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Summary Background Progressive disability in multiple sclerosis occurs because CNS axons degenerate as a late consequence of demyelination. In animals, retinoic acid receptor RXR-gamma agonists promote remyelination. We aimed to assess the safety and efficacy of a non-selective retinoid X receptor agonist in promoting remyelination in people with multiple sclerosis. Methods This randomised, double-blind, placebo-controlled, parallel-group, phase 2a trial (CCMR One) recruited patients with relapsing-remitting multiple sclerosis from two centres in the UK. Eligible participants were aged 18–50 years and had been receiving dimethyl fumarate for at least 6 months. Via a web-based system run by an independent statistician, participants were randomly assigned (1:1), by probability-weighted minimisation using four binary factors, to receive 300 mg/m2 of body surface area per day of oral bexarotene or oral placebo for 6 months. Participants, investigators, and outcome assessors were masked to treatment allocation. MRI scans were done at baseline and at 6 months. The primary safety outcome was the number of adverse events and withdrawals attributable to bexarotene. The primary efficacy outcome was the patient-level change in mean lesional magnetisation transfer ratio between baseline and month 6 for lesions that had a baseline magnetisation transfer ratio less than the within-patient median. We analysed the primary safety outcome in the safety population, which comprised participants who received at least one dose of their allocated treatment. We analysed the primary efficacy outcome in the intention-to-treat population, which comprised all patients who completed the study. This study is registered in the ISRCTN Registry, 14265371, and has been completed. Findings Between Jan 17, 2017, and May 17, 2019, 52 participants were randomly assigned to receive either bexarotene (n=26) or placebo (n=26). Participants who received bexarotene had a higher mean number of adverse events (6·12 [SD 3·09]; 159 events in total) than did participants who received placebo (1·63 [SD 1·50]; 39 events in total). All bexarotene-treated participants had at least one adverse event, which included central hypothyroidism (n=26 vs none on placebo), hypertriglyceridaemia (n=24 vs none on placebo), rash (n=13 vs one on placebo), and neutropenia (n=10 vs none on placebo). Five (19%) participants on bexarotene and two (8%) on placebo discontinued the study drug due to adverse events. One episode of cholecystitis in a placebo-treated participant was the only serious adverse event. The change in mean lesional magnetisation transfer ratio was not different between the bexarotene group (0·25 percentage units [pu; SD 0·98]) and the placebo group (0·09 pu [0·84]; adjusted bexarotene–placebo difference 0·16 pu, 95% CI –0·39 to 0·71; p=0·55). Interpretation We do not recommend the use of bexarotene to treat patients with multiple sclerosis because of its poor tolerability and negative primary efficacy outcome. However, statistically significant effects were seen in some exploratory MRI and electrophysiological analyses, suggesting that other retinoid X receptor agonists might have small biological effects that could be investigated in further studies. Funding Multiple Sclerosis Society of the United Kingdom.

Funder: MS Society of the United Kingdom, Funder: NIHR UCLH Biomedical Research Centre, Funder: UCL, Funder: University College London, Funder: NIHR, Funder: Thorne Family Foundation, Funder: Adeslon Medical Research Foundation, OBJECTIVE: In multiple sclerosis chronic demyelination is associated with axonal loss, and ultimately contributes to irreversible progressive disability. Enhancing remyelination may slow, or even reverse, disability. We recently trialled bexarotene versus placebo in 49 people with multiple sclerosis. While the primary MRI outcome was negative, there was converging neurophysiological and MRI evidence of efficacy. Multiple factors influence lesion remyelination. In this study we undertook a systematic exploratory analysis to determine whether treatment response - measured by change in magnetisation transfer ratio - is influenced by location (tissue type and proximity to CSF) or the degree of abnormality (using baseline magnetisation transfer ratio and T1 values). METHODS: We examined treatment effects at the whole lesion level, the lesion component level (core, rim and perilesional tissues) and at the individual lesion voxel level. RESULTS: At the whole lesion level, significant treatment effects were seen in GM but not WM lesions. Voxel-level analyses detected significant treatment effects in WM lesion voxels with the lowest baseline MTR, and uncovered gradients of treatment effect in both WM and CGM lesional voxels, suggesting that treatment effects were lower near CSF spaces. Finally, larger treatment effects were seen in the outer and surrounding components of GM lesions compared to inner cores. INTERPRETATION: Remyelination varies markedly within and between lesions. The greater remyelinating effect in GM lesions is congruent with neuropathological observations. For future remyelination trials, whole GM lesion measures require less complex post-processing compared to WM lesions (which require voxel level analyses) and markedly reduce sample sizes.

PurposeMultiple sclerosis (MS) is an immune-mediated, neuroinflammatory disease of the central nervous system and in industrialised countries is the most common cause of progressive neurological disability in working age persons. While treatable, there is substantial interindividual heterogeneity in disease activity and response to treatment. Currently, the ability to predict at diagnosis who will have a benign, intermediate or aggressive disease course is very limited. There is, therefore, a need for integrated predictive tools to inform individualised treatment decision making.ParticipantsEstablished with the aim of addressing this need for individualised predictive tools, FutureMS is a nationally representative, prospective observational cohort study of 440 adults with a new diagnosis of relapsing-remitting MS living in Scotland at the time of diagnosis between May 2016 and March 2019.Findings to dateThe study aims to explore the pathobiology and determinants of disease heterogeneity in MS and combines detailed clinical phenotyping with imaging, genetic and biomarker metrics of disease activity and progression. Recruitment, baseline assessment and follow-up at year 1 is complete. Here, we describe the cohort design and present a profile of the participants at baseline and 1 year of follow-up.Future plansA third follow-up wave for the cohort has recently begun at 5 years after first visit and a further wave of follow-up is funded for year 10. Longer-term follow-up is anticipated thereafter.

