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1.
J Comput Assist Tomogr ; 44(2): 248-254, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32195804

RESUMO

We aim to review the imaging appearance of fulminant demyelinating disorders of central nervous system that have different pathological features, clinical course, clinical features, and imaging findings different from classic multiple sclerosis. Routine magnetic resonance imaging (MRI) can help in accurate localization of the lesions, detection of associated lesions, and monitoring of these patients. Advanced MRI combined with routine MRI can aid in differentiation fulminant demyelinating lesions from simulating malignancy. Tumefactive demyelination lesions are located in supratentorial white matter mainly frontal and parietal regions with incomplete rim enhancement. Baló concentric sclerosis shows characteristic concentric onion skin appearance. Schilder disease is subacute or acute demyelinating disorders with one or more lesions commonly involving the centrum semiovale. Marburg disease is the most severe demyelinating disorder with diffuse infiltrative lesions and massive edema involving both the cerebral hemisphere and brain stem.


Assuntos
Encéfalo/diagnóstico por imagem , Doenças Desmielinizantes/diagnóstico por imagem , Imagem por Ressonância Magnética/métodos , Encéfalo/patologia , Doenças Desmielinizantes/patologia , Humanos
2.
PLoS One ; 15(1): e0228109, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31978144

RESUMO

Irradiation of food at 50-55 kGy results in a profound, chronic demyelinating-remyelinating disease of the entire central nervous system (CNS) in cats, named Feline Irradiated Diet-Induced Demyelination (FIDID). This study examines the early stages of demyelination and long-term consequences of demyelination and remyelination on axon survival or loss. Myelin vacuolation is the primary defect leading to myelin breakdown, demyelination then prompt remyelination in the spinal cord and brain. There is no evidence of oligodendrocyte death. The spinal cord dorsal column is initially spared yet eventually becomes severely demyelinated with subsequent loss of axons in the core and then surface of the fasciculus gracilis. However remyelination of the sub-pial axons in the dorsal column results in their protection. While there was a lack of biochemical evidence of Vitamin B12 deficiency, the pathological similarities of FIDID with sub-acute combined degeneration (SCD) led us to explore treatment with Vitamin B12. Treatment led to recovery or improvement in some cats and neurologic relapse on cessation of B12 therapy. While the reason that irradiated food is myelinotoxic in the cat remains unresolved, nonetheless the neuropathological changes match exactly what is seen in SCD and its models and provide an ideal model to study the cellular and molecular basis of remyelination.


Assuntos
Doenças Desmielinizantes/patologia , Dieta , Degeneração Neural/patologia , Radiação , Doença Aguda , Animais , Axônios/patologia , Gatos , Doença Crônica , Doenças Desmielinizantes/sangue , Doenças Desmielinizantes/fisiopatologia , Modelos Animais de Doenças , Feminino , Macrófagos/patologia , Masculino , Metaboloma , Microglia/patologia , Bainha de Mielina/metabolismo , Degeneração Neural/sangue , Degeneração Neural/fisiopatologia , Neuropatologia , Remielinização , Medula Espinal/patologia , Medula Espinal/fisiopatologia , Fatores de Tempo , Vitamina B 12/sangue
3.
Med Sci Monit ; 25: 9679-9689, 2019 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-31848329

RESUMO

BACKGROUND The aim of this study was to determine the association between white matter lesions (WML) and diabetes-associated cognitive decline (DACD) in rat models of type 2 diabetes (T2DM). MATERIAL AND METHODS Sixty Sprague-Dawley male rats were divided into 4 groups: control, control+metformin, T2DM, and T2DM+metformin groups. The T2DM groups were fed a diet high in fat and glucose to induce impaired glucose tolerance (IGT) and then were injected with streptozotocin to induce T2DM. The Morris water maze test was used to evaluate cognitive function. Brain diffusion tensor imaging scans were performed for WML. The expression of myelin basic protein (MBP), oligodendrocyte transcription factor 1 (OLIG1), and OLIG2 (markers of brain damage and repair) was determined using immunofluorescence. After IGT, the fractional anisotropy (FA) values of the right thalamus area were significantly lower in both T2DM groups compared with controls. RESULTS Eight weeks after streptozotocin injection, the FA values of the thalamus were lower in the T2DM (bilateral thalamus) group and T2DM+metformin (left thalamus) group than in controls, while the FA values in the left thalamus area were lower in the T2DM+metformin group than in the control and control+metformin groups. The maze escape latency was longer and the number of rats passing through the platform was smaller in the T2DM and T2DM+metformin groups than in the control group. MBP levels were lower and OLIG1 and OLIG2 levels were higher in both T2DM groups than in controls. CONCLUSIONS WML is associated with DACD and appears before the onset of T2DM and signs of DACD and plays a role in diabetes-associated cognitive decline. Metformin reduces WMLs but does not rescue cognitive dysfunction.


