Publications
219 results found
Wagley S, Bokori-Brown M, Morcrette H, et al., 2019, Evidence of Clostridium perfringens epsilon toxin associated with multiple sclerosis, MULTIPLE SCLEROSIS JOURNAL, Vol: 25, Pages: 653-660, ISSN: 1352-4585
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Gafson AR, Savva C, Thorne T, et al., Breaking the cycle: reversal of flux in the tricarboxylic acid cycle by dimethyl fumarate, Neurology, Neuroimmunology and Neuroinflammation, ISSN: 2332-7812
ObjectiveTo infer possible molecular effectors of therapeutic effects and adverse events for the pro-drug dimethyl fumarate (DMF, Tecfidera) in the plasma of relapsing-remitting MS patients (RRMS) based on untargeted blood plasma metabolomics. MethodsBlood samples were collected from 27 RRMS patients at baseline and six weeks after initiation of treatment with DMF (BG-12; Tecfidera). Patients were separated into a discovery (n=15) and a validation cohort (n=12). Ten healthy controls were also recruited and blood samples were collected over the same time intervals. Untargeted metabolomic profiling using ultrahigh performance liquid chromatography-tandem mass spectrometry (UPLC-MS) was performed on plasma samples from the discovery cohort and healthy controls at Metabolon Inc. (Durham, NC). UPLC-MS was then performed on samples from the validation cohort at the National Phenome Centre (Imperial College, UK). Plasma neurofilament concentration (NfL) was also assayed for all subjects using the Simoa platform (Quanterix, Lexington, MA). Time course and cross-sectional statistical analyses were performed to identify pharmacodynamic changes in the metabolome secondary to DMF and relate these to adverse events. Results In the discovery cohort, tricarboxylic acid (TCA) cycle intermediates fumarate and succinate and TCA cycle metabolites succinyl-carnitine and methyl succinyl-carnitine were increased 6-weeks after the start of treatment (q < 0.05). We confirmed that methyl succinyl carnitine was also increased in the validation cohort 6-weeks after the start of treatment (q < 0.05). Changes in concentrations of these metabolites were not seen over a similar time period in blood from the untreated healthy control population. Increased succinyl-carnitine and methyl succinyl-carnitine were associated with adverse events from DMF (flushing, abdominal symptoms. The mean plasma NfL concentration before treatment was higher in the RRMS patients than in the healthy contro
Sridharan S, Raffel J, Nandoskar A, et al., 2019, Confirmation of Specific Binding of the 18-kDa Translocator Protein (TSPO) Radioligand [18F]GE-180: a Blocking Study Using XBD173 in Multiple Sclerosis Normal Appearing White and Grey Matter., Mol Imaging Biol
PURPOSE: Measurements of non-displaceable binding (VND) of positron emission tomography (PET) ligands are not often made in vivo in humans because they require ligands to displace binding to target receptors and there are few readily available, safe ones to use. A technique to measure VND for ligands for the 18-kDa translocator protein (TSPO) has recently been developed which compares the total volume of distribution (VT) before and after administration of the TSPO ligand XBD173. Here, we used XBD173 with an occupancy plot to quantify VND for two TSPO radiotracers, [18F]GE-180 and [11C]PBR28, in cohorts of people with multiple sclerosis (MS). Additionally, we compared plots of subjects carrying high (HAB) or mixed binding (MAB) affinity polymorphisms of TSPO to estimate VND without receptor blockade. PROCEDURES: Twelve people with MS underwent baseline MRI and 90-min dynamic [18F]GE-180 PET or [11C]PBR28 PET (n = 6; three HAB, three MAB each). Arterial blood sampling was used to generate plasma input functions for the two-tissue compartment model. VND was calculated using two independent methods: the occupancy plot (by modelling the differences in signal post XBD173) and the polymorphism plot (by modelling the differences in signal across presence and absence of rs6971 genotypes). RESULTS: Whole brain VT (mean ± standard deviation) was 0.29 ± 0.17 ml/cm3 for [18F]GE-180 and 5.01 ± 1.88 ml/cm3 for [11C]PBR28. Using the occupancy and polymorphism plots respectively, VND for [18F]GE-180 was 0.11 ml/cm3 (95 % CI = 0.02, 0.16) and 0.20 ml/cm3 (0.16, 0.34), accounting for, on average, 55 % of VT in the whole brain. For [11C]PBR28, these values were 3.81 ml/cm3 (3.02, 4.21) and 3.49 ml/cm3 (1.38, 4.27), accounting for 67 % of average whole brain VT. CONCLUSIONS: Although VT for [18F]GE-180 is low, indicating low brain penetration, half the signal shown
