Progressive Stage Of Multiple Sclerosis Research Articles

Investigation of differentially expressed genes and dysregulated pathways involved in multiple sclerosis.

Multiple Sclerosis (MS) is a neurodegenerative autoimmune and organ-specific demyelinating disorder, known to affect the central nervous system (CNS). While genetic studies have revealed several critical genes and diagnostic biomarkers associated with MS, the etiology of the disease remains poorly understood. This study is aimed at screening and identifying the key genes and canonical pathways associated with MS. Gene expression profiling of the microarray dataset GSE38010 was used to analyze two control brain samples (control 1; GSM931812, control 2; GSM931813), active inflammation stage samples (CAP1; GSM931815, CAP2; GSM931816) and late subsided stage samples (CP1; GSM931817, CP2; GSM931818) collected from patients ranging between 23 and 54years and both genders. This analysis yielded a list of 58,866 DEGs (29,433 for active-inflammation stage and 29,433 for late-subsided Stage). The interactions between the DEGs were then studied using STRING, Cytoscape software, and MCODE was employed to find the genes that form clusters. Functional enrichment and integrative analysis were performed using ClueGO/CluePedia and MetaCore™. Our data revealed dysregulated key canonical pathways in MS patients. In addition, we identified three hub genes (SCN2A, HTR2A, and HCN1) that may serve as potential biomarkers for the prognosis of MS. Furthermore, the expression patterns of HPCA and PLCB1 provide insights into the progressive stages of MS, indicating that these genes could be used in predicting MS progression. We were able to map potential biomarkers that could be used for the prognosis and diagnosis of MS.

Sudomotor Dysfunction in a Patient with Primary Progressive Multiple Sclerosis

Autonomic dysfunction (AD) is known to be frequent among multiple sclerosis (MS) patients, even in early stages of the disease. During the course of disease, AD becomes more pronounced, with patients in progressive stages of MS experiencing a higher autonomic burden than MS patients in relapsing-remitting stages. The same pattern of AD progression is true for sudomotor dysfunction, with 35% of MS patients with a relapsing-remitting phenotype experiencing sudomotor dysfunction compared to 73% of MS patients with a progressive phenotype. We present the case of a patient with primary progressive MS suffering from severe sudomotor dysfunction. The presented patient had avoided physical therapy as he could not tolerate the accompanying temperature rise. One way to deal with this obstacle is to cool the patient down prior to physical therapy or let the patient workout at a cooler room temperature. From a research point of view, sudomotor dysfunction detected in MS patients may actually be a sign of small fiber neuropathy and not just a reflection of central nervous system dysfunction, a possibility which requires further investigation.

Iron related changes in MS lesions and their validity to characterize MS lesion types and dynamics with Ultra-high field magnetic resonance imaging.

Iron accumulates with age in the normal human brain. This process is altered at several levels in the brain of multiple sclerosis (MS) patients. Since iron is mainly stored in oligodendrocytes and myelin in the normal brain, its liberation in demyelinating lesions may amplify tissue damage in demyelinating lesions and its uptake in macrophages and microglia may help to more precisely define activity stages of the lesions. In addition, glia cells change their iron import, export and storage properties in MS lesions, which is reflected by alterations in the expression of iron transport molecules. Changes of iron distribution in the brain can be reliably detected by MRI, particularly upon application of Ultra‐high magnetic field (7 Tesla). Iron‐sensitive MRI allows to more accurately distinguish the lesions in MS from those in other inflammatory brain diseases, to visualize a subset of slowly expanding lesions in the progressive stage of MS and to increase the sensitivity for lesion detection in the gray matter, such as the cerebral cortex or deep gray matter nuclei.

In vivo evidence of oxidative stress in brains of patients with progressive multiple sclerosis

Background: The oxidative stress hypothesis links neurodegeneration in the later, progressive stages of multiple sclerosis (MS) to the loss of a major brain antioxidant, glutathione (GSH). Objective: We measured GSH concentrations among major MS subtypes and examined the relationships with other indices of disease status including physical disability and magnetic resonance imaging (MRI) measures. Methods: GSH mapping was performed on the fronto-parietal region of patients with relapsing-remitting multiple sclerosis (RRMS, n = 21), primary progressive multiple sclerosis (PPMS, n = 20), secondary progressive multiple sclerosis (SPMS, n = 20), and controls (n = 28) using GSH chemical shift imaging. Between-group comparisons were performed on all variables (GSH, T2-lesion, atrophy, Expanded Disability Status Scale (EDSS)). Results: Patients with MS had substantially lower GSH concentrations than controls, and GSH was lower in progressive MS (PPMS and SPMS) compared with RRMS. GSH concentrations were not significantly different between PPMS and SPMS, or between RRMS and controls. Brain atrophy was significant in both RRMS and progressive MS compared with controls. Conclusion: Markedly lower GSH in progressive MS than RRMS indicates more prominent involvement of oxidative stress in the progressive stage of MS than the inflammatory stage. The association between GSH and brain atrophy suggests the important role of oxidative stress contributing to neurodegeneration in progressive MS, as suggested in other neurodegenerative diseases.

