A Natural History Study to TRACK Brain and Spinal Cord Changes in Individuals with Friedreich Ataxia (TRACK-FA)
Overview
- Phase
- N/A
- Intervention
- Not specified
- Conditions
- Friedreich Ataxia
- Sponsor
- Monash University
- Enrollment
- 300
- Locations
- 7
- Primary Endpoint
- Slope of change in superior cerebellar peduncle fractional anisotropy
- Status
- Active, Not Recruiting
- Last Updated
- last year
Overview
Brief Summary
This is a natural history study prospectively investigating neuroimaging markers of disease progression in children and adults with Friedreich ataxia (FA). There will be three assessment periods (baseline, 12 and 24 months). The study will include approximately 200 individuals with FA and 100 matched controls recruited across the six international academic sites. Other assessments will include secondary clinical and cognitive markers, as well as exploratory blood markers.
Detailed Description
Friedreich ataxia (FA) is a multi-system progressive disorder with the most prevalent and prominent symptoms relating to dysfunction in the central and peripheral nervous system, including, loss of balance and coordination, frequent falls, loss of ambulation, dysarthria, dysphagia and loss of vision and hearing. Other symptoms include cardiomyopathy, diabetes, scoliosis and fatigue. Age of onset can vary but most often presents during childhood, ages 5-15 years. There is currently no cure and no disease-modifying treatment. Drug candidates to potentially treat FA are under development; however, there is a lack of well- characterized neuroimaging biomarkers for testing their efficacy in clinical trials, hampering this process. Establishing disease-specific neuroimaging biomarkers to track disease progression requires high-quality longitudinal data from large cohorts of patients, compared to controls. In rare diseases, such as FA, this can only be achieved through multi-site collaboration. The aim of TRACK-FA is to develop an FA neuroimaging dataset from brain and spinal cord that is suitable for assessing the potential value of neuroimaging biomarkers and providing a basis for instituting them in clinical trials. The dataset will comprise a range of neuroimaging measures to assess changes in spinal cord and brain regions that have previously shown to be compromised in individuals with FA. In addition to neuroimaging measures, TRACK-FA will also include clinical, cognitive data and biospecimen data. The TRACK-FA dataset will provide a unique opportunity for academic researchers in collaboration with industry partners to access the images, subsidiary data, and associated clinical data for community research. This multi-centre study is a collaborative effort across six academic institutions, together with industry partners and the Friedreich's Ataxia Research Alliance USA (FARA).
Investigators
Nellie Georgiou-Karistianis
Professor Nellie Georgiou-Karistianis
Monash University
Eligibility Criteria
Inclusion Criteria
- •Age ≥ 5 years
- •Written informed consent provided
- •Individuals with FA must have a genetic confirmation of diagnosis and be biallelic for a GAA repeat length \> 55 in intron 1 of FXN and/or have a GAA repeat length \> 55 in intron 1 of FXN in one allele and another type of mutation that is inferred to cause loss of function in the second FXN allele
- •Individuals with FA must have an age of disease onset ≤ 25 years
- •Individuals with FA must have a disease duration ≤ 25 years
- •Individuals with FA must have a Friedreich Ataxia Rating Scale (FARS) Functional staging score of ≤ 5 and total modified FARS (mFARS) score of ≤ 65 on enrolment
Exclusion Criteria
- •Age \< 5 years
- •Unable to provide written informed consent
- •Magnetic resonance contraindications (e.g. pacemaker or other metallic surgical implants)
- •Presence of metallic dental braces
- •Pregnancy (ascertained via a question or test as mandated at particular sites)
- •Individuals with FA must not have acute or ongoing medical or other conditions that, after discussion between the Site Investigator and steering committee, is deemed to interfere with the conduct and assessments of the study
- •Individuals with FA must not have another neurological condition apart from FA
- •Individuals with FA must not have other neurologic conditions that, in the opinion of the Site Investigator, would interfere with the conduct and assessments of the study
- •Controls must not have a diagnosed psychiatric or neurological condition
- •Controls must not have acute or ongoing medical or other conditions that would interfere with the conduct and assessments of the study
Outcomes
Primary Outcomes
Slope of change in superior cerebellar peduncle fractional anisotropy
Time Frame: Baseline to 24 months
Fractional anisotropy of the superior cerebellar peduncles will be measured using diffusion tensor magnetic resonance imaging. The within-person slope of superior cerebellar peduncle fractional anisotropy over the three study visits will be estimated and compared between the Friedreich ataxia and control groups. This measurement will be obtained for participants aged 11 years and over.