Background: Evidence for a role of human gut microbiota in multiple sclerosis (MS) risk is mounting, yet large variability is seen across studies. This is, in part, due to the lack of standardization of study protocols, sample collection methods, and sequencing approaches. Objective: This study aims to address the effect of a household experimental design, sample collection, and sequencing approaches in a gut microbiome study in MS subjects from a multi-city study population. Methods: We analyzed 128 MS patient and cohabiting healthy control pairs from the International MS Microbiome Study (iMSMS). A total of 1005 snap-frozen or desiccated Q-tip stool samples were collected and evaluated using 16S and shallow whole-metagenome shotgun sequencing. Results: The intra-individual variance observed by different collection strategies was dramatically lower than inter-individual variance. Shallow shotgun highly correlated with 16S sequencing. Participant house and recruitment site accounted for the two largest sources of microbial variance, while higher microbial similarity was seen in household-matched participants as hypothesized. A significant proportion of the variance in dietary intake was also dominated by geographic distance. Conclusion: A household pair study largely overcomes common inherent limitations and increases statistical power in population-based microbiome studies.

Background:\ud Neurodegeneration is the pathological substrate that causes major disability in secondary progressive multiple sclerosis. A synthesis of preclinical and clinical research identified three neuroprotective drugs acting on different axonal pathobiologies. We aimed to test the efficacy of these drugs in an efficient manner with respect to time, cost, and patient resource.\ud Methods:\ud We did a phase 2b, multiarm, parallel group, double-blind, randomised placebo-controlled trial at 13 clinical neuroscience centres in the UK. We recruited patients (aged 25–65 years) with secondary progressive multiple sclerosis who were not on disease-modifying treatment and who had an Expanded Disability Status Scale (EDSS) score of 4·0–6·5. Participants were randomly assigned (1:1:1:1) at baseline, by a research nurse using a centralised web-based service, to receive twice-daily oral treatment of either amiloride 5 mg, fluoxetine 20 mg, riluzole 50 mg, or placebo for 96 weeks. The randomisation procedure included minimisation based on sex, age, EDSS score at randomisation, and trial site. Capsules were identical in appearance to achieve masking. Patients, investigators, and MRI readers were unaware of treatment allocation. The primary outcome measure was volumetric MRI percentage brain volume change (PBVC) from baseline to 96 weeks, analysed using multiple regression, adjusting for baseline normalised brain volume and minimisation criteria. The primary analysis was a complete-case analysis based on the intention-to-treat population (all patients with data at week 96). This trial is registered with ClinicalTrials.gov, NCT01910259.\ud Findings:\ud Between Jan 29, 2015, and June 22, 2016, 445 patients were randomly allocated amiloride (n=111), fluoxetine (n=111), riluzole (n=111), or placebo (n=112). The primary analysis included 393 patients who were allocated amiloride (n=99), fluoxetine (n=96), riluzole (n=99), and placebo (n=99). No difference was noted between any active treatment and placebo in PBVC (amiloride vs placebo, 0·0% [95% CI −0·4 to 0·5; p=0·99]; fluoxetine vs placebo −0·1% [–0·5 to 0·3; p=0·86]; riluzole vs placebo −0·1% [–0·6 to 0·3; p=0·77]). No emergent safety issues were reported. The incidence of serious adverse events was low and similar across study groups (ten [9%] patients in the amiloride group, seven [6%] in the fluoxetine group, 12 [11%] in the riluzole group, and 13 [12%] in the placebo group). The most common serious adverse events were infections and infestations. Three patients died during the study, from causes judged unrelated to active treatment; one patient assigned amiloride died from metastatic lung cancer, one patient assigned riluzole died from ischaemic heart disease and coronary artery thrombosis, and one patient assigned fluoxetine had a sudden death (primary cause) with multiple sclerosis and obesity listed as secondary causes.\ud Interpretation:\ud The absence of evidence for neuroprotection in this adequately powered trial indicates that exclusively targeting these aspects of axonal pathobiology in patients with secondary progressive multiple sclerosis is insufficient to mitigate neuroaxonal loss. These findings argue for investigation of different mechanistic targets and future consideration of combination treatment trials. This trial provides a template for future simultaneous testing of multiple disease-modifying medicines in neurological medicine.\ud Funding:\ud Efficacy and Mechanism Evaluation (EME) Programme, an MRC and NIHR partnership, UK Multiple Sclerosis Society, and US National Multiple Sclerosis Society.

In addition to motor disability, "hidden disability" such as depression, anxiety, fatigue, sleep disturbance, cognitive impairment and pain is a major complaint of people with multiple sclerosis. We explored changes in hidden disability burden in the early post-diagnostic period and examined the hypothesis that disease modifying therapies have a beneficial effect on hidden disability burden.Adults with recently diagnosed (6 months) relapsing-remitting multiple sclerosis (n = 440, mean age 37.4 ± 10.4, 76% female), from a national multicentre cohort study (FutureMS) underwent testing with clinical and neuropsychological instruments as well as brain MRI at baseline and after 12-months. Disease modifying therapies were only started after baseline assessment and were classified into injectables (n = 70, interferons, glatiramer acetate), other DMTs (n = 215) and no DMT (n = 117, reference). Sensitivity analyses were undertaken using alternative classifications (disease modifying therapy vs none, and a 3-category system). We performed latent transition analysis with hidden disability burden as the latent variable including propensity score weights.We identified three classes with low (58%), moderate (25%) and high (17%) hidden disability burden. 70% did not transition ("unchanged", reference), 26% transitioned into a lower burden class ("improvement") and 4% transitioned into a higher burden class ("worsening"). Median treatment duration was 11 months (IQR 9-12). Injectables [OR 1.3 (95%CIs 0.7, 2.3); P = 0.4] and other DMTs [OR 1.4 (95%CIs 0.9, 2.1); P = 0.2] were not associated with significant change in hidden disability burden in either direction ("improvement" or "worsening"). In the alternative 3-category classification, category 2 treatment (fingolimod, cladribine, n = 22) was associated with improvement [OR 4.3 (2.6, 7.0); P 0.001].Hidden disability was present in most newly diagnosed people with multiple sclerosis. The majority remained unchanged and approximately a quarter improved over the immediate post-diagnostic period. Disease modifying therapy had no significant influence on hidden disability burden in the study period of one year following diagnosis. The trend towards favourable outcomes with fingolimod and cladribine should be interpreted with caution due to the small sample size. Our exploratory data are observational, with scope for attendant biases, but highlight the need for further study including longer-term evaluation as well as randomised trials for non-motor disability.

