Potential Biomarkers Associated with Multiple Sclerosis Pathology

Multiple sclerosis (MS) is a complex disease of the central nervous system (CNS) that involves an intricate and aberrant interaction of immune cells leading to inflammation, demyelination, and neurodegeneration. Due to the heterogeneity of clinical subtypes, their diagnosis becomes challenging and the best treatment cannot be easily provided to patients. Biomarkers have been used to simplify the diagnosis and prognosis of MS, as well as to evaluate the results of clinical treatments. In recent years, research on biomarkers has advanced rapidly due to their ability to be easily and promptly measured, their specificity, and their reproducibility. Biomarkers are classified into several categories depending on whether they address personal or predictive susceptibility, diagnosis, prognosis, disease activity, or response to treatment in different clinical courses of MS. The identified members indicate a variety of pathological processes of MS, such as neuroaxonal damage, gliosis, demyelination, progression of disability, and remyelination, among others. The present review analyzes biomarkers in cerebrospinal fluid (CSF) and blood serum, the most promising imaging biomarkers used in clinical practice. Furthermore, it aims to shed light on the criteria and challenges that a biomarker must face to be considered as a standard in daily clinical practice.

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Multiple Sclerosis Biomarker Discoveries by Proteomics and Metabolomics Approaches

Biomarker Insights ◽

10.1177/11772719211013352 ◽

2021 ◽

Vol 16 ◽

pp. 117727192110133

Author(s):

Ameneh Jafari ◽

Amirhesam Babajani ◽

Mostafa Rezaei-Tavirani

Keyword(s):

Multiple Sclerosis ◽

Complex Disease ◽

Biomarker Discovery ◽

Response To Treatment ◽

Inflammatory Disorder ◽

Protein Marker ◽

Complex Disorders ◽

New Information ◽

The Central Nervous System ◽

Monitoring Treatment

Multiple sclerosis (MS) is an autoimmune inflammatory disorder of the central nervous system (CNS) resulting in demyelination and axonal loss in the brain and spinal cord. The precise pathogenesis and etiology of this complex disease are still a mystery. Despite many studies that have been aimed to identify biomarkers, no protein marker has yet been approved for MS. There is urgently needed for biomarkers, which could clarify pathology, monitor disease progression, response to treatment, and prognosis in MS. Proteomics and metabolomics analysis are powerful tools to identify putative and novel candidate biomarkers. Different human compartments analysis using proteomics, metabolomics, and bioinformatics approaches has generated new information for further clarification of MS pathology, elucidating the mechanisms of the disease, finding new targets, and monitoring treatment response. Overall, omics approaches can develop different therapeutic and diagnostic aspects of complex disorders such as multiple sclerosis, from biomarker discovery to personalized medicine.

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Molecular biomarkers in multiple sclerosis

Journal of Neuroinflammation ◽

10.1186/s12974-019-1674-2 ◽

2019 ◽

Vol 16 (1) ◽

Cited By ~ 16

Author(s):

Tjalf Ziemssen ◽

Katja Akgün ◽

Wolfgang Brück

Keyword(s):

Multiple Sclerosis ◽

Central Nervous System ◽

Therapy Response ◽

Molecular Biomarkers ◽

Imaging Biomarkers ◽

Diagnosis And Prognosis ◽

Disease Characteristics ◽

Long Time ◽

The Central Nervous System ◽

New Biomarkers

AbstractMultiple sclerosis (MS) is an inflammatory-neurodegenerative disease of the central nervous system presenting with significant inter- and intraindividual heterogeneity. However, the application of clinical and imaging biomarkers is currently not able to allow individual characterization and prediction. Complementary, molecular biomarkers which are easily quantifiable come from the areas of immunology and neurobiology due to the causal pathomechanisms and can excellently complement other disease characteristics. Only a few molecular biomarkers have so far been routinely used in clinical practice as their validation and transfer take a long time. This review describes the characteristics that an ideal MS biomarker should have and the challenges of establishing new biomarkers. In addition, clinically relevant and promising biomarkers from the blood and cerebrospinal fluid are presented which are useful for MS diagnosis and prognosis as well as for the assessment of therapy response and side effects.

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Potential Pathological Biomarkers in Multiple Sclerosis

10.20944/preprints202009.0293.v1 ◽

2020 ◽

Author(s):

Deepali Mathur ◽

Soumyashree Rout ◽

Bikash Kumar Mishra ◽

Gerardo Lopez Rodas ◽

Jayalakshmi Vallamkondu ◽

...

