Publications
246 results found
Nicholas R, Nicholas E, Hannides M, et al., 2021, Influence of individual, illness and environmental factors on place of death among people with neurodegenerative diseases: a retrospective, observational, comparative cohort study., BMJ Support Palliat Care
BACKGROUND: In long-term neurological conditions, location of death is poorly understood but is seen as a marker of quality of dying. OBJECTIVE: To examine individual, illness and environmental factors on place of death among people with multiple sclerosis (MS) and Parkinson's disease (PD) in isolation or in combination and compare them with people without either condition. METHODS: Retrospective, observational, comparative cohort study of 582 people with MS, 579 people with PD and 95 controls from UK Multiple Sclerosis and Parkinson's Disease Tissue Bank. A subset of people with MS and PD were selected for analysis of individual clinical encounters 2 years before death and further subset of all groups for analysis of impact of advance care planning (ACP) and recognition of dying. RESULTS: People with MS died more often (50.8%) in hospital than those with PD (35.3%). Examining individual clinical encounters over 2 years (4931 encounters) identified increased contact with services 12 months before death (F(1, 58)=69.71, p<0.0001) but was not associated with non-hospital deaths (F(1, 58)=1.001, p=0.321). The presence of ACPs and recognition of dying were high among people with MS and PD and both associated with a non-hospital death. ACPs were more likely to prevent hospital deaths when initiated by general practitioners (GPs) compared with other professional groups (χ2=68.77, p=0.0007). CONCLUSIONS: For people with MS and PD, ACPs contribute to reducing dying in hospital. ACPs appear to be most effective when facilitated by GPs underlining the importance of primary care involvement in delivering holistic care at the end of life.
Pitteri M, Magliozzi R, Nicholas R, et al., 2021, Cerebrospinal fluid inflammatory profile of cognitive impairment in newly diagnosed multiple sclerosis patients, MULTIPLE SCLEROSIS JOURNAL, ISSN: 1352-4585
Huang Y, Rodgers WJ, Middleton RM, et al., 2021, Willingness to receive a COVID-19 vaccine in people with multiple sclerosis - UK MS Register survey., Mult Scler Relat Disord, Vol: 55
BACKGROUND & METHODS: We conducted an online COVID-19 survey as the vaccines became available, utilising the UK MS Register, to understand people with multiple sclerosis (pwMS) views on COVID-19 vaccination and the subsequent vaccine uptake rates. RESULTS & CONCLUSION: 94.4% of 3191 pwMS surveyed indicated they would get a COVID-19 vaccine, while 5.6% would not. PwMS who have previously had an influenza vaccine, increasing age and the perception of having sufficient information about the vaccine were associated with increased likelihood of getting a vaccine. 51.7% of 3191 pwMS completed a follow-up survey indicating they received at least 1 dose of a COVID-19 vaccine. The proportion having had the vaccination based on their prior opinions was 53.2% in 'Yes' group and 27.0% in 'No' group, the latter reflecting a change based on their initial views. More information on COVID-19 vaccine safety in pwMS would be helpful for people to make informed decisions.
