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1.
J Exp Med ; 218(3)2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33433624

RESUMO

Although COVID-19 is considered to be primarily a respiratory disease, SARS-CoV-2 affects multiple organ systems including the central nervous system (CNS). Yet, there is no consensus on the consequences of CNS infections. Here, we used three independent approaches to probe the capacity of SARS-CoV-2 to infect the brain. First, using human brain organoids, we observed clear evidence of infection with accompanying metabolic changes in infected and neighboring neurons. However, no evidence for type I interferon responses was detected. We demonstrate that neuronal infection can be prevented by blocking ACE2 with antibodies or by administering cerebrospinal fluid from a COVID-19 patient. Second, using mice overexpressing human ACE2, we demonstrate SARS-CoV-2 neuroinvasion in vivo. Finally, in autopsies from patients who died of COVID-19, we detect SARS-CoV-2 in cortical neurons and note pathological features associated with infection with minimal immune cell infiltrates. These results provide evidence for the neuroinvasive capacity of SARS-CoV-2 and an unexpected consequence of direct infection of neurons by SARS-CoV-2.


Assuntos
Anticorpos Bloqueadores/química , Córtex Cerebral , Neurônios , /metabolismo , /antagonistas & inibidores , Animais , /patologia , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Córtex Cerebral/virologia , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Neurônios/metabolismo , Neurônios/patologia , Neurônios/virologia , Organoides/metabolismo , Organoides/patologia , Organoides/virologia
2.
PLoS One ; 15(9): e0238037, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32886703

RESUMO

Spectral Counts approaches (SpCs) are largely employed for the comparison of protein expression profiles in label-free (LF) differential proteomics applications. Similarly, to other comparative methods, also SpCs based approaches require a normalization procedure before Fold Changes (FC) calculation. Here, we propose new Complexity Based Normalization (CBN) methods that introduced a variable adjustment factor (f), related to the complexity of the sample, both in terms of total number of identified proteins (CBN(P)) and as total number of spectral counts (CBN(S)). Both these new methods were compared with the Normalized Spectral Abundance Factor (NSAF) and the Spectral Counts log Ratio (Rsc), by using standard protein mixtures. Finally, to test the robustness and the effectiveness of the CBNs methods, they were employed for the comparative analysis of cortical protein extract from zQ175 mouse brains, model of Huntington Disease (HD), and control animals (raw data available via ProteomeXchange with identifier PXD017471). LF data were also validated by western blot and MRM based experiments. On standard mixtures, both CBN methods showed an excellent behavior in terms of reproducibility and coefficients of variation (CVs) in comparison to the other SpCs approaches. Overall, the CBN(P) method was demonstrated to be the most reliable and sensitive in detecting small differences in protein amounts when applied to biological samples.


Assuntos
Biomarcadores/metabolismo , Córtex Cerebral/metabolismo , Modelos Animais de Doenças , Doença de Huntington/metabolismo , Proteoma/análise , Animais , Biomarcadores/análise , Córtex Cerebral/patologia , Proteínas de Escherichia coli/metabolismo , Doença de Huntington/patologia , Camundongos , Camundongos Endogâmicos C57BL , Modelos Teóricos , Padrões de Referência , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem
3.
Life Sci ; 260: 118418, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32931799

RESUMO

AIMS: Stroke is a devastating event with a limited choice of intervention. Benzoinum is frequently used to treat stroke in traditional Chinese medicine. Our team has found that the neuroprotection of benzoinum may related to angiogenesis, but the exact biological mechanism is unclear. The objective of this study was to explore its biological mechanism of angiogenesis in cerebral ischemia model rats. MAIN METHODS: First, network pharmacology and molecular docking were performed to predict the possible targets and mechanisms of benzoinum in treating ischemic stroke. The best dose was then selected according to pharmacodynamic indexes such as those for neurological deficit, cerebral infarction rate, and brain histopathology in middle cerebral artery occlusion (MCAO) model rats. Finally, RT-PCR, Western Blot and immunohistochemical analysis were applied to verify the prediction results from molecular docking. KEY FINDINGS: Network pharmacology and molecular docking demonstrated that the targets of treating cerebral ischemia were PDE4D, ACE and TTR, and the mechanism may be related to the ACE-AngI-VEGF signaling pathway. Experimental verification results suggested that 0.50 g/kg and 1.00 g/kg benzoinum could significantly protect against neurological deficit and reduce cerebral infarction rate in the cerebral cortex and hippocampus in MCAO model rats. At an optimal dose, benzoinum could significantly up-regulate VEGF, SHH and ANG-1, yet down-regulate ACE expression in MCAO model rats. SIGNIFICANCE: Balsamic acid is the active ingredient of benzoinum that protects against ischemic stroke and the possible mechanism is related to the promotion of angiogenesis via regulating ACE-AngI-VEGF pathway.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Infarto da Artéria Cerebral Média/complicações , Fármacos Neuroprotetores/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Isquemia Encefálica/etiologia , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/patologia , Masculino , Simulação de Acoplamento Molecular , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Ribonuclease Pancreático/genética , Ribonuclease Pancreático/metabolismo , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
4.
Int J Nanomedicine ; 15: 5299-5315, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32884256

