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Longitudinal structural brain changes in Friedreich ataxia depend on disease severity: the IMAGE-FRDA study

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Abstract

Background

Friedreich ataxia is an inherited neurodegenerative disease, with cerebral and cerebellar pathology evident. Despite an increased understanding of its neuropathology, disease progression in this disease remains poorly understood. This study aimed to characterise longitudinal change in brain structure using a multi-modal approach across cerebral and cerebellar grey and white matter.

Methods

T1-weighted, diffusion-tensor, and magnetisation transfer magnetic resonance images were obtained from 28 individuals with Friedreich ataxia and 29 age- and gender-matched controls at two time-points, 2 years apart. Region-of-interest and exploratory between-group comparisons assessed changes in brain macrostructure (cerebellar lobule volume, cerebral cortical thickness/gyrification, brain white matter volume) and microstructure (white matter fractional anisotropy, mean/axial/radial diffusivity, magnetisation transfer ratio). Rates of change were correlated against change in neurological severity, Time 1 severity, and onset age.

Results

Individuals with Friedreich ataxia had a greater rate of white matter volume loss than controls in the superior cerebellar peduncles and right peri-thalamic/posterior cerebral regions, and greater reduction in left primary motor cortex gyrification. Greater cerebellar/brainstem white matter volume loss and right dorsal premotor gyrification loss was observed amongst individuals with less severe neurological symptoms at Time 1. Conversely, cerebral atrophy and changes in axial diffusivity were observed in individuals with more severe Time 1 symptoms. Progression in radial diffusivity was more pronounced amongst individuals with earlier disease onset. Greater right ventral premotor gyrification loss correlated with greater neurological progression.

Conclusion

Heterogeneity in Friedreich ataxia progression is observed at the neurobiological level, with evidence of earlier cerebellar and later cerebral degeneration.

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Availability of data and material

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy and ethical restrictions.

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Acknowledgements

The authors thank the individuals with Friedreich ataxia and the control participants who took part in the study, and Monique Stagnitti for participant recruitment and scanning.

Funding

The IMAGE-FRDA study was funded by the Australian National Health and Medical Research Council (Project Grant 1046037).

Author information

Author notes

  1. Ian H. Harding and Louise A. Corben contributed equally to the work.

Authors and Affiliations

  1. School of Psychological Sciences and Turner Institute for Brain and Mental Health, Monash University, Clayton Campus, Clayton, VIC, 3800, Australia

    Louisa P. Selvadurai, Nellie Georgiou-Karistianis, Rosita Shishegar, Cathlin Sheridan, Gary F. Egan & Louise A. Corben

  2. The Australian E-Health Research Centre, CSIRO, Melbourne, Australia

    Rosita Shishegar

  3. Monash Biomedical Imaging, Monash University, Clayton, Australia

    Gary F. Egan & Ian H. Harding

  4. Bruce Lefroy Centre for Genetic Health Research, Murdoch Children’s Research Institute, Parkville, Australia

    Martin B. Delatycki & Louise A. Corben

  5. Department of Paediatrics, The University of Melbourne, Parkville, Australia

    Martin B. Delatycki & Louise A. Corben

  6. Victorian Clinical Genetics Services, Parkville, Australia

    Martin B. Delatycki

  7. Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Australia

    Ian H. Harding

Authors
  1. Louisa P. Selvadurai
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  2. Nellie Georgiou-Karistianis
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  4. Cathlin Sheridan
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  8. Louise A. Corben
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Contributions

Study conception and design were conducted by NG-K, GFE, MBD, and LAC. Data processing and statistical analyses were conducted by LPS, RS, and IHH. Additional data processing was conducted by CS. The first draft of the manuscript was written by LPS and all authors reviewed, critiqued, and edited subsequent versions of the manuscript. All authors approved the final manuscript.

Corresponding author

Correspondence to Nellie Georgiou-Karistianis.

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On behalf of all authors, the corresponding author states that there is no conflict of interest.

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Selvadurai, L.P., Georgiou-Karistianis, N., Shishegar, R. et al. Longitudinal structural brain changes in Friedreich ataxia depend on disease severity: the IMAGE-FRDA study. J Neurol 268, 4178–4189 (2021). https://doi.org/10.1007/s00415-021-10512-x

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  • DOI: https://doi.org/10.1007/s00415-021-10512-x

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