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1.
APMIS ; 128(11): 583-592, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32865844

RESUMO

Multiple sclerosis (MS) is an immune-mediated inflammatory disease which affects the central nervous system (CNS). In the present study, the in vivo effects of ATRA, calcitriol, and their combinations on the expression of murine CD4+ T cell cytokines and their specific transcription factors in experimental autoimmune encephalomyelitis (EAE)-induced mice were explored. Thirty-two EAE induced inbred C57BL/6 female mice with an age ranged from 8 to 10 weeks were divided into four categories in a random manner. The first, second, and third groups received ATRA, calcitriol, ATRA+ calcitriol, respectively, and the fourth group received vehicle. The treatment started on the day prior to immunization and through the IP injections every other days for 21 days. The dosages of administration for calcitriol, ATRA, and calcitriol+ ATRA were 100 ng, 250 µg, and 50ng + 125 µg, respectively per mouse. An equal volume of excipient was administered for the vehicle group. T-bet, IFN-γ, GATA-3, and IL-4 genes expression were assessed in the splenocytes of EAE -induced mice. The expression of T-bet and IFN-γ genes in the splenocytes of ATRA, calcitriol and combination- treated mice were significantly reduced compared to vehicle group (p < 0.05). A significant decrease in T-bet expression was observed in the combination-treated group compared to the ATRA-treated group (p < 0.05). The expression of GATA3 and IL-4 genes was significantly increased in the ATRA-, calcitriol-, and combination-treated mice when compared with the control group (p < 0.05). Furthermore, the effect of calcitriol alone and in combination with ATRA was more considerable than that of ATRA alone. The nutraceutical approaches may be promising in the prevention and/or treatment of MS.


Assuntos
Calcitriol/farmacologia , Encefalomielite Autoimune Experimental/tratamento farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Fatores Imunológicos/farmacologia , Fármacos Neuroprotetores/farmacologia , Tretinoína/farmacologia , Animais , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Esquema de Medicação , Quimioterapia Combinada , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Feminino , Fator de Transcrição GATA3/genética , Fator de Transcrição GATA3/imunologia , Interferon gama/genética , Interferon gama/imunologia , Interleucina-4/genética , Interleucina-4/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Glicoproteína Mielina-Oligodendrócito/administração & dosagem , Transdução de Sinais , Medula Espinal/efeitos dos fármacos , Medula Espinal/imunologia , Medula Espinal/patologia , Proteínas com Domínio T/genética , Proteínas com Domínio T/imunologia
2.
Proc Natl Acad Sci U S A ; 117(39): 24464-24474, 2020 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-32929007

RESUMO

Microglia are considered both pathogenic and protective during recovery from demyelination, but their precise role remains ill defined. Here, using an inhibitor of colony stimulating factor 1 receptor (CSF1R), PLX5622, and mice infected with a neurotropic coronavirus (mouse hepatitis virus [MHV], strain JHMV), we show that depletion of microglia during the time of JHMV clearance resulted in impaired myelin repair and prolonged clinical disease without affecting the kinetics of virus clearance. Microglia were required only during the early stages of remyelination. Notably, large deposits of extracellular vesiculated myelin and cellular debris were detected in the spinal cords of PLX5622-treated and not control mice, which correlated with decreased numbers of oligodendrocytes in demyelinating lesions in drug-treated mice. Furthermore, gene expression analyses demonstrated differential expression of genes involved in myelin debris clearance, lipid and cholesterol recycling, and promotion of oligodendrocyte function. The results also demonstrate that microglial functions affected by depletion could not be compensated by infiltrating macrophages. Together, these results demonstrate that microglia play key roles in debris clearance and in the initiation of remyelination following infection with a neurotropic coronavirus but are not necessary during later stages of remyelination.