Fatigue is common and disabling in multiple sclerosis, yet its mechanisms are poorly understood. In particular, overlap in measures of fatigue and depression complicates interpretation. A clearer understanding of relationships between fatigue and key clinical, neuropsychiatric and imaging variables including depression could yield clinically relevant mechanistic insight. We applied a data-driven multivariate network approach to quantify relationships between fatigue and other variables in early multiple sclerosis.Data were collected from Scottish patients with newly diagnosed, immunotherapy-naïve, relapsing-remitting multiple sclerosis at baseline and month 12 follow-up in FutureMS, a nationally representative multicentre cohort. Subjective fatigue was assessed using the validated Fatigue Severity Scale. Detailed phenotyping included measures assessing physical disability, affective disorders, objective cognitive performance, subjective sleep quality, and structural brain imaging. Bivariate correlations between fatigue and other variables were calculated. Network analysis was then conducted to estimate partial correlations between variables, after accounting for all other included variables. Secondary networks included individual depressive symptoms, to control for overlapping symptom items in measures of fatigue and depression.Data from 322 participants at baseline, and 323 at month 12, were included. At baseline, 49.5% of the cohort reported clinically significant fatigue. Bivariate correlations confirmed that fatigue severity was significantly correlated with all included measures of physical disability, affective disturbance (anxiety and depression), cognitive performance (processing speed and memory/attention), and sleep quality, but not with structural brain imaging variables including normalized lesion and grey matter volumes. In the network analysis, fatigue showed strong correlations with depression, followed by Expanded Disability Status Scale. Weak connections with walking speed, subjective sleep quality and anxiety were identified. After separately controlling for measurement of “tiredness” in our measure of depression, some key depressive symptoms (anhedonia, subjective concentration deficits, subjectively altered speed of movement, and appetite) remained linked to fatigue. Conversely, fatigue was not linked to objective cognitive performance, white matter lesion volume, or grey matter volumes (cortical, subcortical or thalamic). Results were consistent at baseline and month 12. Depression was identified as the most central variable in the networks. Correlation stability coefficients and bootstrapped confidence intervals of the edge weights supported stability of the estimated networks.Our findings support robust links between subjective fatigue and depression in early relapsing-remitting multiple sclerosis, despite absence of links between fatigue and either objective cognitive performance, or structural brain imaging variables. Depression, including specific depressive symptoms, could be a key target of treatment and research in multiple sclerosis-related fatigue.

ObjectivesMotor neuron disease (MND) is an incurable progressive neurodegenerative disease with limited treatment options. There is a pressing need for innovation in identifying therapies to take to clinical trial. Here, we detail a systematic and structured evidence-based approach to inform consensus decision making to select the first two drugs for evaluation in Motor Neuron Disease-Systematic Multi-arm Adaptive Randomised Trial (MND-SMART:NCT04302870), an adaptive platform trial. We aim to identify and prioritise candidate drugs which have the best available evidence for efficacy, acceptable safety profiles and are feasible for evaluation within the trial protocol.MethodsWe conducted a two-stage systematic review to identify potential neuroprotective interventions. First, we reviewed clinical studies in MND, Alzheimer’s disease, Huntington’s disease, Parkinson’s disease and multiple sclerosis, identifying drugs described in at least one MND publication or publications in two or more other diseases. We scored and ranked drugs using a metric evaluating safety, efficacy, study size and study quality. In stage two, we reviewed efficacy of drugs in MND animal models, multicellular eukaryotic models and human induced pluripotent stem cell (iPSC) studies. An expert panel reviewed candidate drugs over two shortlisting rounds and a final selection round, considering the systematic review findings, late breaking evidence, mechanistic plausibility, safety, tolerability and feasibility of evaluation in MND-SMART.ResultsFrom the clinical review, we identified 595 interventions. 66 drugs met our drug/disease logic. Of these, 22 drugs with supportive clinical and preclinical evidence were shortlisted at round 1. Seven drugs proceeded to round 2. The panel reached a consensus to evaluate memantine and trazodone as the first two arms of MND-SMART.DiscussionFor future drug selection, we will incorporate automation tools, text-mining and machine learning techniques to the systematic reviews and consider data generated from other domains, including high-throughput phenotypic screening of human iPSCs.

Fatigue is common and disabling in multiple sclerosis (MS), yet its mechanisms are poorly understood. In particular, overlap in measures of fatigue and depression complicates interpretation. We applied a multivariate network approach to quantify relationships between fatigue and other variables in early MS.Data were collected from patients with newly diagnosed immunotherapy-naïve relapsing-remitting MS at baseline and month 12 follow-up in FutureMS, a Scottish nationally representative cohort. Subjective fatigue was assessed by Fatigue Severity Scale. Detailed phenotyping included measures assessing each of physical disability, affective disorders, cognitive performance, sleep quality, and structural brain imaging. Network analysis was conducted to estimate partial correlations between variables. Baseline networks were compared between those with persistent and remitted fatigue at one-year follow up.Data from 322 participants at baseline, and 323 at month 12, were included. At baseline, 154 patients (47.8%) reported clinically significant fatigue. In the network analysis, fatigue severity showed strongest connections with depression, followed by Expanded Disability Status Scale. Conversely, fatigue severity was not linked to objective cognitive performance or brain imaging variables. Even after controlling for measurement of "tiredness" in our measure of depression, four specific depressive symptoms remained linked to fatigue. Results were consistent at baseline and month 12. Overall network strength was not significantly different between groups with persistent and remitted fatigue (4.89 vs 2.90, p = 0.11).Our findings support robust links between subjective fatigue and depression in early relapsing-remitting MS. Shared mechanisms between specific depressive symptoms and fatigue could be key targets of treatment and research in MS-related fatigue.

Recurrent neuroinflammation in relapsing-remitting MS (RRMS) is thought to lead to neurodegeneration, resulting in progressive disability. Repeated magnetic resonance imaging (MRI) of the brain provides non-invasive measures of atrophy over time, a key marker of neurodegeneration. This study investigates regional neurodegeneration of the brain in early-stage RRMS using volumetry and voxel-based morphometry (VBM).RRMS patients (N=354) underwent 3T structural MRI at diagnosis and 1-year follow-up, as part of the Scottish multicentre ‘FutureMS’ study. MRI data were processed using FreeSurfer to derive volumetrics, and FSL for VBM (grey matter (GM) only), to establish patterns of change in GM and normal-appearing white matter (NAWM) over time throughout the cerebrum, cerebellum and brainstem.Volumetric analyses showed a decrease over time (qWidespread neurodegeneration was observed in early-stage RRMS; particularly in the brainstem, cerebellar GM, and subcortical and occipital-temporal regions. Volumetric and VBM results emphasise different as well as overlapping patterns of longitudinal change, and provide potential response markers for existing therapies and trials of neuroprotective agents.