RESUMO

Purpose: Zinc oxide nanoparticles (ZnONPs) are one of the most important nanomaterials that are widely used in the food, cosmetic and medical industries. Humans are often exposed to ZnONPs via inhalation, and they may reach the brain where neurotoxic effects could occur via systemic distribution. However, the mechanisms underlying how ZnONPs produce neurotoxic effects in the brain remain unclear. In this study, we aimed to investigate the novel mechanism involved in ZnONPs-induced neurotoxicity. Methods and Results: We demonstrated for the first time that pulmonary exposure to ZnONPs by intratracheal instillation could trigger ferroptosis, a new form of cell death, in the neuronal cells of mouse cerebral cortex. A similar phenomenon was also observed in cultured neuron-like PC-12 cell line. By using a specific inhibitor of ferroptosis ferrostatin-1 (Fer-1), our results showed that inhibition of ferroptosis by Fer-1 could significantly alleviate the ZnONPs-induced neuronal cell death both in vivo and in vitro. Mechanistic investigation revealed that ZnONPs selectively activated the JNK pathway and thus resulted in the ferroptotic phenotypes, JNK inhibitor SP600125 could reverse lipid peroxidation upregulation and ferroptotic cell death induced by ZnONPs in PC-12 cells. Conclusion: Taken together, this study not only demonstrates that pulmonary exposure of ZnONPs can induce JNK-involved ferroptotic cell death in mouse cortex and PC-12 cells, but also provides a clue that inhibition of ferroptosis by specific agents or drugs may serve as a feasible approach for reducing the untreatable neurotoxicity induced by ZnONPs.


Assuntos
Ferroptose/efeitos dos fármacos , Nanopartículas Metálicas/toxicidade , Neurônios/efeitos dos fármacos , Síndromes Neurotóxicas/patologia , Óxido de Zinco/toxicidade , Administração por Inalação , Animais , Antracenos/farmacologia , Morte Celular/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/patologia , Cicloexilaminas/farmacologia , Ferroptose/fisiologia , Peroxidação de Lipídeos/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Nanopartículas Metálicas/administração & dosagem , Camundongos Endogâmicos C57BL , Neurônios/patologia , Síndromes Neurotóxicas/etiologia , Células PC12 , Fenilenodiaminas/farmacologia , Ratos , Óxido de Zinco/administração & dosagem
5.
J Stroke Cerebrovasc Dis ; 29(10): 105126, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32912499

RESUMO

BACKGROUND: Long non-coding RNAs (LncRNAs) have been reported to play important roles in the pathogenesis and development of many diseases, including cerebral ischemia and reperfusion (I/R) injury. In this study, we aimed to investigate the role of LncRNA-Potassium Voltage-Gated Channel Subfamily Q Member 1 opposite strand/antisense transcript 1 (KCNQ1OT1) in cerebral I/R induced neuronal injury, and its underlying mechanisms. METHODS: Primary mouse cerebral cortical neurons treated with oxygen-glucose deprivation and reoxygenation (OGD/R) in vitro and mice subjected to middle cerebral artery occlusion (MCAO) and reperfusion were used to mimic cerebral I/R injury. Small inference RNA (siRNA) was used to knockdown KCNQ1OT1 or microRNA-153-3p (miR-153-3p). Dual-luciferase assay was performed to detect the interaction between KCNQ1OT1 and miR-153-3p and interaction between miR-153-3p and Fork head box O3a (Foxo3). Flow cytometry analysis was performed to detect neuronal apoptosis. qRT-PCR and Western blotting were performed to detect RNA and protein expressions. RESULTS: KCNQ1OT1 and Foxo3 expressions were significantly increased in neurons subjected to I/R injury in vitro and in vivo, and miR-153-3p expression were significantly decreased. Knockdown of KCNQ1OT1 or overexpression of miR-153-3p weakened OGD/R-induced neuronal injury and regulated Foxo3 expressions. Dual-luciferase analysis showed that KCNQ1OT1 directly interacted with miR-153-3p and Foxo3 is a direct target of miR-153-3p. CONCLUSIONS: Our results indicate that LncRNA-KCNQ1OT1 promotes OGD/R-induced neuronal injury at least partially through acting as a competing endogenous RNA (ceRNA) for miR-153-3p to regulate Foxo3a expression, suggesting LncRNA-KCNQ1OT1 as a potential therapeutic target for cerebral I/R injury.