Assuntos
Infecções por Coronavirus/patologia , Doenças Desmielinizantes/patologia , Microglia/patologia , Remielinização , Animais , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Doenças Desmielinizantes/imunologia , Doenças Desmielinizantes/virologia , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Imunidade Celular/efeitos dos fármacos , Inflamação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/metabolismo , Vírus da Hepatite Murina/efeitos dos fármacos , Vírus da Hepatite Murina/fisiologia , Bainha de Mielina/metabolismo , Bainha de Mielina/patologia , Oligodendroglia/patologia , Compostos Orgânicos/administração & dosagem , Compostos Orgânicos/efeitos adversos , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Remielinização/genética , Medula Espinal/imunologia , Medula Espinal/patologia
3.
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
4.
N Engl J Med ; 383(2): 151-158, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32640133

RESUMO

Two patients with familial amyotrophic lateral sclerosis (ALS) and mutations in the gene encoding superoxide dismutase 1 (SOD1) were treated with a single intrathecal infusion of adeno-associated virus encoding a microRNA targeting SOD1. In Patient 1, SOD1 levels in spinal cord tissue as analyzed on autopsy were lower than corresponding levels in untreated patients with SOD1-mediated ALS and in healthy controls. Levels of SOD1 in cerebrospinal fluid were transiently and only slightly lower in Patient 1 but were not affected in Patient 2. In Patient 1, meningoradiculitis developed after the infusion; Patient 2 was pretreated with immunosuppressive drugs and did not have this complication. Patient 1 had transient improvement in the strength of his right leg, a measure that had been relatively stable throughout his disease course, but there was no change in his vital capacity. Patient 2 had stable scores on a composite measure of ALS function and a stable vital capacity during a 12-month period. This study showed that intrathecal microRNA can be used as a potential treatment for SOD1-mediated ALS.


Assuntos
Esclerose Amiotrófica Lateral/terapia , MicroRNAs/uso terapêutico , Superóxido Dismutase-1/líquido cefalorraquidiano , Esclerose Amiotrófica Lateral/líquido cefalorraquidiano , Esclerose Amiotrófica Lateral/genética , Dependovirus , Evolução Fatal , Inativação Gênica , Terapia Genética , Vetores Genéticos , Humanos , Injeções Espinhais , Masculino , Meningoencefalite , Pessoa de Meia-Idade , Mutação , Estudo de Prova de Conceito , Medula Espinal/química , Medula Espinal/patologia , Superóxido Dismutase-1/análise , Superóxido Dismutase-1/genética , Capacidade Vital , Adulto Jovem
5.
Proc Natl Acad Sci U S A ; 117(30): 18018-18028, 2020 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-32651278

RESUMO

CCN3 is a matricellular protein that promotes oligodendrocyte progenitor cell differentiation and myelination in vitro and ex vivo. CCN3 is therefore a candidate of interest in central nervous system (CNS) myelination and remyelination, and we sought to investigate the expression and role of CCN3 during these processes. We found CCN3 to be expressed predominantly by neurons in distinct areas of the CNS, primarily the cerebral cortex, hippocampus, amygdala, suprachiasmatic nuclei, anterior olfactory nuclei, and spinal cord gray matter. CCN3 was transiently up-regulated following demyelination in the brain of cuprizone-fed mice and spinal cord lesions of mice injected with lysolecithin. However, CCN3-/- mice did not exhibit significantly different numbers of oligodendroglia or differentiated oligodendrocytes in the healthy or remyelinating CNS, compared to WT controls. These results suggest that despite robust and dynamic expression in the CNS, CCN3 is not required for efficient myelination or remyelination in the murine CNS in vivo.


Assuntos
Sistema Nervoso Central/metabolismo , Doenças Desmielinizantes/etiologia , Regulação da Expressão Gênica , Proteína Sobre-Expressa em Nefroblastoma/genética , Remielinização/genética , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Modelos Animais de Doenças , Imunofluorescência , Camundongos , Bainha de Mielina/metabolismo , Proteína Sobre-Expressa em Nefroblastoma/metabolismo , Células Precursoras de Oligodendrócitos/metabolismo , Oligodendroglia/metabolismo , Medula Espinal/metabolismo , Medula Espinal/patologia
6.
Neurology ; 95(8): e1027-e1040, 2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32651286

