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1.
J Neurovirol ; 26(5): 631-641, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32876900

RESUMO

A subset of patients with coronavirus 2 disease (COVID-19) experience neurological complications. These complications include loss of sense of taste and smell, stroke, delirium, and neuromuscular signs and symptoms. The etiological agent of COVID-19 is SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), an RNA virus with a glycoprotein-studded viral envelope that uses ACE2 (angiotensin-converting enzyme 2) as a functional receptor for infecting the host cells. Thus, the interaction of the envelope spike proteins with ACE2 on host cells determines the tropism and virulence of SARS-CoV-2. Loss of sense of taste and smell is an initial symptom of COVID-19 because the virus enters the nasal and oral cavities first and the epithelial cells are the receptors for these senses. Stroke in COVID-19 patients is likely a consequence of coagulopathy and injury to cerebral vascular endothelial cells that cause thrombo-embolism and stroke. Delirium and encephalopathy in acute and post COVID-19 patients are likely multifactorial and secondary to hypoxia, metabolic abnormalities, and immunological abnormalities. Thus far, there is no clear evidence that coronaviruses cause inflammatory neuromuscular diseases via direct invasion of peripheral nerves or muscles or via molecular mimicry. It appears that most of neurologic complications in COVID-19 patients are indirect and as a result of a bystander injury to neurons.


Assuntos
Betacoronavirus/patogenicidade , Encefalopatias/complicações , Infecções por Coronavirus/complicações , Transtornos do Olfato/complicações , Pneumonia Viral/complicações , Embolia Pulmonar/complicações , Acidente Vascular Cerebral/complicações , Encéfalo/irrigação sanguínea , Encéfalo/patologia , Encéfalo/virologia , Encefalopatias/imunologia , Encefalopatias/patologia , Encefalopatias/virologia , Efeito Espectador , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Células Epiteliais/patologia , Células Epiteliais/virologia , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Pulmão/irrigação sanguínea , Pulmão/patologia , Pulmão/virologia , Neurônios/patologia , Neurônios/virologia , Transtornos do Olfato/imunologia , Transtornos do Olfato/patologia , Transtornos do Olfato/virologia , Pandemias , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/imunologia , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Embolia Pulmonar/imunologia , Embolia Pulmonar/patologia , Embolia Pulmonar/virologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Acidente Vascular Cerebral/imunologia , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/virologia
2.
PLoS One ; 15(8): e0237883, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32866169

RESUMO

Although whole-genome sequencing has provided novel insights into Neisseria meningitidis, many open reading frames have only been annotated as hypothetical proteins with unknown biological functions. Our previous genetic analyses revealed that the hypothetical protein, NMB1345, plays a crucial role in meningococcal infection in human brain microvascular endothelial cells; however, NMB1345 has no homology to any identified protein in databases and its physiological function could not be elucidated using pre-existing methods. Among the many biological technologies to examine transient protein-protein interaction in vivo, one of the developed methods is genetic code expansion with non-canonical amino acids (ncAAs) utilizing a pyrrolysyl-tRNA synthetase/tRNAPyl pair from Methanosarcina species: However, this method has never been applied to assign function-unknown proteins in pathogenic bacteria. In the present study, we developed a new method to genetically incorporate ncAAs-encoded photocrosslinking probes into N. meningitidis by utilizing a pyrrolysyl-tRNA synthetase/tRNAPyl pair and elucidated the biological function(s) of the NMB1345 protein. The results revealed that the NMB1345 protein directly interacts with PilE, a major component of meningococcal pili, and further physicochemical and genetic analyses showed that the interaction between the NMB1345 protein and PilE was important for both functional pilus formation and meningococcal infectious ability in N. meningitidis. The present study using this new methodology for N. meningitidis provides novel insights into meningococcal pathogenesis by assigning the function of a hypothetical protein.


