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Special Issue "Advances in Multiple Sclerosis 2016"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 September 2016).

Special Issue Editors

Guest Editor
Prof. Dr. Christoph Kleinschnitz

Universitätsklinikum Essen (AöR), Klinik für Neurologie, Hufelandstraße 55, D-45147 Essen, Germany
Website | E-Mail
Interests: neuroimmunology; emphasis on Multiple Sclerosis; stroke (experimental/clinical); thromboinflammation; immune system/inflammation; neuroprotection; cellular and molecular neuroimaging by magnetic resonance imaging
Guest Editor
Prof. Dr. Sven G. Meuth

Westfalische Wilhelms-Universitat Munster, Department of Neurology, Munster, Germany
Website | E-Mail
Interests: animal models of autoimmune inflammation; ion channels in inflammation and degeneration; neuroimmune interactio

Special Issue Information

Dear Colleagues,

Study of Multiple Sclerosis (MS) is one of the most exciting, emerging fields in neurology. Recent pathophysiological insights, derived from both animal models and clinical studies, paved the way for the regulatory approval of novel MS treatments, most recently the novel B-cell depleting antibody ocrelizumab showed promising results in phase III trials in relapsing-remitting (RRMS) and primary progressive MS (PPMS). Some of these compounds possibly act beyond their well-established immunomodulatory properties, for instance, by inducing direct neuroprotection or neuroregeneration (e.g., Anti-LINGO-1). Of note, even childhood MS has been recognized as a significant medical problem demonstrating axonal degeneration early in the disease course and novel therapies are increasingly tested for this population. However, important, unmet medical needs remain and the quest for even more sophisticated treatment strategies continues. For example, promising preclinical data exist regarding the modulation of certain ion channels expressed on immune cells, B cell function in PPMS, and the functional state of the blood-brain-barrier. Additionally, the search for novel biomarkers predicting treatment responses and/or disease progression is ongoing. Improved imaging techniques, such as diffusion tensor imaging or optical coherence tomography, have helped gain in vivo insights into the pathophysiological processes directly acting in MS patients.

The upcoming Special Issue on "Advances in Multiple Sclerosis" will cover all aspects of this most prevalent neuroimmunological disease. We invite authors to submit original articles or state-of-the art reviews on MS pathophysiology, therapy, epidemiology, environmental factors, and imaging. All contributions will undergo a rapid, fair, and concise review process to minimize publication times.

We look forward to receiving your valuable submissions.

Prof. Christoph Kleinschnitz
Prof. Sven Meuth
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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
  • therapy
  • epidemiology
  • diagnosis
  • imaging
  • environmental factors

Published Papers (18 papers)

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Research

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Open AccessArticle
Expression of the Antioxidative Enzyme Peroxiredoxin 2 in Multiple Sclerosis Lesions in Relation to Inflammation
Int. J. Mol. Sci. 2017, 18(4), 760; https://doi.org/10.3390/ijms18040760
Received: 25 November 2016 / Revised: 28 March 2017 / Accepted: 29 March 2017 / Published: 4 April 2017
Cited by 8 | PDF Full-text (3631 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Multiple sclerosis is a chronic inflammatory disease of the central nervous system, characterized by demyelination and axonal damage as well as neuronal degeneration. Since oxygen-derived free radicals are an important factor leading to tissue damage in inflammatory multiple sclerosis (MS) lesions, research on [...] Read more.
Multiple sclerosis is a chronic inflammatory disease of the central nervous system, characterized by demyelination and axonal damage as well as neuronal degeneration. Since oxygen-derived free radicals are an important factor leading to tissue damage in inflammatory multiple sclerosis (MS) lesions, research on antioxidative systems is essential to identify endogenous factors which can possibly counteract oxidative damage. As an important scavenging enzyme family, peroxiredoxins (PRDXs) play a crucial role in preventing oxidative damage; however little is known about their expression and function in MS lesions. In the present study we examined the expression of PRDX2 in white matter lesions of MS patients with long-standing, chronic disease. PRDX2 expression was investigated by immunohistochemistry in the context of oxidative stress and inflammation (determined by microglia/macrophage and T cell infiltration) in ten MS autopsy cases as well as seven control autopsy cases. PRDX2 was found to be upregulated in white matter MS lesions mainly in astrocytes, and its expression level was positively correlated with the degree of inflammation and oxidative stress. Our data suggest that PRDX2 expression contributes to the resistance of astrocytes against oxidative damage. Full article
(This article belongs to the Special Issue Advances in Multiple Sclerosis 2016)
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Open AccessArticle
Dimethyl Fumarate Therapy Significantly Improves the Responsiveness of T Cells in Multiple Sclerosis Patients for Immunoregulation by Regulatory T Cells
Int. J. Mol. Sci. 2017, 18(2), 271; https://doi.org/10.3390/ijms18020271
Received: 23 December 2016 / Revised: 14 January 2017 / Accepted: 22 January 2017 / Published: 28 January 2017
Cited by 12 | PDF Full-text (2724 KB) | HTML Full-text | XML Full-text
Abstract
Multiple sclerosis (MS) is a chronic autoimmune disease caused by an insufficient suppression of autoreactive T lymphocytes. One reason for the lack of immunological control is the reduced responsiveness of T effector cells (Teff) for the suppressive properties of regulatory T cells (Treg), [...] Read more.