RESUMO

OBJECTIVE: To evaluate efficacy, safety, and tolerability of laquinimod in patients with primary progressive multiple sclerosis (PPMS). METHODS: In the randomized, double-blind, placebo-controlled, phase 2 study, ARPEGGIO (A Randomized Placebo-controlled Trial Evaluating Laquinimod in PPMS, Gauging Gradations in MRI and Clinical Outcomes), eligible patients with PPMS were randomized 1:1:1 to receive once-daily oral laquinimod 0.6 mg or 1.5 mg or matching placebo. Percentage brain volume change (PBVC; primary endpoint) from baseline to week 48 was assessed by MRI. Secondary and exploratory endpoints included clinical and MRI measures. Efficacy endpoints were evaluated using a predefined, hierarchical statistical testing procedure. Safety was monitored throughout the study. The laquinimod 1.5 mg dose arm was discontinued on January 1, 2016, due to findings of cardiovascular events. RESULTS: A total of 374 patients were randomized to laquinimod 0.6 mg (n = 139) or 1.5 mg (n = 95) or placebo (n = 140). ARPEGGIO did not meet the primary endpoint of significant treatment effect with laquinimod 0.6 mg vs placebo on PBVC from baseline to week 48 (adjusted mean difference = 0.016%, p = 0.903). Laquinimod 0.6 mg reduced the number of new T2 brain lesions at week 48 (risk ratio 0.4; 95% confidence interval, 0.26-0.69; p = 0.001). Incidence of adverse events was higher among patients treated with laquinimod 0.6 mg (83%) vs laquinimod 1.5 mg (66%) and placebo (78%). CONCLUSIONS: Laquinimod 0.6 mg did not demonstrate a statistically significant effect on brain volume loss in PPMS at week 48. CLINICALTRIALSGOV IDENTIFIER: NCT02284568. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that, although well tolerated, laquinimod 0.6 mg did not demonstrate a significant treatment effect on PBVC in patients with PPMS.


Assuntos
Encéfalo/patologia , Esclerose Múltipla Crônica Progressiva/tratamento farmacológico , Quinolonas/uso terapêutico , Adulto , Atrofia , Encéfalo/efeitos dos fármacos , Progressão da Doença , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Crônica Progressiva/patologia , Medula Espinal/efeitos dos fármacos , Medula Espinal/patologia , Resultado do Tratamento
7.
BMC Neurol ; 20(1): 265, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32611422

RESUMO

BACKGROUND: Bilateral thalamic lesions are rare. Here, we describe a case of probable acute disseminating encephalomyelitis (ADEM) with symmetrical bilateral thalamic lesions. CASE PRESENTATION: An 85-year-old man presented with weakness of the lower limbs and urinary retention for 1 day, soon followed by coma. He had an H1N1 influenza vaccination 3 months ago. A lumbar puncture showed positive oligoclonal bands and negative results for anti-AQP4 antibodies. A head MRI demonstrated focal symmetrical bilateral thalamic lesions. An MRI of the thoracic spinal cord showed longitudinally extensive lesions in the spinal cord. He was diagnosed with probable ADEM. Despite being treated with IVIG, the patient remained unconscious and died a month later from pneumonia. CONCLUSIONS: In cases with bilateral thalamic lesions, the possibility of ADEM should be considered. The characteristics of the thalamic lesions and imaging findings in other parts of the brain or spinal cord should be taken into account in association with the clinical and laboratory information in making a correct diagnosis.


Assuntos
Encéfalo/patologia , Encefalomielite Aguda Disseminada/diagnóstico , Idoso de 80 Anos ou mais , Coma/etiologia , Humanos , Imagem por Ressonância Magnética , Masculino , Probabilidade , Medula Espinal/patologia , Punção Espinal/efeitos adversos , Inconsciência/etiologia
8.
PLoS One ; 15(6): e0235110, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32584865

RESUMO

Programmed axonal degeneration, also known as Wallerian degeneration, occurs in immune-mediated central nervous system (CNS) inflammatory disorders such as multiple sclerosis and the animal model experimental allergic encephalomyelitis (EAE). Sterile alpha and TIR domain containing protein 1 (SARM1) functions to promote programmed axonal degeneration. To test the hypothesis that loss of SARM1 will reduce axonal degeneration in immune-mediated CNS inflammatory disorders, the course and pathology of EAE was compared in Sarm1 knockout mice and wild type littermates. The clinical course of EAE was similar in Sarm1 knockout and wild type. Analysis of EAE in mice expressing neuronal yellow fluorescent protein (YFP) showed significantly less axonal degeneration in Sarm1 knockout mice compared to wild type littermates at 14 days post-induction of EAE. At 21 days post-induction, however, difference in axonal degeneration was not significant. At 42 days post-induction, Sarm1 knockout mice were indistinguishable from wild type with respect to markers of axonal injury, and were similar with respect to axonal density in the lumbar cords. There was no significant change in peripheral immune activation or CNS inflammatory cell infiltration associated with EAE in Sarm1 knockout mice. In conclusion, Sarm1 deletion delayed axonal degeneration early in the course of CNS inflammation, but did not confer long-term protection from axonal degeneration in an animal model of immune-mediated CNS inflammation.


