Spinal Cord MRI Reveals Clues to Pathology in Friedreich's Ataxia

Sherrie R. Webb, PA-C, for Medscape

April 27, 2022

The study covered in this summary was published on MedRxiv.org as a preprint and has not yet been peer reviewed.


Key Takeaways

  • This study lends support to the theory that Friedreich's ataxia (FRDA) affects certain motor and sensory pathways of the spinal cord through distinct mechanisms.

  • Abnormalities of the corticospinal tract, the major pathway for voluntary motor function, may have both developmental and degenerative origins. These abnormalities are present in early disease and progressively worsen with age and disease severity.

  • Alterations in the spinal dorsal column, which enables an individual to sense fine touch, position, vibration, and two-point differentiation, are developmental and typically remain stable over time.

  • Spinal cord MRI may be a suitable biomarker to track progression of FRDA.

Why This Matters

  • FRDA is a genetic, autosomal recessive disease that results in progressive neurologic dysfunction, and most commonly affects individuals in late childhood or adolescence. Previous neuroimaging studies with MRI and magnetic resonance spectroscopy have shown correlations between disease severity and spinal cord MRI metrics.

  • Previous studies from single centers, based on modest sample sizes, have been reported. This study is based upon larger sample sizes from an international collaboration, the ENIGMA-Ataxia working group.

  • This study assessed spinal cord eccentricity (a measure of anterior-posterior flattening), and spinal cord cross-sectional area (CSA) from C1 to C4 in patients with FRDA and in age- and sex-matched control subjects. Eccentricity is considered a surrogate MRI marker for dorsal column damage, such as can occur with certain sensory neuronopathies. CSA reduction can occur with either dorsal column or lateral column pathology, which is associated with certain motor diseases such as amyotrophic lateral sclerosis (Lou Gehrig's disease) or pure subtypes of hereditary spastic paraplegia. Findings are consistent with those of previous studies.

Study Design

  • Investigators conducted a retrospective, cross-sectional analysis of data from 256 patients across eight sites. All patients had molecular confirmation of FRDA. Patients were age- and sex-matched with 223 controls without ataxia. Clinical data and disease severity was documented for all FRDA patients.

  • High-resolution T1-weighted MRI of the brain and upper cervical spinal cord was obtained on all patients and control subjects. To measure cross-sectional area and eccentricity, investigators used the Spinal Cord Toolbox (version 4.2.2) software program.

  • In addition to the main analysis, investigators analyzed data for patients younger than age 18 years, and in those with late-onset Friedreich's ataxia (LOFA) defined as patients who developed symptoms after age 25 years, along with matched controls for both groups.

Key Results

  • Individuals with FRDA had significantly reduced spinal cross-sectional area (CSA) and significantly increased eccentricity at all C1-C4 vertebral levels compared with controls. Similar findings were seen in patients under age 18 years with FRDA.

  • Individuals with FRDA had a progressive decline in spinal CSA with increasing age, but in control subjects, spinal CSA remained stable over the lifespan.

  • Significant correlations were observed between disease severity and duration with spinal CSA (but not eccentricity) at all C1-C4 vertebral levels. In those with LOFA, disease severity was correlated with spinal CSA for the C1-C3 vertebrae.

  • Spinal CSA and eccentricity were abnormal in the earliest stages of disease compared with controls. CSA was significantly reduced in those with symptom duration of 10 years or greater, compared with those with symptom duration of 5 years of less. Eccentricity was stable regardless of symptom duration.

  • Abnormalities in CSA and eccentricity were observed in those with mild disease relative to controls. CSA was reduced in those with moderate or severe disease, relative to those with mild disease. In patients with mild-to-moderate disease, CSA was reduced only in C1 and C2, relative to those with mild disease. Eccentricity remained stable across subgroups of disease severity.


  • Because this is a cross-sectional study, results should be confirmed through prospective, longitudinal neuroimaging studies.

  • Use of T1-weighted brain MRI limits the evaluation to upper portions of the cervical spinal cord.

  • Different clinical scales were used at study sites.


  • This study was supported by the Friedreich's Ataxia Research Alliance, the São Paulo Research Foundation, the German Research Foundation, and the European Joint Programme on Rare Diseases. The methods of harmonization and multisite data alliance elements of the work were supported by a grant from NIH Big Data to Knowledge and grants from the Australian National Health and Medical Research Council.

  • Dr Marcondes França Jr was supported by grants from the National Institutes of Health. Dr Pierre-Gilles Henry and Dr Christophe Lenglet also acknowledge support from Game On for Autism Research (GoFAR), Ataxia UK, and the Bob Allison Ataxia Research Center.

  • Authors report the following potential conflicts of interest: Henry and Lenglet received research grants from Minoryx Therapeutics. Ludger Schöls served on an advisory board for VICO Therapeutics. Dr Paul Thompson, Dr Neda Jahanshad, and Dr Lenglet acknowledged research grants from Biogen, Inc unrelated to the topic of the manuscript. Dr Matthis Synofzik acknowledged receiving consultancy honoraria from Janssen Pharmaceuticals, Ionis Pharmaceuticals, and Orphazyme Pharmaceuticals, all unrelated to the manuscript.

This is a summary of a preprint research study, "Spinal cord damage in Friedreich's ataxia: Results from the ENIGMA-Ataxia," written by Thiago JR Rezende from University of Campinas, Brazil and colleagues on MedRxiv.org, provided to you by Medscape. This study has not yet been peer reviewed. The full text of the study can be found on MedRxiv.org.

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