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Judith M Greer, Pamela A McCombeThe University of Queensland, UQ Centre for Clinical Research, Brisbane, Queensland, AustraliaAbstract: The lack of complete concordance of autoimmune disease in identical twins suggests that nongenetic factors play a major role in determining disease susceptibility. In this review, we consider how epigenetic mechanisms could affect the immune system and effector mechanisms in autoimmunity and/or the target organ of autoimmunity and thus affect the development of autoimmune diseases. We also consider the types of stimuli that lead to epigenetic modifications and how these relate to the epidemiology of autoimmune diseases and the biological pathways operative in different autoimmune diseases. Increasing our knowledge of these epigenetic mechanisms and processes will increase the prospects for controlling or preventing autoimmune diseases in the future through the use of drugs that target the epigenetic pathways.Keywords: twins, concordance, autoimmune disease, nongenetic factors, immune system, epigenetic modifications

Background: Antibodies with reactivity to peripheral nerve myelin have previously been found in the serum, and bound to peripheral nerves of patients with Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP).Aim: To investigate the presence of antibodies reactive to specific peptide sequences within the myelin proteins P0 and P2 in patients with GBS, in patients with CIDP, in healthy controls and in patients with other neuropathies (ON).Methods: Blood was obtained from 48 patients with GBS, 36 with CIDP, 48 with ON and 38 controls. ELISA was used to detect antibody responses to peptides of the human peripheral myelin proteins P0 and P2. Blood samples were collected from patients with GBS in early, peak and recovery stages of GBS to analyse antibody levels throughout the course of the disease.Results: Significantly increased total IgG levels were found in patients with GBS compared with other groups. A higher percentage of patients with GBS at the peak of disease had antibody reactivity to P2(14-25) compared with patients with CIDP and control groups. In patients with GBS and CIDP, the percentages of patients with antibody reactivity to P2(61-70), and peptides derived from P0, were comparable to the control groups. Although some individual patients with GBS had high titres of reactivity to the peptide antigens tested, most patients with GBS and CIDP had levels of antibody similar to controls.Conclusion: Our data suggest that increased IgG levels and increased antibody reactivity to P2(14-25) in patients with GBS at the peak of disease may play a contributory role in the disease process in some patients with demyelinating forms of GBS. [ABSTRACT FROM AUTHOR]

Objectives: It has been suggested that autoimmunity to peripheral myelin proteins is involved in the pathogenesis of Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). We aimed to compare reactivity of peripheral blood mononuclear cells (PBMC) to antigens of peripheral myelin proteins in patients with GBS and patients with CIDP with that of healthy controls and patients with other non-immune mediated neuropathies (ON).Methods: We prepared PBMC from blood from 83 healthy controls and from 64 patients with GBS, 54 with CIDP, and 62 with ON. PBMC were tested in antigen specific proliferation assays against peptides from myelin proteins P0, P2, PMP22, and myelin basic protein (MBP), which is identical to myelin P1, and against whole human MBP. Interferon-gamma (IFN-gamma) and interleukin (IL)-5 enzyme linked immunospot (ELISPOT) assays were also performed in some subjects to assess spontaneous and peripheral myelin antigen specific PBMC cytokine secretion.Results: Antigen specific PBMC proliferation assays showed no significant elevation of peptide specific T cell responsiveness in patients with GBS or CIDP compared with healthy controls or patients with ON. Levels of spontaneous ELISPOT IFN-gamma secretion were increased in patients with GBS and significantly increased in those with CIDP compared with healthy controls and patients with ON. No convincing differences in antigen specific ELISPOT IFN-gamma secretion levels to individual peptides were detectable in patients with GBS. The proportion of patients with CIDP with an increased number of PBMC producing IFN-gamma in response to peptide PMP-22(51-64) was significantly increased compared with healthy controls and patients with ON. No significant differences in antigen specific ELISPOT IL-5 secretion levels were detectable in patients with GBS or CIDP compared with controls, but levels of spontaneous IL-5 secretion were significantly higher in patients with CIDP than in healthy controls or patients with ON.Conclusions: Although the lack of significantly increased antigen specific PBMC proliferation in GBS and CIDP does not support a role for T cells, the more sensitive ELISPOT technique detected increased numbers of PBMC secreting IFN-gamma spontaneously in 25% of patients with GBS, providing further evidence for a role of T cells in the immunopathology of GBS. Increased numbers of spontaneous IFN-gamma and IL-5 secreting cells, and increased IFN-gamma secretion in response to PMP-22(51-64), in patients with CIDP provide further evidence for a role of myelin specific T cells in CIDP. [ABSTRACT FROM AUTHOR]

Morphological studies have shown that macrophages and microglia undergo apoptosis in the central nervous system (CNS) in acute experimental autoimmune encephalomyelitis (EAE) in the Lewis rat. To assess the relative levels of macrophage and microglial apoptosis, and the molecular mechanisms involved in this process, we used three-colour flow cytometry to identify CD45lowCD11b/c+ microglial cells and CD45highCD11b/c+ macrophages in the inflammatory cells isolated from the spinal cords of Lewis rats 13 days after immunization with myelin basic protein (MBP) and complete Freund's adjuvant. Simultaneously, we analyzed the DNA content of these cell populations to assess the proportions of cells undergoing apoptosis and in different stages of the cell cycle or examined their expression of three apoptosis-regulating proteins, i.e Fas (CD95), Fas ligand (FasL) and Bcl-2. Microglia were highly vulnerable to apoptosis and were over-represented in the apoptotic population. Macrophages were less susceptible to apoptosis than microglia and underwent mitosis more frequently than microglia. The different susceptibilities of microglia and macrophages to apoptosis did not appear to be due to variations in Fas, FasL or Bcl-2 expression, as the proportions of microglia and macrophages expressing these proteins were similar, and were relatively high. Furthermore, in contrast to T cell apoptosis, apoptosis or microglia/macrophages did not occur more frequently in cells expressing Fas or FasL, or less frequently in cells expressing Bcl-2. These results indicate that the apoptosis of microglia and CNS macrophages in EAE is not mediated through the Fas pathway, and that Bcl-2 expression does not protect them from apoptosis. Expression of FasL by macrophages and microglia may contribute to the pathogenesis and immunoregulation of EAE through interactions with Fas+ oligodendrocytes and Fas+ T cells. The high level of microglial apoptosis in EAE indicates that microglial apoptosis may be an important homeostatic mechanism for controlling the number of microglia in the CNS following microglial activation and proliferation. [ABSTRACT FROM PUBLISHER]

Abstract Background There is reported to be a decline in immune function and an alteration in the frequency of circulating lymphocytes with advancing age. There are also differences in ageing and lifespan between males and females. We performed this study to see if there were differences between males and females in the frequency of the different lymphocyte subsets with age. Results Using flow cytometry we have examined different populations of peripheral blood leukocytes purified from healthy subjects with age ranging from the third to the tenth decade. We used linear regression analysis to determine if there is a linear relationship between age and cell frequencies. For the whole group, we find that with age there is a significant decline in the percentage of naïve T cells and CD8+ T cells, and an increase in the percentage of effector memory cells, CD4+foxp3+ T cells and NK cells. For all cells where there was an effect of ageing, the slope of the curve was greater for men than for women and this was statistically significant for CD8+αβ+ T cells and CD3+CD45RA-CCR7- effector memory cells. There was also a difference for naïve cells but this was not significant. Conclusion The cause of the change in percentage of lymphocyte subsets with age, and the different effects on males and females is not fully understood but warrants further study.

