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1.
BMC Bioinformatics ; 21(1): 443, 2020 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-33028195

RESUMO

BACKGROUND: Gene-set analysis tools, which make use of curated sets of molecules grouped based on their shared functions, aim to identify which gene-sets are over-represented in the set of features that have been associated with a given trait of interest. Such tools are frequently used in gene-centric approaches derived from RNA-sequencing or microarrays such as Ingenuity or GSEA, but they have also been adapted for interval-based analysis derived from DNA methylation or ChIP/ATAC-sequencing. Gene-set analysis tools return, as a result, a list of significant gene-sets. However, while these results are useful for the researcher in the identification of major biological insights, they may be complex to interpret because many gene-sets have largely overlapping gene contents. Additionally, in many cases the result of gene-set analysis consists of a large number of gene-sets making it complicated to identify the major biological insights. RESULTS: We present GeneSetCluster, a novel approach which allows clustering of identified gene-sets, from one or multiple experiments and/or tools, based on shared genes. GeneSetCluster calculates a distance score based on overlapping gene content, which is then used to cluster them together and as a result, GeneSetCluster identifies groups of gene-sets with similar gene-set definitions (i.e. gene content). These groups of gene-sets can aid the researcher to focus on such groups for biological interpretations. CONCLUSIONS: GeneSetCluster is a novel approach for grouping together post gene-set analysis results based on overlapping gene content. GeneSetCluster is implemented as a package in R. The package and the vignette can be downloaded at https://github.com/TranslationalBioinformaticsUnit.


Assuntos
Interface Usuário-Computador , Linhagem Celular , Análise por Conglomerados , Metilação de DNA/efeitos dos fármacos , Mineração de Dados , Fumarato de Dimetilo/farmacologia , Humanos , Esclerose Múltipla/genética , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Espécies Reativas de Oxigênio/metabolismo
2.
Neurol Neurochir Pol ; 54(5): 410-415, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33085075

RESUMO

Magnetic resonance imaging (MRI) is a widely used method for the diagnosis of multiple sclerosis that is essential for the detection and follow-up of the disease. OBJECTIVE: The Polish Medical Society of Radiology (PLTR) and the Polish Society of Neurology (PTN) present the second version of their recommendations for investigations routinely conducted in magnetic resonance imaging departments in patients with multiple sclerosis. This version includes new data and practical comments for electroradiology technologists and radiologists. The recommended protocol aims to improve the MRI procedure and, most importantly, to standardise the method of conducting scans in all MRI departments. This is crucial for the initial diagnostics necessary for establishing a diagnosis, as well as for MS patient monitoring, which directly translates into significant clinical decisions. INTRODUCTION: Multiple sclerosis (MS) is a chronic immune mediated inflammatory demyelinating disease of the central nervous system (CNS), the aetiology of which is still unknown. The nature of the disease lies in a CNS destruction process disseminated in time (DIT) and space (DIS). MRI detects focal lesions in the white and grey matter with high sensitivity (although with significantly lower specificity in the latter). It is also the best tool to assess brain atrophy in patients with MS in terms of grey matter volume (GMV) and white matter volume (WMV) as well as local atrophy (by measuring the volume of thalamus, corpus callosum, subcortical nuclei, and hippocampus) as parameters that correlate with disability progression and cognitive dysfunctions. Progress in MR techniques, as well as advances in postprocessing the obtained data, has driven the dynamic development of computer programs that allow for a more repeatable assessment of brain atrophy in both cross-sectional and longitudinal studies. MR imaging is unquestionably the best diagnostic tool available to follow up the course of the disease and support clinicians in choosing the most appropriate treatment strategy for their MS patient. However, to diagnose and follow up MS patients on the basis of MRI in accordance with the latest standards, the MRI study must adhere to certain quality criteria. Such criteria are the subject of this paper.


Assuntos
Esclerose Múltipla , Neurologia , Atrofia/patologia , Encéfalo/patologia , Estudos Transversais , Humanos , Imagem por Ressonância Magnética , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/patologia , Polônia , Sociedades Médicas
3.
Sensors (Basel) ; 20(18)2020 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-32899946

RESUMO

Gait deterioration caused by prolonged walking represents one of the main consequences of multiple sclerosis (MS). This study aims at proposing quantitative indices to measure the gait deterioration effects. The experimental protocol consisted in a 6-min walking test and it involved nine patients with MS and twenty-six healthy subjects. Pathology severity was assessed through the Expanded Disability Status Scale. Seven inertial units were used to gather lower limb kinematics. Gait variability and asymmetry were assessed by coefficient of variation (CoV) and symmetry index (SI), respectively. The evolution of ROM (range of motion), CoV, and SI was computed analyzing data divided into six 60-s subgroups. Maximum difference among subgroups and the difference between the first minute and the remaining five were computed. The indices were analyzed for intra- and inter-day reliability and repeatability. Correlation with clinical scores was also evaluated. Good to excellent reliability was found for all indices. The computed standard deviations allowed us to affirm the good repeatability of the indices. The outcomes suggested walking-related fatigue leads to an always more variable kinematics in MS, in terms of changes in ROM, increase of variability and asymmetry. The hip asymmetry strongly correlated with the clinical disability.


