Publications
230 results found
Nicholas R, Brooks D, Owen D, 2020, 18F-GE180, a radioligand for the TSPO protein: not ready for clinical trials in multiple sclerosis, EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING, ISSN: 1619-7070
Reali C, Magliozzi R, Roncaroli F, et al., 2020, B cell rich meningeal inflammation associates with increased spinal cord pathology in multiple sclerosis, Brain Pathology, ISSN: 1015-6305
Increased inflammation in the cerebral meninges is associated with extensive subpial cortical grey matter pathology in the forebrain and a more severe disease course in a substantial proportion of secondary progressive multiple sclerosis (SPMS) cases. It is not known whether this relationship extends to spinal cord pathology. We assessed the contribution of meningeal and parenchymal immune infiltrates to spinal cord pathology in SPMS cases characterised by the presence (F+) or absence (F‐) of lymphoid‐like structures in the forebrain meninges. Transverse cryosections of cervical, thoracic and lumbar cord of 22 SPMS and 5 control cases were analysed for CD20+ B cells, CD4+ and CD8+ T cells, microglia/macrophages (IBA‐1+), demyelination (myelin oligodendrocyte glycoprotein+) and axon density (neurofilament‐H+). Lymphoid‐like structures containing follicular dendritic cell networks and dividing B cells were seen in the spinal meninges of three out of 11 F+SPMS cases. CD4+ and CD20+ cell counts were increased in F+SPMS compared to F‐SPMS and controls, whilst axon loss was greatest in motor and sensory tracts of the F+SPMS cases (p<0.01). The density of CD20+ B cells of the spinal leptomeninges correlated with: CD4+ T cells and total B and T cells of the meninges; with the density of white matter perivascular CD20+ and CD4+ lymphocytes (p<0.05); with white matter lesion area (p<0.05); and the extent of axon loss (p<0.05) in F+SPMS cases only. We show that the presence of lymphoid‐like structures in the forebrain is associated with a profound spinal cord pathology, and local B cell rich meningeal inflammation associates with the extent of cord pathology. Our work supports a principal role for B cells in sustaining inflammation and tissue injury throughout the CNS in the progressive disease stage.
Nicholas R, Brooks D, Owen D, 2020, Letter to the Editor re: Confirmation of Specific Binding of the 18-kDa Translocator Protein (TSPO) Radioligand [F-18]GE-180: a Blocking Study Using XBD173 in Multiple Sclerosis Normal Appearing White and Grey Matter In Response, MOLECULAR IMAGING AND BIOLOGY, Vol: 22, Pages: 13-14, ISSN: 1536-1632
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- Citations: 2
Nicholas RS, Heaven ML, Middleton RM, et al., 2020, Personal and societal costs of multiple sclerosis in the UK: A population-based MS Registry study., Mult Scler J Exp Transl Clin, Vol: 6, ISSN: 2055-2173
Objectives: To investigate through survey and data linkage, healthcare resource use and costs (except drugs), including who bears the cost, of multiple sclerosis in the United Kingdom by disease severity and type. Methods: The United Kingdom Multiple Sclerosis Register deployed a cost of illness survey, completed by people with multiple sclerosis and linked this with data within the United Kingdom Multiple Sclerosis Register and from their hospital records. Resource consumption was categorised as being medical or non-medical and costed by National Health Service and social services estimates for 2018. Results: We calculated £509,003 in non-medical costs over a year and £435,488 in medical costs generated over 3 months. People with multiple sclerosis reported self-funding 75% of non-medical costs with non-medical interventions having long-term potential benefits. Costs increased with disability as measured by patient-reported Expanded Disability Status Score and Multiple Sclerosis Impact Scale, with Multiple Sclerosis Impact Scale physical being a more powerful predictor of costs than the patient-reported Expanded Disability Status Score. Two distinct groups were identified: medical and non-medical interventions (n = 138); and medical interventions only (n = 399). The medical and non-medical group reported increased disease severity and reduced employment but incurred 80% more medical costs per person than the medical-only group. Conclusions: The importance of disability in driving costs is illustrated with balance between medical and non-medical costs consistent with the United Kingdom health environment. People with multiple sclerosis and their families fund a considerable proportion of non-medical costs but non-medical interventions with longer term impact could affect future medical costs.
Kalam S, Hill J, Baheerathan A, et al., 2019, OUTCOME IN A HIGHLY ACTIVE MULTIPLE SCLEROSIS COHORT IN THE UK, Annual Meeting of the Association-of-British-Neurologists (ABN), Publisher: BMJ PUBLISHING GROUP, Pages: E55-E55, ISSN: 0022-3050
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, Vol: 69, Pages: 1757-1763, 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.
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
Nicholas R, Chang K, Romozzi M, et al., 2019, Programmed cell death ligand 1 (PD-L1) in multiple sclerosis (MS) serum and cerebrospinal fluid (CSF), 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: 444-445, ISSN: 1352-4585
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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- Citations: 3
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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- Citations: 12
Wilkie D, Solari A, Nicholas R, 2019, 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
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
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
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
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
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
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
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
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
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: 562-563, ISSN: 0028-3878
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