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Background: Patient satisfaction is predictive of adherence, malpractice litigation and doctor-switching. Objective: To investigate which factors of the first diagnostic consultation (FDC) influence patient satisfaction and which topics persons with multiple sclerosis (PwMS) thought were missing. Methods: Using retrospective patient-reported data of the Swiss Multiple Sclerosis Registry from PwMS with relapsing disease onset, we fitted ordered logistic regression models on satisfaction with FDC, with socio-demographic and FDC features as explanatory factors. Results: 386 PwMS diagnosed after 1995 were included. Good satisfaction with the FDC was associated with a conversation more than 20 min [multivariable odds ratio, 95% confidence interval 3.9 (2.42; 6.27)], covering many topics [1.35 (1.19; 1.54) per additional topic], the presence of a significant others [1.74 (1.03; 2.94) ], and shared decision making [3.39 (1.74; 6.59)]. Not receiving a specific diagnosis was main driver for low satisfaction [0.29 (0.15; 0.55)]. Main missing topics concerned long-term consequences (reported by 6.7%), psychological aspects (6.2%) and how to obtain support and further information (5.2%). Conclusions: A conversation of more than 20 min covering many MS relevant topics, a clear communication of the diagnosis, the presence of a close relative or significant other, as well as shared decision making enhanced patient satisfaction with the FDC. ClinicalTrials.gov Identifier: NCT02980640 [ABSTRACT FROM AUTHOR]

Objective: To investigate the longitudinal dynamics of serum glial fibrillary acidic protein (sGFAP) and serum neurofilament light chain (sNfL) levels in people with multiple sclerosis (pwMS) under B-cell depleting therapy (BCDT) and their capacity to prognosticate future progression independent of relapse activity (PIRA) events., Methods: A total of 362 pwMS (1,480 samples) starting BCDT in the Swiss Multiple Sclerosis (MS) Cohort were included. sGFAP levels in 2,861 control persons (4,943 samples) provided normative data to calculate adjusted Z scores., Results: Elevated sGFAP levels (Z score >1) at 1 year were associated with a higher hazard for PIRA (hazard ratio [HR]: 1.80 [95% CI: 1.17-2.78]; p = 0.0079) than elevated sNfL levels (HR, 1.45 [0.95-2.24], p = 0.0886) in a combined model. Independent of PIRA events, sGFAP levels longitudinally increased by 0.49 Z score units per 10 years follow-up (estimate, 0.49 [0.29, 0.69], p < 0.0001). In patients experiencing PIRA, sGFAP Z scores were 0.52 Z score units higher versus stable patients (0.52 [0.22, 0.83], p = 0.0009). Different sNfL Z score trajectories were found in pwMS with versus without PIRA (interaction p = 0.0028), with an average decrease of 0.92 Z score units per 10 years observed without PIRA (-0.92 [-1.23, -0.60], p < 0.0001), whereas levels in patients with PIRA remained high., Interpretation: Elevated sGFAP and lack of drop in sNfL after BCDT start are associated with increased risk of future PIRA. These findings provide a rationale for combined monitoring of sNfL and sGFAP in pwMS starting BCDT to predict the risk of PIRA, and to use sGFAP as an outcome in clinical trials aiming to impact on MS progressive disease biology. ANN NEUROL 2024., (© 2024 The Author(s). Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Environmental and lifestyle factors are associated with an increased risk of Multiple Sclerosis (MS). Metabolic syndrome (MetS) contributes to systemic inflammation, which is associated with poorer MS disease evolution. We compared persons with MS (PwMS) and controls to assess metabolic and lifestyle parameters associated with MS., Methods: We pooled data from two prospective observational studies with the same eligibility criteria, matching PwMS and controls (1:2 ratio) by sex, age, and body mass index (BMI). We compared anthropometric, biological and lifestyle parameters, including sleep and physical activity., Results: We included 53 PwMS and 106 controls with a median age of 35 years and 79% of women. PwMS had low Expanded Disability Status Scale (median 1.5). Compared to controls, PwMS had increased waist-to-hip (p<0.001) and waist-to-height (p=0.007) ratios, and practiced less physical activity (p=0.03). In regression models, lifestyle factors with the strongest factor loadings to predict central obesity were processed food consumption, and vigorous physical activity., Discussion: Although both groups were matched by age, sex, and BMI, we found increased central obesity in PwMS. Even with minimal neurological impairment, PwMS practiced less physical activity. This suggests that improvement of lifestyle and metabolic parameters should be targeted in MS., Competing Interests: Declaration of competing interest G.T., N.E.P., J.R., P.L.D.F., A.R., A.G.J., S.P., T.H.C. have nothing to disclose. J.K. received speaker fees, research support, travel support, and/or served on advisory boards by the Progressive MS Alliance, Swiss MS Society, Swiss National Research Foundation (320030-189140), University of Basel, Biogen, Celgene, Merck, Novartis, Octave Bioscience, Roche, Sanofi. M.T. received travel grants, advisory board/lecture and consultancy fees from Biogen, Sanofi, Novartis, Merck and Roche. R.D.P. reports that the Lausanne University Hospital received speaker honoraria and travel grants for his activities with Biogen, Genzyme, Merck, Novartis, Roche, and Sanofi. None of them were related to this work. C.P. reports that the Lausanne University Hospital received speaker honoraria, travel grants and consulting services for her activities with Novartis, Roche, Biogen, Merck, Sanofi-Aventis none related to this work., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Treatment decisions for persons with relapsing-remitting multiple sclerosis (RRMS) rely on clinical and radiological disease activity, the benefit-harm profile of drug therapy, and preferences of patients and physicians. However, there is limited evidence to support evidence-based personalized decision-making on how to adapt disease-modifying therapy treatments targeting no evidence of disease activity, while achieving better patient-relevant outcomes, fewer adverse events, and improved care. Serum neurofilament light chain (sNfL) is a sensitive measure of disease activity that captures and prognosticates disease worsening in RRMS. sNfL might therefore be instrumental for a patient-tailored treatment adaptation. We aim to assess whether 6-monthly sNfL monitoring in addition to usual care improves patient-relevant outcomes compared to usual care alone., Methods: Pragmatic multicenter, 1:1 randomized, platform trial embedded in the Swiss Multiple Sclerosis Cohort (SMSC). All patients with RRMS in the SMSC for ≥ 1 year are eligible. We plan to include 915 patients with RRMS, randomly allocated to two groups with different care strategies, one of them new (group A) and one of them usual care (group B). In group A, 6-monthly monitoring of sNfL will together with information on relapses, disability, and magnetic resonance imaging (MRI) inform personalized treatment decisions (e.g., escalation or de-escalation) supported by pre-specified algorithms. In group B, patients will receive usual care with their usual 6- or 12-monthly visits. Two primary outcomes will be used: (1) evidence of disease activity (EDA3: occurrence of relapses, disability worsening, or MRI activity) and (2) quality of life (MQoL-54) using 24-month follow-up. The new treatment strategy with sNfL will be considered superior to usual care if either more patients have no EDA3, or their health-related quality of life increases. Data collection will be embedded within the SMSC using established trial-level quality procedures., Discussion: MultiSCRIPT aims to be a platform where research and care are optimally combined to generate evidence to inform personalized decision-making in usual care. This approach aims to foster better personalized treatment and care strategies, at low cost and with rapid translation to clinical practice., Trial Registration: ClinicalTrials.gov NCT06095271. Registered on October 23, 2023., (© 2024. The Author(s).)

