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Biomedicines
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Multiple Sclerosis: Diagnosis and Treatment II
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Multiple Sclerosis: Diagnosis and Treatment II

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Neurobiology and Clinical Neuroscience".

Deadline for manuscript submissions: closed (15 August 2020) | Viewed by 63416

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editor

Prof. Dr. Víctor M. Rivera

E-Mail Website
Guest Editor
Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA
Interests: demyelinating disorders; multiple sclerosis; epidemiology and genetic aspects; therapeutic trials
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is the second volume of our previous Special Issue “Multiple Sclerosis: Diagnosis and Treatment”. Multiple Sclerosis (MS), an inflammatory demyelinating disease of the CNS, has acquired world-wide recognition with its increasing global prevalence, including populations previously considered not to be commonly affected. Genetics and environmental factors play a determining role in its pathogenesis. Notable progress has been accomplished in diagnostic criteria (which evolve continuously) as well as therapeutic advances. In fact, in less than three decades, more therapies with diverse mechanisms of action (MOAs) for relapsing and progressive MS have been developed for MS than for any other neurological disorder. Magnetic resonance imaging (MRI), the golden tool for diagnosis, is essential for monitoring the evolution of the disease and the response to therapy.

Despite this progress, substantial challenges have arisen, including the need for differential diagnosis with respect to other major inflammatory/demyelinating disorders that have been identified relatively recently (totally different in mechanism and management), such as neuromyelitis optica (NMO) and anti-MOG syndromes, and the role of environment and epigenetic factors in the mechanism of MS.

We cordially invite authors and investigators within this complex field of universal interest to submit original research or review articles pertaining to this Special Issue. Studies and opinions on risk factors related to the development of the disease, molecular aspects of its pathogenesis, diagnostic intricacies despite current criteria, and the status of disease-modifying therapies’ effects in relapsing and progressive forms of MS, and what is foreseen on the horizon are welcome.

Prof. Víctor M. Rivera
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • multiple sclerosis
  • pathogenesis
  • progressive MS
  • MRI
  • monoclonal antibodies
  • demyelinating disorders
  • cognitive dysfunction
  • intestinal microbiota

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Published Papers (10 papers)

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Editorial

Jump to: Research, Review

5 pages, 180 KiB  
Editorial
Editorial of Special Issue “Multiple Sclerosis: Diagnosis and Treatment II”
by Victor M. Rivera
Biomedicines 2021, 9(11), 1605; https://doi.org/10.3390/biomedicines9111605 - 3 Nov 2021
Cited by 1 | Viewed by 1613
Abstract
The special issue on Multiple Sclerosis: Diagnosis and Treatment II, reflects advances and discoveries in the molecular and cellular mechanisms of disease, and novel laboratory techniques providing more sensitivity to diagnostic techninques and the understanding of neuroinflammation. Mitochondrial-mediated apoptosis in isolated peripheral blood [...] Read more.
The special issue on Multiple Sclerosis: Diagnosis and Treatment II, reflects advances and discoveries in the molecular and cellular mechanisms of disease, and novel laboratory techniques providing more sensitivity to diagnostic techninques and the understanding of neuroinflammation. Mitochondrial-mediated apoptosis in isolated peripheral blood mononuclear cells and the role of reactive oxygen species are studied as indicators of activity of MS. In these cells, downregulation of circular and linera RNAs are reported as markers of highly active disease in MS. Progress and importance of Neurofilaments determinations in early diagnosis and as a marker of disease activity, and the analysis of the complex mechanisms and therapeutic potential of Sphingosine-1-phosphate receptor modulator are discussed. Epidemiologic observations from a highly diversified area of the world provide more insights into this important aspect of MS; discussions on the clinical challenges posed by spinal cord involvement in demyelinatind disorders and the latest aspects of pediatric onset MS, complement this fine collection of scientific papers. Full article
(This article belongs to the Special Issue Multiple Sclerosis: Diagnosis and Treatment II)

