Publications
385 results found
Samjoo IA, Worthington E, Haltner A, et al., 2020, The importance of considering differences in study and patient characteristics before undertaking indirect treatment comparisons: a case study of siponimod for secondary progressive multiple sclerosis, CURRENT MEDICAL RESEARCH AND OPINION, Vol: 36, Pages: 1145-1156, ISSN: 0300-7995
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- Citations: 6
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: 46
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.
Papadopoulos D, Magliozzi R, Mitsikostas DD, et al., 2020, Aging, cellular Senescence, and progressive multiple sclerosis, Frontiers in Cellular Neuroscience, Vol: 14, ISSN: 1662-5102
Aging is one of the most important risk factors for the development of several neurodegenerative diseases including progressive multiple sclerosis (MS). Cellular senescence (CS) is a key biological process underlying aging. Several stressors associated with aging and MS pathology, such as oxidative stress, mitochondrial dysfunction, cytokines and replicative exhaustion are known triggers of cellular senescence. Senescent cells exhibit stereotypical metabolic and functional changes, which include cell-cycle arrest and acquiring a pro-inflammatory phenotype secreting cytokines, growth factors, metalloproteinases and reactive oxygen species. They accumulate with aging and can convert neighboring cells to senescence in a paracrine manner. In MS, accelerated cellular senescence may drive disease progression by promoting chronic non-remitting inflammation, loss or altered immune, glial and neuronal function, failure of remyelination, impaired blood-brain barrier integrity and ultimately neurodegeneration. Here we discuss the evidence linking cellular senescence to the pathogenesis of MS and the putative role of senolytic and senomorphic agents as neuroprotective therapies in tackling disease progression.
Kolanko M, Win Z, Patel N, et al., 2020, Using Amyloid PET imaging to diagnose Alzheimer’s disease in patients with Multiple Sclerosis, Journal of Neurology, Vol: 267, Pages: 3268-3273, ISSN: 0340-5354
BackgroundCognitive dysfunction affects 40–60% of individuals with multiple sclerosis (MS). The neuropsychological profile commonly consists of a subcortical pattern of deficits, although a proportion of patients have a severe progressive cortical dementia. However, patients with MS can be affected by other neurodegenerative diseases, such as Alzheimer’s disease (AD). Little is known about the co-existence of these two conditions but distinguishing dementia due to MS alone from a coexisting neurodegenerative disease is challenging. Amyloid PET imaging has allowed improved AD diagnosis, especially in patients with atypical presentations or multiple possible causes of cognitive impairment. Amyloid PET demonstrates increased cortical signal in AD, whereas reductions in subcortical uptake are associated with demyelination. To the authors knowledge, there are no reports of clinical Amyloid PET use in MS patients with dementia.MethodsHere, three MS patients presenting to the Cognitive Neurology Clinic with progressive cognitive impairment are described. Due to lack of diagnostic clarity from standard investigations, they underwent Amyloid PET Imaging with 18F-florbetapir according to established appropriate use criteria and after review by a multidisciplinary team.ResultsTwo patients were diagnosed with AD based on positive Amyloid PET imaging and were subsequently started on cholinesterase inhibitor treatment. The other patient had a negative scan, leading to further investigations and identification of another potential cause of worsening cognitive impairment.ConclusionsThe experience from this case series suggests that Amyloid PET Imaging may be of diagnostic value in selected patients with MS and dementia. In these individuals, it may provide diagnostic clarity and assist with therapeutic decisions.
Marastoni D, Bar-Or A, Fadda G, et al., 2020, A substantial 'ependymal-in' gradient of thalamic damage in progressive multiple sclerosis, 6th Congress of the European-Academy-of-Neurology (EAN), Publisher: WILEY, Pages: 345-345, ISSN: 1351-5101
Middleton R, Pearson O, Ingram G, et al., 2020, The MSiDMT- a tablet based cognitive assessment tool for MS patients, Annual Meeting of the American-Academy-of-Neurology, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0028-3878
Forsberg L, Stahmann A, Middleton R, et al., 2020, Comparison of the proportions of Secondary Progressive Multiple Sclerosis between three registries within the SPMS Research Collaboration Network, Annual Meeting of the American-Academy-of-Neurology, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0028-3878
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- Citations: 1
Kondratiuk A, Muraro P, Johnson M, et al., 2020, The Use of Rituximab in Neurological Diseases; Real World Data from a Neuroscience Centre, Annual Meeting of the American-Academy-of-Neurology, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0028-3878
Nicholas R, Bandiera S, Reynolds R, et al., 2020, Demyelinated White Matter Exhibits Upregulated DNA Damage Response and Cellular Senescence in Progressive Multiple Sclerosis, Annual Meeting of the American-Academy-of-Neurology, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0028-3878
Chataway J, De Angelis F, Connick P, et al., 2020, Efficacy of three neuroprotective drugs in secondary progressive multiple sclerosis (MS-SMART): a phase 2b, multiarm, double-blind, randomised placebo-controlled trial, LANCET NEUROLOGY, Vol: 19, Pages: 214-225, ISSN: 1474-4422
