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Magnetic resonance imaging (MRI) biomarkers are vital for multiple sclerosis (MS) clinical research and trials but quantifying them requires multi-contrast protocols and limits the use of abundant single-contrast hospital archives. We developed MindGlide, a deep learning model to extract brain region and white matter lesion volumes from any single MRI contrast. We trained MindGlide on 4247 brain MRI scans from 2934 MS patients across 592 scanners, and externally validated it using 14,952 scans from 1,001 patients in two clinical trials (primary-progressive MS and secondary-progressive MS trials) and a routine-care MS dataset. The model outperformed two state-of-the-art models when tested against expert-labelled lesion volumes. In clinical trials, MindGlide detected treatment effects on T2-lesion accrual and cortical and deep grey matter volume loss. In routine-care data, T2-lesion volume increased with moderate-efficacy treatment but remained stable with high-efficacy treatment. MindGlide uniquely enables quantitative analysis of archival single-contrast MRIs, unlocking insights from untapped hospital datasets. Here, the authors develop an AI tool called MindGlide that can extract key information from brain images acquired as part of the routine care of multiple-sclerosis patients to help interpret treatment effects, which previously required manual analysis.

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.

This study was undertaken to learn whether the principle of functional specialization that is evident at the level of the prestriate visual cortex extends to areas that are involved in grouping visual stimuli according to attribute, and specifically according to colour and motion. Subjects viewed, in an fMRI scanner, visual stimuli composed of moving dots, which could be either coloured or achromatic; in some stimuli the moving coloured dots were randomly distributed or moved in random directions; in others, some of the moving dots were grouped together according to colour or to direction of motion, with the number of groupings varying from 1 to 3. Increased activation was observed in area V4 in response to colour grouping and in V5 in response to motion grouping while both groupings led to activity in separate though contiguous compartments within the intraparietal cortex. The activity in all the above areas was parametrically related to the number of groupings, as was the prominent activity in Crus I of the cerebellum where the activity resulting from the two types of grouping overlapped. This suggests (a) that, the specialized visual areas of the prestriate cortex have functions beyond the processing of visual signals according to attribute, namely that of grouping signals according to colour (V4) or motion (V5); (b) that the functional separation evident in visual cortical areas devoted to motion and colour, respectively, is maintained at the level of parietal cortex, at least as far as grouping according to attribute is concerned; and (c) that, by contrast, this grouping-related functional segregation is not maintained at the level of the cerebellum. ► Subjects viewed stimuli containing groups defined by motion or colour. ► There was grouping related activity in cerebellum, in prestriate and parietal cortex. ► Activity in parietal cortex, but not cerebellum, was segregated according to modality.

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. 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. 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. 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. Efficacy and Mechanism Evaluation (EME) Programme, an MRC and NIHR partnership, UK Multiple Sclerosis Society, and US National Multiple Sclerosis Society.

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. 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. 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). 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. Multiple Sclerosis Society of the United Kingdom.

ObjectiveIn multiple sclerosis (MS), MRI measures at the whole brain or regional level are only modestly associated with disability, while network-based measures are emerging as promising prognostic markers. We sought to demonstrate whether data-driven patterns of covarying regional grey matter (GM) volumes predict future disability in secondary progressive MS (SPMS).MethodsWe used cross-sectional structural MRI, and baseline and longitudinal data of Expanded Disability Status Scale, Nine-Hole Peg Test (9HPT) and Symbol Digit Modalities Test (SDMT), from a clinical trial in 988 people with SPMS. We processed T1-weighted scans to obtain GM probability maps and applied spatial independent component analysis (ICA). We repeated ICA on 400 healthy controls. We used survival models to determine whether baseline patterns of covarying GM volume measures predict cognitive and motor worsening.ResultsWe identified 15 patterns of regionally covarying GM features. Compared with whole brain GM, deep GM and lesion volumes, some ICA components correlated more closely with clinical outcomes. A mainly basal ganglia component had the highest correlations at baseline with the SDMT and was associated with cognitive worsening (HR=1.29, 95% CI 1.09 to 1.52, p<0.005). Two ICA components were associated with 9HPT worsening (HR=1.30, 95% CI 1.06 to 1.60, p<0.01 and HR=1.21, 95% CI 1.01 to 1.45, p<0.05). ICA measures could better predict SDMT and 9HPT worsening (C-index=0.69–0.71) compared with models including only whole and regional MRI measures (C-index=0.65–0.69, p value for all comparison <0.05).ConclusionsThe disability progression was better predicted by some of the covarying GM regions patterns, than by single regional or whole-brain measures. ICA, which may represent structural brain networks, can be applied to clinical trials and may play a role in stratifying participants who have the most potential to show a treatment effect.

