Publications
186 results found
Farina G, Magliozzi R, Pitteri M, et al., 2017, Increased cortical lesion load and intrathecal inflammation is associated with oligoclonal bands in multiple sclerosis patients: a combined CSF and MRI study, JOURNAL OF NEUROINFLAMMATION, Vol: 14, ISSN: 1742-2094
Background:Although IgG oligoclonal bands (OCBs) in the cerebrospinal fluid (CSF) are a frequent phenomenon in multiple sclerosis (MS) patients, their relationship with grey matter lesions, intrathecal/meningeal inflammation and clinical evolution has not been clarified yet.The aim of our study was to assess the relationship between the OCBs, the inflammatory/neurodegenerative CSF profile at diagnosis, the cortical lesion load and the clinical evolution after 10 years.Methods:This is a 10-year observational, cross-sectional study based on a combined MRI, cognitive and CSF profiling of the examined patients.Forty consecutive OCB-negative (OCB−) and 50 OCB-positive (OCB+) MS patients were included in this study. Both groups had mean disease duration of 10 years and were age and gender matched. Each patient underwent neurological and neuropsychological evaluation and 3-T MRI. Analysis of the presence and levels of 28 inflammatory mediators was performed in the CSF obtained from 10 OCB− MS, 11 OCB+ MS and 10 patients with other neurological conditions.Results:Increased number of CLs was found in OCB+ compared to OCB− patients (p < 0.0001), whereas no difference was found in white matter lesion (WML) load (p = 0.36). The occurrence of OCB was also associated with increased levels of neurofilament light chains and of several inflammatory mediators linked to B lymphocyte activity and lymphoid-neogenesis (CXCL13, CXCL12, CXCL10, TNFSF13, TNFSF13B, IL6, IL10) and other pro-inflammatory molecules, such as IFN-γ, TNF, MMP2, GM-CSF, osteopontin and sCD163. Finally, the occurrence of OCB was found associated with poor prognosis, from both physical and cognitive points of view.Conclusions:OCB at MS onset are associated with more severe GM pathology and with a more severe physical disability and cognitive impairment after 10 years. Increased levels of cytokines linked to B cell activation, lymphoid-neogenesis, and pro-inflamma
Watkins LM, Neal JW, Loveless S, et al., 2016, Complement is activated in progressive multiple sclerosis cortical grey matter lesions., Journal of Neuroinflammation, Vol: 13, ISSN: 1742-2094
BACKGROUND: The symptoms of multiple sclerosis (MS) are caused by damage to myelin and nerve cells in the brain and spinal cord. Inflammation is tightly linked with neurodegeneration, and it is the accumulation of neurodegeneration that underlies increasing neurological disability in progressive MS. Determining pathological mechanisms at play in MS grey matter is therefore a key to our understanding of disease progression. METHODS: We analysed complement expression and activation by immunocytochemistry and in situ hybridisation in frozen or formalin-fixed paraffin-embedded post-mortem tissue blocks from 22 progressive MS cases and made comparisons to inflammatory central nervous system disease and non-neurological disease controls. RESULTS: Expression of the transcript for C1qA was noted in neurons and the activation fragment and opsonin C3b-labelled neurons and glia in the MS cortical and deep grey matter. The density of immunostained cells positive for the classical complement pathway protein C1q and the alternative complement pathway activation fragment Bb was significantly increased in cortical grey matter lesions in comparison to control grey matter. The number of cells immunostained for the membrane attack complex was elevated in cortical lesions, indicating complement activation to completion. The numbers of classical (C1-inhibitor) and alternative (factor H) pathway regulator-positive cells were unchanged between MS and controls, whilst complement anaphylatoxin receptor-bearing microglia in the MS cortex were found closely apposed to cortical neurons. Complement immunopositive neurons displayed an altered nuclear morphology, indicative of cell stress/damage, supporting our finding of significant neurodegeneration in cortical grey matter lesions. CONCLUSIONS: Complement is activated in the MS cortical grey matter lesions in areas of elevated numbers of complement receptor-positive microglia and suggests that complement over-activation may contribute to the wo
