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Magnetic resonance imaging has improved the diagnosis and evaluation of disease activity in multiple sclerosis (MS), and its widespread use has contributed to creating the concept of radiologically isolated syndrome (RIS) to describe patients without symptoms of MS whose magnetic resonance imaging findings suggest they might be at risk of future demyelinating events. Indeed, using the revised McDonald criteria now allows some patients who would have been diagnosed with clinically isolated syndrome (CIS) in the era of Poser criteria to be diagnosed as having MS before a second episode. The present review discusses the current concepts of RIS and CIS, and the risk factors for conversion from these conditions to MS. Clinical trials involving participants with CIS at high risk of developing clinically definite MS have shown that disease-modifying drugs significantly suppressed the conversion from CIS to MS, and that early treatment with these drugs could improve future disease prognosis in patients who subsequently developed MS. When a patient presents with RIS or CIS, the primary concern for the physician and patient should be the probability of conversion to MS, and the patient should be followed up taking into consideration the risk factors for conversion from RIS or CIS to MS.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system. In the past few decades, several disease-modifying drugs including interferon (IFN)-β have become available for treating MS. IFN-β belongs to the type I IFN family, and thus is an endogenous molecule whose primary role is thought to be host defense against viruses. In addition, type I IFN are constitutively produced at low amounts and involved in the homeostasis of various tissues. In contrast, it is suggested that type I IFN play a pathogenic role in other autoimmune diseases, such as lupus. Several lines of evidence from studies using MS samples and animal models suggest the protective role of endogenous type I IFN in MS. Correspondingly, MS patients with a higher endogenous type I IFN signature show lower disease activity. Paradoxically, these patients have been shown to respond poorly to IFN-β therapy. In addition, an animal model with a defective regulatory mechanism in type I IFN signaling has been shown to develop augmented central nervous system autoimmunity, suggesting that type I IFN responses need to be appropriately regulated in MS. Multiple endogenous molecules participate in the regulation of type I IFN responses, but their roles in MS have not been studied extensively. Further study delineating the role of endogenous type I IFN and their regulatory mechanisms in MS should enhance our understanding of the disease, and could lead to improvements in the therapeutic effects of IFN-β in MS.

The development of multiple sclerosis (MS) is based on complex interactions between genetic and environmental factors. Epigenetic regulation is a biological phenomenon defined as the modification of gene expression without alteration of the DNA sequence, and is currently thought to underlie the interactions between the genetic and environmental risks of MS. The molecular mechanisms of epigenetics include DNA methylation, histone modification, and microRNAs. Observational data obtained from epidemiological studies of MS, such as the parent-of-origin effect and the longitudinal increase in female patients, suggest that epigenetic mechanisms are involved in MS development, although the molecular basis remains unclear. Interestingly, environmental factors related to the development of MS, such as Epstein-Barr virus, smoking, and vitamin D, have been shown to regulate gene expression through epigenetic mechanisms in some experimental settings. One study showed no reproducible differences among DNA methylation profiles in peripheral blood CD4+ T cells between three monozygotic twin pairs discordant for MS. However, several studies have shown that dysregulated DNA methylation of genes is related to abnormal immune reactions and post-translational modifications of myelin proteins in MS brain samples. In addition, abnormal microRNA profiles have been reported in brain tissues and peripheral blood immune cells obtained from MS patients. In this article, we will review the studies on the epigenetics of MS and discuss the perspectives for future research.

Objective To clarify the potential association of copy number variations (CNVs) with multiple sclerosis (MS) and neuromyelitis optica (NMO) in Japanese cases. Methods Genome-wide association analyses of CNVs among 277 MS patients, 135 NMO/NMO spectrum disorder (NMOSD) patients, and 288 healthy individuals as a discovery cohort, and among 296 MS patients, 76 NMO/NMOSD patients, and 790 healthy individuals as a replication cohort were performed using high-density single nucleotide polymorphism microarrays. Results A series of discovery and replication studies revealed that most identified CNVs were 5 to 50kb deletions at particular T cell receptor (TCR) gamma and alpha loci regions. Among these CNVs, a TCR gamma locus deletion was found in 16.40% of MS patients (p = 2.44E-40, odds ratio [OR] = 52.6), and deletion at the TCR alpha locus was found in 17.28% of MS patients (p = 1.70E-31, OR = 13.0) and 13.27% of NMO/NMOSD patients (p = 5.79E-20, OR = 54.6). These CNVs were observed in peripheral blood T-cell subsets only, suggesting the CNVs were somatically acquired. NMO/NMOSD patients carrying the CNV tended to be seronegative for anti–aquaporin-4 antibody or had significantly lower titers than those without CNV. Interpretation Deletion-type CNVs at specific TCR loci regions contribute to MS and NMO susceptibility. Ann Neurol 2015;78:Ann Neurol 2015;78:679–696

