Publications
223 results found
Nicholas RS, Han E, Raffel J, et al., 2019, 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, MULTIPLE SCLEROSIS JOURNAL, Vol: 25, Pages: 1462-1471, ISSN: 1352-4585
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, Molecular Imaging and Biology, Vol: 21, Pages: 935-944, ISSN: 1536-1632
Purpose: Positron emission tomography (PET) ligands exhibit different levels of non-displaceable binding in vivo. In the case of ligands for the 18 kDa translocator protein (TSPO), the component of non-displaceable binding for the most widely used radiotracer, [11C]-(R)-PK11195, is relatively high compared to that for newer TSPO ligands. Non-displaceable binding is not often quantified in humans in vivo, partially due to a lack of available ligands that are known to be safe with which to displace binding to the target receptor. Recently, however, a technique has been developed to quantify the non-displaceable binding of TSPO tracers in vivo, by blocking the receptor with the TSPO ligand XBD173 and comparing the total volume of distribution ( ) pre and post-blockade. Here, we used an occupancy plot to quantify the non-displaceable binding ( ) of the TSPO PET tracers [18F]GE-180 and [11C]PBR28 in cohorts of people with multiple sclerosis (MS). We also compared plots of subjects carrying both high and mixed binding affinity polymorphisms of TSPO to estimate while potentially avoiding the need for receptor blockade.Procedures: Twelve people with multiple sclerosis (MS) and high (HAB) or mixed (MAB) affinity binding for TSPO underwent baseline MRI and 90-minute dynamic [18F]GE-180 PET (n=6; 3 HAB and 3 MAB) or [11C]PBR28 PET (n=6; 3 HAB, 3 MAB). Either one week later ([18F]GE-180) or the same afternoon ([11C]PBR28), participants had repeat PET following a 90mg dose of XBD173. PET images were co-registered with T1 MR volumetric images and regions of interest (ROIs) were defined using the 83-region Hammers atlas. Arterial blood sampling was used to generate plasma input functions for the two-tissue compartment model to quantify . The non-displaceable fraction of the total volume of distribution ( ) 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
Cencioni MT, Yusuf S, Palmisano I, et al., 2019, Soluble CD27 a biomarker of T cell activity in intrathecal inflammation in patients with relapsing-remitting multiple sclerosis, 35th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS) / 24th Annual Conference of Rehabilitation in MS, Publisher: SAGE PUBLICATIONS LTD, Pages: 110-111, ISSN: 1352-4585
Scalfari A, Pisani A, Romualdi C, et al., 2019, Predictors of long term brain atrophy among multiple sclerosis patients, 5th Congress of the European-Academy-of-Neurology (EAN), Publisher: WILEY, Pages: 247-247, ISSN: 1351-5101
Eshaghi A, Kievit RA, Prados F, et al., 2019, Applying causal models to explore the mechanism of action of simvastatin in progressive multiple sclerosis, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 116, Pages: 11020-11027, ISSN: 0027-8424
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Uccelli A, Laroni A, Brundin L, et al., 2019, MEsenchymal StEm cells for Multiple Sclerosis (MESEMS): a randomized, double blind, cross-over phase I/II clinical trial with autologous mesenchymal stem cells for the therapy of multiple sclerosis, Trials, Vol: 20, Pages: 1-13, ISSN: 1745-6215
BackgroundMultiple sclerosis (MS) is an inflammatory disease of the central nervous system with a degenerative component, leading to irreversible disability. Mesenchymal stem cells (MSC) have been shown to prevent inflammation and neurodegeneration in animal models of MS, but no large phase II clinical trials have yet assessed the exploratory efficacy of MSC for MS.Methods/designThis is an academic, investigator-initiated, randomized, double-blind, placebo-compared phase I/II clinical trial with autologous, bone-marrow derived MSC in MS. Enrolled subjects will receive autologous MSC at either baseline or at week 24, through a cross-over design. Primary co-objectives are to test safety and efficacy of MSC treatment compared to placebo at 6 months. Secondary objectives will evaluate the efficacy of MSC at clinical and MRI levels. In order to overcome funding constraints, the MEsenchymal StEm cells for Multiple Sclerosis (MESEMS) study has been designed to merge partially independent clinical trials, following harmonized protocols and sharing some key centralized procedures, including data collection and analyses.DiscussionResults will provide patients and the scientific community with data on the safety and efficacy of MSC for MS. The innovative approach utilized to obtain funds to support the MESEMS trial could represent a new model to circumvent limitation of funds encountered by academic trials.