Slope of change in superior cerebellar peduncle mean diffusivity
Time Frame: Baseline to 24 months
Mean diffusivity of the superior cerebellar peduncles will be measured using diffusion tensor magnetic resonance imaging. The within-person slope of superior cerebellar peduncle mean diffusivity over the three study visits will be estimated and compared between the Friedreich ataxia and control groups. This measurement will be obtained for participants aged 11 years and over.
Baseline superior cerebellar peduncle radial diffusivity
Time Frame: Baseline
Radial diffusivity of the superior cerebellar peduncles will be measured using diffusion tensor magnetic resonance imaging. Baseline superior cerebellar peduncle radial diffusivity will be compared between the Friedreich ataxia and control groups. This measurement will be obtained for participants aged 11 years and over.
Baseline dentate volume
Time Frame: Baseline
Volume of the dentate nuclei will be measured using T2\*-weighted multiecho magnetic resonance imaging and quantitative susceptibility mapping processing. Baseline dentate nuclei volume will be compared between the Friedreich ataxia and control groups. This measurement will be obtained for participants aged 11 years and over.
Baseline dentate nuclei magnetic susceptibility
Time Frame: Baseline
Magnetic susceptibility of the dentate nuclei will be measured using T2\*-weighted multiecho magnetic resonance imaging and quantitative susceptibility mapping processing. Baseline dentate nuclei susceptibility will be compared between the Friedreich ataxia and control groups. This measurement will be obtained for participants aged 11 years and over.
Slope of change in dentate nuclei magnetic susceptibility
Time Frame: Baseline to 24 months
Magnetic susceptibility of the dentate nuclei will be measured using T2\*-weighted multiecho magnetic resonance imaging and quantitative susceptibility mapping processing. The within-person slope of dentate nuclei susceptibility over the three study visits will be estimated and compared between the Friedreich ataxia and control groups. This measurement will be obtained for participants aged 11 years and over.
Baseline superior cerebellar peduncle volume
Time Frame: Baseline
Volume of the superior cerebellar peduncles will be measured using T1- and T2-weighted magnetic resonance imaging. Baseline superior cerebellar peduncle volume will be compared between the Friedreich ataxia and control groups.
Slope of change in superior cerebellar peduncle volume
Time Frame: Baseline to 24 months
Volume of the superior cerebellar peduncles will be measured using T1- and T2-weighted magnetic resonance imaging. The within-person slope of superior cerebellar peduncle volume over the three study visits will be estimated and compared between the Friedreich ataxia and control groups.
Baseline superior cerebellar peduncle axial diffusivity
Time Frame: Baseline
Axial diffusivity of the superior cerebellar peduncles will be measured using diffusion tensor magnetic resonance imaging. Baseline superior cerebellar peduncle axial diffusivity will be compared between the Friedreich ataxia and control groups. This measurement will be obtained for participants aged 11 years and over.
Slope of change in dentate volume
Time Frame: Baseline to 24 months
Volume of the dentate nuclei will be measured using T2\*-weighted multiecho magnetic resonance imaging and quantitative susceptibility mapping processing. The within-person slope of dentate nuclei volume over the three study visits will be estimated and compared between the Friedreich ataxia and control groups. This measurement will be obtained for participants aged 11 years and over.
