MRI end-points for clinical trials in ataxias: recommendations from the Ataxia Global Initiative MRI Biomarkers...

Disease-modifying therapies for degenerative ataxias, including emerging gene therapies, are in the clinical trial pipeline. Sensitive outcome measures are urgently needed for treatment monitoring and participant selection to improve trial feasibility in these rare diseases. In hereditary ataxias, the ability to identify people who carry disease-causing mutations before symptom onset also raises the possibility of enrolment into trials before symptom manifestation, but biomarker data are key for participant selection and outcome monitoring in such preventive trials. Quantitative neuroimaging readouts have emerged as viable candidate biomarkers of ataxia pathology and progression that could supplement traditional clinical outcome assessments as clinical trial end-points. In this Consensus Statement, the Ataxia Global Initiative MRI Biomarkers Working Group critically reviews candidate MRI end-points for trials in the most common spinocerebellar ataxias (SCA1, SCA2 and SCA3) and Friedreich ataxia and provides evidence-based, disease-specific recommendations for the selection of MRI end-points for trials in these diseases. Recommendations are also provided for further research to address remaining knowledge gaps.