Assuntos
Proteínas do Domínio Armadillo , Axônios , Proteínas do Citoesqueleto , Encefalomielite Autoimune Experimental , Técnicas de Inativação de Genes , Medula Espinal , Animais , Proteínas do Domínio Armadillo/genética , Proteínas do Domínio Armadillo/metabolismo , Axônios/metabolismo , Axônios/patologia , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/metabolismo , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Encefalomielite Autoimune Experimental/prevenção & controle , Camundongos , Camundongos Knockout , Medula Espinal/metabolismo , Medula Espinal/patologia , Fatores de Tempo
9.
Nature ; 582(7810): 89-94, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32483373

RESUMO

A hexanucleotide-repeat expansion in C9ORF72 is the most common genetic variant that contributes to amyotrophic lateral sclerosis and frontotemporal dementia1,2. The C9ORF72 mutation acts through gain- and loss-of-function mechanisms to induce pathways that are implicated in neural degeneration3-9. The expansion is transcribed into a long repetitive RNA, which negatively sequesters RNA-binding proteins5 before its non-canonical translation into neural-toxic dipeptide proteins3,4. The failure of RNA polymerase to read through the mutation also reduces the abundance of the endogenous C9ORF72 gene product, which functions in endolysosomal pathways and suppresses systemic and neural inflammation6-9. Notably, the effects of the repeat expansion act with incomplete penetrance in families with a high prevalence of amyotrophic lateral sclerosis or frontotemporal dementia, indicating that either genetic or environmental factors modify the risk of disease for each individual. Identifying disease modifiers is of considerable translational interest, as it could suggest strategies to diminish the risk of developing amyotrophic lateral sclerosis or frontotemporal dementia, or to slow progression. Here we report that an environment with reduced abundance of immune-stimulating bacteria10,11 protects C9orf72-mutant mice from premature mortality and significantly ameliorates their underlying systemic inflammation and autoimmunity. Consistent with C9orf72 functioning to prevent microbiota from inducing a pathological inflammatory response, we found that reducing the microbial burden in mutant mice with broad spectrum antibiotics-as well as transplanting gut microflora from a protective environment-attenuated inflammatory phenotypes, even after their onset. Our studies provide further evidence that the microbial composition of our gut has an important role in brain health and can interact in surprising ways with well-known genetic risk factors for disorders of the nervous system.


Assuntos
Proteína C9orf72/genética , Microbioma Gastrointestinal/fisiologia , Gliose/microbiologia , Gliose/patologia , Inflamação/genética , Inflamação/microbiologia , Medula Espinal/patologia , Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/patologia , Animais , Antibacterianos/farmacologia , Autoimunidade/efeitos dos fármacos , Autoimunidade/genética , Autoimunidade/imunologia , Movimento Celular/efeitos dos fármacos , Citocinas/imunologia , Transplante de Microbiota Fecal , Feminino , Demência Frontotemporal/genética , Demência Frontotemporal/patologia , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/imunologia , Gliose/genética , Gliose/prevenção & controle , Inflamação/patologia , Inflamação/prevenção & controle , Mutação com Perda de Função/genética , Masculino , Camundongos , Microglia/imunologia , Microglia/microbiologia , Microglia/patologia , Medula Espinal/imunologia , Medula Espinal/microbiologia , Taxa de Sobrevida
12.
Adv Clin Exp Med ; 29(4): 441-448, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32369275

