Dataset Information

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.

SUBMITTER: Georgiou-Karistianis N

PROVIDER: S-EPMC9678384 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Publications

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

Georgiou-Karistianis Nellie N Corben Louise A LA Reetz Kathrin K Adanyeguh Isaac M IM Corti Manuela M Deelchand Dinesh K DK Delatycki Martin B MB Dogan Imis I Evans Rebecca R Farmer Jennifer J França Marcondes C MC Gaetz William W Harding Ian H IH Harris Karen S KS Hersch Steven S Joules Richard R Joers James J JJ Krishnan Michelle L ML Lax Michelle M Lock Eric F EF Lynch David D Mareci Thomas T Muthuhetti Gamage Sahan S Pandolfo Massimo M Papoutsi Marina M Rezende Thiago J R TJR Roberts Timothy P L TPL Rosenberg Jens T JT Romanzetti Sandro S Schulz Jörg B JB Schilling Traci T Schwarz Adam J AJ Subramony Sub S Yao Bert B Zicha Stephen S Lenglet Christophe C Henry Pierre-Gilles PG

PloS one 20221121 11

<h4>Introduction</h4>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 ...[more]

PMID: 36410013

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Project description:Background- The understanding of the natural history of Friedreich's ataxia has improved considerably recently, but patterns of neurologic deterioration are not fully clarified, compromising the assessment of the clinical relevance of effects and guidance for study design. The goal of this work was to acknowledge the broad genetic diversity of the population, especially with respect to younger individuals and to provide analyses stratified by age to guide population selection in future studies.Methods- Based on a large natural history study, the Friedreich's Ataxia Clinical Outcome Measures study (FACOMS) that at the current data cut enrolled 1115 participants, followed up for 5287 yearly visits, we present results from the modified Friedreich's Ataxia Rating Scale and its sub scores. Secondary outcomes included the patient-reported activities of daily living scale, the timed 25-foot walk and the 9-hole peg test. Long-term progression was modeled using slope analyses within Early, Typical, Intermediate and Late Onset Friedreich's Ataxia. To reflect recruitment in clinical trials, short term changes were analyzed within age-based sub-populations. All analyses were stratified by ambulation status.Findings- Long term progression models stratified by disease severity indicated highly differential disease progression, especially at earlier ages of onset. In the ambulatory phase, decline was driven by axial items assessed by the Upright Stability sub score of the mFARS. The analyses of short-term changes showed slower progression with increasing population age, as a result of decreasing genetic severity. Future clinical studies could reduce population diversity, inter-patient variability, and the risk of imbalanced treatment groups by selecting the study population based on the functional capacity (e.g., ambulatory status) and by strict age-based stratification.Interpretation- Understanding of the diversity within Friedreich's ataxia populations and their patterns of functional decline provides an essential foundation for future clinical trial design including patient selection and facilitates the interpretation of the clinical relevance of progression detected in Friedreich's ataxia.

Project description:With emerging applications of spinal cord electrical stimulation in restoring autonomic and motor function after spinal cord injury, understanding the neuroanatomical substrates of the human spinal cord after spinal cord injury using neuroimaging techniques can play a critical role in optimizing the outcomes of these stimulation-based interventions. In this study, we have introduced a neuroimaging acquisition and analysis protocol of the spinal cord in order to identify: (i) spinal cord levels at the lumbosacral enlargement using nerve root tracing; (ii) variability in the neuroanatomical characteristics of the spinal cord among individuals; (iii) location of the epidural stimulation paddle electrode and contacts with respect to the spinal cord levels at lumbosacral enlargement; and (iv) the links between the anatomical levels of stimulation and the corresponding neurophysiological motor responses. Twelve individuals with chronic, motor complete spinal cord injury implanted with a spinal cord epidural stimulator were included in the study (age: 34 ± 10.9 years, sex: 10 males, 2 females, time since injury: 8.2 ± 9.9 years, American Spinal Injury Association Impairment Scale: 6 A, 6 B). High-resolution MRI scans of the spinal cord were recorded pre-implant. An analysis of neuroanatomical substrates indicates that the length of the spinal column and spinal cord, location of the conus tip and the relationship between the spinal cord levels and vertebral levels, particularly at the lumbosacral enlargement, are variable across individuals. There is no statistically significant correlation between the length of the spinal column and the length of the spinal cord. The percentage of volumetric coverage of the lumbosacral spinal cord by the epidural stimulation paddle electrode ranges from 33.4 to 90.4% across participants. The location of the spinal cord levels with respect to the electrode contacts varies across individuals and impacts the recruitment patterns of neurophysiological responses. Finally, MRI-based spinal cord modelling can be used as a guide for the prediction and preplanning of optimum epidural stimulation paddle placement prior to the implant surgery to ensure maximizing functional outcomes. These findings highlight the crucial role that the neuroanatomical characteristics of the spinal cord specific to each individual play in achieving maximum functional benefits with spinal cord electrical stimulation.

Dataset Information

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

Introduction

Methods

Discussion

Clinical trial registration

Publications

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

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