Multiple sclerosis (MS) is a chronic autoimmune disease caused by an insufficient suppression of autoreactive T lymphocytes. One reason for the lack of immunological control is the reduced responsiveness of T effector cells (Teff) for the suppressive properties of regulatory T cells (Treg), a process termed Treg resistance. Here we investigated whether the disease-modifying therapy of relapsing-remitting MS (RRMS) with dimethyl fumarate (DMF) influences the sensitivity of T cells in the peripheral blood of patients towards Treg-mediated suppression. We demonstrated that DMF restores responsiveness of Teff to the suppressive function of Treg in vitro, presumably by down-regulation of interleukin-6R (IL-6R) expression on T cells. Transfer of human immune cells into immunodeficient mice resulted in a lethal graft-versus-host reaction triggered by human CD4+ Teff. This systemic inflammation can be prevented by activated Treg after transfer of immune cells from DMF-treated MS patients, but not after injection of Treg-resistant Teff from therapy-naïve MS patients. Furthermore, after DMF therapy, proliferation and expansion of T cells and the immigration into the spleen of the animals is reduced and modulated by activated Treg. In summary, our data reveals that DMF therapy significantly improves the responsiveness of Teff in MS patients to immunoregulation. Full article
(This article belongs to the Special Issue Advances in Multiple Sclerosis 2016)
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Open AccessArticle
Contribution of Gray and White Matter Abnormalities to Cognitive Impairment in Multiple Sclerosis
Int. J. Mol. Sci. 2017, 18(1), 46; https://doi.org/10.3390/ijms18010046
Received: 15 September 2016 / Revised: 10 December 2016 / Accepted: 16 December 2016 / Published: 27 December 2016
Cited by 11 | PDF Full-text (2477 KB) | HTML Full-text | XML Full-text
Abstract
Patients with multiple sclerosis (MS) commonly exhibit cognitive impairments (CI). However, the neural mechanisms underlying CI remain unclear. The current study applied diffusion tensor imaging (DTI) and voxel-based morphometric (VBM) magnetic resonance imaging (MRI) techniques to evaluate differences in white matter (WM) integrity [...] Read more.
Patients with multiple sclerosis (MS) commonly exhibit cognitive impairments (CI). However, the neural mechanisms underlying CI remain unclear. The current study applied diffusion tensor imaging (DTI) and voxel-based morphometric (VBM) magnetic resonance imaging (MRI) techniques to evaluate differences in white matter (WM) integrity and gray matter (GM) volume between MS patients with CI and MS patients with cognitive preservation (CP). Neuropsychological assessment and MRI were obtained from 39 relapsing-remitting MS (RRMS) patients and 29 healthy controls (HCs). Patients were classified as CI or CP according to cognitive ability, and demographic characteristics and MRI images were compared. Compared with HCs, MS patients exhibited widespread damage in WM integrity, and GM loss in several regions. Compared with CP patients, CI patients exhibited more extensive WM impairments, particularly in the corpus callosum, cerebellar peduncle, corona radiata, optic radiation, superior longitudinal fasciculus, anterior limb of the internal capsule, and cingulate, as well as decreased GM volume in the bilateral caudate, left insula and right temporal lobe. MS patients with CI exhibited more significant structural abnormalities than those with CP. Widespread impairments of WM integrity and selective GM atrophy both appear to be associated with impaired cognition in RRMS. Full article
(This article belongs to the Special Issue Advances in Multiple Sclerosis 2016)
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Open AccessArticle
Dysregulated Homeostasis of Acetylcholine Levels in Immune Cells of RR-Multiple Sclerosis Patients
Int. J. Mol. Sci. 2016, 17(12), 2009; https://doi.org/10.3390/ijms17122009
Received: 24 September 2016 / Revised: 10 November 2016 / Accepted: 22 November 2016 / Published: 30 November 2016
Cited by 6 | PDF Full-text (1349 KB) | HTML Full-text | XML Full-text
Abstract
Multiple sclerosis (MS) is characterized by pro-inflammatory cytokine production. Acetylcholine (ACh) contributes to the modulation of central and peripheral inflammation. We studied the homeostasis of the cholinergic system in relation to cytokine levels in immune cells and sera of relapsing remitting-MS (RR-MS) patients. [...] Read more.