ObjectiveMultiple sclerosis (MS) is an inflammatory degenerative condition of central nervous system. The disease course and presentation of MS is highly heterogeneous. Advanced retinal imaging techniques such as optic coherence tomography (OCT) can capture abnormalities of anterior visual pathway with high resolution, which may contribute greater insights into the pathophysiology of MS.MethodsPeople with newly diagnosed relapsing-remitting MS were recruited for FutureMS retinal imaging study from two study centres in Scotland. The baseline visit was completed within 6 months of diagnosis with initial follow-up 12 months after the baseline visit. The assessments included in FutureMS retinal imaging study were visual acuity test, self-reported eye questionnaire and OCT scan.ResultsA total of 196 FutureMS participants completed the retinal imaging study of FutureMS with 185 participants at M0 and 155 at M12. A total of 144 participants completed both M0 and M12 visits. At the whole cohort level, the distribution of retinal measures is generally consistent between baseline and follow-up.ConclusionThe FutureMS retinal imaging study aims to demonstrate that patient with MS present with different extent of retinal abnormalities that can be captured by retinal imaging modalities such as OCT soon after diagnosis. These changes may sensitively mirror the brain atrophy or serve as predictors for disease activity. By developing sensitive, quantifiable and objective retinal biomarkers, FutureMS retinal imaging study will provide an opportunity to stratify patient with MS at an early stage and support future therapeutic strategies for a better outcome.

BackgroundEvidence-based treatment of pain in people with MS presents a major unmet need.ObjectiveWe aimed to establish if use of Fluoxetine, Riluzole or Amiloride improved neuropathic pain outcomes in comparison to placebo, in adults with secondary progressive MS participating in a trial of these putative neuroprotectants.MethodsIn pre-specified secondary analyses of the MS SMART phase-2b double-blind randomised controlled trial (NCT01910259), we analyzed reports of neuropathic pain, overall pain, and pain interference. Multivariate analyses included adjustment for baseline pain severity. Additionally, we explored associations of pain severity with clinical and MRI brain imaging variables.Results445 Participants were recruited from 13 UK neuroscience centres. We found no statistically significant benefit of active intervention on any rating of neuropathic pain, or pain overall. Compared to placebo, adjusted mean difference in pain intensity was 0.38 (positive values favouring placebo, 95%CI -0.30 to 1.07, p = 0.27) for Amiloride; 0.52 (-0.17 to 1.22, p = 0.14) for Fluoxetine; and 0.40 (-0.30 to 1.10, p = 0.26) for Riluzole. Pain severity was positively correlated with depressive symptoms (Spearman correlation 0.19, 95%CI 0.10–0.28) and fatigue (Rho 0.30, 95%CI 0.20–0.39).ConclusionUse of Fluoxetine, Riluzole or Amiloride was not associated with improvement in neuropathic pain symptoms, in comparison to placebo.

Multiple sclerosis (MS) is an immune-mediated, neuroinflammatory disease of the central nervous system and in industrialised countries is the most common cause of progressive neurological disability in working age persons. However, there is significant inter-individual heterogeneity in disease activity and response to treatment. Currently, the ability to predict at diagnosis who will have a benign, intermediate, or aggressive disease course is very limited. There is therefore a need for integrated predictive tools to inform individualised treatment decision-making. FutureMS is a nationally representative, prospective observation cohort study comprising of 440 participants with a new diagnosis of relapsing remitting MS living in Scotland between May 2016 and March 2019. Established with the aim of addressing this need for individualised predictive tools, the cohort is designed to combine detailed clinical phenotyping with imaging, genetic and biomarker metrics of disease activity and progression. Recruitment, baseline assessment and follow up at year one is complete and longer term follow up is planned, beginning at five years after first visit. The study aims to explore the pathobiology and determinants of disease heterogeneity in MS. Here we describe the cohort design and present a profile of the participants at baseline and one year of follow up.

IntroductionMultiple sclerosis (MS) is a chronic neuroinflammatory and neurodegenerative disease. MS prevalence varies geographically and is notably high in Scotland. Disease trajectory varies significantly between individuals and the causes for this are largely unclear. Biomarkers predictive of disease course are urgently needed to allow improved stratification for current disease modifying therapies and future targeted treatments aimed at neuroprotection and remyelination. MRI can detect disease activity and underlying damage non-invasively in vivo at the micro and macrostructural level. FutureMS is a prospective Scottish longitudinal multi-centre cohort study, which focuses on deeply phenotyping patients with recently diagnosed relapsing-remitting MS (RRMS). Neuroimaging is a central component of the study and provides two main primary endpoints for disease activity and neurodegeneration. FutureMS aims to reduce uncertainty around disease course and allow for targeted treatment in RRMS by exploring the role of conventional and advanced MRI measures as biomarkers of disease severity and progression. This paper provides an overview of MRI data acquisition, management and processing in FutureMS.Methods and analysisMRI is acquired at baseline (N=431) and 1-year follow-up, in Dundee, Glasgow and Edinburgh (3T Siemens) and in Aberdeen (3T Philips), and managed and processed in Edinburgh. The core structural MRI protocol comprises T1-weighted, T2-weighted, FLAIR and proton density images. Primary imaging outcome measures are new/enlarging white matter lesions (WML) and reduction in brain volume over one year. Secondary imaging outcome measures comprise WML volume as an additional quantitative structural MRI measure, rim lesions on susceptibility-weighted imaging, and microstructural MRI measures, including diffusion tensor imaging and neurite orientation dispersion and density imaging metrics, relaxometry, magnetisation transfer (MT) ratio, MT saturation and derived g-ratio measures.Ethics and disseminationThe study received ethical approval from the South East Scotland Research Ethics Committee 02 (reference 15/SS/0233). Results will be made available to study participants and funders.STRENGTHS AND LIMITATIONS OF THE STUDYBrain imaging acquired within six months after relapsing-remitting multiple sclerosis (RRMS) diagnosis allows for detection of abnormalities at a very early stage of disease.Longitudinal structural and microstructural brain MRI are integrated with multi-modal clinical, blood biomarker, genetic and retinal imaging data to allow comprehensive evaluation of early RRMS stratifiers.MR protocol optimization was implemented mid-study to improved image quality and protocol harmonization, resulting in some between-subject protocol variation.Multiplatform MRI acquisition required to allow access for a large MS population across Scotland introduces inevitable inter-site data variance.Contrast enhanced MRI was not acquired, limiting imaging evaluation of active inflammatory lesions.