RESUMO

BACKGROUND: Several studies have identified changes in the spinal cord DTI measurements in patients with multiple sclerosis (MS). However, correlations between changes in DTI parameters in normal appearing cervical spine and neurological findings have not been clearly established. OBJECTIVES: To determine whether diffusion tensor imaging (DTI) measurements such as fractional anisotropy (FA) and apparent diffusion coefficient (ADC) are sufficiently sensitive in detecting microstructure alterations in normal-appearing spinal cords in patients with MS and whether they reflect these patients' clinical disability. MATERIAL AND METHODS: Fifteen patients diagnosed with relapsing-remitting MS (RRMS) with normal-appearing cervical spinal cords on plain MRI and 11 asymptomatic volunteers were enrolled in the study. Overall, 75 cervical spinal segments were analyzed. The regions of interest were drawn from the entire spinal cord cross-section and in the normal-appearing white matter tracts: the superior and inferior cerebellar peduncles and the posterior limbs of the internal capsules. Neurological deficit and the level of disability were evaluated using the Expanded Disability Status Scale (EDSS), the timed 25-foot walk test (T25FW) and the 9-hole peg test (9HPT) for manual dexterity. RESULTS: A significant difference (p < 0.05) in FA values between patients with MS and the control group was found at levels C2 (p = 0.047) and C3 (p = 0.023). No significant changes in ADC values were found. There was correlation between FA and ADC values in selected white matter tracts and at particular spinal cord levels. We also observed significant correlations between diffusion tensor imaging parameters and manual dexterity. CONCLUSIONS: Our preliminary results may suggest that the spinal cord's structural loss is the dominant factor in the inflammatory/demyelinating component in patients with MS. Diffusion tensor imaging changes in the spinal cord correlate with brain DTI changes. Manual functioning seems to be more affected than walking.


Assuntos
Encéfalo/diagnóstico por imagem , Medula Cervical/diagnóstico por imagem , Imagem de Tensor de Difusão/métodos , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Esclerose Múltipla/diagnóstico por imagem , Medula Espinal/anatomia & histologia , Medula Espinal/patologia , Anisotropia , Humanos , Esclerose Múltipla/fisiopatologia , Esclerose Múltipla Recidivante-Remitente/fisiopatologia , Fibras Nervosas Mielinizadas/patologia
13.
J Clin Neurosci ; 77: 222-224, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32409214

RESUMO

Fibrocartilaginous embolism (FCE) is a rare and probably under diagnosed cause of spinal cord infarction presumably due to acute embolization of nucleus pulposus fragments into the spinal circulation. Concomitant cerebral involvement is much rarer and often asymptomatic. Although the definitive diagnosis is histologic, certain criteria have been proposed to support the diagnosis in living patients, such as absence of vascular risk factors, acute onset or antecedent of valsalva maneuver before the episode and the exclusion of potential differential diagnoses. A 56 years-old patient, without any medical history was referred for sudden back pain while carrying heavy load at work. Clinical examination showed a Brown-Sequard syndrome. Brain and spine MRI disclosed spinal cord infarction at the C4-C5 level associated with brain infarctions involving exclusively the vertebrobasilar circulation. The exhaustive etiological assessment was normal. In our case, the acute symptoms onset, the clinical and imaging data and lack of evidence for other plausible diagnoses in the setting of a valsalva-like maneuver are highly suggestive of FCE diagnosis.


Assuntos
Encéfalo/irrigação sanguínea , Doenças das Cartilagens/complicações , Embolia/complicações , Infarto/etiologia , Medula Espinal/irrigação sanguínea , Síndrome de Brown-Séquard/etiologia , Doenças das Cartilagens/diagnóstico , Doenças das Cartilagens/patologia , Diagnóstico Diferencial , Embolia/diagnóstico , Embolia/patologia , Humanos , Infarto/diagnóstico , Infarto/patologia , Imagem por Ressonância Magnética/efeitos adversos , Masculino , Pessoa de Meia-Idade , Medula Espinal/patologia
14.
J Vis Exp ; (157)2020 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-32281968