Assuntos
Fadiga/fisiopatologia , Transtornos Neurológicos da Marcha/diagnóstico , Marcha/fisiologia , Esclerose Múltipla/diagnóstico , Índice de Gravidade de Doença , Caminhada/fisiologia , Adulto , Idoso , Fenômenos Biomecânicos/fisiologia , Estudos de Casos e Controles , Avaliação da Deficiência , Progressão da Doença , Teste de Esforço/métodos , Feminino , Transtornos Neurológicos da Marcha/etiologia , Indicadores Básicos de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/patologia , Esclerose Múltipla/fisiopatologia , Reprodutibilidade dos Testes , Projetos de Pesquisa , Fatores de Tempo
4.
Ann Agric Environ Med ; 27(3): 326-334, 2020 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-32955210

RESUMO

INTRODUCTION AND OBJECTIVE: αB-crystallin belongs to the ubiquitous family of small heat-shock proteins. It was discovered as a physiological protein of the eye lens, maintaining its liquid-like property. Furthermore, αB-crystallin was proved to playa bipolar role in both physiological and pathophysiological conditions. This review discusses current knowledge about the biology and genetics of αB-crystallin, and summarizes recent advances in understanding its role in ophthalmic and neurological disorders, as well as breast cancer, renal cancer and other malignancies. STATE OF KNOWLEDGE: α-crystallins are established as important elements of the protein quality control network, and consequently their defects are related to multiple human diseases. New studies highlight αB-crystallin's involvement in proliferative diabetic retinopathy angiogenesis and point out its therapeutic potential in age-related macular degeneration. αB-crystallin is thought to be associated with the disease-causing protein aggregates, leading to its connection with such neurological disturbances as anaplastic astrocytoma, Parkinson disease, aging deficits in the peripheral nervous system and multiple sclerosis. In breast cancer, it was proven to be a marker of aggressive behaviur and cerebral metastases. Strong expression of αB-crystallin promoted growth and migration of clear cell renal cell carcinoma cells and was correlated with lower overall survival rate. Considering other malignancies, its various roles were established in colorectal and gastric cancers, head and neck squamous cell carcinomas and osteosarcomas. CONCLUSIONS: Further studies concerning αB-crystallin seem to be enormously promising, as they might improve our understanding of common human pathologies as well as contemporary diagnostics and treatment.


Assuntos
Astrocitoma/patologia , Neoplasias da Mama/patologia , Cristalinas/metabolismo , Retinopatia Diabética/patologia , Esclerose Múltipla/patologia , Doenças do Sistema Nervoso/patologia , Doença de Parkinson/patologia , Feminino , Humanos , Sistema Nervoso Periférico/patologia
5.
Scand J Immunol ; 92(5): e12963, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32851668

RESUMO

Myeloid cells represent the major cellular component of innate immune responses. Myeloid cells include monocytes and macrophages, granulocytes (neutrophils, basophils and eosinophils) and dendritic cells (DC). The role of myeloid cells has been broadly described both in physiological and in pathological conditions. All tissues or organs are equipped with resident myeloid cells, such as parenchymal microglia in the brain, which contribute to maintaining homeostasis. Moreover, in case of infection or tissue damage, other myeloid cells such as monocytes or granulocytes (especially neutrophils) can be recruited from the circulation, at first to promote inflammation and later to participate in repair and regeneration. This review aims to address the regulatory roles of myeloid cells in inflammatory diseases of the central nervous system (CNS), with a particular focus on recent work showing induction of suppressive function via stimulation of innate signalling in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE).