Assuntos
Córtex Cerebral/metabolismo , Proteína Forkhead Box O3/metabolismo , Infarto da Artéria Cerebral Média/terapia , MicroRNAs/metabolismo , Neurônios/metabolismo , RNA Longo não Codificante/metabolismo , Traumatismo por Reperfusão/metabolismo , Reperfusão/efeitos adversos , Animais , Hipóxia Celular , Células Cultivadas , Córtex Cerebral/patologia , Proteína Forkhead Box O3/genética , Regulação da Expressão Gênica , Glucose/deficiência , Infarto da Artéria Cerebral Média/genética , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Neurônios/patologia , RNA Longo não Codificante/genética , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/patologia , Transdução de Sinais
6.
J Stroke Cerebrovasc Dis ; 29(10): 105152, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32912518

RESUMO

Sirtuins, class III histone deacetylases, are involved in the regulation of tissue repair processes and brain functions after a stroke. The ability of some isoforms of sirtuins to circulate between the nucleus and cytoplasm may have various pathophysiological effects on the cells. In present work, we focused on the role of non-mitochondrial sirtuins SIRT1, SIRT2, and SIRT6 in the restoration of brain cells following ischemic stroke. Here, using a photothrombotic stroke (PTS) model in mice, we studied whether local stroke affects the level and intracellular localization of SIRT1, SIRT2, and SIRT6 in neurons and astrocytes of the intact cerebral cortex adjacent to the ischemic ipsilateral hemisphere and in the analogous region of the contralateral hemisphere at different time points during the recovery period after a stroke. We evaluated the co-localization of sirtuins with growth-associated protein-43 (GAP-43), the presynaptic marker synaptophysin (SYN) and acetylated α-tubulin (Ac-α-Tub), that are associated with brain plasticity and are known to be involved in brain repair after a stroke. The results show that during the recovery period, an increase in SIRT1 and SIRT2 levels occurred. The increase of SIRT1 level was associated with an increase in synaptic plasticity proteins, whereas the increase of SIRT2 level was associated with an acetylated of α-tubulin, that can reduce the mobility of neurites. SIRT6 co-localized with GAP-43, but not with SYN. Moreover, we showed that SIRT1, SIRT2, and SIRT6 are not involved in the PTS-induced apoptosis of penumbra cells. Taken together, our results suggest that sirtuins functions differ depending on cell type, intracellular localization, specificity of sirtuins isoforms to different substrates and nature of post-translational modifications of enzymes.


Assuntos
Astrócitos/enzimologia , Córtex Cerebral/enzimologia , Trombose Intracraniana/complicações , Plasticidade Neuronal , Neurônios/enzimologia , Sirtuína 1/metabolismo , Sirtuína 2/metabolismo , Sirtuínas/metabolismo , Acidente Vascular Cerebral/enzimologia , Animais , Apoptose , Astrócitos/patologia , Córtex Cerebral/patologia , Córtex Cerebral/fisiopatologia , Modelos Animais de Doenças , Masculino , Camundongos , Neurônios/patologia , Recuperação de Função Fisiológica , Transdução de Sinais , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/fisiopatologia , Fatores de Tempo
7.
J Stroke Cerebrovasc Dis ; 29(10): 105029, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32912542

RESUMO

BACKGROUND: We investigated whether exogenous lysophosphatidic acid (LPA), a phospholipid extracellular signaling molecule, would increase infarct size and blood-brain barrier (BBB) disruption during the early stage of cerebral ischemia-reperfusion, and whether it works through Akt-mTOR-S6K1 intracellular signaling. MATERIAL AND METHODS: Rats were given either vehicle or LPA 1 mg/kg iv three times during reperfusion after one hour of middle cerebral artery (MCA) occlusion. In another group, prior to administration of LPA, 30 mg/kg of PF-4708671, an S6K1 inhibitor, was injected. After one hour of MCA occlusion and two hours of reperfusion the transfer coefficient (Ki) of 14C-α-aminoisobutyric acid and the volume of 3H-dextran distribution were determined to measure the degree of BBB disruption. At the same time, the size of infarct was determined and western blot analysis was performed to determine the levels of phosphorylated Akt (p-Akt) and phosphorylated S6 (pS6). RESULTS: LPA increased the Ki in the ischemic-reperfused cortex (+43%) when compared with Control rats and PF-4708671 pretreatment prevented the increase of Ki by LPA. LPA increased the percentage of cortical infarct out of total cortical area (+36%) and PF-4708671 pretreatment prevented the increase of the infarct size. Exogenous LPA did not significantly change the levels of p-Akt as well as pS6 in the ischemic-reperfused cortex. CONCLUSION: Our data demonstrate that the increase in BBB disruption could be one of the reasons of the increased infarct size by LPA. S6K1 may not be the major target of LPA. A decrease of LPA during early cerebral ischemia-reperfusion might be beneficial for neuronal survival.


Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Permeabilidade Capilar/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Infarto da Artéria Cerebral Média/terapia , Lisofosfolipídeos/toxicidade , Traumatismo por Reperfusão/induzido quimicamente , Reperfusão , Animais , Barreira Hematoencefálica/fisiopatologia , Córtex Cerebral/enzimologia , Córtex Cerebral/patologia , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/enzimologia , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/fisiopatologia , Masculino , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Endogâmicos F344 , Traumatismo por Reperfusão/enzimologia , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/fisiopatologia , Proteínas Quinases S6 Ribossômicas/metabolismo
8.
Am J Hum Genet ; 107(4): 753-762, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32910914

RESUMO

Lamin B1 plays an important role in the nuclear envelope stability, the regulation of gene expression, and neural development. Duplication of LMNB1, or missense mutations increasing LMNB1 expression, are associated with autosomal-dominant leukodystrophy. On the basis of its role in neurogenesis, it has been postulated that LMNB1 variants could cause microcephaly. Here, we confirm this hypothesis with the identification of de novo mutations in LMNB1 in seven individuals with pronounced primary microcephaly (ranging from -3.6 to -12 SD) associated with relative short stature and variable degree of intellectual disability and neurological features as the core symptoms. Simplified gyral pattern of the cortex and abnormal corpus callosum were noted on MRI of three individuals, and these individuals also presented with a more severe phenotype. Functional analysis of the three missense mutations showed impaired formation of the LMNB1 nuclear lamina. The two variants located within the head group of LMNB1 result in a decrease in the nuclear localization of the protein and an increase in misshapen nuclei. We further demonstrate that another mutation, located in the coil region, leads to increased frequency of condensed nuclei and lower steady-state levels of lamin B1 in proband lymphoblasts. Our findings collectively indicate that de novo mutations in LMNB1 result in a dominant and damaging effect on nuclear envelope formation that correlates with microcephaly in humans. This adds LMNB1 to the growing list of genes implicated in severe autosomal-dominant microcephaly and broadens the phenotypic spectrum of the laminopathies.


Assuntos
Nanismo/genética , Deficiência Intelectual/genética , Lamina Tipo B/genética , Microcefalia/genética , Mutação , Lâmina Nuclear/genética , Sequência de Aminoácidos , Sequência de Bases , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Pré-Escolar , Corpo Caloso/diagnóstico por imagem , Corpo Caloso/metabolismo , Corpo Caloso/patologia , Nanismo/diagnóstico por imagem , Nanismo/metabolismo , Nanismo/patologia , Feminino , Expressão Gênica , Humanos , Lactente , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/metabolismo , Deficiência Intelectual/patologia , Lamina Tipo B/metabolismo , Linfócitos/metabolismo , Linfócitos/patologia , Imagem por Ressonância Magnética , Masculino , Microcefalia/diagnóstico por imagem , Microcefalia/metabolismo , Microcefalia/patologia , Lâmina Nuclear/metabolismo , Lâmina Nuclear/patologia
9.
Nat Commun ; 11(1): 4038, 2020 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-32788587

RESUMO

Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Here, we identify biallelic missense and frameshift mutations in NARS1 in seven patients from three unrelated families with microcephaly and neurodevelopmental delay. Patient cells show reduced NARS1 protein, impaired NARS1 activity and impaired global protein synthesis. Cortical brain organoid modeling shows reduced proliferation of radial glial cells (RGCs), leading to smaller organoids characteristic of microcephaly. Single-cell analysis reveals altered constituents of both astrocytic and RGC lineages, suggesting a requirement for NARS1 in RGC proliferation. Our findings demonstrate that NARS1 is required to meet protein synthetic needs and to support RGC proliferation in human brain development.


Assuntos
Aspartato-tRNA Ligase/deficiência , Aspartato-tRNA Ligase/genética , Córtex Cerebral/patologia , Microcefalia/genética , Células-Tronco Neurais/patologia , Organoides/patologia , Aminoacil-RNA de Transferência/genética , Adolescente , Adulto , Sequência de Bases , Diferenciação Celular , Proliferação de Células , Tamanho Celular , Sobrevivência Celular , Criança , Família , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Células HEK293 , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Antígeno Ki-67/metabolismo , Masculino , Mutação/genética , Células-Tronco Neurais/metabolismo , Neuroglia/metabolismo , Linhagem , Adulto Jovem
10.
J Stroke Cerebrovasc Dis ; 29(9): 105041, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32807453

RESUMO

BACKGROUND AND PURPOSE: Ischemia-reperfusion injuries (IRIs) can aggravate the condition of some patients with acute occlusion of major intracranial artery (AOMIA) who received endovascular thrombectomy. Here, we provided data confirming the association of Repressor Element-1 Silencing Transcription factor (REST) with the long-term neuroprotective effect of the middle cerebral artery occlusion (MCAO) rats underwent Gradual Flow Restoration (GFR). METHODS: Long term neuroprotective effects of GFR intervention were evaluated on MCAO rats model after 3d and 7d reperfusion. The neurological deficit score and TTC staining were performed to evaluate the degree of brain damage in GFR and other interventions at different time. Differentially expressed genes related to cerebral ischemia reperfusion injury (CIRI) were initially screened and identified using GSE32529 microarray analysis. REST protein expression in rat brain cortex infarction was detected by Western blot analysis. RESULTS: MCAO rats intervened with GFR exhibited reduced neurological deficit (P < 0.05) and alleviated brain infarction volume (P < 0.01). The REST gene with up-regulated expression and its downstream genes with down-regulated expression were screened by Microarray analysis. The brain cortex infarction in MCAO rats produced high levels of REST expression. The GFR intervention inhibited REST expression, and alleviated brain injury on MCAO rats. CONCLUSION: Our results demonstrated that GFR intervention plays a long-term neuroprotective role and reduces brain edema and damage at reperfusion, possibly by inhibiting REST expression.


