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The role of immune cells, glia and neurons in white and gray matter pathology in multiple sclerosis.

ABSTRACT: Multiple sclerosis is one of the most common causes of chronic neurological disability beginning in early to middle adult life. Multiple sclerosis is idiopathic in nature, yet increasing correlative evidence supports a strong association between one's genetic predisposition, the environment and the immune system. Symptoms of multiple sclerosis have primarily been shown to result from a disruption in the integrity of myelinated tracts within the white matter of the central nervous system. However, recent research has also highlighted the hitherto underappreciated involvement of gray matter in multiple sclerosis disease pathophysiology, which may be especially relevant when considering the accumulation of irreversible damage and progressive disability. This review aims at providing a comprehensive overview of the interplay between inflammation, glial/neuronal damage and regeneration throughout the course of multiple sclerosis via the analysis of both white and gray matter lesional pathology. Further, we describe the common pathological mechanisms underlying both relapsing and progressive forms of multiple sclerosis, and analyze how current (as well as future) treatments may interact and/or interfere with its pathology. Understanding the putative mechanisms that drive disease pathogenesis will be key in helping to develop effective therapeutic strategies to prevent, mitigate, and treat the diverse morbidities associated with multiple sclerosis.

SUBMITTER: Mallucci G

PROVIDER: S-EPMC4578232 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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The role of immune cells, glia and neurons in white and gray matter pathology in multiple sclerosis.

Mallucci Giulia G Peruzzotti-Jametti Luca L Bernstock Joshua D JD Pluchino Stefano S

Progress in neurobiology 20150321

Multiple sclerosis is one of the most common causes of chronic neurological disability beginning in early to middle adult life. Multiple sclerosis is idiopathic in nature, yet increasing correlative evidence supports a strong association between one's genetic predisposition, the environment and the immune system. Symptoms of multiple sclerosis have primarily been shown to result from a disruption in the integrity of myelinated tracts within the white matter of the central nervous system. However ...[more]

PMID: 25802011

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Project description:Therapeutic management and research in Amyotrophic Laterals Sclerosis (ALS) have been limited by the substantial heterogeneity in progression and anatomical spread that are endemic of the disease. Neuroimaging biomarkers represent powerful additions to the current monitoring repertoire but have yielded inconsistent associations with clinical scores like the ALS functional rating scale. The D50 disease progression model was developed to address limitations with clinical indices and the difficulty obtaining longitudinal data in ALS. It yields overall disease aggressiveness as time taken to reach halved functionality (D50); individual disease covered in distinct phases; and calculated functional state and calculated functional loss as acute descriptors of local disease activity. It greatly reduces the noise of the ALS functional rating scale and allows the comparison of highly heterogeneous disease and progression subtypes. In this study, we performed Voxel-Based Morphometry for 85 patients with ALS (60.1 ± 11.5 years, 36 female) and 62 healthy controls. Group-wise comparisons were performed separately for gray matter and white matter using ANCOVA testing with threshold-free cluster enhancement. ALS-related widespread gray and white matter density decreases were observed in the bilateral frontal and temporal lobes (p < 0.001, family-wise error corrected). We observed a progressive spread of structural alterations along the D50-derived phases, that were primarily located in frontal, temporal and occipital gray matter areas, as well as in supratentorial neuronal projections (p < 0.001 family-wise error corrected). ALS patients with higher overall disease aggressiveness (D50 < 30 months) showed a distinct pattern of supratentorial white matter density decreases relative to patients with lower aggressiveness; no significant differences were observed for gray matter density (p < 0.001 family-wise error corrected). The application of the D50 disease progression model separates measures of disease aggressiveness from disease accumulation. It revealed a strong correlation between disease phases and in-vivo measures of cerebral structural integrity. This study underscores the proposed corticofugal spread of cerebral pathology in ALS. We recommend application of the D50 model in studies linking clinical data with neuroimaging correlates.

Project description:Neuroaxonal pathology is a main determinant of disease progression in multiple sclerosis; however, its underlying pathophysiological mechanisms, including its link to inflammatory demyelination and temporal occurrence in the disease course are still unknown. We used ultra-high field (7 T), ultra-high gradient strength diffusion and T1/T2-weighted myelin-sensitive magnetic resonance imaging to characterize microstructural changes in myelin and neuroaxonal integrity in the cortex and white matter in early stage multiple sclerosis, their distribution in lesional and normal-appearing tissue, and their correlations with neurological disability. Twenty-six early stage multiple sclerosis subjects (disease duration ?5 years) and 24 age-matched healthy controls underwent 7 T T2*-weighted imaging for cortical lesion segmentation and 3 T T1/T2-weighted myelin-sensitive imaging and neurite orientation dispersion and density imaging for assessing microstructural myelin, axonal and dendrite integrity in lesional and normal-appearing tissue of the cortex and the white matter. Conventional mean diffusivity and fractional anisotropy metrics were also assessed for comparison. Cortical lesions were identified in 92% of early multiple sclerosis subjects and they were characterized by lower intracellular volume fraction (P = 0.015 by paired t-test), lower myelin-sensitive contrast (P = 0.030 by related-samples Wilcoxon signed-rank test) and higher mean diffusivity (P = 0.022 by related-samples Wilcoxon signed-rank test) relative to the contralateral normal-appearing cortex. Similar findings were observed in white matter lesions relative to normal-appearing white matter (all P < 0.001), accompanied by an increased orientation dispersion (P < 0.001 by paired t-test) and lower fractional anisotropy (P < 0.001 by related-samples Wilcoxon signed-rank test) suggestive of less coherent underlying fibre orientation. Additionally, the normal-appearing white matter in multiple sclerosis subjects had diffusely lower intracellular volume fractions than the white matter in controls (P = 0.029 by unpaired t-test). Cortical thickness did not differ significantly between multiple sclerosis subjects and controls. Higher orientation dispersion in the left primary motor-somatosensory cortex was associated with increased Expanded Disability Status Scale scores in surface-based general linear modelling (P < 0.05). Microstructural pathology was frequent in early multiple sclerosis, and present mainly focally in cortical lesions, whereas more diffusely in white matter. These results suggest early demyelination with loss of cells and/or cell volumes in cortical and white matter lesions, with additional axonal dispersion in white matter lesions. In the cortex, focal lesion changes might precede diffuse atrophy with cortical thinning. Findings in the normal-appearing white matter reveal early axonal pathology outside inflammatory demyelinating lesions.

Dataset Information

The role of immune cells, glia and neurons in white and gray matter pathology in multiple sclerosis.

Publications

The role of immune cells, glia and neurons in white and gray matter pathology in multiple sclerosis.

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