Assuntos
Aminoácidos/genética , Reagentes para Ligações Cruzadas/metabolismo , Luz , Neisseria meningitidis/genética , Proteínas de Bactérias/genética , Proteínas de Bactérias/isolamento & purificação , Encéfalo/irrigação sanguínea , Endocitose , Células Endoteliais/microbiologia , Fímbrias Bacterianas/metabolismo , Humanos , Microvasos/patologia , Mutação/genética , Plasmídeos/genética
3.
Medicine (Baltimore) ; 99(36): e22068, 2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-32899073

RESUMO

INTRODUCTION: Nearly 20% of night shift nurses will cause shift work disorder (SWD) due to the disruption of sleep-wake cycle, which not only affects the daily work efficiency, but also brings a huge burden on physical and mental health. Acupuncture is a safe and effective intervention on SWD. This trial will combine with functional magnetic resonance imaging (fMRI) to study the clinical effects and potential mechanism of acupuncture in the treatment of SWD. METHODS AND ANALYSIS: This is a randomized controlled neuroimaging trial, with enrolled participants, outcome assessors, and data statisticians blinded. 60 patients with SWD and 30 healthy controls who sleep regularly will be recruited and divided into divided into a control group, a true acupoints treatment group (TATG) and a sham acupoints treatment group (SATG) by the ratio of 1:1:1. The TATG and SATG will receive 8 sessions of acupuncture treatment in 4 weeks. Cognitive function scales and MRI scanning will be performed before and after 4-week acupuncture treatment. The control group will receive no intervention. Functional connectivity of intra-network and inter-network will be the primary outcome and effect indicator. The secondary outcomes included Repeatable Battery for the Assessment of Neuropsychological Status, Attentional Network Test, Pittsburgh Sleep Quality Index scale and needle sensation assessment scale. Neuroimage indicators will be correlated with clinical data and scores of cognitive function assessment to explore the possible mechanisms underlying the changes of brain activity caused by acupuncture treatment. DISCUSSION: The results of this study will enable us to verify the therapeutic effect of acupuncture on SWD and explore the potential central mechanism of acupuncture on SWD from the change of brain activity.


Assuntos
Terapia por Acupuntura/métodos , Encéfalo/diagnóstico por imagem , Imagem por Ressonância Magnética/métodos , Transtornos do Sono do Ritmo Circadiano/terapia , Pontos de Acupuntura , Terapia por Acupuntura/efeitos adversos , Adulto , Encéfalo/irrigação sanguínea , Encéfalo/fisiopatologia , Estudos de Casos e Controles , China/epidemiologia , Cognição/fisiologia , Feminino , Humanos , Testes Neuropsicológicos , Enfermeiras e Enfermeiros/psicologia , Avaliação de Resultados em Cuidados de Saúde , Transtornos do Sono do Ritmo Circadiano/psicologia
4.
J Neurovirol ; 26(5): 631-641, 2020 10.
Artigo em Inglês | MEDLINE | ID: covidwho-739689

RESUMO

A subset of patients with coronavirus 2 disease (COVID-19) experience neurological complications. These complications include loss of sense of taste and smell, stroke, delirium, and neuromuscular signs and symptoms. The etiological agent of COVID-19 is SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), an RNA virus with a glycoprotein-studded viral envelope that uses ACE2 (angiotensin-converting enzyme 2) as a functional receptor for infecting the host cells. Thus, the interaction of the envelope spike proteins with ACE2 on host cells determines the tropism and virulence of SARS-CoV-2. Loss of sense of taste and smell is an initial symptom of COVID-19 because the virus enters the nasal and oral cavities first and the epithelial cells are the receptors for these senses. Stroke in COVID-19 patients is likely a consequence of coagulopathy and injury to cerebral vascular endothelial cells that cause thrombo-embolism and stroke. Delirium and encephalopathy in acute and post COVID-19 patients are likely multifactorial and secondary to hypoxia, metabolic abnormalities, and immunological abnormalities. Thus far, there is no clear evidence that coronaviruses cause inflammatory neuromuscular diseases via direct invasion of peripheral nerves or muscles or via molecular mimicry. It appears that most of neurologic complications in COVID-19 patients are indirect and as a result of a bystander injury to neurons.


Assuntos
Betacoronavirus/patogenicidade , Encefalopatias/complicações , Infecções por Coronavirus/complicações , Transtornos do Olfato/complicações , Pneumonia Viral/complicações , Embolia Pulmonar/complicações , Acidente Vascular Cerebral/complicações , Encéfalo/irrigação sanguínea , Encéfalo/patologia , Encéfalo/virologia , Encefalopatias/imunologia , Encefalopatias/patologia , Encefalopatias/virologia , Efeito Espectador , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Células Epiteliais/patologia , Células Epiteliais/virologia , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Pulmão/irrigação sanguínea , Pulmão/patologia , Pulmão/virologia , Neurônios/patologia , Neurônios/virologia , Transtornos do Olfato/imunologia , Transtornos do Olfato/patologia , Transtornos do Olfato/virologia , Pandemias , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/imunologia , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Embolia Pulmonar/imunologia , Embolia Pulmonar/patologia , Embolia Pulmonar/virologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Acidente Vascular Cerebral/imunologia , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/virologia
5.
J Comput Assist Tomogr ; 44(5): 708-713, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32936578

