Abstract
BackgroundPathology of gray matter is associated with development of physical and cognitive disability in patients with multiple sclerosis. In particular, glutamatergic dysregulation in the cortex-basal ganglia-thalamus (CxBGTh) circuit could be associated with decline in these behaviors.ObjectivesTo investigate the effect of an immunomodulatory therapy (teriflunomide, Aubagio®) on changes of the CxBGTh loop in the Theiler’s Murine Encephalomyelitis Virus, (TMEV) mouse model of MS.MethodsForty-eight (48) mice were infected with TMEV, treated with teriflunomide (24) or control vehicle (24) and followed for 39 weeks. Mice were examined with MRS and volumetric MRI scans (0, 8, 26, and 39 weeks) in the cortex, basal ganglia and thalamus, using a 9.4T scanner, and with behavioral tests (0, 4, 8, 12, 17, 26, and 39 weeks). Within conditions, MRI measures were compared between two time points by paired samples t-test and across multiple time points by repeated measures ANOVA (rmANOVA), and between conditions by independent samples t-test and rmANOVA, respectively. Data were considered as significant at the p<0.01 level and as a trend at p<0.05 level.ResultsIn the thalamus, the teriflunomide arm exhibited trends toward decreased glutamate levels at 8 and 26 weeks compared to the control arm (p = 0.039 and p = 0.026), while the control arm exhibited a trend toward increased glutamate between 0 to 8 weeks (p = 0.045). In the basal ganglia, the teriflunomide arm exhibited a trend toward decreased glutamate earlier than the control arm, from 0 to 8 weeks (p = 0.011), resulting in decreased glutamate compared to the control arm at 8 weeks (p = 0.016).ConclusionsTeriflunomide may reduce possible excitotoxicity in the thalamus and basal ganglia by lowering glutamate levels.
Highlights
The teriflunomide arm exhibited trends toward decreased glutamate levels at 8 and 26 weeks compared to the control arm (p = 0.039 and p = 0.026), while the control arm exhibited a trend toward increased glutamate between 0 to 8 weeks (p = 0.045)
The teriflunomide arm exhibited a trend toward decreased glutamate earlier than the control arm, from 0 to 8 weeks (p = 0.011), resulting in decreased glutamate compared to the control arm at 8 weeks (p = 0.016)
Multiple Sclerosis (MS) is a disease characterized by neurological disability [1] and cognitive dysfunction, [2] traditionally characterized by areas of demyelination and inflammation and brain atrophy. [3, 4] In particular, gray matter (GM) atrophy is associated with cognitive impairment, [5] and has a stronger relationship with disease progression and disability than white matter (WM) atrophy
Summary
Multiple Sclerosis (MS) is a disease characterized by neurological disability [1] and cognitive dysfunction, [2] traditionally characterized by areas of demyelination and inflammation and brain atrophy. [3, 4] In particular, gray matter (GM) atrophy is associated with cognitive impairment, [5] and has a stronger relationship with disease progression and disability than white matter (WM) atrophy. [6] The understanding of the role of the thalamus in MS has gained increasing interest, [3] as its volume reduction correlates with cognitive impairment [7, 8] and fatigue. [9]These observations lead to the question of whether disparate GM regions connected by WM tracts could be pathologically affecting one another. Multiple Sclerosis (MS) is a disease characterized by neurological disability [1] and cognitive dysfunction, [2] traditionally characterized by areas of demyelination and inflammation and brain atrophy. Considering that apoptotic neurons are significantly increased in demyelinated cortex in MS, [12] the meninges may be involved in the pathological process which affects GM, suggesting the cortex may be one of the first GM structures involved in the disease initiation. The cortex-basal ganglia-thalamus (CxBGTh) loop (Fig 1) is crucially influential for motor, cognitive, and affective behaviors. [21] dysregulated glutamate within the CxBGTh loop could lead to parallel and/or exacerbating pathology within structures in this circuit in MS patients. Glutamatergic dysregulation in the cortexbasal ganglia-thalamus (CxBGTh) circuit could be associated with decline in these behaviors
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