Involvement of the thalamus in the progression of multiple sclerosis: A study of the musculus counterpart in Theiler's murine encephalomyelitis virus infection
Modica, Claire Michaella
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Multiple sclerosis (MS) has long been known as a disease of demyelination involving the white matter (WM), but atrophy of the gray matter (GM) is also seen in MS, and is associated with clinical symptoms of the disease. The thalamus in particular is area structure that undergoes atrophy and iron deposition in MS. The aim of this research was to investigate the role of the circuit traversing the structures of the cortex to the basal ganglia, then to the thalamus, returning back to the cortex (CxBGTh) in demyelinating disease. In order to examine the central nervous system (CNS) from the very onset of disease, an animal model of MS in which a genetically susceptible mouse in intracerebrally (IC) infected with Theiler’s Murine Encephalomyelitis Virus (TMEV), was examined with a 9.4T magnetic resonance imaging (MRI) longitudinally over the TMEV disease course. Tissue volume, tissue integrity, iron deposition, neurochemical composition, motor disability, and cognitive decline were measured. The longitudinal nature of the study allowed for investigation of disease progress within each subject in relation to its pre-disease baseline and helped to delineate temporal mechanisms of pathological progression in TMEV disease. Normal growth was observed in many structures, and atrophy or hydrocephaly may have led to increased lateral ventricle volume. Growth was not observed in the cortex, which was attributed to TMEV-related atrophy competing with growth. Developmental myelination was observed in the form of decreased susceptibility, though latter increase in susceptibility in the corpus callosum, combined with increased diffusivity, was attributed to demyelination and/or inflammation. Motor and cognitive ability both declined over time, exhibiting a pattern of acute and chronic infection-associated decline compared to saline-injected mice. Neurotransmitter differences suggested excitatory and inhibitory stimulation imbalance indicating possible excitotoxic conditions, while glucose and lactate changes suggested metabolic dysregulation. Several patterns of tissue change were associated with motor and clinical outcome. The effect of terflunomide therapy intervention on the TMEV disease course was investigated. Teriflunomide changed the excitatory and inhibitory conditions, decreasing potentially excitotoxic conditions, no patterns of tissue change were associated with motor outcome, and few patterns were associated with clinical outcome. The extent of contagiousness of the disease from live animal-to-live animal was assessed, and no examples were found.