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The S-Factor, a New Measure of Disease Severity in Spinocerebellar Ataxia: Findings and Implications

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Abstract

Spinocerebellar ataxias (SCAs) are progressive neurodegenerative disorders, but there is no metric that predicts disease severity over time. We hypothesized that by developing a new metric, the Severity Factor (S-Factor) using immutable disease parameters, it would be possible to capture disease severity independent of clinical rating scales. Extracting data from the CRC-SCA and READISCA natural history studies, we calculated the S-Factor for 438 participants with symptomatic SCA1, SCA2, SCA3, or SCA6, as follows: ((length of CAG repeat expansion – maximum normal repeat length) /maximum normal repeat length) × (current age – age at disease onset) × 10). Within each SCA type, the S-Factor at the first Scale for the Assessment and Rating of Ataxia (SARA) visit (baseline) was correlated against scores on SARA and other motor and cognitive assessments. In 281 participants with longitudinal data, the slope of the S-Factor over time was correlated against slopes of scores on SARA and other motor rating scales. At baseline, the S-Factor showed moderate-to-strong correlations with SARA and other motor rating scales at the group level, but not with cognitive performance. Longitudinally the S-Factor slope showed no consistent association with the slope of performance on motor scales. Approximately 30% of SARA slopes reflected a trend of non-progression in motor symptoms. The S-Factor is an observer-independent metric of disease burden in SCAs. It may be useful at the group level to compare cohorts at baseline in clinical studies. Derivation and examination of the S-factor highlighted challenges in the use of clinical rating scales in this population.

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Acknowledgements

The authors would like to thank Dr Gilbert J. L’Italien (Global Health Outcomes and Epidemiology, Biohaven Pharmaceuticals, New Haven, CT, USA) for guidance with the statistical approaches.

Funding

Supported in part by the National Ataxia Foundation and the MINDlink Foundation. LPS was supported by an Australian-American Fulbright Commission scholarship. The READISCA project was supported by the National Institute of Neurological Disorders and Stroke (NINDS) grant U01 NS104326.

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Author notes

  1. Vikram G. Shakkottai

    Present address: Department of Neurology, University of Michigan, Ann Arbor, MI, USA

Authors and Affiliations

  1. Ataxia Center, Cognitive Behavioral Neurology Unit, Laboratory for Neuroanatomy and Cerebellar Neurobiology, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Louisa P. Selvadurai & Jeremy D. Schmahmann

  2. Department of Neurology, University of California, Los Angeles, Los Angeles, CA, USA

    Susan L. Perlman

  3. Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA

    George R. Wilmot

  4. Department of Neurology, University of Florida College of Medicine, McKnight Brain Institute, Gainesville, FL, USA

    Sub H. Subramony

  5. Department of Neurology, University of Chicago, Chicago, IL, USA

    Christopher M. Gomez

  6. Department of Neurology, Houston Methodist Research Institute, Houston, TX, USA

    Tetsuo Ashizawa

  7. Department of Neurology, University of Michigan, Ann Arbor, MI, USA

    Henry L. Paulson

  8. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Chiadi U. Onyike

  9. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Liana S. Rosenthal

  10. Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Haris I. Sair

  11. Department of Neurology, Columbia University, New York, NY, USA

    Sheng-Han Kuo

  12. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Eva-Maria Ratai

  13. Department of Neurology, Ataxia Research Center, University of South Florida, Tampa, FL, USA

    Theresa A. Zesiewicz

  14. Department of Neurology, University of Minnesota, Minneapolis, MN, USA

    Khalaf O. Bushara

  15. Center for Magnetic Resonance Research, Department of Radiology, University of Minnesota, Minneapolis, MN, USA

    Gülin Öz

  16. Department of Neurology, University of California, San Francisco, CA, USA

    Cameron Dietiker, Michael D. Geschwind & Alexandra B. Nelson

  17. Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Puneet Opal

  18. Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, USA

    Talene A. Yacoubian

  19. Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, USA

    Peggy C. Nopoulos

  20. Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Vikram G. Shakkottai

  21. Department of Neurology, University of Utah, Salt Lake City, UT, USA

    Karla P. Figueroa & Stefan M. Pulst

  22. Department of Neurology, University of Rochester Medical Center, Rochester, NY, USA

    Peter E. Morrison

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  1. Louisa P. Selvadurai
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Correspondence to Jeremy D. Schmahmann.

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Conflict of Interest

E.M.R. serves on the BrainSpec Inc. Scientific Advisory Board. G.Ö. consults for IXICO Technologies Limited and uniQure biopharma B.V., serves on the Scientific Advisory Board of BrainSpec Inc., and receives research support from Biogen. J.D.S. is site PI for Biohaven Pharma, consults for Biogen and MedAvante, and holds the copyright with the General Hospital Corporation to the Brief Ataxia Rating scale, Patient Reported outcome Measure of Ataxia, and the Cerebellar Cognitive Affective/Schmahmann Syndrome Scale.

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Selvadurai, L.P., Perlman, S.L., Wilmot, G.R. et al. The S-Factor, a New Measure of Disease Severity in Spinocerebellar Ataxia: Findings and Implications. Cerebellum 22, 790–809 (2023). https://doi.org/10.1007/s12311-022-01424-1

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