Keyword(s):

Multiple Sclerosis ◽

Treatment Outcome ◽

Disease Activity ◽

Complex Disease ◽

Myelin Oligodendrocyte Glycoprotein ◽

Imaging Biomarkers ◽

Disability Progression ◽

Cerebrospinal Fluid Biomarkers ◽

The Central Nervous System ◽

Monitoring Treatment

Multiple Sclerosis (MS) is a complex disease of the central nervous system (CNS) that involves the intricate interplay of different immune cells going awry leading to inflammation, demyelination, and neurodegeneration. Its diagnosis is quite arduous because of the baffling number of symptoms it elicits and the varied clinical manifestation it presents. The simplified criteria (in form of Macdonald’s Criteria) which have got modified several times is now the single most important criteria accepted by neurology bodies for diagnosing MS. Biomarkers from time to time have been explored to simplify the diagnosis and prognosticate MS along with anecessity to monitor treatment outcome. In recent years, research on biomarkers has advanced rapidly due to their ability to be easily and rapidly measured, their specificity, safety, and their ability to yield precise results. Biomarkers are classified into various categories including predictive, diagnostic, prognostic, related to disease activity, and monitoring treatment outcome. Each representative of the disease activity category reflects a variety of pathological processes of MS such as neuroaxonal loss, gliosis, demyelination, disability progression, remyelination, etc. This review discusses several promising serum and cerebrospinal fluid biomarkers and imaging biomarkers used in clinical practice. Myelin oligodendrocyte glycoprotein antibody disease which is recently recognized as a definite disease will also be discussed. Furthermore, it sheds light on the criteria and the challenges a biomarker faces to be considered as a standard one.

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Expression of CYP24A1 and other multiple sclerosis risk genes in peripheral blood indicates response to vitamin D in homeostatic and inflammatory conditions

Genes and Immunity ◽

10.1038/s41435-021-00144-6 ◽

2021 ◽

Author(s):

Samantha P. L. Law ◽

Prudence N. Gatt ◽

Stephen D. Schibeci ◽

Fiona C. McKay ◽

Steve Vucic ◽

...

Keyword(s):

Multiple Sclerosis ◽

Vitamin D ◽

Immune Cells ◽

Peripheral Blood ◽

Mononuclear Cells ◽

Immunological Response ◽

Response To Treatment ◽

Peripheral Blood Mononuclear ◽

Risk Genes ◽

Inflammatory Models

AbstractAlthough genetic and epidemiological evidence indicates vitamin D insufficiency contributes to multiple sclerosis (MS), and serum levels of vitamin D increase on treatment with cholecalciferol, recent metanalyses indicate that this vitamin D form does not ameliorate disease. Genetic variation in genes regulating vitamin D, and regulated by vitamin D, affect MS risk. We evaluated if the expression of vitamin D responsive MS risk genes could be used to assess vitamin D response in immune cells. Peripheral blood mononuclear cells (PBMCs) were isolated from healthy controls and people with MS treated with dimethyl fumarate. We assayed changes in expression of vitamin D responsive MS risk (VDRMS) genes in response to treatment with 25 hydroxy vitamin D in the presence or absence of inflammatory stimuli. Expression of CYP24A1 and other VDRMS genes was significantly altered in PBMCs treated with vitamin D in the homeostatic and inflammatory models. Gene expression in MS samples had similar responses to controls, but lower initial expression of the risk genes. Vitamin D treatment abrogated these differences. Expression of CYP24A1 and other MS risk genes in blood immune cells indicate vitamin D response and could enable assessment of immunological response to vitamin D in clinical trials and on therapy.

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Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility

Science ◽

10.1126/science.aav7188 ◽

2019 ◽

Vol 365 (6460) ◽

pp. eaav7188 ◽

Cited By ~ 122

Author(s):

Keyword(s):

Multiple Sclerosis ◽

Immune Cells ◽

Expression Profiles ◽

Human Microglia ◽

Histocompatibility Complex ◽

The Central Nervous System ◽

Reference Map ◽

Peripheral Immune Cells ◽

Genomic Map ◽

Cellular Components

We analyzed genetic data of 47,429 multiple sclerosis (MS) and 68,374 control subjects and established a reference map of the genetic architecture of MS that includes 200 autosomal susceptibility variants outside the major histocompatibility complex (MHC), one chromosome X variant, and 32 variants within the extended MHC. We used an ensemble of methods to prioritize 551 putative susceptibility genes that implicate multiple innate and adaptive pathways distributed across the cellular components of the immune system. Using expression profiles from purified human microglia, we observed enrichment for MS genes in these brain-resident immune cells, suggesting that these may have a role in targeting an autoimmune process to the central nervous system, although MS is most likely initially triggered by perturbation of peripheral immune responses.

