Brain MRI detects early-stage alterations and disease progression in Friedreich ataxia

Isaac M. Adanyeguh, James M. Joers, Dinesh K. Deelchand, Diane H. Hutter, Lynn E. Eberly, Bin Guo, Isabelle Iltis, Khalaf O. Bushara, Pierre Gilles Henry, Christophe Lenglet

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Friedreich ataxia is a progressive neurodegenerative disorder characterized by cerebellar and spinal atrophy. However, studies to elucidate the longitudinal progression of the pathology in the brain are somewhat inconsistent and limited, especially for early-stage Friedreich ataxia. Using a multimodal neuroimaging protocol, combined with advanced analysis methods, we sought to identify macrostructural and microstructural alterations in the brain of patients with early-stage Friedreich ataxia to better understand its distribution patterns and progression. We enrolled 28 patients with Friedreich ataxia and 20 age- and gender-matched controls. Longitudinal clinical and imaging data were collected in the patients at baseline, 12, 24 and 36 months. Macrostructural differences were observed in patients with Friedreich ataxia, compared to controls, including lower volume of the cerebellar white matter (but not cerebellar grey matter), superior cerebellar peduncle, thalamus and brainstem structures, and higher volume of the fourth ventricle. Diffusion tensor imaging and fixel-based analysis metrics also showed microstructural differences in several brain regions, especially in the cerebellum and corticospinal tract. Over time, many of these macrostructural and microstructural alterations progressed, especially cerebellar grey and white matter volumes, and microstructure of the superior cerebellar peduncle, posterior limb of the internal capsule and superior corona radiata. In addition, linear regressions showed significant associations between many of those imaging metrics and clinical scales. This study provides evidence of early-stage macrostructural and microstructural alterations and of progression over time in the brain in Friedreich ataxia. Moreover, it allows to non-invasively map such brain alterations over a longer period (3 years) than any previous study, and identifies several brain regions with significant involvement in the disease progression besides the cerebellum. We show that fixel-based analysis of diffusion MRI data is particularly sensitive to longitudinal change in the cerebellar peduncles, as well as motor and sensory white matter tracts. In combination with other morphometric measures, they may therefore provide sensitive imaging biomarkers of disease progression for clinical trials.

Original languageEnglish (US)
Article numberfcad196
JournalBrain Communications
Issue number4
StatePublished - 2023

Bibliographical note

Funding Information:
This work was supported primarily by the Friedreich’s Ataxia Research Alliance (FARA), with additional support from Ataxia UK, Go Friedreich’s Ataxia Research (GoFAR), the CureFA Foundation and the Bob Allison Ataxia Research Center (BAARC). The Center for Magnetic Resonance Research is supported by National Institutes of Health grants P41EB027061 and P30NS076408. The 3 Tesla scanner upgrade was funded in part by National Institutes of Health instrumentation grant 1S10OD017974.

Funding Information:
C.L. and P.G.H. received research grants from Minoryx Therapeutics. All other authors report no competing interests.

Publisher Copyright:
© 2023 The Author(s). Published by Oxford University Press on behalf of the Guarantors of Brain.


  • diffusion imaging
  • fixel-based analysis
  • imaging biomarkers
  • longitudinal imaging
  • magnetic resonance imaging

Center for Magnetic Resonance Research (CMRR) tags

  • ANDI
  • BFC

PubMed: MeSH publication types

  • Journal Article


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