Background and Objectives: Women with multiple sclerosis (MS) are at risk of disease reactivation in the early postpartum period. Ocrelizumab (OCR) is an anti-CD20 therapy highly effective at reducing MS disease activity. Data remain limited regarding use of disease-modifying therapies (DMTs), including OCR, and disease activity during peripregnancy periods., Methods: We performed a retrospective cohort study using data from the MSBase Registry including pregnancies conceived after December 31, 2010, from women aged 18 years and older, with relapsing-remitting MS or clinically isolated syndrome. Women were classified by preconception exposure to DMTs, including OCR, rituximab (RTX), natalizumab (NAT), stratified into active (NAT-A; continued ≥28 weeks of gestation, restarted ≤1 month postpartum) or conservative (NAT-C; continued ≤4 weeks of gestation, restarted >1 month postpartum) strategies, dimethyl fumarate (DMF) or low-efficacy DMTs (interferon-beta, glatiramer acetate). Annualized relapse rates (ARRs) were calculated for 12-month prepregnancy, pregnancy, and 6-month postpartum periods., Results: A total of 2,009 live births from 1,744 women were analyzed, including 73 live births from 69 women treated with preconception OCR. For OCR, no within-pregnancy relapse was observed and 3 women (4.1%) experienced 1 relapse in the postpartum period (ARR 0.09 [95% CI 0.02-0.27]). For NAT-A, 3 (3.7%) of 82 women relapsed during pregnancy (0.05 [0.01-0.15]) and 4 (4.9%) relapsed during postpartum (0.10 [0.03-0.26]). However, for NAT-C, 13 (15.9%) of 82 women relapsed within pregnancy (0.32 [0.20-0.51]) and 25 (30.5%) relapsed during postpartum (0.74 [0.50-1.06]). In the low-efficacy DMT group, 101 (7.6%) of 1,329 women experienced within-pregnancy relapse (0.12 [0.10-0.14]), followed by an increase in postpartum relapse activity with 234 women (17.6%) relapsing (0.43 [0.38-0.48]). This was similarly seen in the DMF group with 13 (7.9%) of 164 women experiencing within-pregnancy relapse (0.12 [0.06-0.20]) and 25 (15.2%) of 164 relapsing postpartum (0.39 [0.26-0.57]). Our RTX cohort had 0 of 24 women experiencing within-pregnancy relapse and 3 (12.5%) of 24 experiencing postpartum relapse., Discussion: Women treated with OCR or NAT-A were observed to have low relapse rates during pregnancy and postpartum. NAT-C was associated with increased risk of relapses. There was no within-pregnancy relapse in our RTX cohort, although we caution overinterpretation due to our sample size. An effective DMT strategy with a favorable safety profile for the mother and infant should be discussed and implemented well in advance of planning a family., Classification of Evidence: This study provides Class III evidence that for women with relapsing-remitting MS or clinically isolated syndrome who become pregnant, ocrelizumab, rituximab, and natalizumab (continued ≥28 weeks of gestation and restarted ≤1 month postpartum) were associated with reduced risk of relapses, compared with other therapeutic strategies.

Background: Neuromyelitis optica spectrum disorder (NMOSD) can be categorised into aquaporin-4 antibody (AQP4-IgG) NMOSD or seronegative NMOSD. While our knowledge of AQP4-IgG NMOSD has evolved significantly in the past decade, seronegative NMOSD remains less understood. This study aimed to evaluate the predictors of relapses and treatment responses in AQP4-IgG NMOSD and seronegative NMOSD., Methods: This was a multicentre, international, retrospective cohort study using the MSBase registry. Recurrent relapse risk was assessed using an Andersen-Gill model and risk of first relapse was evaluated using a Cox proportional hazards model. Covariates that putatively influence relapse risk included demographic factors, clinical characteristics and immunosuppressive therapies; the latter was assessed as a time-varying covariate., Results: A total of 398 patients (246 AQP4-IgG NMOSD and 152 seronegative NMOSD) were included. The AQP4-IgG NMOSD and seronegative NMOSD patients did not significantly differ by age at disease onset, ethnicity or annualised relapse rate. Both low-efficacy and high-efficacy immunosuppressive therapies were associated with significant reductions in recurrent relapse risk, with notably greater protection conferred by high-efficacy therapies in both AQP4-IgG NMOSD (HR 0.27, 95% CI 0.15 to 0.49, p<0.001) and seronegative NMOSD (HR 0.21, 95% CI 0.08 to 0.51, p<0.001). Longer disease duration (HR 0.97, 95% CI 0.95 to 0.99, p<0.001) and male sex (HR 0.52, 95% CI 0.34 to 0.84, p=0.007) were additional protective variables in reducing the recurrent relapse risk for the AQP4-IgG NMOSD group., Conclusion: Although further studies are needed to improve our understanding of seronegative NMOSD, our findings underscore the importance of aggressive treatment with high-efficacy immunotherapies in both NMOSD subtypes, regardless of serostatus., Competing Interests: Competing interests: The author(s) would like to disclose the following. PSiriratnam has received travel support from Novartis and Biogen; AvdW has received travel support and served on advisory boards for Novartis, Biogen, Merck Serono, Roche and Teva, she receives grant support from the National Health and Medical Research Council of Australia; HB served on scientific advisory boards for Biogen, Novartis and Sanofi-Aventis and received conference travel support from Novartis, Biogen and Sanofi Aventis, he serves on steering committees for trials conducted by Biogen and Novartis and received research support from Merck, Novartis and Biogen, Medical Research Council and MS Research Australia; YCF has received travel support from Roche and Biogen, he receives grant support from Australian National Health Medical Research Council, Australia and New Zealand Association of Neurologists, AVANT foundation and MS Research Australia; WZY has received speaker honoraria from Merck and Novartis; CZ receives fellowship from the Trish Multiple Sclerosis Research Foundation; VJ receives fellowship and research support from the National Health and Medical Research Council of Australia, she also receives research grant support form F.Hoffmann La-Roche and the International Progressive MS Alliance; SH receives research support from academic entity - National Institute for Health Research (NIHR304529): Research funding; MM has served on advisory board for Merck, and Novartis and has received speaker honoraria from Merck, Biogen and Novartis, her institution receives funding from Merck, Australian National Health; TK served on scientific advisory boards for MS International Federation and WHO, BMS, Roche, Janssen, Sanofi Genzyme, Novartis, Merck and Biogen, steering committee for Brain Atrophy Initiative by Sanofi Genzyme, received conference travel support and/or speaker honoraria from WebMD Global, Eisai, Novartis, Biogen, Roche, Sanofi-Genzyme, Teva, BioCSL and Merck and received research or educational event support from Biogen, Novartis, Genzyme, Roche, Celgene and Merck; SJK received compensation for scientific advisory board activity from Merck and Roche, and received compensation for serving on the IDMC for Biogen; TC received speaker honoraria/conference travel support from Biogen, Merck, Novartis, Roche, Sanofi-Aventis and Teva; BW received honoraria for acting as a member of Scientific Advisory Boards/Consultancy for Alexion, Almirall, Biogen, Celgene/BMS, Merck, Janssen, Novartis, Roche, Sandoz, Sanofi-Genzyme and speaker honoraria and travel support from Biogen, Celgene/BMS, Merck, Novartis, Roche, Sanofi-Genzyme, research and/or patient support grants from Biogen, Janssen, Merck, Sanofi-Genzyme, Roche, Honoraria and grants were paid to UZA/UZA Foundation, further, B.W. received research funding from FWO-TBM, Belgian Charcot Foundation, Start2Cure Foundation, Queen Elisabeth Medical Foundation for Neurosciences and the National MS Society USA; PN received speaker honoraria and consultant fees from Biogen Idec, Novartis, Merck, Roche, Jannsen, Astra Zeneca and financial support for research activities from Roche and Merck, the work of PN was supported by Ministry of Health of the Czech Republic, grant nr. NU23-05-00462; AA received speaker honoraria from Novartis and Alexion; AA-A received personal compensation for serving as a Scientific Advisory or speaker/moderator for Novartis, Biogen, Roche, Sanofi-Genzyme, and Merck; BY received honoraria as a speaker and member of scientific advisory boards from Sanofi, Bayer, Biogen, Merck, Janssen, Novartis, Roche and Aspen; GL received travel and/or consultancy compensation from Sanofi-Genzyme, Roche, Teva, Merck, Novartis, Celgene, Biogen; FP received personal compensation for serving on advisory board by Almirall, Alexion, Biogen, Bristol, Janssen, Merck, Novartis and Roche, he further received research grant by Alexion, Almirall, Biogen, Bristol, Merck, Novartis and Roche and by FISM, Reload Association (Onlus), Italian Health Minister and University of Catania. Magdolna Simo received speaker honoraria from Novartis, Biogen, Bayer Schering, Sanofi, Merck, Roche, congress/travel compensation from Teva, Biogen, Merck, Bayer Schering Novartis, Roche; MF received travel and meeting attendance support from Novartis, Biogen, Roche, Sanofi-Genzyme and Merck; ASoysal received travel and meeting attendance support from Novartis, Biogen, Roche, Merck, Bristol, Sanofi-Genzyme, Almirall, Piam; PAM received honoraria and consulting fees from Novartis, Bayer Schering and Sanofi and travel grants from Novartis, Biogen and Bayer Schering; RA received honoraria as a speaker and for serving on scientific advisory boards from Bayer, Biogen, GSK, Merck, Novartis, Roche and Sanofi-Genzyme; JLS-M, accepted travel compensation from Novartis, Merck and Biogen, speaking honoraria from Biogen, Novartis, Sanofi, Merck, Almirall, Bayer and Teva and has participated in clinical trials by Biogen, Merck and Roche; JLS received travel compensation from Novartis, Biogen, Roche and Merck, her institution receives the honoraria for talks and advisory board commitment as well as research grants from Biogen, Merck, Roche, TEVA and Novartis., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: In aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4-IgG NMOSD), disability accrual is mostly attributed to relapses. This study aimed to assess the prevalence of progression independent of relapse activity (PIRA) and relapse-associated worsening (RAW) in AQP4-IgG NMOSD., Methods: This was a retrospective cohort study of patients with AQP4-IgG NMOSD enrolled in the MSBase international data registry. Patients required a minimum of 3 recorded Expanded Disability Status Scale (EDSS) scores: baseline, event, and a 6-month confirmation score. Presence and absence of relapses between the baseline and event EDSS scores determined RAW and PIRA, respectively. Descriptive statistics were used to present the results., Results: A total of 181 patients followed for a median of 4.5 years (Q1 1.7, Q3 7.8) were included. Most patients were female (88.4%), and the median age at disease onset was 38.1 years. Overall, 4 patients (2.2%) developed 5 incidences of PIRA and 13 patients developed RAW (7.2%)., Discussion: This multicenter study highlights that PIRA is very rare in AQP4-IgG NMOSD. Limitations of this study include the sole focus of overall EDSS to measure disability, lack of requirement for a second EDSS score to confirm baseline EDSS, and the absence of magnetic resonance imaging information for all patients.

