Remyelination failure in multiple sclerosis (MS) contributes to progression of disability. The deficient repair results from neuroinflammation and deposition of inhibitors including chondroitin sulfate proteoglycans (CSPGs). Which CSPG member is repair-inhibitory or alters local inflammation to exacerbate injury is unknown. Here, we correlate high versican-V1 expression in MS lesions with deficient premyelinating oligodendrocytes, and highlight its selective upregulation amongst CSPG members in experimental autoimmune encephalomyelitis (EAE) lesions modeling MS. In culture, purified versican-V1 inhibits oligodendrocyte precursor cells (OPCs) and promotes T helper 17 (Th17) polarization. Versican-V1-exposed Th17 cells are particularly toxic to OPCs. In NG2^CreER:MAPT^mGFP mice illuminating newly formed GFP⁺ oligodendrocytes/myelin, difluorosamine (peracetylated,4,4-difluoro-N-acetylglucosamine) treatment from peak EAE reduces lesional versican-V1 and Th17 frequency, while enhancing GFP⁺ profiles. We suggest that lesion-elevated versican-V1 directly impedes OPCs while it indirectly inhibits remyelination through elevating local Th17 cytotoxic neuroinflammation. We propose CSPG-lowering drugs as potential dual pronged repair and immunomodulatory therapeutics for MS.

Background: A common problem in resting-state neuroimaging studies is that subjects become drowsy or fall asleep. Although this could drastically affect neurophysiological measurements, such as magnetoencephalography (MEG), its specific impact remains understudied. We aimed to systematically investigate how often drowsiness is present during resting-state MEG recordings, and how the state changes alter quantitative estimates of oscillatory activity, functional connectivity, and network topology.Methods: About 8-min MEG recordings of 19 healthy subjects, split into ~13-s epochs, were scored for the presence of eyes-open (EO), alert eyes-closed (A-EC), or drowsy eyes-closed (D-EC) states. After projection to source-space, results of spectral, functional connectivity, and network analyses in 6 canonical frequency bands were compared between these states on a global and regional levels. Functional connectivity was analyzed using the phase lag index (PLI) and corrected amplitude envelope correlation (AECc), and network topology was analyzed using the minimum spanning tree (MST).Results: Drowsiness was present in >55% of all epochs that did not fulfill the AASM criteria for sleep. There were clear differences in spectral results between the states (A-EC vs. D-EC) and conditions (EO vs. A-EC). The influence of state and condition was far less pronounced for connectivity analyses, with only minimal differences between D-EC and EO in the AECc in the delta band. There were no effects of drowsiness on any of the MST measures.Conclusions: Drowsiness during eyes-closed resting-state MEG recordings is present in the majority of epochs, despite the instructions to stay awake. This has considerable influence on spectral properties, but much less so on functional connectivity and network topology. These findings are important for interpreting the results of EEG/MEG studies using spectral analyses in neurological disease, where recordings should be evaluated for the presence of drowsiness. For connectivity analyses or studies on network topology, this seems of far less importance.

Importance: Increasing numbers of people with multiple sclerosis (MS) use disease-modifying therapy (DMT). Long-term stable disease while taking such medications provides a rationale for considering DMT discontinuation given patient burden, costs, and potential adverse effects of immunomodulating therapy.Objective: To investigate whether first-line DMT can be safely discontinued in patients with long-term stable MS.Design, Setting, and Participants: This multicenter, rater-blinded, noninferiority randomized clinical trial was conducted between July 1, 2020, and March 20, 2023, at 14 Dutch centers. Data analysis was performed between July 2023 and January 2024. Key inclusion criteria were relapse-onset MS, aged 18 years or older, without relapses, and without substantial magnetic resonance imaging (MRI) activity in the previous 5 years under first-line DMT. Participants were randomized 1:1 to discontinue or continue first-line DMT.Intervention: Discontinuation of first-line DMT.Main Outcome and Measure: The primary outcome was significant inflammatory disease activity, defined as relapse and/or 3 or more new T2 lesions or 2 or more contrast-enhancing lesions on brain MRI.Results: Of 163 potentially eligible participants, 89 participants were included in the trial at the moment of early termination. Forty-four participants (49.4%) were assigned to the continue group and 45 participants (50.6%) were assigned to the discontinue group. Median (IQR) age was 54.0 (49.0-59.0) years, and 60 participants (67.4%) were female. Two participants in the continue group were lost to follow-up. After a median (IQR) follow-up time of 15.3 (11.4-23.9) months, the trial was prematurely terminated because of inflammatory disease activity recurrence above the predefined limit. In total, 8 of 45 participants in the discontinue group (17.8%) vs 0 of 44 participants in the continue group reached the primary end point and had recurrent, mostly radiological inflammation. Two of these 8 participants had a clinical relapse. Median (IQR) time to disease activity was 12.0 (6.0-12.0) months.Conclusions and Relevance: In this randomized clinical trial, even in patients with long-term MS stable for over 5 years, first-line DMT discontinuation can lead to recurrence of inflammatory disease activity. Although this study cohort was relatively small, the recurrence of inflammation in the discontinue group was significantly higher than in the continue group and also higher than in the previously published DISCOMS trial, which only included individuals aged 55 years or older. This study provides additional data, especially in a younger population and including longitudinal biomarker measurements, for informed decision-making in cases when treatment discontinuation is considered.Trial Registration: ClinicalTrials.gov Identifier: NCT04260711