Assuntos
Sistema Nervoso Central/imunologia , Células Dendríticas/imunologia , Granulócitos/imunologia , Inflamação/imunologia , Macrófagos/imunologia , Células Mieloides/imunologia , Animais , Sistema Nervoso Central/patologia , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Humanos , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia
6.
Proc Natl Acad Sci U S A ; 117(37): 22932-22943, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32859762

RESUMO

Central nervous system B cells have several potential roles in multiple sclerosis (MS): secretors of proinflammatory cytokines and chemokines, presenters of autoantigens to T cells, producers of pathogenic antibodies, and reservoirs for viruses that trigger demyelination. To interrogate these roles, single-cell RNA sequencing (scRNA-Seq) was performed on paired cerebrospinal fluid (CSF) and blood from subjects with relapsing-remitting MS (RRMS; n = 12), other neurologic diseases (ONDs; n = 1), and healthy controls (HCs; n = 3). Single-cell immunoglobulin sequencing (scIg-Seq) was performed on a subset of these subjects and additional RRMS (n = 4), clinically isolated syndrome (n = 2), and OND (n = 2) subjects. Further, paired CSF and blood B cell subsets (RRMS; n = 7) were isolated using fluorescence activated cell sorting for bulk RNA sequencing (RNA-Seq). Independent analyses across technologies demonstrated that nuclear factor kappa B (NF-κB) and cholesterol biosynthesis pathways were activated, and specific cytokine and chemokine receptors were up-regulated in CSF memory B cells. Further, SMAD/TGF-ß1 signaling was down-regulated in CSF plasmablasts/plasma cells. Clonally expanded, somatically hypermutated IgM+ and IgG1+ CSF B cells were associated with inflammation, blood-brain barrier breakdown, and intrathecal Ig synthesis. While we identified memory B cells and plasmablast/plasma cells with highly similar Ig heavy-chain sequences across MS subjects, similarities were also identified with ONDs and HCs. No viral transcripts, including from Epstein-Barr virus, were detected. Our findings support the hypothesis that in MS, CSF B cells are driven to an inflammatory and clonally expanded memory and plasmablast/plasma cell phenotype.


Assuntos
Linfócitos B/imunologia , Esclerose Múltipla/genética , Esclerose Múltipla/imunologia , Adulto , Linfócitos B/metabolismo , Sistema Nervoso Central/imunologia , Quimiocinas/metabolismo , Citocinas/metabolismo , Feminino , Citometria de Fluxo , Humanos , Imunoglobulina G/metabolismo , Cadeias Pesadas de Imunoglobulinas/metabolismo , Inflamação/patologia , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/patologia , Transcriptoma
7.
Nature ; 585(7823): 102-106, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32848245

RESUMO

Accumulating evidence indicates that gut microorganisms have a pathogenic role in autoimmune diseases, including in multiple sclerosis1. Studies of experimental autoimmune encephalomyelitis (an animal model of multiple sclerosis)2,3, as well as human studies4-6, have implicated gut microorganisms in the development or severity of multiple sclerosis. However, it remains unclear how gut microorganisms act on the inflammation of extra-intestinal tissues such as the spinal cord. Here we show that two distinct signals from gut microorganisms coordinately activate autoreactive T cells in the small intestine that respond specifically to myelin oligodendrocyte glycoprotein (MOG). After induction of experimental autoimmune encephalomyelitis in mice, MOG-specific CD4+ T cells are observed in the small intestine. Experiments using germ-free mice that were monocolonized with microorganisms from the small intestine demonstrated that a newly isolated strain in the family Erysipelotrichaceae acts similarly to an adjuvant to enhance the responses of T helper 17 cells. Shotgun sequencing of the contents of the small intestine revealed a strain of Lactobacillus reuteri that possesses peptides that potentially mimic MOG. Mice that were co-colonized with these two strains showed experimental autoimmune encephalomyelitis symptoms that were more severe than those of germ-free or monocolonized mice. These data suggest that the synergistic effects that result from the presence of these microorganisms should be considered in the pathogenicity of multiple sclerosis, and that further study of these microorganisms may lead to preventive strategies for this disease.


Assuntos
Encefalomielite Autoimune Experimental/microbiologia , Microbioma Gastrointestinal/imunologia , Inflamação/patologia , Medula Espinal/patologia , Linfócitos T/imunologia , Linfócitos T/patologia , Animais , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Encefalomielite Autoimune Experimental/prevenção & controle , Feminino , Vida Livre de Germes , Inflamação/imunologia , Intestino Delgado/imunologia , Intestino Delgado/microbiologia , Intestino Delgado/patologia , Lactobacillus reuteri/química , Lactobacillus reuteri/imunologia , Lactobacillus reuteri/patogenicidade , Masculino , Camundongos , Esclerose Múltipla/imunologia , Esclerose Múltipla/microbiologia , Esclerose Múltipla/patologia , Glicoproteína Mielina-Oligodendrócito/química , Glicoproteína Mielina-Oligodendrócito/imunologia , Medula Espinal/imunologia , Células Th17/imunologia , Células Th17/patologia
8.
PLoS One ; 15(8): e0235615, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32745132