Introduction: The neutrophil-to-lymphocyte ratio (NLR) has previously been reported to be associated with survival in ALS. To provide further information about the role of NLR as a biomarker in ALS, we performed a systematic review, analyzed data from our local cohort of ALS subjects and performed a meta-analysis., Methods: (1) The systematic review used established methods. (2) Using data from our cohort of subjects, we analyzed the association of NLR with survival. (3) Meta-analysis was performed using previous studies and our local data., Results: (1) In the systematic review, higher NLR was associated with shorter survival in all studies. (2) In our subjects, survival was significantly shorter in patients in the highest NLR groups. (3) Meta-analysis showed subjects with highest NLR tertile or with NLR >3 had significantly shorter survival than other subjects., Discussion: This study supports NLR as a biomarker in ALS; high NLR is associated with poor survival.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Clinical heterogeneity and complex genetics pose challenges to understanding disease mechanisms and producing effective cures. To model clinical heterogeneity, we generated human induced pluripotent stem cells (iPSCs) from two sporadic ALS patients (sporadic ALS and sporadic ALS with frontotemporal dementia), two familial ALS patients (familial SOD1 mutation positive and familial C9orf72 repeat expansion positive), and four age- and sex-matched healthy controls. These iPSCs can be used to generate 2D and 3D in vitro models of ALS to investigate mechanisms of disease and screen for therapeutics., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Timothy J Tracey reports financial support was provided by Motor Neurone Disease Research Australia. Shyuan T Ngo reports financial support was provided by National Health and Medical Research Council. Shyuan T Ngo reports financial support was provided by Motor Neurone Disease Research Australia. Shyuan T Ngo reports financial support was provided by FightMND. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Neuromyelitis optica spectrum disorder (NMOSD) is a relapsing, autoimmune, inflammatory astrocytopathy. Rituximab for B-cell suppression is a common treatment for NMOSD; however, large-scale randomised controlled trials are lacking., Objective: Evaluate long-term efficacy and safety of rituximab for NMOSD., Methods: Retrospective observational study of patients with NMOSD treated with rituximab. Annualised relapse rates (ARRs) before and during rituximab treatment were evaluated; Modified Rankin Scores (mRS) were measured as a marker of disability., Results: In total, 37 patients were included: 27 aquaporin-4-IgG-seropositive and 10 seronegative NMOSD. The predominant rituximab dosing regimen was an initial 1000 mg, split over two 500 mg infusions, two weeks apart, followed by single 500 mg doses. Over a median follow-up of 54 months, ARR for the whole cohort was 0.136 (95% CI 0.088-0.201), significantly lower than the pretreatment ARR of 0.366 (95% CI 0.271-0.483, p  < 0.001). There was a significant reduction in ARR for the seropositive subgroup, but not seronegative. Significant improvement in mRS was seen post-treatment. Infections were reported in 32% of patients during follow-up; most were mild., Conclusion: Rituximab, at doses lower than traditionally used, may be an efficacious therapy for NMOSD, with a favourable safety profile., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2024.)

Background and Objectives: Altered metabolism is observed in amyotrophic lateral sclerosis (ALS). However, without a standardized methodology to define metabolic changes, our understanding of factors contributing to and the clinical significance of altered metabolism in ALS is limited., Methods: We aimed to determine how geographic variation in metabolic rates influences estimates and accuracy of predicted resting energy expenditure (REE) in patients with ALS and controls, while validating the effectiveness of cohort-specific approaches in predicting altered metabolic rate in ALS. Participants from 3 geographically distinct sites across Australia, China, and the Netherlands underwent REE assessments, and we considered 22 unique equations for estimating REE. Analyses evaluated equation performance and the influence of demographics on metabolic status. Comparisons were made using standardized and local reference values to identify metabolic alterations., Results: 606 participants were included from Australia (patients with ALS: 140, controls: 154), the Netherlands (patients with ALS: 79, controls: 37) and China (patients with ALS: 67, controls: 129). Measured REE was variable across geographic cohorts, with fat-free mass contributing to this variation across all patients ( p = 0.002 to p < 0.001). Of the 22 predication equations assessed, the Sabounchi Structure 4 (S4) equation performed relatively well across all control cohorts. Use of prediction thresholds generated using data from Australian controls generally increased the prevalence of hypermetabolism in Chinese (55%, [43%-67%]) and Dutch (44%, [33%-55%]) cases when compared with Australian cases (30%, [22%-38%]). Adjustment of prediction thresholds to consider geographically distinct characteristics from matched control cohorts resulted in a decrease in the proportion of hypermetabolic cases in Chinese and Dutch cohorts (25%-31% vs 55% and 20%-34% vs 43%-44%, respectively), and increased prevalence of hypometabolism in Dutch cases with ALS (1% to 8%-10%)., Discussion: The identification of hypermetabolism in ALS is influenced by the formulae and demographic-specific prediction thresholds used for defining alterations in metabolic rate. A consensus approach is needed for identification of metabolic changes in ALS and will facilitate improved understanding of the cause and clinical significance of this in ALS.

