulting feesUCB (commercial) consulting feesVico (commercial) consulting feesUniqure (commercial) consulting fees
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
BMBF “IDSEM-Verbundprojekt. Integrative Datensemantik für Neurodegenerative Forschung, Teilprojekt C”, 2016 - 2021EU Joint Programme Neurodegenerative Disease Research (JPND) “European Spinocerebellar Ataxia Type 3/Machado-Joseph Disease Initiative (ESMI)”, 2016 - 2020BMG “Versorgung von Menschen mit seltenen Erkrankungen (Kinder und Erwachsene) (TRANSLATE-NAMSE), 2017 - 2020NIH “Clinical trial readiness for SCA1 and SCA3” (1U01NS104326-01), 2018 - 2022EU Joint Programme Neurodegenerative Disease Research (JPND) “Spinocerebellar ataxias: Advanced imaging with ultra-high field MRI (SCAIFIELD)”, 2021 - 2024National Ataxia Foundation/Ataxia UK “Assessment of ataxia severity under real-life conditions with SARAhome: A multicenter study in spinocerebellar ataxia type 3 (SCA3)”, 2021 - 2023Innovative Medicines Initiative (IMI) “European Platform for Neurodegenerative Diseases (EPND)”, 2021 - 2025EU Joint Programme Rare Diseases (JPND) “Patient-reported, health economic and psychosocial outcomes in Friedreich Ataxia (PROFA)”, 2022 - 2025
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
From the Division Translational Genomics of Neurodegenerative Diseases (C.W., D.M., M.S.) and Department of Neurodegenerative Diseases (L.S., H.H., R.S.), Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen; German Center for Neurodegenerative Diseases (DZNE) (C.W., D.M., L.S., H.H., R.S., M.S.), Tübingen, Germany; First Department of Neurology (M.R.), Institute of Psychiatry and Neurology, Warsaw, Poland; Department of Neurology (T.K.), University Hospital Bonn; German Center for Neurodegenerative Diseases (DZNE) (T.K., H.J.), Bonn, Germany; Sorbonne Université (A.D.), Paris Brain Institute, APHP, INSERM, CNRS, France; Department of Neuroscience and Reproductive and Odontostomatological Sciences (A.F.), Federico II University Naples, Italy; Department of Medical Genetics and Szentagothai Research Center (B.M.), University of Pécs Medical School, Hungary; Department of Neurology (K.R.), RWTH Aachen University; JARA-BRAIN Institute Molecular Neuroscience and Neuroimaging (K.R.), Forschungszentrum Jülich, RWTH Aachen; and Department of Neurology (H.J.), University Hospital of Heidelberg, Germany.
Disclosure
Scientific Advisory Boards:
1.
I serve on the SAB of Wavelife, Triplet Therapeutics.
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
(1) Neurology Genetics, associated editor, (2)Journal of Huntington's Disease, associated editor; (3) International Advisory Committee for JamaNeurology, associated editor
Patents:
1.
‘Anaplerotic therapy of Huntington disease and other polyglutamine diseases’, BIO06353 Mochel/Durr (EP 06291873.5, 12/4/2006)
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
(1) F.Hoffmann La Roche, (3) Wavelife
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
READISCA National Institut of Health (RO1) 2018-2022AAPG ANR 2017: Restoring brain cholesterol metabolism:Development of clinical Gene therapy for Huntington's disease (HDcyp)U01 NS104326-02, board member, 2018-2023
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
‘Anaplerotic therapy of Huntington disease and other polyglutamine diseases’, BIO06353 Mochel/Durr (EP 06291873.5, 12/4/2006)
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Alessandro Filla, Professor, MD
From the Division Translational Genomics of Neurodegenerative Diseases (C.W., D.M., M.S.) and Department of Neurodegenerative Diseases (L.S., H.H., R.S.), Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen; German Center for Neurodegenerative Diseases (DZNE) (C.W., D.M., L.S., H.H., R.S., M.S.), Tübingen, Germany; First Department of Neurology (M.R.), Institute of Psychiatry and Neurology, Warsaw, Poland; Department of Neurology (T.K.), University Hospital Bonn; German Center for Neurodegenerative Diseases (DZNE) (T.K., H.J.), Bonn, Germany; Sorbonne Université (A.D.), Paris Brain Institute, APHP, INSERM, CNRS, France; Department of Neuroscience and Reproductive and Odontostomatological Sciences (A.F.), Federico II University Naples, Italy; Department of Medical Genetics and Szentagothai Research Center (B.M.), University of Pécs Medical School, Hungary; Department of Neurology (K.R.), RWTH Aachen University; JARA-BRAIN Institute Molecular Neuroscience and Neuroimaging (K.R.), Forschungszentrum Jülich, RWTH Aachen; and Department of Neurology (H.J.), University Hospital of Heidelberg, Germany.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Bela Melegh, MD