Disruption of gut barrier function and intestinal immune cell homeostasis are increasingly considered critical players in pathogenesis of extra-intestinal inflammatory diseases, including multiple sclerosis (MS) and its prototypical animal model, the experimental autoimmune encephalomyelitis (EAE). Breakdown of epithelial barriers increases intestinal permeability and systemic dissemination of microbiota-derived molecules. However, whether the gut-vascular barrier (GVB) is altered during EAE has not been reported. Here, we demonstrate that endothelial cell proliferation and vessel permeability increase before EAE clinical onset, leading to vascular remodeling and expansion of intestinal villi capillary bed during disease symptomatic phase in an antigen-independent manner. Concomitant to onset of angiogenesis observed prior to neurological symptoms, we identify an increase of intestinal perivascular immune cells characterized by the surface marker lymphatic vessel endothelial hyaluronic acid receptor 1 (LYVE-1). LYVE-1 + is expressed more frequently on B cells that show high levels of CD73 and have proangiogenic properties. B cell depletion was sufficient to mitigate enteric blood endothelial cell proliferation following immunization for EAE. In conclusion, we propose that altered intestinal vasculature driven by a specialized LYVE-1 + B cell subset promotes angiogenesis and that loss of GVB function is implicated in EAE development and autoimmunity., Competing Interests: Declaration of competing interest Authors declare that they have no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The detection of contrast-enhancing lesions (CELs) is fundamental for the diagnosis and monitoring of patients with multiple sclerosis (MS). This task is time-consuming and suffers from high intra- and inter-rater variability in clinical practice. However, only a few studies proposed automatic approaches for CEL detection. This study aimed to develop a deep learning model that automatically detects and segments CELs in clinical Magnetic Resonance Imaging (MRI) scans. A 3D UNet-based network was trained with clinical MRI from the Swiss Multiple Sclerosis Cohort. The dataset comprised 372 scans from 280 MS patients: 162 showed at least one CEL, while 118 showed no CELs. The input dataset consisted of T1-weighted before and after gadolinium injection, and FLuid Attenuated Inversion Recovery images. The sampling strategy was based on a white matter lesion mask to confirm the existence of real contrast-enhancing lesions. To overcome the dataset imbalance, a weighted loss function was implemented. The Dice Score Coefficient and True Positive and False Positive Rates were 0.76, 0.93, and 0.02, respectively. Based on these results, the model developed in this study might well be considered for clinical decision support.

Background and Objectives: Up to 46% of patients with presumed autoimmune limbic encephalitis are seronegative for all currently known central nervous system (CNS) antigens. We developed a cell-based assay (CBA) to screen for novel neural antibodies in serum and cerebrospinal fluid (CSF) using neurons and astrocytes derived from human-induced pluripotent stem cells (hiPSCs)., Methods: Human iPSC-derived astrocytes or neurons were incubated with serum/CSF from 99 patients [42 with inflammatory neurological diseases (IND) and 57 with non-IND (NIND)]. The IND group included 11 patients with previously established neural antibodies, six with seronegative neuromyelitis optica spectrum disorder (NMOSD), 12 with suspected autoimmune encephalitis/paraneoplastic syndrome (AIE/PNS), and 13 with other IND (OIND). IgG binding to fixed CNS cells was detected using fluorescently-labeled antibodies and analyzed through automated fluorescence measures. IgG neuronal/astrocyte reactivity was further analyzed by flow cytometry. Peripheral blood mononuclear cells (PBMCs) were used as CNS-irrelevant control target cells. Reactivity profile was defined as positive using a Robust regression and Outlier removal test with a false discovery rate at 10% following each individual readout., Results: Using our CBA, we detected antibodies recognizing hiPSC-derived neural cells in 19/99 subjects. Antibodies bound specifically to astrocytes in nine cases, to neurons in eight cases, and to both cell types in two cases, as confirmed by microscopy single-cell analyses. Highlighting the significance of our comprehensive 96-well CBA assay, neural-specific antibody binding was more frequent in IND (15 of 42) than in NIND patients (4 of 57) (Fisher's exact test, p = 0.0005). Two of four AQP4+ NMO and four of seven definite AIE/PNS with intracellular-reactive antibodies [1 GFAP astrocytopathy, 2 Hu+, 1 Ri+ AIE/PNS)], as identified in diagnostic laboratories, were also positive with our CBA. Most interestingly, we showed antibody-reactivity in two of six seronegative NMOSD, six of 12 probable AIE/PNS, and one of 13 OIND. Flow cytometry using hiPSC-derived CNS cells or PBMC-detected antibody binding in 13 versus zero patients, respectively, establishing the specificity of the detected antibodies for neural tissue., Conclusion: Our unique hiPSC-based CBA allows for the testing of novel neuron-/astrocyte-reactive antibodies in patients with suspected immune-mediated neurological syndromes, and negative testing in established routine laboratories, opening new perspectives in establishing a diagnosis of such complex diseases., Competing Interests: RBV received travel grants from Roche and received speaker honoraria from Novartis. None were related to this work. AH has served as an expert in advisory boards from Novocure and Bayer and received speaker honoraria from Novocure, all paid to the institution and not related to this work. AZ has patents submitted for Tensacin-R IgG, PDE10A-IgG, and DACH1-IgG as biomarkers of neurological autoimmunity, receives research funding from Roche/Genetech non-relevant to this work, and has consulted for Alexion Pharmaceutical without personal compensation. MT has served as an expert in advisory boards for Biogen, Genzyme-Sanofi, Merck, Novartis, and Roche; received travel grants from Biogen, Genzyme-Sanofi, Merck, Novartis, and Roche; and received speaker honoraria from Biogen, Novartis, and Merck. None were related to this work. CP has served as an expert in advisory boards and received travel grants from Biogen, Genzyme-Sanofi, Merck, Novartis, and Roche. None were related to this work. RDP has served on scientific advisory boards for Biogen, BMS, Merck, Novartis, Roche, and Sanofi-Genzyme and has received funding for travel or speaker honoraria from Biogen, Merck, Roche, and Sanofi-Genzyme. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Mathias, Perriot, Jones, Canales, Bernard-Valnet, Gimenez, Torcida, Oberholster, Hottinger, Zekeridou, Theaudin, Pot and Du Pasquier.)