Assuntos
Disfunção Cognitiva/complicações , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 2/complicações , Estado Pré-Diabético/complicações , Substância Branca/patologia , Animais , Anisotropia , Disfunção Cognitiva/fisiopatologia , Doenças Desmielinizantes/complicações , Doenças Desmielinizantes/patologia , Doenças Desmielinizantes/fisiopatologia , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Tipo 2/fisiopatologia , Imagem de Tensor de Difusão , Modelos Animais de Doenças , Masculino , Aprendizagem em Labirinto , Proteínas do Tecido Nervoso/metabolismo , Oligodendroglia/patologia , Estado Pré-Diabético/fisiopatologia , Ratos Sprague-Dawley , Natação , Tálamo/patologia , Tálamo/fisiopatologia , Substância Branca/fisiopatologia
4.
Life Sci ; 237: 116954, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31610192

RESUMO

Sirt3 enzyme and mitochondrial abnormality can be related to excess fatigue or muscular dysfunction in multiple sclerosis (MS).Ellagic acid (EA) has a mitochondrial protector, iron chelator, antioxidant, and axon regenerator in neurons.In this study the effect of EAon muscle dysfunction, its mitochondria, and Sirt3 enzyme incuprizone-induced model of MSwas examined. Demyelination was induced by a diet containing 0.2% w/w cuprizone (Cup) for 42 days and EA administered daily (5, 50, and 100 mg/kg P.O) either with or without cuprizone in mice. Behavioral tests were assessed, and muscle tissue markers ofoxidative stress, mitochondrial parameters, mitochondrial respiratory chain activity, the Sirt3 protein level, and Sirt3 expression were also determined. Luxol fast blue staining and the behavioral tests were performed toassess the implemented model. In Cup group an increased oxidative stress in their muscle tissues was observed. Also, muscle mitochondria exhibited mitochondria dysfunction, lowered mitochondrial respiratory chain activity, Sirt3 protein level, and Sirt3 expression.EA prevented most of these anomalous alterations. Sub-chronicEA co-treatment dose-dependently ameliorated behavioral and muscular impairment in mice that received Cup.EA can effectively protect muscle tissue against cuprizone-induced demeylination via the mitochondrial protection, oxidative stress prevention and Sirt3 overexpression.


Assuntos
Comportamento Animal/efeitos dos fármacos , Cuprizona/toxicidade , Doenças Desmielinizantes/tratamento farmacológico , Ácido Elágico/farmacologia , Mitocôndrias Musculares/efeitos dos fármacos , Doenças Musculares/prevenção & controle , Sirtuína 3/metabolismo , Animais , Quelantes/toxicidade , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/metabolismo , Doenças Desmielinizantes/patologia , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias Musculares/metabolismo , Mitocôndrias Musculares/patologia , Estresse Oxidativo/efeitos dos fármacos
5.
Int J Mol Sci ; 20(20)2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31623261

RESUMO

Hallmarks of Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease (TMEV-IDD) include spinal cord (SC) inflammation, demyelination and axonal damage occurring approximately 5-8 weeks after classical intracerebral (i.c.) infection. The aim of this study was to elucidate the consequences of intraspinal (i.s.) TMEV infection and a direct comparison of classical i.c. and intraspinal infection. Swiss Jim Lambert (SJL)-mice were i.s. infected with the BeAn strain of TMEV. Clinical investigations including a scoring system and rotarod analysis were performed on a regular basis. Necropsies were performed at 3, 7, 14, 28 and 63 days post infection (dpi) following i.s. and at 4, 7, 14, 28, 56, 98, 147 and 196 dpi following i.c. infection. Serial sections of formalin-fixed, paraffin-embedded SC and peripheral nerves (PN) were investigated using hematoxylin and eosin (HE) and immunohistochemistry. I.s. infected mice developed clinical signs and a deterioration of motor coordination approximately 12 weeks earlier than i.c. infected animals. SC inflammation, demyelination and axonal damage occurred approximately 6 weeks earlier in i.s. infected animals. Interestingly, i.s. infected mice developed PN lesions, characterized by vacuolation, inflammation, demyelination and axonal damage, which was not seen following i.c. infection. The i.s. infection model offers the advantage of a significantly earlier onset of clinical signs, inflammatory and demyelinating SC lesions and additionally enables the investigation of virus-mediated PN lesions.


Assuntos
Doenças Desmielinizantes/etiologia , Doenças Desmielinizantes/patologia , Poliomielite/patologia , Poliomielite/virologia , Theilovirus , Animais , Axônios/patologia , Encéfalo/patologia , Encéfalo/virologia , Modelos Animais de Doenças , Feminino , Imuno-Histoquímica , Camundongos , Camundongos Transgênicos , Medula Espinal/patologia , Medula Espinal/virologia , Carga Viral
6.
Neurology ; 93(20): e1852-e1866, 2019 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-31611336

