Regional 9.4T MRI analysis of Theiler’s Murine Encephalomyelitis Viral infection, a model of MS
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Background: Multiple sclerosis (MS) is a complex demyelinating and neurodegenerative disease of the central nervous system (CNS). It is suggested that a putative cause could be a combination of viral exposure, environmental factors, and genetic heredity, which all contribute to disease susceptibility. Several animal models have been introduced in the last 50 years in order to elucidate these various pathogenic theories. Experimental Autoimmune Encephalomyelitis (EAE) is a murine model that induces an allergy to endogenous myelin protein resulting in an immune response similar to MS. EAE is often used to investigate immunological aspects of MS, but lacks in providing clarity to origins of demyelination. Theiler’s Murine Encephalomyelitis Viral (TMEV) infection is utilized to generate a viral induced immune response within the CNS. This coupled with murine genetic susceptibility results in a biphasic progressive demyelinating disease; closely resembling MS. MS disease progression is associated with demyelinating plaques, brain and spinal cord atrophy, cognitive decline, motor impairment, loss of tissue integrity, as well as iron accumulation within the deep gray matter (GM) regions of the CNS. Therefore, we attempted to investigate markers of pathology within specific brain regions in a longitudinal TMEV murine model, utilizing 9.4T magnetic resonance imaging (MRI) and behavioral measures. Objectives: We aimed to longitudinally characterize TMEV induced demyelinating disease, and quantify its region specific effect on tissue composition, volume, and behavioral output. Methods: We used a 9.4 T Bruker Biospec MRI scanner to measure volume and quantitative susceptibility mapping (QSM) in regions of interest (ROI) at 4 time points over 9 months, in 24 TMEV infected and 24 saline injected Swiss Jim Lambert (SJL) mice. Further, we performed Tmaze Continuous Alternation Task (TCAT) to test cognition, Rotamex Rotarod paradigm to quantify motor performance, and clinical monitoring to measure disease progression relative to saline controls. Results: TMEV infected mice presented gait abnormalities about 4-8weeks post injection (wPI), with a progressive hind limb paralysis over 39wPI. Clinical severity was associated with reductions in basal ganglia (BG), cortex (Cx), and thalamus (Th) volumes in TMEV infected mice. A decline in TMEV cohort motor performance was observed from 17-39wPI, while saline controls improved their performance. In addition, TCAT performance at the final time point was positively associated with overall change in the cerebellum (CB) and negatively with overall change in QSM in the BG of TMEV infected mice, suggesting that as CB volume declines and BG susceptibility increases, cognitive performance declines. Conclusions: TMEV infection in susceptible murine strains results in a degenerative disease resulting in regional specific pathology in the BG, Th, Cx, and CB that was associated with clinical severity, hind limb paralysis, motor performance decline, and cognitive dysfunction.