Background: Diagnosis of primary diffuse large B-cell lymphoma of the central nervous system (PCNSL) is challenging and often delayed. MRI imaging, CSF cytology and flow cytometry have a low sensitivity and even brain biopsies can be misleading. We report three cases of PCNSL with various clinical presentation and radiological findings where the diagnosis was suggested by novel CSF biomarkers and subsequently confirmed by brain biopsy or autopsy., Case Presentations: The first case is a 79-year-old man with severe neurocognitive dysfunction and static ataxia evolving over 5 months. Brain MRI revealed a nodular ventriculitis. An open brain biopsy was inconclusive. The second case is a 60-year-old woman with progressive sensory symptoms in all four limbs, evolving over 1 year. Brain and spinal MRI revealed asymmetric T2 hyperintensities of the corpus callosum, corona radiata and corticospinal tracts. The third case is a 72-year-old man recently diagnosed with primary vitreoretinal lymphoma of the right eye. A follow-up brain MRI performed 4 months after symptom onset revealed a T2 hyperintense fronto-sagittal lesion, with gadolinium uptake and perilesional edema. In all three cases, CSF flow cytometry and cytology were negative. Mutation analysis on the CSF (either by digital PCR or by next generation sequencing) identified the MYD88 L265P hotspot mutation in all three cases. A B-cell clonality study, performed in case 1 and 2, identified a monoclonal rearrangement of the immunoglobulin light chain lambda (IGL) and kappa (IGK) gene. CSF CXCL-13 and IL-10 levels were high in all three cases, and IL-10/IL-6 ratio was high in two. Diagnosis of PCNSL was later confirmed by autopsy in case 1, and by brain biopsy in case 2 and 3., Conclusions: Taken together, 5 CSF biomarkers (IL-10, IL-10/IL-6 ratio, CXCL13, MYD88 mutation and monoclonal IG gene rearrangements) were strongly indicative of a PCNSL. Using innovative CSF biomarkers can be sensitive and complementary to traditional CSF analysis and brain biopsy in the diagnosis of PCNSL, potentially allowing for earlier diagnosis and treatment., (© 2024. The Author(s).)

Aging in multiple sclerosis (MS) leads to altered clinical manifestations, where the pathophysiology shifts towards compartmentalized inflammation that drives clinical progression independent of relapse activity. Consequently, the effectiveness of disease-modifying therapies (DMTs) diminishes in older patients, coinciding with an elevated risk of adverse events. This raises the question of whether MS therapies should be discontinued after a certain age, which is often proposed for patients over 55 years. Studies on treatment discontinuation have shown a slight increase in disease activity, yet without significant disability progression. This suggests that the decision to stop DMTs should be discussed with older patients, considering existing comorbidities. Following the cessation of therapy, meticulous monitoring is essential., Competing Interests: Le Dr R. Bernard-Valnet a reçu un soutien pour des congrès et des honoraires pour des présentations de la part de Roche et Novartis et des fonds de recherche de la part de la fondation Novartis (en dehors des sujets traités ici). Le Pr P. Lalive a reçu des honoraires pour des conférences et/ou des frais de déplacement de Biogen, Merck, Novartis et Roche, des honoraires de consultation de Biogen, GeNeuro, Merck, Novartis et Roche, un soutien à la recherche de Roche et Novartis. Aucun n’était lié à ce travail. La Dre M. Théaudin a reçu un soutien pour des congrès et des honoraires pour des présentations et participation à des conseils consultatifs de la part de Biogen, Roche, Sanofi et Novartis. La Pre C. Pot a reçu des honoraires pour des conférences et/ou des frais de déplacement de Biogen, Merck, Novartis et Roche, tous versés au CHUV. Aucun n’était lié à ce travail. Le Pr R. Du Pasquier rapporte que le CHUV a reçu un soutien pour des congrès et des honoraires pour des présentations et participation à des conseils consultatifs de la part de Biogen, Genzyme, Merck, Novartis, Roche et Sanofi. Le Dr G. Breville n’a déclaré aucun conflit d’intérêts en relation avec cet article.

The management of multiple sclerosis (MS) has undergone a veritable revolution in recent years, with the arrival of highly effective treatments. In some cases, therapeutic discussions even precede the first clinical signs of the disease. The aim of this review is to present the therapeutic arsenal of progression-preventing treatments available in 2024 for MS, with anti-CD20 antibodies taking pride of place, also available for certain progressive forms of MS. The use of these immunosuppressants requires in-depth knowledge of their mechanisms of action, in order to understand their risks, such as the occurrence of opportunistic infections., Competing Interests: La Pre C. Pot a reçu des honoraires pour des conférences et/ou des frais de déplacement de Biogen, Merck, Novartis et Roche, tous versés au CHUV. Aucun n’était lié à ce travail. Le Pr R. Du Pasquier rapporte que le CHUV a reçu un soutien pour des congrès et des honoraires pour des présentations et participation à des conseils consultatifs de la part de Biogen, Genzyme, Merck, Novartis, Roche et Sanofi. Le Pr P. Lalive a reçu des honoraires pour des conférences et/ou des frais de déplacement de Biogen, Merck, Novartis et Roche, des honoraires de consultation de Biogen, GeNeuro, Merck, Novartis et Roche, un soutien à la recherche de Roche et Novartis. Aucun n’était lié à ce travail. Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

Myelin Oligodendrocyte Glycoprotein Antibody Associated Disease (MOGAD) is an autoimmune disease responsible for demyelination of the central nervous system that can occur in adults or children. Overlapping phenotypes between MOGAD, multiple sclerosis (MS) and neuromyelitis optica spectrum disease (NMOSD) have been described. The diagnostic criteria for MOGAD were proposed by a panel of international experts and published in 2023. Defining clinical, biological and imaging characteristics specific to this entity helps to improve diagnostic specificity. In this article, we present the clinical characteristics suggestive of MOGAD and discuss the importance of the antibody detection method and therapeutic management., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

