scholarly journals Proteomics of Multiple Sclerosis: Inherent Issues in Defining the Pathoetiology and Identifying (Early) Biomarkers

2021 ◽  
Vol 22 (14) ◽  
pp. 7377
Author(s):  
Monokesh K. Sen ◽  
Mohammed S. M. Almuslehi ◽  
Peter J. Shortland ◽  
David A. Mahns ◽  
Jens R. Coorssen
Keyword(s):  
Multiple Sclerosis ◽  
Animal Models ◽  
Demyelinating Disease ◽  
Clinical Symptoms ◽  
Literature Mining ◽  
Targeted Therapeutics ◽  
Single Model ◽  
Human Central Nervous System ◽  
Early Biomarkers ◽  
Analytical Approaches

Multiple Sclerosis (MS) is a demyelinating disease of the human central nervous system having an unconfirmed pathoetiology. Although animal models are used to mimic the pathology and clinical symptoms, no single model successfully replicates the full complexity of MS from its initial clinical identification through disease progression. Most importantly, a lack of preclinical biomarkers is hampering the earliest possible diagnosis and treatment. Notably, the development of rationally targeted therapeutics enabling pre-emptive treatment to halt the disease is also delayed without such biomarkers. Using literature mining and bioinformatic analyses, this review assessed the available proteomic studies of MS patients and animal models to discern (1) whether the models effectively mimic MS; and (2) whether reasonable biomarker candidates have been identified. The implication and necessity of assessing proteoforms and the critical importance of this to identifying rational biomarkers are discussed. Moreover, the challenges of using different proteomic analytical approaches and biological samples are also addressed.

Discrepancies in the interpretation of clinical symptoms and signs in the diagnosis of multiple sclerosis. A proposal for standardization

2005 ◽  
Vol 11 (2) ◽  
pp. 227-231 ◽  
Author(s):  
Bernard MJ Uitdehaag ◽  
Ludwig Kappos ◽  
Lars Bauer ◽  
Mark S Freedman ◽  
David Miller ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Demyelinating Disease ◽  
Clinical Symptoms ◽  
Clinical Findings ◽  
Large Trial ◽  
Mri Findings ◽  
Mcdonald Criteria ◽  
Magnetic Resonance Imaging Mri ◽  
Eligibility Assessment

The new McDonald diagnostic criteria for multiple sclerosis (MS) incorporate detailed criteria for the interpretation and classification of magnetic resonance imaging (MRI) findings, but, in contrast, provide no instructions for the interpretation of clinical findings. Because MS according to the McDonald criteria is one of the primary endpoints in a large trial enrolling patients after the first manifestation suggestive for a demyelinating disease (BENEFIT study), it was decided to organize a centralized eligibility assessment for this trial. During this eligibility assessment it was observed that there were marked inconsistencies in the decisions of participating neurologists with respect to the classification of clinical symptoms as being caused by one or more lesions provoking discussions in about one in every five patients. This paper describes these inconsistencies and their sources, and recommends a systematic approach that attempts to reduce the variability in interpreting clinical findings.

scholarly journals A Pathogenic Role for Myelin-Specific Cd8+ T Cells in a Model for Multiple Sclerosis

2001 ◽  
Vol 194 (5) ◽  
pp. 669-676 ◽  
Author(s):  
Eric S. Huseby ◽  
Denny Liggitt ◽  
Thea Brabb ◽  
Bryan Schnabel ◽  
Claes Öhlén ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Demyelinating Disease ◽  
Clinical Symptoms ◽  
Autoimmune Encephalomyelitis ◽  
Effector Cells ◽  
Cns Autoimmunity ◽  
The Central Nervous System

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) characterized by plaques of infiltrating CD4+ and CD8+ T cells. Studies of MS and experimental autoimmune encephalomyelitis (EAE), an animal model of MS, focus on the contribution of CD4+ myelin-specific T cells. The role of CD8+ myelin-specific T cells in mediating EAE or MS has not been described previously. Here, we demonstrate that myelin-specific CD8+ T cells induce severe CNS autoimmunity in mice. The pathology and clinical symptoms in CD8+ T cell–mediated CNS autoimmunity demonstrate similarities to MS not seen in myelin-specific CD4+ T cell–mediated EAE. These data suggest that myelin-specific CD8+ T cells could function as effector cells in the pathogenesis of MS.