RESUMO

OBJECTIVE: To characterize the distribution and regional evolution of cervical cord atrophy in patients with multiple sclerosis (MS) in a multicenter dataset. METHODS: MRI and clinical evaluations were acquired from 179 controls and 435 patients (35 clinically isolated syndromes [CIS], 259 relapsing-remitting multiple sclerosis [RRMS], 99 secondary progressive multiple sclerosis [SPMS], and 42 primary progressive multiple sclerosis [PPMS]). Sixty-nine controls and 178 patients underwent a 1-year MRI and clinical follow-up. Patients were classified as clinically stable/worsened according to their disability change. Longitudinal changes of cord atrophy were investigated with linear mixed-effect models. Sample size calculations were performed using age-, sex- and site-adjusted annualized percentage normalized cord cross-sectional area (CSAn) changes. RESULTS: Baseline CSAn was lower in patients with MS vs controls (p < 0.001), but not different between controls and patients with CIS or between patients with early RRMS (disease duration ≤5 years) and patients with CIS. Patients with late RRMS (disease duration >5 years) showed significant cord atrophy vs patients with early RRMS (p = 0.02). Patients with progressive MS had decreased CSAn (p < 0.001) vs patients with RRMS. Atrophy was located between C1/C2 and C5 in patients with RRMS vs patients with CIS, and widespread along the cord in patients with progressive MS vs patients with RRMS, with an additional C5/C6 involvement in patients with SPMS vs patients with PPMS. At follow-up, CSAn decreased in all phenotypes (p < 0.001), except CIS. Cord atrophy rates were highest in patients with early RRMS and clinically worsened patients, who had a more widespread cord involvement than stable patients. The sample size per arm required to detect a 50% treatment effect was 118 for patients with early RRMS. CONCLUSIONS: Cord atrophy increased in MS during 1 year, except for CIS. Faster atrophy contributed to explain clinical worsening.


Assuntos
Esclerose Múltipla Crônica Progressiva/diagnóstico por imagem , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Medula Espinal/diagnóstico por imagem , Adolescente , Adulto , Idoso , Atrofia , Vértebras Cervicais , Doenças Desmielinizantes/diagnóstico por imagem , Doenças Desmielinizantes/patologia , Doenças Desmielinizantes/fisiopatologia , Progressão da Doença , Feminino , Humanos , Estudos Longitudinais , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/patologia , Esclerose Múltipla/fisiopatologia , Esclerose Múltipla Crônica Progressiva/patologia , Esclerose Múltipla Crônica Progressiva/fisiopatologia , Esclerose Múltipla Recidivante-Remitente/patologia , Esclerose Múltipla Recidivante-Remitente/fisiopatologia , Medula Espinal/patologia , Adulto Jovem
7.
Exp Eye Res ; 188: 107783, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31473258

RESUMO

Placing diffusers in front of the eyes induces deprivation myopia in a variety of animal models. As a result of the low pass filtering of the retinal images, less spatial information is available to the retina which should reduce neural activity. Since it has been found that myelination of axons in the central nervous system is modulated by neuronal activity, we have studied whether ganglion cell axons may shrink in response to the restricted visual input. Young chickens were treated for 5 h or 7 days with frosted diffusers to induce deprivation myopia. Nerve fiber layer thickness was measured in vivo, using B-scan OCT. Refractive states were tracked by IR photoretinoscopy, and UV fundus reflectivity by a custom-built device which flashed an LED centered in the camera aperture and recorded pupil brightness after refractive errors were corrected by trial lenses. Moreover, structure and histology of the retinal nerve fibers layer (RNFL) were analyzed ex vivo using transmission electron microscopy and immunohistochemistry. Since chicks have both non-myelinated and myelinated fibers in their RNFL, the thickness of myelin sheaths (G ratio) was measured, as well as the percentage of myelinated axons and the diameters of unmyelinated axons. Short-term deprivation caused an increase in UV fundus reflectivity already after 5 h (measured as pixel grey levels in the pupil: 28 ±â€¯5 vs. 36 ±â€¯10, p < 0.05) and thinning of the myelin sheaths (higher G ratio), compared to untreated control eyes (0.74 ±â€¯0.01 vs. 0.79 ±â€¯0.03, p < 0.05). Neither axon diameters (0.81 ±â€¯0.05 µm vs. 0.82 ±â€¯0.15 µm) nor thickness of the RNFL had changed after only 5 h (42.9 ±â€¯1.3 µm vs. 42.3 ±â€¯2.5 µm). However, after 7 days of diffuser wear, axons had become thinner (0.56 ±â€¯0.14 µm vs. 0.78 ±â€¯0.09 µm vs, p < 0.05), which could explain the thinning of the RNFL (36.3 ±â€¯2.7 µm vs. 42.1 ±â€¯2.4 µm, p < 0.01). Furthermore, myopic eyes had 38% less myelinated axons than untreated eyes as determined by immunohistochemical labelling against myelin basic protein (immunopositive areas in the central retina 1406 ±â€¯341 µm2 vs. 2185 ±â€¯290 µm2 in controls, p < 0.001). Myelin sheaths in the remaining axons remained unchanged (G ratio 0.76 ±â€¯0.02 vs. 0.76 ±â€¯0.03). Our study shows that deprivation myopia is associated with a significant loss of myelinated axons and shrinkage of the axon diameters of certain fibers in the RNFL. Early changes were already detected after 5 h and were accompanied by an increased fundus reflectivity in UV light. These parameters could therefore serve as the biomarkers for myopia development, at least in the chicken.