RESUMO

OBJECTIVE: Assessing collateral status is important in acute ischemic stroke (AIS). The purpose of this study was to establish an easy and rapid method for evaluating collateral flow. METHODS: A total of 60 patients with AIS were enrolled. The patients were aged 18 to 85 years with endovascular therapy treatment within 10 hours after the appearance of stroke symptoms, prestroke modified Rankin Scale ≤1, Alberta Stroke Program Early CT Score ≥6, and the occlusion of large vessels in anterior circulation. We reformed imaging strategies by conducting a small-dose group-injection test before normal computed tomography angiography (CTA) scanning and selected the visual collateral score and the regional leptomeningeal score scales as the single-phase CTA collateral flow assessment scales with the replacement of the parasagittal anterior cerebral artery territory by anterior cerebral artery regions adjacent to the longitudinal fissure and then verified, respectively, the consistencies between the 2 single-phase CTA-based collateral scales and the digital subtraction angiography (DSA)-based American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology scale and compared the prognosis of endovascular therapy between the AIS patients in the poor-collateral-flow group and the other patients' group assessed by 2 single-phase CTA-based collateral scales. RESULTS: There was a high consistency between the 2 single-phase CTA-based collateral flow scales with DSA-based American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology scale. The assessment by using CTA-based collateral flow assessment methods generated consistent results. CONCLUSION: The single-phase CTA-based visual collateral score scale and regional leptomeningeal score scale can be used as the imaging evidence for the evaluation of collateral flow in AIS patients in the majority of grassroots hospitals where DSA is difficult to carry out.


Assuntos
Isquemia Encefálica/diagnóstico por imagem , Angiografia Cerebral/métodos , Circulação Colateral/fisiologia , Angiografia por Tomografia Computadorizada/métodos , Acidente Vascular Cerebral/diagnóstico por imagem , Idoso , Angiografia Digital/métodos , Encéfalo/irrigação sanguínea , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Isquemia Encefálica/complicações , Isquemia Encefálica/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/fisiopatologia
6.
J Neurovirol ; 26(5): 802-804, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32797352
7.
PLoS One ; 15(8): e0235691, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32857763

RESUMO

Exercise exerts a beneficial effect on the major pathological and clinical symptoms associated with Alzheimer's disease in humans and mouse models of the disease. While numerous mechanisms for such benefits from exercise have been proposed, a clear understanding of the causal links remains elusive. Recent studies also suggest that cerebral blood flow in the brain of both Alzheimer's patients and mouse models of the disease is decreased and that the cognitive symptoms can be improved when blood flow is restored. We therefore hypothesized that the mitigating effect of exercise on the development and progression of Alzheimer's disease may be mediated through an increase in the otherwise reduced brain blood flow. To test this idea, we performed a pilot study to examine the impact of three months of voluntary wheel running in a small cohort of ~1-year-old APP/PS1 mice on short-term memory function, brain inflammation, amyloid deposition, and baseline cerebral blood flow. Our findings that exercise led to a trend toward improved spatial short-term memory, reduced brain inflammation, markedly increased neurogenesis in the dentate gyrus, and a reduction in hippocampal amyloid-beta deposits are consistent with other reports on the impact of exercise on the progression of Alzheimer's related symptoms in mouse models. Notably, we did not observe any impact of wheel running on overall baseline blood flow nor on the incidence of non-flowing capillaries, a mechanism we recently identified as one contributing factor to cerebral blood flow deficits in mouse models of Alzheimer's disease. Overall, our findings add to the emerging picture of differential effects of exercise on cognition and blood flow in Alzheimer's disease pathology by showing that capillary stalling is not decreased following exercise.