BackgroundDeterminants of multiple sclerosis aetiology and natural history remain unknown.ObjectivesTo determine factors associated with level of disability measured by Expanded Disability Severity Scale (EDSS) and Multiple Sclerosis Functional Composite (MSFC) in patients newly diagnosed with relapsing-remitting multiple sclerosis (RRMS).MethodsWe collected demographic, clinical, smoking and alcohol history in an incidence cohort of patients with RRMS recruited within six months of diagnosis. Ordinal logistic regression was used to examine association of EDSS with clinical and demographic features. Linear regression was used to examine asso- ciation between the same variables and MSFC.ResultsWe recruited 440 patients. Mean age at onset was 33.61 and 75.9% were female. Age at onset was shown to be associated with higher disability as measured by EDSS and MSFC. Sex was not signifi- cantly associated with outcome. After adjustment for age and sex, time to diagnosis, current smoking, having ever smoked and obesity were associated with higher EDSS whereas having ever smoked were associated with worse MSFC scores.ConclusionsDisability in relapsing-remitting multiple sclerosis is partly determined by demographic features and modifiable risk factors even early in disease course. Much of the variation remains to be elucidated and individualised risk prediction is an unmet need.fraser@tonnard.co.uk

BackgroundThere is increasing emphasis on earlier diagnosis in patients with relapsing remitting multiple sclerosis (RRMS) as evidence is accumulating that earlier treatment reduces long-term disability accumu- lation. Much inter-individual variability in time to diagnosis remains unexplained.ObjectivesTo examine factors associated with longer time to diagnosis in a cohort of adult patients diagnosed with RRMS in Scotland between January 2016 and February 2019.MethodsClinical and demographic features were collected as part of an incidence cohort study. Time to diagnosis was defined as interval between date of first symptom to date of diagnosis and considered prolonged if it was greater than the median value. Age at onset, sex, weight, smoking status, employ- ment status, socioeconomic status and onset symptom type were examined for association with time to diagnosis using logistic regression.ResultsWe recruited 440 patients. Median time to diagnosis was 1.75 years. Current employment (OR2.016 [1.186–3.428] p=0.010) was associated with longer time to diagnosis. We found no association with other variables measured.ConclusionsTime to diagnosis in RRMS in Scotland is employment status-dependent. A considerable proportion of variance in time to diagnosis remains unexplained in RRMS.fraser@tonnard.co.uk

BackgroundIn rodents, retinoid acid X receptor [RXR]-gamma agonists promote CNS remyelination.MethodsIn this double-blind phase 2a trial, participants with relapsing remitting multiple sclerosis (RRMS), stable on dimethyl fumarate, were randomised to bexarotene 300mg/m2 (a non-specific RXR agonist) or placebo for 6 months. The primary efficacy outcome was change in mean lesional magnetisation transfer ratio (MTR) for lesions below the within-patient median MTR. The secondary efficacy outcome was change in visual evoked potential (VEP) latency in eyes with electrophysiological evidence of optic neuropathy.Results52 patients were randomised to bexarotene or placebo. All bexarotene patients experienced adverse effects, notably central hypothyroidism (26 [100%]), hypertriglyceridaemia (24 [92%]), rash (13 [50%]) and neutropenia (10 [38%]). Two discontinued placebo and five discontinued bexarotene through adverse events.The primary efficacy outcome was negative (mean submedian lesion MTR change 0.25pu (bexarotene) vs 0.09pu (placebo), p=0.54), but significant effects were seen in grey matter lesions (p=0.008). Bexarotene reduced VEP latency in those with optic neuropathy (group difference 4·66 ms/eye, p=0·014).ConclusionsDespite a negative primary outcome, we found imaging and electrophysiological evidence of remyelination following RXR agonism in people with RRMS. Bexarotene’s safety profile precludes it’s use, but these data support selective RXR-gamma agonist development.william.brown@doctors.org.uk

BackgroundPrediction of individual disease course in relapsing remitting multiple sclerosis (RRMS) is chal- lenging. This has important implications for informed decision making in clinical practice.ObjectivesTo conduct a systematic review in order to establish methodological quality of published prediction models in RRMS.MethodsWe searched Medline, Embase and Web of Science. Reviewers screened abstracts and full text for eligibility and assessed risk of bias. Studies reporting development or validation of prediction models for adults with RRMS were included. Data collection was guided by checklist for critical appraisal and data extraction for systematic reviews and applicability and methodological quality assessment by prediction model risk of bias assessment tool.Results30 studies were included. Applicability was assessed as high risk of concern in 29 studies. Risk of bias was assessed as high for all studies. The single most frequently included predictor was baseline EDSS (n=11). T2 Lesion volume or number and brain atrophy were each retained in seven studies. Five studies included external validation. None included impact analysis.ConclusionsAlthough a number of prediction models for RRMS have been reported, most are at high risk of bias and lack external validation and impact analysis, restricting their application in clinical practice.fraser@tonnard.co.uk

The natural history of relapsing remitting multiple sclerosis (RRMS) is variable and prediction of individual prognosis challenging. The inability to reliably predict prognosis at diagnosis has important implications for informed decision making especially in relation to disease modifying therapies. We conducted a systematic review in order to collate, describe and assess the methodological quality of published prediction models in RRMS. We searched Medline, Embase and Web of Science. Two reviewers independently screened abstracts and full text for eligibility and assessed risk of bias. Studies reporting development or validation of prediction models for RRMS in adults were included. Data collection was guided by the checklist for critical appraisal and data extraction for systematic reviews (CHARMS) and applicability and methodological quality assessment by the prediction model risk of bias assessment tool (PROBAST). 30 studies were included in the review. Applicability was assessed as high risk of concern in 27 studies. Risk of bias was assessed as high for all studies. The single most frequently included predictor was baseline EDSS (n = 11). T2 Lesion volume or number and brain atrophy were each retained in seven studies. Five studies included external validation and none included impact analysis. Although a number of prediction models for RRMS have been reported, most are at high risk of bias and lack external validation and impact analysis, restricting their application to routine clinical practice.