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Metabolomic Biomarkers of Multiple Sclerosis: A Systematic Review

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2020.574133 ◽

2020 ◽

Vol 7 ◽

Author(s):

Lachlan Porter ◽

Alireza Shoushtarizadeh ◽

George A. Jelinek ◽

Chelsea R. Brown ◽

Chai K. Lim ◽

...

Keyword(s):

Multiple Sclerosis ◽

Magnetic Resonance ◽

High Throughput Sequencing ◽

Cochrane Library ◽

Clinical Criteria ◽

Diagnosis And Prognosis ◽

Csf Analysis ◽

Potential Biomarker ◽

Magnetic Resonance Imaging Mri ◽

Potential Biomarkers

BackgroundMagnetic resonance imaging (MRI), cerebrospinal fluid (CSF) analysis, and the McDonald’s clinical criteria are currently utilized tools in diagnosing multiple sclerosis. However, a more conclusive, consistent, and efficient way of diagnosing multiple sclerosis (MS) is yet to be discovered. A potential biomarker, discovered using advances in high-throughput sequencing such as nuclear magnetic resonance (NMR) spectroscopy and other “Omics”-based techniques, may make diagnosis and prognosis more reliable resulting in a more personalized and targeted treatment regime and improved outcomes. The aim of this review was to systematically search the literature for potential biomarkers from any bodily fluid that could consistently and accurately diagnose MS and/or indicate disease progression.MethodsA systematic literature review of EMBASE, PubMed (MEDLINE), The Cochrane Library, and CINAHL databases produced over a thousand potential studies. Inclusion criteria stated studies with potential biomarker outcomes for people with MS were to be included in the review. Studies were limited to those with human participants who had a clinically defined diagnosis of MS and published in English, with no limit placed on date of publication or the type of bodily fluid sampled.ResultsA total of 1,805 studies were recorded from the literature search. A total of 1,760 studies were removed based on their abstract, with a further 18 removed after considering the full text. A total of 30 studies were considered relevant and had their data retrieved and analyzed. Due to the heterogeneity of focus and results from the refined studies, a narrative synthesis was favored.ConclusionSeveral promising candidate biomarkers suitable for clinical application in MS have been studied. It is recommended follow-up studies with larger sample sizes be completed on several potential biomarkers.

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A Review of Various Antioxidant Compounds and their Potential Utility as Complementary Therapy in Multiple Sclerosis

Nutrients ◽

10.3390/nu11071528 ◽

2019 ◽

Vol 11 (7) ◽

pp. 1528 ◽

Cited By ~ 15

Author(s):

Elzbieta Dorota Miller ◽

Angela Dziedzic ◽

Joanna Saluk-Bijak ◽

Michal Bijak

Keyword(s):

Oxidative Stress ◽

Multiple Sclerosis ◽

Complex Disease ◽

Early Stage ◽

Symptomatic Treatment ◽

Complementary Therapy ◽

Antioxidant Compounds ◽

Inflammatory Processes ◽

The Central Nervous System ◽

Stress Mediators

Multiple sclerosis (MS) is a complex disease of the central nervous system (CNS). The etiology of this multifactorial disease has not been clearly defined. Conventional medical treatment of MS has progressed, but is still based on symptomatic treatment. One of the key factors in the pathogenesis of MS is oxidative stress, enhancing inflammation and neurodegeneration. In MS, both reactive oxygen and nitrogen species are formed in the CNS mainly by activated macrophages and microglia structures, which can lead to demyelination and axon disruption. The course of MS is associated with the secretion of many inflammatory and oxidative stress mediators, including cytokines (IL-1b, IL-6, IL-17, TNF-α, INF-γ) and chemokines (MIP-1a, MCP-1, IP10). The early stage of MS (RRMS) lasts about 10 years, and is dominated by inflammatory processes, whereas the chronic stage is associated with neurodegenerative axon and neuron loss. Since oxidative damage has been known to be involved in inflammatory and autoimmune-mediated processes, antioxidant therapy could contribute to the reduction or even prevention of the progression of MS. Further research is needed in order to establish new aims for novel treatment and provide possible benefits to MS patients. The present review examines the roles of oxidative stress and non-pharmacological anti-oxidative therapies in MS.