RESUMO

No single neuroimaging technique or sequence is capable of reflecting the functional deficits manifest in MS. Given the interest in imaging biomarkers for short- to medium-term studies, we aimed to assess which imaging metrics might best represent functional impairment for monitoring in clinical trials. Given the complexity of functional impairment in MS, however, it is useful to isolate a particular functionally relevant pathway to understand the relationship between imaging and neurological function. We therefore analyzed existing data, combining multiparametric MRI and OCT to describe MS associated visual impairment. We assessed baseline data from fifty MS patients enrolled in ReBUILD, a prospective trial assessing the effect of a remyelinating drug (clemastine). Subjects underwent 3T MRI imaging, including Neurite Orientation Dispersion and Density Imaging (NODDI), myelin content quantification, and retinal imaging, using OCT. Visual function was assessed, using low-contrast letter acuity. MRI and OCT data were studied to model visual function in MS, using a partial, least-squares, regression analysis. Measures of neurodegeneration along the entire visual pathway, described most of the observed variance in visual disability, measured by low contrast letter acuity. In those patients with an identified history of ON, however, putative myelin measures also showed correlation with visual performance. In the absence of clinically identifiable inflammatory episodes, residual disability correlates with neurodegeneration, whereas after an identifiable exacerbation, putative measures of myelin content are additionally informative.


Assuntos
Esclerose Múltipla/diagnóstico por imagem , Visão Ocular , Adulto , Encéfalo/diagnóstico por imagem , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/patologia , Esclerose Múltipla/fisiopatologia , Bainha de Mielina/patologia , Retina/diagnóstico por imagem , Tomografia de Coerência Óptica
9.
Mult Scler Relat Disord ; 45: 102377, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32698095

RESUMO

SARS-CoV-2 infection can produce neurological features. The most common are headache, anosmia and dysgeusia but patients may also develop other central nervous system (CNS) injuries. We present a patient affected by Covid-19 who initially consulted for decreased visual acuity. The MRI showed inflammation in the right optic nerve and demyelinating lesions in the CNS. We speculate that an immune mechanism induced by SARS-CoV-2, which can activate lymphocytes and an inflammatory response, plays a role in the clinical onset of the disease. This pathogen may be associated with either the triggering or the exacerbation of inflammatory/demyelinating disease.


Assuntos
Infecções por Coronavirus/complicações , Esclerose Múltipla/epidemiologia , Pneumonia Viral/complicações , Adulto , Betacoronavirus , Feminino , Humanos , Esclerose Múltipla/patologia , Pandemias
10.
Lancet Neurol ; 19(8): 678-688, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32702337

RESUMO

The treatment of multiple sclerosis has been transformed by the successful development of immunotherapies that efficiently reduce disease activity and related clinical relapses during the relapsing-remitting phase of the disease. However, the prevention of disability progression, which is due to axonal and neuronal damage and loss, has yet to be achieved and is therapeutically challenging, particularly during the progressive phase of the disease. One strategy to counteract neurodegeneration is to promote neuroprotection by enhancing myelin regeneration, hence restoring nerve conduction and metabolic support to the axon. Animal studies have provided targets for interventions to improve brain and spinal cord remyelination, paving the way for the translation of this research to humans. From these initial and promising forays, further problems have emerged, including questions on how best to design these clinical trials and appropriately measure the outcomes. Solving these problems will need additional work before efficacious pro-remyelination therapies will be ready for people with multiple sclerosis, but there is a real sense of hope that researchers are getting closer to a successful therapy.


Assuntos
Esclerose Múltipla/patologia , Esclerose Múltipla/fisiopatologia , Remielinização/fisiologia , Progressão da Doença , Humanos , Esclerose Múltipla/diagnóstico por imagem , Bainha de Mielina/fisiologia
11.
PLoS One ; 15(7): e0235562, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32614900

RESUMO

INTRODUCTION: The incidence rate of MS is a valuable indicator of the recent changes in the risk of this disease, and it is widely implicated for health planning purposes. OBJECTIVES: This study aims to determine the MS incidence over the past eleven years in Mazandaran province and to compare it with the other parts of Iran and the world. MATERIALS AND METHODS: This retrospective study is conducted in Mazandaran province by using registered data in the files of the patients with their consent. The yearly crude incidence rates, age, and sex-specific incidence rates and directly standardized incidence rates of this population are calculated, and the temporal changes in the incidence rates are analyzed. RESULTS: 662 (26%) male patients with the mean (SD) age of 32.6 (9.48) and 1884 (74%) female patients with the mean (SD) age of 31.9 (9.15) are studied. The direct standardized incidence rate of MS was 3.28 in 100.000 in 2008 and reached 4.17 in 100.000 in 2018, and this increase was significant (p<0.05). Also, the yearly prevalence of MS increased from 24.4 to 72.5 in this period. CONCLUSIONS: The MS incidence has increased in Mazandaran. The potential role of some genetic or environmental factors needs further investigation.