Research

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16 pages, 2318 KiB  
Article
Whole-Transcriptome Analysis in Peripheral Blood Mononuclear Cells from Patients with Lipid-Specific Oligoclonal IgM Band Characterization Reveals Two Circular RNAs and Two Linear RNAs as Biomarkers of Highly Active Disease
by Leire Iparraguirre, Danel Olaverri, Telmo Blasco, Lucía Sepúlveda, Tamara Castillo-Triviño, Mercedes Espiño, Lucienne Costa-Frossard, Álvaro Prada, Luisa María Villar, David Otaegui and Maider Muñoz-Culla
Biomedicines 2020, 8(12), 540; https://doi.org/10.3390/biomedicines8120540 - 26 Nov 2020
Cited by 7 | Viewed by 3428
Abstract
The presence of anti-myelin lipid-specific oligoclonal IgM bands (LS-OCMBs) has been defined as an accurate predictor of an aggressive evolution of multiple sclerosis. However, the detection of this biomarker is performed in cerebrospinal fluid, a quite invasive liquid biopsy. In the present study [...] Read more.
The presence of anti-myelin lipid-specific oligoclonal IgM bands (LS-OCMBs) has been defined as an accurate predictor of an aggressive evolution of multiple sclerosis. However, the detection of this biomarker is performed in cerebrospinal fluid, a quite invasive liquid biopsy. In the present study we aimed at studying the expression profile of miRNA, snoRNA, circRNA and linearRNA in peripheral blood mononuclear cells (PBMCs) from patients with lipid-specific oligoclonal IgM band characterization. We included a total of 89 MS patients, 47 with negative LS-OCMB status and 42 with positive status. Microarray (miRNA and snoRNA) and RNA-seq (circular and linear RNAs) were used to perform the profiling study in the discovery cohort and candidates were validated by RT-qPCR in the whole cohort. The biomarker potential of the candidates was evaluated by ROC curve analysis. RNA-seq and RT-qPCR validation revealed that two circular (hsa_circ_0000478 and hsa_circ_0116639) and two linear RNAs (IRF5 and MTRNR2L8) are downregulated in PBMCs from patients with positive LS-OCMBs. Finally, those RNAs show a performance of a 70% accuracy in some of the combinations. The expression of hsa_circ_0000478, hsa_circ_0116639, IRF5 and MTRNR2L8 might serve as minimally invasive biomarkers of highly active disease. Full article
(This article belongs to the Special Issue Multiple Sclerosis: Diagnosis and Treatment II)
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Graphical abstract

11 pages, 857 KiB  
Article
Multiple Sclerosis in a Multi-Ethnic Population in Houston, Texas: A Retrospective Analysis
by Vicki Mercado, Deepa Dongarwar, Kristen Fisher, Hamisu M. Salihu, George J. Hutton and Fernando X. Cuascut
Biomedicines 2020, 8(12), 534; https://doi.org/10.3390/biomedicines8120534 - 25 Nov 2020
Cited by 8 | Viewed by 2650
Abstract
Multiple Sclerosis (MS) is a progressive neurodegenerative disease that affects more than 2 million people worldwide. Increasing knowledge about MS in different populations has advanced our understanding of disease epidemiology and variation in the natural history of MS among White and minority populations. [...] Read more.
Multiple Sclerosis (MS) is a progressive neurodegenerative disease that affects more than 2 million people worldwide. Increasing knowledge about MS in different populations has advanced our understanding of disease epidemiology and variation in the natural history of MS among White and minority populations. In addition to differences in incidence, African American (AA) and Hispanic patients have greater disease burden and disability in earlier stages of disease compared to White patients. To further characterize MS in AA and Hispanic populations, we conducted a retrospective chart analysis of 112 patients treated at an MS center in Houston, Texas. Here, we describe similarities and differences in clinical presentation, MRI findings, treatment regimens, disability progression, and relapse rate. While we found several similarities between the groups regarding mean age, disability severity, and degree of brain atrophy at diagnosis, we also describe a few divergences. Interestingly, we found that patients who were evaluated by a neurologist at symptom onset had significantly decreased odds of greater disability [defined as Expanded Disability Status Scale (EDSS) > 4.5] at last presentation compared to patients who were not evaluated by a neurologist (OR: 0.04, 95% CI: 0.16–0.9). We also found that active smokers had significantly increased odds of greater disability both at diagnosis and at last clinical encounter compared to nonsmokers (OR: 2.44, 95% CI: 1.10–7.10, OR= 2.44, 95% CI: 1.35–6.12, p = 0.01, respectively). Additionally, we observed significant differences in treatment adherence between groups. Assessment of the degree of brain atrophy and progression over time, along with an enumeration of T1, T2, and gadolinium-enhancing brain lesions, did not reveal differences across groups. Full article
(This article belongs to the Special Issue Multiple Sclerosis: Diagnosis and Treatment II)
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Graphical abstract