Mehra V, Rhone E, Widya S, et al., 2019, Epstein-Barr Virus and Monoclonal Gammopathy of Clinical Significance in Autologous Stem Cell Transplantation for Multiple Sclerosis., Clin Infect Dis
INTRODUCTION: Autologous hematopoietic stem cell transplantation (AHSCT) with anti-thymocyte globulin (ATG) conditioning as treatment of active multiple sclerosis (MS) is rapidly increasing across Europe (EBMT registry data 2017). Clinically significant Epstein-Barr virus reactivation (EBV-R) following AHSCT with ATG for severe autoimmune conditions is an underrecognized complication relative to T-cell deplete transplants performed for hematological diseases. This retrospective study reports EBV-R associated significant clinical sequelae in MS patients undergoing AHSCT with rabbit ATG. METHODS: Retrospective data were analyzed for 36 consecutive MS-AHSCT patients at Kings College Hospital, London. All patients routinely underwent weekly EBV DNA polymerase chain reaction monitoring and serum electrophoresis for monoclonal gammopathy (MG or M-protein). EBV-R with rising Epstein-Barr viral load, M-protein, and associated clinical sequelae were captured from clinical records. RESULTS: All patients had evidence of rising EBV DNA-emia, including 7 who were lost to long-term follow-up, with a number of them developing high EBV viral load and associated lymphoproliferative disorder (LPD). Nearly 72% (n = 18/29) developed de novo MG, some with significant neurological consequences with high M-protein and EBV-R. Six patients required anti-CD20 therapy (rituximab) with complete resolution of EBV related symptoms. Receiver operating characteristics estimated a peak EBV viremia of >500 000 DNA copies/mL correlated with high sensitivity (85.5%) and specificity (82.5%) (area under the curve: 0.87; P = .004) in predicting EBV-R related significant clinical events. CONCLUSION: Symptomatic EBV reactivation increases risk of neurological sequelae and LPD in MS-AHSCT. We recommend regular monitoring for EBV and serum electrophoresis for MG in MS patients in the first 3 months post-AHSCT.
Wilkie DD, Solari A, Nicholas R, 2019, Initiating disease-modifying treatments in multiple sclerosis: Measuring the decision process using decisional conflict and decisional regret scales., Mult Scler J Exp Transl Clin, Vol: 5, ISSN: 2055-2173
Introduction: Initiating disease-modifying treatments (DMTs) in multiple sclerosis (MS) is a major decision for people with (pw)MS but little is known about how the decision is perceived by the individual. Objectives: The aim of the study was to determine if decisional conflict (DC) and decisional regret reflect different stages of the decision-making process when initiating DMTs. Methods: This was a cross-sectional study of three cohorts of pwMS (n = 254), a 'MS conference attendees', 'on treatment' and an 'offered treatment' cohort. Questionnaires assessing DC, decisional regret and control preference were performed. Results: Forty-four per cent (113/254) of pwMS were dissatisfied with their treatment status and 53% (135/254) had DC. DC (p = 0.013) and decisional regret (p = 0.027) increase in treatment-naïve pwMS and also in those 'offered treatment' dissatisfied with their treatment status (p < 0.0001), whilst those 'on treatment' have low Decisional Regret Scale (DRS) score (p = 0.0005). DC and DRS were only correlated with treatment status in those on treatment and not in treatment-naïve patients. F (58/135) pwMS satisfied with treatment had DC. DC (n = 236, adjusted R2 0.137, p = 0.000) and DRS (n = 235, adjusted R2 0.232, p = 0.000) were increased by dissatisfaction with treatment, lower potency treatment, being from the 'MS conference attendees' cohort and reliance on the doctor's decision, with DC additionally associated with being employed. Conclusions: DC and decisional regret vary in populations at different stages of initiating DMTs and are impacted by non-treatment issues.
