SARA captures disparate progression and responsiveness in spinocerebellar ataxias

Emilien Petit¹, Tanja Schmitz-Hübsch², Giulia Coarelli³, Heike Jacobi⁴, Anna Heinzmann³, Karla P Figueroa⁵, Susan L Perlman⁶, Christopher M Gomez⁷, George R Wilmot⁸, Jeremy D Schmahmann⁹, Sarah H Ying¹⁰, Theresa A Zesiewicz¹¹, Henry L Paulson¹², Vikram G Shakkottai¹², Khalaf O Bushara¹³, Sheng-Han Kuo¹⁴, Michael D Geschwind¹⁵, Guangbin Xia¹⁶, Stefan M Pulst⁵, S H Subramony¹⁶, Claire Ewenczyk³, Alexis Brice³, Alexandra Durr³, Thomas Klockgether¹⁷, Tetsuo Ashizawa¹⁸, Sophie Tezenas du Montcel³

Affiliations

¹ Sorbonne Université, Paris Brain Institute - ICM, Inserm, CNRS, Inria, AP-HP, Paris, France. emilien.petit@icm-institute.org.
² Experimental and Clinical Research Center, A Cooperation of Max-Delbrueck Center of Molecular Medicine and Charité - Universitätsmedizin Berlin, Berlin, Germany.
³ Sorbonne Université, Paris Brain Institute - ICM, Inserm, CNRS, Inria, AP-HP, Paris, France.
⁴ Department of Neurology, University Hospital Heidelberg, Heidelberg, Germany.
⁵ Department of Neurology, University of Utah, Salt Lake City, UT, 84132, USA.
⁶ Department of Neurology, University of California, Los Angeles, Los Angeles, CA, USA.
⁷ Department of Neurology, University of Chicago, Chicago, IL, USA.
⁸ Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA.
⁹ Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
¹⁰ Department of Neurology, Johns Hopkins University, Baltimore, MD, USA.
¹¹ Department of Neurology, University of South Florida, Tampa, FL, USA.
¹² Department of Neurology, University of Michigan, Ann Arbor, MI, USA.
¹³ Department of Neurology, University of Minnesota, Minneapolis, MN, USA.
¹⁴ Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
¹⁵ Department of Neurology, University of California, San Francisco, CA, USA.
¹⁶ Department of Neurology and McKnight Brain Institute, University of Florida, Gainesville, FL, USA.
¹⁷ German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
¹⁸ Weill Cornell Medicine at Houston Methodist Hospital, Houston, TX, USA.

PMID: 38822840
PMCID: PMC11571887
DOI: 10.1007/s00415-024-12475-1

SARA captures disparate progression and responsiveness in spinocerebellar ataxias

Emilien Petit et al. J Neurol. 2024 Jul.

. 2024 Jul;271(7):3743-3753.

doi: 10.1007/s00415-024-12475-1. Epub 2024 Jun 1.

Authors

Affiliations

¹ Sorbonne Université, Paris Brain Institute - ICM, Inserm, CNRS, Inria, AP-HP, Paris, France. emilien.petit@icm-institute.org.
² Experimental and Clinical Research Center, A Cooperation of Max-Delbrueck Center of Molecular Medicine and Charité - Universitätsmedizin Berlin, Berlin, Germany.
³ Sorbonne Université, Paris Brain Institute - ICM, Inserm, CNRS, Inria, AP-HP, Paris, France.
⁴ Department of Neurology, University Hospital Heidelberg, Heidelberg, Germany.
⁵ Department of Neurology, University of Utah, Salt Lake City, UT, 84132, USA.
⁶ Department of Neurology, University of California, Los Angeles, Los Angeles, CA, USA.
⁷ Department of Neurology, University of Chicago, Chicago, IL, USA.
⁸ Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA.
⁹ Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
¹⁰ Department of Neurology, Johns Hopkins University, Baltimore, MD, USA.
¹¹ Department of Neurology, University of South Florida, Tampa, FL, USA.
¹² Department of Neurology, University of Michigan, Ann Arbor, MI, USA.
¹³ Department of Neurology, University of Minnesota, Minneapolis, MN, USA.
¹⁴ Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
¹⁵ Department of Neurology, University of California, San Francisco, CA, USA.
¹⁶ Department of Neurology and McKnight Brain Institute, University of Florida, Gainesville, FL, USA.
¹⁷ German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
¹⁸ Weill Cornell Medicine at Houston Methodist Hospital, Houston, TX, USA.