Gender inequality in STEM fields remains pervasive and undermines the ability for talented individuals to excel. Despite advances, women still encounter obstacles in pursuing academic careers and reaching leadership positions. This commentary discusses the "scissor-shaped curve" and examines effective strategies to fix it, including data-driven initiatives that we have implemented at our university., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background and Objectives: Histopathologic studies have identified immunoglobulin (Ig) deposition and complement activation as contributors of CNS tissue damage in multiple sclerosis (MS). Intrathecal IgM synthesis is associated with higher MS disease activity and severity, and IgM is the strongest complement-activating immunoglobulin. In this study, we investigated whether complement components (CCs) and complement activation products (CAPs) are increased in persons with MS, especially in those with an intrathecal IgM synthesis, and whether they are associated with disease severity and progression., Methods: CC and CAP levels were quantified in plasma and CSF of 112 patients with clinically isolated syndrome (CIS), 127 patients with MS (90 relapsing-remitting, 14 primary progressive, and 23 secondary progressive), 31 inflammatory neurologic disease, and 44 symptomatic controls from the Basel CSF databank study. Patients with CIS/MS were followed in the Swiss MS cohort study (median 6.3 years). Levels of CC/CAP between diagnosis groups were compared; in CIS/MS, associations of CC/CAP levels with intrathecal Ig synthesis, baseline Expanded Disability Status Scale (EDSS) scores, MS Severity Score (MSSS), and neurofilament light chain (NfL) levels were investigated by linear regression, adjusted for age, sex, and albumin quotient., Results: CSF (but not plasma) levels of C3a, C4a, Ba, and Bb were increased in patients with CIS/MS, being most pronounced in those with an additional intrathecal IgM production. In CIS, doubling of C3a and C4a in CSF was associated with 0.31 (CI 0.06-0.56; p = 0.016) and 0.32 (0.02-0.62; p = 0.041) increased EDSS scores at lumbar puncture. Similarly, doubling of C3a and Ba in CIS/MS was associated with 0.61 (0.19-1.03; p < 0.01) and 0.74 (0.18-1.31; p = 0.016) increased future MSSS. In CIS/MS, CSF levels of C3a, C4a, Ba, and Bb were associated with increased CSF NfL levels, e.g., doubling of C3a was associated with an increase of 58% (Est. 1.58; CI 1.37-1.81; p < 0.0001)., Discussion: CNS-compartmentalized activation of the classical and alternative pathways of complement is increased in CIS/MS and associated with the presence of an intrathecal IgM production. Increased complement activation within the CSF correlates with EDSS, future MSSS, and NfL levels, supporting the concept that complement activation contributes to MS pathology and disease progression. Complement inhibition should be explored as therapeutic target to attenuate disease severity and progression in MS.

Background and Objectives: Progression independent of relapse activity (PIRA) is a crucial determinant of overall disability accumulation in multiple sclerosis (MS). Accelerated brain atrophy has been shown in patients experiencing PIRA. In this study, we assessed the relation between PIRA and neurodegenerative processes reflected by (1) longitudinal spinal cord atrophy and (2) brain paramagnetic rim lesions (PRLs). Besides, the same relationship was investigated in progressive MS (PMS). Last, we explored the value of cross-sectional brain and spinal cord volumetric measurements in predicting PIRA., Methods: From an ongoing multicentric cohort study, we selected patients with MS with (1) availability of a susceptibility-based MRI scan and (2) regular clinical and conventional MRI follow-up in the 4 years before the susceptibility-based MRI. Comparisons in spinal cord atrophy rates (explored with linear mixed-effect models) and PRL count (explored with negative binomial regression models) were performed between: (1) relapsing-remitting (RRMS) and PMS phenotypes and (2) patients experiencing PIRA and patients without confirmed disability accumulation (CDA) during follow-up (both considering the entire cohort and the subgroup of patients with RRMS). Associations between baseline MRI volumetric measurements and time to PIRA were explored with multivariable Cox regression analyses., Results: In total, 445 patients with MS (64.9% female; mean [SD] age at baseline 45.0 [11.4] years; 11.2% with PMS) were enrolled. Compared with patients with RRMS, those with PMS had accelerated cervical cord atrophy (mean difference in annual percentage volume change [MD-APC] -1.41; p = 0.004) and higher PRL load (incidence rate ratio [IRR] 1.93; p = 0.005). Increased spinal cord atrophy (MD-APC -1.39; p = 0.0008) and PRL burden (IRR 1.95; p = 0.0008) were measured in patients with PIRA compared with patients without CDA; such differences were also confirmed when restricting the analysis to patients with RRMS. Baseline volumetric measurements of the cervical cord, whole brain, and cerebral cortex significantly predicted time to PIRA (all p ≤ 0.002)., Discussion: Our results show that PIRA is associated with both increased spinal cord atrophy and PRL burden, and this association is evident also in patients with RRMS. These findings further point to the need to develop targeted treatment strategies for PIRA to prevent irreversible neuroaxonal loss and optimize long-term outcomes of patients with MS.