Assuntos
Doença de Alzheimer/fisiopatologia , Precursor de Proteína beta-Amiloide/metabolismo , Encéfalo/irrigação sanguínea , Terapia por Exercício , Presenilina-1/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/terapia , Precursor de Proteína beta-Amiloide/genética , Animais , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Circulação Cerebrovascular , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Mutação , Neurogênese , Condicionamento Físico Animal , Projetos Piloto , Presenilina-1/genética , Transgenes
8.
J Neurovirol ; 26(5): 802-804, 2020 10.
Artigo em Inglês | MEDLINE | ID: covidwho-716427
9.
Proc Natl Acad Sci U S A ; 117(28): 16626-16637, 2020 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-32601236

RESUMO

Neuronal activity leads to an increase in local cerebral blood flow (CBF) to allow adequate supply of oxygen and nutrients to active neurons, a process termed neurovascular coupling (NVC). We have previously shown that capillary endothelial cell (cEC) inwardly rectifying K+ (Kir) channels can sense neuronally evoked increases in interstitial K+ and induce rapid and robust dilations of upstream parenchymal arterioles, suggesting a key role of cECs in NVC. The requirements of this signal conduction remain elusive. Here, we utilize mathematical modeling to investigate how small outward currents in stimulated cECs can elicit physiologically relevant spread of vasodilatory signals within the highly interconnected brain microvascular network to increase local CBF. Our model shows that the Kir channel can act as an "on-off" switch in cECs to hyperpolarize the cell membrane as extracellular K+ increases. A local hyperpolarization can be amplified by the voltage-dependent activation of Kir in neighboring cECs. Sufficient Kir density enables robust amplification of the hyperpolarizing stimulus and produces responses that resemble action potentials in excitable cells. This Kir-mediated excitability can remain localized in the stimulated region or regeneratively propagate over significant distances in the microvascular network, thus dramatically increasing the efficacy of K+ for eliciting local hyperemia. Modeling results show how changes in cEC transmembrane current densities and gap junctional resistances can affect K+-mediated NVC and suggest a key role for Kir as a sensor of neuronal activity and an amplifier of retrograde electrical signaling in the cerebral vasculature.


Assuntos
Neurônios/metabolismo , Acoplamento Neurovascular , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Potássio/metabolismo , Animais , Encéfalo/irrigação sanguínea , Encéfalo/metabolismo , Circulação Cerebrovascular , Células Endoteliais/química , Células Endoteliais/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Biológicos , Neurônios/química , Potássio/química , Canais de Potássio Corretores do Fluxo de Internalização/química , Canais de Potássio Corretores do Fluxo de Internalização/genética , Transdução de Sinais , Canais de Cátion TRPV/química , Canais de Cátion TRPV/genética , Canais de Cátion TRPV/metabolismo
10.
Neuroradiol J ; 33(5): 368-373, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32666873

RESUMO

Central nervous system involvement in severe acute respiratory syndrome caused by coronavirus disease 2019 (COVID-19) has increasingly been recognised in the literature, and possible mechanisms of neuroinvasion, neurotropism and neurovirulence have been described. Neurological signs have been described in 84% of COVID-19 intensive care unit patients, and haemostatic abnormalities in such patients may play an important role, with a broad spectrum of neuroimaging findings. This report describes the magnetic resonance imaging neurovascular findings in an acutely ill patient with COVID-19, including perfusion abnormalities depicted in the arterial spin labelling technique.


Assuntos
Encéfalo/diagnóstico por imagem , Circulação Cerebrovascular , Infecções por Coronavirus/diagnóstico por imagem , Pneumonia Viral/diagnóstico por imagem , Hemorragia Subaracnóidea/diagnóstico por imagem , Idoso , Betacoronavirus , Encéfalo/irrigação sanguínea , Infecções por Coronavirus/complicações , Infecções por Coronavirus/fisiopatologia , Corpo Caloso , Lobo Frontal , Humanos , Hemorragias Intracranianas , Imagem por Ressonância Magnética , Masculino , Pandemias , Lobo Parietal , Imagem de Perfusão , Pneumonia Viral/complicações , Pneumonia Viral/fisiopatologia , Marcadores de Spin , Hemorragia Subaracnóidea/complicações , Tálamo
12.
Arterioscler Thromb Vasc Biol ; 40(9): 2171-2186, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32640906

