Progressive Spinal Cord Degeneration in Friedreich's Ataxia: Results from ENIGMA-Ataxia

Abstract

Background: Spinal cord damage is a hallmark of Friedreich's ataxia (FRDA), but its progression and clinical correlates remain unclear.

Objective: The objective of this study was to perform a characterization of cervical spinal cord structural damage in a large multisite FRDA cohort.

Methods: We performed a cross-sectional analysis of cervical spinal cord (C1-C4) cross-sectional area (CSA) and eccentricity using magnetic resonance imaging data from eight sites within the ENIGMA-Ataxia initiative, including 256 individuals with FRDA and 223 age- and sex-matched control subjects. Correlations and subgroup analyses within the FRDA cohort were undertaken based on disease duration, ataxia severity, and onset age.

Results: Individuals with FRDA, relative to control subjects, had significantly reduced CSA at all examined levels, with large effect sizes (d > 2.1) and significant correlations with disease severity (r < -0.4). Similarly, we found significantly increased eccentricity (d > 1.2), but without significant clinical correlations. Subgroup analyses showed that CSA and eccentricity are abnormal at all disease stages. However, although CSA appears to decrease progressively, eccentricity remains stable over time.

Conclusions: Previous research has shown that increased eccentricity reflects dorsal column (DC) damage, while decreased CSA reflects either DC or corticospinal tract (CST) damage, or both. Hence our data support the hypothesis that damage to the DC and damage to CST follow distinct courses in FRDA: developmental abnormalities likely define the DC, while CST alterations may be both developmental and degenerative. These results provide new insights about FRDA pathogenesis and indicate that CSA of the cervical spinal cord should be investigated further as a potential biomarker of disease progression. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords: ENIGMA-ataxia; Friedreich's ataxia; MRI; SCT; spinal cord.

FIG 1

Study design and imaging processing pipeline. For healthy control subject numbers, see Supporting Information Table S S1. N is the number of patients with Friedreich's ataxia (FRDA) enrolled by each site, and C1, C2, C3, and C4 are the sample sizes available for each vertebral level assessed. SCT, Spinal Cord Toolbox. [Color figure can be viewed at wileyonlinelibrary.com]

FIG 2

Boxplots displaying group differences at each spinal cord segment, C1 to C4, for the total cohort. (A) All patients with Friedreich's ataxia (FRDA) versus all matched control subjects. (B) Children (age < 18 years) with FRDA versus matched control subjects. (C) Individuals with late‐onset Friedreich ataxia (LOFA) versus matched control subjects. CSA, cross‐sectional area. [Color figure can be viewed at wileyonlinelibrary.com]

FIG 3

(A) Plot of spinal cord cross‐sectional area (CSA) versus age in patients and control subjects for all assessed vertebral levels. (B) Significant correlations between normalized disease severity and CSA in individuals with Friedreich's ataxia (FRDA) at vertebral levels C1, C2, C3, and C4. [Color figure can be viewed at wileyonlinelibrary.com]

FIG 4

Results showing the progressive atrophy of the cervical spinal cord area (cross‐sectional area [CSA]) (A, B) and eccentricity (C, D) in participants with Friedreich's ataxia (FRDA) and healthy control subjects. (A, C) Subgroups based on disease duration (DD). (B, D) Subgroups based on disease severity (DS). To the healthy control subjects, the measures represent the mean cervical spinal cord area or eccentricity; error bars represent standard error of the mean. Subgroups are based on disease duration: DD1, time from ataxia onset <5 years; DD2, time from ataxia onset between 5 and 10 years; DD3, time from ataxia onset between 10 and 15 years; DD4, time from ataxia onset between 15 and 20 years; DD5, time from ataxia onset >20 years. Subgroups are based on disease severity: DS1, normalized disease severity <0.25; DS2, normalized disease severity between 0.26 and 0.50; DS3, normalized disease severity between 0.51 and 0.75; DS4, normalized disease severity >0.75. [Color figure can be viewed at wileyonlinelibrary.com]