Assuntos
Esclerose Múltipla/patologia , Adolescente , Adulto , Fatores Etários , Idoso , Criança , Feminino , Humanos , Irã (Geográfico)/epidemiologia , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/epidemiologia , Prevalência , Estudos Retrospectivos , Fatores Sexuais , Adulto Jovem
12.
PLoS One ; 15(7): e0235449, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32716916

RESUMO

BACKGROUND: Several disease modifying drugs (DMDs) have been approved for the treatment of multiple sclerosis (MS), however, little is known about their differential impact on peripheral blood (PB) B cell subsets. METHODS: We performed a cross sectional study on PB B cells in MS patients treated with interferon-ß (n = 25), glatiramer acetate (n = 19), dimethyl fumarate (n = 15), fingolimod (n = 16) or natalizumab (n = 22), untreated MS patients (n = 20), and in patients with non-inflammatory neurological diseases (n = 12). Besides analyzing routine laboratory data, flow cytometry was performed to analyze naïve B cells (CD19+CD20+CD27-IgD+), non-class switched (CD19+CD20+CD27+IgD+) and class-switched memory B cells (CD19+CD20+CD27+IgD-), double negative B cells (CD19+CD20lowCD27-IgD-) and plasmablasts (CD19+CD20lowCD27+CD38++). RESULTS: Treatment associated changes were found for the overall B cell pool as well as for all B cell subsets. Natalizumab increased absolute numbers and percentage of all B cells mainly by expanding the memory B cell pool. Fingolimod decreased absolute numbers of all B cell subsets and the percentage of total B cells. Fingolimod, dimethyl fumarate and interferon-ß treatments were associated with an increase in the fraction of naïve B cells while class switched and non-class switched memory B cells showed decreased percentages. CONCLUSION: Our results highlight differential effects of DMDs on the PB B cell compartment. Across the examined treatments, a decreased percentage of memory B cells was found in dimethyl fumarate, interferon-ß and fingolimod treated patients which might contribute to the drugs' mode of action in MS. Further studies are necessary to decipher the exact role of B cell subsets during MS pathogenesis.


Assuntos
Subpopulações de Linfócitos B/efeitos dos fármacos , Linfócitos B/efeitos dos fármacos , Memória Imunológica/efeitos dos fármacos , Esclerose Múltipla/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/classificação , Antígenos CD/imunologia , Antígenos CD19 , Subpopulações de Linfócitos B/classificação , Subpopulações de Linfócitos B/imunologia , Linfócitos B/imunologia , Estudos Transversais , Fumarato de Dimetilo/administração & dosagem , Feminino , Cloridrato de Fingolimode/administração & dosagem , Citometria de Fluxo , Acetato de Glatiramer/administração & dosagem , Humanos , Memória Imunológica/imunologia , Imunofenotipagem , Imunossupressores/administração & dosagem , Imunossupressores/imunologia , Interferon beta/administração & dosagem , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/sangue , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia , Natalizumab/administração & dosagem , Adulto Jovem
13.
PLoS One ; 15(7): e0236090, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32702050

RESUMO

OBJECTIVES: To evaluate retinal axonal density and retinal capillary flow density (CFD) variations in patients affected by multiple sclerosis (MS) as documented by Optical Coherence Tomography Angiography (OCT-A). MATERIAL AND METHODS: A cross-sectional study was performed in a tertiary university eye hospital on 94 eyes from 48 MS patients compared to 37 eyes from 23 matched controls. MS patients were divided in two groups: those with previous episodes of optic neuritis (MS ON+, 71.4%) and those without any previous visual complaint (no optic neuritis group, MS ON, 28.6%). Patients underwent macular and optic nerve head OCT-A with Optovue XR Avanti (Optovue, Freemont, California) after that preliminary evaluation of the ganglion cell complex (GCC) and of the retinal nerve fiber layer (RNFL) was achieved for each single eye by SD-OCT. CFD was evaluated in three different retinal layers of MS patients and controls: superficial capillary plexus (SCP), deep capillary plexus (DCP) and the choriocapillaris layer (CL). Each layer was analyzed in 18 preset subregions automatically detected by the system. CFD values were then correlated to the RNFL thickness and GCC thickness in the groups: p values were computed by t-tests between each group of MS patients and controls. A p-value of <0.05 was considered significant. RESULTS: A significant difference in the overall CFD values was found between ON+ and ON- patients when compared to controls in 18 subregions of SCP. Furthermore, a significant difference was found between MS patients and controls in 16 subregions analyzed corresponding to the CL layer without difference between the two MS subgroups (ON+ and ON-). CONCLUSIONS: OCT-A when performed at the optic nerve head level and at the macular region is characterized by a reduction of retinal perfusion in a significant portion of MS patients independently if they had a previous history of optic nerve inflammation or not.