Nicholas RS, Rhone EE, Mariottini A, et al., 2021, Autologous Haematopoietic Stem Cell Transplantation in Active Multiple Sclerosis: a Real-world Case Series., Neurology
OBJECTIVE: to examine outcomes in people with multiple sclerosis (PwMS) treated with autologous hematopoietic stem cell transplantation (AHSCT) in a real-world setting. METHODS: retrospective cohort study on PwMS treated with AHSCT at two centers in London, UK, consecutively between 2012 and 2019 who had ≥ 6 months of follow-up or died at any time. Primary outcomes were survival free of MS relapses, MRI new lesions and worsening of expanded disability status scale (EDSS). Adverse events rates were also examined. RESULTS: the cohort includes 120 PwMS; 52% had progressive MS (primary or secondary) and 48% had relapsing-remitting MS (RRMS). At baseline, the median expanded disability status scale (EDSS) was 6.0; 90% of the evaluable cases showed MRI activity in the 12 months preceding AHSCT. Median follow-up after AHSCT was 21 months (range 6-85). MS relapse-free survival was 93% at 2 years and 87% at 4 years after AHSCT. No new MRI lesions were detected in 90% of subjects at 2 years and 85% at 4 years. EDSS progression-free survival (PFS) was 75% at 2 years and 65% at 4 years. EBV reactivation and monoclonal paraproteinemia were associated with worse PFS. There were 3 transplant-related deaths within 100 days (2.5%), all following fluid overload and cardiac or respiratory failure. CONCLUSIONS: efficacy outcomes of AHSCT in this real-world cohort are similar to those reported in more stringently selected clinical trial populations, although the risks may be higher. CLASSIFICATION OF EVIDENCE: this study is rated Class IV because of the uncontrolled, open-label design.
Garjani A, Hunter R, Law GR, et al., 2021, Mental health of people with multiple sclerosis during the COVID-19 outbreak: A prospective cohort and cross-sectional case-control study of the UK MS Register, MULTIPLE SCLEROSIS JOURNAL, ISSN: 1352-4585
Magliozzi R, Pitteri M, Ziccardi S, et al., 2021, CSF parvalbumin levels reflect interneuron loss linked with cortical pathology in multiple sclerosis, Annals of Clinical and Translational Neurology, Vol: 8, Pages: 534-547, ISSN: 2328-9503
INTRODUCTION AND METHODS: In order to verify whether parvalbumin (PVALB), a protein specifically expressed by GABAergic interneurons, could be a MS-specific marker of grey matter neurodegeneration, we performed neuropathology/molecular analysis of PVALB expression in motor cortex of 40 post-mortem progressive MS cases, with/without meningeal inflammation, and 10 control cases, in combination with cerebrospinal fluid (CSF) assessment. Analysis of CSF PVALB and neurofilaments (Nf-L) levels combined with physical/cognitive/3TMRI assessment was performed in 110 naïve MS patients and in 32 controls at time of diagnosis. RESULTS: PVALB gene expression was downregulated in MS (fold change = 3.7 ± 1.2, P < 0.001 compared to controls) reflecting the significant reduction of PVALB+ cell density in cortical lesions, to a greater extent in MS patients with high meningeal inflammation (51.8, P < 0.001). Likewise, post-mortem CSF-PVALB levels were higher in MS compared to controls (fold change = 196 ± 36, P < 0.001) and correlated with decreased PVALB+ cell density (r = -0.64, P < 0.001) and increased MHC-II+ microglia density (r = 0.74, P < 0.01), as well as with early age of onset (r = -0.69, P < 0.05), shorter time to wheelchair (r = -0.49, P < 0.05) and early age of death (r = -0.65, P < 0.01). Increased CSF-PVALB levels were detected in MS patients at diagnosis compared to controls (P = 0.002). Significant correlation was found between CSF-PVALB levels and cortical lesion number on MRI (R = 0.28, P = 0.006) and global cortical thickness (R = -0.46, P < 0.001), better than Nf-L levels. CSF-PVALB levels increased in MS patients with severe cognitive impairment (mean ± SEM:25.2 ± 7.5
Evangelou N, Garjani A, dasNair R, et al., 2021, Self-diagnosed COVID-19 in people with multiple sclerosis: a community-based cohort of the UK MS Register, JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY, Vol: 92, Pages: 107-+, ISSN: 0022-3050
