No abstract

BackgroundThe European Friedreich's Ataxia Consortium for Translational Studies (EFACTS) is a prospective international registry investigating the natural history of Friedreich ataxia (FRDA). We report one-and two-year longitudinal data to delineate potential outcomes for clinical trials. MethodsWe enrolled genetically confirmed FRDA patients from eleven European study sites. Patients were seen on an annual basis at three visits. Our primary endpoint was the Scale for the Assessment and Rating of Ataxia (SARA). Secondary outcomes were the Inventory of Non-Ataxia Signs (INAS), the Spinocerebellar Ataxia Functional Index (SCAFI), phonemic verbal fluency (PVF) and the quality of life measures activities of daily living (ADL) and EQ-5D-3L index. Disease progression was analyzed with linear mixed effect models. This study is registered with ClinicalTrials.gov, number NCT02069509. Patients with more than 353 GAA repeats on the shorter allele had a higher SARA progression rate (by 0·09 [0·02] per additional 100 repeats). Annual worsening for INAS was 0·10 (0·03), for SCAFI -0·04 (0·01), for ADL 0·93 (0·06) and for EQ-5D-3L -0·02 (0·004). PVF performance improved by 0·99 [0·14] words per year. 548 or 184 patients would be needed to detect a 50% reduction in SARA progression at 80% power in a one-year or two-year clinical trial, respectively. InterpretationThe EFACTS longitudinal analysis provides suitable outcome measures and sample size calculation for upcoming clinical trial designs in FRDA.

BackgroundThe European Friedreich's Ataxia Consortium for Translational Studies (EFACTS) is a prospective international registry investigating the natural history of Friedreich ataxia (FRDA). Based on our 1 year and 2 year data we aimed to delineate potential outcomes for clinical trials. MethodsWe enrolled patients with genetically confirmed FRDA from 11 European study sites. Patients were seen on an yearly basis at three visits. Our primary endpoint was the Scale for the Assessment and Rating of Ataxia (SARA). Secondary outcomes were the Inventory of Non-Ataxia Signs (INAS), the Spinocerebellar Ataxia Functional Index (SCAFI), phonemic verbal fluency (PVF), and the quality of life measures activities of daily living (ADL) and EQ-5D-3L index. Disease progression was analysed with linear mixed effect models.This study is registered with ClinicalTrials.gov, number NCT02069509. Findings 605 FRDA patients were enrolled between 15-Sep-2010 and 21-Nov-2013. 546 patients (90%) contributed data with at least one follow-up visit. Annual progression rate for SARA was 0•77 points (SE 0•06) in the overall cohort. Deterioration in SARA was associated with a lower age of onset (by -0•02 [0•01] points per year) and a lower SARA baseline score (-0•07 [0•01] per baseline-point). Patients with more than 353 GAA repeats on the shorter allele had a higher SARA progression rate (by 0•09 [0•02] per additional 100 repeats).Annual worsening for INAS was 0•10 (0•03), for SCAFI -0•04 (0•01), for ADL 0•93 (0•06) and for EQ-5D-3L -0•02 (0•004). PVF performance improved by 0•99 [0•14] words per year. 548 or 184 patients would be needed to detect a 50% reduction in SARA progression at 80% power in a one-year or two-year clinical trial, respectively. InterpretationThe EFACTS longitudinal analysis provides suitable outcome measures and sample size calculation for upcoming clinical trial designs in FRDA.

ObjectiveFriedreich's ataxia (FRDA) is a spinocerebellar degenerative disorder, in which cognitive deficits are sparsely explored. In this behavioral and multimodal magnetic resonance imaging (MRI) study, we investigated the neurocognitive profile and cortico‐cerebellar dysfunctions underlying executive functioning in individuals with FRDA.Methods22 FRDA patients and 22 controls were clinically and neuropsychologically examined. Fifteen of each underwent structural and functional MRI using a verbal‐fluency task with phonemic and semantic conditions. Gray (GM) and white matter (WM) alterations were assessed by means of voxel‐based morphometry and diffusion‐tensor imaging.ResultsThe neuropsychological profile demonstrated deficits in verbal fluency, working memory and social cognition. Functional MRI data showed most pronounced group‐differences in phonemic fluency with patients exhibiting enhanced activity in the cerebellum (VI, Crus I), fronto‐insular, premotor and temporo‐occipital regions. The semantic condition only revealed reduced activity in the anterior cerebellum; for overt speech, we found increased activity in the motor cortex. Functional connectivity‐analysis showed higher co‐activation within cerebellar and cortical regions, respectively, and impaired interregional coupling between the cerebellum and fronto‐insular cortex for phonemic processing, which was also related to poorer task performance. GM reduction in FRDA was mainly found in lobule VI, whereas WM degeneration was more pronounced including brainstem, cerebellum, and cortex. Decreased cerebellar GM was associated with enhanced activity in the fronto‐insular cortex, while loss of WM integrity may translate cortico‐cerebellar pathway disruptions.InterpretationThe pattern of increased neural response with both cerebellar and cortical involvement underlying executive functioning indicates functional reorganization driven by disease‐related structural damage in FRDA.