Assuntos
Esclerose Múltipla/diagnóstico por imagem , Tomografia de Coerência Óptica , Axônios/metabolismo , Capilares/diagnóstico por imagem , Capilares/metabolismo , Estudos de Casos e Controles , Estudos Transversais , Reações Falso-Positivas , Humanos , Esclerose Múltipla/patologia , Esclerose Múltipla/fisiopatologia , Fibras Nervosas/metabolismo , Retina/diagnóstico por imagem , Retina/fisiopatologia
15.
AJNR Am J Neuroradiol ; 41(5): 751-757, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32354707

RESUMO

Conventional MR imaging techniques are sensitive to pathologic changes of the brain and spinal cord seen in MS, but they lack specificity for underlying axonal and myelin integrity. By isolating the signal contribution from different tissue compartments, newly developed advanced multicompartment diffusion MR imaging models have the potential to detect specific tissue subtypes and associated injuries with increased pathologic specificity. These models include neurite orientation dispersion and density imaging, diffusion basis spectrum imaging, multicompartment microscopic diffusion MR imaging with the spherical mean technique, and models enabled through high-gradient diffusion MR imaging. In this review, we provide an appraisal of the current literature on the physics principles, histopathologic validation, and clinical applications of each of these techniques in both brains and spinal cords of patients with MS. We discuss limitations of each of the methods and directions that future research could take to provide additional validation of their roles as biomarkers of axonal and myelin injury in MS.


Assuntos
Encéfalo/diagnóstico por imagem , Esclerose Múltipla/diagnóstico por imagem , Neuroimagem/métodos , Medula Espinal/diagnóstico por imagem , Encéfalo/patologia , Imagem de Difusão por Ressonância Magnética/métodos , Humanos , Esclerose Múltipla/patologia , Medula Espinal/patologia
16.
AJNR Am J Neuroradiol ; 41(5): 804-808, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32381540

RESUMO

BACKGROUND AND PURPOSE: Recent studies showed thalamic atrophy in the early stages of MS. We investigated the impact of intracortical lesions on the volumes of subcortical structures (especially the thalamus) compared with other lesions in MS. MATERIALS AND METHODS: Seventy-one patients with MS were included. The volumes of intracortical lesions and white matter lesions were identified on double inversion recovery and FLAIR, respectively, by using 3D Slicer. Volumes of white matter T1 hypointensities and subcortical gray matter, thalamus, caudate, putamen, and pallidum volumes were calculated using FreeSurfer. Age, MS duration, and the Expanded Disability Status Scale score were assessed. RESULTS: Patients with intracortical lesions were older (P = .003), had longer disease duration (P < .001), and higher Expanded Disability Status Scale scores (P = .02). The presence of intracortical lesions was associated with a significant decrease of subcortical gray matter volume (P = .02). In our multiple regression model, intracortical lesion volume was the only predictor of thalamic volume (R 2 = 0.4, b* = -0.28, P = .03) independent of white matter lesion volume and T1 hypointensity volume. White matter lesion volume showed an impact on subcortical gray matter volume in patients with relapsing-remitting MS (P = .04) and those with disease duration of <5 years (P = .04) and on thalamic volume in patients with Expanded Disability Status Scale scores of <4.0 (P = .01). By contrast, intracortical lesion volume showed an impact on subcortical gray matter and thalamic volumes in the secondary-progressive MS subgroup (P = .02 and P < .001) in patients with a long-standing disease course (P < .001 and P = .001) and more profound disability (P < .001 and P < .001). CONCLUSIONS: Thalamic atrophy was explained better by intracortical lesions than by white matter lesion and T1 hypointensity volumes, especially in patients with more profound disability.