Multiple sclerosis (MS) is characterized by pro-inflammatory cytokine production. Acetylcholine (ACh) contributes to the modulation of central and peripheral inflammation. We studied the homeostasis of the cholinergic system in relation to cytokine levels in immune cells and sera of relapsing remitting-MS (RR-MS) patients. We demonstrated that lower ACh levels in serum of RR-MS patients were inversely correlated with the increased activity of the hydrolyzing enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Interestingly, the expression of the ACh biosynthetic enzyme and the protein carriers involved in non-vesicular ACh release were found overexpressed in peripheral blood mononuclear cells of MS patients. The inflammatory state of the MS patients was confirmed by increased levels of TNFα, IL-12/IL-23p40, IL-18. The lower circulating ACh levels in sera of MS patients are dependent on the higher activity of cholinergic hydrolyzing enzymes. The smaller ratio of ACh to TNFα, IL-12/IL-23p40 and IL-18 in MS patients, with respect to healthy donors (HD), is indicative of an inflammatory environment probably related to the alteration of cholinergic system homeostasis. Full article
(This article belongs to the Special Issue Advances in Multiple Sclerosis 2016)
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Open AccessArticle
Internet-Supported Physical Exercise Training for Persons with Multiple Sclerosis—A Randomised, Controlled Study
Int. J. Mol. Sci. 2016, 17(10), 1667; https://doi.org/10.3390/ijms17101667
Received: 9 August 2016 / Revised: 22 September 2016 / Accepted: 26 September 2016 / Published: 30 September 2016
Cited by 15 | PDF Full-text (1119 KB) | HTML Full-text | XML Full-text
Abstract
Physical exercise is effective in improving functional outcomes in persons with multiple sclerosis (pwMS). We evaluated the feasibility and effectiveness of internet-based exercise training (e-training) for pwMS on health-related quality of life (HrQoL). Secondary outcomes were muscle strength, aerobic capacity, lung function, physical [...] Read more.
Physical exercise is effective in improving functional outcomes in persons with multiple sclerosis (pwMS). We evaluated the feasibility and effectiveness of internet-based exercise training (e-training) for pwMS on health-related quality of life (HrQoL). Secondary outcomes were muscle strength, aerobic capacity, lung function, physical activity, and fatigue. This is a randomised, controlled trial with a wait-list control group. Data were collected at baseline, after three and six months, and analysed using a hybrid linear model. One-hundred twenty-six pwMS participated in the home-based aerobic (1×/week) and strength training (2×/week) intervention that was supervised and documented via an internet-platform. The intervention group received e-training for six months, and the control group received e-training after a three months waiting period. Significant differences between the groups were only observed for muscle strength (knee flexion (effect size ES = 0.3, p = 0.003), knee extension (ES = 0.24, p = 0.015)), peak expiratory flow (ES = 0.2, p = 0.039), and sports activity (ES = 0.33, p = 0.001) after three months. E-training had no effect on HrQoL but did on muscle strength, lung function, and physical activity. It is a promising and feasible approach to facilitate large-scale, yet individual, training support. Full article
(This article belongs to the Special Issue Advances in Multiple Sclerosis 2016)
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Open AccessArticle
Disease Activity and Conversion into Multiple Sclerosis after Optic Neuritis Is Treated with Erythropoietin
Int. J. Mol. Sci. 2016, 17(10), 1666; https://doi.org/10.3390/ijms17101666
Received: 28 July 2016 / Revised: 20 September 2016 / Accepted: 28 September 2016 / Published: 30 September 2016
Cited by 2 | PDF Full-text (438 KB) | HTML Full-text | XML Full-text
Abstract
Changes in cerebral lesion load by magnetic resonance imaging (MRI) in patients from a double-blind, placebo-controlled, phase II study on erythropoietin in clinically isolated optic neuritis (ClinicalTrials.gov, NCT00355095) were analyzed. Therefore, patients with acute optic neuritis were assigned to receive either 33,000 IU [...] Read more.