We thank Lisa Grech and colleagues for their Correspondence concerning our Article on the MS-SMART trial. This multiarm phase 2b trial effectively condensed, into one well powered trial, the study of three re-purposed drugs with distinct mechanisms of action potentially relevant to slowing progression in secondary progressive multiple sclerosis. Despite positive experimental and early clinical work, unfortunately none of the drugs had any effect on slowing the rate of whole-brain atrophy (primary outcome), nor on a variety of secondary outcome measures.

Introduction Neuroinflammation, which contributes to neurodegeneration, is a consistent hallmark of dementia. Emerging evidence suggests that systemic inflammation also contributes to disease progression. Methods The ability of systemically administered lipopolysaccharide (LPS - 500 μg/kg) to effect acute and chronic behavioural changes in C57BL/6 and P301S tauopathy mice was assessed. Markers of pathology were assessed in the brain and spinal cord. Results P301S mice display regional microgliosis. Systemic LPS treatment induced exaggerated acute sickness behaviour and motor dysfunction in P301S mice compared with wild-type controls and advanced the onset and accelerated chronic decline. LPS treatment was associated with increased tau pathology 24 hours after LPS injection and spinal cord microgliosis at the end stage. Discussion This is the first demonstration that a single systemic inflammatory episode causes exaggerated acute functional impairments and accelerates the long-term trajectory of functional decline associated with neurodegeneration in a mouse model of human tauopathy. The findings have relevance to management of human dementias., Highlights • P301S microgliosis is regional; activation occurs in the spinal cord but not in the cortex. • Systemic LPS injection caused acute neurological deficits in P301S mice. • This was associated with increased tau pathology 24 hours after LPS injection. • This was independent of microglial priming as measured by IL-1β hyperexpression. • LPS injection advanced the onset of chronic decline in P301S mice.

Summary Myelination is essential for central nervous system (CNS) formation, health, and function. Emerging evidence of oligodendrocyte heterogeneity in health and disease and divergent CNS gene expression profiles between mice and humans supports the development of experimentally tractable human myelination systems. Here, we developed human iPSC-derived myelinating organoids (“myelinoids”) and quantitative tools to study myelination from oligodendrogenesis through to compact myelin formation and myelinated axon organization. Using patient-derived cells, we modeled a monogenetic disease of myelinated axons (Nfasc155 deficiency), recapitulating impaired paranodal axo-glial junction formation. We also validated the use of myelinoids for pharmacological assessment of myelination—both at the level of individual oligodendrocytes and globally across whole myelinoids—and demonstrated reduced myelination in response to suppressed synaptic vesicle release. Our study provides a platform to investigate human myelin development, disease, and adaptive myelination., Graphical abstract, Highlights • A human stem cell-derived organoid model of widespread and compact myelination • Recapitulated impaired paranode formation in patient-derived cultures • Pharmacological modulation of oligodendrocyte morphology and global myelin levels • Blocking synaptic vesicle release leads to hypomyelination, James et al. describe a human stem cell-derived quantitative model of compact myelination that recapitulates structural organization of myelinated axons. They show impaired paranode formation using patient-derived cells, develop methods to analyze myelinating oligodendrocyte morphology and global myelination, and demonstrate hypomyelination in response to reduced synaptic vesicle release.

Genetic understanding of motor neuron disease (MND) has evolved greatly in the past 10 years, including the recent identification of association between MND and variants in TBK1 and NEK1. Our aim was to determine the frequency of pathogenic variants in known MND genes and to assess whether variants in TBK1 and NEK1 contribute to the burden of MND in the Scottish population. SOD1, TARDBP, OPTN, TBK1, and NEK1 were sequenced in 441 cases and 400 controls. In addition to 44 cases known to carry a C9orf72 hexanucleotide repeat expansion, we identified 31 cases and 2 controls that carried a loss-of-function or pathogenic variant. Loss-of-function variants were found in TBK1 in 3 cases and no controls and, separately, in NEK1 in 3 cases and no controls. This study provides an accurate description of the genetic epidemiology of MND in Scotland and provides support for the contribution of both TBK1 and NEK1 to MND susceptibility in the Scottish population.

Fifteen regional studies of multiple sclerosis rates have been published in Scotland; spanning some six decades and surveying prevalence, mortality and hospital admissions. However, only one national study has attempted to compare regional rates (using admissions data).We used the Scottish Multiple Sclerosis Register to investigate incidence rates (IR). We present crude and age-adjusted IRs, cumulative incidences, and the sex ratio of cases and rates, for all regions of Scotland: 01/01/2010 to 31/12/2017.The overall IR for Scotland was 8.76/100,000 person-years (standardized: 8.54), which is high, but likely a conservative estimate of the total burden, including only definite cases. The female-male ratio was 2.3. Regional rates and sex ratios varied significantly – up to threefold – between Health Boards (pThis study is the first attempt to analyse the patterns of incidence for the whole of Scotland from prospectively collected data and benefits from a high level of completeness and ascertainment. The wide variation in incidence rates and sex-ratios is unexplained.

BackgroundDepression has a point prevalence of 25% and lifetime prevalence of 50% in people with MS (pwMS). Due to its convenience, the PHQ9 may be a useful tool in clinical practice for screening and monitoring of depression in pwMSObjectivesTo evaluate the internal and external reliability of the PHQ-9 measure of depressive symptoms in people with MS. Secondary objectives are; to evaluate the validity of the PHQ-9 as a measure of depressive symptoms in people with MS and to evaluate the acceptability of the PHQ-9 to people with MSDesign: A cross section validation studySubjects: People with Multiple SclerosisMethodsPeople with MS were recruited from the Rowling Care registry at the Anne Rowling Regenerative Neurology Clinic. Participants complete three questionnaires during a 4 week period using online questionnaires. Statistical analysis will be performed at the end of the study using R StudioResultsThe study is ongoing and now in the follow up phase. Provisional results are based on 92 completed participant datasets- Internal reliability of the PHQ-9 using Cronbach’s Alpha was 0.88. External reliability of the PHQ-9 using intraclass coefficient was 0.72.ConclusionsFinal conclusions are pending due to ongoing data collection.

