A natural history study to track brain and spinal cord changes in individuals with Friedreich’s ataxia: TRACK-FA study protocol

Abstract

Introduction Drug development for neurodegenerative diseases such as Friedreich’s ataxia (FRDA) is limited by a lack of validated, sensitive biomarkers of pharmacodynamic response in affected tissue and disease progression. Studies employing neuroimaging measures to track FRDA have thus far been limited by their small sample sizes and limited follow up. TRACK-FA, a longitudinal, multi-site, and multi-modal neuroimaging natural history study, aims to address these shortcomings by enabling better understanding of underlying pathology and identifying sensitive, clinical trial ready, neuroimaging biomarkers for FRDA. Methods 200 individuals with FRDA and 104 control participants will be recruited across seven international study sites. Inclusion criteria for participants with genetically confirmed FRDA involves, age of disease onset ≤ 25 years, Friedreich’s Ataxia Rating Scale (FARS) functional staging score of ≤ 5, and a total modified FARS (mFARS) score of ≤ 65 upon enrolment. The control cohort is matched to the FRDA cohort for age, sex, handedness, and years of education. Participants will be evaluated at three study visits over two years. Each visit comprises of a harmonized multimodal Magnetic Resonance Imaging (MRI) and Spectroscopy (MRS) scan of the brain and spinal cord; clinical, cognitive, mood and speech assessments and collection of a blood sample. Primary outcome measures, informed by previous neuroimaging studies, include measures of: spinal cord and brain morphometry, spinal cord and brain microstructure (measured using diffusion MRI), brain iron accumulation (using Quantitative Susceptibility Mapping) and spinal cord biochemistry (using MRS). Secondary and exploratory outcome measures include clinical, cognitive assessments and blood biomarkers. Discussion Prioritising immediate areas of need, TRACK-FA aims to deliver a set of sensitive, clinical trial-ready neuroimaging biomarkers to accelerate drug discovery efforts and better understand disease trajectory. Once validated, these potential pharmacodynamic biomarkers can be used to measure the efficacy of new therapeutics in forestalling disease progression. Clinical trial registration ClinicalTrails.gov Identifier: NCT04349514.

MR Imaging in Ataxias: Consensus Recommendations by the Ataxia Global Initiative Working Group on MRI Biomarkers

“…Furthermore, dMRI metrics have been shown to detect the progression of microstructural changes with high sensitivity [21]. Finally, two large international consortia, READISCA [5] for SCA1 and SCA3 and TRACK-FA [6] for FRDA, are currently using the proposed AGI dMRI protocol for clinical trial readiness studies.…”

“…Prospective longitudinal studies will be particularly important to validate MRI biomarkers for clinical trial readiness. While several multi-site longitudinal imaging studies are ongoing in common degenerative ataxias [5,6], the majority of the MRI studies thus far have demonstrated cross-sectional group differences, and more longitudinal studies are needed to evaluate the sensitivity of MR biomarkers to progressive pathology [3].…”

Automated Dentate Nucleus Segmentation from QSM Images Using Deep Learning

“…Images of FRDA and MS patients were selected to account for anatomical variability in DN caused by neurodegeneration throughout the course of the diseases. The corresponding MRI acquisition protocols have been previously published 11,23,24 and are summarized in Table 1.…”

“…The ethics committee or institutional review board (IRB) respective to each project data source or site approved the use or ethics waiver for this retrospective study, and all participants provided written informed consent prior to original data collection. The TRACK-FA steering committee approved the data use, and IRB reference numbers were previously published 23 (Monash Health Human Research Ethics Committee: RES-20-0000-139A; Children’s Hospital of Philadelphia: IRB 20-017611; University of Minnesota: IRB STUDY00009047; University of Florida: IRB202000399; RWTH Aachen University: EK195/20; University of Campinas (CAAE NO): 83241318.3.1001.5404; McGill IRB Approved Project Number: 2022-8676). Ethics approval was obtained independently for the remaining studies, respectively: Ethical Committee “Carlo Romano” of the University of Naples “Federico II” (Naples A: 209/13, Naples B: 47/15), Monash University Human Research Ethics Committee (IMAGE-FRDA: 13201B, INFLAM-FRDA: 7810), and University of Minnesota IRB (1210M22281).…”

Reproducible Spinal Cord Quantitative MRI Analysis with the Spinal Cord Toolbox

“…The spine-generic protocol has been adopted in recent multi-center studies involving patients with multiple sclerosis, 25 , 26 traumatic spinal cord injury, 27 degenerative cervical myelopathy, 28 and Friedreich’s ataxia. 29 …”