Changes in cerebral lesion load by magnetic resonance imaging (MRI) in patients from a double-blind, placebo-controlled, phase II study on erythropoietin in clinically isolated optic neuritis (ClinicalTrials.gov, NCT00355095) were analyzed. Therefore, patients with acute optic neuritis were assigned to receive either 33,000 IU of recombinant human erythropoietin (IV) daily for three days, or a placebo, as an add-on to methylprednisolone. Of 35 patients, we investigated changes in cerebral lesion load in MRIs obtained at baseline and at weeks 4, 8, and 16. In 5 of the 35 patients, we found conversion into multiple sclerosis (MS) based on MRI progression only. These five patients had received the placebo. Another five patients showed MRI progression together with relapses. Three of these patients had received erythropoietin, and two the placebo. Yet, analyzing the change in absolute numbers of periventricular, juxtacortical, and infratentorial lesions including gadolinium-enhancing lesions, there were no significant differences between the groups. Although effective in terms of retinal nerve fiber layer protection, erythropoietin treatment of acute isolated optic neuritis did not influence further evolution of MRI lesions in the brain when comparing absolute numbers. However, early conversion from clinically isolated syndrome to MS assessed by MRI activity seemed to occur more frequently in the placebo-treated group. Full article
(This article belongs to the Special Issue Advances in Multiple Sclerosis 2016)
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Open AccessArticle
McDonald Criteria 2010 and 2005 Compared: Persistence of High Oligoclonal Band Prevalence Despite Almost Doubled Diagnostic Sensitivity
Int. J. Mol. Sci. 2016, 17(9), 1592; https://doi.org/10.3390/ijms17091592
Received: 28 July 2016 / Revised: 7 September 2016 / Accepted: 9 September 2016 / Published: 21 September 2016
Cited by 15 | PDF Full-text (404 KB) | HTML Full-text | XML Full-text
Abstract
The 2010 McDonald criteria were developed to allow a more rapid diagnosis of relapsing-remitting multiple sclerosis (MS) by only one MRI of the brain. Although cerebrospinal fluid (CSF) is not a mandatory part of the latest criteria, the evidence of an intrathecal humoral [...] Read more.
The 2010 McDonald criteria were developed to allow a more rapid diagnosis of relapsing-remitting multiple sclerosis (MS) by only one MRI of the brain. Although cerebrospinal fluid (CSF) is not a mandatory part of the latest criteria, the evidence of an intrathecal humoral immunoreaction in the form of oligoclonal bands (OCB) is crucial in the diagnostic workup. To date, the impact of the 2010 McDonald criteria on the prevalence of OCB has not been investigated. We retrospectively evaluated data of 325 patients with a clinical relapse suggestive of demyelination that were treated in a German university hospital between 2010 and 2015. One hundred thirty-six patients (42%) were diagnosed with MS and 189 patients with CIS when the criteria of 2010 were applied. The criteria of 2005 allowed only 70 patients (22%) to be designated as MS. In contrast, the prevalence of OCB was marginal affected in MS patients with 96% for the criteria of 2010 and 98.5% for the criteria of 2005. In conclusion, OCB are prevalent in most MS patients and reflect the chronic inflammatory nature of the disease. We recommend CSF examination to exclude alternative diagnoses and reevaluation of the diagnosis MS in patients with negative OCB. Full article
(This article belongs to the Special Issue Advances in Multiple Sclerosis 2016)
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Open AccessArticle
Regulatory Cell Populations in Relapsing-Remitting Multiple Sclerosis (RRMS) Patients: Effect of Disease Activity and Treatment Regimens
Int. J. Mol. Sci. 2016, 17(9), 1398; https://doi.org/10.3390/ijms17091398
Received: 13 July 2016 / Revised: 10 August 2016 / Accepted: 19 August 2016 / Published: 25 August 2016
Cited by 2 | PDF Full-text (5617 KB) | HTML Full-text | XML Full-text
Abstract
Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) of autoimmune etiology that results from an imbalance between CNS-specific T effector cells and peripheral suppressive mechanisms mediated by regulatory cells (RC). In this research, we collected blood samples from [...] Read more.
Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) of autoimmune etiology that results from an imbalance between CNS-specific T effector cells and peripheral suppressive mechanisms mediated by regulatory cells (RC). In this research, we collected blood samples from 83 relapsing remitting MS (RRMS) patients and 45 healthy persons (HC), to assess the sizes of their RC populations, including CD4+CD25highFoxp3+ (nTregs), CD3+CD4+HLAG+, CD3+CD8+CD28, CD3+CD56+, and CD56bright cells, and how RC are affected by disease activity (acute phase or remission) and types of treatment (methylprednisolone, interferon, or natalizumab). In addition, we isolated peripheral blood mononuclear cells (PBMC) and cultured them with peptides mapping to myelin antigens, to determine RC responsiveness to autoantigens. The results showed decreased levels of nTregs in patients in the acute phase ± methylprednisolone and in remission + natalizumab, but HC levels in patients in remission or receiving interferon. Patients + interferon had the highest levels of CD3+CD4+HLAG+ and CD3+CD8+CD28 RC, and patients in the acute phase + methylprednisolone the lowest. Patients in remission had the highest levels of CD3+CD56+, and patients in remission + natalizumab the highest levels of CD56bright cells. Only nTregs responded to autoantigens in culture, regardless of disease activity or treatment. The highest suppressive activity was exhibited by nTregs from patients in remission. In conclusion, in RRMS disease activity and type of treatment affect different RC populations. nTregs respond to myelin antigens, indicating that it is possible to restore immunological tolerance through nTreg induction. Full article
(This article belongs to the Special Issue Advances in Multiple Sclerosis 2016)
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Open AccessArticle
Meta-Analysis of Differential Connectivity in Gene Co-Expression Networks in Multiple Sclerosis
Int. J. Mol. Sci. 2016, 17(6), 936; https://doi.org/10.3390/ijms17060936
Received: 1 March 2016 / Revised: 9 May 2016 / Accepted: 24 May 2016 / Published: 15 June 2016
Cited by 1 | PDF Full-text (2097 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Differential gene expression analyses to investigate multiple sclerosis (MS) molecular pathogenesis cannot detect genes harboring genetic and/or epigenetic modifications that change the gene functions without affecting their expression. Differential co-expression network approaches may capture changes in functional interactions resulting from these alterations. We [...] Read more.