Background and Purpose: Loss of appetite contributes to weight loss and faster disease progression in amyotrophic lateral sclerosis (ALS). Impairment of appetite control in ALS may include altered production or action of orexigenic (i.e., ghrelin) and anorexigenic (i.e., liver-expressed antimicrobial peptide 2 [LEAP2] and leptin) hormones. We aimed to determine if postprandial circulating ghrelin levels, LEAP2 levels, LEAP2:ghrelin molar ratio and leptin levels differ in ALS patients compared to non-neurodegenerative disease controls, and whether they are associated with disease progression and body composition., Methods: In this prospective natural history study, we assessed postprandial plasma levels of ghrelin, LEAP2 and leptin in patients with ALS (cases; n = 46) and controls (controls; n = 43). For cases, measures were compared to changes in body weight, body composition and clinical outcomes., Results: Postprandial ghrelin level was decreased by 52% in cases compared to controls (p = 0.013). LEAP2:ghrelin molar ratio was increased by 249% (p = 0.009), suggesting greater ghrelin resistance. Patients with lower LEAP2:ghrelin tended to have better functional capacity at assessment, as inferred by the ALS Functional Rating Scale-Revised (τ = -0.179, p = 0.086). Furthermore, ghrelin and LEAP2:ghrelin molar ratio correlated with diagnostic delay (ghrelin, τ = 0.223, p = 0.029; LEAP2:ghrelin, τ = -0.213, p = 0.037). Baseline ghrelin level, LEAP2 level, LEAP2:ghrelin ratio and leptin level were, however, not predictive of change in functional capacity during follow-up. Also, patients with higher postprandial ghrelin levels (hazard ratio [HR] 1.375, p = 0.048), and lower LEAP2:ghelin ratios (HR 0.828, p = 0.051) had an increased risk of earlier death., Conclusions: Reduced postprandial ghrelin levels, coupled with increased LEAP2:ghrelin molar ratios, suggests a loss of ghrelin action in patients with ALS. Given ghrelin's actions on appetite, metabolism and neuroprotection, reduced ghrelin and greater ghrelin resistance could contribute to impaired capacity to tolerate the physiological impact of disease. Comprehensive studies are needed to explain how ghrelin and LEAP2 contribute to body weight regulation and disease progression in ALS., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: Simultaneous comparisons of multiple disease-modifying therapies for relapsing-remitting multiple sclerosis (RRMS) over an extended follow-up are lacking. Here we emulate a randomised trial simultaneously comparing the effectiveness of six commonly used therapies over 5 years., Methods: Data from 74 centres in 35 countries were sourced from MSBase. For each patient, the first eligible intervention was analysed, censoring at change/discontinuation of treatment. The compared interventions included natalizumab, fingolimod, dimethyl fumarate, teriflunomide, interferon beta, glatiramer acetate and no treatment. Marginal structural Cox models (MSMs) were used to estimate the average treatment effects (ATEs) and the average treatment effects among the treated (ATT), rebalancing the compared groups at 6-monthly intervals on age, sex, birth-year, pregnancy status, treatment, relapses, disease duration, disability and disease course. The outcomes analysed were incidence of relapses, 12-month confirmed disability worsening and improvement., Results: 23 236 eligible patients were diagnosed with RRMS or clinically isolated syndrome. Compared with glatiramer acetate (reference), several therapies showed a superior ATE in reducing relapses: natalizumab (HR=0.44, 95% CI=0.40 to 0.50), fingolimod (HR=0.60, 95% CI=0.54 to 0.66) and dimethyl fumarate (HR=0.78, 95% CI=0.66 to 0.92). Further, natalizumab (HR=0.43, 95% CI=0.32 to 0.56) showed a superior ATE in reducing disability worsening and in disability improvement (HR=1.32, 95% CI=1.08 to 1.60). The pairwise ATT comparisons also showed superior effects of natalizumab followed by fingolimod on relapses and disability., Conclusions: The effectiveness of natalizumab and fingolimod in active RRMS is superior to dimethyl fumarate, teriflunomide, glatiramer acetate and interferon beta. This study demonstrates the utility of MSM in emulating trials to compare clinical effectiveness among multiple interventions simultaneously., Competing Interests: Competing interests: The authors report the following relationships: speaker honoraria, advisory board or steering committee fees, research support and/or conference travel support from Acthelion (EKH, RA), Almirall (MT, FG, RB, CRT, JLS-M), Bayer (MT, AL, PS, RA, MT, CB, JL-S, EP, VVP, RB, DS, RA, JO, JLSM, SH, CR, AGK, TC, NS, BT, MS, CAS), BioCSL (TK, AGK, BT), Biogen (TK, TS, DH, EKH, MT, GI, AL, MG, PD, PG, VJ, AVW, FG, PS, DF, RA, RH, CB, JLS, EP, VVP, FG, RB, RA, CRT, JP, JO, MB, JLSM, SH, CR, CSh, OGerlach, AGK, TC, BS, NS, BT, MS, HB), Biologix (RA), BMS/Celgene (EKH, AL), Genpharm (RA), Genzyme-Sanofi (TK, EKH, MT, GI, AL, MG, PD, PG, AVW, FG, PS, DF, RA, RH, MT, CB, JLS, EP, EP, VVP, FG, RB, RB, DS, CRT, JP, JO, MB, JLSM, SH, O Gerlach, AGK, HB), GSK (RA), Innate Immunotherapeutics (AGK), Lundbeck (EP), Merck / EMD (TK, DH, EKH, MT, GI, AL(Merck Serono), MG, PD, PG, VJ, AVW, PS, DF, RA, RH, MT, CB, JLS, EP, VVP, FG, RB, DS, RA, JO, MB, JLSM, CR, FM, O Gerlach, AGK, TC, BS, MS, HB), Mitsubishi (FG),Novartis (TK, TS, DH, EKH, MT, GI, AL, MG, PD, PG, VJ, AVW, FG, PS, DF, RA, RH, MT, CB, JLS, EP, VVP, FG, RB, DS, RA, CRT, JP, JO, MB, JLSM, SH, CR, FM, CSh, OG, AGK, TC, NS, BT, MS, HB), ONO Pharmaceuticals (FG), Roche (TK, EKH, AL, MT, CB, VVP, BT), Teva (TK, DH, EKH, MT, GI, AL, MG, PD, PG, VJ, FG, PS, DF, RH, MT, CB, JLS, VVP, RB, DS, RA, JP, JO, JLSM, CR, AGK, TC, MS, CAS), WebMD (TK), UCB (EP)., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Increased amplitude of persistent inward currents (PICs) is observed in pre-symptomatic genetically modified SOD1 mice models of amyotrophic lateral sclerosis (ALS). However, at the symptomatic stage this reverses and there is a large reduction in PIC amplitude. It remains unclear whether these changes in PICs can be observed in humans, with cross-sectional studies in humans reporting contradictory findings. In people with ALS, we estimated the PIC contribution to self-sustained firing of motoneurons, using the paired-motor unit analysis to calculate the Δfrequency (ΔF), to compare the weaker and stronger muscles during the course of disease. We hypothesised that, with disease progression, ΔFs would relatively increase in the stronger muscles; and decline in the weaker muscles. Forty-three individuals with ALS were assessed in two occasions on average 17 weeks apart. Tibialis anterior high-density electromyograms were recorded during dorsiflexion (40% of maximal capacity) ramped contractions, followed by clinical tests. ∆F increased from 3.14 (2.57, 3.71) peaks per second (pps) to 3.55 (2.94, 4.17) pps on the stronger muscles (0.41 (0.041, 0.781) pps, standardised difference (d) = 0.287 (0.023, 0.552), P = 0.030). ∆F reduced from 3.38 (95% CI 2.92, 3.84) pps to 2.88 (2.40, 3.36) pps on the weaker muscles (-0.50 (-0.80, -0.21) pps, d = 0.353 (0.138, 0.567), P = 0.001). The ALSFRS-R score reduced 3.9 (2.3, 5.5) points. These data indicate that the contribution of PICs to motoneuron self-sustained firing increases over time in early stages of the disease when there is little weakness before decreasing as the disease progresses and muscle weakness exacerbates, in alignment with the findings from studies using SOD1 mice. KEY POINTS: Research on mouse model of amyotrophic lateral sclerosis (ALS) suggests that the amplitude of persistent inward currents (PICs) is increased in early stages before decreasing as the disease progresses. Cross-sectional studies in humans have reported contradictory findings with both higher and lower PIC contributions to motoneuron self-sustained firing. In this longitudinal (∼17 weeks) study we tracked changes in PIC contribution to motoneuron self-sustained firing, using the ΔF calculation (i.e. onset-offset hysteresis of motor unit pairs), in tibialis anterior muscles with normal strength and with clinical signs of weakness in people with ALS. ΔFs decreased over time in muscles with clinical signs of weakness. The PIC contribution to motoneuron self-sustained firing increases before the onset of muscle weakness, and subsequently decreases when muscle weakness progresses., (© 2023 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