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Recent Advances in Antigen-Specific Immunotherapies for the Treatment of Multiple Sclerosis

Brain Sciences ◽

10.3390/brainsci10060333 ◽

2020 ◽

Vol 10 (6) ◽

pp. 333 ◽

Cited By ~ 4

Author(s):

Olga Kammona ◽

Costas Kiparissides

Keyword(s):

Multiple Sclerosis ◽

Cell Receptor ◽

Myelin Proteins ◽

Dna Encoding ◽

Disease Modifying Therapies ◽

Tolerogenic Dendritic Cells ◽

The Central Nervous System ◽

Myelin Antigens ◽

Shed Light

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system and is considered to be the leading non-traumatic cause of neurological disability in young adults. Current treatments for MS comprise long-term immunosuppressant drugs and disease-modifying therapies (DMTs) designed to alter its progress with the enhanced risk of severe side effects. The Holy Grail for the treatment of MS is to specifically suppress the disease while at the same time allow the immune system to be functionally active against infectious diseases and malignancy. This could be achieved via the development of immunotherapies designed to specifically suppress immune responses to self-antigens (e.g., myelin antigens). The present study attempts to highlight the various antigen-specific immunotherapies developed so far for the treatment of multiple sclerosis (e.g., vaccination with myelin-derived peptides/proteins, plasmid DNA encoding myelin epitopes, tolerogenic dendritic cells pulsed with encephalitogenic epitopes of myelin proteins, attenuated autologous T cells specific for myelin antigens, T cell receptor peptides, carriers loaded/conjugated with myelin immunodominant peptides, etc.), focusing on the outcome of their recent preclinical and clinical evaluation, and to shed light on the mechanisms involved in the immunopathogenesis and treatment of multiple sclerosis.

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Role of Immune Cells in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis

10.20944/preprints202011.0477.v1 ◽

2020 ◽

Author(s):

Sarah Dhaiban ◽

Mena Al-Ani ◽

Noha Mousaad Elemam ◽

Mahmood H Al-Aawad ◽

Zeinab Al-Rawi ◽

...

Keyword(s):

Multiple Sclerosis ◽

Experimental Autoimmune Encephalomyelitis ◽

Immune Cells ◽

T Regulatory Cells ◽

Cell Types ◽

Autoimmune Encephalomyelitis ◽

The Central Nervous System ◽

Chronic Autoimmune Disease ◽

Experimental Autoimmune

Multiple sclerosis (MS) is a chronic autoimmune disease that affects the central nervous system (CNS) characterized by varying degrees of demyelination of uncertain etiology, and is associated with specific environmental and genetic factors. Upon recognition of CNS antigens, the immune cells initiate an inflammatory process which leads to destruction and deterioration of the neurons. Innate immune cells such as macrophages, dendritic cells and natural killer cells are known to play critical roles in the pathogenesis of MS. Also, the activation of peripheral CD4+ T cells by CNS antigens leads to their extravasation into the CNS causing damages that exacerbates the disease. This could be accompanied by dysregulation of T regulatory cells and other cell types functions. Experimental autoimmune encephalomyelitis (EAE) is a mouse model used to study the pathophysiology of MS disease. In this review, we highlight the roles of innate and adaptive immune players in the pathogenesis of MS and EAE.

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The Benefits and Detriments of Macrophages/Microglia in Models of Multiple Sclerosis

Clinical and Developmental Immunology ◽

10.1155/2013/948976 ◽

2013 ◽

Vol 2013 ◽

pp. 1-13 ◽

Cited By ~ 114

Author(s):

Khalil S. Rawji ◽

V. Wee Yong

Keyword(s):

Multiple Sclerosis ◽

Immune Cells ◽

Neurotrophic Factors ◽

Neurological Diseases ◽

Oligodendrocyte Precursor Cells ◽

Activated Macrophages ◽

Autoimmune Encephalomyelitis ◽

The Central Nervous System ◽

Oligodendrocyte Precursor ◽

Experimental Autoimmune

The central nervous system (CNS) is immune privileged with access to leukocytes being limited. In several neurological diseases, however, infiltration of immune cells from the periphery into the CNS is largely observed and accounts for the increased representation of macrophages within the CNS. In addition to extensive leukocyte infiltration, the activation of microglia is frequently observed. The functions of activated macrophages/microglia within the CNS are complex. In three animal models of multiple sclerosis (MS), namely, experimental autoimmune encephalomyelitis (EAE) and cuprizone- and lysolecithin-induced demyelination, there have been many reported detrimental roles associated with the involvement of macrophages and microglia. Such detriments include toxicity to neurons and oligodendrocyte precursor cells, release of proteases, release of inflammatory cytokines and free radicals, and recruitment and reactivation of T lymphocytes in the CNS. Many studies, however, have also reported beneficial roles of macrophages/microglia, including axon regenerative roles, assistance in promoting remyelination, clearance of inhibitory myelin debris, and the release of neurotrophic factors. This review will discuss the evidence supporting the detrimental and beneficial aspects of macrophages/microglia in models of MS, provide a discussion of the mechanisms underlying the dichotomous roles, and describe a few therapies in clinical use in MS that impinge on the activity of macrophages/microglia.

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