CSA Spinal Cord Damage Identified as Potential Biomarker of Friedreich Ataxia Disease Progression


A study on patients with Friedreich ataxia showed that cervical spinal cord cross-sectional area is a potential biomarker for disease progression, particularly at C1 level.

Thiago J.R. Rezende, PhD, a research associate at the University of Campinas

Thiago J.R. Rezende, PhD

In a recently published study assessing cervical spinal cord damage of patients with Friedreich ataxia (FA), findings showed that cross-sectional area (CSA) and eccentricity were abnormal at all disease stages; however, although CSA appears to disease progressively, while eccentricity remained stable over time.1

Above all, these data point to the potential of CSA in the cervical spinal cord as a biomarker of disease progression in FA as well as support the hypothesis that damage to the spinal dorsal column and corticospinal tract follow distinct courses in the disease: developmental stage likely defines the former, while alterations in the latter may be both developmental and degenerative in origin.

Led by Thiago J.R. Rezende, PhD, a research associate at the University of Campinas, the cross-sectional analysis featured 256 patients with FA and 223 age- and sex-matched controls. The study assessed cervical spinal cords using high-resolution T1-weighted MRIs covering the brain and upper cervical vertebrae acquired on 3T clinical scanners with spatial resolution not inferior to 1 mm isotropic. Investigators evaluated between-group differences in CSA and eccentricity at each vertebral level from C1 to C4 using analyses of covariance with age, sex, and site as covariates of no interest.

In comparison with controls, patients with FA had significantly reduced CSA at all vertebral levels with very large ESs (C1 ES = 2.6; C2 ES = 2.6; C3 ES = 2.3; C4 ES = 2.1). While less significant, investigators also observed increased eccentricity at all vertebral levels (C1 ES = 1.2, C2 ES = 1.4, C3 ES = 1.3, C4 ES = 1.4) for patients with FA. Notably, when looking at the spinal cord growth curve over time, CSA appeared to be stable in controls (C1: r = −0.050, P = 0.999; C2: r = −0.045, P = 0.999; C3: r = −0.068, P = 0.999; C4: r = −0.039, P = 0.999) whereas it showed progressive decline with age among patients with FA (C1: r = −0.247, P < 0.001; C2: r = −0.216, P = 0.003; C3: r = −0.227, P = 0.002; C4: r = −0.244, P = 0.006).

"From a clinical perspective, our data indicate that CSA at C1 level is a potential biomarker candidate because it showed the highest correlation coefficient with disease severity and the highest ES compared with control subjects," Rezende et al wrote.1 "CSA at C1 level also had the highest ES in a recent single-site longitudinal study. However, this may not be the case for all FRDA stages or subphenotypes. For the pediatric cohort (age < 18 years), we did not find any significant correlations between CSA and normalized disease severity, whereas such associations were evident in the adult cohort."

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Additional findings showed signification correlations between the normalized disease severity or ataxia duration and CSA at all vertebral levels assessed after Bonferroni adjustment for multiple comparisons (normalized disease severity—C1: r = −0.424, P < 0.001; C2: r = −0.395, P < 0.001; C3: r = −0.399, P < 0.001; C4: r = −0.435, P < 0.001; ataxia duration—C1: r = −0.174, P = 0.006; C2: r = −0.146, P = 0.044; C3: r = −0.164, P = 0.026; C4: r = −0.237, P = 0.004). Investigators did not observe any significant correlations between eccentricity and normalized disease severity or ataxia duration.

In an analysis of clinical subtypes, children with FA demonstrated abnormal CSA and eccentricity when compared with matched nonataxic controls (CSA: C1 ES = 1.7, C2 ES = 2.1, C3 ES = 2.0, C4 ES = 2.1; eccentricity: C1 ES = 1.3, C2 ES = 1.8, C3 ES = 1.8, C4 ES = 1.5); however, differences relative to adults with FA did not reach statistical significant. In addition, CSA and eccentricity were found to be abnormal in the earliest stages of the disease, but tailed off in different directions over time. At 10-15 years postsymptom duration, 15-20 years duration, and 20+ years duration were compared with the earliest stages (<5 years duration), CSA was reduced at all vertebral levels whereas eccentricity remained stable across all subgroups.

Similar findings were observed in terms of disease severity. Abnormalities in CSA and eccentricity were observed in those with normalized disease severity, considered <0.25. Despite this, investigators observed significantly reduced CSA when comparing normalized disease severity of 0.51-0.75 and severity greater than 0.75 with those with DS1 (severity <0.25). Meanwhile, DS2 (severity 0.26-0.50) showed reduced CSA, relative to DS1, for only C1 and C2; eccentricity remained stable across the subgroups.

1. Rezende TJR, Adanyeguh IM, Arrigoni F, et al. Progressive spinal cord degeneration in Friedreich’s ataxia: results from ENIGMA-Ataxia. Mov Disord. 2023;38(1):45-56. doi:10.1002/mds.29261

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