Assuntos
Córtex Cerebral/patologia , Esclerose Múltipla/patologia , Tálamo/patologia , Adulto , Atrofia/diagnóstico por imagem , Atrofia/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Córtex Cerebral/diagnóstico por imagem , Estudos Transversais , Progressão da Doença , Feminino , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/patologia , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/diagnóstico por imagem , Estudos Retrospectivos , Tálamo/diagnóstico por imagem , Substância Branca/diagnóstico por imagem , Substância Branca/patologia
17.
AJNR Am J Neuroradiol ; 41(5): 929-937, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32414903

RESUMO

BACKGROUND AND PURPOSE: The inhomogeneous magnetization transfer technique has demonstrated high specificity for myelin, and has shown sensitivity to multiple sclerosis-related impairment in brain tissue. Our aim was to investigate its sensitivity to spinal cord impairment in MS relative to more established MR imaging techniques (volumetry, magnetization transfer, DTI). MATERIALS AND METHODS: Anatomic images covering the cervical spinal cord from the C1 to C6 levels and DTI, magnetization transfer/inhomogeneous magnetization transfer images at the C2/C5 levels were acquired in 19 patients with MS and 19 paired healthy controls. Anatomic images were segmented in spinal cord GM and WM, both manually and using the AMU40 atlases. MS lesions were manually delineated. MR metrics were analyzed within normal-appearing and lesion regions in anterolateral and posterolateral WM and compared using Wilcoxon rank tests and z scores. Correlations between MR metrics and clinical scores in patients with MS were evaluated using the Spearman rank correlation. RESULTS: AMU40-based C1-to-C6 GM/WM automatic segmentations in patients with MS were evaluated relative to manual delineation. Mean Dice coefficients were 0.75/0.89, respectively. All MR metrics (WM/GM cross-sectional areas, normal-appearing and lesion diffusivities, and magnetization transfer/inhomogeneous magnetization transfer ratios) were observed altered in patients compared with controls (P < .05). Additionally, the absolute inhomogeneous magnetization transfer ratio z scores were significantly higher than those of the other MR metrics (P < .0001), suggesting a higher inhomogeneous magnetization transfer sensitivity toward spinal cord impairment in MS. Significant correlations with the Expanded Disability Status Scale (ρ = -0.73/P = .02, ρ = -0.81/P = .004) and the total Medical Research Council scale (ρ = 0.80/P = .009, ρ = -0.74/P = .02) were observed for inhomogeneous magnetization transfer and magnetization transfer ratio z scores, respectively, in normal-appearing WM regions, while weaker and nonsignificant correlations were obtained for DTI metrics. CONCLUSIONS: With inhomogeneous magnetization transfer being highly sensitive to spinal cord damage in MS compared with conventional magnetization transfer and DTI, it could generate great clinical interest for longitudinal follow-up and potential remyelinating clinical trials. In line with other advanced myelin techniques with which it could be compared, it opens perspectives for multicentric investigations.


Assuntos
Interpretação de Imagem Assistida por Computador/métodos , Imagem por Ressonância Magnética/métodos , Esclerose Múltipla/diagnóstico por imagem , Neuroimagem/métodos , Medula Espinal/diagnóstico por imagem , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/patologia , Sensibilidade e Especificidade , Medula Espinal/patologia
18.
AJNR Am J Neuroradiol ; 41(6): 1001-1008, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32439639

RESUMO

BACKGROUND AND PURPOSE: Previous studies have suggested that the central vein sign and iron rims are specific features of MS lesions. Using 3T SWI, we aimed to compare the frequency of lesions with central veins and iron rims in patients with clinically isolated syndrome and MS-mimicking disorders and test their diagnostic value in predicting conversion from clinically isolated syndrome to MS. MATERIALS AND METHODS: For each patient, we calculated the number of brain lesions with central veins and iron rims. We then identified a simple rule involving an absolute number of lesions with central veins and iron rims to predict conversion from clinically isolated syndrome to MS. Additionally, we tested the diagnostic performance of central veins and iron rims when combined with evidence of dissemination in space. RESULTS: We included 112 patients with clinically isolated syndrome and 35 patients with MS-mimicking conditions. At follow-up, 94 patients with clinically isolated syndrome developed MS according to the 2017 McDonald criteria. Patients with clinically isolated syndrome had a median of 2 central veins (range, 0-19), while the non-MS group had a median of 1 central vein (range, 0-6). Fifty-six percent of patients who developed MS had ≥1 iron rim, and none of the patients without MS had iron rims. The sensitivity and specificity of finding ≥3 central veins and/or ≥1 iron rim were 70% and 86%, respectively. In combination with evidence of dissemination in space, the 2 imaging markers had higher specificity than dissemination in space and positive findings of oligoclonal bands currently used to support the diagnosis of MS. CONCLUSIONS: A single 3T SWI scan offers valuable diagnostic information, which has the potential to prevent MS misdiagnosis.