12 pages, 3147 KiB  
Article
Longitudinal Serum Neurofilament Levels of Multiple Sclerosis Patients Before and After Treatment with First-Line Immunomodulatory Therapies
by André Huss, Makbule Senel, Ahmed Abdelhak, Benjamin Mayer, Jan Kassubek, Albert C. Ludolph, Markus Otto and Hayrettin Tumani
Biomedicines 2020, 8(9), 312; https://doi.org/10.3390/biomedicines8090312 - 28 Aug 2020
Cited by 16 | Viewed by 3619
Abstract
Serum neurofilament light chain (NfL) has been shown to correlate with neuroaxonal damage in multiple sclerosis (MS) and various other neurological diseases. While serum NfL is now regularly reported in clinical approval studies, there is a lack of longitudinal data from patients treated [...] Read more.
Serum neurofilament light chain (NfL) has been shown to correlate with neuroaxonal damage in multiple sclerosis (MS) and various other neurological diseases. While serum NfL is now regularly reported in clinical approval studies, there is a lack of longitudinal data from patients treated with established basic immunotherapies outside of study conditions. In total, 34 patients with early relapsing-remitting MS (RRMS) were included. The follow-up period was 24 months with regular follow-up visits after 3, 6, 9, 12 and 18 months. Therapy with glatiramer acetate was initiated in 20 patients and with interferon-beta in 12 patients. The disease course was monitored by the events of relapses, Expanded Disability Status Scale (EDSS) score and MRI parameters. Overall, serum NfL levels were higher at time points with a current relapse event than at time points without relapse (12.8 pg/mL vs. 9.7 pg/mL, p = 0.011). At follow-up, relapse-free patients showed significantly reduced serum NfL levels starting from 9 months compared to baseline (p < 0.05) and reduced levels after 12 months compared to baseline (p = 0.013) in patients without EDSS progression for 12 months. In this explorative observational study, our data suggest that the longitudinal measurement of serum NfL may be useful in addition to MRI to monitor disease activity and therapy response. Full article
(This article belongs to the Special Issue Multiple Sclerosis: Diagnosis and Treatment II)
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11 pages, 1865 KiB  
Article
PBMC of Multiple Sclerosis Patients Show Deregulation of OPA1 Processing Associated with Increased ROS and PHB2 Protein Levels
by Domenico De Rasmo, Anna Ferretta, Silvia Russo, Maddalena Ruggieri, Piergiorgio Lasorella, Damiano Paolicelli, Maria Trojano and Anna Signorile
Biomedicines 2020, 8(4), 85; https://doi.org/10.3390/biomedicines8040085 - 11 Apr 2020
Cited by 22 | Viewed by 3766
Abstract
Multiple sclerosis (MS) is an autoimmune disease in which activated lymphocytes affect the central nervous system. Increase of reactive oxygen species (ROS), impairment of mitochondria-mediated apoptosis and mitochondrial alterations have been reported in peripheral lymphocytes of MS patients. Mitochondria-mediated apoptosis is regulated by [...] Read more.
Multiple sclerosis (MS) is an autoimmune disease in which activated lymphocytes affect the central nervous system. Increase of reactive oxygen species (ROS), impairment of mitochondria-mediated apoptosis and mitochondrial alterations have been reported in peripheral lymphocytes of MS patients. Mitochondria-mediated apoptosis is regulated by several mechanisms and proteins. Among others, optic atrophy 1 (OPA1) protein plays a key role in the regulating mitochondrial dynamics, cristae architecture and release of pro-apoptotic factors. Very interesting, mutations in OPA1 gene, have been associated with multiple sclerosis-like disorder. We have analyzed OPA1 and some factors involved in its regulation. Fifteen patients with MS and fifteen healthy control subjects (HC) were enrolled into the study and peripheral blood mononuclear cells (PBMCs) were isolated. H2O2 level was measured spectrofluorimetrically, OPA1, PHB2, SIRT3, and OMA1 were analyzed by western blotting. Statistical analysis was performed using Student’s t-test. The results showed that PBMC of MS patients were characterized by a deregulation of OPA1 processing associated with increased H2O2 production, inactivation of OMA1 and increase of PHB2 protein level. The presented data suggest that the alteration of PHB2, OMA1, and OPA1 processing could be involved in resistance towards apoptosis. These molecular parameters could also be useful to assess disease activity. Full article
(This article belongs to the Special Issue Multiple Sclerosis: Diagnosis and Treatment II)
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Review