There is wide regional variability in incidence of multiple sclerosis (MS) in Scotland. Extreme high-incidence is well known in Orkney, but most of the Scottish population (98%) lives on the mainland where local patterns are understudied. Well-designed small-areal units of geography and a national prospective incidence register allow us to examine the scale at which incident cases of MS cluster.Using the Scottish Multiple Sclerosis Register (1/1/2010 to 31/12/2017) we created multivariable linear regression models of small area incidence rates adjusted for population structure and latitude on the mainland. To examine the spatial distribution and independence of adjusted-rates, we calculated Moran’s I test for global autocorrelation on the residuals. We then used Getis-Ord Gi* and the isotonic, iterative SatScan statistic to identify local areas with significant positive spatial autocorrelation adjusting for multiple testing and spatial dependency.We can with confidence assert that incidence rates are not spatially random after controlling for latitude. Several localities on the mainland are identified which, over this period, had incidence rates (and populations) higher than Orkney. These may be worthy of monitoring, may generate aetiological hypotheses or be suitable for trials of putative-preventative therapies. Unexplained local variation of incidence suggests missing environmental risk factors.

Objective To develop and implement an evidence based framework to select, from drugs already licenced, candidate oral neuroprotective drugs to be tested in secondary progressive multiple sclerosis. Design Systematic review of clinical studies of oral putative neuroprotective therapies in MS and four other neurodegenerative diseases with shared pathological features, followed by systematic review and meta-analyses of the in vivo experimental data for those interventions. We presented summary data to an international multi-disciplinary committee, which assessed each drug in turn using pre-specified criteria including consideration of mechanism of action. Results We identified a short list of fifty-two candidate interventions. After review of all clinical and pre-clinical evidence we identified ibudilast, riluzole, amiloride, pirfenidone, fluoxetine, oxcarbazepine, and the polyunsaturated fatty-acid class (Linoleic Acid, Lipoic acid; Omega-3 fatty acid, Max EPA oil) as lead candidates for clinical evaluation. Conclusions We demonstrate a standardised and systematic approach to candidate identification for drug rescue and repurposing trials that can be applied widely to neurodegenerative disorders.

Clinical trials of neuroprotective interventions in multiple sclerosis require outcome measures that reflect the disease pathology. Measures of neuroaxonal integrity in the anterior visual pathways are of particular interest in this context, however imaging of the optic nerve is technically challenging. We therefore developed a 3T optic nerve diffusion tensor imaging protocol incorporating fat and cerebrospinal fluid suppression and without parallel imaging. The sequence used a scheme with six diffusion-weighted directions, b = 600 smm(-2) plus one b ≈ 0 (b(0)) and 40 repetitions, averaged offline, giving an overall scan time of 30 minutes. A coronal oblique orientation was used with voxel size 1.17 mm x 1.17 mm x 4 mm, We validated the sequence in 10 MS patients with a history of optic neuritis and 11 healthy controls: mean fractional anisotropy was reduced in the patients: 0.346(±0.159) versus 0.528(±0.123), p

Randomised, placebo-controlled trials are the gold standard for the assessment of safety and efficacy of new treatments. Although study design is challenging, success ultimately depends on recruitment and retention of subjects. MS-SMART [NCT01910259] is a multi-arm, phase 2b study in secondary progressive multiple sclerosis (SPMS), currently recruiting 440 patients in the UK. We describe here in detail our recruitment experience so far in the largest centre (planned 40% of total). Potentially eligible participants were identified through a number of routes: consultant referrals (22%); dedicated website [www.ms-smart.org] (76%); presentations at MS centres (0.4%), referrals from MS nurses (2%). Of c700 patients, 150 were uncontactable, and so 550 underwent a simple pre-screening telephone questionnaire. Two hundred were eligible of which 150 agreed to attend for formal screening and 130 were randomised. We conclude that direct consultant referral and a dedicated website are the most successful recruiting methods in this SPMS trial. This independent research is awarded by the Efficacy and Mechanism Evaluation. Programme (EME) and funded by the Medical Research Council (MRC) and the Multiple Sclerosis Society (MS Society) and managed by the National Institute for Health Research (NIHR) on behalf of the MRC-NIHR partnership.

MS-SMART is an ongoing multicentre, multi-arm, double blind, placebo-controlled phase IIb randomised controlled trial to establish whether putative neuroprotective drugs (fluoxetine,riluzole,amiloride or placebo) can slow down the progression of brain volume loss in secondary progressive multiple sclerosis (SPMS) over 96 weeks using MRI-derived Percentage Brain Volume Change (PBVC) as the primary outcome. 360 patients have been screened so far, 328 (92%) consented and 272 randomized (65% of the total UK cohort–440). Patients will have outcome-data collected after 0,24,48 and 96 weeks. The trial is using a range of conventional and novel imaging techniques to better understand neuroprotection in SPMS. Core data includes: new and enlarging T2 lesions count, persistent new T1 hypointense lesion, whole brain atrophy, grey matter volume, and advanced imaging in 2 centres [cervical cord area change,MR spectroscopy and Magnetic Transfer Ratio (MTR)]. Additional measures include: CSF neurofilament levels and optical coherence tomography (OCT) to measure Retinal Nerve Fibre Layer (RNFL) thickness. This abstract describes the ongoing status of the trial. This independent research is awarded by the Efficacy and Mechanism Evaluation Programme (EME) and funded by the Medical Research Council (MRC) and the Multiple Sclerosis Society (MS Society) and managed by the National Institute for Health Research (NIHR) on behalf of the MRC-NIHR partnership.