Assuntos
Axônios/patologia , Doenças Desmielinizantes/patologia , Miopia/patologia , Células Ganglionares da Retina/patologia , Animais , Axônios/metabolismo , Galinhas , Modelos Animais de Doenças , Imuno-Histoquímica , Masculino , Microscopia Eletrônica de Transmissão , Bainha de Mielina/metabolismo , Miopia/metabolismo , Células Ganglionares da Retina/metabolismo , Retinoscopia , Privação Sensorial , Tomografia de Coerência Óptica/métodos
8.
Neurology ; 93(15): e1439-e1451, 2019 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-31501228

RESUMO

OBJECTIVES: To evaluate intrathecal immunoglobulin M (IgM) production, as compared to previously established risk factors, as risk factor for conversion from clinically isolated syndrome (CIS) to multiple sclerosis (MS) and to explore the association of intrathecal IgM production with onset age and radiologic and CSF findings in CIS/early MS. METHODS: Comprehensive CSF data, including oligoclonal immunoglobulin G (IgG) bands (OCB) and calculated intrathecal IgM and IgG production, were collected in a prospective study of 150 patients with CIS/early MS with regular clinical and MRI assessments. RESULTS: Intrathecal IgM production >0% occurred in 23.2% (33/142) of patients, who were on average 5 years younger at disease onset (p = 0.013) and more frequently had infratentorial lesions (18/32, 56.3%) than patients without intrathecal IgM production (33/104, 31.7%, p = 0.021). In multivariable Cox regression analyses, intrathecal IgM production in patients with a CIS (n = 93, median clinical and MRI follow-up 24 and 21 months) was strongly associated with conversion to MS according to the McDonald 2010 criteria (hazard ratio [95% confidence interval] 3.05 [1.45-6.44], p = 0.003) after adjustment for age (0.96 [0.93-1.00], p = 0.059), OCB (0.92 [0.33-2.61], p = 0.879), intrathecal IgG production (0.98 [0.48-1.99], p = 0.947), and radiologic evidence of dissemination in space (2.63 [1.11-6.22], p = 0.028). CONCLUSION: Intrathecal IgM production is a strong independent risk factor for early conversion to MS and may thus represent a clinically meaningful marker for predicting future disease activity in patients with a CIS.


Assuntos
Doenças Desmielinizantes/metabolismo , Imunoglobulina M/metabolismo , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Adulto , Idade de Início , Idoso , Doenças Desmielinizantes/patologia , Progressão da Doença , Feminino , Humanos , Imunoglobulina G/metabolismo , Masculino , Pessoa de Meia-Idade , Bandas Oligoclonais/metabolismo , Fatores de Risco , Índice de Gravidade de Doença
9.
Exp Neurol ; 321: 113034, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31415741

RESUMO

Depression is the most common comorbidity among patients with epilepsy. Despite prior assumptions that antiepileptic drugs are to blame, more and more pathological studies have shown that latent neurological alterations associated with white matter injury and demyelination may underlie this link. However, whether disturbances in cerebral myelination contribute to the initiation of depression in epilepsy remains unclear. In the present study, we investigated the connection between demyelination disorders and the development of depression comorbidity in epilepsy. We first induced spontaneous recurrent epilepticus seizure (SRS) in young rats with pilocarpine. We then established depressive behaviors by recurrent forced swimming test and evaluate the depression state by sucrose preference test. The ratio of depression comorbidity in SRS rats was then calculated. Next, myelination in SRS-Depressed (SRS-D) rats was explored via PCR, western blotting, and immunohistochemistry for the key myelin promotion factor, Olig2 and inhibition factor, LINGO-1. Finally, in situ RNA hybridization of NCX3, one of the dominant Ca2+ extrusion proteins in oligodendrocytes (OLs) was performed to explore whether Ca2+ homeostasis of OLs was disturbed in epilepsy-induced hypoxic conditions and involved in the epilepsy-depression comorbidity. Our results revealed that one-quarter of the SRS rats displayed typical depressive behaviors, which were defined as SRS-D rats. In SRS-D rats, severe demyelination was also observed, accompanied with reduced expression of MBP, Olig2, and NCX3 and increased expression of LINGO-1 in the cingulate gyrus. In SRS-Non depressed rats, no significant changes were found from the control animals. This work provides new insights into the demyelination in epilepsy-depression comorbidity, which involves dysregulation of Olig2/LINGO-1 and disturbance of Ca2+ homeostasis.


Assuntos
Cálcio/metabolismo , Doenças Desmielinizantes/patologia , Depressão/metabolismo , Estado Epiléptico/patologia , Animais , Doença Crônica , Doenças Desmielinizantes/etiologia , Doenças Desmielinizantes/metabolismo , Depressão/etiologia , Depressão/patologia , Modelos Animais de Doenças , Homeostase , Masculino , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Fator de Transcrição 2 de Oligodendrócitos/metabolismo , Ratos , Ratos Sprague-Dawley , Estado Epiléptico/complicações , Estado Epiléptico/metabolismo
10.
Int J Mol Sci ; 20(16)2019 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-31409036