Assuntos
Edema Encefálico/prevenção & controle , Córtex Cerebral/metabolismo , Circulação Cerebrovascular , Infarto da Artéria Cerebral Média/terapia , Traumatismo por Reperfusão/prevenção & controle , Reperfusão/métodos , Proteínas Repressoras/metabolismo , Animais , Edema Encefálico/metabolismo , Edema Encefálico/patologia , Edema Encefálico/fisiopatologia , Córtex Cerebral/patologia , Córtex Cerebral/fisiopatologia , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/fisiopatologia , Masculino , Ratos Sprague-Dawley , Reperfusão/efeitos adversos , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/fisiopatologia , Proteínas Repressoras/genética , Transdução de Sinais , Fatores de Tempo , Regulação para Cima
11.
Neurology ; 95(12): e1672-e1685, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32675078

RESUMO

OBJECTIVE: To determine whether atrophy relates to phenotypical variants of posterior cortical atrophy (PCA) recently proposed in clinical criteria (i.e., dorsal, ventral, dominant-parietal, and caudal) we assessed associations between latent atrophy factors and cognition. METHODS: We employed a data-driven Bayesian modeling framework based on latent Dirichlet allocation to identify latent atrophy factors in a multicenter cohort of 119 individuals with PCA (age 64 ± 7 years, 38% male, Mini-Mental State Examination 21 ± 5, 71% ß-amyloid positive, 29% ß-amyloid status unknown). The model uses standardized gray matter density images as input (adjusted for age, sex, intracranial volume, MRI scanner field strength, and whole-brain gray matter volume) and provides voxelwise probabilistic maps for a predetermined number of atrophy factors, allowing every individual to express each factor to a degree without a priori classification. Individual factor expressions were correlated to 4 PCA-specific cognitive domains (object perception, space perception, nonvisual/parietal functions, and primary visual processing) using general linear models. RESULTS: The model revealed 4 distinct yet partially overlapping atrophy factors: right-dorsal, right-ventral, left-ventral, and limbic. We found that object perception and primary visual processing were associated with atrophy that predominantly reflects the right-ventral factor. Furthermore, space perception was associated with atrophy that predominantly represents the right-dorsal and right-ventral factors. However, individual participant profiles revealed that the large majority expressed multiple atrophy factors and had mixed clinical profiles with impairments across multiple domains, rather than displaying a discrete clinical-radiologic phenotype. CONCLUSION: Our results indicate that specific brain behavior networks are vulnerable in PCA, but most individuals display a constellation of affected brain regions and symptoms, indicating that classification into 4 mutually exclusive variants is unlikely to be clinically useful.


Assuntos
Atrofia/patologia , Córtex Cerebral/patologia , Doenças Neurodegenerativas/classificação , Doenças Neurodegenerativas/patologia , Idoso , Atrofia/classificação , Teorema de Bayes , Estudos de Coortes , Feminino , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Fenótipo
12.
Nat Commun ; 11(1): 3358, 2020 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-32620757

RESUMO

Neurodevelopmental disorders have a heritable component and are associated with region specific alterations in brain anatomy. However, it is unclear how genetic risks for neurodevelopmental disorders are translated into spatially patterned brain vulnerabilities. Here, we integrated cortical neuroimaging data from patients with neurodevelopmental disorders caused by genomic copy number variations (CNVs) and gene expression data from healthy subjects. For each of the six investigated disorders, we show that spatial patterns of cortical anatomy changes in youth are correlated with cortical spatial expression of CNV genes in neurotypical adults. By transforming normative bulk-tissue cortical expression data into cell-type expression maps, we link anatomical change maps in each analysed disorder to specific cell classes as well as the CNV-region genes they express. Our findings reveal organizing principles that regulate the mapping of genetic risks onto regional brain changes in neurogenetic disorders. Our findings will enable screening for candidate molecular mechanisms from readily available neuroimaging data.


