149 results found
Magliozzi R, Montibiller L, Marastoni D, et al., 2019, Cerebrospinal fluid levels of parvalbumin predict cortical demyelination and atrophy 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: 672-672, ISSN: 1352-4585
Calabrese M, Pisani A, Ziccardi S, et al., 2019, Intrathecal inflammatory profile predicts disease course in multiple sclerosis: a 4-year longitudinal study, 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: 274-274, ISSN: 1352-4585
Poli A, Marastoni D, Nicholas R, et al., 2019, The extent and distribution of fibrinogen deposition in progressive MS correlate with meningeal and choroid plexus inflammation, 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: 10-11, ISSN: 1352-4585
Frisch T, Elkjaer ML, Reynolds R, et al., 2019, The MS Atlas - A molecular map of brain lesion stages in secondary progressive MS, 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: 379-380, ISSN: 1352-4585
Elkjaer ML, Frisch T, Reynolds R, et al., 2019, Molecular signatures of different lesions types in the white matter of SPMS, 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: 76-76, ISSN: 1352-4585
Schirmer L, Velmeshev D, Holmqvist S, et al., 2019, Single-cell genomics reveals neuron subtype vulnerability 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: 673-673, ISSN: 1352-4585
Howell O, Magliozzi R, Calabrese M, et al., 2019, The spectrum of cortical pathology in the MS brain: when, where and why?, 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: 115-115, 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
Smith AM, Khozoie C, Fancy N, et al., 2019, Single nucleus RNA sequencing of post-mortem multiple sclerosis cortical grey matter, 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: 233-233, ISSN: 1352-4585
Van Horssen J, Witte M, Reynolds R, 2019, Potential biological mechanisms behind MS progression, 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: 74-74, ISSN: 1352-4585
Schirmer L, Velmeshev D, Holmqvist S, et al., 2019, Neuronal vulnerability and multilineage diversity in multiple sclerosis, Nature, Vol: 573, Pages: 75-82, ISSN: 0028-0836
Multiple sclerosis (MS) is a neuroinflammatory disease with a relapsing–remitting disease course at early stages, distinct lesion characteristics in cortical grey versus subcortical white matter and neurodegeneration at chronic stages. Here we used single-nucleus RNA sequencing to assess changes in expression in multiple cell lineages in MS lesions and validated the results using multiplex in situ hybridization. We found selective vulnerability and loss of excitatory CUX2-expressing projection neurons in upper-cortical layers underlying meningeal inflammation; such MS neuron populations exhibited upregulation of stress pathway genes and long non-coding RNAs. Signatures of stressed oligodendrocytes, reactive astrocytes and activated microglia mapped most strongly to the rim of MS plaques. Notably, single-nucleus RNA sequencing identified phagocytosing microglia and/or macrophages by their ingestion and perinuclear import of myelin transcripts, confirmed by functional mouse and human culture assays. Our findings indicate lineage- and region-specific transcriptomic changes associated with selective cortical neuron damage and glial activation contributing to progression of MS lesions.
Bartoletti-Stella A, Corrado P, Mometto N, et al., 2019, Analysis of RNA Expression Profiles Identifies Dysregulated Vesicle Trafficking Pathways in Creutzfeldt-Jakob Disease, MOLECULAR NEUROBIOLOGY, Vol: 56, Pages: 5009-5024, ISSN: 0893-7648
Elkjaer ML, Frisch T, Reynolds R, et al., 2019, Unique RNA signature of different lesion types in the brain white matter in progressive multiple sclerosis, Acta Neuropathologica Communications, Vol: 7, ISSN: 2051-5960
The heterogeneity of multiple sclerosis is reflected by dynamic changes of different lesion types in the brain white matter (WM). To identify potential drivers of this process, we RNA-sequenced 73 WM areas from patients with progressive MS (PMS) and 25 control WM. Lesion endophenotypes were described by a computational systems medicine analysis combined with RNAscope, immunohistochemistry, and immunofluorescence. The signature of the normal-appearing WM (NAWM) was more similar to control WM than to lesions: one of the six upregulated genes in NAWM was CD26/DPP4 expressed by microglia. Chronic active lesions that become prominent in PMS had a signature that were different from all other lesion types, and were differentiated from them by two clusters of 62 differentially expressed genes (DEGs). An upcoming MS biomarker, CHI3L1 was among the top ten upregulated genes in chronic active lesions expressed by astrocytes in the rim. TGFβ-R2 was the central hub in a remyelination-related protein interaction network, and was expressed there by astrocytes. We used de novo networks enriched by unique DEGs to determine lesion-specific pathway regulation, i.e. cellular trafficking and activation in active lesions; healing and immune responses in remyelinating lesions characterized by the most heterogeneous immunoglobulin gene expression; coagulation and ion balance in inactive lesions; and metabolic changes in chronic active lesions. Because we found inverse differential regulation of particular genes among different lesion types, our data emphasize that omics related to MS lesions should be interpreted in the context of lesion pathology. Our data indicate that the impact of molecular pathways is substantially changing as different lesions develop. This was also reflected by the high number of unique DEGs that were more common than shared signatures. A special microglia subset characterized by CD26 may play a role in early lesion development, while astrocyte-derived TGF&beta