The key pathological feature in ALS is death of motor neurones from the brain and spinal cord, but the molecular mechanisms underlying this degeneration remain unknown. Quantifying the motor cortex proteome in autopsy brain and comparing tissues from ALS cases and non-ALS controls is critical to understanding these mechanisms. We used Sequential Window Acquisition of All Theoretical Mass Spectra (SWATH-MS) to characterize the proteomes of the motor cortex from ALS cases (n = 8) and control subjects (n = 8). A total of 1427 proteins were identified at a critical local false discovery rate < 5%; 187 of these exhibited significant expression differences between ALS cases and controls. Of these, 91 proteins were significantly upregulated and 96 proteins were significantly downregulated. Bioinformatics analysis revealed that these proteins are involved in molecular transport, protein trafficking, free radical scavenging, lipid metabolism, cell death and survival, nucleic acid metabolism, inflammatory response or amino acid metabolism and carbohydrate metabolism. Differentially expressed proteins were subjected to pathway analysis. This revealed abnormalities in pathways involving mitochondrial function, sirtuin signaling, oxidative phosphorylation, glycolysis, phagosome maturation, SNARE signaling, redox regulation and several others. Core analysis revealed mitochondrial dysfunction to be the top canonical pathway. The top-enriched networks involved JNK activation and inhibition of AKT signaling, suggesting that disruption of these signaling pathways could lead to demise of motor neurons in the ALS motor cortex., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Some studies comparing primary and secondary progressive multiple sclerosis (PPMS, SPMS) report similar ages at onset of the progressive phase and similar rates of subsequent disability accrual. Others report later onset and/or faster accrual in SPMS. Comparisons have been complicated by regional cohort effects, phenotypic differences in sex ratio and management and variable diagnostic criteria for SPMS., Methods: We compared disability accrual in PPMS and operationally diagnosed SPMS in the international, clinic-based MSBase cohort. Inclusion required PPMS or SPMS with onset at age ≥18 years since 1995. We estimated Andersen-Gill hazard ratios for disability accrual on the Expanded Disability Status Scale (EDSS), adjusted for sex, age, baseline disability, EDSS score frequency and drug therapies, with centre and patient as random effects. We also estimated ages at onset of the progressive phase (Kaplan-Meier) and at EDSS milestones (Turnbull). Analyses were replicated with physician-diagnosed SPMS., Results: Included patients comprised 1872 with PPMS (47% men; 50% with activity) and 2575 with SPMS (32% men; 40% with activity). Relative to PPMS, SPMS had older age at onset of the progressive phase (median 46.7 years (95% CI 46.2-47.3) vs 43.9 (43.3-44.4); p<0.001), greater baseline disability, slower disability accrual (HR 0.86 (0.78-0.94); p<0.001) and similar age at wheelchair dependence., Conclusions: We demonstrate later onset of the progressive phase and slower disability accrual in SPMS versus PPMS. This may balance greater baseline disability in SPMS, yielding convergent disability trajectories across phenotypes. The different rates of disability accrual should be considered before amalgamating PPMS and SPMS in clinical trials., Competing Interests: Competing interests: IR served on scientific advisory boards for Novartis and Merck, and received conference travel support and/or speaker honoraria from Roche, Novartis, Biogen, Teva, Sanofi Genzyme, and Merck. A-LN received grants from MS Research Australia; grants, personal fees, and nonfinancial support from Biogen; grants and personal fees from Merck Serono; personal fees from Teva and Novartis; and nonfinancial support from Roche and Sanofi Genzyme. GI received speaking honoraria from Biogen, Novartis, Sanofi, Merck, Roche, Almirall, and Teva. SE received speaker honoraria and consultant fees from Biogen Idec, Novartis, Merck, Bayer, Sanofi Genzyme, Roche, and Teva. FP received speaker honoraria and advisory board fees from Almirall, Bayer, Biogen, Celgene, Merck, Novartis, Roche, Sanofi Genzyme, and Teva, and research funding from Biogen, Merck, FISM (Fondazione Italiana Sclerosi Multipla), Reload Onlus Association, and the University of Catania. DH received speaker honoraria and consulting fees from Biogen, Merck, Teva, Roche, Sanofi Genzyme, and Novartis, and support for research activities from Biogen and the Czech Ministry of Education (project PROGRES Q27/LF1). EVH received honoraria or research support from Biogen, Merck Serono, Novartis, Roche, and Teva; has been a member of advisory boards for Actelion, Biogen, Celgene, Merck Serono, Novartis, and Sanofi Genzyme; and received research support from the Czech Ministry of Education (project PROGRES Q27/LF1). MG received consulting fees from Teva Canada Innovation, Biogen, Novartis, and Sanofi Genzyme; lecture payments from Teva Canada Innovation, Novartis, and EMD; and research support from the Canadian Institutes of Health Research. PD served on editorial boards for, and has been supported to attend meetings by, EMD, Biogen, Novartis, Genzyme, and Teva Neuroscience; he holds grants from the Canadian Institutes of Health Research and the MS Society of Canada, and received funding for investigator-initiated trials from Biogen, Novartis, and Genzyme. FG’M received honoraria or research funding from Biogen, Genzyme, Novartis, Teva Neurosciences, Mitsubishi, and ONO Pharmaceuticals. AL received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities from Biogen, Merck Serono, Mylan, Novartis, Roche, Sanofi Genzyme, and Teva; her institutions have received research grants from Novartis (in the past 4 years). PG served on advisory boards for Novartis, EMD Serono, Roche, Biogen Idec, Sanofi Genzyme, and Pendopharm; received grant support from Genzyme and Roche; and received research grants for his institution from Biogen Idec, Sanofi Genzyme, and EMD Serono. MPA received honoraria as a consultant on scientific advisory boards for Biogen, Bayer Schering, Merck, Teva, and Sanofi-Aventis, and received research grants by Biogen, Bayer Schering, Merck, Teva, and Novartis. PS served on scientific advisory boards for Biogen Idec and Teva; received funding for travel and speaker honoraria from Biogen Idec, Merck, Teva, Sanofi Genzyme, Novartis, and Bayer; and received research grants for her institution from Bayer, Biogen, Merck, Novartis, Sanofi, and Teva. DF received travel grants and/or speaker honoraria from Merck, Teva, Novartis, Biogen, and Sanofi Genzyme. KB received honoraria and consulting fees from Biogen, Teva, Novartis, Sanofi Genzyme, Roche, Merck, CSL, and Grifols. JL-S received travel compensation from Novartis, Biogen, Roche, and Merck; her institution received honoraria for talks and advisory board commitments, as well as research grants from Biogen, Merck, Roche, Teva, and Novartis. RA received honoraria as a speaker and for serving on scientific advisory boards from Bayer, Biogen, GSK, Merck, Novartis, Roche, and Sanofi Genzyme. CB received conference travel support from Biogen, Novartis, Bayer Schering, Merck, and Teva, and participated in clinical trials by Sanofi-Aventis, Roche, and Novartis. VVP received travel grants from Merck, Biogen, Sanofi, Celgene, Almirall, and Roche; his institution received research grants and consultancy fees from Roche, Biogen, Sanofi, Celgene, Merck, and Novartis Pharma. MT received travel grants from Novartis, Bayer Schering, Merck, and Teva, and participated in clinical trials by Sanofi-Aventis, Roche, and Novartis. DM received speaker honoraria for advisory board service and travel grants from Almirall, Biogen, Merck, Novartis, Roche, Sanofi Genzyme, and Teva. CR-T received research funding, compensation for travel, or speaker honoraria from Biogen, Novartis, Genzyme, and Almirall. DLS received honoraria as a consultant on scientific advisory boards from Bayer Schering, Novartis, and Sanofi-Aventis, and compensation for travel from Novartis, Biogen, Sanofi-Aventis, Teva, and Merck. FG received an institutional research grant from Biogen and Sanofi Genzyme; served on scientific advisory boards for Biogen, Novartis, Merck, Sanofi Genzyme, and Roche; and received funding for travel and speaker honoraria from Biogen, Merck, and Sanofi-Aventis. MS participated in, but did not receive honoraria for, advisory board activity for Biogen, Merck, Bayer Schering, Sanofi-Aventis, and Novartis. RB received speaker honoraria from Bayer Schering, Biogen, Genzyme, Merck, Novartis, Sanofi-Aventis, and Teva; research grants from Bayer Schering, Biogen, Merck, Novartis, Sanofi-Aventis, and Teva; and congress, travel, and accommodation expense compensations from Almirall, Bayer Schering, Biogen, Genzyme, Merck, Novartis, Sanofi-Aventis, and Teva. RA received conference travel support from Novartis, Teva, Biogen, Bayer, and Merck, and participated in clinical trials by Biogen, Novartis, Teva, and Actelion. JLS-M received travel compensation from Novartis and Biogen; received speaking honoraria from Biogen, Novartis, Sanofi, Merck, Almirall, Bayer, and Teva; and participated in a clinical trial by Biogen. JP received travel compensation from Novartis, Biogen, Genzyme, and Teva, and speaking honoraria from Biogen, Novartis, Genzyme and Teva. TC-T received speaking or consulting fees and/or travel funding from Bayer, Biogen, Merck, Novartis, Roche, Sanofi Genzyme, and Teva. GL received travel and/or consultancy compensation from Sanofi Genzyme, Roche, Teva, Merck, Novartis, Celgene, and Biogen. JO received research funding from the MS Society of Canada, the National MS Society, Brain Canada, Biogen Idec, Roche, and EMD Serono, and personal compensation for consulting or speaking from EMD Serono, Sanofi Genzyme, Biogen Idec, Roche, Celgene, and Novartis. AA received personal fees and speaker honoraria from Teva, Merck, Biogen Gen Pharma, Roche, Novartis, Bayer, and Sanofi Genzyme, and received travel and registration grants from Merck, Biogen Gen Pharma, Roche, Sanofi Genzyme, and Bayer. HB received compensation for consulting, talks, and advisory or steering board activities from Biogen, Merck, Novartis, Genzyme, Alfred Health, and Oxford Health Policy Forum, and research support from Novartis, Biogen, Roche, Merck, the National Health and Medical Research Council of Australia, Pennycook Foundation, and MS Research Australia MB served on scientific advisory boards for Biogen, Novartis, and Genzyme, received conference travel support from Biogen and Novartis, and serves on steering committees for trials conducted by Novartis; his institution received research support from Biogen, Merck, and Novartis. EC Cristiano received honoraria as a consultant on scientific advisory boards for Biogen, Bayer Schering, Merck, Genzyme, and Novartis, and participated in clinical trials or other research projects by Merck, Roche, and Novartis. SH received honoraria and consulting fees from Novartis, Bayer Schering, and Sanofi, and travel grants from Novartis, Biogen Idec, and Bayer Schering. GI received compensation for travel, accommodations, and meeting expenses from Bayer Schering, Biogen, Merck, Novartis, Sanofi-Aventis, and Teva. LK received research support from Acorda, Actelion, Allozyne, BaroFold, Bayer HealthCare, Bayer Schering, Bayhill Therapeutics, Biogen, Elan, European Union, Genmab, Gianni Rubatto Foundation, GlaxoSmithKline, Glenmark, MediciNova, Merck, Novartis, Novartis Research Foundation, Roche, Roche Research Foundation, Sanofi-Aventis, Santhera, the Swiss MS Society, the Swiss National Research Foundation, Teva Neuroscience, UCB, and Wyeth. BW-G participated in speakers' bureaus and/or served as a consultant for Biogen, EMD Serono, Novartis, Genentech, Celgene/Bristol Meyers Squibb, Sanofi Genzyme, Bayer, Janssen, and Horizon; received grant/research support from these same agencies; and serves on editorial boards for BMJ Neurology, Children, CNS Drugs, MS International, and Frontiers Epidemiology. BVW received research and travel grants and honoraria for advisory and speaking fees from Bayer Schering, Biogen, Sanofi Genzyme, Merck, Novartis, Roche, and Teva. TK served on scientific advisory boards for BMS, Roche, Sanofi Genzyme, Novartis, Merck, and Biogen, and the steering committee for the Brain Atrophy Initiative by Sanofi Genzyme; received conference travel support and/or speaker honoraria from WebMD Global, Novartis, Biogen, Sanofi Genzyme, Teva, BioCSL, and Merck; and received support for research or educational events from Biogen, Novartis, Genzyme, Roche, Celgene, and Merck., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Motor neurone disease [MND] encompasses broad cognitive impairments, which are not fully captured by most screening tools. This study evaluated the specificity and sensitivity of the Edinburgh Cognitive and Behavioral ALS Screen [ECAS] in detecting impairments in executive function and social cognition. Methods: Participants (MND = 64; Healthy Controls = 45) completed the ECAS and standard neuropsychology tests of executive function and social cognition. Sensitivity and specificity of the ECAS were assessed at three levels (ALS-Specific score, executive function domain score, individual subtests: social cognition, inhibition, working memory, alternation). Results: MND patients were impaired on standard social cognition, initiation, visuomotor alternation, and verbal learning tests but not on inhibition or working memory tests, relative to controls. ECAS results revealed that the ALS-Specific score was high in specificity but low-to-moderately sensitive in identifying social cognition, inhibition, and working memory deficits, and that both sensitivity and specificity were high for identifying alternation deficits. The ECAS executive function domain score was high in specificity but poor in sensitivity for all four executive function domain subtests. The individual ECAS subtests were highly specific with good sensitivity, but the social cognition subtest lacked sensitivity. Conclusions: Impairments in social cognition may go undetected when using the ECAS as a screening tool. Thus, social cognition may need to be considered as a standalone component, distinct from the other executive functions. In addition, the test itself may need to be adjusted to encompass other aspects of social cognition that are affected in MND.Key messagesCognitive screening tools are key to detect cognitive changes in MND, with the domains most affected being executive functions, language, and social cognition.The ECAS measure, developed for MND, has good specificity but lacks sensitivity to impairments in social cognition.Clinical implications are that cognitive impairments in social cognition may not be identified in MND patients by the ECAS.Adjustment to the ECAS cognitive screening tool widely-used in MND is suggested.

Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease associated with loss of upper and lower motor neurones. It leads to death by respiratory failure and has a typical prognosis of 2-3 years. The immune system has been shown to play a role in the pathophysiology of ALS. Some of the most important immune genes are within the human leukocyte antigen (HLA) region, and a recent genome-wide association study (GWAS) has identified a risk allele for ALS within the HLA region. Older studies have also suggested an HLA association with ALS, with certain HLA alleles showing differing expression between patients and controls. This systematic review and meta-analysis examines the previous studies performed in this field. Methods: We used established publication search engines. Findings were excluded if they did not meet the selection criteria. We then undertook statistical meta-analysis on the eligible papers, using a fixed effects model. Results: There were eight eligible papers. There were three statistically significant meta-analysis findings, although these would not be significant after correction for multiple comparisons. The frequencies of HLA-A9 and HLA-DR4 genotypes were lower in ALS subjects than controls, and HLA-B35 was higher in ALS subjects. Discussion: This systematic review and meta-analysis do not confirm all the previously reported associations of HLA with ALS, but shows three alleles of interest. However, there are limitations to the studies, which include the use of older serotyping methodology and the small numbers of subjects. Given the recent GWAS association with HLA, further modern HLA studies are warranted.

Background and Purpose: Weight loss in patients with amyotrophic lateral sclerosis (ALS) is associated with faster disease progression and shorter survival. Decreased hypothalamic volume is proposed to contribute to weight loss due to loss of appetite and/or hypermetabolism. We aimed to investigate the relationship between hypothalamic volume and body mass index (BMI) in ALS and Alzheimer's disease (AD), and the associations of hypothalamic volume with weight loss, appetite, metabolism and survival in patients with ALS., Methods: We compared hypothalamic volumes from magnetic resonance imaging scans with BMI for patients with ALS (n = 42), patients with AD (n = 167) and non-neurodegenerative disease controls (n = 527). Hypothalamic volumes from patients with ALS were correlated with measures of appetite and metabolism, and change in anthropomorphic measures and disease outcomes., Results: Lower hypothalamic volume was associated with lower and higher BMI in ALS (quadratic association; probability of direction = 0.96). This was not observed in AD patients or controls. Hypothalamic volume was not associated with loss of appetite (p = 0.58) or hypermetabolism (p = 0.49). Patients with lower BMI and lower hypothalamic volume tended to lose weight (p = 0.08) and fat mass (p = 0.06) over the course of their disease, and presented with an increased risk of earlier death (hazard ratio [HR] 3.16, p = 0.03). Lower hypothalamic volume alone trended for greater risk of earlier death (HR 2.61, p = 0.07)., Conclusion: These observations suggest that lower hypothalamic volume in ALS contributes to positive and negative energy balance, and  is not universally associated with loss of appetite or hypermetabolism. Critically, lower hypothalamic volume with lower BMI was associated with weight loss and earlier death., (© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Neurodegeneration refers to the selective and progressive loss-of-function and atrophy of neurons, and is present in disorders such as Alzheimer's, Huntington's, and Parkinson's disease. Although each disease presents with a unique pattern of neurodegeneration, and subsequent disease phenotype, increasing evidence implicates alterations in energy usage as a shared and core feature in the onset and progression of these disorders. Indeed, disturbances in energy metabolism may contribute to the vulnerability of neurons to apoptosis. In this review we will outline these disturbances in glucose metabolism, and how fatty acids are able to compensate for this impairment in energy production in neurodegenerative disorders. We will also highlight underlying mechanisms that could contribute to these alterations in energy metabolism. A greater understanding of these metabolism-neurodegeneration processes could lead to improved treatment options for neurodegenerative disease patients.