Background Cooling is the single most effective treatment for acute neuronal injury. Understanding the molecular mechanisms that mediate cooling-induced neuroprotection might yield novel therapeutic targets for neurodegenerative disease. Many of these disorders involve modulation of tau, a protein that is enriched in neurons and becomes hyperphosphorylated in hypothermic, injury-resistant rodent brains as well as in Alzheimer's disease. We sought to establish a new model for exploring human tau physiology and its role in neuroprotection in the context of therapeutic hypothermia. Methods Functional cortical neurons (hCNs) were differentiated from three independent human pluripotent stem-cell lines and validated for regional identity and tau status. Matched cultures were incubated at 37°C or clinically targeted temperatures for therapeutic hypothermia (32°C) and suspended animation (28°C). Effects of cooling on tau status and neuronal injury elicited by common neurotoxic stressors were established. Injury experiments were repeated while manipulating tau phosphorylation. Findings hCN differentiation featured transitions in tau status, recapitulating transcriptional and post-translational human in-vivo cortical tau development. Key aspects of this development were reversed by cooling. Notably, cooling induced tau hyperphosphorylation via rapid inhibition of the major tau phosphatase, protein phosphatase 2A (PP2A). Multiplexed injury analysis confirmed that hypothermia robustly protected hCNs from oxidative (100 μM hydrogen peroxide) and excitotoxic (30 μM glutamate) stress (at 28°C, injury was reduced by 78% and 56%, respectively; p Interpretation To our knowledge, this is the first study of human neuronal tau physiology under hypothermic conditions. Although definitive experiments are needed, our findings support previous work linking phospho-tau to neuroprotection. Furthermore, cold-induced tau hyperphosphorylation is a potential trigger for proteostatic priming, a recently discovered mechanism of hypothermic preconditioning in hCNs. Exploiting these cryobiological effects might lead to new treatments for acute and chronic neuronal injury. Funding Wellcome Trust, Anne Rowling Regenerative Neurology Clinic, Euan MacDonald Centre for Motor Neurone Disease Research.

Application of multidimensional assessment batteries is a well-established approach to detect cognitive impairment in multiple sclerosis (MS), the best known example being the Brief Repeatable Neuropsychological Battery. Although relatively easy to administer, these batteries require equipment, training and take 30–60 min.1 Current bedside screening techniques based on the Symbol Digit Modality Test, Paced Auditory Serial Additions Test (PASAT) and Faces Symbol Test are quick to administer (5–10 min), but they also require training and availability of relevant equipment.2 A rapid portable screening test that could be widely applied at the bedside or in the busy clinic is therefore highly desirable. Given that deficits in both phonemic (letter) and semantic (category) fluency are common in progressive MS and have been described among the earliest detectable cognitive features, both are of interest as candidate screening tests.3 Testing requires the subject to generate words beginning with a given letter (eg, p) or semantic category (eg, animals) over a defined time period (usually 1 min). Crucially, minimal test equipment is …

Background Progressive MS is associated with a high frequency of cognitive impairment. 1 However, it is not clear to what extent this reflects global dysfunction, or independent deficits in specific functions.Reduced speed of information processing, together with impairment in executive functions, recall–memory, and attention are the most frequently described deficits, particularly in the most extensively studied patient group with relapsing–remitting disease. 2 However, language and visuospatial functions have rarely been evaluated, despite evidence of involvement in large cohort studies, 3 as well as in studies specifically assessing these domains. 4 It therefore remains unclear whether cognitive dysfunction in MS reflects a universal deficit of all functions, or whether impairment of specific functions occurs independently. Objective To characterise patterns of cognitive impairment in progressive MS on a multi–dimensional cognitive assessment tool well established in neurodegenerative diseases. Methods Patients with secondary (SPMS; n=60) and primary progressive MS (PPMS; n=28) were assessed using the Addenbrooke9s Cognitive Examination–Revised (ACE–R) multi–dimensional cognitive assessment scale. Independent dimensions of impairment and their relative contribution to the overall burden of cognitive dysfunction were then determined by hierarchical factor analysis. Results Two independent dimensions of impairment were seen: frontal–executive (attention, verbal fluency, recall) on one hand, and language and visuospatial functions on the other. These accounted for 55% and 45% respectively of the variance not explained by a global influence (14.2% and 11.6% respectively of total variance). Isolated language and visuospatial dysfunction was seen in both groups, whereas isolated impairment in frontal–executive functions was underrepresented in SPMS (p=0.001) and not seen in PPMS patients (p=0.040). Conclusions In addition to a prominent global influence on cognitive performance, patients with progressive MS commonly exhibit independent language and visuospatial deficits. Evaluation of these abilities should therefore be included in clinical assessment of cognition in progressive MS. The underrepresentation of frontal–executive dysfunction also seen in our study raises the possibility that language and visuospatial deficits may be characteristic of cognitive impairment in progressive MS.

Background Multiple Sclerosis affects over 2.1 million people worldwide, 1 with over half of the prevalent population characterised by progressive forms of disease that result in the steady accumulation of fixed disability. 2 The absence of treatments for progressive MS therefore represents a major unmet clinical need. 3 Based on increasing experimental evidence that mesenchymal stem cells (MSCs) have biological properties of potential therapeutic relevance, 4 and beneficial effects across a range of disease models, 5 we assessed the safety and efficacy of autologous MSCs as a potential neuroprotective therapy for secondary progressive MS. 6 Methods Ten patients with secondary progressive MS involving the visual pathways (EDSS 5.5 to 6.5), received intravenous infusion of autologous bone marrow–derived MSCs derived using the European Group for Blood and Marrow Transplantation ex–vivo expansion procedures in a prospective open label phase IIA proof of concept study, registered at ClinicalTrials.gov NCT00395200. Adverse events were compared between pre–treatment and post–treatment periods of up to 20 and 10 months respectively. Using the anterior visual pathway as a model of wider disease, efficacy outcomes were also chosen to assess change at the point of treatment in functional, structural, and physiological measures. Blinded endpoint analyses were used for electrophysiological and selected imaging outcomes. Results MSCs were successfully isolated, expanded, characterised, and administered in all patients. The mean dose was 1·6×106 cells (min–max range 1·1–2·0) per kg bodyweight. One patient developed a transient rash not requiring treatment shortly after treatment; and two patients had self–limiting bacterial infections 3–4 weeks after treatment. No serious adverse events were observed. Improvement following treatment was seen in visual acuity and VER latency (difference in monthly rates of change: –0·02 LogMAR units [95% CI –0·03 to –0·01], p=0·003); and –1·33 ms [95% CI –2·44 to –0·21], p=0.020), with an increase in optic nerve area (difference in monthly rates of change 0·13 mm2 [95% CI 0·04 to 0·22], p=0·006). Exploratory analysis for non–linear effects showed cessation of treatment effects approximately six months after intravenous infusion. Conclusions Autologous MSCs can be safely administered in secondary progressive MS with evidence to suggest structural, functional and physiological improvement following treatment consistent with neuroprotection. The transient treatment response seen implied a likely requirement for repeat infusions to sustain benefit in the long–term.