Assuntos
Encéfalo/diagnóstico por imagem , Doenças Desmielinizantes/diagnóstico por imagem , Esclerose Múltipla/diagnóstico por imagem , Neuroimagem/métodos , Adulto , Idoso , Encéfalo/patologia , Doenças Desmielinizantes/patologia , Feminino , Humanos , Interpretação de Imagem Assistida por Computador , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/patologia , Sensibilidade e Especificidade , Adulto Jovem
19.
Proc Natl Acad Sci U S A ; 117(22): 12269-12280, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32409602

RESUMO

In multiple sclerosis (MS), Th17 cells are critical drivers of autoimmune central nervous system (CNS) inflammation and demyelination. Th17 cells exhibit functional heterogeneity fostering both pathogenic and nonpathogenic, tissue-protective functions. Still, the factors that control Th17 pathogenicity remain incompletely defined. Here, using experimental autoimmune encephalomyelitis, an established mouse MS model, we report that therapeutic administration of activin-A ameliorates disease severity and alleviates CNS immunopathology and demyelination, associated with decreased activation of Th17 cells. In fact, activin-A signaling through activin-like kinase-4 receptor represses pathogenic transcriptional programs in Th17-polarized cells, while it enhances antiinflammatory gene modules. Whole-genome profiling and in vivo functional studies revealed that activation of the ATP-depleting CD39 and CD73 ectonucleotidases is essential for activin-A-induced suppression of the pathogenic signature and the encephalitogenic functions of Th17 cells. Mechanistically, the aryl hydrocarbon receptor, along with STAT3 and c-Maf, are recruited to promoter elements on Entpd1 and Nt5e (encoding CD39 and CD73, respectively) and other antiinflammatory genes, and control their expression in Th17 cells in response to activin-A. Notably, we show that activin-A negatively regulates the metabolic sensor, hypoxia-inducible factor-1α, and key inflammatory proteins linked to pathogenic Th17 cell states. Of translational relevance, we demonstrate that activin-A is induced in the CNS of individuals with MS and restrains human Th17 cell responses. These findings uncover activin-A as a critical controller of Th17 cell pathogenicity that can be targeted for the suppression of autoimmune CNS inflammation.


Assuntos
5'-Nucleotidase/metabolismo , Ativinas/farmacologia , Antígenos CD/metabolismo , Apirase/metabolismo , Encefalomielite Autoimune Experimental/imunologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Inflamação/prevenção & controle , Esclerose Múltipla/imunologia , Células Th17/imunologia , Animais , Diferenciação Celular , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Proteínas Ligadas por GPI/metabolismo , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Camundongos , Camundongos Endogâmicos C57BL , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Células Th17/metabolismo
20.
J Clin Neurosci ; 78: 307-312, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32376155

RESUMO

Multiple sclerosis (MS) is the most common inflammatory neurodegenerative disease. Neurofilament light chain (NFL) is a novel adverting biomarker of axonal damage that suggested as a useful assistant in the monitoring of MS patients. It has been shown that the auto/mitophagy associated with MS pathogenesis. In this study, we aimed to study correlation between ATG5 and Parkin, as markers of autophagy and mitophagy respectively, with NFL and ANT1 in serum and cerebrospinal fluid (CSF) in MS subjects. ATG5, Parkin, NFL, and ANT1 levels were measured in a cross-sectional study of 40 MS patients compared with gender, age and BMI matching healthy volunteers. Based on our results, levels of ATG5, Parkin, and NFL significantly were elevated in both serum and CSF of MS patients comparing control individuals (p < 0.0001) but ANT1 levels significantly was decreased in both serum and CSF of MS patients comparing control individuals (p < 0.0001). The correlation indices between NFL, ANTI1, ATG5 and Parkin in both case and control groups showed a direct and moderate the correlation between ANTI1 and ATG5 in the CSF level of the control group (r = 0.554, P = 0.011). Our data support the feasibility of quantifying of NFL as a sensitive and clinically meaningful serum/CSF biomarker to follow-up nerve tissue injury in MS condition.


Assuntos
Autofagia , Mitofagia , Esclerose Múltipla/patologia , Translocador 1 do Nucleotídeo Adenina/sangue , Translocador 1 do Nucleotídeo Adenina/líquido cefalorraquidiano , Adulto , Proteína 5 Relacionada à Autofagia/sangue , Proteína 5 Relacionada à Autofagia/líquido cefalorraquidiano , Biomarcadores/análise , Biomarcadores/sangue , Estudos de Casos e Controles , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/sangue , Esclerose Múltipla/líquido cefalorraquidiano , Proteínas de Neurofilamentos/sangue , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Ubiquitina-Proteína Ligases/sangue , Ubiquitina-Proteína Ligases/líquido cefalorraquidiano
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