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Moderate correlation exists between the imaging quantification of brain white matter lesions and cognitive performance in people with multiple sclerosis (MS). This may reflect the greater importance of other features, including subvisible pathology, or methodological limitations of the primary literature. To summarise the cognitive clinico-radiological paradox and explore the potential methodological factors that could influence the assessment of this relationship. Systematic review and meta-analysis of primary research relating cognitive function to white matter lesion burden. Fifty papers met eligibility criteria for review, and meta-analysis of overall results was possible in thirty-two (2050 participants). Aggregate correlation between cognition and T2 lesion burden was r = -0.30 (95% confidence interval: -0.34, -0.26). Wide methodological variability was seen, particularly related to key factors in the cognitive data capture and image analysis techniques. Resolving the persistent clinico-radiological paradox will likely require simultaneous evaluation of multiple components of the complex pathology using optimum measurement techniques for both cognitive and MRI feature quantification. We recommend a consensus initiative to support common standards for image analysis in MS, enabling benchmarking while also supporting ongoing innovation.

Recent findings from several studies have shown that paramagnetic rim lesions identified using susceptibility-based MRI could represent potential diagnostic and prognostic biomarkers in multiple sclerosis (MS). Here, we perform a systematic review and meta-analysis of the existing literature to assess their pooled prevalence at lesion-level and patient-level. Both database searching (PubMed and Embase) and handsearching were conducted to identify studies allowing the lesion-level and/or patient-level prevalence of rim lesions or chronic active lesions to be calculated. Pooled prevalence was estimated using the DerSimonian-Laird random-effects model. Subgroup analysis and meta-regression were performed to explore possible sources of heterogeneity. PROSPERO registration: CRD42020192282. 29 studies comprising 1230 patients were eligible for analysis. Meta-analysis estimated pooled prevalences of 9.8% (95% CI: 6.6-14.2) and 40.6% (95% CI: 26.2-56.8) for rim lesions at lesion-level and patient-level, respectively. Pooled lesion-level and patient-level prevalences for chronic active lesions were 12.0% (95% CI: 9.0-15.8) and 64.8% (95% CI: 54.3-74.0), respectively. Considerable heterogeneity was observed across studies (I2>75%). Subgroup analysis revealed a significant difference in patient-level prevalence between studies conducted at 3T and 7T (p = 0.0312). Meta-regression analyses also showed significant differences in lesion-level prevalence with respect to age (p = 0.0018, R2 = 0.20) and disease duration (p = 0.0018, R2 = 0.48). Other moderator analyses demonstrated no significant differences according to MRI sequence, gender and expanded disability status scale (EDSS). In this study, we show that paramagnetic rim lesions may be present in an important proportion of MS patients, notwithstanding significant variation in their assessment across studies. In view of their possible clinical relevance, we believe that clear guidelines should be introduced to standardise their assessment across research centres to in turn facilitate future analyses.

Purpose Rim lesions, characterised by a paramagnetic rim on susceptibility-based MRI, have been suggested to reflect chronic inflammatory demyelination in multiple sclerosis (MS) patients. Here, we assess, through susceptibility-weighted imaging (SWI), the prevalence, longitudinal volume evolution and clinical associations of rim lesions in subjects with early relapsing–remitting MS (RRMS). Methods Subjects ( n  = 44) with recently diagnosed RRMS underwent 3 T MRI at baseline (M0) and 1 year (M12) as part of a multi-centre study. SWI was acquired at M12 using a 3D segmented gradient-echo echo-planar imaging sequence. Rim lesions identified on SWI were manually segmented on FLAIR images at both time points for volumetric analysis. Results Twelve subjects (27%) had at least one rim lesion at M12. A linear mixed-effects model, with ‘subject’ as a random factor, revealed mixed evidence for the difference in longitudinal volume change between rim lesions and non-rim lesions ( p  = 0.0350 and p  = 0.0556 for subjects with and without rim lesions, respectively). All 25 rim lesions identified showed T1-weighted hypointense signal. Subjects with and without rim lesions did not differ significantly with respect to age, disease duration or clinical measures of disability ( p  > 0.05). Conclusion We demonstrate that rim lesions are detectable in early-stage RRMS on 3 T MRI across multiple centres, although their relationship to lesion enlargement is equivocal in this small cohort. Identification of SWI rims was subjective. Agreed criteria for defining rim lesions and their further validation as a biomarker of chronic inflammation are required for translation of SWI into routine MS clinical practice.