Identification of galectin-3 as a possible antibody target for secondary progressive multiple sclerosis

Background: Recent studies have revealed that the disruption of the blood–brain barrier (BBB) might contribute to the induction of neurodegeneration in the progressive stage of multiple sclerosis (MS). Objective: We investigated a potential target for the serum auto-antibodies responsible for the BBB impairment in patients with secondary progressive MS (SPMS). Methods: We identified undetermined target antigens in human brain microvascular endothelial cells (BMECs) that reacted with auto-antibodies in sera from SPMS patients using a proteomic approach. In addition, we examined how the identified auto-antibodies compromise the BBB integrity. Results: We found that 10 of 11 SPMS sera had auto-antibodies against galectin-3, although the patients with other neurological diseases did not have these antibodies. Downregulation of galectin-3 led to elevated intercellular adhesion molecule-1 (ICAM-1) and phospho-nuclear factor-kappa (NFκ) B p65 expression in the BMECs. Exposure to SPMS patients’ sera also increased the protein levels of ICAM-1 and phospho-NFκB p65 in BMECs, but these effects induced by anti-galectin-3 immunoreactivity were canceled by the downregulation of galectin-3. Conclusion: Galectin-3 is a possible immunological target molecule of the pathogenic auto-antibodies and contributes to the persistent BBB breakdown in patients with SPMS. These antibodies may also serve as a novel biomarker for SPMS.

Oxidative stress and its impact on neurons and glia in multiple sclerosis lesions

Oxidative injury plays a major role in brain damage in many age-related human brain diseases and is particularly pronounced in the progressive stage of multiple sclerosis. In the latter it is related to the chronic inflammatory process and is amplified by brain changes due to aging and accumulation of disease burden. It induces demyelination and neurodegeneration by direct oxidation of lipids, proteins and DNA as well as by the induction of mitochondrial injury, which results in energy deficiency and further amplification of oxygen radical production. It affects neurons and all types of glia cells, but neurons and oligodendrocytes are most vulnerable. Difference in the susceptibility for oxidative injury between different cellular components of the central nervous system appears to be due to cell type specific differences in anti-oxidant defense mechanisms, iron loading, cellular susceptibility to apoptosis induction and energy demand. This article is part of a Special Issue entitled: Neuro Inflammation edited by Helga E. de Vries and Markus Schwaninger.

Reduced gamma-aminobutyric acid concentration is associated with physical disability in progressive multiple sclerosis.

Neurodegeneration is thought to be the major cause of ongoing, irreversible disability in progressive stages of multiple sclerosis. Gamma-aminobutyric acid is the principle inhibitory neurotransmitter in the brain. The aims of this study were to investigate if gamma-aminobutyric acid levels (i) are abnormal in patients with secondary progressive multiple sclerosis compared with healthy controls; and (ii) correlate with physical and cognitive performance in this patient population. Thirty patients with secondary progressive multiple sclerosis and 17 healthy control subjects underwent single-voxel MEGA-PRESS (MEscher-GArwood Point RESolved Spectroscopy) magnetic resonance spectroscopy at 3 T, to quantify gamma-aminobutyric acid levels in the prefrontal cortex, right hippocampus and left sensorimotor cortex. All subjects were assessed clinically and underwent a cognitive assessment. Multiple linear regression models were used to compare differences in gamma-aminobutyric acid concentrations between patients and controls adjusting for age, gender and tissue fractions within each spectroscopic voxel. Regression was used to examine the relationships between the cognitive function and physical disability scores specific for these regions with gamma-aminobuytric acid levels, adjusting for age, gender, and total N-acetyl-aspartate and glutamine-glutamate complex levels. When compared with controls, patients performed significantly worse on all motor and sensory tests, and were cognitively impaired in processing speed and verbal memory. Patients had significantly lower gamma-aminobutyric acid levels in the hippocampus (adjusted difference = -0.403 mM, 95% confidence intervals -0.792, -0.014, P = 0.043) and sensorimotor cortex (adjusted difference = -0.385 mM, 95% confidence intervals -0.667, -0.104, P = 0.009) compared with controls. In patients, reduced motor function in the right upper and lower limb was associated with lower gamma-aminobutyric acid concentration in the sensorimotor cortex. Specifically for each unit decrease in gamma-aminobutyric acid levels (in mM), there was a predicted -10.86 (95% confidence intervals -16.786 to -4.482) decrease in grip strength (kg force) (P < 0.001) and -8.74 (95% confidence intervals -13.943 to -3.015) decrease in muscle strength (P < 0.006). This study suggests that reduced gamma-aminobutyric acid levels reflect pathological abnormalities that may play a role in determining physical disability. These abnormalities may include decreases in the pre- and postsynaptic components of gamma-aminobutyric acid neurotransmission and in the density of inhibitory neurons. Additionally, the reduced gamma-aminobutyric acid concentration may contribute to the neurodegenerative process, resulting in increased firing of axons, with consequent increased energy demands, which may lead to neuroaxonal degeneration and loss of the compensatory mechanisms that maintain motor function. This study supports the idea that modulation of gamma-aminobutyric acid neurotransmission may be an important target for neuroprotection in multiple sclerosis.See De Stefano and Giorgio (doi:10.1093/brain/awv213) for a scientific commentary on this article.

