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Updated: Jun 9, 2026
Comprehensive Autopsy Program for Individuals with Multiple Sclerosis
Published on: July 19, 2019
Brain atrophy correlates with functional outcome in a murine model of multiple sclerosis
I Pirko1, A J Johnson, Yi Chen
1Mayo Clinic, Department of Neurology, College of Medicine, Rochester, MN 55905, USA. pirko@mayo.edu
Abstract:
White matter (WM) lesions are the classic pathological hallmarks of multiple sclerosis (MS). However, MRI-based WM lesion load shows relatively poor correlation with functional outcome, resulting in the "clinico-radiological paradox" of MS. Unlike lesion based measures, volumetric MRI assessment of brain atrophy shows a strong correlation with functional outcome, and the presence of early atrophy predicts a worse disease course. While extensive literature exists describing MRI characteristics of atrophy in MS, the exact pathogenesis and the substrate of atrophy-gray vs. WM loss, axonal/neuronal damage vs. demyelination, or a combination of the above-remain unclear. Animal models of atrophy would allow for detailed investigations of the pathomechanism, and would contribute to an enhanced understanding of structural-functional connections in this complex disease. We now report that in the Theiler's Murine Encephalitis Virus (TMEV) model of MS in SJL/J mice, significant brain atrophy accompanies the development of the progressive MS-like disease. We conducted volumetric MRI studies in 8 cases and 4 age, gender- and strain-matched control mice. While in controls we did not detect any brain atrophy, significant atrophy developed as early as 3 months into the disease course, and reached its peak by 6 months, resulting in ventricular enlargement by 118% (p=0.00003). A strong correlation (r=-0.88) between atrophy and disability, as assessed by rotarod assay, was also demonstrated. We earlier reported another neurodegenerative feature in this model, the presence of deep gray matter T2 hypointensity in thalamic nuclei. Future studies utilizing this model will allow us to investigate key components of MRI detectable neurodegenerative feature development, their tissue correlations and associations with functional outcome measures. These studies are expected to pave the way to a better understanding of the substrate of disability in MS models.
Insights
Brain atrophy in a multiple sclerosis (MS) mouse model correlates with disability. This model helps study neurodegeneration and its link to functional decline in MS.
Area of Science:
- Neuroscience
- Immunology
- Radiology
Background:
- Multiple sclerosis (MS) is characterized by white matter (WM) lesions, but lesion load poorly correlates with functional deficits.
- Brain atrophy, assessed by volumetric MRI, strongly correlates with MS functional outcomes and predicts disease progression.
- The precise mechanisms and tissue basis of MS-related atrophy remain incompletely understood.
Purpose of the Study:
- To investigate brain atrophy in an animal model of MS.
- To explore the relationship between atrophy and functional disability in this model.
- To establish a model for studying the pathomechanisms of neurodegeneration in MS.
Main Methods:
- Volumetric MRI was used to assess brain atrophy in Theiler's Murine Encephalitis Virus (TMEV)-infected SJL/J mice (a model for MS).
- Studies included 8 infected mice and 4 age-, gender-, and strain-matched controls.
- Disability was assessed using the rotarod assay.
Main Results:
- Significant brain atrophy developed in TMEV-infected mice by 3 months post-infection, peaking at 6 months.
- Ventricular enlargement reached 118% in affected mice compared to controls (p=0.00003).
- A strong negative correlation (r=-0.88) was observed between brain atrophy and rotarod performance.
Conclusions:
- The TMEV mouse model exhibits progressive brain atrophy that correlates with functional disability.
- This model provides a platform for investigating the development of MRI-detectable neurodegenerative features in MS.
- Further studies using this model can elucidate the substrate of disability in MS.