RESUMO

OBJECTIVE: Cerebral cavernous malformations (CCM), consisting of dilated capillary channels formed by a single layer of endothelial cells lacking surrounding mural cells. It is unclear why CCM lesions are primarily confined to brain vasculature, although the 3 CCM-associated genes (CCM1, CCM2, and CCM3) are ubiquitously expressed in all tissues. We aimed to determine the role of CCM gene in brain mural cell in CCM pathogenesis. Approach and Results: SM22α-Cre was used to drive a specific deletion of Ccm3 in mural cells, including pericytes and smooth muscle cells (Ccm3smKO). Ccm3smKO mice developed CCM lesions in the brain with onset at neonatal stages. One-third of Ccm3smKO mice survived upto 6 weeks of age, exhibiting seizures, and severe brain hemorrhage. The early CCM lesions in Ccm3smKO neonates were loosely wrapped by mural cells, and adult Ccm3smKO mice had clustered and enlarged capillary channels (caverns) formed by a single layer of endothelium lacking mural cell coverage. Importantly, CCM lesions throughout the entire brain in Ccm3smKO mice, which more accurately mimicked human disease than the current endothelial cell-specific CCM3 deletion models. Mechanistically, CCM3 loss in brain pericytes dramatically increased paxillin stability and focal adhesion formation, enhancing ITG-ß1 (integrin ß1) activity and extracellular matrix adhesion but reducing cell migration and endothelial cell-pericyte associations. Moreover, CCM3-wild type, but not a paxillin-binding defective mutant, rescued the phenotypes in CCM3-deficient pericytes. CONCLUSIONS: Our data demonstrate for the first time that deletion of a CCM gene in the brain mural cell induces CCM pathogenesis.


Assuntos
Proteínas Reguladoras de Apoptose/genética , Encéfalo/irrigação sanguínea , Células Endoteliais/metabolismo , Deleção de Genes , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Microvasos/metabolismo , Miócitos de Músculo Liso/metabolismo , Pericitos/metabolismo , Animais , Proteínas Reguladoras de Apoptose/deficiência , Proteínas Reguladoras de Apoptose/metabolismo , Comunicação Celular , Movimento Celular , Células Cultivadas , Técnicas de Cocultura , Células Endoteliais/patologia , Feminino , Adesões Focais/genética , Adesões Focais/metabolismo , Adesões Focais/patologia , Predisposição Genética para Doença , Hemangioma Cavernoso do Sistema Nervoso Central/metabolismo , Hemangioma Cavernoso do Sistema Nervoso Central/patologia , Humanos , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos Knockout , Microvasos/anormalidades , Miócitos de Músculo Liso/patologia , Paxilina/metabolismo , Pericitos/patologia , Fenótipo , Estabilidade Proteica , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Transdução de Sinais
13.
Proc Natl Acad Sci U S A ; 117(32): 19141-19150, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32703811

RESUMO

Current strategies to direct therapy-loaded nanoparticles to the brain rely on functionalizing nanoparticles with ligands which bind target proteins associated with the blood-brain barrier (BBB). However, such strategies have significant brain-specificity limitations, as target proteins are not exclusively expressed at the brain microvasculature. Therefore, novel strategies which exploit alternative characteristics of the BBB are required to overcome nonspecific nanoparticle targeting to the periphery, thereby increasing drug efficacy and reducing detrimental peripheral side effects. Here, we present a simple, yet counterintuitive, brain-targeting strategy which exploits the higher impermeability of the BBB to selectively label the brain endothelium. This is achieved by harnessing the lower endocytic rate of brain endothelial cells (a key feature of the high BBB impermeability) to promote selective retention of free, unconjugated protein-binding ligands on the surface of brain endothelial cells compared to peripheral endothelial cells. Nanoparticles capable of efficiently binding to the displayed ligands (i.e., labeled endothelium) are consequently targeted specifically to the brain microvasculature with minimal "off-target" accumulation in peripheral organs. This approach therefore revolutionizes brain-targeting strategies by implementing a two-step targeting method which exploits the physiology of the BBB to generate the required brain specificity for nanoparticle delivery, paving the way to overcome targeting limitations and achieve clinical translation of neurological therapies. In addition, this work demonstrates that protein targets for brain delivery may be identified based not on differential tissue expression, but on differential endocytic rates between the brain and periphery.


Assuntos
Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Portadores de Fármacos/metabolismo , Sistemas de Liberação de Medicamentos/instrumentação , Células Endoteliais/metabolismo , Nanopartículas/metabolismo , Animais , Transporte Biológico , Encéfalo/irrigação sanguínea , Endotélio/metabolismo , Humanos , Ratos , Ratos Sprague-Dawley
14.
Magn Reson Imaging ; 73: 111-117, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32717203

