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Researchers detected annual changes in patients with preataxic and early ataxic spinocerebellar ataxia in brain MRI imaging, clinical scores, gait parameters, and retinal thickness.
Giulia Coarelli, MD, PhD
(Credit: Pitié-Salpêtrière University Hospital)
Despite a small sample size, a group of researchers in a new longitudinal trial (NCT04288128) identified significant changes across biological, clinical, and imaging biomarkers among patients with spinocerebellar ataxia (SCA) 2 and SCA7 over 1 year. Published in Neurology, the authors noted these measurements could potentially serve as end points in a 1-year trial with a sample size of fewer than 40 patients in the preataxic phase.1
After 1-year of follow-up, researchers observed significant pons (-144 mm3 ± 60) and cerebellum (-1508 mm3 ±580) volume loss, and a worsening of gait assessment in SCA2 carriers (n = 15). In SCA7 carriers (n = 15), the Scale for the Assessment and Rating of Ataxia (SARA) score significantly increased (+1.3 ±0.4) and outer retinal nuclear layer thickness reduced (-15.4 μm ±1.6). In both SCA groups, authors reported that orofacial motor assessment significantly worsened. Notably, among preataxic and early ataxic carriers, the strongest longitudinal deterioration on outcome measures was orofacial motility in SCA2 and retinal thickness in SCA7.
“Our findings reveal significant changes over 1 year in both clinical and imaging biomarkers for SCA2 and SCA7 carriers, identified even before the ataxia onset. This insight allows us to foresee therapeutic strategies for preataxic individuals, leveraging the utility of these end points that are reasonably likely to predict clinical outcomes,” lead author Giulia Coarelli, MD, PhD, a neurologist in the department of genetics at Pitié-Salpêtrière University Hospital, and colleagues wrote.1
In this study, investigators researched SCA2 and SCA7 carriers and controls (n = 10) between May 2020 and April 2021 at the Paris Brain Institute. For inclusion criteria for the study, participants with SCA were eligible if they had SARA scores between 0 and 15.2 Researchers performed assessments that comprised of neurologic, quality of life, orofacial motor, neuropsychological, and ophthalmologic examinations at baseline, 6 months, and 12 months. The authors also evaluated gait and oculomotor recordings, brain MRI, cerebrospinal fluid, and blood sampling during the 3 visits. Overall, the primary outcome of the study was longitudinal change observed by the investigators from these evaluations in patients with SCAs over the span of 1 year.
“One of the limitations of our study is the small sample size. This was primarily due to the rarity of SCA2 and SCA7. In addition, setting the inclusion criterion at a SARA score below 15 further narrowed the pool of potential participants. Given the exploratory nature of the multimodal approach, adjusting for multiple comparisons reduced the significance threshold for each variable,” Coarelli et al noted.1 “The inclusion of preataxic and early ataxic patients, who will be the target of future disease-modifying therapies is a strength of the study.”
At baseline, ages were similar among the 3 groups (SCA2, 41 years [range, 37-46]; SCA7, 38 years [range, 28.5-39.8]; controls, 39.5 years [range, 31-54.5]; P = .78), as well as sex (P = .61). Notably, SARA scores were low but differed from each group at baseline (SCA2, 4 [Q1, 1.25; Q3, 6.5]; SCA7, 2 [Q1, 0; Q3, 11.5]; controls, 0; P <.01). The authors reported that patients with SCAs had smaller pons and medulla volumes (P <.05) and only the SCA2 group had smaller cerebellum volume (P = .01). Investigators also observed higher plasma neurofilament light chain levels among patients with SCAs (SCA2, 14.2 pg/mL [Q1, 11.52; Q3, 15.89]; SCA7, 15.53 [Q1, 13.27; Q3, 23.23]) in comparison with the controls (4.88 [Q1, 3.56; Q3, 6.17]; P <.001).
“The overall usefulness of these data lies in the effect size calculations for significant outcomes that showed longitudinal changes, demonstrating that the sample sizes do not exceed those required for the ataxic stages,” Coarelli et al noted.1 “[Outer nuclear layer] thickness stands out as the strongest end point for a clinical trial in SCA7, rendering a study targeting the retina very feasible. In SCA2, clinical end points appear more powerful than imaging end points, as evidenced by the smaller required sample sizes.”