RESUMO

Incomplete spinal cord injury (SCI) often leads to impairments of sensorimotor functions and is clinically the most frequent type of SCI. Human Brown-Séquard syndrome is a common type of incomplete SCI caused by a lesion to one half of the spinal cord which results in paralysis and loss of proprioception on the same (or ipsilesional) side as the injury, and loss of pain and temperature sensation on the opposite (or contralesional) side. Adequate methodologies for producing a spinal cord lateral hemisection (HX) and assessing neurological impairments are essential to establish a reliable animal model of Brown-Séquard syndrome. Although lateral hemisection model plays a pivotal role in basic and translational research, standardized protocols for creating such a hemisection and assessing unilateralized function are lacking. The goal of this study is to describe step-by-step procedures to produce a rat spinal lateral HX at the 9th thoracic (T9) vertebral level. We, then, describe a combined behavior scale for HX (CBS-HX) that provides a simple and sensitive assessment of asymmetric neurological performance for unilateral SCI. The CBS-HX, ranging from 0 to 18, is composed of 4 individual assessments which include unilateral hindlimb stepping (UHS), coupling, contact placing, and grid walking. For CBS-HX, the ipsilateral and contralateral hindlimbs are assessed separately. We found that, after a T9 HX, the ipsilateral hindlimb showed impaired behavior function whereas the contralateral hindlimb showed substantial recovery. The CBS-HX effectively discriminated behavioral functions between ipsilateral and contralateral hindlimbs and detected temporal progression of recovery of the ipsilateral hindlimb. The CBS-HX components can be analyzed separately or in combination with other measures when needed. Although we only provided visual descriptions of the surgical procedures and behavioral assessments of a thoracic HX, the principle may be applied to other incomplete SCIs and at other levels of the injury.


Assuntos
Traumatismos da Medula Espinal/fisiopatologia , Medula Espinal/cirurgia , Animais , Comportamento Animal , Modelos Animais de Doenças , Masculino , Ratos , Medula Espinal/patologia
15.
Am J Obstet Gynecol ; 223(2): 256.e1-256.e9, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32283072

RESUMO

BACKGROUND: Despite undisputable benefits, midtrimester prenatal surgery is not a cure for myelomeningocele (MMC): residual intracranial and motor deficits leading to lifelong handicap question the timing of prenatal surgery. Indeed, the timing and intensity of intrauterine spinal cord injury remains ill defined. OBJECTIVE: We aimed to describe the natural history of neuronal loss in MMC in utero based on postmortem pathology. STUDY DESIGN: Pathology findings were analyzed in 186 cases of myelomeningocele with lesion level between S1 and T1. Using a case-control, cross-sectional design, we investigated the timewise progression and topographic extension of neuronal loss between 13 and 39 weeks. Motor neurons were counted on histology at several spinal levels in 54 isolated MMC meeting quality criteria for cell counting. These were expressed as observed-to-expected ratios, after matching for gestational age and spinal level with 41 controls. RESULTS: Chiari II malformation increased from 30.7% to 91.6% after 16 weeks. The exposed spinal cord displayed early, severe, and progressive neuronal loss: the observed-to-expected count dropped from 17% to ≤2% after 16 weeks. Neuronal loss extended beyond the lesion to the upper levels: in cases <16 weeks, the observed-to-expected motor neuron count was 60% in the adjacent spinal cord, decreasing at a rate of 16% per week. Progressive loss was also found in the upper thoracic cord, but in much smaller proportions. The observed-over-expected ratio of motor neurons was not correlated with the level of myelomeningocele. CONCLUSIONS: Significant neuronal loss is present ≤16 weeks in the exposed cord and progressively extends cranially. Earlier prenatal repair (<16 weeks) could prevent Chiari II malformation in 69.3% of cases, rescue the 17% remaining motor neurons in the exposed cord, and prevent the extension to the upper spinal cord.


Assuntos
Malformação de Arnold-Chiari/patologia , Idade Gestacional , Meningomielocele/patologia , Neurônios Motores/patologia , Medula Espinal/patologia , Aborto Induzido , Malformação de Arnold-Chiari/embriologia , Autopsia , Progressão da Doença , Feminino , Terapias Fetais , Humanos , Vértebras Lombares , Meningomielocele/embriologia , Meningomielocele/cirurgia , Procedimentos Neurocirúrgicos , Gravidez , Primeiro Trimestre da Gravidez , Segundo Trimestre da Gravidez , Estudos Retrospectivos , Sacro , Vértebras Torácicas
16.
World Neurosurg ; 138: 404-407, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32251830