From the Division Translational Genomics of Neurodegenerative Diseases (C.W., D.M., M.S.) and Department of Neurodegenerative Diseases (L.S., H.H., R.S.), Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen; German Center for Neurodegenerative Diseases (DZNE) (C.W., D.M., L.S., H.H., R.S., M.S.), Tübingen, Germany; First Department of Neurology (M.R.), Institute of Psychiatry and Neurology, Warsaw, Poland; Department of Neurology (T.K.), University Hospital Bonn; German Center for Neurodegenerative Diseases (DZNE) (T.K., H.J.), Bonn, Germany; Sorbonne Université (A.D.), Paris Brain Institute, APHP, INSERM, CNRS, France; Department of Neuroscience and Reproductive and Odontostomatological Sciences (A.F.), Federico II University Naples, Italy; Department of Medical Genetics and Szentagothai Research Center (B.M.), University of Pécs Medical School, Hungary; Department of Neurology (K.R.), RWTH Aachen University; JARA-BRAIN Institute Molecular Neuroscience and Neuroimaging (K.R.), Forschungszentrum Jülich, RWTH Aachen; and Department of Neurology (H.J.), University Hospital of Heidelberg, Germany.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
I'm employee of the University of Pécs. The research activity in the article was partially covered by the EUROSCA project (EU6, contract number LSHM CT 2004-503304)
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Rebecca Schüle, MD
From the Division Translational Genomics of Neurodegenerative Diseases (C.W., D.M., M.S.) and Department of Neurodegenerative Diseases (L.S., H.H., R.S.), Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen; German Center for Neurodegenerative Diseases (DZNE) (C.W., D.M., L.S., H.H., R.S., M.S.), Tübingen, Germany; First Department of Neurology (M.R.), Institute of Psychiatry and Neurology, Warsaw, Poland; Department of Neurology (T.K.), University Hospital Bonn; German Center for Neurodegenerative Diseases (DZNE) (T.K., H.J.), Bonn, Germany; Sorbonne Université (A.D.), Paris Brain Institute, APHP, INSERM, CNRS, France; Department of Neuroscience and Reproductive and Odontostomatological Sciences (A.F.), Federico II University Naples, Italy; Department of Medical Genetics and Szentagothai Research Center (B.M.), University of Pécs Medical School, Hungary; Department of Neurology (K.R.), RWTH Aachen University; JARA-BRAIN Institute Molecular Neuroscience and Neuroimaging (K.R.), Forschungszentrum Jülich, RWTH Aachen; and Department of Neurology (H.J.), University Hospital of Heidelberg, Germany.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
Bundesministerium für Bildung und Forschung (BMBF), 01GM1905A, TreatHSP, coordinating principal investigatorEuropean Union, 01GM1408B, principal investigatorEuropean Union Horizon 2020, Solve-RD, 779257, co-investigatorNIH, 2R01NS072248-06A1, principal investigatorNIH, 5U54NS092091-04 / SPC-000518, site investigator
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
HSP Selbsthilfegruppe e.V.Förderverein HSP-ForschungSpastic Paraplegia FoundationHSP Research Foundation
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Kathrin Reetz, MD
From the Division Translational Genomics of Neurodegenerative Diseases (C.W., D.M., M.S.) and Department of Neurodegenerative Diseases (L.S., H.H., R.S.), Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen; German Center for Neurodegenerative Diseases (DZNE) (C.W., D.M., L.S., H.H., R.S., M.S.), Tübingen, Germany; First Department of Neurology (M.R.), Institute of Psychiatry and Neurology, Warsaw, Poland; Department of Neurology (T.K.), University Hospital Bonn; German Center for Neurodegenerative Diseases (DZNE) (T.K., H.J.), Bonn, Germany; Sorbonne Université (A.D.), Paris Brain Institute, APHP, INSERM, CNRS, France; Department of Neuroscience and Reproductive and Odontostomatological Sciences (A.F.), Federico II University Naples, Italy; Department of Medical Genetics and Szentagothai Research Center (B.M.), University of Pécs Medical School, Hungary; Department of Neurology (K.R.), RWTH Aachen University; JARA-BRAIN Institute Molecular Neuroscience and Neuroimaging (K.R.), Forschungszentrum Jülich, RWTH Aachen; and Department of Neurology (H.J.), University Hospital of Heidelberg, Germany.