Background: Over the decades, several natural history studies on patients with primary (PPMS) or secondary progressive multiple sclerosis (SPMS) were reported from international registries. In PPMS, a consistent heterogeneity on long-term disability trajectories was demonstrated. The aim of this study was to identify subgroups of patients with SPMS with similar longitudinal trajectories of disability over time., Methods: All patients with MS collected within Big MS registries who received an SPMS diagnosis from physicians (cohort 1) or satisfied the Lorscheider criteria (cohort 2) were considered. Longitudinal Expanded Disability Status Scale (EDSS) scores were modelled by a latent class growth analysis (LCGA), using a non-linear function of time from the first EDSS visit in the range 3-4., Results: A total of 3613 patients with SPMS were included in the cohort 1. LCGA detected three different subgroups of patients with a mild (n=1297; 35.9%), a moderate (n=1936; 53.6%) and a severe (n=380; 10.5%) disability trajectory. Median time to EDSS 6 was 12.1, 5.0 and 1.7 years, for the three groups, respectively; the probability to reach EDSS 6 at 8 years was 14.4%, 78.4% and 98.3%, respectively. Similar results were found among 7613 patients satisfying the Lorscheider criteria., Conclusions: Contrary to previous interpretations, patients with SPMS progress at greatly different rates. Our identification of distinct trajectories can guide better patient selection in future phase 3 SPMS clinical trials. Additionally, distinct trajectories could reflect heterogeneous pathological mechanisms of progression., Competing Interests: Competing interests: AS received research support from MSBase. JL received research support from Innosuisse—Swiss Innovation Agency, Biogen and Novartis; he served on advisory boards for Biogen, Novartis, Roche and Teva. SV received consulting and lecture fees, travel grants and research support from Biogen, Celgene, Genentech, Genzyme, Medday Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi-Aventis and Teva Pharma. MT has served on scientific advisory boards for Biogen, Novartis, Roche and Genzyme; has received speaker honoraria and travel support from Biogen Idec, Sanofi-Aventis, Merck Serono, Teva, Genzyme and Novartis; and has received research grants for her institution from Biogen Idec, Merck Serono and Novartis. JH has received honoraria for serving on advisory boards for Biogen, Sanofi-Genzyme and Novartis; and speaker’s fees from Biogen, Novartis, Merck Serono, Bayer-Schering, Teva and Sanofi-Genzyme. He has served as PI for projects or received unrestricted research support from Biogen Idec, Merck Serono, TEVA, Sanofi-Genzyme and Bayer-Schering; his MS research is funded by the Swedish Research Council and the Swedish Brain Foundation. RH is an employee of Biogen and holds a stock. FP is an employee of Biogen. MM has served on scientific advisory board for Biogen Idec and Teva; and has received honoraria for lecturing from Biogen Idec, Merck Serono, Sanofi-Aventis and Teva. NK-H has received honoraria for lecturing and participating in advisory councils, travel expenses for attending congresses and meetings, and financial support for monitoring the Danish Multiple Sclerosis Treatment Register from Bayer-Schering, Merck Serono, Biogen Idec, Teva, Sanofi-Aventis and Novartis. PSS has served on scientific advisory boards for Merck Serono, Teva, Novartis, Sanofi-Aventis and Biogen Idec; has received research support from Biogen Idec, Novartis and Sanofi-Aventis; and received speaker honoraria from Merck Serono, Novartis, Teva, Sanofi-Aventis, Biogen Idec and Genzyme. TS received compensation for serving on scientific advisory boards, honoraria for consultancy and funding for travel from Biogen; and speaker honoraria from Novartis. AvdW reported receiving grants from National Health and Medical Research Council (NHMRC), Novartis, Roche and MS Research Australia; and personal fees from Biogen, Merck, Novartis and Roche. DH received compensation for travel, speaker honoraria and consultant fees from Biogen, Novartis, Merck Healthcare (Darmstadt, Germany), Bayer, Sanofi, Roche and Teva, as well as support for research activities from Biogen. She was also supported by the Charles University: Cooperation Program in neuroscience. EH received honoraria/research support from Biogen, Merck Serono, Novars, Roche and Teva; has been a member of advisory boards for Actelion, Biogen, Celgene, Merck Serono, Novars and Sanofi Genzyme. MG received consulting fees from Teva Canada Innovation, Biogen, Novartis and Genzyme Sanofi; and lecture payments from Teva Canada Innovation, Novartis and EMD. He has also received a research grant from Canadian Institutes of Health Research. SE received speaker honoraria and consultant fees from Biogen Idec, Novartis, Merck, Bayer, Sanofi Genzyme, Roche and Teva. FG received honoraria or research funding from Biogen, Genzyme, Novartis, Teva Neurosciences, Mitsubishi and ONO Pharmaceuticals. OG has nothing to disclose. MT received travel grants from Novartis, Bayer-Schering, Merck and Teva; and has participated in clinical trials by Sanofi Aventis, Roche and Novartis. SO has nothing to disclose. OS has received honoraria and consulting fees from Bayer Schering, Novartis, Merck, Biogen and Genzyme companies. VVP received travel grants from Merck Healthcare (Darmstadt, Germany), Biogen, Sanofi, Bristol Meyer Squibb, Almirall and Roche. His institution has received research grants and consultancy fees from Roche, Biogen, Sanofi, Merck Healthcare (Darmstadt, Germany), Bristol Meyer Squibb, Janssen, Almirall and Novartis Pharma. MJS received consulting fees, speaker honoraria, and/or travel expenses for scientific meetings from Alexion, Bayer Healthcare, Biogen, Bristol Myers Squibb, Celgene, Janssen, Merck-Serono, Novartis, Roche, Sanofi and Teva. JP accepted travel compensation from Novartis, Biogen, Genzyme and Teva; and speaking honoraria from Biogen, Novartis, Genzyme and Teva. RA received honoraria as a speaker and for serving on scientific advisory boards from Bayer, Biogen, GSK, Merck, Novartis, Roche and Sanofi-Genzyme. PAM received speakers fees and travel grants from Novartis, Biogen, T’évalua and Sanofi. RG has nothing to disclose. SM has received a MENACTRIMS clinical fellowship grant (2020). TC-T received speaking/consulting fees and/or travel funding from Bayer, Biogen, Merck, Novartis, Roche, Sanofi-Genzyme and Teva. CZ has nothing to disclose. KdG has nothing to disclose. JLS-M accepted travel compensation from Novartis, Merck and Biogen; speaking honoraria from Biogen, Novartis, Sanofi, Merck, Almirall, Bayer and Teva; and has participated in clinical trials by Biogen, Merck and Roche. BY and SK have nothing to disclose. MPS has received consulting fees from Biogen, Merck, Teva, Genzyme, Roche, Novartis, GeNeuro and MedDay. TK reported receiving grants from MS Research Australia and grants, personal fees and non-financial support from Biogen; personal fees and non-financial support from Sanofi Genzyme and Merck; personal fees from Roche, Novartis, WebMD Global, Teva and BioCSL; and grants from NHMRC, MS Research Australia, ARSEP-OFSEP, UK MS Society and Medical Research Future Fund. HB’s institution (Monash University) received compensation for consulting, talks, and advisory/steering board activities from Alfred Health, Biogen, Merck, Novartis, Roche and UCB pharma; research support from Biogen, Merck, Roche, MS Australia, National Health and Medical Research (Australia) and the Medical Research Future Fund (Australia), the Pennycook Foundation, Novartis and Roche. He has received personal compensation for steering group activities from Oxford Health Policy Forum., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Guillain Barré syndrome (GBS) and its variants, and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP and its variants, are regarded as immune mediated neuropathies. Unlike in many autoimmune disorders, GBS and CIDP are more common in males than females. Sex is not a clear predictor of outcome. Experimental autoimmune neuritis (EAN) is an animal model of these diseases, but there are no studies of the effects of sex in EAN. The pathogenesis of GBS and CIDP involves immune response to non-protein antigens, antigen presentation through non-conventional T cells and, in CIDP with nodopathy, IgG4 antibody responses to antigens. There are some reported sex differences in some of these elements of the immune system and we speculate that these sex differences could contribute to the male predominance of these diseases, and suggest that sex differences in peripheral nerves is a topic worthy of further study., Competing Interests: The 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 © 2022 McCombe, Hardy, Nona and Greer.)

Experimental autoimmune encephalomyelitis (EAE) can be induced in many animal strains by inoculation with central nervous system antigens and adjuvant or by the passive transfer of lymphocytes reactive with these antigens and is widely used as an animal model for multiple sclerosis (MS). There are reports that female sex and pregnancy affect EAE. Here we review the effects of biological sex and the effects of pregnancy on the clinical features (including disease susceptibility) and pathophysiology of EAE. We also review reports of the possible mechanisms underlying these differences. These include sex-related differences in the immune system and in the central nervous system, the effects of hormones and the sex chromosomes and molecules unique to pregnancy. We also review sex differences in the response to factors that can modify the course of EAE. Our conclusion is that the effects of biological sex in EAE vary amongst animal models and should not be widely extrapolated. In EAE, it is therefore essential that studies looking at the effects of biological sex or pregnancy give full information about the model that is used (i.e. animal strain, sex, the inducing antigen, timing of EAE induction in relation to pregnancy, etc.). In addition, it would be preferable if more than one EAE model were used, to show if any observed effects are generalizable. This is clearly a field that requires further work. However, understanding of the mechanisms of sex differences could lead to greater understanding of EAE, and suggest possible therapies for MS., Competing Interests: The 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 © 2022 McCombe and Greer.)

