Objective: – To identify structural CNS changes associated with Friedreich’s ataxia (FRDA).

– To characterize their longitudinal progression.

Background: Friedreich’s ataxia (FRDA), the most common inherited ataxia, is caused by biallelic GAA expansions in the FXN gene, leading to frataxin deficiency, mitochondrial dysfunction, and neuronal loss. MRI has shown macrostructural and microstructural abnormalities in FRDA, but longitudinal studies remain limited.

Method: Twenty-four genetically confirmed FRDA patients and 24 age- and sex-matched healthy controls (heterozygous carriers) were included. Mean age was 35.9 years in patients and 37.2 years in controls. In the FRDA group, mean age at onset was 20.5 years and mean disease duration was 15.8 years. Participants underwent three brain and cervical spinal cord MRI assessments: baseline (2021), first follow-up (2023), and second follow-up (2025), all acquired on the same 3T scanner. The protocol included 3D T1-weighted brain imaging, T2-weighted imaging of the upper cervical spinal cord, and 64-direction DTI (b = 1300 s/mm²). T1 images were processed with FreeSurfer, T2 images were segmented at C2–C3, and diffusion data were reconstructed in DSI Studio. A total of 22 participants were lost to follow-up.

Results: Cross-sectional analysis demonstrated significantly lower cerebellar hemispheric white matter, brainstem, and thalamic volumes in FRDA patients, together with reduced cervical spinal cord volume, area, and diameters (p = 0.0001–0.0006). DTI revealed significant microstructural abnormalities, most notably reduced FA in the superior cerebellar peduncles (p = 2.8 × 10⁻11) and spinal cord (p = 0.00001), but also in the corticospinal and corticopontine tracts and cerebellar white matter. Longitudinally, no changes reached statistical significance, although patients consistently exhibited lower structural measures at all time points. In the longitudinal DTI analysis, patients showed a greater decline in FA and increase in MD over time in the superior cerebellar peduncles.

Conclusion: • FRDA is associated with structural and diffusion MRI abnormalities in the cerebellar pathways, brainstem, thalami, and cervical spinal cord.

• Cross-sectional MRI measures and FA in the superior cerebellar peduncles, appear to be sensitive markers of disease-related damage.

• Multimodal MRI may provide useful biomarkers for tracking disease burden and progression in FRDA.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/cross-sectional-and-longitudinal-mri-biomarkers-of-neurodegeneration-in-friedreichs-ataxia/