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

Louisa P Selvadurai; Susan L Perlman; George R Wilmot; Sub H Subramony; Christopher M Gomez; Tetsuo Ashizawa; Henry L Paulson; Chiadi U Onyike; Liana S Rosenthal; Haris I Sair; Sheng-Han Kuo; Eva-Maria Ratai; Theresa A Zesiewicz; Khalaf O Bushara; Gülin Öz; Cameron Dietiker; Michael D Geschwind; Alexandra B Nelson; Puneet Opal; Talene A Yacoubian; Peggy C Nopoulos; Vikram G Shakkottai; Karla P Figueroa; Stefan M Pulst; Peter E Morrison; Jeremy D Schmahmann

doi:10.1007/s12311-022-01424-1

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

Cerebellum. 2023 Oct;22(5):790-809. doi: 10.1007/s12311-022-01424-1. Epub 2022 Aug 12.

Authors

Louisa P Selvadurai¹, Susan L Perlman², George R Wilmot³, Sub H Subramony⁴, Christopher M Gomez⁵, Tetsuo Ashizawa⁶, Henry L Paulson⁷, Chiadi U Onyike⁸, Liana S Rosenthal⁹, Haris I Sair¹⁰, Sheng-Han Kuo¹¹, Eva-Maria Ratai¹², Theresa A Zesiewicz¹³, Khalaf O Bushara¹⁴, Gülin Öz¹⁵, Cameron Dietiker¹⁶, Michael D Geschwind¹⁶, Alexandra B Nelson¹⁶, Puneet Opal¹⁷, Talene A Yacoubian¹⁸, Peggy C Nopoulos¹⁹, Vikram G Shakkottai²⁰, Karla P Figueroa²¹, Stefan M Pulst²¹, Peter E Morrison²², Jeremy D Schmahmann²³

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.
² Department of Neurology, University of California, Los Angeles, Los Angeles, CA, USA.
³ Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA.
⁴ Department of Neurology, University of Florida College of Medicine, McKnight Brain Institute, Gainesville, FL, USA.
⁵ Department of Neurology, University of Chicago, Chicago, IL, USA.
⁶ Department of Neurology, Houston Methodist Research Institute, Houston, TX, USA.
⁷ Department of Neurology, University of Michigan, Ann Arbor, MI, USA.
⁸ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁹ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁰ Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹¹ Department of Neurology, Columbia University, New York, NY, USA.
¹² Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
¹³ Department of Neurology, Ataxia Research Center, University of South Florida, Tampa, FL, USA.
¹⁴ Department of Neurology, University of Minnesota, Minneapolis, MN, USA.
¹⁵ Center for Magnetic Resonance Research, Department of Radiology, University of Minnesota, Minneapolis, MN, USA.
¹⁶ Department of Neurology, University of California, San Francisco, CA, USA.
¹⁷ Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
¹⁸ Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, USA.
¹⁹ Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, USA.
²⁰ Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
²¹ Department of Neurology, University of Utah, Salt Lake City, UT, USA.
²² Department of Neurology, University of Rochester Medical Center, Rochester, NY, USA.
²³ 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. jschmahmann@mgh.harvard.edu.

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.

Keywords: Disease progression; Natural history; Scale for the Assessment and Rating of Ataxia; Spinocerebellar ataxia.

MeSH terms

Disease Progression
Humans
Patient Acuity
Spinocerebellar Ataxias* / diagnosis
Spinocerebellar Ataxias* / epidemiology
Spinocerebellar Ataxias* / genetics

Abstract

MeSH terms

Grants and funding