B cells have been implicated in the pathology of multiple sclerosis (MS) since the initial observation in the 1940s and 50s of increased immunoglobulin concentrations in the cerebrospinal fluid of MS patients. Until recently, B cells have been considered to participate in MS pathology through the secretion of antibodies specific to central nervous system antigens. However, the successful targeting of B cells with anti-CD20 monoclonal antibodies without affecting immunoglobulin levels suggests that B cells have antibody-independent functions in immune regulation in MS. Furthermore, the recent identification of B cell-rich follicle-like structures in the meninges of patients with secondary progressive MS indicates that B cells also have pathogenic roles within the central nervous system, where they contribute to disease progression by inducing cortical injury. These observations suggest that B cells are key players in the pathogenesis of MS, and are therefore attractive targets for therapeutic intervention. In addition to CD20, several other molecules and pathways related to B cell function are being evaluated as therapeutic targets in other autoimmune diseases. Furthermore, based on the increased understanding of the molecular mechanisms underlying B cell effector function, particularly those involved in MS, therapeutic strategies for specifically inhibiting the pro-inflammatory activity of B cells while preserving or even enhancing their role in protective immune response are under active investigation. Here, we review recent advances in molecular targeted therapies against B cells for MS, and discuss perspectives for future therapies targeting B cells and related molecules.

Objective The aim of the present study was to investigate the association of magnetic resonance imaging (MRI) findings and social activity with cognitive function in Japanese patients with multiple sclerosis (MS). Methods The Brief Repeatable Battery of Neuropsychological tests (BRB-N) was carried out in 184 Japanese patients with MS, and 163 controls matched for age, sex and education. MRI findings of cerebral, brainstem, and cerebellar lesions and social activities of MS patients were further examined. Results MS patients with higher numbers of cerebral lesions on MRI had lower scores in most BRB-N tests. BRB-N scores in the majority of tests were significantly lower in patients with brainstem and cerebellar lesions. Data from an analysis of variance model in which only the main effects of cerebral, brainstem and cerebellar lesions were hypothesized showed an association of cerebral lesions with decreased scores in all BRB-N tests, except symbol digit modalities test (SDMT) and paced auditory serial addition test (PASAT). In contrast, cerebellar lesions were associated with decreased SDMT and PASAT scores. Patients categorized as “unemployed because of MS” had lower BRB-N scores than other social activity groups. Lower SDMT scores had an effect on the “unemployed because of MS” group, whereas the Expanded Disability Status Scale had a significantly greater negative impact on patients in this social category. Conclusions Higher numbers of brain lesions on MRI could have an impact on cognitive function in patients with MS, and impairment of information processing appears significantly associated with cerebellar lesions. Cognitive impairment affects the employment status of patients with MS.

Fingolimod functions as a modulator of sphingosine-1-phosphate (S1P) receptors expressed on the surface of T and B lymphocytes, leading to their internalization. Loss of S1P receptors results in sequestration of central memory T cells enriched by Th17 cells in lymph nodes. After successful treatment of an animal model of multiple sclerosis (MS), clinical trials of oral fingolimod in patients with relapsing-remitting MS showed a 60% reduction in the annualized rate of relapse. The United States Food and Drug Administration approved fingolimod as a first-line drug for MS treatment in 2010, and data have been accumulated thereafter. However, MS experts recommend that the drug should remain as a second-line option, because the long-term risks for infection and malignancy have not been fully elucidated. Also, because of different genetic backgrounds, Asian MS patients might require special attention regarding other infectious agents and secondary cancer as compared with those reported in Caucasian patients. Furthermore, some Japanese patients who developed severe symptoms were later shown to be positive for the anti-aquaporin-4 antibody. In addition, reports of some Western MS patients have noted worsening after initiation, as well as discontinuation of fingolimod treatment. Finally, the optic spinal type of MS and neuromyelitis optica spectrum disorders are more prevalent in Asian than Western countries. Thus, establishment of criteria for determining which Asian MS patients would benefit from fingolimod treatment is mandatory.

