Correlation of Brain Atrophy, Disability, and Spinal Cord Atrophy in a Murine Model of Multiple Sclerosis

Abstract

Background: Disability progression in multiple sclerosis (MS) remains incompletely understood. Unlike lesional measures, central nervous system atrophy has a strong correlation with disability. Theiler's murine encephalomyelitis virus infection in SJL/J mice is an established model of progressive MS. We utilized in vivo MRI to quantify brain and spinal cord atrophy in this model and analyzed the temporal relationship between atrophy and disability.

Methods: Infected and control mice were followed for 12 months. Disability was assessed periodically using rotarod assay. Volumetric MRI datasets were acquired at 7 Tesla. Ventricular volume and C4-5 spinal cord cross-sectional area measurements were performed using Analyze 10.

Results: At 3 months, brain atrophy reached statistical significance (P = .005). In contrast, disability did not differ until 4 months post-infection (P = .0005). Cord atrophy reached significance by 9 months (P = 0.009). By 12 months, brain atrophy resulted in 111.8% increased ventricular volume (P = .00003), while spinal cord cross-sectional area was 25.6% reduced (P = .001) among cases.

Conclusions: Our results suggest that significant brain atrophy precedes and predicts the development of disability, while spinal cord atrophy occurs late and correlates with severe disability. The observed temporal relationship establishes a framework for mechanisms of disability progression and enables further investigations of their underlying substrate.

Keywords: Multiple sclerosis; atrophy; disability; magnetic resonance imaging.

Figure 1. MRI assessed CNS atrophy

Lateral ventricular volume increased from disease onset and peaked by six months post infection in TMEV infected SJL mice (A), but remained stable in controls (B). Spinal cord atrophy worsened from six months through twelve months post infection (C), but remained stable in controls (D).

Figure 2. Disability and CNS atrophy

Brain and spinal cord atrophy were assessed by ventricular volume and spinal cord cross-sectional area, respectively. Functional disability was assessed by rotarod assay. Comparing TMEV infected SJL mice to controls, brain atrophy increased from disease onset and peaked by six months post infection (A). Spinal cord atrophy worsened from six months through twelve months post infection (B). Functional disability was apparent by four months post infection with continued worsening through twelve months (C).

Figure 3. Correlation

Pearson Product Moment Correlation was used to assess dependence. Brain atrophy showed a significant and strong negative correlation with functional disability throughout the observation period (A). Spinal cord atrophy showed a strong correlation with functional disability from months six through twelve (B). Brain atrophy from zero through six months showed a strong correlation with spinal cord atrophy from six through twelve months (C).