RESUMO

BACKGROUND: Spinal dural arteriovenous fistulas (SDAVFs) are the most common type of spinal arteriovenous malformations; they frequently cause progressive myelopathy including gait disturbances and sensory disorders. CASE DESCRIPTION: We report a rare case of a middle-aged man who experienced right-sided chest pain and Th4 radiculopathy, without any other neurologic presentations. Magnetic resonance imaging showed a flow void sign on the dorsal aspect of the spinal cord; spinal angiography revealed an arteriovenous shunt between a radicular artery and an intradural vein. Suspecting SDAVF as the cause of the chest pain, we performed surgical resection. Intraoperatively, we observed compression of the rootlet by the draining vein. Right chest pain disappeared completely after obliteration of the SDAVF. The present patient had vascular compression of the spinal nerve rootlet without any venous congestion. CONCLUSIONS: Our experience shows that SDAVF can present not only as a myelopathy but also as a radiculopathy, indicating that radiculopathy may become a main symptom of SDAVF.


Assuntos
Malformações Vasculares do Sistema Nervoso Central/complicações , Malformações Vasculares do Sistema Nervoso Central/cirurgia , Radiculopatia/etiologia , Medula Espinal/patologia , Medula Espinal/cirurgia , Angiografia Digital , Malformações Vasculares do Sistema Nervoso Central/diagnóstico , Edema , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Doenças da Medula Espinal , Vértebras Torácicas
17.
Nat Commun ; 11(1): 1773, 2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-32286313

RESUMO

In amyotrophic lateral sclerosis (ALS), immune cells and glia contribute to motor neuron (MN) degeneration. We report the presence of NK cells in post-mortem ALS motor cortex and spinal cord tissues, and the expression of NKG2D ligands on MNs. Using a mouse model of familial-ALS, hSOD1G93A, we demonstrate NK cell accumulation in the motor cortex and spinal cord, with an early CCL2-dependent peak. NK cell depletion reduces the pace of MN degeneration, delays motor impairment and increases survival. This is confirmed in another ALS mouse model, TDP43A315T. NK cells are neurotoxic to hSOD1G93A MNs which express NKG2D ligands, while IFNγ produced by NK cells instructs microglia toward an inflammatory phenotype, and impairs FOXP3+/Treg cell infiltration in the spinal cord of hSOD1G93A mice. Together, these data suggest a role of NK cells in determining the onset and progression of MN degeneration in ALS, and in modulating Treg recruitment and microglia phenotype.


Assuntos
Esclerose Amiotrófica Lateral/metabolismo , Células Matadoras Naturais/metabolismo , Neurônios Motores/metabolismo , Adulto , Idoso , Esclerose Amiotrófica Lateral/imunologia , Esclerose Amiotrófica Lateral/patologia , Animais , Modelos Animais de Doenças , Progressão da Doença , Feminino , Humanos , Células Matadoras Naturais/imunologia , Masculino , Camundongos , Pessoa de Meia-Idade , Córtex Motor/imunologia , Córtex Motor/metabolismo , Córtex Motor/patologia , Neurônios Motores/imunologia , Neurônios Motores/patologia , Receptor 1 Desencadeador da Citotoxicidade Natural/genética , Receptor 1 Desencadeador da Citotoxicidade Natural/metabolismo , Medula Espinal/imunologia , Medula Espinal/metabolismo , Medula Espinal/patologia
18.
PLoS One ; 15(4): e0231598, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32310954

RESUMO

The microstructure changes associated with degeneration of spinal axons in amyotrophic lateral sclerosis (ALS) may be reflected in altered water diffusion properties, potentially detectable with diffusion-weighted (DW) MRI. Prior work revealed the classical mono-exponential model fails to precisely depict decay in DW signal at high b-values. In this study, we aim to investigate signal decay behaviors at ultra-high b-values for non-invasive assessment of spinal cord alterations in the transgenic SOD1G93A mouse model of ALS. A multiexponential diffusion analysis using regularized non-negative least squares (rNNLS) algorithm was applied to a series of thirty DW MR images with b-values ranging from 0 to 858,022 s/mm2 on ex vivo spinal cords of transgenic SOD1G93A and age-matched control mice. We compared the distributions of measured diffusion coefficient fractions between the groups. The measured diffusion weighted signals in log-scale showed non-linear decay behaviors with increased b-values. Faster signal decays were observed with diffusion gradients applied parallel to the long axis of the spinal cord compared to when oriented in the transverse direction. Multiexponential analysis at the lumbar level in the spinal cord identified ten subintervals. A significant decrease of diffusion coefficient fractions was found in the ranges of [1.63×10-8,3.70×10-6] mm2/s (P = 0.0002) and of [6.01×10-6,4.20×10-5] mm2/s (P = 0.0388) in SOD1G93A mice. Anisotropic diffusion signals persisted at ultra-high b-value DWIs of the mouse spinal cord and multiexponential diffusion analysis offers the potential to evaluate microstructural alterations of ALS-affected spinal cord non-invasively.