BackgroundNetwork-based measures are emerging MRI markers in multiple sclerosis (MS). We aimed to identify networks of white (WM) and grey matter (GM) damage that predict disability progression and cognitive worsening using data-driven methods.MethodsWe analysed data from 1836 participants with different MS phenotypes (843 in a discovery cohort and 842 in a replication cohort). We calculated standardised T1-weighted/T2-weighted (sT1w/T2w) ratio maps in brain GM and WM, and applied spatial independent component analysis to identify networks of covarying microstructural damage. Clinical outcomes were Expanded Disability Status Scale worsening confirmed at 24 weeks (24-week confirmed disability progression (CDP)) and time to cognitive worsening assessed by the Symbol Digit Modalities Test (SDMT). We used Cox proportional hazard models to calculate predictive value of network measures.ResultsWe identified 8 WM and 7 GM sT1w/T2w networks (of regional covariation in sT1w/T2w measures) in both cohorts. Network loading represents the degree of covariation in regional T1/T2 ratio within a given network. The loading factor in the anterior corona radiata and temporo-parieto-frontal components were associated with higher risks of developing CDP both in the discovery (HR=0.85, p<0.05 and HR=0.83, p<0.05, respectively) and replication cohorts (HR=0.84, p<0.05 and HR=0.80, p<0.005, respectively). The decreasing or increasing loading factor in the arcuate fasciculus, corpus callosum, deep GM, cortico-cerebellar patterns and lesion load were associated with a higher risk of developing SDMT worsening both in the discovery (HR=0.82, p<0.01; HR=0.87, p<0.05; HR=0.75, p<0.001; HR=0.86, p<0.05 and HR=1.27, p<0.0001) and replication cohorts (HR=0.82, p<0.005; HR=0.73, p<0.0001; HR=0.80, p<0.005; HR=0.85, p<0.01 and HR=1.26, p<0.0001).ConclusionsGM and WM networks of microstructural changes predict disability and cognitive worsening in MS. Our approach may be used to identify patients at greater risk of disability worsening and stratify cohorts in treatment trials.

BackgroundOptical coherence tomography (OCT) inner retinal metrics reflect neurodegeneration in multiple sclerosis (MS). We explored OCT measures as biomarkers of disease severity in secondary progressive MS (SPMS).MethodsWe investigated people with SPMS from the Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial OCT substudy, analysing brain MRIs, clinical assessments and OCT at baseline and 96 weeks. We measured peripapillary retinal nerve fibre layer (pRNFL) and macular ganglion cell-inner plexiform layer (GCIPL) thicknesses. Statistical analysis included correlations, multivariable linear regressions and mixed-effects models.ResultsOf the 212 participants recruited at baseline, 192 attended at 96 weeks follow-up. Baseline pRNFL and GCIPL thickness correlated with Symbol Digit Modalities Test (SDMT) (respectively, r=0.33 (95% CI 0.20 to 0.47); r=0.39 (0.26 to 0.51)) and deep grey matter volume (respectively, r=0.21 (0.07 to 0.35); r=0.28 (0.14 to 0.41)).pRNFL was associated with Expanded Disability Status Scale (EDSS) score change (normalised beta (B)=−0.12 (−0.23 to −0.01)). Baseline pRNFL and GCIPL were associated with Timed 25-Foot Walk change (T25FW) (respectively, B=−0.14 (−0.25 to −0.03); B=−0.20 (−0.31 to −0.10)) and 96-week percentage brain volume change (respectively, B=0.14 (0.03 to 0.25); B=0.23 (0.12 to 0.34)). There were significant annualised thinning rates: pRNFL (−0.83 µm/year) and GCIPL (−0.37 µm/year).ConclusionsIn our cohort of people with SPMS and long disease duration, OCT measures correlated with SDMT and deep grey matter volume at baseline; EDSS, T25FW and whole brain volume change at follow-up.