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11 pages, 687 KiB  
Review
Blood Neurofilament Light Chain: The Neurologist’s Troponin?
by Simon Thebault, Ronald A. Booth and Mark S. Freedman
Biomedicines 2020, 8(11), 523; https://doi.org/10.3390/biomedicines8110523 - 21 Nov 2020
Cited by 60 | Viewed by 10055
Abstract
Blood neurofilament light chain (NfL) is a marker of neuro-axonal injury showing promising associations with outcomes of interest in several neurological conditions. Although initially discovered and investigated in the cerebrospinal fluid (CSF), the recent development of ultrasensitive digital immunoassay technologies has enabled reliable [...] Read more.
Blood neurofilament light chain (NfL) is a marker of neuro-axonal injury showing promising associations with outcomes of interest in several neurological conditions. Although initially discovered and investigated in the cerebrospinal fluid (CSF), the recent development of ultrasensitive digital immunoassay technologies has enabled reliable detection in serum/plasma, obviating the need for invasive lumbar punctures for longitudinal assessment. The most evidence for utility relates to multiple sclerosis (MS) where it serves as an objective measure of both the inflammatory and degenerative pathologies that characterise this disease. In this review, we summarise the physiology and pathophysiology of neurofilaments before focusing on the technological advancements that have enabled reliable quantification of NfL in blood. As the test case for clinical translation, we then highlight important recent developments linking blood NfL levels to outcomes in MS and the next steps to be overcome before this test is adopted on a routine clinical basis. Full article
(This article belongs to the Special Issue Multiple Sclerosis: Diagnosis and Treatment II)
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24 pages, 2153 KiB  
Review
Sphingosine-1-Phosphate: Its Pharmacological Regulation and the Treatment of Multiple Sclerosis: A Review Article
by Stanley Cohan, Elisabeth Lucassen, Kyle Smoot, Justine Brink and Chiayi Chen
Biomedicines 2020, 8(7), 227; https://doi.org/10.3390/biomedicines8070227 - 18 Jul 2020
Cited by 41 | Viewed by 6178
Abstract
Sphingosine-1-phosphate (S1P), via its G-protein-coupled receptors, is a signaling molecule with important regulatory properties on numerous, widely varied cell types. Five S1P receptors (S1PR1-5) have been identified, each with effects determined by their unique G-protein-driven downstream pathways. The discovery that lymphocyte egress from [...] Read more.
Sphingosine-1-phosphate (S1P), via its G-protein-coupled receptors, is a signaling molecule with important regulatory properties on numerous, widely varied cell types. Five S1P receptors (S1PR1-5) have been identified, each with effects determined by their unique G-protein-driven downstream pathways. The discovery that lymphocyte egress from peripheral lymphoid organs is promoted by S1P via S1PR-1 stimulation led to the development of pharmacological agents which are S1PR antagonists. These agents promote lymphocyte sequestration and reduce lymphocyte-driven inflammatory damage of the central nervous system (CNS) in animal models, encouraging their examination of efficacy in the treatment of multiple sclerosis (MS). Preclinical research has also demonstrated direct protective effects of S1PR antagonists within the CNS, by modulation of S1PRs, particularly S1PR-1 and S1PR-5, and possibly S1PR-2, independent of effects upon lymphocytes. Three of these agents, fingolimod, siponimod and ozanimod have been approved, and ponesimod has been submitted for regulatory approval. In patients with MS, these agents reduce relapse risk, sustained disability progression, magnetic resonance imaging markers of disease activity, and whole brain and/or cortical and deep gray matter atrophy. Future opportunities in the development of more selective and intracellular S1PR-driven downstream pathway modulators may expand the breadth of agents to treat MS. Full article
(This article belongs to the Special Issue Multiple Sclerosis: Diagnosis and Treatment II)
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15 pages, 3742 KiB  
Review
Possible Correlation between Cholinergic System Alterations and Neuro/Inflammation in Multiple Sclerosis
by Valentina Gatta, Guadalupe Mengod, Marcella Reale and Ada Maria Tata
Biomedicines 2020, 8(6), 153; https://doi.org/10.3390/biomedicines8060153 - 8 Jun 2020
Cited by 31 | Viewed by 6547
Abstract
Multiple sclerosis (MS) is an autoimmune and demyelinating disease of the central nervous system. Although the etiology of MS is still unknown, both genetic and environmental factors contribute to the pathogenesis of the disease. Acetylcholine participates in the modulation of central and peripheral [...] Read more.
Multiple sclerosis (MS) is an autoimmune and demyelinating disease of the central nervous system. Although the etiology of MS is still unknown, both genetic and environmental factors contribute to the pathogenesis of the disease. Acetylcholine participates in the modulation of central and peripheral inflammation. The cells of the immune system, as well as microglia, astrocytes and oligodendrocytes express cholinergic markers and receptors of muscarinic and nicotinic type. The role played by acetylcholine in MS has been recently investigated. In the present review, we summarize the evidence indicating the cholinergic dysfunction in serum and cerebrospinal fluid of relapsing–remitting (RR)-MS patients and in the brains of the MS animal model experimental autoimmune encephalomyelitis (EAE). The correlation between the increased activity of the cholinergic hydrolyzing enzymes acetylcholinesterase and butyrylcholinesterase, the reduced levels of acetylcholine and the increase of pro-inflammatory cytokines production were recently described in immune cells of MS patients. Moreover, the genetic polymorphisms for both hydrolyzing enzymes and the possible correlation with the altered levels of their enzymatic activity have been also reported. Finally, the changes in cholinergic markers expression in the central nervous system of EAE mice in peak and chronic phases suggest the involvement of the acetylcholine also in neuro-inflammatory processes. Full article
(This article belongs to the Special Issue Multiple Sclerosis: Diagnosis and Treatment II)
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Graphical abstract