RESUMO

Astrocytes play a key role in demyelinating diseases, like multiple sclerosis (MS), although many of their functions remain unknown. The aim of this study was to investigate the impact of astrocyte depletion upon de- and remyelination, inflammation, axonal damage, and virus distribution in Theiler`s murine encephalomyelitis (TME). Groups of two to six glial fibrillary acidic protein (GFAP)-thymidine-kinase transgenic SJL mice and SJL wildtype mice were infected with TME virus (TMEV) or mock (vehicle only). Astrocyte depletion was induced by the intraperitoneal administration of ganciclovir during the early and late phase of TME. The animals were clinically investigated while using a scoring system and a rotarod performance test. Necropsies were performed at 46 and 77 days post infection. Cervical and thoracic spinal cord segments were investigated using hematoxylin and eosin (H&E), luxol fast blue-cresyl violet (LFB), immunohistochemistry targeting Amigo2, aquaporin 4, CD3, CD34, GFAP, ionized calcium-binding adapter molecule 1 (Iba1), myelin basic protein (MBP), non-phosphorylated neurofilaments (np-NF), periaxin, S100A10, TMEV, and immunoelectron microscopy. The astrocyte depleted mice showed a deterioration of clinical signs, a downregulation and disorganization of aquaporin 4 in perivascular astrocytes accompanied by vascular leakage. Furthermore, astrocyte depleted mice showed reduced inflammation and lower numbers of TMEV positive cells in the spinal cord. The present study indicates that astrocyte depletion in virus triggered CNS diseases contributes to a deterioration of clinical signs that are mediated by a dysfunction of perivascular astrocytes.


Assuntos
Astrócitos/patologia , Doenças Desmielinizantes/patologia , Inflamação/patologia , Esclerose Múltipla/patologia , Animais , Astrócitos/virologia , Infecções por Cardiovirus/complicações , Infecções por Cardiovirus/patologia , Infecções por Cardiovirus/virologia , Doenças Desmielinizantes/complicações , Doenças Desmielinizantes/virologia , Modelos Animais de Doenças , Feminino , Inflamação/complicações , Inflamação/virologia , Camundongos , Esclerose Múltipla/etiologia , Esclerose Múltipla/virologia , Theilovirus/isolamento & purificação
11.
Nat Commun ; 10(1): 3887, 2019 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-31467299

RESUMO

Oligodendrocyte precursor cells (OPCs) are abundant in the adult central nervous system, and have the capacity to regenerate oligodendrocytes and myelin. However, in inflammatory diseases such as multiple sclerosis (MS) remyelination is often incomplete. To investigate how neuroinflammation influences OPCs, we perform in vivo fate-tracing in an inflammatory demyelinating mouse model. Here we report that OPC differentiation is inhibited by both effector T cells and IFNγ overexpression by astrocytes. IFNγ also reduces the absolute number of OPCs and alters remaining OPCs by inducing the immunoproteasome and MHC class I. In vitro, OPCs exposed to IFNγ cross-present antigen to cytotoxic CD8 T cells, resulting in OPC death. In human demyelinated MS brain lesions, but not normal appearing white matter, oligodendroglia exhibit enhanced expression of the immunoproteasome subunit PSMB8. Therefore, OPCs may be co-opted by the immune system in MS to perpetuate the autoimmune response, suggesting that inhibiting immune activation of OPCs may facilitate remyelination.


Assuntos
Antígenos/imunologia , Sistema Nervoso Central/imunologia , Doenças Desmielinizantes/imunologia , Células Precursoras de Oligodendrócitos/imunologia , Células Precursoras de Oligodendrócitos/metabolismo , Animais , Células Apresentadoras de Antígenos/imunologia , Astrócitos/metabolismo , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Caspase 3/metabolismo , Caspase 7/metabolismo , Diferenciação Celular , Sistema Nervoso Central/metabolismo , Citocinas/genética , Citocinas/metabolismo , Doenças Desmielinizantes/patologia , Modelos Animais de Doenças , Expressão Gênica , Antígenos de Histocompatibilidade Classe I , Humanos , Interferon gama , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia , Bainha de Mielina/metabolismo , Células Precursoras de Oligodendrócitos/efeitos dos fármacos , Células Precursoras de Oligodendrócitos/patologia , Oligodendroglia/metabolismo , Ovalbumina/metabolismo , Remielinização/imunologia , Linfócitos T
12.
Exp Neurol ; 321: 113040, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31445042

RESUMO

Traumatic brain injury (TBI) often damages axons in white matter tracts and causes corpus callosum (CC) atrophy in chronic TBI patients. Injured axons encounter irreversible damage if transected, or alternatively may maintain continuity and subsequently either recover or degenerate. Secondary mechanisms can cause further axon damage, myelin pathology, and neuroinflammation. Molecular mechanisms regulating the progression of white matter pathology indicate potential therapeutic targets. SARM1 is essential for execution of the conserved axon death pathway. We examined white matter pathology following mild TBI with CC traumatic axonal injury in mice with Sarm1 gene deletion (Sarm1-/-). High resolution ultrastructural analysis at 3 days post-TBI revealed dramatically reduced axon damage in Sarm1-/- mice, as compared to Sarm1+/+ wild-type controls. Sarm1 deletion produced larger axons with thinner myelin, and attenuated TBI induced demyelination, i.e. myelin loss along apparently intact axons. At 6 weeks post-TBI, Sarm1-/- mice had less demyelination and thinner myelin than Sarm1+/+ mice, but axonal protection was no longer observed. We next used Thy1-YFP crosses to assess Sarm1 involvement in white matter neurodegeneration and neuroinflammation at 8 weeks post-TBI, when significant CC atrophy indicates chronic pathology. Thy1-YFP expression demonstrated continued CC axon damage yet absence of overt cortical pathology. Importantly, significant CC atrophy in Thy1-YFP/Sarm1+/+ mice was associated with reduced neurofilament immunolabeling of axons. Both effects were attenuated in Thy1-YFP/Sarm1-/- mice. Surprisingly, Thy1-YFP/Sarm1-/- mice had increased CC astrogliosis. This study demonstrates that Sarm1 inactivation reduces demyelination, and white matter atrophy after TBI, while the post-injury stage impacts when axon protection is effective.