Assuntos
Córtex Cerebral/patologia , Variações do Número de Cópias de DNA , Predisposição Genética para Doença , Transtornos do Neurodesenvolvimento/genética , Adolescente , Adulto , Mapeamento Encefálico , Córtex Cerebral/citologia , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/crescimento & desenvolvimento , Criança , Estudos de Coortes , Feminino , Perfilação da Expressão Gênica , Genoma Humano , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Transtornos do Neurodesenvolvimento/diagnóstico , Transtornos do Neurodesenvolvimento/patologia , Neuroimagem , Neurônios/metabolismo , Neurônios/patologia , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Análise Espacial , Adulto Jovem
13.
Neurology ; 95(8): e943-e952, 2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32646955

RESUMO

OBJECTIVE: To evaluate progressive white matter (WM) degeneration in amyotrophic lateral sclerosis (ALS). METHODS: Sixty-six patients with ALS and 43 healthy controls were enrolled in a prospective, longitudinal, multicenter study in the Canadian ALS Neuroimaging Consortium (CALSNIC). Participants underwent a harmonized neuroimaging protocol across 4 centers that included diffusion tensor imaging (DTI) for assessment of WM integrity. Three visits were accompanied by clinical assessments of disability (ALS Functional Rating Scale-Revised [ALSFRS-R]) and upper motor neuron (UMN) function. Voxel-wise whole-brain and quantitative tract-wise DTI assessments were done at baseline and longitudinally. Correction for site variance incorporated data from healthy controls and from healthy volunteers who underwent the DTI protocol at each center. RESULTS: Patients with ALS had a mean progressive decline in fractional anisotropy (FA) of the corticospinal tract (CST) and frontal lobes. Tract-wise analysis revealed reduced FA in the CST, corticopontine/corticorubral tract, and corticostriatal tract. CST FA correlated with UMN function, and frontal lobe FA correlated with the ALSFRS-R score. A progressive decline in CST FA correlated with a decline in the ALSFRS-R score and worsening UMN signs. Patients with fast vs slow progression had a greater reduction in FA of the CST and upper frontal lobe. CONCLUSIONS: Progressive WM degeneration in ALS is most prominent in the CST and frontal lobes and, to a lesser degree, in the corticopontine/corticorubral tracts and corticostriatal pathways. With the use of a harmonized imaging protocol and incorporation of analytic methods to address site-related variances, this study is an important milestone toward developing DTI biomarkers for cerebral degeneration in ALS. CLINICALTRIALSGOV IDENTIFIER: NCT02405182.


Assuntos
Esclerose Amiotrófica Lateral/diagnóstico por imagem , Córtex Cerebral/diagnóstico por imagem , Tratos Piramidais/diagnóstico por imagem , Substância Branca/diagnóstico por imagem , Adulto , Idoso , Esclerose Amiotrófica Lateral/patologia , Córtex Cerebral/patologia , Imagem de Tensor de Difusão , Progressão da Doença , Feminino , Humanos , Interpretação de Imagem Assistida por Computador/métodos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Degeneração Neural/diagnóstico por imagem , Degeneração Neural/patologia , Neuroimagem/métodos , Estudos Prospectivos , Tratos Piramidais/patologia , Substância Branca/patologia
14.
Fortschr Neurol Psychiatr ; 88(8): 528-531, 2020 Aug.
Artigo em Alemão | MEDLINE | ID: mdl-32634845

RESUMO

Posterior cortical atrophy (PCA) is a rare neurodegenerative disease, which manifests with complex visual disturbances. PCA can present in isolation ('PCA-pure') or in association with other neurodegenerative disorders ('PCA-plus'). Diagnosis is nevertheless frequently delayed, as PCA is a less known disease entity and initially a primary ocular disease is taken into consideration.


Assuntos
Atrofia/patologia , Córtex Cerebral/patologia , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/patologia , Transtornos da Visão/diagnóstico , Diagnóstico Tardio , Humanos , Doenças Raras/diagnóstico , Doenças Raras/patologia , Síndrome , Transtornos da Visão/patologia
15.
PLoS Comput Biol ; 16(7): e1008087, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32701953

RESUMO

The dynamics and the sharp onset of action potential (AP) generation have recently been the subject of intense experimental and theoretical investigations. According to the resistive coupling theory, an electrotonic interplay between the site of AP initiation in the axon and the somato-dendritic load determines the AP waveform. This phenomenon not only alters the shape of APs recorded at the soma, but also determines the dynamics of excitability across a variety of time scales. Supporting this statement, here we generalize a previous numerical study and extend it to the quantification of the input-output gain of the neuronal dynamical response. We consider three classes of multicompartmental mathematical models, ranging from ball-and-stick simplified descriptions of neuronal excitability to 3D-reconstructed biophysical models of excitatory neurons of rodent and human cortical tissue. For each model, we demonstrate that increasing the distance between the axonal site of AP initiation and the soma markedly increases the bandwidth of neuronal response properties. We finally consider the Liquid State Machine paradigm, exploring the impact of altering the site of AP initiation at the level of a neuronal population, and demonstrate that an optimal distance exists to boost the computational performance of the network in a simple classification task.


