Important advances in multiple sclerosis (MS) research have been made as a direct or indirect result of experiments in animal models for the disease, although MS is a disease only affecting humans. The cuprizone model is a model for toxic demyelination. In this model, young mice are fed with the copper chelator cuprizone, leading to oligodendrocyte death and a subsequent reversible demyelination. Spontaneous remyelination can be seen as early as 4 days after withdrawal of cuprizone. This article reviews previous research on this model and discusses the potential of the model for future application in MS research. The cuprizone model correlates with newer histopathological data in MS and is a valuable tool for studies on de- and remyelination. The use of the C57BL/6 strain offers the potential for future studies on transgene and knockout mice.

Background and purpose: There is still no curative treatment for multiple sclerosis (MS), but during the last 20 years eight different disease‐modifying compounds have been approved for relapsing−remittingMS(RRMS).Methods: A literature search was conducted on published randomized controlled phase III trials indexed in PubMed on the approved medications until 21 May 2015.Results: In this review the mode of action, documented treatment effects and side effects of the approvedMStherapies are briefly discussed.Conclusions: Based on current knowledge of risk−benefit of the approvedMSmedications, including factors influencing adherence, it is suggested that oral treatment with dimethyl fumarate or teriflunomide should be preferred as a starting therapy amongst the first‐line preparations forde novoRRMS. In the case of breakthrough disease on first‐line therapy, or rapidly evolving severeRRMS, second‐line therapy with natalizumab, fingolimod or alemtuzumab should be chosen based on careful risk−benefit stratification.

Background and objective: We explored which clinical and biochemical variables predict conversion from clinically isolated syndrome (CIS) to clinically definite multiple sclerosis (CDMS) in a large international cohort. Methods: Thirty-three centres provided serum samples from 1047 CIS cases with at least two years’ follow-up. Age, sex, clinical presentation, T2-hyperintense lesions, cerebrospinal fluid (CSF) oligoclonal bands (OCBs), CSF IgG index, CSF cell count, serum 25-hydroxyvitamin D3 (25-OH-D), cotinine and IgG titres against Epstein-Barr nuclear antigen 1 (EBNA-1) and cytomegalovirus were tested for association with risk of CDMS. Results: At median follow-up of 4.31 years, 623 CIS cases converted to CDMS. Predictors of conversion in multivariable analyses were OCB (HR = 2.18, 95% CI = 1.71–2.77, p < 0.001), number of T2 lesions (two to nine lesions vs 0/1 lesions: HR = 1.97, 95% CI = 1.52–2.55, p < 0.001; >9 lesions vs 0/1 lesions: HR = 2.74, 95% CI = 2.04–3.68, p < 0.001) and age at CIS (HR per year inversely increase = 0.98, 95% CI = 0.98–0.99, p < 0.001). Lower 25-OH-D levels were associated with CDMS in univariable analysis, but this was attenuated in the multivariable model. OCB positivity was associated with higher EBNA-1 IgG titres. Conclusions: We validated MRI lesion load, OCB and age at CIS as the strongest independent predictors of conversion to CDMS in this multicentre setting. A role for vitamin D is suggested but requires further investigation.

Microglia are activated in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. Here Shao-Cong Sun and colleagues demonstrate that the E3 ubiquitin ligase Peli1 is expressed in microglia and is required for their activation and expression of inflammatory cytokines and chemokines after the induction of EAE. Disease severity is reduced in Peli1-deficient mice, partly through the effects of Peli1 on TLR signaling and Traf3 degradation. Microglia are crucial for the pathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). Here we show that the E3 ubiquitin ligase Peli1 is abundantly expressed in microglia and promotes microglial activation during the course of EAE induction. Peli1 mediates the induction of chemokines and proinflammatory cytokines in microglia and thereby promotes recruitment of T cells into the central nervous system. The severity of EAE is reduced in Peli1-deficient mice despite their competent induction of inflammatory T cells in the peripheral lymphoid organs. Notably, Peli1 regulates Toll-like receptor (TLR) pathway signaling by promoting degradation of TNF receptor–associated factor 3 (Traf3), a potent inhibitor of mitogen-activated protein kinase (MAPK) activation and gene induction. Ablation of Traf3 restores microglial activation and CNS inflammation after the induction of EAE in Peli1-deficient mice. These findings establish Peli1 as a microglia-specific mediator of autoimmune neuroinflammation and suggest a previously unknown signaling mechanism of Peli1 function.

Objective: To investigate whether serum neurofilament light chain (NF-L) and chitinase 3-like 1 (CHI3L1) predict disease activity in relapsing-remitting MS (RRMS). Methods: A cohort of 85 patients with RRMS were followed for 2 years (6 months without disease-modifying treatment and 18 months with interferon-beta 1a [IFNB-1a]). Expanded Disability Status Scale was scored at baseline and every 6 months thereafter. MRI was performed at baseline and monthly for 9 months and then at months 12 and 24. Serum samples were collected at baseline and months 3, 6, 12, and 24. We analyzed the serum levels of NF-L using a single-molecule array assay and CHI3L1 by ELISA and estimated the association with clinical and MRI disease activity using mixed-effects models. Results: NF-L levels were significantly higher in patients with new T1 gadolinium-enhancing lesions (37.3 pg/mL, interquartile range [IQR] 25.9–52.4) and new T2 lesions (37.3 pg/mL, IQR 25.1–48.5) compared with those without (28.0 pg/mL, IQR 21.9–36.4, β = 1.258, p < 0.001 and 27.7 pg/mL, IQR 21.8–35.1, β = 1.251, p < 0.001, respectively). NF-L levels were associated with the presence of T1 gadolinium-enhanced lesions up to 2 months before (p < 0.001) and 1 month after (p = 0.009) the time of biomarker measurement. NF-L levels fell after initiation of IFNB-1a treatment (p < 0.001). Changes in CHI3L1 were not associated with clinical or MRI disease activity or interferon-beta 1a treatment. Conclusion: Serum NF-L could be a promising biomarker for subclinical MRI activity and treatment response in RRMS. In clinically stable patients, serum NF-L may offer an alternative to MRI monitoring for subclinical disease activity. ClinicalTrials.gov identifier: NCT00360906.

Research from JAMA Neurology — ω-3 Fatty Acid Treatment in Multiple Sclerosis (OFAMS Study) — A Randomized, Double-Blind, Placebo-Controlled Trial