Differential gene expression analyses to investigate multiple sclerosis (MS) molecular pathogenesis cannot detect genes harboring genetic and/or epigenetic modifications that change the gene functions without affecting their expression. Differential co-expression network approaches may capture changes in functional interactions resulting from these alterations. We re-analyzed 595 mRNA arrays from publicly available datasets by studying changes in gene co-expression networks in MS and in response to interferon (IFN)-β treatment. Interestingly, MS networks show a reduced connectivity relative to the healthy condition, and the treatment activates the transcription of genes and increases their connectivity in MS patients. Importantly, the analysis of changes in gene connectivity in MS patients provides new evidence of association for genes already implicated in MS by single-nucleotide polymorphism studies and that do not show differential expression. This is the case of amiloride-sensitive cation channel 1 neuronal (ACCN1) that shows a reduced number of interacting partners in MS networks, and it is known for its role in synaptic transmission and central nervous system (CNS) development. Furthermore, our study confirms a deregulation of the vitamin D system: among the transcription factors that potentially regulate the deregulated genes, we find TCF3 and SP1 that are both involved in vitamin D3-induced p27Kip1 expression. Unveiling differential network properties allows us to gain systems-level insights into disease mechanisms and may suggest putative targets for the treatment. Full article
(This article belongs to the Special Issue Advances in Multiple Sclerosis 2016)
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Open AccessArticle
Offspring Number Does Not Influence Reaching the Disability’s Milestones in Multiple Sclerosis: A Seven-Year Follow-Up Study
Int. J. Mol. Sci. 2016, 17(2), 234; https://doi.org/10.3390/ijms17020234
Received: 5 November 2015 / Revised: 20 January 2016 / Accepted: 21 January 2016 / Published: 12 February 2016
Cited by 3 | PDF Full-text (685 KB) | HTML Full-text | XML Full-text
Abstract
Objectives: data on pregnancy long-term effects on multiple sclerosis (MS) course are still controversial; whether experiencing more than one pregnancy exposes one to risk of the disability‘s accrual is still unknown. We investigated differences existing in terms of disability progression among women with [...] Read more.
Objectives: data on pregnancy long-term effects on multiple sclerosis (MS) course are still controversial; whether experiencing more than one pregnancy exposes one to risk of the disability‘s accrual is still unknown. We investigated differences existing in terms of disability progression among women with MS (wwMS) who had one or more children after their MS onset. Methods: Monoparous and multiparous wwMS were enrolled from the Catania MS Center, Italy, in a monocenter retrospective study. A Cox proportional hazards model was used to examine the effect of the number of parities on time from MS disease onset to EDSS 4.0 and 6.0. The study protocol was approved by the local Ethical Committee. Results: during the seven years of observation, 32.1% and 23.2% of the monoparous group reached expanded disability disease status (EDSS) 4.0 and 6.0 respectively, compared to 13.3% and 3.3% of the multiparous group (p = 0.057 and p = 0.017; respectively). The Kaplan–Meier curve analysis showed no statistically-significant differences between the two groups in reaching the two milestones. The multiparous group showed a longer time to reach the EDSS 4.0 (3.5 vs. 2.6 years, log-rank 0.57, p = 0.45). The Cox regression analysis showed that the EDSS at the time of first pregnancy (Exp(B) 9.4, CI 4.5–19.7, p< 0.001) and the time from MS onset to first pregnancy (Exp(B) 0.96, CI = 0.93–0.98, p < 0.05) were significant predictors of reaching the EDSS 4.0, whereas a model including only the EDSS one year after the first pregnancy significantly predicted (Exp(B) value of 6.4, CI 2.6–15.4, p < 0.001) the reaching of EDSS 6.0. Conclusions: Our results suggest that experiencing more than one pregnancy could not convey a different clinical outcome in wwMS. Further research is needed to confirm our results. Full article
(This article belongs to the Special Issue Advances in Multiple Sclerosis 2016)
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Review

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Open AccessReview
Excitotoxins, Mitochondrial and Redox Disturbances in Multiple Sclerosis
Int. J. Mol. Sci. 2017, 18(2), 353; https://doi.org/10.3390/ijms18020353
Received: 12 October 2016 / Revised: 20 January 2017 / Accepted: 22 January 2017 / Published: 8 February 2017
Cited by 8 | PDF Full-text (911 KB) | HTML Full-text | XML Full-text
Abstract
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). There is increasing evidence that MS is not only characterized by immune mediated inflammatory reactions, but also by neurodegenerative processes. There is cumulating evidence that neurodegenerative processes, for example [...] Read more.