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- Citations: 7
Monaco S, Nicholas R, Reynolds R, et al., 2020, Intrathecal inflammation in progressive multiple sclerosis, International Journal of Molecular Sciences, Vol: 21, Pages: 1-11, ISSN: 1422-0067
Progressive forms of multiple sclerosis (MS) are associated with chronic demyelination, axonal loss, neurodegeneration, cortical and deep gray matter damage, and atrophy. These changes are strictly associated with compartmentalized sustained inflammation within the brain parenchyma, the leptomeninges, and the cerebrospinal fluid. In progressive MS, molecular mechanisms underlying active demyelination differ from processes that drive neurodegeneration at cortical and subcortical locations. The widespread pattern of neurodegeneration is consistent with mechanisms associated with the inflammatory molecular load of the cerebrospinal fluid. This is at variance with gray matter demyelination that typically occurs at focal subpial sites, in the proximity of ectopic meningeal lymphoid follicles. Accordingly, it is possible that variations in the extent and location of neurodegeneration may be accounted for by individual differences in CSF flow, and by the composition of soluble inflammatory factors and their clearance. In addition, “double hit” damage may occur at sites allowing a bidirectional exchange between interstitial fluid and CSF, such as the Virchow–Robin spaces and the periventricular ependymal barrier. An important aspect of CSF inflammation and deep gray matter damage in MS involves dysfunction of the blood–cerebrospinal fluid barrier and inflammation in the choroid plexus. Here, we provide a comprehensive review on the role of intrathecal inflammation compartmentalized to CNS and non-neural tissues in progressive MS.
Wilkie D, Solari A, Nicholas R, 2020, The impact of the face-to-face consultation on decisional conflict in complex decision-making in multiple sclerosis: a pilot study, Multiple Sclerosis Journal - Experimental, Translational and Clinical, Vol: 6, Pages: 1-11, ISSN: 2055-2173
BackgroundThe role of face-to-face consultations in medicine is increasingly being challenged. Disease activity, national guidelines, life goals e.g. pregnancy, multiple therapies and side effects need to be considered on starting disease modifying treatments (DMTs) in people with multiple sclerosis (pwMS). ObjectivesWe studied the impact of a face-to-face consultation on decision making, using decisional conflict (DC) as the primary outcome. MethodsProspective cohort study of 73 pwMS attending clinics who were making decisions about DMTs followed for one year. Prerequisites and consultation features were measured with the SURE scale for DC used as the primary outcome at baseline and at one year.ResultsThe patient activation measure (PAM) was the only driver prior to the consultation associated with DC (p=0.02) showing those less engaged were more likely to have DC. Overall, 51/73 (70%) of people made their treatment decision or reinforced a former decision during the consultation. We found making a treatment decision between the original consultation and the follow-up was associated with resolving DC (p=0.008).Conclusions Patient engagement impacts DC but the HCP delivering the optimal Shared Decision Making (SDM) approach is additionally significant in reducing DC. In complex decisions there is a clear role for face-to-face consultations in current practice.
Middleton RM, Pearson OR, Ingram G, et al., 2020, A Rapid Electronic Cognitive Assessment Measure for Multiple Sclerosis: Validation of Cognitive Reaction, an Electronic Version of the Symbol Digit Modalities Test, JOURNAL OF MEDICAL INTERNET RESEARCH, Vol: 22, ISSN: 1438-8871
Cencioni MT, Ali R, Nicholas R, et al., 2020, Defective CD19+CD24(hi)CD38(hi)transitional B-cell function in patients with relapsing-remitting MS, MULTIPLE SCLEROSIS JOURNAL, Vol: 27, Pages: 1187-1197, ISSN: 1352-4585
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- Citations: 2
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, Vol: 30, Pages: 779-793, 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.
