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Observational Study
. 2025 Aug;98(2):386-397.
doi: 10.1002/ana.27237. Epub 2025 Mar 22.

Neuroimaging Biomarkers for Friedreich Ataxia: A Cross-Sectional Analysis of the TRACK-FA Study

Nellie Georgiou-Karistianis  1 , Louise A Corben  1   2   3 , Eric F Lock  4 , Helena Bujalka  1 , Isaac Adanyeguh  5 , Manuela Corti  6 , Dinesh K Deelchand  5 , Martin B Delatycki  1   2   3   7 , Imis Dogan  8   9 , Jennifer Farmer  10 , Marcondes C França Jr  11 , Anthony S Gabay  12 , William Gaetz  13 , Ian H Harding  14 , James Joers  5 , Michelle A Lax  12 , Jiakun Li  4 , David R Lynch  15 , Thomas H Mareci  16 , Alberto R M Martinez  11 , Massimo Pandolfo  17 , Marina Papoutsi  12 , Richard G Parker  12 , Kathrin Reetz  8   9 , Thiago J R Rezende  11 , Timothy P Roberts  13 , Sandro Romanzetti  8   9 , David A Rudko  17   18   19 , Susmita Saha  1 , Jörg B Schulz  8   9 , Sub H Subramony  20 , Veena G Supramaniam  12 , Christophe Lenglet  5 , Pierre-Gilles Henry  5
Affiliations
Observational Study

Neuroimaging Biomarkers for Friedreich Ataxia: A Cross-Sectional Analysis of the TRACK-FA Study

Nellie Georgiou-Karistianis et al. Ann Neurol. 2025 Aug.

Abstract

Objective: We aimed to quantify differences in the brain and spinal cord between Friedreich ataxia and controls, stratified by age and disease stage, including for the first time in young children.

Methods: TRACK-FA is the largest prospective, longitudinal, multi-modal neuroimaging study in Friedreich ataxia to date. We assessed individuals with Friedreich ataxia and controls, 5 to 42 years, at 7 sites across 4 continents. The 17 imaging primary outcome measures (POMs) were selected from metrics that showed a significant longitudinal change in previous small-scale studies. These included brain and spinal cord morphometry (structural magnetic resonance imaging [MRI]) and microstructure (diffusion MRI); brain iron levels (quantitative susceptibility mapping); and spinal cord biochemistry (magnetic resonance spectroscopy). This study is registered with ClinicalTrials.gov (NCT04349514).

Results: Between February 2021 and August 2023, we assessed 169 individuals with Friedreich ataxia and 95 controls. Compared to controls, individuals with Friedreich ataxia had lower volume of dentate nucleus and superior cerebellar peduncles; smaller cross-sectional area of spinal cord; lower fractional anisotropy and higher diffusivity in spinal cord and superior cerebellar peduncles; and lower total N-acetyl-aspartate/myo-inositol ratio in spinal cord. Morphometric differences in spinal cord and superior cerebellar peduncles increased dramatically with age during childhood, with rapid development in controls, but not in Friedreich ataxia. Many imaging POMs showed significant associations with clinical severity.

Interpretation: Our findings provide strong imaging evidence of impaired development of spinal cord and superior cerebellar peduncles during childhood in Friedreich ataxia and open the way for the use of neuroimaging biomarkers in clinical trials. ANN NEUROL 2025;98:386-397.

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Conflict of interest statement

J.F. is an employee of the FARA, a funder of the study reported here; FARA has received funding from Takeda, PTC Therapeutics, Novartis Gene Therapies, IXICO Technologies and Larimar Therapeutics for the TRACK‐FA study reported in this publication. M.Pap., M.A.L., R.G.P., V.G.S., and A.S.G. are full‐time employees of IXICO, a contract research organization for the study reported here. All other authors declare no conflicts of interests.

Figures

FIGURE 1
FIGURE 1
Boxplots of select primary outcome measures by Friedreich ataxia status and functional staging score. [Color figure can be viewed at www.annalsofneurology.org]
FIGURE 2
FIGURE 2
Non‐linear trends for Friedreich ataxia and control by age, with p‐value for an interaction between Friedreich ataxia status and age obtained via permutation testing. [Color figure can be viewed at www.annalsofneurology.org]
See this image and copyright information in PMC

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