Assuntos
Proteínas do Domínio Armadillo/deficiência , Lesões Encefálicas Traumáticas/patologia , Proteínas do Citoesqueleto/deficiência , Doenças Desmielinizantes/patologia , Substância Branca/patologia , Animais , Atrofia/metabolismo , Atrofia/patologia , Axônios/metabolismo , Axônios/patologia , Lesões Encefálicas Traumáticas/metabolismo , Doenças Desmielinizantes/metabolismo , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Substância Branca/metabolismo
13.
Neurology ; 93(7): e647-e652, 2019 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-31337714

RESUMO

OBJECTIVE: To perform a systematic analysis and scoring of brain MRI white matter hyperintensities (WMH) in adult-onset Krabbe disease. METHODS: We retrospectively collected basic clinical data and the first available brain MRI from patients with confirmed Krabbe disease with first clinical manifestations beyond 10 years of age. Data were obtained from our reference center for lysosomal diseases (n = 6) and from contacted authors of published articles describing patients with adult-onset Krabbe disease (n = 15). T2-weighted fluid-attenuated inversion recovery images of each patient were analyzed and scored using a radiologic score of WMH in a single center. RESULTS: The corticospinal tract was always affected by WMH (100% of patients), however, with some distinctions along the tract: the precentral gyrus (100%), corona radiata (95%), and posterior internal capsule (81%) were highly abnormal, whereas the mesencephalon (57%), pons (52%), and medulla oblongata (5%) were less affected. WMH were also frequently present in the posterior lateral periventricular white matter (95%), optic radiations (86%), postcentral gyrus (71%), medial lemniscus (62%), and corpus callosum, especially in the isthmus (71%), whereas the genu was always normal. A few patients did not have the classical MRI pattern but extensive hyperintensities (n = 3), or patchy distribution of hyperintensities mimicking an acquired etiology (n = 2), or very subtle hyperintensities of the corticospinal tract (n = 1). CONCLUSIONS: We specified the main locations of WMH, which were observed in the earliest stages of the disease and were also present in patients with atypical MRI pattern, highlighting the importance of radiologic features to guide the diagnosis.


Assuntos
Encéfalo/diagnóstico por imagem , Leucodistrofia de Células Globoides/patologia , Adolescente , Adulto , Idade de Início , Idoso , Criança , Corpo Caloso/patologia , Doenças Desmielinizantes/patologia , Feminino , Humanos , Cápsula Interna/patologia , Leucodistrofia de Células Globoides/diagnóstico por imagem , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Tratos Piramidais/patologia , Substância Branca/patologia , Adulto Jovem
14.
Neurol India ; 67(3): 783-786, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31347555

RESUMO

Demyelination, neurofibrillary tangles, and axonal spheroids are neuropathological features rarely encountered in infantile form of Niemann-Pick disease type C compared to swollen neurons and neuronal loss which are more commonly seen. We describe clinico-pathological findings in an autopsy case of an infant who died of suspected inborn error of metabolism. At autopsy, storage cells of Niemann-Pick type were observed in plenty in spleen and lymph nodes, and sparsely in liver and brain. Preterminally, the child also developed fungal meningitis with minimal boderzone encephalitis. The neuropathological findings are unique and have been illustrated in detail.Congenital anomaly of the urogenital system was an incidental associated finding.


Assuntos
Encéfalo/patologia , Doenças Desmielinizantes/diagnóstico , Doenças Desmielinizantes/patologia , Doença de Niemann-Pick Tipo C/diagnóstico , Doença de Niemann-Pick Tipo C/patologia , Encéfalo/diagnóstico por imagem , Doenças Desmielinizantes/complicações , Humanos , Lactente , Masculino , Doença de Niemann-Pick Tipo C/complicações
15.
Mult Scler Relat Disord ; 34: 1-8, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31202958

RESUMO

BACKGROUND: Multiple sclerosis (MS) has been shown to feature oxidative damage, which can be modelled using the cuprizone model of demyelinating disease. Oxidative damage can occur as a result of excessive influx of calcium ions (Ca2+) and oligodendroglia are particularly vulnerable. However, the effects of limiting excess Ca2+ influx on oxidative damage, oligodendroglia and myelin structure are unknown. OBJECTIVE: This study investigated the effects of limiting excess Ca2+ flux on oxidative damage and associated changes in oligodendroglial densities and Node of Ranvier structure in the cuprizone model. METHODS: The effects of three weeks of cuprizone administration and of treatment with a combination of three ion channel inhibitors (Lomerizine, Brilliant Blue G (BBG) and YM872), were semi-quantified immunohistochemically. Outcomes assessed were protein nitration (3-nitrotyrosine (3NT)) oxidative damage to DNA (8-hydroxy deoxyguanosine (8OHDG)), advanced glycation end-products (carboxymethyl lysine (CML)), immunoreactivity of microglia (Iba1) and astrocytes (glial acidic fibrillary protein (GFAP)), densities of oligodendrocyte precursor cells (OPCs) (platelet derived growth factor alpha receptor (PDGFαR) with olig2) and oligodendrocytes (olig2 and CC1), and structural elements of the Node of Ranvier (contactin associated protein (Caspr)). RESULTS: The administration of cuprizone resulted in increased protein nitration, DNA damage, and astrocyte and microglial immunoreactivity, a decrease in the density of oligodendrocytes and OPCs, together with altered structure of the Node of Ranvier and reduced myelin basic protein immunoreactivity. Treatment with the ion channel inhibitor combination significantly lowered protein nitration, increased the density of OPCs and reduced the number of atypical Node of Ranvier complexes; other outcomes were unaffected. CONCLUSION: Our findings suggest that excess Ca2+ influx contributes to protein nitration, and associated changes to OPC densities and Node of Ranvier structure in demyelinating disease.