Cholesterol is easily oxidized and can be transformed into numerous oxidation products, among which oxysterols. Phytosterols are plant sterols related to cholesterol. Both oxysterols and phytosterols can have an impact on human health and diseases.Cholesterol is a member of the sterol family that plays essential roles in biological processes, including cell membrane stability and myelin formation. Cholesterol can be metabolized into several molecules including bile acids, hormones, and oxysterols. On the other hand, phytosterols are plant-derived compounds structurally related to cholesterol, which can also have an impact on human health. Here, we review the current knowledge about the role of oxysterols and phytosterols on human health and focus on the impact of their pathways on diseases of the central nervous system (CNS), autoimmune diseases, including inflammatory bowel diseases (IBD), vascular diseases, and cancer in both experimental models and human studies. We will first discuss the implications of oxysterols and then of phytosterols in different human diseases., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Cholesterol is an essential structural component of all membranes of mammalian cells where it plays a fundamental role not only in cellular architecture, but also, for example, in signaling pathway transduction, endocytosis process, receptor functioning and recycling, or cytoskeleton remodeling. Consequently, intracellular cholesterol concentrations are tightly regulated by complex processes, including cholesterol synthesis, uptake from circulating lipoproteins, lipid transfer to these lipoproteins, esterification, and metabolization into oxysterols that are intermediates for bile acids. Oxysterols have been considered for long time as sterol waste products, but a large body of evidence has clearly demonstrated that they play key roles in central nervous system functioning, immune cell response, cell death, or migration and are involved in age-related diseases, cancers, autoimmunity, or neurological disorders. Among all the existing oxysterols, this review summarizes basic as well as recent knowledge on 25-hydroxycholesterol which is mainly produced during inflammatory or infectious situations and that in turn contributes to immune response, central nervous system disorders, atherosclerosis, macular degeneration, or cancer development. Effects of its metabolite 7α,25-dihydroxycholesterol are also presented and discussed., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Importance: Mechanisms contributing to disability accumulation in multiple sclerosis (MS) are poorly understood. Blood neurofilament light chain (NfL) level, a marker of neuroaxonal injury, correlates robustly with disease activity in people with MS (MS); however, data on the association between NfL level and disability accumulation have been conflicting., Objective: To determine whether and when NfL levels are elevated in the context of confirmed disability worsening (CDW)., Design, Setting, and Participants: This study included 2 observational cohorts: results from the Expression, Proteomics, Imaging, Clinical (EPIC) study at the University of California San Francisco (since 2004) were confirmed in the Swiss Multiple Sclerosis Cohort (SMSC), a multicenter study in 8 centers since 2012. Data were extracted from EPIC in April 2022 (sampling July 1, 2004, to December 20, 2016) and SMSC in December 2022 (sampling June 6, 2012, to September 2, 2021). The study included 2 observational cohorts in tertiary MS centers. All participants of both cohorts with available NfL results were included in the study, and no eligible participants were excluded or declined to participate., Exposure: Association between NfL z scores and CDW., Main Outcome Measures: CDW was defined as Expanded Disability Status Scale (EDSS) worsening that was confirmed after 6 or more months and classified into CDW associated with clinical relapses (CDW-R) or independent of clinical relapses (CDW-NR). Visits were classified in relation to the disability worsening events into CDW(-2) for 2 visits preceding event, CDW(-1) for directly preceding event, CDW(event) for first diagnosis of EDSS increase, and the confirmation visit. Mixed linear and Cox regression models were used to evaluate NfL dynamics and to assess the association of NfL with future CDW, respectively., Results: A total of 3906 EPIC visits (609 participants; median [IQR] age, 42.0 [35.0-50.0] years; 424 female [69.6%]) and 8901 SMSC visits (1290 participants; median [IQR] age, 41.2 [32.5-49.9] years; 850 female [65.9%]) were included. In CDW-R (EPIC, 36 events; SMSC, 93 events), NfL z scores were 0.71 (95% CI, 0.35-1.07; P < .001) units higher at CDW-R(-1) in EPIC and 0.32 (95% CI, 0.14-0.49; P < .001) in SMSC compared with stable MS samples. NfL elevation could be detected preceding CDW-NR (EPIC, 191 events; SMSC, 342 events) at CDW-NR(-2) (EPIC: 0.23; 95% CI, 0.01-0.45; P = .04; SMSC: 0.28; 95% CI, 0.18-0.37; P < .001) and at CDW-NR(-1) (EPIC: 0.27; 95% CI, 0.11-0.44; P < .001; SMSC: 0.09; 95% CI, 0-0.18; P = .06). Those findings were replicated in the subgroup with relapsing-remitting MS. Time-to-event analysis confirmed the association between NfL levels and future CDW-R within approximately 1 year and CDW-NR (in approximately 1-2 years)., Conclusions and Relevance: This cohort study documents the occurrence of NfL elevation in advance of clinical worsening and may hint to a potential window of ongoing dynamic central nervous system pathology that precedes the diagnosis of CDW.

Background: Detecting new and enlarged lesions in multiple sclerosis (MS) patients is needed to determine their disease activity. LeMan-PV is a software embedded in the scanner reconstruction system of one vendor, which automatically assesses new and enlarged white matter lesions (NELs) in the follow-up of MS patients; however, multicenter validation studies are lacking., Purpose: To assess the accuracy of LeMan-PV for the longitudinal detection NEL white-matter MS lesions in a multicenter clinical setting., Study Type: Retrospective, longitudinal., Subjects: A total of 206 patients with a definitive MS diagnosis and at least two follow-up MRI studies from five centers participating in the Swiss Multiple Sclerosis Cohort study. Mean age at first follow-up = 45.2 years (range: 36.9-52.8 years); 70 males., Field Strength/sequence: Fluid attenuated inversion recovery (FLAIR) and T1-weighted magnetization prepared rapid gradient echo (T1-MPRAGE) sequences at 1.5 T and 3 T., Assessment: The study included 313 MRI pairs of datasets. Data were analyzed with LeMan-PV and compared with a manual "reference standard" provided by a neuroradiologist. A second rater (neurologist) performed the same analysis in a subset of MRI pairs to evaluate the rating-accuracy. The Sensitivity (Se), Specificity (Sp), Accuracy (Acc), F1-score, lesion-wise False-Positive-Rate (aFPR), and other measures were used to assess LeMan-PV performance for the detection of NEL at 1.5 T and 3 T. The performance was also evaluated in the subgroup of 123 MRI pairs at 3 T., Statistical Tests: Intraclass correlation coefficient (ICC) and Cohen's kappa (CK) were used to evaluate the agreement between readers., Results: The interreader agreement was high for detecting new lesions (ICC = 0.97, Pvalue < 10 -20 , CK = 0.82, P value = 0) and good (ICC = 0.75, P value < 10 -12 , CK = 0.68, P value = 0) for detecting enlarged lesions. Across all centers, scanner field strengths (1.5 T, 3 T), and for NEL, LeMan-PV achieved: Acc = 61%, Se = 65%, Sp = 60%, F1-score = 0.44, aFPR = 1.31. When both follow-ups were acquired at 3 T, LeMan-PV accuracy was higher (Acc = 66%, Se = 66%, Sp = 66%, F1-score = 0.28, aFPR = 3.03)., Data Conclusion: In this multicenter study using clinical data settings acquired at 1.5 T and 3 T, and variations in MRI protocols, LeMan-PV showed similar sensitivity in detecting NEL with respect to other recent 3 T multicentric studies based on neural networks. While LeMan-PV performance is not optimal, its main advantage is that it provides automated clinical decision support integrated into the radiological-routine flow., Evidence Level: 4 TECHNICAL EFFICACY: Stage 2., (© 2023 The Authors. Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Cognitive disorders are present in 30 to 45% of relapsing-remitting forms of multiple sclerosis and in up to 50-75% of progressive forms. They bear a negative impact on the quality of life and predict an unfavorable disease progression. According to guidelines, screening based on objective measurement such as the Single Digit Modality Test (SDMT) should be performed at the time of diagnosis and then on an annual basis. Confirmation of diagnosis and management are performed in collaboration with neuropsychologists. Increased awareness from patients and healthcare professionals is important to ensure earlier management and prevent negative consequences on the patients professional and family life., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