IntroductionThe major unmet need in multiple sclerosis (MS) is for neuroprotective therapies that can slow (or ideally stop) the rate of disease progression. The UK MS Society Clinical Trials Network (CTN) was initiated in 2007 with the purpose of developing a national, efficient, multiarm trial of repurposed drugs. Key underpinning work was commissioned by the CTN to inform the design, outcome selection and drug choice including animal models and a systematic review. This identified seven leading oral agents for repurposing as neuroprotective therapies in secondary progressive MS (SPMS). The purpose of the Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial (MS-SMART) will be to evaluate the neuroprotective efficacy of three of these drugs, selected with distinct mechanistic actions and previous evidence of likely efficacy, against a common placebo arm. The interventions chosen were: amiloride (acid-sensing ion channel antagonist); fluoxetine (selective serotonin reuptake inhibitor) and riluzole (glutamate antagonist).Methods and analysisPatients with progressing SPMS will be randomised 1:1:1:1 to amiloride, fluoxetine, riluzole or matched placebo and followed for 96 weeks. The primary outcome will be the percentage brain volume change (PBVC) between baseline and 96 weeks, derived from structural MR brain imaging data using the Structural Image Evaluation, using Normalisation, of Atrophy method. With a sample size of 90 per arm, this will give 90% power to detect a 40% reduction in PBVC in any active arm compared with placebo and 80% power to detect a 35% reduction (analysing by analysis of covariance and with adjustment for multiple comparisons of three 1.67% two-sided tests), giving a 5% overall two-sided significance level. MS-SMART is not powered to detect differences between the three active treatment arms. Allowing for a 20% dropout rate, 110 patients per arm will be randomised. The study will take place at Neuroscience centres in England and Scotland.Ethics and disseminationMS-SMART was approved by the Scotland A Research Ethics Committee on 13 January 2013 (REC reference: 13/SS/0007). Results of the study will be submitted for publication in a peer-reviewed journal.Trial registration numbers NCT01910259; 2012-005394-31; ISRCTN28440672.

PurposeMultiple sclerosis (MS) is a chronic neurological condition that affects approximately 150 000 people in the UK and presents a significant healthcare burden, including the high costs of disease-modifying treatments (DMTs). DMTs have substantially reduced the risk of relapse and moderately reduced disability progression. Patients exhibit a wide range of responses to available DMTs. The Predicting Optimal INdividualised Treatment response in MS (POINT-MS) cohort was established to predict the individual treatment response by integrating comprehensive clinical phenotyping with imaging, serum and genetic biomarkers of disease activity and progression. Here, we present the baseline characteristics of the cohort and provide an overview of the study design, laying the groundwork for future analyses.ParticipantsPOINT-MS is a prospective, observational research cohort and biobank of 781 adult participants with a diagnosis of MS who consented to study enrolment on initiation of a DMT at the Queen Square MS Centre (National Hospital of Neurology and Neurosurgery, University College London Hospital NHS Trust, London) between 01/07/2019 and 31/07/2024. All patients were invited for clinical assessments, including the expanded disability status scale (EDSS) score, brief international cognitive assessment for MS and various patient-reported outcome measures (PROMs). They additionally underwent MRI at 3T, optical coherence tomography and blood tests (for genotyping and serum biomarkers quantification), at baseline (i.e., within 3 months from commencing a DMT), and between 6–12 (re-baseline), 18–24, 30–36, 42–48 and 54–60 months after DMT initiation.Findings to date748 participants provided baseline data. They were mostly female (68%) and White (75%) participants, with relapsing–remitting MS (94.3%), and with an average age of 40.8 (±10.9) years and a mean disease duration of 7.9 (±7.4) years since symptom onset. Despite low disability (median EDSS 2.0), cognitive impairment was observed in 40% of participants. Most patients (98.4%) had at least one comorbidity. At study entry, 59.2% were treatment naïve, and 83.2% initiated a high-efficacy DMT. Most patients (76.4%) were in either full- or part-time employment. PROMs indicated heterogeneous impairments in physical and mental health, with a greater psychological than physical impact and with low levels of fatigue. When baseline MRI scans were compared with previous scans (available in 668 (89%) patients; mean time since last scan 9±8 months), 26% and 8.5% of patients had at least one new brain or spinal cord lesion at study entry, respectively. Patients showed a median volume of brain lesions of 6.14 cm3, with significant variability among patients (CI 1.1 to 34.1). When brain tissue volumes z-scores were obtained using healthy subjects (N=113, (mean age 42.3 (± 11.8) years, 61.9% female)) from a local MRI database, patients showed a slight reduction in the volumes of the whole grey matter (−0.16 (−0.22 to –0.09)), driven by the deep grey matter (−0.47 (−0.55 to –0.40)), and of the whole white matter (−0.18 (−0.28 to –0.09)), but normal cortical grey matter volumes (0.10 (0.05 to 0.15)). The mean upper cervical spinal cord cross-sectional area (CSA), as measured from volumetric brain scans, was 62.3 (SD 7.5) mm2. When CSA z-scores were obtained from the same healthy subjects used for brain measures, patients showed a slight reduction in CSA (−0.15 (−0.24 to –0.10)).Future plansModelling with both standard statistics and machine learning approaches is currently planned to predict individualised treatment response by integrating all the demographic, socioeconomic, clinical data with imaging, genetic and serum biomarkers. The long-term output of this research is a stratification tool that will guide the selection of DMTs in clinical practice on the basis of the individual prognostic profile. We will complete long-term follow-up data in 4 years (January 2029). The biobank and MRI repository will be used for collaborative research on the mechanisms of disability in MS.