Assuntos
Algoritmos , Esclerose Amiotrófica Lateral/diagnóstico por imagem , Axônios/patologia , Imagem de Difusão por Ressonância Magnética/métodos , Medula Espinal/diagnóstico por imagem , Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/patologia , Animais , Masculino , Camundongos , Medula Espinal/patologia , Superóxido Dismutase-1/genética
19.
Ann Neurol ; 88(1): 123-136, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32293054

RESUMO

OBJECTIVE: Treatment of relapses in multiple sclerosis (MS) has not advanced beyond steroid use, which reduces acute loss of function, but has little effect on residual disability. Acute loss of function in an MS model (experimental autoimmune encephalomyelitis [EAE]) is partly due to central nervous system (CNS) hypoxia, and function can promptly improve upon breathing oxygen. Here, we investigate the cause of the hypoxia and whether it is due to a deficit in oxygen supply arising from impaired vascular perfusion. We also explore whether the CNS-selective vasodilating agent, nimodipine, may provide a therapy to restore function, and protect from demyelination in 2 MS models. METHODS: A variety of methods have been used to measure basic cardiovascular physiology, spinal oxygenation, mitochondrial function, and tissue perfusion in EAE. RESULTS: We report that the tissue hypoxia in EAE is associated with a profound hypoperfusion of the inflamed spinal cord. Treatment with nimodipine restores spinal oxygenation and can rapidly improve function. Nimodipine therapy also reduces demyelination in both EAE and a model of the early MS lesion. INTERPRETATION: Loss of function in EAE, and demyelination in EAE, and the model of the early MS lesion, seem to be due, at least in part, to tissue hypoxia due to local spinal hypoperfusion. Therapy to improve blood flow not only protects neurological function but also reduces demyelination. We conclude that nimodipine could be repurposed to offer substantial clinical benefit in MS. ANN NEUROL 2020 ANN NEUROL 2020;88:123-136.


Assuntos
Bloqueadores dos Canais de Cálcio/uso terapêutico , Encefalomielite Autoimune Experimental/tratamento farmacológico , Nimodipina/uso terapêutico , Medula Espinal/patologia , Animais , Progressão da Doença , Encefalomielite Autoimune Experimental/patologia , Feminino , Imagem por Ressonância Magnética , Masculino , Bainha de Mielina/patologia , Ratos , Ratos Sprague-Dawley
20.
J Vet Diagn Invest ; 32(3): 486-489, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32242771

RESUMO

A 2-y-old Brahman bull was presented with progressive hindlimb ataxia and paraparesis that led to recumbency. Postmortem examination revealed scattered pinpoint, red-brown foci within the brainstem and gray matter of the spinal cord, and a larger lesion within the spinal cord at the level of T13. Histology of the section of T13 contained cross-sections of nematodes consistent with Parelaphostrongylus tenuis. Evidence of inflammation was present in other affected areas of the spinal cord and brain. DNA extraction and nested PCR were performed, which demonstrated 98% identity and 100% coverage to both P. tenuis and P. andersoni. Our case highlights the utility of DNA sequencing in parasite identification.


Assuntos
Doenças dos Bovinos/parasitologia , Doenças da Medula Espinal/veterinária , Infecções por Strongylida/veterinária , Animais , Ataxia/veterinária , Encéfalo/patologia , Bovinos , Doenças dos Bovinos/patologia , Masculino , Metastrongyloidea , Reação em Cadeia da Polimerase/veterinária , Medula Espinal/patologia , Doenças da Medula Espinal/parasitologia , Infecções por Strongylida/parasitologia , Infecções por Strongylida/patologia
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