Predictive models for ataxia progression and conversion in spinocerebellar ataxia type 1 and 3

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.

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Journal
Brain
Published
2025-10-24
DOI
https://doi.org/10.1093/brain/awaf408
Citations
1
Primary Topic
Genetic Neurodegenerative Diseases
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article
Field-Weighted Citation Impact
0.91
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article

Predictive models for ataxia progression and conversion in spinocerebellar ataxia type 1 and 3

Giulia Coarelli, Alexandra Dürr, Talene A. Yacoubian, Thomas Klockgether et al.
1 citations
Brain
Genetic Neurodegenerative Diseases
0.91
article

Predictive models for ataxia progression and conversion in spinocerebellar ataxia type 1 and 3

Giulia Coarelli, Alexandra Dürr, Talene A. Yacoubian, Thomas Klockgether, Trevor Hawkins, Michael D. Geschwind, Emilien Petit, Tetsuo Ashizawa, Jeremy D. Schmahmann, Paulina Cunha, Gülin Öz, Liana S. Rosenthal, Hortense Hurmic, Henry L. Paulson, Stefan M. Pulst, Sheng‐Han Kuo, Marcus Grobe‐Einsler, Thiago Junqueira Ribeiro de Rezende, Jennifer Faber, David Morgan, Christophe Lenglet, Theresa A. Zesiewicz, Vikram G. Shakkottai, Khalaf Bushara, S. H. Subramony, Susan Perlman, Christopher M. Gomez, George Wilmot, Sophie Tézenas du Montcel, Young Woo-Park
article en
1 citations

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.

Brain
Centre National de la Recherche Scientifique (FR), University of Minnesota (US), Johns Hopkins University (US), Emory University (US), Inserm (FR), University of California, Los Angeles (US), University of California, San Francisco (US), Universidade Estadual de Campinas (UNICAMP) (BR), University of Utah (US), University of South Florida (US), University of Michigan (US), University Hospital Bonn (DE), Johns Hopkins Medicine (US), German Center for Neurodegenerative Diseases (DE), University of Alabama at Birmingham (US), University of Florida (US), Sorbonne Université (FR), University of Chicago (US), Massachusetts General Hospital (US), Assistance Publique – Hôpitaux de Paris (FR), Methodist Hospital (US), Michigan Medicine (US), Institut du Cerveau (FR), Resonance Research (United States) (US), University of Colorado Anschutz Medical Campus (US), Columbia University (US), The University of Texas Southwestern Medical Center (US), Michigan State University (US)
Openalex Percentile: Top 21%
Genetic Neurodegenerative Diseases
0.91
DOIOpen Access PDFOpenAlex
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