Gafson AR, Thorne T, McKechnie CIJ, et al., 2018, Lipoprotein markers associated with disability from multiple sclerosis, SCIENTIFIC REPORTS, Vol: 8, ISSN: 2045-2322
Rhone E, Nicholas R, Olavarria E, et al., 2018, Autologous stem cell transplantation in multiple sclerosis: the London experience, 34th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS), Publisher: SAGE PUBLICATIONS LTD, Pages: 270-271, ISSN: 1352-4585
Wilkie D, Solari A, Nicholas R, 2018, Understanding the role of decisional conflict in making choices about disease modifying therapy in multiple sclerosis?, 34th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS), Publisher: SAGE PUBLICATIONS LTD, Pages: 527-528, ISSN: 1352-4585
Nicholas E, Koffman J, Nicholas R, 2018, The role of advanced care plans in preventing hospital deaths in multiple sclerosis, 34th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS), Publisher: SAGE PUBLICATIONS LTD, Pages: 342-342, ISSN: 1352-4585
Karamital M, Nicholas R, Papazian E, et al., 2018, Age and chronicity of demyelination determine motor impairment in a model of multiple sclerosis, 34th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS), Publisher: SAGE PUBLICATIONS LTD, Pages: 181-182, ISSN: 1352-4585
Eshaghi A, Kievit RA, Prados F, et al., 2018, Simvastatin effect on disability is mediated by brain atrophy but is independent of cholesterol reduction in secondary progressive multiple sclerosis, 34th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS), Publisher: SAGE PUBLICATIONS LTD, Pages: 690-691, ISSN: 1352-4585
Ontaneda D, Tallantyre E, Nakamura K, et al., 2018, Design and rationale of the determining the effectiveness of early intensive versus escalation approaches for the treatment of relapsing-remitting multiple sclerosis (DELIVER-MS) trial, 34th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS), Publisher: SAGE PUBLICATIONS LTD, Pages: 470-471, ISSN: 1352-4585
Gallagher P, McGuigan C, Nicholas R, et al., 2018, Alemtuzumab after natalizumab SWitch in evolving rapidly severe multiple sclerosis (ANSWERS MS): long-term UK & Ireland experience., 34th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS), Publisher: SAGE PUBLICATIONS LTD, Pages: 99-100, ISSN: 1352-4585
Magliozzi R, Fadda G, Bar-Or A, et al., 2018, Substantial 'subependymal-in' gradient of thalamic damage in progressive multiple sclerosis., 34th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS), Publisher: SAGE PUBLICATIONS LTD, Pages: 94-95, ISSN: 1352-4585
Sridharan S, Raffel J, Nandoskar A, et al., 2018, Confirmation of specific binding of the 18 kDa translocator protein (TSPO) radioligand [F-18]GE-180: a blocking study using XDB173 in multiple sclerosis, 34th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS), Publisher: SAGE PUBLICATIONS LTD, Pages: 421-422, ISSN: 1352-4585
Nicholas R, Rogers J, Middleton R, et al., 2018, Categorising the multiple sclerosis impact score 29: performance over 7 years of follow-up in the UK MS Register, 34th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS), Publisher: SAGE PUBLICATIONS LTD, Pages: 160-160, ISSN: 1352-4585
Scalfari A, Pisani AI, Romualdi C, et al., 2018, Early predictors of brain atrophy among MS patients, 34th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS), Publisher: SAGE PUBLICATIONS LTD, Pages: 219-220, ISSN: 1352-4585
Cencioni MT, Yang C-Y, Abrahamsson S, et al., 2018, Mechanisms of dysfunction of regulatory B cell activity in multiple sclerosis, 34th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS), Publisher: SAGE PUBLICATIONS LTD, Pages: 599-599, ISSN: 1352-4585
Nicholas RS, Han E, Raffel J, et al., 2018, Over three decades study populations in progressive multiple sclerosis have become older and more disabled, but have lower on-trial progression rates: A systematic review and meta-analysis of 43 randomised placebo-controlled trials., Mult Scler
BACKGROUND: Progression is the major driver of disability and cost in multiple sclerosis (MS). However, the search for treatments in progressive multiple sclerosis (PMS) has not mirrored the success in relapsing MS. OBJECTIVES: To assess changes in PMS trials over time. METHODS: PubMed, MEDLINE and Embase were searched to identify randomised, double-blind, placebo-controlled trials in PMS. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used, study quality was assessed and trends were examined by regression. RESULTS: Placebo groups of 43 studies published between 1988 and 2018 were included. The mean age at trial entry increased by 9.8 years per decade (95% confidence interval (CI): [2.7; 4.9]; p < 0.001). Mean baseline Expanded Disability Status Scale (EDSS) scores increased by 0.36 points (95% CI: [0.09; 0.62]; p = 0.009) and disease durations at baseline were prolonged by 1.8 years (95% CI: [0.7; 2.9]; p = 0.003) per decade. The trials became larger, specifically placebo groups increased by about 222 patients (95% CI: [36; 409]; p = 0.021) and 88 patients (95% CI: [12; 165]; p = 0.025) per decade for primary progressive multiple sclerosis (PPMS) and secondary progressive multiple sclerosis (SPMS), respectively. The proportion of patients on placebo experiencing disability progression within 24 months decreased by 7.6 percentage points (95% CI: [1.2; 14.1]; p = 0.022) per year. CONCLUSION: Over three decades, PMS trial populations changed and are now older, with a longer disease duration and more disability, with lower on-trial progression rates.