Dixon L, Varley J, Gontsarova A, et al., 2020, COVID-19 related acute necrotizing encephalopathy of the brainstem in a patient with aplastic anemia, Neurology, Neuroimmunology and Neuroinflammation, Vol: 7, Pages: 1-8, ISSN: 2332-7812
Objective To describe a novel case of COVID-19 associated acute necrotizing encephalopathy in a patient with aplastic anemia where there was early brainstem predominant involvement. Methods Evaluation of cause, clinical symptoms, and treatment response.Results A 59-year-old woman with a background of transfusion-dependent aplastic anemia, presented with seizures and reduced level of consciousness, 10 days following the onset of subjective fevers, cough, and headache. Nasopharyngeal swab testing for SARS-CoV-2 was positive and admission CT demonstrated diffuse swelling of the brainstem. She required intubation and mechanical ventilation for airway protection, given her reduced level of consciousness. The patient’s condition deteriorated and MRI on day 6 demonstrated worsening brainstem swelling with symmetrical hemorrhagic lesions in the brainstem, amygdalae, putamina and thalamic nuclei. Appearances were consistent with hemorrhagic acute necrotizing encephalopathy with early brainstem involvement. The patient showed no response to steroid therapy and died on the eighth day of admission.Conclusions COVID-19 may be associated with an acute severe encephalopathy and, in this case, was considered most likely to represent an immune-mediated phenomenon. As the pandemic continues, we anticipate that the spectrum of neurological presentation will broaden. It will be important to delineate the full clinical range of emergent COVID-19 related neurological disease.
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, Vol: 47, Pages: 2242-2243, ISSN: 1619-7070
Cole JH, Raffel J, Friede T, et al., 2020, Longitudinal Assessment of Multiple Sclerosis with the Brain-Age Paradigm, ANNALS OF NEUROLOGY, Vol: 88, Pages: 93-105, ISSN: 0364-5134
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- Citations: 11
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, MULTIPLE SCLEROSIS JOURNAL-EXPERIMENTAL TRANSLATIONAL AND CLINICAL, Vol: 6
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.
Magliozzi R, Hametner S, Facchiano F, et al., 2019, Iron homeostasis, complement, and coagulation cascade as CSF signature of cortical lesions in early multiple sclerosis, Annals of Clinical and Translational Neurology, Vol: 6, Pages: 2150-2163, ISSN: 2328-9503
ObjectiveIntrathecal inflammation, compartmentalized in cerebrospinal fluid (CSF) and in meningeal infiltrates, has fundamental role in inflammation, demyelination, and neuronal injury in cerebral cortex in multiple sclerosis (MS). Since the exact link between intrathecal inflammation and mechanisms of cortical pathology remains unknown, we aimed to investigate a detailed proteomic CSF profiling which is able to reflect cortical damage in early MS.MethodsWe combined new proteomic method, TRIDENT, CSF analysis, and advanced 3T magnetic resonance imaging (MRI), in 64 MS patients at the time of diagnosis and 26 controls with other neurological disorders. MS patients were stratified according to cortical lesion (CL) load.ResultsWe identified 227 proteins differently expressed between the patients with high and low CL load. These were mainly related to complement and coagulation cascade as well as to iron homeostasis pathway (30 and 6% of all identified proteins, respectively). Accordingly, in the CSF of MS patients with high CL load at diagnosis, significantly higher levels of sCD163 (P < 0.0001), free hemoglobin (Hb) (P < 0.05), haptoglobin (P < 0.0001), and fibrinogen (P < 0.01) were detected. By contrast, CSF levels of sCD14 were significantly (P < 0.05) higher in MS patients with low CL load. Furthermore, CSF levels of sCD163 positively correlated (P < 0.01) with CSF levels of neurofilament, fibrinogen, and B cell‐related molecules, such as CXCL13, CXCL12, IL10, and BAFF.InterpretationIntrathecal dysregulation of iron homeostasis and coagulation pathway as well as B‐cell and monocyte activity are strictly correlated with cortical damage at early disease stages.
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
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- Citations: 1
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
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
Cole J, Raffel J, Friede T, et al., 2019, Accelerated brain ageing and disability in 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: 721-722, ISSN: 1352-4585
Sovetkina A, Scalfari A, Tona F, et al., 2019, Development of auto-immune thyroid dysfunction in Alemtuzumab treated multiple sclerosis patients is associated with better clinical outcome, 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: 917-917, 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
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