Bevan RJ, Evans R, Griffiths L, et al., 2018, Meningeal inflammation and cortical demyelination in acute multiple sclerosis, Annals of Neurology, Vol: 84, Pages: 829-842, ISSN: 0364-5134
ObjectiveCortical gray matter (GM) pathology, involving demyelination and neurodegeneration, associated with meningeal inflammation, could be important in determining disability progression in multiple sclerosis (MS). However, we need to know more about how cortical demyelination, neurodegeneration, and meningeal inflammation contribute to pathology at early stages of MS to better predict long‐term outcome.MethodsTissue blocks from short disease duration MS (n = 12, median disease duration = 2 years), progressive MS (n = 21, disease duration = 25 years), non‐diseased controls (n = 11), and other neurological inflammatory disease controls (n = 6) were quantitatively analyzed by immunohistochemistry, immunofluorescence, and in situ hybridization.ResultsCortical GM demyelination was extensive in some cases of acute MS (range = 1–48% of total cortical GM), and subpial lesions were the most common type (62%). The numbers of activated (CD68+) microglia/macrophages were increased in cases with subpial lesions, and the density of neurons was significantly reduced in acute MS normal appearing and lesion GM, compared to controls (p < 0.005). Significant meningeal inflammation and lymphoid‐like structures were seen in 4 of 12 acute MS cases. The extent of meningeal inflammation correlated with microglial/macrophage activation (p < 0.05), but not the area of cortical demyelination, reflecting the finding that lymphoid‐like structures were seen adjacent to GM lesions as well as areas of partially demyelinated/remyelinated, cortical GM.InterpretationOur findings demonstrate that cortical demyelination, neuronal loss, and meningeal inflammation are notable pathological hallmarks of acute MS and support the need to identify early biomarkers of this pathology to better predict outcome. Ann Neurol 2018;84:829–842
Jelcic I, Al Nimer F, Wang J, et al., 2018, Memory B cells activate brain-homing, autoreactive CD4(+) T cells in multiple sclerosis, Cell, Vol: 175, Pages: 85-100.e23, ISSN: 0092-8674
Multiple sclerosis is an autoimmune disease that is caused by the interplay of genetic, particularly the HLA-DR15 haplotype, and environmental risk factors. How these etiologic factors contribute to generating an autoreactive CD4+ T cell repertoire is not clear. Here, we demonstrate that self-reactivity, defined as “autoproliferation” of peripheral Th1 cells, is elevated in patients carrying the HLA-DR15 haplotype. Autoproliferation is mediated by memory B cells in a HLA-DR-dependent manner. Depletion of B cells in vitro and therapeutically in vivo by anti-CD20 effectively reduces T cell autoproliferation. T cell receptor deep sequencing showed that in vitro autoproliferating T cells are enriched for brain-homing T cells. Using an unbiased epitope discovery approach, we identified RASGRP2 as target autoantigen that is expressed in the brain and B cells. These findings will be instrumental to address important questions regarding pathogenic B-T cell interactions in multiple sclerosis and possibly also to develop novel therapies.
Magliozzi R, Reynolds R, Calabrese M, 2018, MRI of cortical lesions and its use in studying their role in MS pathogenesis and disease course, BRAIN PATHOLOGY, Vol: 28, Pages: 735-742, ISSN: 1015-6305
Zeis T, Howell OW, Reynolds R, et al., 2018, Molecular pathology of Multiple Sclerosis lesions reveals a heterogeneous expression pattern of genes involved in oligodendrogliogenesis, EXPERIMENTAL NEUROLOGY, Vol: 305, Pages: 76-88, ISSN: 0014-4886
Elson JL, Kochaj R, Reynolds R, et al., 2018, Temporal-Spatial Profiling of Pedunculopontine Galanin-Cholinergic Neurons in the Lactacystin Rat Model of Parkinson's Disease, NEUROTOXICITY RESEARCH, Vol: 34, Pages: 16-31, ISSN: 1029-8428
Magliozzi R, Howell OW, Nicholas R, et al., 2018, Inflammatory intrathecal profiles and cortical damage in multiple sclerosis, Annals of Neurology, Vol: 83, Pages: 739-755, ISSN: 0364-5134
OBJECTIVE: Grey matter (GM) damage and meningeal inflammation have been associated with early disease onset and a more aggressive disease course in Multiple Sclerosis (MS), but can these changes be identified in the patient early in the disease course? METHODS: To identify possible biomarkers linking meningeal inflammation, GM damage and disease severity, gene and protein expression were analysed in meninges and CSF from 27 post-mortem secondary progressive MS (SPMS) and 14 control cases. Combined cytokine/chemokine CSF profiling and 3T-MRI were performed at diagnosis in two independent cohorts of MS patients (35 and 38 subjects) and in 26 non-MS patients. RESULTS: Increased expression of pro-inflammatory cytokines (IFNγ, TNF, IL2 and IL22) and molecules related to sustained B-cell activity and lymphoid-neogenesis (CXCL13, CXCL10, LTα, IL6, IL10) was detected in the meninges and CSF of post-mortem MS cases with high levels of meningeal inflammation and GM demyelination. Similar pro-inflammatory patterns, including increased levels of CXCL13, TNF, IFNγ, CXCL12, IL6, IL8 and IL10, together with high levels of BAFF, APRIL, LIGHT, TWEAK, sTNFR1, sCD163, MMP2 and pentraxin III, were detected in the CSF of MS patients with higher levels of GM damage at diagnosis. INTERPRETATION: A common pattern of intrathecal (meninges and CSF) inflammatory profile strongly correlates with increased cortical pathology, both at time of the diagnosis and of death. These results suggest a role for detailed CSF analysis combined with MRI, as a prognostic marker for more aggressive MS. This article is protected by copyright. All rights reserved.