Therapeutic Targeting of Chemokines and Chemokine Receptors in Multiple Sclerosis: Opportunities and Challenges

2018 ◽  
Vol 17 (7) ◽  
pp. 496-508 ◽  
Author(s):  
Tahereh Sadeghian-Rizi ◽  
Hossein Khanahmad ◽  
Ali Jahanian-Najafabadi
Keyword(s):  
Multiple Sclerosis ◽  
Chemokine Receptors ◽  
Demyelinating Disease ◽  
Unknown Etiology ◽  
Main Role ◽  
Medical Studies ◽  
Human Central Nervous System ◽  
Potential Therapeutic Target ◽  
Demyelinating Lesions ◽  
The Relationship

Background & Objective: Multiple sclerosis is an autoimmune demyelinating disease of the human central nervous system with still unknown etiology. Infiltration, accumulation and activation of autoreactive T cells, macrophages and other inflammatory immune cells in the CNS are the crucial steps in MS neuropathogenesis and development. Chemokines and their receptors play the main role in the attraction of the pathogenic cells into the CNS in MS. Specific chemokines and chemokine receptors are up-regulated in the actively demyelinating lesions and cerebrospinal fluid of MS patients. Many medical studies investigated how changes in levels or activities of chemokines and their receptors are implicated in leukocyte migration into CNS and consequently causing MS. These chemokines and their receptors are under intense focus to introduce new therapeutic strategies for MS. Conclusion: The aim of this review is to summarize previous findings on the relationship between chemokines network and MS development. Furthermore, opportunities and challenges in the chemokine system intervention as a potential therapeutic target for the treatment of MS will be outlined.

scholarly journals Animal models of multiple sclerosis: From rodents to zebrafish

2018 ◽  
Vol 25 (3) ◽  
pp. 306-324 ◽  
Author(s):  
David John Burrows ◽  
Alexander McGown ◽  
Saurabh A Jain ◽  
Milena De Felice ◽  
Tennore M Ramesh ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Animal Models ◽  
Demyelinating Disease ◽  
Genetic Manipulation ◽  
Rapid Development ◽  
Disease Course ◽  
Autoimmune Encephalomyelitis ◽  
Immune Mediated ◽  
The Central Nervous System ◽  
Experimental Autoimmune

Multiple sclerosis (MS) is a chronic, immune-mediated demyelinating disease of the central nervous system. Animal models of MS have been critical for elucidating MS pathological mechanisms and how they may be targeted for therapeutic intervention. Here we review the most commonly used animal models of MS. Although these animal models cannot fully replicate the MS disease course, a number of models have been developed to recapitulate certain stages. Experimental autoimmune encephalomyelitis (EAE) has been used to explore neuroinflammatory mechanisms and toxin-induced demyelinating models to further our understanding of oligodendrocyte biology, demyelination and remyelination. Zebrafish models of MS are emerging as a useful research tool to validate potential therapeutic candidates due to their rapid development and amenability to genetic manipulation.

scholarly journals Pathogenic T cell cytokines in multiple sclerosis

2019 ◽  
Vol 217 (1) ◽  
Author(s):  
Catriona A. Wagner ◽  
Pamela J. Roqué ◽  
Joan M. Goverman
Keyword(s):  
Multiple Sclerosis ◽  
Central Nervous System ◽  
T Cells ◽  
Nervous System ◽  
Young Adults ◽  
T Cell ◽  
Animal Models ◽  
Demyelinating Disease ◽  
The Central Nervous System ◽  
Autoimmune Etiology

Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system that is believed to have an autoimmune etiology. As MS is the most common nontraumatic disease that causes disability in young adults, extensive research has been devoted to identifying therapeutic targets. In this review, we discuss the current understanding derived from studies of patients with MS and animal models of how specific cytokines produced by autoreactive CD4 T cells contribute to the pathogenesis of MS. Defining the roles of these cytokines will lead to a better understanding of the potential of cytokine-based therapies for patients with MS.