Assuntos
Potenciais de Ação , Segmento Inicial do Axônio/fisiologia , Axônios/fisiologia , Neurônios/fisiologia , Algoritmos , Animais , Córtex Cerebral/patologia , Biologia Computacional , Simulação por Computador , Dendritos/fisiologia , Humanos , Imageamento Tridimensional , Modelos Lineares , Aprendizado de Máquina , Modelos Neurológicos , Neocórtex/fisiologia , Canais de Potássio/fisiologia , Ratos
16.
Proc Natl Acad Sci U S A ; 117(29): 17359-17368, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32636265

RESUMO

Sleep disorders are among the most debilitating comorbidities of Parkinson's disease (PD) and affect the majority of patients. Of these, the most common is insomnia, the difficulty to initiate and maintain sleep. The degree of insomnia correlates with PD severity and it responds to treatments that decrease pathological basal ganglia (BG) beta oscillations (10-17 Hz in primates), suggesting that beta activity in the BG may contribute to insomnia. We used multiple electrodes to record BG spiking and field potentials during normal sleep and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism in nonhuman primates. MPTP intoxication resulted in severe insomnia with delayed sleep onset, sleep fragmentation, and increased wakefulness. Insomnia was accompanied by the onset of nonrapid eye movement (NREM) sleep beta oscillations that were synchronized across the BG and cerebral cortex. The BG beta oscillatory activity was associated with a decrease in slow oscillations (0.1-2 Hz) throughout the cortex, and spontaneous awakenings were preceded by an increase in BG beta activity and cortico-BG beta coherence. Finally, the increase in beta oscillations in the basal ganglia during sleep paralleled decreased NREM sleep, increased wakefulness, and more frequent awakenings. These results identify NREM sleep beta oscillation in the BG as a neural correlate of PD insomnia and suggest a mechanism by which this disorder could emerge.


Assuntos
Gânglios da Base/fisiopatologia , Doença de Parkinson/complicações , Distúrbios do Início e da Manutenção do Sono/complicações , Sono/fisiologia , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/efeitos adversos , Animais , Ritmo beta/fisiologia , Córtex Cerebral/patologia , Haplorrinos , Humanos , Doença de Parkinson/fisiopatologia , Distúrbios do Início e da Manutenção do Sono/fisiopatologia , Vigília
17.
Neurology ; 95(9): e1174-e1187, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32586896

RESUMO

OBJECTIVE: To elucidate the timeframe and spatial patterns of cortical reorganization after different stroke-induced basal ganglia lesions, we measured cortical thickness at 5 time points over a 6-month period. We hypothesized that cortical reorganization would occur very early and that, along with motor recovery, it would vary based on the stroke lesion site. METHODS: Thirty-three patients with unilateral basal ganglia stroke and 23 healthy control participants underwent MRI scanning and behavioral testing. To further decrease heterogeneity, we split patients into 2 groups according to whether or not the lesions mainly affect the striatal motor network as defined by resting-state functional connectivity. A priori measures included cortical thickness and motor outcome, as assessed with the Fugl-Meyer scale. RESULTS: Within 14 days poststroke, cortical thickness already increased in widespread brain areas (p = 0.001), mostly in the frontal and temporal cortices rather than in the motor cortex. Critically, the 2 groups differed in the severity of motor symptoms (p = 0.03) as well as in the cerebral reorganization they exhibited over a period of 6 months (Dice overlap index = 0.16). Specifically, the frontal and temporal regions demonstrating cortical thickening showed minimal overlap between these 2 groups, indicating different patterns of reorganization. CONCLUSIONS: Our findings underline the importance of assessing patients early and of considering individual differences, as patterns of cortical reorganization differ substantially depending on the precise location of damage and occur very soon after stroke. A better understanding of the macrostructural brain changes following stroke and their relationship with recovery may inform individualized treatment strategies.


Assuntos
Doença Cerebrovascular dos Gânglios da Base/fisiopatologia , Infarto Encefálico/fisiopatologia , Córtex Cerebral/diagnóstico por imagem , Plasticidade Neuronal , Paresia/fisiopatologia , Recuperação de Função Fisiológica , Adulto , Doença Cerebrovascular dos Gânglios da Base/diagnóstico por imagem , Infarto Encefálico/diagnóstico por imagem , Estudos de Casos e Controles , Córtex Cerebral/patologia , Feminino , Neuroimagem Funcional , Humanos , Estudos Longitudinais , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neostriado/diagnóstico por imagem , Neostriado/fisiopatologia , Vias Neurais , Tamanho do Órgão , Índice de Gravidade de Doença , Reabilitação do Acidente Vascular Cerebral
18.
J Vis Exp ; (160)2020 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-32597878

RESUMO

Cerebral contusion is a severe medical problem affecting millions of people worldwide each year. There is an urgent need to understand the pathophysiological mechanism and to develop effective therapeutic strategy for this devastating neurological disorder. Intraparenchymal hemorrhage and post-traumatic inflammatory response induced by initial physical impact can aggravate microglia/macrophage activation and neuroinflammation which subsequently worsen brain pathology. We provide here a controlled cortical impact (CCI) protocol that can reproduce experimental cortical contusion in mice by using a pneumatic impactor system to deliver mechanical force with controllable magnitude and velocity onto the dural surface. This preclinical model allows researchers to induce moderately severe focal cerebral contusion in mice and to investigate a wide range of post-traumatic pathological progressions including hemorrhage contusion, microglia/macrophage activation, iron toxicity, axonal injury, as well as short-term and long-term neurobehavioral deficits. The present protocol can be useful for exploring the long-term effects of and potential interventions for cerebral contusion.