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). There is increasing evidence that MS is not only characterized by immune mediated inflammatory reactions, but also by neurodegenerative processes. There is cumulating evidence that neurodegenerative processes, for example mitochondrial dysfunction, oxidative stress, and glutamate (Glu) excitotoxicity, seem to play an important role in the pathogenesis of MS. The alteration of mitochondrial homeostasis leads to the formation of excitotoxins and redox disturbances. Mitochondrial dysfunction (energy disposal failure, apoptosis, etc.), redox disturbances (oxidative stress and enhanced reactive oxygen and nitrogen species production), and excitotoxicity (Glu mediated toxicity) may play an important role in the progression of the disease, causing axonal and neuronal damage. This review focuses on the mechanisms of mitochondrial dysfunction (including mitochondrial DNA (mtDNA) defects and mitochondrial structural/functional changes), oxidative stress (including reactive oxygen and nitric species), and excitotoxicity that are involved in MS and also discusses the potential targets and tools for therapeutic approaches in the future. Full article
(This article belongs to the Special Issue Advances in Multiple Sclerosis 2016)
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Open AccessReview
Fingolimod Associated Bilateral Cystoid Macular Edema—Wait and See?
Int. J. Mol. Sci. 2016, 17(12), 2106; https://doi.org/10.3390/ijms17122106
Received: 29 July 2016 / Accepted: 7 December 2016 / Published: 14 December 2016
Cited by 1 | PDF Full-text (18937 KB) | HTML Full-text | XML Full-text
Abstract
Fingolimod 0.5-mg once-daily is an approved therapy for patients with relapsing–remitting multiple sclerosis (MS). Several pivotal and real-world studies have demonstrated that fingolimod is associated with the development of macular edema (ME). Herein, we present a case of a diabetic MS patient who [...] Read more.
Fingolimod 0.5-mg once-daily is an approved therapy for patients with relapsing–remitting multiple sclerosis (MS). Several pivotal and real-world studies have demonstrated that fingolimod is associated with the development of macular edema (ME). Herein, we present a case of a diabetic MS patient who developed severe bilateral ME during fingolimod treatment. By means of this case study we provide a detailed review about fingolimod associated macular edema (FAME), its current incidence with or without diabetes mellitus, and previous therapy attempts and outcomes in MS patients. Intravitreal administration of antibodies raised against vascular endothelial growth factor A (VEGF-A) has not yet been used in the management of FAME, however, the excellent therapeutic response in our patient may justify the use of anti-VEGF-A agents in combination with cessation of fingolimod to achieve fast resolution of FAME and to prevent visual deficits, particularly in bilateral FAME. Full article
(This article belongs to the Special Issue Advances in Multiple Sclerosis 2016)
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Open AccessReview
Prolactin: Friend or Foe in Central Nervous System Autoimmune Inflammation?
Int. J. Mol. Sci. 2016, 17(12), 2026; https://doi.org/10.3390/ijms17122026
Received: 9 October 2016 / Revised: 19 November 2016 / Accepted: 28 November 2016 / Published: 2 December 2016
Cited by 4 | PDF Full-text (405 KB) | HTML Full-text | XML Full-text
Abstract
The higher prevalence of multiple sclerosis (MS) in females, along with the modulation of disease activity observed during pregnancy and the post-partum period, has suggested a hormonal influence in MS. Even if prolactin (PRL) does not belong to the sex hormones family, its [...] Read more.