Changes of some serum fatty acids and lipids in relation to the clinical course of multiple sclerosis.

Serum total lipids, lipid phosphorus, total cholesterol, five subfractions of cholesterol esters, lysolecithin, sphingomyelin, lecithin, phophati-dylethanolamine, free fatty acids, free cholesterol, triglycerides and esterified cholesterol were analysed in 108 cases of multiple sclerosis subdivided into four groups according to the activity of clinical symptoms of the disease and compared with 34 control blood donors. A decrease of cholesterol linoleate and an increase of tri- and tetra-unsaturated fatty acid cholesterides were found to be constant changes in the progressive stages of multiple sclerosis. Other alterations of lipid composition and concentration were not substantial.

A mitochondrial component of neurodegeneration in multiple sclerosis.

Neurodegeneration is the main pathological correlate of accumulating disability in progressive stages of Multiple Sclerosis (MS), but both histologic and imaging studies detect significant tissue loss even in early disease. These observations raise the question as to whether neurodegeneration in MS is a primary mechanism or whether it develops secondary to inflammation and demyelination. Recent data suggest that the atrophy of brain and cord is directly linked to inflammation and may partly be independent of demyelination. Released products of both residential and infiltrating immune cells can induce ultrastructural changes and celldeath by multiple mechanism. We propose that the inflammation-induced tissue response is controlled by genetic variations and to some extent involves a mitochondrion-driven mechanism in MS, similar to that described in the final pathway of other neurodegenerative disorders. Current therapeutic strategies primarily target the immune system which results in a successful down-regulation of plaque formation and of relapse rate. However, measures of clinical disability best correlate with the degree of neurodegeneration rather than with the volume of plaques, and these immune-modulating regimens may only incompletely affect the accumulating tissue loss. Considering the need for additional therapeutic strategies, we emphasize the degenerative components, and review a mitochondrial mechanism of tissue loss potentially involved in the process of MS.

Defective post-thymic tolerance mechanisms during the chronic progressive stage of multiple sclerosis.

We have recently isolated a panel of T-cell clones from chronic progressive multiple sclerosis (MS) patients that are capable of functioning as antigen-presenting cells and of expressing the costimulatory molecules B7-1 and B7-2. In this report we show that these T-cell clones are resistant to inhibitory regulation, including the induction of anergy and sensitivity to tumor growth factor-beta (TGF-beta)-induced growth inhibition. The resistance to anergy induction was associated with expression of B7 costimulatory molecules. These data suggest that lack of responsiveness to peripheral inhibitory signals may account for the entry of autoimmune diseases into a chronic progressive phase.

Chronic progressive multiple sclerosis: serial magnetic resonance brain imaging over six months.

Eight patients in the chronic progressive stage of multiple sclerosis were studied prospectively with magnetic resonance imaging of the head and neurological examination every 2 weeks for 6 months. There were no clinical relapses and disability ratings did not change between the start and completion of the study. Despite the clinical inactivity, a total of 86 active events (new, reappearing, or enlarging lesions) were identified by magnetic resonance imaging over the 6 months, with 50 (51%) of 98 follow-up scans showing evidence of one or more active lesions. New and changing lesions were indistinguishable in appearance, distribution, and temporal pattern from those previously seen in patients who had relapsing and remitting multiple sclerosis. However, as noted previously, the patients in the chronic progressive stage had many more confluent lesions than did the group in relapse. These results strongly suggest that the frequently observed clinical evolution of multiple sclerosis into a chronic progressive course is not accompanied by a fundamental change in the disease process. In fact the chronic progressive stage seems associated with more active changes demonstrated by scans than does relapsing and remitting multiple sclerosis. This study also confirms our previous experience that serial magnetic resonance imaging is much more sensitive than clinical examination in detecting disease activity in multiple sclerosis.