Baseline superior cerebellar peduncle mean diffusivity
Time Frame: Baseline
Mean diffusivity of the superior cerebellar peduncles will be measured using diffusion tensor magnetic resonance imaging. Baseline superior cerebellar peduncle mean diffusivity will be compared between the Friedreich ataxia and control groups. This measurement will be obtained for participants aged 11 years and over.
Baseline cervical spinal cord cross-sectional area
Time Frame: Baseline
Cross-sectional area of the cervical portion of the spinal cord will be measured using T2-weighted magnetic resonance imaging. Baseline cervical spinal cord cross-sectional area will be compared between the Friedreich ataxia and control groups.
Baseline cervical spinal cord axial diffusivity
Time Frame: Baseline
Axial diffusivity of the cervical portion of the spinal cord will be measured using diffusion tensor magnetic resonance imaging. Baseline cervical spinal cord axial diffusivity will be compared between the Friedreich ataxia and control groups. This measurement will be obtained for participants aged 11 years and over.
Baseline total cerebellar volume
Time Frame: Baseline
Total volume of the cerebellum will be measured using T1- and T2-weighted magnetic resonance imaging. Baseline total cerebellar volume will be compared between the Friedreich ataxia and control groups.
Slope of change in total cerebellar volume
Time Frame: Baseline to 24 months
Total volume of the cerebellum will be measured using T1- and T2-weighted magnetic resonance imaging. The within-person slope of total cerebellar volume over the three study visits will be estimated and compared between the Friedreich ataxia and control groups.
Baseline superior cerebellar peduncle fractional anisotropy
Time Frame: Baseline
Fractional anisotropy of the superior cerebellar peduncles will be measured using diffusion tensor magnetic resonance imaging. Baseline superior cerebellar peduncle fractional anisotropy will be compared between the Friedreich ataxia and control groups. This measurement will be obtained for participants aged 11 years and over.
Slope of change in superior cerebellar peduncle axial diffusivity
Time Frame: Baseline to 24 months
Axial diffusivity of the superior cerebellar peduncles will be measured using diffusion tensor magnetic resonance imaging. The within-person slope of superior cerebellar peduncle axial diffusivity over the three study visits will be estimated and compared between the Friedreich ataxia and control groups. This measurement will be obtained for participants aged 11 years and over.
Baseline cervical spinal cord radial diffusivity
Time Frame: Baseline
Radial diffusivity of the cervical portion of the spinal cord will be measured using diffusion tensor magnetic resonance imaging. Baseline cervical spinal cord radial diffusivity will be compared between the Friedreich ataxia and control groups. This measurement will be obtained for participants aged 11 years and over.
Slope of change in superior cerebellar peduncle radial diffusivity
Time Frame: Baseline to 24 months
Radial diffusivity of the superior cerebellar peduncles will be measured using diffusion tensor magnetic resonance imaging. The within-person slope of superior cerebellar peduncle radial diffusivity over the three study visits will be estimated and compared between the Friedreich ataxia and control groups. This measurement will be obtained for participants aged 11 years and over.
Slope of change in cervical spinal cord cross-sectional area
Time Frame: Baseline to 24 months
Cross-sectional area of the cervical portion of the spinal cord will be measured using T2-weighted magnetic resonance imaging. The within-person slope of cervical spinal cord cross-sectional area over the three study visits will be estimated and compared between the Friedreich ataxia and control groups.
Slope of change in cervical spinal cord fractional anisotropy
Time Frame: Baseline to 24 months
Fractional anisotropy of the cervical portion of the spinal cord will be measured using diffusion tensor magnetic resonance imaging. The within-person slope of cervical spinal cord fractional anisotropy over the three study visits will be estimated and compared between the Friedreich ataxia and control groups. This measurement will be obtained for participants aged 11 years and over.