Calabrese M, Castellaro M, Bertoldo A, et al., 2016, Epilepsy in multiple sclerosis: The role of temporal lobe damage., Multiple Sclerosis Journal, ISSN: 1477-0970
BACKGROUND: Although temporal lobe pathology may explain some of the symptoms of multiple sclerosis (MS), its role in the pathogenesis of seizures has not been clarified yet. OBJECTIVES: To investigate the role of temporal lobe damage in MS patients suffering from epilepsy, by the application of advanced multimodal 3T magnetic resonance imaging (MRI) analysis. METHODS: A total of 23 relapsing remitting MS patients who had epileptic seizures (RRMS/E) and 23 disease duration matched RRMS patients without any history of seizures were enrolled. Each patient underwent advanced 3T MRI protocol specifically conceived to evaluate grey matter (GM) damage. This includes grey matter lesions (GMLs) identification, evaluation of regional cortical thickness and indices derived from the Neurite Orientation Dispersion and Density Imaging model. RESULTS: Regional analysis revealed that in RRMS/E, the regions most affected by GMLs were the hippocampus (14.2%), the lateral temporal lobe (13.5%), the cingulate (10.0%) and the insula (8.4%). Cortical thinning and alteration of diffusion metrics were observed in several regions of temporal lobe, in insular cortex and in cingulate gyrus of RRMS/E compared to RRMS (p< 0.05 for all comparisons). CONCLUSIONS: Compared to RRMS, RRMS/E showed more severe damage of temporal lobe, which exceeds what would be expected on the basis of the global GM damage observed.
Matthews PM, Roncaroli F, Waldman A, et al., 2016, A practical review of the neuropathology and neuroimaging of multiple sclerosis, Practical Neurology, Vol: 16, Pages: 279-287, ISSN: 1474-7766
The variability in the severity and clinical course of multiple sclerosis (MS) has as its basis an extreme heterogeneity in the location, nature and extent of pathology in the brain and spinal cord. Understanding the underlying neuropathology and associated pathogenetic mechanisms of the disease helps to communicate the rationale for treatment and disease monitoring to patients. Neuroimaging is an important tool for this: it allows clinicians to relate neuropathological changes to clinical presentations and to monitor the course of their disease. Here, we review MS neuropathology and its imaging correlates to provide a practical guide for using MRI to assess disease severity and treatment responses. This provides a foundation for optimal management of patients based on the principle that they show 'no evidence of disease activity'.
Nicholas R, Magliozzi R, Campbell G, et al., 2016, Temporal lobe cortical pathology and inhibitory GABA interneuron cell loss are associated with seizures in multiple sclerosis, Multiple Sclerosis Journal, Vol: 22, Pages: 25-35, ISSN: 1477-0970
Background: Seizures are recognised in multiple sclerosis (MS), but their true incidence and the mechanismby which they are associated with MS is unclear.Objective: The objective of this paper is to determine the lifetime frequency of seizures in the UnitedKingdom MS Tissue Bank (UKMSTB) population and any pathological features associated with seizures.Methods: We evaluated 255 individuals from the UKMSTB. A subset underwent analysis of corticalthickness, grey matter lesion (GML) (type and number) and cortical neuronal numbers (total and GABAergic).Results: A total of 37/255 patients had seizures (14.5% lifetime incidence); in 47% they were associatedwith concurrent infection. In those with seizures, death and wheelchair use occurred earlier and in 59%seizures developed after 15 years of disease. Seizures were associated with Type 1 GMLs and reducedcortical thickness in the middle temporal gyrus. Localised selective GABAergic interneuron loss in layersIV and VI was related to GMLs but was not explained by the presence of inflammation or by mitochondrial dysfunction within Type I GMLs. Conclusion: We confirm that seizure frequency rises in MS. Type I GMLs in the temporal lobe underlie a loss of inhibitory interneurons in cortical layers IV and VI and these changes could together with concurrent infection enhance susceptibility to seizures.