RESUMO

PURPOSE: Arterial spin labeling MRI can quantify the cerebral blood flow (CBF) without exogenous tracer. However, the variation of arterial transit time across different brain regions introduces bias for measuring local CBF, especially for those subjects with long arterial transit time (ATT). Long post-labeling delay (PLD) or multi-PLD methods could mitigate the problem of heterogenous ATT at the expense of the signal-to-noise ratio (SNR). Long-label ASL might address the low SNR problem by increasing the amount of labeled arterial blood. Thus, we hypothesized that with the same relatively long PLD, long-label pCASL may be more robust and reproducible than standard-label pCASL in population with potentially prolonged ATT. The purpose of the study was to investigate the reliability and reproducibility of long-label pCASL in the whole brain and vascular regions of interest in an elderly population, compared with standard-label pCASL. METHOD: Twenty adult volunteers (14 males, 6 females; age, 56.6 ± 17.2 years) were scanned twice on one 3.0 T scanner by standard-label pCASL (label duration (LD) = 1500 ms, PLD = 2000 ms) and long-label pCASL (LD = 3500 ms, PLD = 2000 ms). The intraclass correlation coefficient (ICC), within-subject coefficient of variation (wsCV), random noise and signal coefficient of variation(CoV) were used to assess global and regional reliability and reproducibility. Measurement agreement and difference were compared in different brain regions using correlation coefficient plots and Bland-Altman plots respectively. RESULTS: CBF value measured by long-label pCASL was overall higher than standard-label pCASL in all ROIs. Long-label pCASL had higher ICC than standard-label pCASL in most ROIs, and lower wsCV, random noise and CoV in all ROIs. Regardless of ASL method used, anterior circulation flow territories (ICC, 0.93-0.97; wsCV, 0.03-0.06) had higher CBF reliability and reproducibility than posterior circulation flow territories (ICC, 0.89; wsCV, 0.06-0.08). In all ROIs, the correlation analysis showed higher test-retest agreement (rlong-label > rstandard-label) and the Bland-Altman plots demonstrated lower measurement difference in long-label pCASL. CONCLUSION: The study demonstrated good reliability and reproducibility of long-label pCASL in anterior brain regions in the elderly population. To further improve CBF quantification in a long-ATT population while proper PLD is already used, increasing the label duration may help.


Assuntos
Encéfalo/irrigação sanguínea , Circulação Cerebrovascular/fisiologia , Processamento de Imagem Assistida por Computador/métodos , Imagem por Ressonância Magnética/métodos , Encéfalo/diagnóstico por imagem , Encéfalo/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valores de Referência , Reprodutibilidade dos Testes , Razão Sinal-Ruído , Marcadores de Spin
15.
Science ; 369(6500): 167-173, 2020 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-32646997

RESUMO

Reversing brain aging may be possible through systemic interventions such as exercise. We found that administration of circulating blood factors in plasma from exercised aged mice transferred the effects of exercise on adult neurogenesis and cognition to sedentary aged mice. Plasma concentrations of glycosylphosphatidylinositol (GPI)-specific phospholipase D1 (Gpld1), a GPI-degrading enzyme derived from liver, were found to increase after exercise and to correlate with improved cognitive function in aged mice, and concentrations of Gpld1 in blood were increased in active, healthy elderly humans. Increasing systemic concentrations of Gpld1 in aged mice ameliorated age-related regenerative and cognitive impairments by altering signaling cascades downstream of GPI-anchored substrate cleavage. We thus identify a liver-to-brain axis by which blood factors can transfer the benefits of exercise in old age.


Assuntos
Envelhecimento/sangue , Encéfalo/fisiologia , Cognição/fisiologia , Fígado/enzimologia , Neurogênese , Fosfolipase D/sangue , Condicionamento Físico Animal , Animais , Circulação Sanguínea , Encéfalo/irrigação sanguínea , Disfunção Cognitiva/sangue , Disfunção Cognitiva/fisiopatologia , Glicosilfosfatidilinositóis/metabolismo , Camundongos , Fosfolipase D/metabolismo , Regeneração , Transdução de Sinais
16.
Nature ; 583(7816): 425-430, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32612231

RESUMO

The vascular interface of the brain, known as the blood-brain barrier (BBB), is understood to maintain brain function in part via its low transcellular permeability1-3. Yet, recent studies have demonstrated that brain ageing is sensitive to circulatory proteins4,5. Thus, it is unclear whether permeability to individually injected exogenous tracers-as is standard in BBB studies-fully represents blood-to-brain transport. Here we label hundreds of proteins constituting the mouse blood plasma proteome, and upon their systemic administration, study the BBB with its physiological ligand. We find that plasma proteins readily permeate the healthy brain parenchyma, with transport maintained by BBB-specific transcriptional programmes. Unlike IgG antibody, plasma protein uptake diminishes in the aged brain, driven by an age-related shift in transport from ligand-specific receptor-mediated to non-specific caveolar transcytosis. This age-related shift occurs alongside a specific loss of pericyte coverage. Pharmacological inhibition of the age-upregulated phosphatase ALPL, a predicted negative regulator of transport, enhances brain uptake of therapeutically relevant transferrin, transferrin receptor antibody and plasma. These findings reveal the extent of physiological protein transcytosis to the healthy brain, a mechanism of widespread BBB dysfunction with age and a strategy for enhanced drug delivery.