The higher prevalence of multiple sclerosis (MS) in females, along with the modulation of disease activity observed during pregnancy and the post-partum period, has suggested a hormonal influence in MS. Even if prolactin (PRL) does not belong to the sex hormones family, its crucial role in female reproduction and lactation has prompted great efforts to understand if PRL could represent a gender factor in the pathogenesis of MS and experimental autoimmune encephalomyelitis (EAE), the animal model for this disease. Extensive literature has documented a remarkable immune-stimulating potential for this hormone, indicating PRL as a disease-promoting factor in MS and EAE. However, recent work has pointed out that PRL is endowed with important neuroprotective and remyelinating properties and has encouraged a reinterpretation of the involvement of this hormone in MS. In this review we summarize both the protective functions that PRL exerts in central nervous system tissue as well as the inflammatory activity of this hormone in the context of autoimmune responses against myelin. Last, we draw future lines of research that might help to better clarify the impact of PRL on MS pathology. Full article
(This article belongs to the Special Issue Advances in Multiple Sclerosis 2016)
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Open AccessReview
Optical Coherence Tomography and Magnetic Resonance Imaging in Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorder
Int. J. Mol. Sci. 2016, 17(11), 1894; https://doi.org/10.3390/ijms17111894
Received: 17 September 2016 / Revised: 4 November 2016 / Accepted: 6 November 2016 / Published: 15 November 2016
Cited by 11 | PDF Full-text (1457 KB) | HTML Full-text | XML Full-text
Abstract
Irreversible disability in multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) is largely attributed to neuronal and axonal degeneration, which, along with inflammation, is one of the major pathological hallmarks of these diseases. Optical coherence tomography (OCT) is a non-invasive imaging tool [...] Read more.
Irreversible disability in multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) is largely attributed to neuronal and axonal degeneration, which, along with inflammation, is one of the major pathological hallmarks of these diseases. Optical coherence tomography (OCT) is a non-invasive imaging tool that has been used in MS, NMOSD, and other diseases to quantify damage to the retina, including the ganglion cells and their axons. The fact that these are the only unmyelinated axons within the central nervous system (CNS) renders the afferent visual pathway an ideal model for studying axonal and neuronal degeneration in neurodegenerative diseases. Structural magnetic resonance imaging (MRI) can be used to obtain anatomical information about the CNS and to quantify evolving pathology in MS and NMOSD, both globally and in specific regions of the visual pathway including the optic nerve, optic radiations and visual cortex. Therefore, correlations between brain or optic nerve abnormalities on MRI, and retinal pathology using OCT, may shed light on how damage to one part of the CNS can affect others. In addition, these imaging techniques can help identify important differences between MS and NMOSD such as disease-specific damage to the visual pathway, trans-synaptic degeneration, or pathological changes independent of the underlying disease process. This review focuses on the current knowledge of the role of the visual pathway using OCT and MRI in patients with MS and NMOSD. Emphasis is placed on studies that employ both MRI and OCT to investigate damage to the visual system in these diseases. Full article
(This article belongs to the Special Issue Advances in Multiple Sclerosis 2016)
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Open AccessReview
Taking Advantage of Nature’s Gift: Can Endogenous Neural Stem Cells Improve Myelin Regeneration?
Int. J. Mol. Sci. 2016, 17(11), 1895; https://doi.org/10.3390/ijms17111895
Received: 15 September 2016 / Revised: 28 October 2016 / Accepted: 9 November 2016 / Published: 14 November 2016
Cited by 5 | PDF Full-text (515 KB) | HTML Full-text | XML Full-text
Abstract
Irreversible functional deficits in multiple sclerosis (MS) are directly correlated to axonal damage and loss. Neurodegeneration results from immune-mediated destruction of myelin sheaths and subsequent axonal demyelination. Importantly, oligodendrocytes, the myelinating glial cells of the central nervous system, can be replaced to some [...] Read more.
Irreversible functional deficits in multiple sclerosis (MS) are directly correlated to axonal damage and loss. Neurodegeneration results from immune-mediated destruction of myelin sheaths and subsequent axonal demyelination. Importantly, oligodendrocytes, the myelinating glial cells of the central nervous system, can be replaced to some extent to generate new myelin sheaths. This endogenous regeneration capacity has so far mainly been attributed to the activation and recruitment of resident oligodendroglial precursor cells. As this self-repair process is limited and increasingly fails while MS progresses, much interest has evolved regarding the development of remyelination-promoting strategies and the presence of alternative cell types, which can also contribute to the restoration of myelin sheaths. The adult brain comprises at least two neurogenic niches harboring life-long adult neural stem cells (NSCs). An increasing number of investigations are beginning to shed light on these cells under pathological conditions and revealed a significant potential of NSCs to contribute to myelin repair activities. In this review, these emerging investigations are discussed with respect to the importance of stimulating endogenous repair mechanisms from germinal sources. Moreover, we present key findings of NSC-derived oligodendroglial progeny, including a comprehensive overview of factors and mechanisms involved in this process. Full article
(This article belongs to the Special Issue Advances in Multiple Sclerosis 2016)
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Open AccessReview
The Gas6/TAM System and Multiple Sclerosis
Int. J. Mol. Sci. 2016, 17(11), 1807; https://doi.org/10.3390/ijms17111807
Received: 16 September 2016 / Revised: 22 October 2016 / Accepted: 26 October 2016 / Published: 28 October 2016
Cited by 6 | PDF Full-text (814 KB) | HTML Full-text | XML Full-text
Abstract
Growth arrest specific 6 (Gas6) is a multimodular circulating protein, the biological actions of which are mediated by the interaction with three transmembrane tyrosine kinase receptors: Tyro3, Axl, and MerTK, collectively named TAM. Over the last few decades, many progresses have been done [...] Read more.