Sellebjerg F, Cadavid D, Steiner D, et al., 2015, Exploring potential mechanisms of action of natalizumab in secondary progressive multiple sclerosis, Therapeutic Advances in Neurological Disorders, Vol: 9, Pages: 31-43, ISSN: 1756-2864
Multiple sclerosis (MS) is a common and chronic central nervous system (CNS) demyelinating disease and a leading cause of permanent disability. Patients most often present with a relapsing–remitting disease course, typically progressing over time to a phase of relentless advancement in secondary progressive MS (SPMS), for which approved disease-modifying therapies are limited. In this review, we summarize the pathophysiological mechanisms involved in the development of SPMS and the rationale and clinical potential for natalizumab, which is currently approved for the treatment of relapsing forms of MS, to exert beneficial effects in reducing disease progression unrelated to relapses in SPMS. In both forms of MS, active brain-tissue injury is associated with inflammation; but in SPMS, the inflammatory response occurs at least partly behind the blood–brain barrier and is followed by a cascade of events, including persistent microglial activation that may lead to chronic demyelination and neurodegeneration associated with irreversible disability. In patients with relapsing forms of MS, natalizumab therapy is known to significantly reduce intrathecal inflammatory responses which results in reductions in brain lesions and brain atrophy as well as beneficial effects on clinical measures, such as reduced frequency and severity of relapse and reduced accumulation of disability. Natalizumab treatment also reduces levels of cerebrospinal fluid chemokines and other biomarkers of intrathecal inflammation, axonal damage and demyelination, and has demonstrated the ability to reduce innate immune activation and intrathecal immunoglobulin synthesis in patients with MS. The efficacy of natalizumab therapy in SPMS is currently being investigated in a randomized, double-blind, placebo-controlled trial.
Gautier HOB, Evans KA, Volbracht K, et al., 2015, Neuronal activity regulates remyelination via glutamate signalling to oligodendrocyte progenitors, Nature Communications, Vol: 6, ISSN: 2041-1723
Myelin regeneration can occur spontaneously in demyelinating diseases such as multiple sclerosis (MS). However, the underlying mechanisms and causes of its frequent failure remain incompletely understood. Here we show, using an in-vivo remyelination model, that demyelinated axons are electrically active and generate de novo synapses with recruited oligodendrocyte progenitor cells (OPCs), which, early after lesion induction, sense neuronal activity by expressing AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)/kainate receptors. Blocking neuronal activity, axonal vesicular release or AMPA receptors in demyelinated lesions results in reduced remyelination. In the absence of neuronal activity there is a ~6-fold increase in OPC number within the lesions and a reduced proportion of differentiated oligodendrocytes. These findings reveal that neuronal activity and release of glutamate instruct OPCs to differentiate into new myelinating oligodendrocytes that recover lost function. Co-localization of OPCs with the presynaptic protein VGluT2 in MS lesions implies that this mechanism may provide novel targets to therapeutically enhance remyelination.
Calabrese M, Reynolds R, Magliozzi R, et al., 2015, Regional distribution and evolution of gray matter damage in different populations of multiple sclerosis patients, PLOS One, Vol: 10, ISSN: 1932-6203
BackgroundBoth gray-matter (GM) atrophy and lesions occur from the earliest stages of Multiple Sclerosis (MS) and are one of the major determinants of long-term clinical outcomes. Nevertheless, the relationship between focal and diffuse GM damage has not been clarified yet. Here we investigate the regional distribution and temporal evolution of cortical thinning and how it is influenced by the local appearance of new GM lesions at different stages of the disease in different populations of MS patients.MethodsWe studied twenty MS patients with clinically isolated syndrome (CIS), 27 with early relapsing-remitting MS (RRMS, disease duration <5 years), 29 with late RRMS (disease duration ≥ 5 years) and 20 with secondary-progressive MS (SPMS). The distribution and evolution of regional cortical thickness and GM lesions were assessed during 5-year follow-up.ResultsThe results showed that new lesions appeared more frequently in hippocampus and parahippocampal gyri (9.1%), insula (8.9%), cingulate cortex (8.3%), superior frontal gyrus (8.1%), and cerebellum (6.5%). The aforementioned regions showed the greatest reduction in thickness/volume, although (several) differences were observed across subgroups. The correlation between the appearance of new cortical lesions and cortical thinning was stronger in CIS (r2 = 50.0, p<0.001) and in early RRMS (r2 = 52.3, p<0.001), compared to late RRMS (r2 = 25.5, p<0.001) and SPMS (r2 = 6.3, p = 0.133).ConclusionsWe conclude that GM atrophy and lesions appear to be different signatures of cortical disease in MS having in common overlapping spatio-temporal distribution patterns. However, the correlation between focal and diffuse damage is only moderate and more evident in the early phase of the disease.
