Effect of dimethyl fumarate on gray and white matter pathology in subjects with relapsing multiple sclerosis: a longitudinal study.

BACKGROUND AND PURPOSE: Dimethyl fumarate (DMF) is an oral treatment for relapsing-remitting multiple sclerosis (MS) with anti-inflammatory and possible neuroprotective properties. Its effect on white matter and gray matter pathology is still not fully understood. The aim of the study was to characterize the effect of DMF on normal-appearing white matter (NAWM) and thalamic pathology longitudinally. METHODS: In this observational, longitudinal, 24-month magnetic resonance imaging study, 75 patients with relapsing-remitting MS treated with DMF and 40 age- and sex-matched healthy individuals were enrolled. Regional diffusion tensor imaging metrics and tract-based spatial statistics analyses were used to assess differences between groups. Mean diffusivity, axial diffusivity, radial diffusivity and fractional anisotropy were measured in the thalamus and NAWM. Baseline differences and changes over time were evaluated within and between study groups. RESULTS: At baseline, patients with MS showed significantly increased diffusivity and decreased fractional anisotropy in the thalamus (P < 0.001 for mean diffusivity, axial diffusivity and radial diffusivity) and NAWM (all P < 0.016) compared with healthy individuals. No significant within-group difference was found in diffusion tensor imaging measures over 24 months in either group. Healthy individuals showed a significantly greater rate of increased diffusivity parameters in the thalamus and NAWM compared with patients with MS, over 24 months (P < 0.05). CONCLUSIONS: The lack of changes in diffusion tensor imaging metrics in patients with MS over 24 months possibly indicates a neuroprotective role of DMF. These findings provide additional evidence of the beneficial effect of DMF on MS-related pathology.

Retinal nerve fiber layer thickness and thalamus pathology in multiple sclerosis patients.

BACKGROUND AND PURPOSE: Visual impairments are frequent in multiple sclerosis (MS). Optic neuritis can directly reduce retinal nerve fiber layer (RNFL) thickness. Our objectives were to evaluate associations of the RNFL thickness (RNFLT) of MS patients with magnetic resonance imaging (MRI) measures of regional brain atrophy and tissue injury in the post-chiasmatic deep gray matter (GM) section of the visual pathway. METHODS: Retinal nerve fiber layer thickness was measured using optical coherence tomography (OCT) in 96 relapsing-remitting MS (RR-MS) patients and 46 controls. MRI was obtained within ±3 months of OCT. RNFLT associations with MRI measures from diffusion tensor imaging and regional and tissue specific atrophy were assessed. RESULTS: In RR-MS, lower RNFLT was associated with lower white matter volume and lower whole brain volume. Lower RNFLT was associated with lower total deep gray matter volume and lower thalamus volume. Lower RNFLT was associated with greater mean diffusivity (MD) in normal appearing (NA) brain tissue and NA gray matter. Trends were found for lower RNFLT with greater MD in NA white matter and thalamus. RNFLT in controls was not associated with MD. CONCLUSIONS: Lower RNFLT is associated with microscopic tissue injury in NA regions of the brain and with neurodegeneration of the deep gray matter and thalamus in RR-MS.

Memory impairment in multiple sclerosis: correlation with deep grey matter and mesial temporal atrophy.

BACKGROUND: MRI research in multiple sclerosis (MS) samples reveals pathology in both the cerebral cortex and deep grey matter (DGM). The classical subcortical dementia hypothesis has been ascribed to MS and is supported by studies highlighting the role of thalamic atrophy in neuropsychological outcomes. However, the importance of mesial temporal lobe (MTL) atrophy in MS is largely untested and poorly understood. New structural imaging techniques permit volumetric measures of multiple regions within the MTL lobe and DGM. OBJECTIVE: To determine the relative importance of MTL and DGM structures in predicting MS performance on memory tests presented in the auditory/verbal and visual/spatial spheres. METHODS: Cross sectional analysis of 50 patients with MS undergoing structural brain MRI and neuropsychological testing. Using Freesurfer software, the volumes of the MTL (hippocampus, amygdala) and DGM (thalamus, caudate) structures were calculated and compared with control values. Neuropsychological testing contributed measures of new learning, delayed recall and recognition memory, in the auditory/verbal and visual/spatial memory modalities. RESULTS: Significant correlations between lower regional volume and poorer test performance were observed across all memory tests. For measures of free recall or new learning, DGM volumes were most strongly predictive of outcomes. In contrast, measures of recognition memory were predicted only by MTL volumetric measures. CONCLUSION: For the first time, the predictive validity of MTL and DGM atrophy were simultaneously compared with MS using reliable and validated neuropsychological measures. This study found that both compartments play significant but different roles in the amnesia of MS.

Thalamic atrophy and cognition in multiple sclerosis.

OBJECTIVES: Recent studies have indicated that brain atrophy is more closely associated with cognitive impairment in multiple sclerosis (MS) than are conventional MRI lesion measures. Enlargement of the third ventricle shows a particularly strong correlation with cognitive impairment, suggesting clinical relevance of damage to surrounding structures, such as the thalamus. Previous imaging and pathology studies have demonstrated thalamic involvement in MS. In this study, we tested the hypothesis that thalamic volume is lower in MS than in normal subjects, and that thalamic atrophy in MS correlates with cognitive function. METHODS: We studied 79 patients with MS and 16 normal subjects. A subgroup of 31 MS subjects underwent cognitive testing. The thalamus was segmented in whole from three-dimensional MRI scans. We also determined whole brain atrophy (brain parenchymal fraction), third ventricular width, and whole brain T2-weighted (fluid-attenuated inversion recovery) hyperintense, T1 hypointense, and gadolinium-enhanced lesion volumes. RESULTS: Normalized thalamic volume was 16.8% lower in the MS group (p < 0.0001) vs controls. Cognitive performance in all domains was moderately to strongly related to thalamic volume in the MS group (r = 0.506 to 0.724, p < 0.005), and thalamic volume entered and remained in all regression models predicting cognitive performance. Thalamic volume showed a weak relationship to physical disability score (r = -0.316, p = 0.005). CONCLUSION: These findings suggest that thalamic atrophy is a clinically relevant biomarker of the neurodegenerative disease process in multiple sclerosis.