Background: Substantial physical-disability worsening in relapsing-remitting multiple sclerosis (RRMS) occurs outside of clinically recorded relapse. This phenomenon, termed progression independent of relapse activity (PIRA), is yet to be established for cognitive decline. Methods: Retrospective analysis of RRMS patients. Cognitive decline was defined using reliable-change-index cut-offs for each test (Symbol Digit Modalities Test, Brief Visuospatial Memory Test–Revised, California Verbal Learning Test–II). Decline was classified as PIRA if the following conditions were met: no relapse observed between assessments nor within 9 months of cognitive decline. Results: The study sample ( n = 336) was 80.7% female with a mean (standard deviation (SD)) age, disease duration, and observation period of 43.1 (9.5), 10.8 (8.4), and 8.1 (3.1) years, respectively. A total of 169 (50.3%) subjects were cognitively impaired at baseline relative to age-, sex-, and education-matched HCs. Within subjects who experienced cognitive decline ( n = 167), 89% experienced cognitive PIRA. A total of 141 (68.1%) cognitive decline events were observed independent of EDSS worsening. Cognitive PIRA was more likely to be observed with increased assessments ( p < 0.001) and lower assessment density ( p < 0.001), accounting for baseline clinical factors. Conclusion: These results establish the concept of cognitive PIRA and further our understanding of progressive cognitive decline in RRMS.

Multiple sclerosis (MS) typically presents in early to middle adulthood, but owing to advancements in health care, many individuals with MS now live a normal lifespan, and approximately half of the people currently living with MS are ≥50 years of age. As people living with MS age, their diagnosis, treatment and disease management become more complex owing to the effects of ageing, immunosenescence and comorbidities. Furthermore, diagnosis of late-onset MS (onset above 50 years of age) often requires additional tests, such as spinal cord imaging and cerebrospinal fluid analysis, to differentiate the disease from age-associated conditions such as cerebrovascular disease. Monitoring disease progression also becomes more complicated with increasing age, as physiological age-related changes can confound MRI findings and measurements of disability and cognition. Treatment decisions in older people with MS are also challenging, as high-efficacy treatments carry increased risks with ageing and their benefits can be reduced, yet little evidence is available to guide treatment in older adults. In this Consensus statement, we present the outcomes of an International Advisory Committee on Clinical Trials (IACCT) in MS workshop on ageing and MS; we review the current status of the field and identify knowledge gaps, and provide recommendations to advance the areas of unmet need.

Objective To describe the disease course of carryover progressive multifocal leukoencephalopathy (PML) after switching from natalizumab to ocrelizumab in 2 patients with relapsing-remitting MS. Methods Two case reports with 1 year of follow-up and retrospective longitudinal measurements of serum neurofilament light (NfL) levels and B-cells. Results PML was diagnosed 78 days (case 1) and 97 days (case 2) after discontinuation of natalizumab. Both patients developed mild immune reconstitution inflammatory syndrome (IRIS) despite B-cell depletion caused by ocrelizumab. NfL levels increased in both patients during PML-IRIS. PML-IRIS lesions stabilized after treatment with mefloquine and mirtazapine, followed by methylprednisolone, and both patients continued therapy with ocrelizumab when B-cells started to repopulate. Conclusions The clinical course of carryover PML was mild in both patients, suggesting that B-cell depletion possibly did not aggravate PML-IRIS in these 2 patients.