Gafson AR, Savva C, Thorne T, et al., 2019, Breaking the cycle: reversal of flux in the tricarboxylic acid cycle by dimethyl fumarate, Neurology, Neuroimmunology and Neuroinflammation, Vol: 6, 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
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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Wilkie D, Solari A, Nicholas R, Initiating disease modifying treatments in multiple sclerosis: measuring the decision process using decisional conflict and decisional regret scales, Multiple Sclerosis Journal - Experimental, Translational and Clinical, ISSN: 2055-2173
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., Clinical Infectious Diseases, Pages: 1-7, ISSN: 1058-4838
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.
Gafson AR, Thorne T, McKechnie CIJ, et al., 2018, Lipoprotein markers associated with disability from multiple sclerosis, Scientific Reports, Vol: 8, ISSN: 2045-2322
Altered lipid metabolism is a feature of chronic infammatory disorders. Increased plasma lipids andlipoproteins have been associated with multiple sclerosis (MS) disease activity. Our objective was tocharacterise the specifc lipids and associated plasma lipoproteins increased in MS and to test for anassociation with disability. Plasma samples were collected from 27 RRMS patients (median EDSS,1.5, range 1–7) and 31 healthy controls. Concentrations of lipids within lipoprotein sub-classes weredetermined from NMR spectra. Plasma cytokines were measured using the MesoScale DiscoveryV-PLEX kit. Associations were tested using multivariate linear regression. Diferences between thepatient and volunteer groups were found for lipids within VLDL and HDL lipoprotein sub-fractions(p<0.05). Multivariate regression demonstrated a high correlation between lipids within VLDLsub-classes and the Expanded Disability Status Scale (EDSS) (p<0.05). An optimal model for EDSSincluded free cholesterol carried by VLDL-2, gender and age (R2=0.38, p<0.05). Free cholesterolcarried by VLDL-2 was highly correlated with plasma cytokines CCL-17 and IL-7 (R2=0.78, p<0.0001).These results highlight relationships between disability, infammatory responses and systemic lipidmetabolism in RRMS. Altered lipid metabolism with systemic infammation may contribute to immuneactivation.
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
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
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
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
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
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
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
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
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
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
Baheerathan A, McNamara C, Kalam S, et al., 2018, The utility of FDG-PET imaging in distinguishing PML-IRIS from PML in a patient treated with natalizumab., Neurology, Vol: 91, Pages: 572-573
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, Pages: 1-9, ISSN: 1664-2295
Background: The timed 25-foot walk (T25FW) is widely used as a clinic performance measure, but has yet to be directly validated against gait speed in the home environment.Objectives: To develop an accurate method for remote assessment of walking speed and to test how predictive the clinic T25FW is for real-life walking.Methods: An AX3-Axivity tri-axial accelerometer was positioned on 32 MS patients (Expanded Disability Status Scale [EDSS] 0–6) in the clinic, who subsequently wore it at home for up to 7 days. Gait speed was calculated from these data using both a model developed with healthy volunteers and individually personalized models generated from a machine learning algorithm.Results: The healthy volunteer model predicted gait speed poorly for more disabled people with MS. However, the accuracy of individually personalized models was high regardless of disability (R-value = 0.98, p-value = 1.85 × 10−22). With the latter, we confirmed that the clinic T25FW is strongly predictive of the maximum sustained gait speed in the home environment (R-value = 0.89, p-value = 4.34 × 10−8).Conclusion: Remote gait monitoring with individually personalized models is accurate for patients with MS. Using these models, we have directly validated the clinical meaningfulness (i.e., predictiveness) of the clinic T25FW for the first time.