Assuntos
Lesões Encefálicas Traumáticas/complicações , Córtex Cerebral/patologia , Contusões/complicações , Contusões/patologia , Hemorragia/complicações , Hemorragia/patologia , Inflamação/patologia , Animais , Lesões Encefálicas Traumáticas/patologia , Craniotomia , Modelos Animais de Doenças , Inflamação/complicações , Masculino , Camundongos Endogâmicos C57BL , Bainha de Mielina/metabolismo , Técnicas Estereotáxicas
19.
Nat Med ; 26(8): 1256-1263, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32572268

RESUMO

Alzheimer's disease (AD) causes unrelenting, progressive cognitive impairments, but its course is heterogeneous, with a broad range of rates of cognitive decline1. The spread of tau aggregates (neurofibrillary tangles) across the cerebral cortex parallels symptom severity2,3. We hypothesized that the kinetics of tau spread may vary if the properties of the propagating tau proteins vary across individuals. We carried out biochemical, biophysical, MS and both cell- and animal-based-bioactivity assays to characterize tau in 32 patients with AD. We found striking patient-to-patient heterogeneity in the hyperphosphorylated species of soluble, oligomeric, seed-competent tau. Tau seeding activity correlates with the aggressiveness of the clinical disease, and some post-translational modification (PTM) sites appear to be associated with both enhanced seeding activity and worse clinical outcomes, whereas others are not. These data suggest that different individuals with 'typical' AD may have distinct biochemical features of tau. These data are consistent with the possibility that individuals with AD, much like people with cancer, may have multiple molecular drivers of an otherwise common phenotype, and emphasize the potential for personalized therapeutic approaches for slowing clinical progression of AD.


Assuntos
Doença de Alzheimer/genética , Disfunção Cognitiva/genética , Agregação Patológica de Proteínas/genética , Proteínas tau/genética , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Disfunção Cognitiva/patologia , Feminino , Heterogeneidade Genética , Humanos , Masculino , Pessoa de Meia-Idade , Emaranhados Neurofibrilares/genética , Emaranhados Neurofibrilares/metabolismo , Emaranhados Neurofibrilares/patologia , Fosforilação , Agregação Patológica de Proteínas/patologia , Índice de Gravidade de Doença
20.
Proc Natl Acad Sci U S A ; 117(27): 15967-15976, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32571909

RESUMO

The insular cortex (INS) is extensively connected to the central nucleus of the amygdala (CEA), and both regions send convergent projections into the caudal lateral hypothalamus (LHA) encompassing the parasubthalamic nucleus (PSTN). However, the organization of the network between these structures has not been clearly delineated in the literature, although there has been an upsurge in functional studies related to these structures, especially with regard to the cognitive and psychopathological control of feeding. We conducted tract-tracing experiments from the INS and observed a pathway to the PSTN region that runs parallel to the canonical hyperdirect pathway from the isocortex to the subthalamic nucleus (STN) adjacent to the PSTN. In addition, an indirect pathway with a relay in the central amygdala was also observed that is similar in its structure to the classic indirect pathway of the basal ganglia that also targets the STN. C-Fos experiments showed that the PSTN complex reacts to neophobia and sickness induced by lipopolysaccharide or cisplatin. Chemogenetic (designer receptors exclusively activated by designer drugs [DREADD]) inhibition of tachykininergic neurons (Tac1) in the PSTN revealed that this nucleus gates a stop "no-eat" signal to refrain from feeding when the animal is subjected to sickness or exposed to a previously unknown source of food. Therefore, our anatomical findings in rats and mice indicate that the INS-PSTN network is organized in a similar manner as the hyperdirect and indirect basal ganglia circuitry. Functionally, the PSTN is involved in gating feeding behavior, which is conceptually homologous to the motor no-go response of the adjacent STN.


Assuntos
Gânglios da Base/fisiologia , Córtex Cerebral/patologia , Comportamento Alimentar/fisiologia , Hipotálamo/fisiologia , Córtex Olfatório/fisiologia , Animais , Comportamento Animal , Núcleo Central da Amígdala , Masculino , Camundongos , Modelos Animais , Vias Neurais/fisiologia , Neurônios/metabolismo , Ratos , Ratos Sprague-Dawley , Núcleo Subtalâmico
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