Assuntos
Envelhecimento/metabolismo , Envelhecimento/patologia , Barreira Hematoencefálica/metabolismo , Transcitose , Fosfatase Alcalina/metabolismo , Animais , Anticorpos/metabolismo , Transporte Biológico , Proteínas Sanguíneas/administração & dosagem , Proteínas Sanguíneas/metabolismo , Proteínas Sanguíneas/farmacocinética , Encéfalo/irrigação sanguínea , Encéfalo/metabolismo , Sistemas de Liberação de Medicamentos , Saúde , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Plasma/metabolismo , Proteoma/administração & dosagem , Proteoma/metabolismo , Proteoma/farmacocinética , Receptores da Transferrina/imunologia , Transcrição Genética , Transferrina/metabolismo
17.
Neuroradiol J ; 33(5): 368-373, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: covidwho-646969

RESUMO

Central nervous system involvement in severe acute respiratory syndrome caused by coronavirus disease 2019 (COVID-19) has increasingly been recognised in the literature, and possible mechanisms of neuroinvasion, neurotropism and neurovirulence have been described. Neurological signs have been described in 84% of COVID-19 intensive care unit patients, and haemostatic abnormalities in such patients may play an important role, with a broad spectrum of neuroimaging findings. This report describes the magnetic resonance imaging neurovascular findings in an acutely ill patient with COVID-19, including perfusion abnormalities depicted in the arterial spin labelling technique.


Assuntos
Encéfalo/diagnóstico por imagem , Circulação Cerebrovascular , Infecções por Coronavirus/diagnóstico por imagem , Pneumonia Viral/diagnóstico por imagem , Hemorragia Subaracnóidea/diagnóstico por imagem , Idoso , Betacoronavirus , Encéfalo/irrigação sanguínea , Infecções por Coronavirus/complicações , Infecções por Coronavirus/fisiopatologia , Corpo Caloso , Lobo Frontal , Humanos , Hemorragias Intracranianas , Imagem por Ressonância Magnética , Masculino , Pandemias , Lobo Parietal , Imagem de Perfusão , Pneumonia Viral/complicações , Pneumonia Viral/fisiopatologia , Marcadores de Spin , Hemorragia Subaracnóidea/complicações , Tálamo
18.
Lancet ; 396(10244): 129-142, 2020 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-32653056

RESUMO

Stroke is a major cause of death and disability globally. Diagnosis depends on clinical features and brain imaging to differentiate between ischaemic stroke and intracerebral haemorrhage. Non-contrast CT can exclude haemorrhage, but the addition of CT perfusion imaging and angiography allows a positive diagnosis of ischaemic stroke versus mimics and can identify a large vessel occlusion target for endovascular thrombectomy. Management of ischaemic stroke has greatly advanced, with rapid reperfusion by use of intravenous thrombolysis and endovascular thrombectomy shown to reduce disability. These therapies can now be applied in selected patients who present late to medical care if there is imaging evidence of salvageable brain tissue. Both haemostatic agents and surgical interventions are investigational for intracerebral haemorrhage. Prevention of recurrent stroke requires an understanding of the mechanism of stroke to target interventions, such as carotid endarterectomy, anticoagulation for atrial fibrillation, and patent foramen ovale closure. However, interventions such as lowering blood pressure, smoking cessation, and lifestyle optimisation are common to all stroke subtypes.


Assuntos
Encéfalo/diagnóstico por imagem , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/mortalidade , Acidente Vascular Cerebral/prevenção & controle , Administração Intravenosa , Idoso , Idoso de 80 Anos ou mais , Amilose/uso terapêutico , Anticoagulantes/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/prevenção & controle , Encéfalo/irrigação sanguínea , Encéfalo/patologia , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/fisiopatologia , Isquemia Encefálica/cirurgia , Hemorragia Cerebral/complicações , Hemorragia Cerebral/tratamento farmacológico , Hemorragia Cerebral/fisiopatologia , Hemorragia Cerebral/cirurgia , Angiografia por Tomografia Computadorizada/métodos , Intervenção Médica Precoce/métodos , Endarterectomia das Carótidas/métodos , Procedimentos Endovasculares/métodos , Forame Oval Patente/cirurgia , Humanos , Pessoa de Meia-Idade , Seleção de Pacientes , Imagem de Perfusão/métodos , Polímeros/uso terapêutico , Recidiva , Acidente Vascular Cerebral/epidemiologia , Succinatos/uso terapêutico , Trombectomia/métodos , Terapia Trombolítica/métodos , Tomografia Computadorizada por Raios X/métodos
19.
Biochem Biophys Res Commun ; 528(3): 413-419, 2020 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-32513532