Background and Objectives: To evaluate the rate of return of disease activity after cessation of multiple sclerosis (MS) disease-modifying therapy., Methods: This was a retrospective cohort study from 2 large observational MS registries: MSBase and OFSEP. Patients with relapsing-remitting MS who had ceased a disease-modifying therapy and were followed up for the subsequent 12 months were included in the analysis. The primary study outcome was annualized relapse rate in the 12 months after disease-modifying therapy discontinuation stratified by patients who did, and did not, commence a subsequent therapy. The secondary endpoint was the predictors of first relapse and disability accumulation after treatment discontinuation., Results: A total of 14,213 patients, with 18,029 eligible treatment discontinuation epochs, were identified for 7 therapies. Annualized rates of relapse (ARRs) started to increase 2 months after natalizumab cessation (month 2-4 ARR 0.47, 95% CI 0.43-0.51). Commencement of a subsequent therapy within 2-4 months reduced the magnitude of disease reactivation (mean ARR difference: 0.15, 0.08-0.22). After discontinuation of fingolimod, rates of relapse increased overall (month 1-2 ARR: 0.80, 0.70-0.89) and stabilized faster in patients who started a new therapy within 1-2 months (mean ARR difference: 0.14, -0.01 to 0.29). The magnitude of disease reactivation for other therapies was low but reduced further by commencement of another treatment 1-10 months after treatment discontinuation. Predictors of relapse were a higher relapse rate in the year before cessation, female sex, younger age, and higher EDSS score. Commencement of a subsequent therapy reduced both the risk of relapse (HR 0.76, 95% CI 0.72-0.81) and disability accumulation (0.73, 0.65-0.80)., Discussion: The rate of disease reactivation after treatment cessation differs among MS treatments, with the peaks of relapse activity ranging from 1 to 10 months in untreated cohorts that discontinued different therapies. These results suggest that untreated intervals should be minimized after stopping antitrafficking therapies (natalizumab and fingolimod)., Classification of Evidence: This study provides Class III that disease reactivation occurs within months of discontinuation of MS disease-modifying therapies. The risk of disease activity is reduced by commencement of a subsequent therapy., (© 2022 American Academy of Neurology.)

Objective: To investigate changes in immune markers and frequencies throughout disease progression in patients with amyotrophic lateral sclerosis (ALS). Methods : In this longitudinal study, serial blood samples were collected from 21 patients with ALS over a time period of up to 16 months. Flow cytometry was used to quantitate CD14, HLA-DR, and CD16 marker expression on monocyte subpopulations and neutrophils, as well as their cell population frequencies. A Generalized Estimating Equation model was used to assess the association between changes in these immune parameters and disease duration and the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R). Results : CD14 expression on monocyte subpopulations increased with both disease duration and a decrease in ALSFRS-R score in patients with ALS. HLA-DR expression on monocyte subpopulations also increased with disease severity and/or duration. The expression of CD16 did not change relative to disease duration or ALSFRS-R. Finally, patients had a reduction in non-classical monocytes and an increase in the classical to non-classical monocyte ratio throughout disease duration. Conclusion : The progressive immunological changes observed in this study provide further support that monocytes are implicated in ALS pathology. Monocytic CD14 and HLA-DR surface proteins may serve as a therapeutic target or criteria for the recruitment of patients with ALS into clinical trials for immunomodulatory therapies.

Background and Objectives: The severity of multiple sclerosis (MS) varies widely among individuals. Understanding the determinants of this heterogeneity will help clinicians optimize the management of MS. The aim of this study was to investigate the association between latitude of residence, UV B radiation (UVB) exposure, and the severity of MS., Methods: This observational study used the MSBase registry data. The included patients met the 2005 or 2010 McDonald diagnostic criteria for MS and had a minimum dataset recorded in the registry (date of birth, sex, clinic location, date of MS symptom onset, disease phenotype at baseline and censoring, and ≥1 Expanded Disability Status Scale score recorded). The latitude of each study center and cumulative annualized UVB dose at study center (calculated from National Aeronautics and Space Administration's Total Ozone Mapping Spectrometer) at ages 6 and 18 years and the year of disability assessment were calculated. Disease severity was quantified with Multiple Sclerosis Severity Score (MSSS). Quadratic regression was used to model the associations between latitude, UVB, and MSSS., Results: The 46,128 patients who contributed 453,208 visits and a cumulative follow-up of 351,196 patient-years (70% women, mean age 39.2 ± 12 years, resident between latitudes 19°35' and 56°16') were included in this study. Latitude showed a nonlinear association with MS severity. In latitudes <40°, more severe disease was associated with higher latitudes (β = 0.08, 95% CI 0.04-0.12). For example, this translates into a mean difference of 1.3 points of MSSS between patients living in Madrid and Copenhagen. No such association was observed in latitudes <40° (β = -0.02, 95% CI -0.06 to 0.03). The overall disability accrual was faster in those with a lower level of estimated UVB exposure before the age of 6 years (β = - 0.5, 95% CI -0.6 to 0.4) and 18 years (β = - 0.6, 95% CI -0.7 to 0.4), as well as with lower lifetime UVB exposure at the time of disability assessment (β = -1.0, 95% CI -1.1 to 0.9)., Discussion: In temperate zones, MS severity is associated with latitude. This association is mainly, but not exclusively, driven by UVB exposure contributing to both MS susceptibility and severity., (© 2022 American Academy of Neurology.)

Glutamate transporter 1 is the principal transporter that mediates glutamate clearance in the mammalian brain. In rodents, it is referred to as GLT-1, whereas in humans it is referred to as EAAT2. We have cloned a novel and abundantly expressed carboxyl-terminal splice variant of this transporter in both rodents and humans, which we denote as GLT-1d/EAAT2d. The novel splice variant results from usage of internal splice sites and the splicing event leads to novel extra sequence spliced in after exon 10. The open reading frames of GLT-1d and EAAT2d encode proteins of 572 and 566 amino acids respectively; both contain a C-terminal PDZ motif. When expressed in COS7 cells, the proteins function as glutamate transporters that are inhibited by dihydrokainate (a GLT-1/EAAT2 transporter inhibitor). RT-PCR amplification using GLT-1d specific primers confirmed expression of message in all brain regions examined (forebrain, midbrain, hindbrain and cerebellum) as well as spinal cord, astrocyte cultures, retina and peripheral tissues (liver, testis, small intestine and lung). Quantitative RT-PCR analysis showed that expression of GLT-1d is developmentally regulated. In adult human brain, EAAT2d message is ∼ 30% of the level of EAAT2a message (the most abundant form), potentially making it the second most abundantly expressed form of EAAT2 in the brain. The amino terminal region of GLT-1d is also alternately spliced; the brain and testis forms contain a sequence corresponding to the amino acid sequence MASTEG whereas the corresponding liver sequence is MVS. In summary, we have cloned a novel EAAT2/GLT-1 splice variant from human and rodent brains. The splice variant is abundantly expressed in the brain, spinal cord, retina, liver and testis; it is a functional glutamate transporter; therefore, we conclude that it will likely have a functional role in glutamate homeostasis in the rodent and human nervous system, during development, adulthood, and plausibly in pathological states., (Copyright © 2022. Published by Elsevier B.V.)

Introduction: Multiple sclerosis (MS) is more prevalent in women than in men. The sex of the patient, and pregnancy, are reported to be associated with the clinical features of MS. The mechanism of this is unclear., Areas Covered: This review summarizes data about sex differences in MS and the role of pregnancy. Possible mechanisms for the effects of sex and pregnancy are summarized, and practical suggestions for addressing these issues are provided., Expert Opinion: There is considerable interdependence of the variables that are associated with MS. Men have a worse outcome of MS, and this could be due to the same factors that lead to greater incidence of neurodegenerative disease in men. The possible role of parity on the long-term outcome of MS is of interest. Future studies that look at the mechanisms of the effects of the sex of the patient on the outcome of MS are required. However, there are some actions that can be taken without further research. We can concentrate on public health measures that address the modifiable risk factors for MS and ensure that disease is controlled in women who intend to become pregnant and use appropriate disease modifying agents during pregnancy.

Amyotrophic Lateral Sclerosis (ALS) is recognised to be a complex neurodegenerative disease involving both genetic and non-genetic risk factors. The underlying causes and risk factors for the majority of cases remain unknown; however, ever-larger genetic data studies and methodologies promise an enhanced understanding. Recent analyses using published summary statistics from the largest ALS genome-wide association study (GWAS) (20,806 ALS cases and 59,804 healthy controls) identified that schizophrenia (SCZ), cognitive performance (CP) and educational attainment (EA) related traits were genetically correlated with ALS. To provide additional evidence for these correlations, we built single and multi-trait genetic predictors using GWAS summary statistics for ALS and these traits, (SCZ, CP, EA) in an independent Australian cohort (846 ALS cases and 665 healthy controls). We compared methods for generating the risk predictors and found that the combination of traits improved the prediction (Nagelkerke-R 2 ) of the case-control logistic regression. The combination of ALS, SCZ, CP, and EA, using the SBayesR predictor method gave the highest prediction (Nagelkerke-R 2 ) of 0.027 (P value = 4.6 × 10 -8 ), with the odds-ratio for estimated disease risk between the highest and lowest deciles of individuals being 3.15 (95% CI 1.96-5.05). These results support the genetic correlation between ALS, SCZ, CP and EA providing a better understanding of the complexity of ALS., (© 2021. The Author(s), under exclusive licence to European Society of Human Genetics.)