The vasculature is a key regulator of leukocyte trafficking into the central nervous system (CNS) during inflammatory diseases including multiple sclerosis (MS). However, the impact of endothelial-derived factors on CNS immune responses remains unknown. Bioactive lipids, in particular oxysterols downstream of Cholesterol-25-hydroxylase (Ch25h), promote neuroinflammation but their functions in the CNS are not well-understood. Using floxed-reporter Ch25h knock-in mice, we trace Ch25h expression to CNS endothelial cells (ECs) and myeloid cells and demonstrate that Ch25h ablation specifically from ECs attenuates experimental autoimmune encephalomyelitis (EAE). Mechanistically, inflamed Ch25h-deficient CNS ECs display altered lipid metabolism favoring polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) expansion, which suppresses encephalitogenic T lymphocyte proliferation. Additionally, endothelial Ch25h-deficiency combined with immature neutrophil mobilization into the blood circulation nearly completely protects mice from EAE. Our findings reveal a central role for CNS endothelial Ch25h in promoting neuroinflammation by inhibiting the expansion of immunosuppressive myeloid cell populations., (© 2023 The Authors. Published under the terms of the CC BY 4.0 license.)

Importance: There is a lack of validated biomarkers for disability progression independent of relapse activity (PIRA) in multiple sclerosis (MS)., Objective: To determine how serum glial fibrillary acidic protein (sGFAP) and serum neurofilament light chain (sNfL) correlate with features of disease progression vs acute focal inflammation in MS and how they can prognosticate disease progression., Design, Setting, and Participants: Data were acquired in the longitudinal Swiss MS cohort (SMSC; a consortium of tertiary referral hospitals) from January 1, 2012, to October 20, 2022. The SMSC is a prospective, multicenter study performed in 8 centers in Switzerland. For this nested study, participants had to meet the following inclusion criteria: cohort 1, patients with MS and either stable or worsening disability and similar baseline Expanded Disability Status Scale scores with no relapses during the entire follow-up; and cohort 2, all SMSC study patients who had initiated and continued B-cell-depleting treatment (ie, ocrelizumab or rituximab)., Exposures: Patients received standard immunotherapies or were untreated., Main Outcomes and Measures: In cohort 1, sGFAP and sNfL levels were measured longitudinally using Simoa assays. Healthy control samples served as the reference. In cohort 2, sGFAP and sNfL levels were determined cross-sectionally., Results: This study included a total of 355 patients (103 [29.0%] in cohort 1: median [IQR] age, 42.1 [33.2-47.6] years; 73 female patients [70.9%]; and 252 [71.0%] in cohort 2: median [IQR] age, 44.3 [33.3-54.7] years; 156 female patients [61.9%]) and 259 healthy controls with a median [IQR] age of 44.3 [36.3-52.3] years and 177 female individuals (68.3%). sGFAP levels in controls increased as a function of age (1.5% per year; P < .001), were inversely correlated with BMI (-1.1% per BMI unit; P = .01), and were 14.9% higher in women than in men (P = .004). In cohort 1, patients with worsening progressive MS showed 50.9% higher sGFAP levels compared with those with stable MS after additional sNfL adjustment, whereas the 25% increase of sNfL disappeared after additional sGFAP adjustment. Higher sGFAP at baseline was associated with accelerated gray matter brain volume loss (per doubling: 0.24% per year; P < .001) but not white matter loss. sGFAP levels remained unchanged during disease exacerbations vs remission phases. In cohort 2, median (IQR) sGFAP z scores were higher in patients developing future confirmed disability worsening compared with those with stable disability (1.94 [0.36-2.23] vs 0.71 [-0.13 to 1.73]; P = .002); this was not significant for sNfL. However, the combined elevation of z scores of both biomarkers resulted in a 4- to 5-fold increased risk of confirmed disability worsening (hazard ratio [HR], 4.09; 95% CI, 2.04-8.18; P < .001) and PIRA (HR, 4.71; 95% CI, 2.05-9.77; P < .001)., Conclusions and Relevance: Results of this cohort study suggest that sGFAP is a prognostic biomarker for future PIRA and revealed its complementary potential next to sNfL. sGFAP may serve as a useful biomarker for disease progression in MS in individual patient management and drug development.

Objective: This study explored the impact of time-restricted eating (TRE) versus standard dietary advice (SDA) on bone health., Methods: Adults with ≥1 component of metabolic syndrome were randomized to TRE (ad libitum eating within 12 hours) or SDA (food pyramid brochure). Bone turnover markers and bone mineral content/density by dual energy x-ray absorptiometry were assessed at baseline and 6-month follow-up. Statistical analyses were performed in the total population and by weight loss response., Results: In the total population (n = 42, 76% women, median age 47 years [IQR: 31-52]), there were no between-group differences (TRE vs. SDA) in any bone parameter. Among weight loss responders (≥0.6 kg weight loss), the bone resorption marker β-carboxyterminal telopeptide of type I collagen tended to decrease after TRE but increase after SDA (between-group differences p = 0.041), whereas changes in the bone formation marker procollagen type I N-propeptide did not differ between groups. Total body bone mineral content decreased after SDA (p = 0.028) but remained unchanged after TRE (p = 0.31) in weight loss responders (between-group differences p = 0.028). Among nonresponders (<0.6 kg weight loss), there were no between-group differences in bone outcomes., Conclusions: TRE had no detrimental impact on bone health, whereas, when weight loss occurred, it was associated with some bone-sparing effects compared with SDA., (© 2022 The Authors. Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society.)