Several genetic and environmental factors are thought to be associated with an increased risk of multiple sclerosis (MS), the influence of which can differ between ethnicities. One of the most important risk factors for MS is low serum levels of vitamin D, and these levels also differ between ethnicities, probably mainly because of differences in skin pigmentation. Furthermore, genetic influences in vitamin D-related genes might also vary between ethnicities, reflecting different genetic backgrounds. The present review article discusses the association between vitamin D and MS, with a focus on Asians and Caucasians.

Objectives There has been no large-scale study of methylprednisolone pulse therapy in Asian patients with multiple sclerosis (MS) or neuromyelitis optica (NMO), despite it being widely used for acute relapse. We aimed to clarify treatment response of MS and NMO patients to methylprednisolone pulse therapy and post-pulse oral corticosteroids in real clinical practice in a multicenter study in Japan. Methods Investigators at 28 institutions collected changes in neurological symptoms/signs and Expanded Disability Status Scale (EDSS) scores before and within 1 week of completion of methylprednisolone pulse therapy carried out in 2010, and after post-pulse oral corticosteroids therapy, by retrospective review of medical records. Results In 345 patients (95.1% of all registered patients), 457 series of methylprednisolone pulse therapy were carried out for treatment of acute relapse. EDSS scores improved by 0.8 ± 1.1 (mean ± SD) after the first course. The second and third courses also produced sufficient improvements (by 0.7 and 0.6, respectively), but much smaller improvements were observed thereafter. The target neurological symptoms and signs improved in 79.5% of patients. Improvement rates were 5–20% lower after a course of pulse therapy than after a series of pulse therapy. A half dose (500 mg/day) produced less improvement than a standard dose (1000 mg/day; 65.9 vs 79.5%). During post-pulse oral corticosteroid therapy, EDSS scores decreased by 0.6 ± 0.9. No significant adverse effects were observed. Conclusions Methylprednisolone pulse therapy is beneficial in nearly 80% of Japanese MS and NMO patients, and EDSS score improvements after therapy are compatible with those in Western MS patients.

Objective Vitamin D levels are one of the most likely environmental factors related to the development of multiple sclerosis (MS). As vitamin D levels differ between ethnicities, the associated risk of MS also differs. We aimed to determine the associations of serum vitamin D levels in Japanese patients with MS. Methods Serum levels of 25-hydroxyvitamin D (25[OH]D), 1,25-dihydroxyvitamin D (1,25[OH]2D), and vitamin D-binding protein (DBP) were measured in 29 patients with relapsing-remitting (RR) and secondary-progressive (SP) MS, and in 34 healthy controls. Results The serum levels of 25(OH)D in SPMS patients were significantly decreased compared with those of controls and RRMS patients at remitting phase (7.9 ± 7.2 nM vs 24.2 ± 14.2 nM vs 22.5 ± 13.2 nM, respectively; P

Osteopontin (OPN), which was originally identified as a bone matrix protein, is a pro-inflammatory cytokine implicated in autoimmune diseases, such as experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS). Indeed, OPN is highly upregulated in EAE and MS lesions. Recent studies have shown that Th17 cell responses, which are involved in the pathogenesis of EAE and MS, are regulated by OPN. This review provides an overview of the current body of literature on the immunological functions of OPN and its role in EAE and MS. (Clin. Exp. Neuroimmunol. doi: 10.1111/j.1759-1961.2011.00019.x, May 2011)