RESUMO

Coronavirus disease 2019 (COVID-19) is a worldwide pandemic. It has a high transmission rate among humans, and is a threat to global public health. However, there are no effective prophylactics or therapeutics available. It is necessary to identify vulnerable and susceptible groups for adequate protection and care against this disease. Recent studies have reported that COVID-19 has angiotensin-converting enzyme 2 (ACE2) as a functional receptor, which may lead to the development of severe cerebrovascular diseases (CVD), including strokes, in patients with risk factors for CVD such as diabetes and smoking. Thus, the World Health Organization (WHO) advised caution against COVID-19 for smokers and patients with underlying clinical symptoms, including cardiovascular diseases. Here, we observed ACE2 expression in the brain of rat middle cerebral artery occlusion (MCAO) model and evaluated the effects of cigarette smoke extract (CSE) and diabetes on ACE2 expression in vessels. We showed that the levels of ACE2 expression was increased in the cortex penumbra after ischemic injuries. CSE treatment significantly elevated ACE2 expression in human brain vessels. We found that ACE2 expression was upregulated in primary cultured human blood vessels with diabetes compared to healthy controls. This study demonstrates that ACE2 expression is increased in ischemic brains and vessels exposed to diabetes or smoking, makes them vulnerable to COVID-19 infection.


Assuntos
Betacoronavirus/metabolismo , Isquemia Encefálica/virologia , Encéfalo/irrigação sanguínea , Diabetes Mellitus , Peptidil Dipeptidase A/biossíntese , Receptores Virais/biossíntese , Fumantes , Acidente Vascular Cerebral/virologia , Regulação para Cima , Animais , Betacoronavirus/patogenicidade , Encéfalo/efeitos dos fármacos , Isquemia Encefálica/genética , Isquemia Encefálica/metabolismo , Infecções por Coronavirus/genética , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Diabetes Mellitus/genética , Diabetes Mellitus/metabolismo , Modelos Animais de Doenças , Suscetibilidade a Doenças , Infarto da Artéria Cerebral Média/complicações , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pandemias , Peptidil Dipeptidase A/genética , Pneumonia Viral/genética , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , Ratos , Ratos Sprague-Dawley , Receptores Virais/genética , Fumaça/efeitos adversos , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/metabolismo , Regulação para Cima/efeitos dos fármacos
20.
Medicine (Baltimore) ; 99(24): e20411, 2020 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-32541463

RESUMO

OBJECTIVE: The aim of this systematic review and meta-analysis is to improve the understanding of the pathophysiology of tension-type headache (TTH), as well as propose avenues for future neuroimaging studies of TTH. METHODS: From the inception dates to May 1, 2020, a systematic literature will search in Medline (Ovid SP), Embase (Ovid SP), Cochrane Central Register of Controlled Trials, Web of Science, and 4 Chinese databases without limitation on language or publication. Additionally, International Clinical Trials Registry Platform , reference lists, and relevant gray literatures will be searched. After screening of eligible references, included studies will be determined according to included criteria, and then data extraction and a methodological quality assessment with a customized checklist will be conducted. Each process will be independently implemented by 2 reviewers, any disagreement will be resolved by consensus to the third researcher. If the extracted data is feasible, anisotropic effect-size version of signed differential mapping will be conducted to perform the meta-analysis of the structural and functional brain alterations in TTH patients.


Assuntos
Encéfalo/diagnóstico por imagem , Neuroimagem/métodos , Cefaleia do Tipo Tensional/fisiopatologia , Anisotropia , Encéfalo/irrigação sanguínea , Encéfalo/metabolismo , Mapeamento Encefálico/instrumentação , Lista de Checagem , Feminino , Humanos , Masculino , Neuroimagem/tendências , Avaliação de Resultados em Cuidados de Saúde , Prevalência , Cefaleia do Tipo Tensional/epidemiologia , Escala Visual Analógica
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