Background and Objective: Depleting CD20 + B cells is the primary mechanism by which ocrelizumab (OCRE) is efficient in persons with multiple sclerosis (pwMS). However, the exact role of OCRE on other immune cell subsets directly or indirectly remains elusive. The purpose of this study is to characterize the dynamics of peripheral immune cells of pwMS on OCRE., Methods: We collected blood samples from 38 pwMS before OCRE onset (T0) and at 6 and 12 months (T6, T12) after initiation. To cover the immune cell diversity, using mass cytometry time of flight, we designed a 38-parameter panel to analyze B, T, and innate immune cell markers and CNS migratory markers. In parallel, viral-specific CD8 + T-cell responses were assessed by the quantification of interferon-γ secretion using the enzyme-linked immunospot assay on cytomegalovirus, Epstein-Barr virus, and influenza stimulations., Results: Beside B-cell depletion, we observed a loss in memory CD8 + CD20 + and central memory CD8 + T cells but not in CD4 + CD20 + T cells already at T6 and T12 ( p < 0.001). The loss of memory CD8 + T cells correlated with a lower CXCR3 expression ( p < 0.001) and CNS-related LFA-1 integrin expression ( p < 0.001) as well as a reduced antiviral cellular immune response observed at both time points ( p < 0.001). Of note, we did not observe major changes in the phenotype of the other cell types studied. Seven of 38 (18.4%) patients in our cohort presented with infections while on OCRE; 4 of which were switched from dimethyl fumarate. Finally, using a mixed linear model on mass cytometry data, we demonstrated that the immunomodulation induced by previous disease-modifying therapies (DMTs) was prolonged over the period of the study., Discussion: In addition to its well-known role on B cells, our data suggest that OCRE also acts on CD8 + T cells by depleting the memory compartment. These changes in CD8 + T cells may be an asset in the action of OCRE on MS course but might also contribute to explain the increased occurrence of infections in these patients. Finally, although more data are needed to confirm this observation, it suggests that clinicians should pay a special attention to an increased infection risk in pwMS switched from other DMTs to OCRE., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: The increasing availability of "real-world" data in the form of written text holds promise for deepening our understanding of societal and health-related challenges. Textual data constitute a rich source of information, allowing the capture of lived experiences through a broad range of different sources of information (eg, content and emotional tone). Interviews are the "gold standard" for gaining qualitative insights into individual experiences and perspectives. However, conducting interviews on a large scale is not always feasible, and standardized quantitative assessment suitable for large-scale application may miss important information. Surveys that include open-text assessments can combine the advantages of both methods and are well suited for the application of natural language processing (NLP) methods. While innovations in NLP have made large-scale text analysis more accessible, the analysis of real-world textual data is still complex and requires several consecutive steps., Objective: We developed and subsequently examined the utility and scientific value of an NLP pipeline for extracting real-world experiences from textual data to provide guidance for applied researchers., Methods: We applied the NLP pipeline to large-scale textual data collected by the Swiss Multiple Sclerosis (MS) registry. Such textual data constitute an ideal use case for the study of real-world text data. Specifically, we examined 639 text reports on the experienced impact of the first COVID-19 lockdown from the perspectives of persons with MS. The pipeline has been implemented in Python and complemented by analyses of the "Linguistic Inquiry and Word Count" software. It consists of the following 5 interconnected analysis steps: (1) text preprocessing; (2) sentiment analysis; (3) descriptive text analysis; (4) unsupervised learning-topic modeling; and (5) results interpretation and validation., Results: A topic modeling analysis identified the following 4 distinct groups based on the topics participants were mainly concerned with: "contacts/communication;" "social environment;" "work;" and "errands/daily routines." Notably, the sentiment analysis revealed that the "contacts/communication" group was characterized by a pronounced negative emotional tone underlying the text reports. This observed heterogeneity in emotional tonality underlying the reported experiences of the first COVID-19-related lockdown is likely to reflect differences in emotional burden, individual circumstances, and ways of coping with the pandemic, which is in line with previous research on this matter., Conclusions: This study illustrates the timely and efficient applicability of an NLP pipeline and thereby serves as a precedent for applied researchers. Our study thereby contributes to both the dissemination of NLP techniques in applied health sciences and the identification of previously unknown experiences and burdens of persons with MS during the pandemic, which may be relevant for future treatment., (©Deborah Chiavi, Christina Haag, Andrew Chan, Christian Philipp Kamm, Chloé Sieber, Mina Stanikić, Stephanie Rodgers, Caroline Pot, Jürg Kesselring, Anke Salmen, Irene Rapold, Pasquale Calabrese, Zina-Mary Manjaly, Claudio Gobbi, Chiara Zecca, Sebastian Walther, Katharina Stegmayer, Robert Hoepner, Milo Puhan, Viktor von Wyl. Originally published in JMIR Medical Informatics (https://medinform.jmir.org), 10.11.2022.)

Background: Electronic health diaries hold promise in complementing standardized surveys in prospective health studies but are fraught with numerous methodological challenges., Objective: The study aimed to investigate participant characteristics and other factors associated with response to an electronic health diary campaign in persons with multiple sclerosis, identify recurrent topics in free-text diary entries, and assess the added value of structured diary entries with regard to current symptoms and medication intake when compared with survey-collected information., Methods: Data were collected by the Swiss Multiple Sclerosis Registry during a nested electronic health diary campaign and during a regular semiannual Swiss Multiple Sclerosis Registry follow-up survey serving as comparator. The characteristics of campaign participants were descriptively compared with those of nonparticipants. Diary content was analyzed using the Linguistic Inquiry and Word Count 2015 software (Pennebaker Conglomerates, Inc) and descriptive keyword analyses. The similarities between structured diary data and follow-up survey data on health-related quality of life, symptoms, and medication intake were examined using the Jaccard index., Results: Campaign participants (n=134; diary entries: n=815) were more often women, were not working full time, did not have a higher education degree, had a more advanced gait impairment, and were on average 5 years older (median age 52.5, IQR 43.25-59.75 years) than eligible nonparticipants (median age 47, IQR 38-55 years; n=524). Diary free-text entries (n=632; participants: n=100) most often contained references to the following standard Linguistic Inquiry and Word Count word categories: negative emotion (193/632, 30.5%), body parts or body functioning (191/632, 30.2%), health (94/632, 14.9%), or work (67/632, 10.6%). Analogously, the most frequently mentioned keywords (diary entries: n=526; participants: n=93) were "good," "day," and "work." Similarities between diary data and follow-up survey data, collected 14 months apart (median), were high for health-related quality of life and stable for slow-changing symptoms such as fatigue or gait disorder. Similarities were also comparatively high for drugs requiring a regular application, including interferon beta-1a (Avonex) and glatiramer acetate (Copaxone), and for modern oral therapies such as fingolimod (Gilenya) and teriflunomide (Aubagio)., Conclusions: Diary campaign participation seemed dependent on time availability and symptom burden and was enhanced by reminder emails. Electronic health diaries are a meaningful complement to regular structured surveys and can provide more detailed information regarding medication use and symptoms. However, they should ideally be embedded into promotional activities or tied to concrete research study tasks to enhance regular and long-term participation., (©Chloé Sieber, Deborah Chiavi, Christina Haag, Marco Kaufmann, Andrea B Horn, Holger Dressel, Chiara Zecca, Pasquale Calabrese, Caroline Pot, Christian Philipp Kamm, Viktor von Wyl, Swiss Multiple Sclerosis Registry. Originally published in JMIR mHealth and uHealth (https://mhealth.jmir.org), 05.10.2022.)

