Brain. 2025 Oct 28:awaf408. doi: 10.1093/brain/awaf408. Online ahead of print.
ABSTRACT
The READISCA study aims to prepare for clinical trials in SCA1 and SCA3. Hence, we searched for predictive variables of ataxia onset (phenoconversion) and progression. Individuals with SCA1 or SCA3 and controls were enrolled from 2018-2021 in US and Europe. Clinical scores, MRI measures and NfL levels were assessed annually for 5 years. In the pre-ataxic group at baseline, we compared phenoconverters with non-converters. A Bayesian mixed model was used to model the longitudinal progression of clinical scores and NfL levels. The impact of data-driven selected baseline variables (demographic, clinical, MRI) on the expected SARA progression was tested. Forty-three controls, 55 SCA1 and 124 SCA3 carriers were included; a subset of the cohort (n=109) had MRI data. Converters from pre-ataxic to ataxic stages represented 5/22 (22%) and 12/38 (32%) for SCA1 and SCA3. Converters were more depressed (PHQ9: 3.9±2.9 vs 2.3±2.6 p = 0.04), had higher plasma NfL levels (17.6±5.7 pg.mL-1 vs 11.1±5.9, p<0.0001), more cerebellar white matter atrophy (1.44±0.12 % of total intracranial volume vs 1.54±0.16, p=0.032) and more INAS signs (1.8±1.3 vs 0.7±0.8, p = 0.002). All clinical scores except CCAS significantly worsened during the study. NfL levels significantly increased in non-converters and ataxic SCA3 (1.06±0.33 pg.mL-1/year, p=0.002 and 0.57±0.21, p=0.01) but not in controls and ataxic SCA1 (0.31±0.26, p=0.24 and 0.26±0.42, p=0.55). In the best predictive model of SARA progression after 1 year (R2=0.54), factors linked with faster progression were higher functional stage (p<0.001), higher CCFS score (p=0.002), and higher total creatine in cerebellar white matter (p=0.026). Factors significantly linked to conversion, namely NfL levels, depression, and lower motor neuron involvement, differ from those driving disease progression. NfL levels and lower motoneuron signs could be used as predictors of phenoconversion and MRI variables as ataxia progression predictors. Psychological care should be provided in the pre-ataxic phase of the disease.
PMID:41150672 | DOI:10.1093/brain/awaf408
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