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- Citations: 65
Nicholas R, Brooks D, Owen D, 2020, Letter to the Editor re: Confirmation of Specific Binding of the 18-kDa Translocator Protein (TSPO) Radioligand [<SUP>18</SUP>F]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: 3
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
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- Citations: 7
Dixon L, Varley J, Gontsarova A, et al., 2020, COVID-19-related acute necrotizing encephalopathy with brain stem involvement in a patient with aplastic anemia, Neurology-Neuroimmunology Neuroinflammation, Vol: 7
Magliozzi R, Howell OW, Durrenberger P, et al., 2019, Meningeal inflammation changes the balance of TNF signalling in cortical grey matter in multiple sclerosis, Journal of Neuroinflammation, Vol: 16, Pages: 1-16, ISSN: 1742-2094
BackgroundRecent studies of cortical pathology in secondary progressive multiple sclerosis have shown that a more severe clinical course and the presence of extended subpial grey matter lesions with significant neuronal/glial loss and microglial activation are associated with meningeal inflammation, including the presence of lymphoid-like structures in the subarachnoid space in a proportion of cases.MethodsTo investigate the molecular consequences of pro-inflammatory and cytotoxic molecules diffusing from the meninges into the underlying grey matter, we carried out gene expression profiling analysis of the motor cortex from 20 post-mortem multiple sclerosis brains with and without substantial meningeal inflammation and 10 non-neurological controls.ResultsGene expression profiling of grey matter lesions and normal appearing grey matter not only confirmed the substantial pathological cell changes, which were greatest in multiple sclerosis cases with increased meningeal inflammation, but also demonstrated the upregulation of multiple genes/pathways associated with the inflammatory response. In particular, genes involved in tumour necrosis factor (TNF) signalling were significantly deregulated in MS cases compared with controls. Increased meningeal inflammation was found to be associated with a shift in the balance of TNF signalling away from TNFR1/TNFR2 and NFkB-mediated anti-apoptotic pathways towards TNFR1- and RIPK3-mediated pro-apoptotic/pro-necroptotic signalling in the grey matter, which was confirmed by RT-PCR analysis. TNFR1 was found expressed preferentially on neurons and oligodendrocytes in MS cortical grey matter, whereas TNFR2 was predominantly expressed by astrocytes and microglia.ConclusionsWe suggest that the inflammatory milieu generated in the subarachnoid space of the multiple sclerosis meninges by infiltrating immune cells leads to increased demyelinating and neurodegenerative pathology in the underlying grey matter due to changes in the balance of
Tilley BS, Romozzi M, Hession CM, et al., 2019, GAIT SYMPTOMS CORRELATE WITH COGNITIVE PROBLEMS IN PARKINSON'S, Annual Meeting of the Association-of-British-Neurologists (ABN), Publisher: BMJ PUBLISHING GROUP, Pages: E21-E21, ISSN: 0022-3050
Middleton R, Allen-Philbey K, Schmierer K, et al., 2019, A MODEL FOR PARTICIPANT ENGAGEMENT IN RESEARCH: THE MS REGISTER, Annual Meeting of the Association-of-British-Neurologists (ABN), Publisher: BMJ PUBLISHING GROUP, Pages: E55-E55, ISSN: 0022-3050
Tilley BS, Romozzi M, Hession CM, et al., 2019, GAIT SYMPTOMS CORRELATE WITH COGNITIVE PROBLEMS IN PARKINSON'S, Annual Meeting of the Association-of-British-Neurologists (ABN), Publisher: BMJ PUBLISHING GROUP, Pages: E19-E20, ISSN: 0022-3050
Dorsey R, Williams T, Singh-Curry V, et al., 2019, MANAGING RITUXIMAB DELIVERY IN A NEUROSCIENCES CENTRE, Annual Meeting of the Association-of-British-Neurologists (ABN), Publisher: BMJ PUBLISHING GROUP, Pages: E28-E28, ISSN: 0022-3050
Marastoni D, Lai-Cheong J, Magliozzi R, et al., 2019, SCLEROSING DERMOPATHY AFTER ALEMTUZUMAB FOR MULTIPLE SCLEROSIS, Annual Meeting of the Association-of-British-Neurologists (ABN), Publisher: BMJ PUBLISHING GROUP, Pages: E55-E55, ISSN: 0022-3050
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.
Vermersch P, Eralinna JP, Nicholas R, et al., 2019, Efficacy and safety of ocrelizumab in patients with relapsing-remitting multiple sclerosis with a suboptimal response to previous disease-modifying therapies (1-year interim results), World Congress of Neurology (WCN), Publisher: ELSEVIER, ISSN: 0022-510X
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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
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: 3
Rigoni E, Singh-Curry V, Nandoskar A, et al., 2019, Alemtuzumab as induction versus escalation therapy: efficacy and adverse events in the real-world, 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: 773-773, 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
Marastoni D, Magliozzi R, Howell O, et al., 2019, High levels of perivascular inflammation and active white matter lesions at time of death are associated with rapidly progressive 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: 76-77, ISSN: 1352-4585
Glaser A, Trojano M, Laffaldano P, et al., 2019, Opportunities and challenges for conducting research on secondary progressive multiple sclerosis across international multiple sclerosis registries through a research network collaboration, 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: 152-153, ISSN: 1352-4585
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