Microbiota-derived metabolites are important molecules connecting the gut to the brain. Over the last decade, several studies have highlighted the importance of gut-derived metabolites in the development of multiple sclerosis (MS). Indeed, microbiota-derived metabolites modulate the immune system and affect demyelination. Here, we discuss the current knowledge about microbiota-derived metabolites implications in MS and in different mouse models of neuroinflammation. We focus on the main families of microbial metabolites that play a role during neuroinflammation. A better understanding of the role of those metabolites may lead to new therapeutical avenues to treat neuroinflammatory diseases targeting the gut-brain axis.

Importance: The mechanisms driving neurodegeneration and brain atrophy in relapsing multiple sclerosis (RMS) are not completely understood., Objective: To determine whether disability progression independent of relapse activity (PIRA) in patients with RMS is associated with accelerated brain tissue loss., Design, Setting, and Participants: In this observational, longitudinal cohort study with median (IQR) follow-up of 3.2 years (2.0-4.9), data were acquired from January 2012 to September 2019 in a consortium of tertiary university and nonuniversity referral hospitals. Patients were included if they had regular clinical follow-up and at least 2 brain magnetic resonance imaging (MRI) scans suitable for volumetric analysis. Data were analyzed between January 2020 and March 2021., Exposures: According to the clinical evolution during the entire observation, patients were classified as those presenting (1) relapse activity only, (2) PIRA episodes only, (3) mixed activity, or (4) clinical stability., Main Outcomes and Measures: Mean difference in annual percentage change (MD-APC) in brain volume/cortical thickness between groups, calculated after propensity score matching. Brain atrophy rates, and their association with the variables of interest, were explored with linear mixed-effect models., Results: Included were 1904 brain MRI scans from 516 patients with RMS (67.4% female; mean [SD] age, 41.4 [11.1] years; median [IQR] Expanded Disability Status Scale score, 2.0 [1.5-3.0]). Scans with insufficient quality were excluded (n = 19). Radiological inflammatory activity was associated with increased atrophy rates in several brain compartments, while an increased annualized relapse rate was linked to accelerated deep gray matter (GM) volume loss. When compared with clinically stable patients, patients with PIRA had an increased rate of brain volume loss (MD-APC, -0.36; 95% CI, -0.60 to -0.12; P = .02), mainly driven by GM loss in the cerebral cortex. Patients who were relapsing presented increased whole brain atrophy (MD-APC, -0.18; 95% CI, -0.34 to -0.02; P = .04) with respect to clinically stable patients, with accelerated GM loss in both cerebral cortex and deep GM. No differences in brain atrophy rates were measured between patients with PIRA and those presenting relapse activity., Conclusions and Relevance: Our study shows that patients with RMS and PIRA exhibit accelerated brain atrophy, especially in the cerebral cortex. These results point to the need to recognize the insidious manifestations of PIRA in clinical practice and to further evaluate treatment strategies for patients with PIRA in clinical trials.

Objective: Intrathecal Immunoglobulin M synthesis (IgM Intrathecal Fraction (IF) + ) and spinal MRI lesions are both strong independent predictors of higher disease activity and severity in multiple sclerosis (MS). We investigated whether IgM IF + is associated with spinal cord manifestation and higher neuroaxonal damage in early MS., Methods: In 122 patients with a first demyelinating event associations between (1) spinal versus (vs) non-spinal clinical syndrome (2) spinal vs cerebral T2-weighted (T2w) and (3) contrast-enhancing (CE) lesion counts with IgG IF + (vs IgG IF - ) or IgM IF + (vs IgM IF - ) were investigated by logistic regression adjusted for age and sex, respectively. For serum neurofilament light chain (sNfL) analysis patients were categorized for presence or absence of oligoclonal IgG bands (OCGB), IgG IF and IgM IF (>0% vs 0%, respectively): (1) OCGB - /IgG IF - /IgM IF - ; (2) OCGB + /IgG IF - /IgM IF - ; (3) OCGB + /IgG IF + /IgM IF - ; and (4) OCGB + /IgG IF + /IgM IF + . Associations between categories 2 to 4 vs category 1 with sNfL concentrations were analyzed by robust linear regression, adjusted for sex and MRI parameters., Results: Patients with a spinal syndrome had a 8.36-fold higher odds of IgM IF + (95%CI 3.03-23.03; p < 0.01). Each spinal T2w lesion (odds Ratio 1.39; 1.02-1.90; p = 0.037) and CE lesion (OR 2.73; 1.22-6.09; p = 0.014) was associated with an increased risk of IgM IF + (but not of IgG IF + ); this was not the case for cerebral lesions. OCGB + /IgG IF + /IgM IF + category patients showed highest sNfL levels (estimate:1.80; 0.55-3.06; p < 0.01)., Interpretation: Intrathecal IgM synthesis is strongly associated with spinal manifestation and independently more pronounced neuroaxonal injury in early MS, suggesting a distinct clinical phenotype and pathophysiology. ANN NEUROL 2022;91:814-820., (© 2022 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Dimethyl fumarate (DMF), a drug used for the treatment of multiple sclerosis (MS) and psoriasis, has been shown to activate the Keap1/Nrf2 antioxidant response. Nrf2 exerts pleiotropic roles in the thyroid gland; among others, single nucleotide polymorphisms (SNPs) in the gene encoding Nrf2 modulate the risk of Hashimoto's thyroiditis (HT), suggesting that pharmacological activation of Nrf2 might also be protective. However, a patient with acute exacerbation of HT after starting DMF for MS was recently reported, raising questions about the thyroidal safety of Nrf2 activators., Methods: In a retrospective observational study, we investigated the prevalence and incidence of thyroid disorders (TD) among 163 patients with MS treated with DMF., Results: Only 7/163 patients (4.3%) were diagnosed with functional TD; most (5/163, 3.0%) were diagnosed before DMF treatment. Functional TD were diagnosed under or after DMF in only 2 patients (1.2%). Under DMF, one patient developed transient mild hypothyroidism with negative thyroid autoantibodies. After DMF discontinuation, another patient developed hyperthyroidism due to Graves' disease. No patient developed thyroid structural disease under or after DMF., Conclusions: The very low incidence of functional TD indicates an overall very good thyroid tolerance of DMF, arguing against screening for TD in MS patients considered for or treated with DMF, and supporting the further study of Nrf2 activators for the prevention and treatment of TD.