Gafson A, Kicheol K, Cencioni M, et al., 2018, Mononuclear cell transcriptome changes associated with dimethyl fumarate in multiple sclerosis., Neurology, Neuroimmunology and Neuroinflammation, Vol: 5, ISSN: 2332-7812
Objective To identify short-term changes in gene expression in peripheral blood mononuclear cells (PBMCs) associated with treatment response to dimethyl fumarate (DMF, Tecfidera) in patients with relapsing-remitting MS (RRMS).Methods Blood samples were collected from 24 patients with RRMS (median Expanded Disability Status Scale score, 2.0; range 1–7) at baseline, 6 weeks, and 15 months after the initiation of treatment with DMF (BG-12; Tecfidera). Seven healthy controls were also recruited, and blood samples were collected over the same time intervals. PBMCs were extracted from blood samples and sequenced using next-generation RNA sequencing. Treatment responders were defined using the composite outcome measure “no evidence of disease activity” (NEDA-4). Time-course and cross-sectional differential expression analyses were performed to identify transcriptomic markers of treatment response.Results Treatment responders (NEDA-4 positive, 8/24) over the 15-month period had 478 differentially expressed genes (DEGs) 6 weeks after the start of treatment. These were enriched for nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and inhibition of nuclear factor κB (NFκB) pathway transcripts. For patients who showed signs of disease activity, there were no DEGs at 6 weeks relative to their (untreated) baseline. Contrasting transcriptomes expressed at 6 weeks with those at 15 months of treatment, 0 and 1,264 DEGs were found in the responder and nonresponder groups, respectively. Transcripts in the nonresponder group (NEDA-4 negative, 18/24) were enriched for T-cell signaling genes.Conclusion Short-term PBMC transcriptome changes reflecting activation of the Nrf2 and inhibition of NFκB pathways distinguish patients who subsequently show a medium-term treatment response with DMF. Relative stabilization of gene expression patterns may accompany treatment-associated suppression of disease activity.
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
Objective To investigate the relationship among cortical radiologic changes, the number of early relapses (ERs), and the long-term course of multiple sclerosis (MS).Methods In this cohort study, we assessed the number of cortical lesions (CLs) and white matter (WM) lesions and the cortical thickness (Cth) at clinical onset and after 7.9 mean years among 219 patients with relapsing remitting (RR) MS with 1 (Low-ER), 2 (Mid-ER), and ≥3 (High-ER) ERs during the first 2 years. Kaplan-Meier and Cox regression analyses investigated early factors influencing the risk of secondary progressive (SP) MS.Results Fifty-nine patients (27%) converted to SPMS in 6.1 mean years. A larger number of CLs at onset predicted a higher risk of SPMS (hazard ratio [HR] 2.16, 4.79, and 12.3 for 2, 5, and 7 CLs, respectively, p < 0.001) and shorter latency to progression. The High-ER compared to the Low-ER and Mid-ER groups had a larger volume of WM lesions and CLs at onset, accrued more CLs, experienced more severe cortical atrophy over time, and entered the SP phase more rapidly. In the multivariate model, older age at onset (HR 1.97, p < 0.001), a larger baseline CL (HR 2.21, p = 0.005) and WM lesion (HR 1.32, p = 0.03) volume, early changes of global Cth (HR 1.36, p = 0.03), and ≥3 ERs (HR 6.08, p < 0.001) independently predicted a higher probability of SP.Conclusions Extensive cortical damage at onset is associated with florid inflammatory clinical activity and predisposes to a rapid occurrence of the progressive phase. Age at onset, the number of early attacks, and the extent of baseline focal cortical damage can identify groups at high risk of progression who may benefit from more active therapy.
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
OBJECTIVE: Grey matter (GM) damage and meningeal inflammation have been associated with early disease onset and a more aggressive disease course in Multiple Sclerosis (MS), but can these changes be identified in the patient early in the disease course? METHODS: To identify possible biomarkers linking meningeal inflammation, GM damage and disease severity, gene and protein expression were analysed in meninges and CSF from 27 post-mortem secondary progressive MS (SPMS) and 14 control cases. Combined cytokine/chemokine CSF profiling and 3T-MRI were performed at diagnosis in two independent cohorts of MS patients (35 and 38 subjects) and in 26 non-MS patients. RESULTS: Increased expression of pro-inflammatory cytokines (IFNγ, TNF, IL2 and IL22) and molecules related to sustained B-cell activity and lymphoid-neogenesis (CXCL13, CXCL10, LTα, IL6, IL10) was detected in the meninges and CSF of post-mortem MS cases with high levels of meningeal inflammation and GM demyelination. Similar pro-inflammatory patterns, including increased levels of CXCL13, TNF, IFNγ, CXCL12, IL6, IL8 and IL10, together with high levels of BAFF, APRIL, LIGHT, TWEAK, sTNFR1, sCD163, MMP2 and pentraxin III, were detected in the CSF of MS patients with higher levels of GM damage at diagnosis. INTERPRETATION: A common pattern of intrathecal (meninges and CSF) inflammatory profile strongly correlates with increased cortical pathology, both at time of the diagnosis and of death. These results suggest a role for detailed CSF analysis combined with MRI, as a prognostic marker for more aggressive MS. This article is protected by copyright. All rights reserved.
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