Growth arrest specific 6 (Gas6) is a multimodular circulating protein, the biological actions of which are mediated by the interaction with three transmembrane tyrosine kinase receptors: Tyro3, Axl, and MerTK, collectively named TAM. Over the last few decades, many progresses have been done in the understanding of the biological activities of this highly pleiotropic system, which plays a role in the regulation of immune response, inflammation, coagulation, cell growth, and clearance of apoptotic bodies. Recent findings have further related Gas6 and TAM receptors to neuroinflammation in general and, specifically, to multiple sclerosis (MS). In this paper, we review the biology of the Gas6/TAM system and the current evidence supporting its potential role in the pathogenesis of MS. Full article
(This article belongs to the Special Issue Advances in Multiple Sclerosis 2016)
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Open AccessReview
The Inflammatory Role of Platelets: Translational Insights from Experimental Studies of Autoimmune Disorders
Int. J. Mol. Sci. 2016, 17(10), 1723; https://doi.org/10.3390/ijms17101723
Received: 7 September 2016 / Revised: 4 October 2016 / Accepted: 8 October 2016 / Published: 14 October 2016
Cited by 6 | PDF Full-text (1623 KB) | HTML Full-text | XML Full-text
Abstract
Beyond their indispensable role in hemostasis, platelets have shown to affect the development of inflammatory disorders, as they have been epidemiologically and mechanistically linked to diseases featuring an inflammatory reaction in inflammatory diseases like multiple sclerosis, rheumatoid arthritis and inflammatory bowel disorders. The [...] Read more.
Beyond their indispensable role in hemostasis, platelets have shown to affect the development of inflammatory disorders, as they have been epidemiologically and mechanistically linked to diseases featuring an inflammatory reaction in inflammatory diseases like multiple sclerosis, rheumatoid arthritis and inflammatory bowel disorders. The identification of novel molecular mechanisms linking inflammation and to platelets has highlighted them as new targets for therapeutic interventions. In particular, genetic and pharmacological studies have identified an important role for platelets in neuroinflammation. This review summarizes the main molecular links between platelets and inflammation, focusing on immune regulatory factors, receptors, cellular targets and signaling pathways by which they can amplify inflammatory reactions and that make them potential therapeutic targets. Full article
(This article belongs to the Special Issue Advances in Multiple Sclerosis 2016)
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Open AccessReview
The Immunology of Neuromyelitis Optica—Current Knowledge, Clinical Implications, Controversies and Future Perspectives
Int. J. Mol. Sci. 2016, 17(3), 273; https://doi.org/10.3390/ijms17030273
Received: 12 January 2016 / Revised: 31 January 2016 / Accepted: 16 February 2016 / Published: 2 March 2016
Cited by 32 | PDF Full-text (1941 KB) | HTML Full-text | XML Full-text
Abstract
Neuromyelitis optica (NMO) is an autoimmune, demyelinating disorder of the central nervous system (CNS) with typical clinical manifestations of optic neuritis and acute transverse myelitis attacks. Previously believed to be a variant of multiple sclerosis (MS), it is now considered an independent disorder [...] Read more.
Neuromyelitis optica (NMO) is an autoimmune, demyelinating disorder of the central nervous system (CNS) with typical clinical manifestations of optic neuritis and acute transverse myelitis attacks. Previously believed to be a variant of multiple sclerosis (MS), it is now considered an independent disorder which needs to be differentiated from MS. The discovery of autoantibodies against aquaporin-4 (AQP4-IgGs) changed our understanding of NMO immunopathogenesis and revolutionized the diagnostic process. AQP4-IgG is currently regarded as a specific biomarker of NMO and NMO spectrum disorders (NMOsd) and a key factor in its pathogenesis. Nevertheless, AQP4-IgG seronegativity in 10%–25% of NMO patients suggests that there are several other factors involved in NMO immunopathogenesis, i.e., autoantibodies against aquaporin-1 (AQP1-Abs) and antibodies against myelin oligodendrocyte glycoprotein (MOG-IgGs). This manuscript reviews current knowledge about NMO immunopathogenesis, pointing out the controversial issues and showing potential directions for future research. Further efforts should be made to broaden our knowledge of NMO immunology which could have important implications for clinical practice, including the use of potential novel biomarkers to facilitate an early and accurate diagnosis, and modern treatment strategies improving long-term outcome of NMO patients. Full article
(This article belongs to the Special Issue Advances in Multiple Sclerosis 2016)
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