Baseline cervical spinal cord mean diffusivity
Time Frame: Baseline
Mean diffusivity of the cervical portion of the spinal cord will be measured using diffusion tensor magnetic resonance imaging. Baseline cervical spinal cord mean diffusivity will be compared between the Friedreich ataxia and control groups. This measurement will be obtained for participants aged 11 years and over.
Slope of change in cervical spinal cord radial diffusivity
Time Frame: Baseline to 24 months
Radial diffusivity of the cervical portion of the spinal cord will be measured using diffusion tensor magnetic resonance imaging. The within-person slope of cervical spinal cord radial diffusivity over the three study visits will be estimated and compared between the Friedreich ataxia and control groups. This measurement will be obtained for participants aged 11 years and over.
Baseline cervical spinal cord fractional anisotropy
Time Frame: Baseline
Fractional anisotropy of the cervical portion of the spinal cord will be measured using diffusion tensor magnetic resonance imaging. Baseline cervical spinal cord fractional anisotropy will be compared between the Friedreich ataxia and control groups. This measurement will be obtained for participants aged 11 years and over.
Slope of change in cervical spinal cord mean diffusivity
Time Frame: Baseline to 24 months
Mean diffusivity of the cervical portion of the spinal cord will be measured using diffusion tensor magnetic resonance imaging. The within-person slope of cervical spinal cord mean diffusivity over the three study visits will be estimated and compared between the Friedreich ataxia and control groups. This measurement will be obtained for participants aged 11 years and over.
Slope of change in cervical spinal cord axial diffusivity
Time Frame: Baseline to 24 months
Axial diffusivity of the cervical portion of the spinal cord will be measured using diffusion tensor magnetic resonance imaging. The within-person slope of cervical spinal cord axial diffusivity over the three study visits will be estimated and compared between the Friedreich ataxia and control groups. This measurement will be obtained for participants aged 11 years and over.
Baseline cervical spine tNAA/mIns ratio
Time Frame: Baseline
The ratio of N-acetylaspartate (tNAA) and myo-inositol (mIns) within cervical spinal cord will be measured using sLASER magnetic resonance spectroscopy. The baseline tNAA/mIns ratio will be compared between the Friedreich ataxia and control groups. This measurement will be obtained for participants aged 11 years and over.
Slope of the cervical spine tNAA/mIns ratio
Time Frame: Baseline to 24 months
The ratio of N-acetylaspartate (tNAA) and myo-inositol (mIns) within cervical spinal cord will be measured using sLASER magnetic resonance spectroscopy. The within-person slope of the tNAA/mIns ratio over the three study visits will be estimated and compared between the Friedreich ataxia and control groups. This measurement will be obtained for participants aged 11 years and over.
Secondary Outcomes
- Upright Stability (US) score(Baseline to 24 months)
- 9 Hole Peg Test times(Baseline to 24 months)
- Junior Hayling Sentence Completion Test (Junior HSCT) scores(Baseline to 24 months)
- Revised Children's Anxiety and Depression scale (RCADS) scores(Baseline to 24 months)
- Speech analysis scores(Baseline to 24 months)
- Paediatric Cerebellar Cognitive Affective/Schmahmann Syndrome (CCAS) scale score(Baseline to 24 months)
- Modified Friedreich Ataxia Rating Scale (mFARS) score(Baseline to 24 months)
- Activities of Daily Living (ADL) score(Baseline to 24 months)
- Cerebellar Cognitive Affective/Schmahmann Syndrome (CCAS) scale score(Baseline to 24 months)
- Hayling Sentence Completion Test (HSCT) scores(Baseline to 24 months)
- Hospital Anxiety and Depression Scale (HADS) scores(Baseline to 24 months)
- Scale for the Assessment and Rating of Ataxia (SARA) score(Baseline to 24 months)
- Low-Contrast Sloan Letter Chart (LCSLC) test score(Baseline to 24 months)