PMID: 38822840
PMCID: PMC11571887
DOI: 10.1007/s00415-024-12475-1

Abstract

Background: The Scale for Assessment and Rating of Ataxia (SARA) is a widely used clinical scale to assess cerebellar ataxia but faces some criticisms about the relevancy of all its items.

Objectives: To prepare for future clinical trials, we analyzed the progression of SARA and its items in several polyQ spinocerebellar ataxias (SCA) from various cohorts.

Methods: We included data from patients with SCA1, SCA2, SCA3, and SCA6 from four cohorts (EUROSCA, RISCA, CRC-SCA, and SPATAX) for a total of 850 carriers and 3431 observations. Longitudinal progression of the SARA and its items was measured. Cohort, stage and genetic effects were tested. We looked at the respective contribution of each item to the total scale. Sensitivity to change of the scale and the impact of item removal was evaluated by calculating sample sizes needed in various scenarios.

Results: Longitudinal progression was significantly different between cohorts in SCA1, SCA2 and SCA3, the EUROSCA cohort having the fastest progression. Advanced-stage patients were progressing slower in SCA2 and SCA6. Items were not contributing equally to the full scale through ataxia severity: gait, stance, hand movement, and heel-shin contributed the most in the early stage, and finger-chase, nose-finger, and sitting in later stages. Few items drove the sensitivity to the change of SARA, but changes in the scale structure could not improve its sensitivity in all populations.

Conclusion: SARA and its item's progression pace showed high heterogeneity across cohorts and SCAs. However, no combinations of items improved the responsiveness in all SCAs or populations taken separately.

Keywords: Clinical score; Natural history; Spinocerebellar ataxia.

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Figures

**Figure 1:. Contribution to the SARA scale of each individual item of the scale**
Each point represents the average (with 95% CI) of a normalized item score for a group of visits in increments of 5 SARA points. For each class, the point is displayed in the middle of the class: for instance, the point referring to the 0–5 SARA group is displayed at SARA = 2.5. Non-overlapping CI are considered significant differences. The black line represents how the curve would be if all items were contributing equally throughout the disease, namely an x=y curve.

**Figure 2:. Cohort, stage and CAG effect on item progression**
The estimations (with 95% CI) of the interaction between the covariables and time in the linear mixed effect model are displayed. Quadratic and cubic effects were tested for all items, but not shown in this graph if significant as their effects are negligible in early years . Significance of effects are represented as *** if p-value < 0.001, ** if p-value < 0.01 and * if p-value < 0.05. For cohort effects, the p-value indicates that it exists a significant difference of the linear progression between cohorts. For CAG, the p-value indicates that the CAG effect is significantly different from 0. For stage groups, the p-value indicates that at least one group is progressing faster or slower than the reference group (Intermediate group).

**Figure 3:. Stepwise-optimized SARA by stage, SCA and cohort**
The left panels show the sample size estimation for each SO-SARA created. The right panels show in which order the items were added to the SO-SARAS to ensure maximum increase (or minimum decrease) of sensitivity to change.

See this image and copyright information in PMC

References

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SARA captures disparate progression and responsiveness in spinocerebellar ataxias

Affiliations

SARA captures disparate progression and responsiveness in spinocerebellar ataxias

Authors

Affiliations

Abstract

Figures

References

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Research Materials