Durrenberger PF, Fernando FS, Kashefi SN, et al., 2015, Common mechanisms in neurodegeneration and neuroinflammation: a BrainNet Europe gene expression microarray study, JOURNAL OF NEURAL TRANSMISSION, Vol: 122, Pages: 1055-1068, ISSN: 0300-9564
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- Citations: 88
Calabrese M, Magliozzi R, Ciccarelli O, et al., 2015, Exploring the origins of grey matter damage in multiple sclerosis, NATURE REVIEWS NEUROSCIENCE, Vol: 16, Pages: 147-158, ISSN: 1471-003X
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- Citations: 267
Zhang A, Desmazieres A, Zonta B, et al., 2015, Neurofascin 140 is an embryonic neuronal neurofascin isoform that promotes the assembly of the node of ranvier, Journal of Neuroscience, Vol: 35, Pages: 2246-2254, ISSN: 1529-2401
Rapid nerve conduction in myelinated nerves requires the clustering of voltage-gated sodium channels at nodes of Ranvier. The Neurofascin (Nfasc) gene has a unique role in node formation because it encodes glial and neuronal isoforms of neurofascin (Nfasc155 and Nfasc186, respectively) with key functions in assembling the nodal macromolecular complex. A third neurofascin, Nfasc140, has also been described; however, neither the cellular origin nor function of this isoform was known. Here we show that Nfasc140 is a neuronal protein strongly expressed during mouse embryonic development. Expression of Nfasc140 persists but declines during the initial stages of node formation, in contrast to Nfasc155 and Nfasc186, which increase. Nevertheless, Nfasc140, like Nfasc186, can cluster voltage-gated sodium channels (Nav) at the developing node of Ranvier and can restore electrophysiological function independently of Nfasc155 and Nfasc186. This suggests that Nfasc140 complements the function of Nfasc155 and Nfasc186 in initial stages of the assembly and stabilization of the nodal complex. Further, Nfasc140 is reexpressed in demyelinated white matter lesions of postmortem brain tissue from human subjects with multiple sclerosis. This expands the critical role of the Nfasc gene in the function of myelinated axons and reveals further redundancy in the mechanisms required for the formation of this crucial structure in the vertebrate nervous system.
Giannetti P, Politis M, Su P, et al., 2014, Increased PK11195-PET binding in normal-appearing white matter in clinically isolated syndrome, Brain, Vol: 138, Pages: 110-119, ISSN: 0006-8950
Lieury A, Chanal M, Androdias G, et al., 2014, Tissue Remodeling in Periplaque Regions of Multiple Sclerosis Spinal Cord Lesions, GLIA, Vol: 62, Pages: 1645-1658, ISSN: 0894-1491
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- Citations: 34
Markoullis K, Sargiannidou I, Schiza N, et al., 2014, Oligodendrocyte Gap Junction Loss and Disconnection From Reactive Astrocytes in Multiple Sclerosis Gray Matter, JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY, Vol: 73, Pages: 865-879, ISSN: 0022-3069
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- Citations: 44
Sellmann C, Pildain LV, Schmitt A, et al., 2014, Gene expression in superior temporal cortex of schizophrenia patients, EUROPEAN ARCHIVES OF PSYCHIATRY AND CLINICAL NEUROSCIENCE, Vol: 264, Pages: 297-309, ISSN: 0940-1334
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- Citations: 14
Schirmer L, Srivastava R, Kalluri SR, et al., 2014, Differential Loss of KIR4.1 Immunoreactivity in Multiple Sclerosis Lesions, ANNALS OF NEUROLOGY, Vol: 75, Pages: 810-828, ISSN: 0364-5134
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- Citations: 38
Giannetti P, Politis M, Su P, et al., 2014, Microglia activation in multiple sclerosis black holes predicts outcome in progressive patients: An in vivo [(11)C](R)-PK11195-PET pilot study, NEUROBIOLOGY OF DISEASE, Vol: 65, Pages: 203-210, ISSN: 0969-9961