Assuntos
Doenças Desmielinizantes/tratamento farmacológico , Doenças Desmielinizantes/patologia , Canais Iônicos/antagonistas & inibidores , Fármacos Neuroprotetores/farmacologia , Animais , Cálcio/metabolismo , Cátions Bivalentes/metabolismo , Corpo Caloso/efeitos dos fármacos , Corpo Caloso/metabolismo , Corpo Caloso/patologia , Cuprizona , Doenças Desmielinizantes/metabolismo , Modelos Animais de Doenças , Quimioterapia Combinada , Masculino , Camundongos Endogâmicos C57BL , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Neuroglia/patologia , Estresse Oxidativo/efeitos dos fármacos , Distribuição Aleatória
16.
Glia ; 67(9): 1775-1792, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31184779

RESUMO

Oligodendrocytes (OLs) provide the myelin sheath surrounding axons that propagates action potentials in the central nervous system (CNS). The metabolism of myelinated membranes and proteins is strictly regulated in the OLs and is closely associated with OL differentiation and maturation. The ubiquitination-associated proteasome and endosomal system have not yet been well studied during OL differentiation and maturation. Here, we determined the functions of the Lys63-linked ubiquitination (K63Ub) and K63-specific deubiquitination (DUB) systems regulated by BRCA1/BRCA2-containing complex subunit 3 (BRCC3) during OL differentiation. The competitive inhibition of K63Ub by overexpression of mutant ubiquitin (K63R) in oligodendrocyte precursor cells (OPCs) indicated that the two major CNS myelin proteins, myelin basic protein (MBP) and proteolipid protein (PLP), were upregulated in OLs derived from K63R OPCs. In contrast, the knockdown of BRCC3 (BRCC3-KD) through the application of lentivirus-mediated shRNA delivery system into OPCs suppressed OL differentiation by decreasing MBP expression and PLP production. Further immunoprecipitation assays revealed higher levels of sphingolipid GalC, MBP, and PLP, which were associated with K63Ub-immunoprecipitants and detected in endosome/lysosomal compartments, in BRCC3-KD OLs than those in OLs transfected with the scrambled shRNA (scramble OLs). The differentiation of OLs from BRCC3-KD OPCs was impaired in the demyelinating corpus callosum of rats receiving a cuprizone-containing diet. In the demyelinating tissues from human patients suffering from multiple sclerosis, we detected a decreased number of BRCC3-expressing OLs at the lesion site, accompanied by a greater number of OLs expressing EEA1 and K63Ub at high levels. Altogether, the counterbalance of the K63Ub machinery and BRCC3-triggered DUB machinery are important for the cellular trafficking of myelin proteins and OL differentiation.


Assuntos
Enzimas Desubiquitinantes/metabolismo , Neurogênese/fisiologia , Oligodendroglia/metabolismo , Ubiquitinação/fisiologia , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Células Cultivadas , Doenças Desmielinizantes/metabolismo , Doenças Desmielinizantes/patologia , Endossomos/metabolismo , Endossomos/patologia , Humanos , Lisossomos/metabolismo , Lisossomos/patologia , Masculino , Proteínas da Mielina/metabolismo , Células Precursoras de Oligodendrócitos/metabolismo , Células Precursoras de Oligodendrócitos/patologia , Oligodendroglia/patologia , Ratos Sprague-Dawley
17.
PLoS Genet ; 15(6): e1008180, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31170158

RESUMO

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system characterized by myelin loss and neuronal dysfunction. Although the majority of patients do not present familial aggregation, Mendelian forms have been described. We performed whole-exome sequencing analysis in 132 patients from 34 multi-incident families, which nominated likely pathogenic variants for MS in 12 genes of the innate immune system that regulate the transcription and activation of inflammatory mediators. Rare missense or nonsense variants were identified in genes of the fibrinolysis and complement pathways (PLAU, MASP1, C2), inflammasome assembly (NLRP12), Wnt signaling (UBR2, CTNNA3, NFATC2, RNF213), nuclear receptor complexes (NCOA3), and cation channels and exchangers (KCNG4, SLC24A6, SLC8B1). These genes suggest a disruption of interconnected immunological and pro-inflammatory pathways as the initial event in the pathophysiology of familial MS, and provide the molecular and biological rationale for the chronic inflammation, demyelination and neurodegeneration observed in MS patients.