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.

Vascular risk factors are associated with increased disease activity and disability progression in multiple sclerosis (MS). This has been studied mainly in cohorts with relapsing-remitting MS. However, the association between vascular comorbidities (VCM) and clinical disability in secondary progressive MS (SPMS) is less well studied. Our aim was to investigate the association between VCM, non-VCM, comorbidity burden and both physical and cognitive performance in SPMS. Longitudinal analysis of 445 patients from the MS secondary progressive multi-arm trial (MS-SMART)-a multi-arm multicentre phase-2b randomised placebo-controlled trial of three agents in SPMS (NCT01910259). VCM (hypertension and hyperlipidaemia) and non-VCM (asthma, hypothyroidism and osteoporosis) were recorded. A comorbidity score was also determined (0, 1, ≥ 2). Physical disability and processing speed were assessed at baseline, 48- and 96 weeks. Multiple linear regression and mixed models were used to investigate the cross-sectional and longitudinal relationships between baseline VCM, non-VCM, comorbidity score and clinical outcome measures. The cohort was predominantly female (67%), median Expanded Disability Status Scale (EDSS) 6.0. 13% and 9% had hypertension and hyperlipidaemia (VCM), respectively. 7%, 9% and 5% had asthma, hypothyroidism and osteoporosis (non-VCM), respectively. Co-morbidity counts were 0,63%; 1, 23% and with > = 2, 11%. In cross-sectional models, both hypertension (β = 0.36, 95% CI 0.18-0.54) and an increased comorbidity count (β = 0.47, 95% CI 0.28-0.67) were associated with higher EDSS scores. In longitudinal models, hyperlipidaemia (β = 0.22, 95% CI 0.02-0.42) and increased comorbidity count (β = 0.21, 95% CI 0.01-0.41) were associated with increased EDSS scores over 48/96 weeks. No associations were seen with the non-VCM. VCM and also increased comorbidity burden per se are associated with increased disability. Disability worsening over 96 weeks was most evident in those with hyperlipidaemia and increased comorbidity burden.

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.