Disclosure
Scientific Advisory Boards:
1.
KR has received honoraria for presentations or advisory boards from Biogen and Roche.
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
KR has received honoraria for presentations or advisory boards from Biogen and Roche.
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
KR has received grants from the German Federal Ministry of Education and Research (BMBF 01GQ1402, 01DN18022), the German Research Foundation (IRTG 2150), Alzheimer Forschung Initiative e.V. (AFI 13812, NL-18002CB), Friedreich's Ataxia Research Alliance (FARA).
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Heike Jacobi, MD
From the Division Translational Genomics of Neurodegenerative Diseases (C.W., D.M., M.S.) and Department of Neurodegenerative Diseases (L.S., H.H., R.S.), Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen; German Center for Neurodegenerative Diseases (DZNE) (C.W., D.M., L.S., H.H., R.S., M.S.), Tübingen, Germany; First Department of Neurology (M.R.), Institute of Psychiatry and Neurology, Warsaw, Poland; Department of Neurology (T.K.), University Hospital Bonn; German Center for Neurodegenerative Diseases (DZNE) (T.K., H.J.), Bonn, Germany; Sorbonne Université (A.D.), Paris Brain Institute, APHP, INSERM, CNRS, France; Department of Neuroscience and Reproductive and Odontostomatological Sciences (A.F.), Federico II University Naples, Italy; Department of Medical Genetics and Szentagothai Research Center (B.M.), University of Pécs Medical School, Hungary; Department of Neurology (K.R.), RWTH Aachen University; JARA-BRAIN Institute Molecular Neuroscience and Neuroimaging (K.R.), Forschungszentrum Jülich, RWTH Aachen; and Department of Neurology (H.J.), University Hospital of Heidelberg, Germany.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
From the Division Translational Genomics of Neurodegenerative Diseases (C.W., D.M., M.S.) and Department of Neurodegenerative Diseases (L.S., H.H., R.S.), Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen; German Center for Neurodegenerative Diseases (DZNE) (C.W., D.M., L.S., H.H., R.S., M.S.), Tübingen, Germany; First Department of Neurology (M.R.), Institute of Psychiatry and Neurology, Warsaw, Poland; Department of Neurology (T.K.), University Hospital Bonn; German Center for Neurodegenerative Diseases (DZNE) (T.K., H.J.), Bonn, Germany; Sorbonne Université (A.D.), Paris Brain Institute, APHP, INSERM, CNRS, France; Department of Neuroscience and Reproductive and Odontostomatological Sciences (A.F.), Federico II University Naples, Italy; Department of Medical Genetics and Szentagothai Research Center (B.M.), University of Pécs Medical School, Hungary; Department of Neurology (K.R.), RWTH Aachen University; JARA-BRAIN Institute Molecular Neuroscience and Neuroimaging (K.R.), Forschungszentrum Jülich, RWTH Aachen; and Department of Neurology (H.J.), University Hospital of Heidelberg, Germany.
Disclosure
Scientific Advisory Boards:
1.
Orphazyme Pharmaceuticals, Scientific Advisory Board.
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
Movement Disorders Society, speakers honoraria.
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
Janssen Pharmaceuticals, consultancy honoraria; Ionis Pharmaceuticals, consultancy honoraria.
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
research grants by JPND, Else Kröner Fresenius Stiftung, EJPRD/DFG, E-RAREProgram/BMBF, Deutsche Hereditäre Ataxie Gesellschaft(DHAG), and Center for Rare Diseases Tübingen, Germany.
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE

Notes

Correspondence Dr. Wilke [email protected]
Submitted and externally peer reviewed. The handling editor was Peter Hedera, MD, PhD.
This manuscript was prepublished in MedRxiv (doi: https://doi.org/10.1101/2021.09.14.21263261).
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
*
These authors contributed equally to this work as first authors.

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