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- Citations: 61
Campbell GR, Reeve AK, Ziabreva I, et al., 2013, No excess of mitochondrial DNA deletions within muscle in progressive multiple sclerosis, MULTIPLE SCLEROSIS JOURNAL, Vol: 19, Pages: 1858-1866, ISSN: 1352-4585
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- Citations: 10
Kalk NJ, Owen DR, Tyacke RJ, et al., 2013, Are Prescribed Benzodiazepines Likely to Affect the Availability of the 18 kDa Translocator Protein (TSPO) in PET Studies?, SYNAPSE, Vol: 67, Pages: 909-912, ISSN: 0887-4476
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- Citations: 16
Gardner C, Magliozzi R, Durrenberger PF, et al., 2013, Cortical grey matter demyelination can be induced by elevated pro-inflammatory cytokines in the subarachnoid space of MOG-immunized rats, Brain
Abrahamsson SV, Angelini DF, Dubinsky AN, et al., 2013, Non-myeloablative autologous haematopoietic stem cell transplantation expands regulatory cells and depletes IL-17 producing mucosal-associated invariant T cells in multiple sclerosis., Brain
Mathew A, Pakan JMP, Collin EC, et al., 2013, An <i>ex</i>-<i>vivo</i> multiple sclerosis model of inflammatory demyelination using hyperbranched polymer, BIOMATERIALS, Vol: 34, Pages: 5872-5882, ISSN: 0142-9612
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- Citations: 3
Campbell GR, Reeve A, Ziabreva I, et al., 2013, Mitochondrial DNA deletions and depletion within paraspinal muscles, NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY, Vol: 39, Pages: 377-389, ISSN: 0305-1846
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- Citations: 17
Mechelli R, Umeton R, Policano C, et al., 2013, A "Candidate-Interactome" Aggregate Analysis of Genome-Wide Association Data in Multiple Sclerosis, PLOS ONE, Vol: 8, ISSN: 1932-6203
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- Citations: 31
Magliozzi R, Serafini B, Rosicarelli B, et al., 2013, B-Cell Enrichment and Epstein-Barr Virus Infection in Inflammatory Cortical Lesions in Secondary Progressive Multiple Sclerosis, JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY, Vol: 72, Pages: 29-41, ISSN: 0022-3069
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- Citations: 85
Fhlathartaigh MN, McMahon J, Reynolds R, et al., 2013, Calreticulin and other components of endoplasmic reticulum stress in rat and human inflammatory demyelination, ACTA NEUROPATHOLOGICA COMMUNICATIONS, Vol: 1, ISSN: 2051-5960
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- Citations: 40
Durrenberger PF, Fernando FS, Magliozzi R, et al., 2012, Selection of novel reference genes for use in the human central nervous system: a BrainNet Europe Study, ACTA NEUROPATHOLOGICA, Vol: 124, Pages: 893-903, ISSN: 0001-6322
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- Citations: 92
McMahon JM, McQuaid S, Reynolds R, et al., 2012, Increased expression of ER stress- and hypoxia-associated molecules in grey matter lesions in multiple sclerosis, MULTIPLE SCLEROSIS JOURNAL, Vol: 18, Pages: 1437-1447, ISSN: 1352-4585
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- Citations: 40
Schmitt A, Leonardi-Essmann F, Durrenberger PF, et al., 2012, Structural synaptic elements are differentially regulated in superior temporal cortex of schizophrenia patients, EUROPEAN ARCHIVES OF PSYCHIATRY AND CLINICAL NEUROSCIENCE, Vol: 262, Pages: 565-577, ISSN: 0940-1334
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- Citations: 26
Choi SR, Howell OW, Carassiti D, et al., 2012, Meningeal inflammation plays a role in the pathology of primary progressive multiple sclerosis, BRAIN, Vol: 135, Pages: 2925-2937, ISSN: 0006-8950
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- Citations: 253
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