Spinal cord gray matter atrophy is associated with disability in spinal muscular atrophy

Abstract

Background: With the approval of disease-modifying treatments for 5q-spinal muscular atrophy (SMA), there is an increasing need for biomarkers for disease course and therapeutic response monitoring. Radially sampled Averaged Magnetization Inversion Recovery Acquisitions (rAMIRA) MR-imaging enables spinal cord (SC) gray matter (GM) delineation and quantification in vivo. This study aims to assess SC GM atrophy in patients with 5q-SMA and its associations with clinical disability.

Methods: Twenty-one patients with 5q-SMA and twenty-one age- and sex-matched healthy controls (HCs) prospectively underwent 3 T axial 2D-rAMIRA MR-imaging at the intervertebral disc levels C2/C3-C5/C6 and T_max (lumbar enlargement level). Associations between SC GM areas with muscle strength tested by dynamometry, Motor Function Measure (MFM), revised upper limb module (RULM), Revised Hammersmith Scale (RHS), and SMA-Functional Rating Scale (SMA-FRS) were assessed by Spearman Rank correlations and linear regression analysis.

Results: Compared to HCs, patients had significantly reduced SC GM areas at levels C3/C4 (relative reduction (RR) = 13.6%, p < 0.0001); C4/C5 (RR = 16.7%, p < 0.0001), C5/C6 (RR = 17.1%, p < 0.0001), and T_max (RR = 17.4%, p < 0.0001). Significant correlations were found between cervical SC GM areas and muscle strength, RULM, MFM, RHS, and SMA-FRS. In linear regression analysis, GM area C3/C4 explained 33% of RHS variance.

Conclusion: SC GM atrophy is detectable in patients with 5q-SMA and is consistently associated with clinical measures of upper limb function, physiotherapeutic assessments, and SMA-FRS indicating the clinical relevance of the observed atrophy. Further longitudinal investigations are necessary next steps to evaluate this novel and easily applicable imaging marker as a potential disease course and therapeutic response marker.

Keywords: Magnetic resonance imaging; SMA; Spinal cord atrophy; Spinal cord imaging; Spinal muscular atrophy.

Fig. 1

Axial 2D rAMIRA imaging at the intervertebral disc levels C2/C3-C5C/6 and T_max (level of the lumbar enlargement) (axial in-plane resolution 0.5 × 0.5mm2, slice thickness 8 mm) of an SMA patient (19 years, female) (A1–A5) compared to her age- and sex-matched HC (B1–B5). C shows the T2 sagittal overview of the spinal cord with the planning of the axial images, which are acquired perpendicular to the cervical spinal cord

Fig. 2

Spinal cord gray matter area (GMA) (in mm²) and total cord area (TCA) (in mm²) in patients with SMA Type 2, 3a, 3b and healthy controls at the intervertebral disc levels C2/C3-C5/C6 and the level of the lumbar enlargement (T_max). Mean values are indicated as (─). Group differences (student’s t, all pairwise comparisons) are summarized as follows: p values < 0.05 are marked with *, p values < 0.01 with **, and p values < 0.001 with ***. Note that patients with SMA type 2 could not be imaged at T_max due to osteosynthesis material