Objective: Our objective was to study in vivo biological effects of natalizumab on immune cell phenotype and function in multiple sclerosis (MS) patients. Methods: Blood was obtained before and after serial monthly natalizumab infusions to track functional expression of VLA-4 and migratory capacity of immune cells. The impact of infusion on activation thresholds of immune cells was evaluated. Results: Preinfusion VLA-4 expression differed across immune cell subsets. Natalizumab significantly, albeit partially, diminished VLA-4 expression on circulating immune cells. Cell subsets were differentially affected. Treatment significantly decreased migratory capacity of immune cells, correlating well with changes in VLA-4 expression. Effects of a single dose were not saturating and did not persist through the monthly dose interval. Infusion effect varied across patients but was remarkably stable in individual patients, over multiple infusions. Treatment significantly modulated proliferative responses of immune cells. Interpretation: To our knowledge, we provide first proof of concept that natalizumab diminishes migratory capacity of immune cells. Our prospective study further shows that effects of therapy likely (1) differ for distinct immune cell subsets, (2) are not sustained over current dose interval, (3) have unique profiles in individual patients, and (4) include modulation of activation threshold of immune cells. Monitoring these parameters could be relevant to ongoing safety and efficacy considerations.

Brefeldin A (BFA) is a fungus metabolite that is known to cause the disassembly of the Golgi complex and apoptosis in exposed cells, both of which have been suggested as playing roles in the pathogenesis of neurodegenerative diseases, particularly amyotrophic lateral sclerosis (ALS). This study showed that BFA caused neurotoxicity and apoptotic nuclear changes in cultured spinal neurons of rat spinal cord in a dose- and time-dependent manner. The spinal motor neurons were more vulnerable to this neurotoxicity. The cultured spinal neurons showed irreversible disassembly of the Golgi apparatus as early as 1 hr after exposure to BFA. BFA induced the expression and activation of caspase-12 beginning 8 hr after exposure. The level of the cleaved form of caspase-3 had increased 12 hr after the addition of BFA. Free radical generation and loss of mitochondrial membrane potential were observed in the later stages of neurotoxicity caused by BFA. Collectively, our data suggests that BFA is an excellent agent for reproducing the pathophysiological features of ALS. This in vitro model may be useful in attempts to study the mechanisms of this neurodegenerative disease and to examine therapeutic potentials.

Despite the strength of the association of multiple sclerosis (MS) and human leukocyte antigen (HLA)-DR2, other genetic elements could have a role in the pathophysiology of MS. We investigated possible associations with polymorphic susceptibility genes located within the HLA complex, i.e., heat-shock protein (HSP)70-1, HSP70-2, and HSP70-hom in Japanese patients with MS. Furthermore, we analyzed the influence of HSP70 gene polymorphisms on the severity of the disease, clinical course, magnetic resonance imaging findings, and oligoclonal bands in the cerebrospinal fluid, and HLA in MS patients. The results of the present study indicated that there were no significant differences in the distribution of all HSP70 genotypes and allele frequencies between Japanese MS patients and controls. In MS patients, there were no associations between HSP70 gene polymorphisms and the clinical data. Moreover, there were no significant differences in HSP70 genotype or allele frequencies between MS patients positive for HLA-DRB1*1501 alleles and matched controls. Our data indicate that HSP70 gene polymorphisms are not relevant in the susceptibility to or the severity of Japanese MS patients.

We have identified a novel mutation in exon 4 of the Cu/Zn superoxide dismutase (superoxide dismutase 1: SOD1) gene (GAC to GTC), which resulted in an Asp90 to Val substitution in a Japanese family with amyotrophic lateral sclerosis (ALS) inherited as an autosomal dominant trait. The patients in this family usually died in 2–3 years without sensory or urinary impairment. The SOD1 activity was lower in the proband as compared to the normal controls. The clinical characteristics of this family resemble those of some patients heterozygous for the Asp90Ala mutation, but both the clinical features and SOD1 activity of this family differ from those of patients homozygous for the ASP90Ala mutation.

The non-glycosylated protein, leptin, plays a key role in regulating energy intake and energy expenditure. It was also recently shown to be involved in regulating innate and adaptive immune responses. Ehsan et al. reported significantly higher serum leptin levels in patients with multiple sclerosis and neuromyelitis optica, and these levels were correlated with disability in those with progressive multiple sclerosis. Leptin's role as a mediator in the link between the immune responses and metabolic function is clearly important to consider in developing immune therapeutic targets for reducing inflammation and autoimmunity.