Cencioni MT, Magliozzi R, Nicholas R, et al., 2017, Programmed death 1 is highly expressed on CD8(+) CD57(+) T cells in patients with stable multiple sclerosis and inhibits their cytotoxic response to Epstein-Barr virus., Immunology, Vol: 152, Pages: 660-676, ISSN: 0019-2805
Growing evidence points to a deregulated response to Epstein-Barr virus (EBV) in the central nervous system of patients with multiple sclerosis (MS) as a possible cause of disease. We have investigated the response of a subpopulation of effector CD8(+) T cells to EBV in 36 healthy donors and in 35 patients with MS in active and inactive disease. We have measured the expression of markers of degranulation, the release of cytokines, cytotoxicity and the regulation of effector functions by inhibitory receptors, such as programmed death 1 (PD-1) and human inhibitor receptor immunoglobulin-like transcript 2 (ILT2). We demonstrate that polyfunctional cytotoxic CD8(+) CD57(+) T cells are able to kill EBV-infected cells in healthy donors. In contrast, an anergic exhaustion-like phenotype of CD8(+) CD57(+) T cells with high expression of PD-1 was observed in inactive patients with MS compared with active patients with MS or healthy donors. Detection of CD8(+) CD57(+) T cells in meningeal inflammatory infiltrates from post-mortem MS tissue confirmed the association of this cell phenotype with the disease pathological process. The overall results suggest that ineffective immune control of EBV in patietns with MS during remission may be one factor preceding and enabling the reactivation of the virus in the central nervous system and may cause exacerbation of the disease.
Raffel J, Wallace A, Gveric D, et al., 2017, Patient-reported outcomes and survival in multiple sclerosis: a 10-year retrospective cohort study using the Multiple Sclerosis Impact Scale-29, PLOS Medicine, Vol: 14, ISSN: 1549-1277
BackgroundThere is increasing emphasis on using patient-reported outcomes (PROs) to complement traditional clinical outcomes in medical research, including in multiple sclerosis (MS). Research, particularly in oncology and heart failure, has shown that PROs can be prognostic of hard clinical endpoints such as survival time (time from study entry until death). However, unlike in oncology or cardiology, it is unknown whether PROs are associated with survival time in neurological diseases. The Multiple Sclerosis Impact Scale–29 (MSIS-29) is a PRO sensitive to short-term change in MS, with questions covering both physical and psychological quality of life. This study aimed to investigate whether MSIS-29 scores can be prognostic for survival time in MS, using a large observational cohort of people with MS.Methods and findingsFrom 15 July 2004 onwards, MSIS-29 questionnaires were completed by people with MS registered with the MS Society Tissue Bank (n = 2,126, repeated 1 year later with n = 872 of the original respondents). By 2014, 264 participants (12.4%) had died. Higher baseline MSIS-29 physical (MSIS-29-PHYS) score was associated with reduced survival time (subgroup with highest scores versus subgroup with lowest scores: hazard ratio [HR] 5.7, 95% CI 3.1–10.5, p < 0.001). Higher baseline MSIS-29 psychological score was also associated with reduced survival time (subgroup with highest scores versus subgroup with lowest scores: HR 2.8, 95% CI 1.8–4.4, p < 0.001). In those with high baseline MSIS-29 scores, mortality risk was even greater if the MSIS-29 score worsened over 1 year (HR 2.3, 95% CI 1.2–4.4, p = 0.02). MSIS-29-PHYS scores were associated with survival time independent of age, sex, and patient-reported Expanded Disability Status Scale score in a Cox regression analysis (per 1-SD increase in MSIS-29-PHYS score: HR 1.8, 95% CI 1.1–2.9, p = 0.03). A limitation of the study is that this cohort had high baseline age and disabi
Castellaro M, Magliozzi R, Palombit A, et al., 2017, Heterogeneity of Cortical Lesion Susceptibility Mapping in Multiple Sclerosis, AMERICAN JOURNAL OF NEURORADIOLOGY, Vol: 38, Pages: 1087-1095, ISSN: 0195-6108
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.
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