Supratak A, Datta G, Gafson AR, et al., 2018, Remote Monitoring in the Home Validates Clinical Gait Measures for Multiple Sclerosis, FRONTIERS IN NEUROLOGY, Vol: 9, ISSN: 1664-2295
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Gafson AR, Kim K, Cencioni MT, et al., 2018, Mononuclear cell transcriptome changes associated with dimethyl fumarate in MS, NEUROLOGY-NEUROIMMUNOLOGY & NEUROINFLAMMATION, Vol: 5, ISSN: 2332-7812
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Scalfari A, Romualdi C, Nicholas RS, et al., 2018, The cortical damage, early relapses, and onset of the progressive phase in multiple sclerosis, NEUROLOGY, Vol: 90, Pages: E2107-E2118, ISSN: 0028-3878
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- Citations: 3
Vermersch P, Comi G, Siva A, et al., 2018, Baseline characteristics of the CASTING Study population: a Phase IIIB Trial evaluating Ocrelizumab in patients with relapsing-remitting Multiple Sclerosis and suboptimal response to disease-modifying therapies, 4th Congress of the European-Academy-of-Neurology (EAN), Publisher: WILEY, Pages: 190-190, ISSN: 1351-5101
Karamita M, Nicholas R, Kokoti L, et al., 2018, Cellular Senescence Correlates with Demyelination, Brain Atrophy and Motor Impairment in a Model of Multiple Sclerosis, 70th Annual Meeting of the American-Academy-of-Neurology (AAN), Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0028-3878
Magliozzi R, Howell OW, Nicholas R, et al., 2018, Inflammatory intrathecal profiles and cortical damage in multiple sclerosis, ANNALS OF NEUROLOGY, Vol: 83, Pages: 739-755, ISSN: 0364-5134
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- Citations: 12
Cencioni MT, Magliozzi R, Nicholas R, et al., 2017, Programmed death 1 is highly expressed on CD8(+) CD57(+) T cells in patients with stable multiple sclerosis and inhibits their cytotoxic response to Epstein-Barr virus, IMMUNOLOGY, Vol: 152, Pages: 660-676, ISSN: 0019-2805
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Datta G, Colasanti A, Rabiner EA, et al., 2017, Neuroinflammation and its relationship to changes in brain volume and white matter lesions in multiple sclerosis, BRAIN, Vol: 140, Pages: 2927-2938, ISSN: 0006-8950
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- Citations: 9
Magliozzi R, Roncaroli F, Muraro P, et al., 2017, The impact of high level of perivenular inflammation on active white matter lesions and disease progression in multiple sclerosis, 7th Joint European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS)-Americas-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ACTRIMS), Publisher: SAGE PUBLICATIONS LTD, Pages: 172-172, ISSN: 1352-4585
Dorsey-Campbell R, Motlagh BE, Quinn T, et al., 2017, Discontinuation of dimethyl fumarate in relapsing multiple sclerosis in a single centre, 7th Joint European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS)-Americas-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ACTRIMS), Publisher: SAGE PUBLICATIONS LTD, Pages: 893-894, ISSN: 1352-4585
Datta G, Violante IR, Scott G, et al., 2017, Translocator positron-emission tomography and magnetic resonance spectroscopic imaging of brain glial cell activation in multiple sclerosis, MULTIPLE SCLEROSIS JOURNAL, Vol: 23, Pages: 1469-1478, ISSN: 1352-4585
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- Citations: 6
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