25 pages, 2230 KiB  
Review
Spinal Cord Involvement in MS and Other Demyelinating Diseases
by Mariano Marrodan, María I. Gaitán and Jorge Correale
Biomedicines 2020, 8(5), 130; https://doi.org/10.3390/biomedicines8050130 - 22 May 2020
Cited by 12 | Viewed by 18961
Abstract
Diagnostic accuracy is poor in demyelinating myelopathies, and therefore a challenge for neurologists in daily practice, mainly because of the multiple underlying pathophysiologic mechanisms involved in each subtype. A systematic diagnostic approach combining data from the clinical setting and presentation with magnetic resonance [...] Read more.
Diagnostic accuracy is poor in demyelinating myelopathies, and therefore a challenge for neurologists in daily practice, mainly because of the multiple underlying pathophysiologic mechanisms involved in each subtype. A systematic diagnostic approach combining data from the clinical setting and presentation with magnetic resonance imaging (MRI) lesion patterns, cerebrospinal fluid (CSF) findings, and autoantibody markers can help to better distinguish between subtypes. In this review, we describe spinal cord involvement, and summarize clinical findings, MRI and diagnostic characteristics, as well as treatment options and prognostic implications in different demyelinating disorders including: multiple sclerosis (MS), neuromyelitis optica spectrum disorder, acute disseminated encephalomyelitis, anti-myelin oligodendrocyte glycoprotein antibody-associated disease, and glial fibrillary acidic protein IgG-associated disease. Thorough understanding of individual case etiology is crucial, not only to provide valuable prognostic information on whether the disorder is likely to relapse, but also to make therapeutic decision-making easier and reduce treatment failures which may lead to new relapses and long-term disability. Identifying patients with monophasic disease who may only require acute management, symptomatic treatment, and subsequent rehabilitation, rather than immunosuppression, is also important. Full article
(This article belongs to the Special Issue Multiple Sclerosis: Diagnosis and Treatment II)
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Graphical abstract

14 pages, 223 KiB  
Review
Current Advances in Pediatric Onset Multiple Sclerosis
by Kristen S. Fisher, Fernando X. Cuascut, Victor M. Rivera and George J. Hutton
Biomedicines 2020, 8(4), 71; https://doi.org/10.3390/biomedicines8040071 - 28 Mar 2020
Cited by 32 | Viewed by 5478
Abstract
Multiple sclerosis (MS) is an autoimmune inflammatory disease affecting the central nervous system leading to demyelination. MS in the pediatric population is rare, but has been shown to lead to significant disability over the duration of the disease. As we have learned more [...] Read more.
Multiple sclerosis (MS) is an autoimmune inflammatory disease affecting the central nervous system leading to demyelination. MS in the pediatric population is rare, but has been shown to lead to significant disability over the duration of the disease. As we have learned more about pediatric MS, there has been a development of improved diagnostic criteria leading to earlier diagnosis, earlier initiation of disease-modifying therapies (DMT), and an increasing number of DMT used in the treatment of pediatric MS. Over time, treatment with DMT has trended towards the initiation of higher efficacy treatment at time of diagnosis to help prevent further disease progression and accrual of disability over time, and there is evidence in current literature that supports this change in treatment patterns. In this review, we discuss the current knowledge in diagnosis, treatment, and clinical outcomes in pediatric MS. Full article
(This article belongs to the Special Issue Multiple Sclerosis: Diagnosis and Treatment II)
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