Background Multiple sclerosis (MS) is a highly variable disease of the central nervous system with inflammatory and neurodegenerative components, associated with both physical and cognitive disability. Abnormalities are visible on routine magnetic resonance imaging (MRI) of the brain, with 'white matter hyperintensities' (WMHs) representing sites of previous inflammation. Techniques for measuring WMHs have not been standardised, although manual outlining is conventionally taken to be the reference standard, despite its subjective element. WMHs have been found to only partly explain the degree of cognitive impairment, forming part of the 'clinico-radiological paradox'. Research interest has largely moved to advanced imaging techniques, one such technique being diffusion tensor imaging (DTI). Through sensitivity to water molecule movement, DTI reflects the integrity of white matter tracts and thus its measures may be relevant to both the inflammatory and degenerative disease components. Aims The work described in this thesis aims to improve our understanding of the true relationship between measures of white matter damage and cognitive impairment in people with MS, to determine the optimum measurement technique(s) for quantifying WMHs, including developing and testing a novel visual rating scale, and to assess whether information provided by DTI can strengthen the association of imaging and clinical findings. Methods A systematic review of the literature and meta-analysis relating WMHs to cognition was conducted, focussing on image analysis technique. Three separate methods for quantifying WMHs were then investigated. The reproducibility of manual outlining was assessed using scans available from 43 people with secondary progressive MS (SPMS). An automated software method was optimised for the same cohort, based on the results of the manual outlining. A novel semi-quantitative visual rating scale was developed, with validation using the same scans within a larger, more varied cohort. All available information regarding the participants studied was then used to construct a linear regression model predicting cognitive outcomes and determining the utility of the various imaging markers derived from conventional imaging techniques. A non-linear relationship for WMHs was also considered. White matter DTI metrics in the same smaller cohort of 43 people were then investigated, primarily considering tissue outwith WMHs, as well as that within major tracts and the novel diffusion marker `peak width of skeletonised mean diffusivity'. The additional explanatory power of DTI metrics within the linear models developed previously was then determined. Results High variability was found in the literature regarding imaging marker measurement and reporting of technique reproducibility. Manual outlining was found to be associated with considerable measurement error, dependent on observer and cohort factors. It was possible to optimise the automated software for a particular cohort, either for volumetric or spatial outputs. Visual rating of MS imaging features was found to be feasible and measures of WMH burden were closely related to fully quantitative measures. The overall association of WMHs to cognitive function was similar to that found in the published literature, with no additional association following addition of DTI metrics. A trend towards a greater effect of WMH volume at higher levels was found, consistent with a non-linear relationship between imaging metrics and cognitive phenotype. Conclusions Substantial heterogeneity in the reporting of the reproducibility of WMH measurement supports a move towards benchmarking against reference datasets. Poor reliability of the current reference standard, manual segmentation, should be recognised as a key limitation for the field. Rich information can be captured quickly using visual rating of imaging features. The close correlation of visual ratings of WMHs with quantitative measures may represent a practical alternative in the appropriate circumstances. Combining visual rating features provided additional explanatory power, supporting a multidimensional substrate for the cognitive phenotype. Finally, both automated and visual rating analyses support a non-linear relationship between disease burden and cognitive performance in MS.

Introduction CT angiography (CTA) is often used for assessing patients with acute ischaemic stroke. Only limited observer reliability data exist. We tested inter- and intra-observer reliability for the assessment of CTA in acute ischaemic stroke. Methods We selected 15 cases from the Third International Stroke Trial (IST-3, ISRCTN25765518) with various degrees of arterial obstruction in different intracranial locations on CTA. To assess inter-observer reliability, seven members of the IST-3 expert image reading panel (>5 years experience reading CTA) and seven radiology trainees (<2 years experience) rated all 15 scans independently and blind to clinical data for: presence (versus absence) of any intracranial arterial abnormality (stenosis or occlusion), severity of arterial abnormality using relevant scales (IST-3 angiography score, Thrombolysis in Cerebral Infarction (TICI) score, Clot Burden Score), collateral supply and visibility of a perfusion defect on CTA source images (CTA-SI). Intra-observer reliability was assessed using independently repeated expert panel scan ratings. We assessed observer agreement with Krippendorff’s-alpha (K-alpha). Results Among experienced observers, inter-observer agreement was substantial for the identification of any angiographic abnormality (K-alpha = 0.70) and with an angiography assessment scale (K-alpha = 0.60–0.66). There was less agreement for grades of collateral supply (K-alpha = 0.56) or for identification of a perfusion defect on CTA-SI (K-alpha = 0.32). Radiology trainees performed as well as expert readers when additional training was undertaken (neuroradiology specialist trainees). Intra-observer agreement among experts provided similar results (K-alpha = 0.33–0.72). Conclusion For most imaging characteristics assessed, CTA has moderate to substantial observer agreement in acute ischaemic stroke. Experienced readers and those with specialist training perform best.

Proton magnetic resonance spectroscopy yields metabolic information and has proved to be a useful addition to structural imaging in neurological diseases. We applied short-echo time Spectroscopic Imaging in a cohort of 42 patients with secondary progressive multiple sclerosis (SPMS). Linear modelling with respect to brain tissue type yielded metabolite levels that were significantly different in white matter lesions compared with normal-appearing white matter, suggestive of higher myelin turnover (higher choline), higher metabolic rate (higher creatine) and increased glial activity (higher myo-inositol) within the lesions. These findings suggest that the lesions have ongoing cellular activity that is not consistent with the usual assumption of ‘chronic’ lesions in SPMS, and may represent a target for repair therapies.