Differential Temporal Dynamics of Axial and Appendicular Ataxia in SCA3

Abstract

Background Disease severity in spinocerebellar ataxia type 3 (SCA3) is commonly defined by the Scale for the Assessment and Rating of Ataxia (SARA) sum score, but little is known about the contributions and progression patterns of individual items. Objectives To investigate the temporal dynamics of SARA item scores in SCA3 patients and evaluate if clinical and demographic factors are differentially associated with evolution of axial and appendicular ataxia. Methods In a prospective, multinational cohort study involving 11 European and 2 US sites, SARA scores were determined longitudinally in 223 SCA3 patients with a follow‐up assessment after 1 year. Results An increase in SARA score from 10 to 20 points was mainly driven by axial and speech items, with a markedly smaller contribution of appendicular items. Finger chase and nose‐finger test scores not only showed the lowest variability at baseline, but also the least deterioration at follow‐up. Compared with the full set of SARA items, omission of both tests would result in lower sample size requirements for therapeutic trials. Sex was associated with change in SARA sum score and appendicular, but not axial, subscore, with a significantly faster progression in men. Despite considerable interindividual variability, the average annual progression rate of SARA score was approximately three times higher in subjects with a disease duration over 10 years than in those within 10 years from onset. Conclusion Our findings provide evidence for a difference in temporal dynamics between axial and appendicular ataxia in SCA3 patients, which will help inform the design of clinical trials and development of new (etiology‐specific) outcome measures. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Capturing clinical progression in multisystemic genetic ataxias: lessons from a prospective study of 884 patients with autosomal recessive or early-onset ataxia

“…First, our correlation-based analysis showed limited responsiveness in several subitems and disease stages, with varying patterns: ceiling effects for gait and stance , floor effects for sitting , and non-responsive (‘static’) periods at moderate stages particularly for speech, finger-chase , and nose-finger . These findings extend partly similar recent observations in a monocentric FA 26 and multicentric SCA3 cohort 15 , but now demonstrate these SARA properties for a more comprehensive set of items in a multicenter cohort and in particular across a large number of genetic ataxias, i.e. for the SARA as a generic COA across ataxias.…”

“…We show that a data-driven roSARA which omits these two upper limb subitems allows to reduce trial size by up to 25%, and that a composite of only 3-4 most responsive subitems may appear superior to the total SARA, but still have suboptimal sensitivity. This finding extends recent findings limited to SCA3 15 to a large across-genotype cohort, thus demonstrating their general applicability to genetic ataxias. In combination with the suggested metric optimizations, such a rank-optimized SARA might help to facilitate its regulatory qualification for upcoming trials 42 .…”

“…However, our study is fully in line with smaller genotype-specific studies, e.g. in FA 26 or SCA3 15 , which focused on some of the aspects now identified here as part of a larger set of findings with general applicability across genetic ataxias. Moreover, for many of these ultra-rare ataxias, genotype-specific validation will not be realistic in the near future.…”

“…The SARA has been applied in large observational cohort studies to estimate disease progression and trial sizes in Spinocerebellar Ataxia (SCA) Type 1, 2, 3 and 6, or Friedreich Ataxia (FA) 3,4 , and as primary endpoint in several randomized controlled trials [5][6][7][8][9][10][11] . However, while validity and reliability of the SARA are excellent 1,[12][13][14] , regulatory agencies and recent studies in SCA3 have raised concerns given its insufficiently understood sensitivity to change and functional relevance, especially at the level of single subitems [15][16][17] . Repeated home-based video assessments have recently highlighted the strong intra-individual variability of the SARA 18 , which might be particularly driven by certain subitems.…”

“…However, while validity and reliability of the SARA are excellent 1, 12-14 , regulatory agencies and recent studies in SCA3 have raised concerns given its insufficiently understood sensitivity to change and functional relevance, especially at the level of single subitems 15-17 . Repeated home-based video assessments have recently highlighted the strong intra-individual variability of the SARA 18 , which might be particularly driven by certain subitems.…”