Multiple sclerosis risk in radiologically uncovered asymptomatic possible inflammatory-demyelinating disease

2009 ◽  
Vol 15 (8) ◽  
pp. 918-927 ◽  
Author(s):  
A Siva ◽  
S Saip ◽  
A Altintas ◽  
A Jacob ◽  
BM Keegan ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Demyelinating Disease ◽  
Clinical Symptoms ◽  
Tertiary Care ◽  
Similar Rate ◽  
Randomized Controlled Studies ◽  
History Of ◽  
Magnetic Resonance Imaging Mri ◽  
Mri Study

Background Natural history of patients with incidentally discovered lesions that fulfill magnetic resonance imaging (MRI) criteria for multiple sclerosis (MS) in the absence of objective clinical symptoms suggestive of central nervous system (CNS) inflammatory-demyelinating disease is not well defined. Objective We evaluated the risk of developing symptomatic MS in patients with radiologically uncovered asymptomatic possible inflammatory-demyelinating disease (RAPIDD). Methods We identified and longitudinally followed a cohort of 22 patients from two tertiary care MS centers: Istanbul University, Cerrahpasa School of Medicine, Istanbul, Turkey, and Mayo Clinic, Rochester, Minnesota, after an initial MRI study fulfilling the Barkhof–Tintore MRI criteria completed for other reasons unrelated to MS. Results Eight of 22 patients developed an objective clinical symptom consistent with a CNS inflammatory-demyelinating syndrome and fulfilled dissemination in space and time criteria for definite MS. Median age at the time of diagnosis of MS was 44.8 years (range 28.3–71.4 years). Time taken for the development of definite MS was studied by survival analysis. Cumulative event rates were; 12 months: 9%, 24 months: 15%, 36 months: 30.4%, and 60 months: 44.6%. Six of 22 patients were followed beyond 60 months. Two of these six patients developed MS later (at 66 and 112 months, respectively). Three patients remained asymptomatic despite follow-up of 10 years. Conclusions Patients with RAPIDD develop MS at a similar rate to treated patients (and less frequently than placebo groups) with clinically isolated syndromes from prior randomized controlled studies. Some patients with RAPIDD continue to have radiological evolution of subclinical disease without MS symptoms despite long follow-up periods.

scholarly journals Cerebrospinal Fluid Analysis in Multiple Sclerosis Diagnosis: An Update

Medicina ◽  
2019 ◽  
Vol 55 (6) ◽  
pp. 245 ◽  
Author(s):  
Bruna Lo Sasso ◽  
Luisa Agnello ◽  
Giulia Bivona ◽  
Chiara Bellia ◽  
Marcello Ciaccio
Keyword(s):  
Multiple Sclerosis ◽  
Cerebrospinal Fluid ◽  
Demyelinating Disease ◽  
Clinical Symptoms ◽  
Current Knowledge ◽  
Clinical Manifestations ◽  
Laboratory Diagnosis ◽  
Oligoclonal Bands ◽  
Csf Biomarkers ◽  
Laboratory Findings

Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system (CNS) with brain neurodegeneration. MS patients present heterogeneous clinical manifestations in which both genetic and environmental factors are involved. The diagnosis is very complex due to the high heterogeneity of the pathophysiology of the disease. The diagnostic criteria have been modified several times over the years. Basically, they include clinical symptoms, presence of typical lesions detected by magnetic resonance imaging (MRI), and laboratory findings. The analysis of cerebrospinal fluid (CSF) allows an evaluation of inflammatory processes circumscribed to the CNS and reflects changes in the immunological pattern due to the progression of the pathology, being fundamental in the diagnosis and monitoring of MS. The detection of the oligoclonal bands (OCBs) in both CSF and serum is recognized as the “gold standard” for laboratory diagnosis of MS, though presents analytical limitations. Indeed, current protocols for OCBs assay are time-consuming and require an operator-dependent interpretation. In recent years, the quantification of free light chain (FLC) in CSF has emerged to assist clinicians in the diagnosis of MS. This article reviews the current knowledge on CSF biomarkers used in the diagnosis of MS, in particular on the validated assays and on the alternative biomarkers of intrathecal synthesis.

scholarly journals Multiple sclerosis reduces synchrony of the magnocellular pathway

PLoS ONE ◽  
2021 ◽  
Vol 16 (8) ◽  
pp. e0255324
Author(s):  
Masoud Seraji ◽  
Maryam Mohebbi ◽  
Amirhossein Safari ◽  
Bart Krekelberg
Keyword(s):  
Multiple Sclerosis ◽  
Functional Connectivity ◽  
Disease Progression ◽  
Information Transfer ◽  
Demyelinating Disease ◽  
Clinical Symptoms ◽  
Visual Stimuli ◽  
Clustering Coefficient ◽  
Magnocellular Pathway ◽  
Characteristic Path Length

Multiple Sclerosis (MS) is an autoimmune demyelinating disease that damages the insulation of nerve cell fibers in the brain and spinal cord. In the visual system, this demyelination results in a robust delay of visually evoked potentials (VEPs), even in the absence of overt clinical symptoms such as blurred vision. VEPs, therefore, offer an avenue for early diagnosis, monitoring disease progression, and, potentially, insight into the differential impairment of specific pathways. A primary hypothesis has been that visual stimuli driving the magno-, parvo-, and konio-cellular pathways should lead to differential effects because these pathways differ considerably in terms of myelination. Experimental tests of this hypothesis, however, have led to conflicting results. Some groups reported larger latency effects for chromatic stimuli, while others found equivalent effects across stimulus types. We reasoned that this lack of pathway specificity could, at least in part, be attributed to the relatively coarse measure of pathway impairment afforded by the latency of a VEP. We hypothesized that network synchrony could offer a more sensitive test of pathway impairments. To test this hypothesis, we analyzed the synchrony of occipital electroencephalography (EEG) signals during the presentation of visual stimuli designed to bias activity to one of the three pathways. Specifically, we quantified synchrony in the occipital EEG using two graph-theoretic measures of functional connectivity: the characteristic path length (L; a measure of long-range connectivity) and the clustering coefficient (CC; a measure of short-range connectivity). Our main finding was that L and CC were both smaller in the MS group than in controls. Notably, this change in functional connectivity was limited to the magnocellular pathway. The effect sizes (Hedge’s g) were 0.89 (L) and 1.26 (CC) measured with magno stimuli. Together, L and CC define the small-world nature of a network, and our finding can be summarized as a reduction in the small-worldness of the magnocellular network. We speculate that the reduced efficiency of information transfer associated with a reduction in small-worldness could underlie visual deficits in MS. Relating these measures to differential diagnoses and disease progression is an important avenue for future work.

Cell-based Tolerogenic Therapy, Experience from Animal Models of Multiple Sclerosis, Type 1 Diabetes and Rheumatoid Arthritis

2017 ◽  
Vol 23 (18) ◽  
Author(s):  
Ivana Stojanovic ◽  
Mirjana Dimitrijevic ◽  
Marta Vives-Pi ◽  
Maria Jose Mansilla ◽  
Irma Pujol-Autonell ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Multiple Sclerosis ◽  
Type 1 Diabetes ◽  
Animal Models
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