Assuntos
Predisposição Genética para Doença , Inflamação/genética , Esclerose Múltipla/genética , Transcriptoma/genética , Adulto , Códon sem Sentido , Doenças Desmielinizantes/genética , Doenças Desmielinizantes/patologia , Exoma/genética , Feminino , Humanos , Inflamação/metabolismo , Inflamação/patologia , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Bainha de Mielina/genética , Bainha de Mielina/patologia , Degeneração Neural/genética , Degeneração Neural/patologia , Neurônios/metabolismo , Neurônios/patologia , Linhagem , Sequenciamento Completo do Exoma , Adulto Jovem
18.
Neurochem Res ; 44(8): 1964-1976, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31218567

RESUMO

Schwann cells are essential glial cells in the peripheral nervous system (PNS), and dysfunction of Schwann cells can induce various peripheral neurodegenerative diseases. Oxidative stress has been implicated as a causative factor in degenerative nerve diseases; however, there no effective molecules are available to inhibit nerve degeneration in peripheral neurodegenerative diseases. Ethyl pyruvate (EP) is a candidate regulator of oxidative stress, targeting Schwann cells during peripheral nerve degeneration. Here, we investigated the effects of EP on axonal degradation, demyelination, transcriptional regulation, and macrophage recruitment during Wallerian degeneration of the sciatic nerve, ex vivo and in vivo. EP prevented the expression of neuronal nitric oxide synthase (NOS1), but not that of inducible nitric oxide synthase (NOS2), during Wallerian degeneration. These results suggest that effect of EP on Schwann cells may protect against peripheral nerve degeneration through its NOS1-specific regulation.


Assuntos
Inibidores Enzimáticos/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Óxido Nítrico Sintase Tipo I/antagonistas & inibidores , Piruvatos/uso terapêutico , Células de Schwann/efeitos dos fármacos , Degeneração Walleriana/prevenção & controle , Animais , Axônios/efeitos dos fármacos , Doenças Desmielinizantes/patologia , Doenças Desmielinizantes/prevenção & controle , Macrófagos/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Bainha de Mielina/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-jun/metabolismo , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/patologia , Degeneração Walleriana/patologia
19.
Elife ; 82019 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-31063129

RESUMO

Oligodendrocytes (OLs) support neurons and signal transmission in the central nervous system (CNS) by enwrapping axons with myelin, a lipid-rich membrane structure. We addressed the significance of fatty acid (FA) synthesis in OLs by depleting FA synthase (FASN) from OL progenitor cells (OPCs) in transgenic mice. While we detected no effects in proliferation and differentiation along the postnatal OL lineage, we found that FASN is essential for accurate myelination, including myelin growth. Increasing dietary lipid intake could partially compensate for the FASN deficiency. Furthermore, FASN contributes to correct myelin lipid composition and stability of myelinated axons. Moreover, we depleted FASN specifically in adult OPCs to examine its relevance for remyelination. Applying lysolecithin-induced focal demyelinating spinal cord lesions, we found that FA synthesis is essential to sustain adult OPC-derived OLs and efficient remyelination. We conclude that FA synthesis in OLs plays key roles in CNS myelination and remyelination.


Assuntos
Sistema Nervoso Central/citologia , Sistema Nervoso Central/metabolismo , Ácidos Graxos/metabolismo , Bainha de Mielina/metabolismo , Células-Tronco Neurais/fisiologia , Oligodendroglia/metabolismo , Remielinização , Animais , Diferenciação Celular , Proliferação de Células , Doenças Desmielinizantes/patologia , Modelos Animais de Doenças , Ácido Graxo Sintase Tipo I/deficiência , Ácido Graxo Sintase Tipo I/metabolismo , Camundongos Transgênicos
20.
Physiol Rev ; 99(3): 1381-1431, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31066630

RESUMO

Oligodendrocytes generate multiple layers of myelin membrane around axons of the central nervous system to enable fast and efficient nerve conduction. Until recently, saltatory nerve conduction was considered the only purpose of myelin, but it is now clear that myelin has more functions. In fact, myelinating oligodendrocytes are embedded in a vast network of interconnected glial and neuronal cells, and increasing evidence supports an active role of oligodendrocytes within this assembly, for example, by providing metabolic support to neurons, by regulating ion and water homeostasis, and by adapting to activity-dependent neuronal signals. The molecular complexity governing these interactions requires an in-depth molecular understanding of how oligodendrocytes and axons interact and how they generate, maintain, and remodel their myelin sheaths. This review deals with the biology of myelin, the expanded relationship of myelin with its underlying axons and the neighboring cells, and its disturbances in various diseases such as multiple sclerosis, acute disseminated encephalomyelitis, and neuromyelitis optica spectrum disorders. Furthermore, we will highlight how specific interactions between astrocytes, oligodendrocytes, and microglia contribute to demyelination in hereditary white matter pathologies.


Assuntos
Sistema Nervoso Central/patologia , Sistema Nervoso Central/fisiologia , Bainha de Mielina/fisiologia , Envelhecimento/patologia , Envelhecimento/fisiologia , Animais , Doenças Desmielinizantes/patologia , Humanos , Bainha de Mielina/ultraestrutura
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