Background and Objectives In spinocerebellar ataxia, ataxia onset can be preceded by mild clinical manifestation, cerebellar and/or brainstem alterations, or biomarker modifications. READISCA is a prospective, longitudinal observational study of patients with spinocerebellar ataxia type 1 (SCA1) and 3 (SCA3) to provide essential markers for therapeutic interventions. We looked for clinical, imaging, or biological markers that are present at an early stage of the disease. Methods We enrolled carriers of a pathologic ATXN1 or ATXN3 expansion and controls from 18 US and 2 European ataxia referral centers. Clinical, cognitive, quantitative motor, neuropsychological measures and plasma neurofilament light chain (NfL) measurements were compared between expansion carriers with and without ataxia and controls. Results We enrolled 200 participants: 45 carriers of a pathologic ATXN1 expansion (31 patients with ataxia [median Scale for the Assessment and Rating of Ataxia: 9; 7-10] and 14 expansion carriers without ataxia [1; 0-2]) and 116 carriers of a pathologic ATXN3 expansion (80 patients with ataxia [7; 6-9] and 36 expansion carriers without ataxia [1; 0-2]). In addition, we enrolled 39 controls who did not carry a pathologic expansion in ATXN1 or ATXN3. Plasma NfL levels were significantly higher in expansion carriers without ataxia than controls, despite similar mean age (controls: 5.7 pg/mL, SCA1: 18.0 pg/mL [p < 0.0001], SCA3: 19.8 pg/mL [p < 0.0001]). Expansion carriers without ataxia differed from controls by significantly more upper motor signs (SCA1 p = 0.0003, SCA3 p = 0.003) and by the presence of sensor impairment and diplopia in SCA3 (p = 0.0448 and 0.0445, respectively). Functional scales, fatigue and depression scores, swallowing difficulties, and cognitive impairment were worse in expansion carriers with ataxia than those without ataxia. Ataxic SCA3 participants showed extrapyramidal signs, urinary dysfunction, and lower motor neuron signs significantly more often than expansion carriers without ataxia. Discussion READISCA showed the feasibility of harmonized data acquisition in a multinational network. NfL alterations, early sensory ataxia, and corticospinal signs were quantifiable between preataxic participants and controls. Patients with ataxia differed in many parameters from controls and expansion carriers without ataxia, with a graded increase of abnormal measures from control to preataxic to ataxic cohorts.
Bibliographical noteFunding Information:
S. Tezenas du Montcel receives research support from Biogen. S.H. Subramony receives research support from National Ataxia Foundation, Biohaven, NIH, FDA, MDA, Wyck Foundation, FARA, Reata, PTC therapeutics, Retrotope, Avidity Biosciences, Fulcrum therapeutics, Reneo Pharma, and AAVANTIBio and serves on the Scientific Advisory Board for Reata, Avidity, and Dyne therapeutics. G. Öz consults for IXICO Technologies Limited and uniQure biopharma B.V., serves on the Scientific Advisory Board of BrainSpec Inc., and receives research support from Biogen. T. Ashizawa received grants from NAF and Biogen and participates in Biohaven clinical trials NCT03952806 and NCT03701399. The other authors report no relevant disclosures. Go to Neurology.org/N for full disclosures.
The READISCA investigators thank all participants for their enduring willingness and interest in this research. We extend gratitude to all study coordinators at READISCA sites (readisca.org/readisca-team/#Coordinators) and Chantel Potvin for outstanding project management. We further thank the National Ataxia Foundation for assistance with traveling logistics of participants. This work was supported by the National Institute of Neurological Disorders and Stroke grant U01 NS104326 to T.A., H.L.P., G.O., A.D., and T.K. D. Morgan received a Michigan ADRC grant (P30 AG072931).
This work was supported by the National Institute of Neurological Disorders and Stroke grant U01 NS104326 to T.A., H.L.P., G.O., A.D., and T.K. D. Morgan received a Michigan ADRC grant (P30 AG072931).
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- Prospective Studies
- Spinocerebellar Ataxias
- Cerebellar Ataxia
- Machado-Joseph Disease/diagnosis
PubMed: MeSH publication types
- Observational Study
- Journal Article
- Research Support, N.I.H., Extramural