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1.
Psychiatr Danub ; 32(1): 60-69, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32303031

RESUMO

BACKGROUND: Schizophrenia is a multifactorial neurodevelopmental disorder associated with cognitive dysfunction and changes in primary sensory processing. This article aims to explore the current insights into the relationship between schizophrenia and different visual disturbances. METHODS: To provide a literature review of visual impairments in schizophrenia, we performed a PubMed/MEDLINE and Scopus search to identify all articles in English on the topic up to the end of 2018. RESULTS: Multiple retinal functional and structural abnormalities are found in patients with schizophrenia. Wider retinal venules suggest chronically insufficient brain supply of oxygen and this could contribute to the occurrence of psychotic symptoms. Optical coherence tomography studies showed that retinal nerve fiber layer, macular thickness, and macular volume were significantly lowered in the chronic phase of schizophrenia. Results from electroretinogram recordings have demonstrated different declinations such as abnormalities of a - wave activity in the photoreceptors or b - wave activity in the bipolar and Muller cells. Abnormalities in eye movements, such as a notable decrease in saccades and smooth pursuit eye movements, are one of the most reliable and reproducible impairments associated with schizophrenia. Disrupted visual processing of the magnocellular pathway may result in a decrease of contrast sensitivity, sensory processing, orientation discrimination, visual integration, trajectory and spatial localization, backward masking and motion tracking. Visual perceptual abnormalities occur in more than 60% of schizophrenic patients and these are visual hallucinations, perceptual distortion of colors, shapes and light intensity, decrease in contour integration and surround suppression. Other, frequently present eye disorders include impaired visual acuity, strabismus and nystagmus. CONCLUSION: Visual impairments are one of the most important features of schizophrenia, which could help in defining the disease state and assigning appropriate treatment.


Assuntos
Oftalmopatias/complicações , Oftalmopatias/fisiopatologia , Esquizofrenia/complicações , Esquizofrenia/fisiopatologia , Oftalmopatias/patologia , Alucinações , Humanos , Transtornos Psicóticos/complicações , Transtornos Psicóticos/fisiopatologia , Acompanhamento Ocular Uniforme , Movimentos Sacádicos , Esquizofrenia/patologia , Percepção Visual
2.
PLoS Biol ; 18(1): e3000604, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31935214

RESUMO

Schizophrenia is a severe mental disorder with an unclear pathophysiology. Increased expression of the immune gene C4 has been linked to a greater risk of developing schizophrenia; however, it is not known whether C4 plays a causative role in this brain disorder. Using confocal imaging and whole-cell electrophysiology, we demonstrate that overexpression of C4 in mouse prefrontal cortex neurons leads to perturbations in dendritic spine development and hypoconnectivity, which mirror neuropathologies found in schizophrenia patients. We find evidence that microglia-mediated synaptic engulfment is enhanced with increased expression of C4. We also show that C4-dependent circuit dysfunction in the frontal cortex leads to decreased social interactions in juvenile and adult mice. These results demonstrate that increased expression of the schizophrenia-associated gene C4 causes aberrant circuit wiring in the developing prefrontal cortex and leads to deficits in juvenile and adult social behavior, suggesting that altered C4 expression contributes directly to schizophrenia pathogenesis.


Assuntos
Complemento C4/genética , Neurônios/fisiologia , Córtex Pré-Frontal/citologia , Esquizofrenia/genética , Comportamento Social , Envelhecimento/genética , Envelhecimento/metabolismo , Envelhecimento/patologia , Animais , Animais Recém-Nascidos , Comunicação Celular/genética , Células Cultivadas , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Vias Neurais/metabolismo , Córtex Pré-Frontal/patologia , Esquizofrenia/patologia , Regulação para Cima/genética
3.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 51(1): 35-41, 2020 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-31950787

RESUMO

Objective: We analyzed the brain structure of schizophrenia patients from multiple perspectives to explore the relationship between the duration of untreated psychosis (DUP) and clinical outcomes. Methods: For 85 patients and 86 controls, clinical symptoms and cognitive function were evaluated, magnetic resonance imaging (MRI) and free surfer analysis were used to extract the cortical indicator, such as brain cortex thickness, surface area, volume, and so on. The patients were divided into four subgroups according to the boundary of March, June and two year due to the distribution and median of DUP. Finally multi-group comparison and correlation analysis for above indicators were analysed. Results: DUP was associated with the surface area of the left insula, parsorbitalis, right hippocampus, superior frontal gyrus, frontal pole, and temporal pole; DUP mainly influenced the cortical thickness of left posterior cingulate gyrus, postcentral gyrus, right lateral occipital cortex, parsopercularis, medial orbitofrontal cortex, and the bilateral precentral gyrus. For cortical volume, DUP significantly affected left postcentral gyrus, right precuneus, lateral occipital cortex, parsopercularis, lingual gyrus, superior temporal gyrus, bilateral cuneus, pericalcarine cortex, precentral gyrus,superior parietal lobule, and insula.The first three months after onset is a critical period for the deterioration of cortical morphology and clinical function. Conclusion: DUP in first-episode schizophrenia is associated with cortical morphological changes of temporal lobe, precentral, orbitofrontal cortex and the majority of medial regions of occipital lobe, it is very important to conduct early intervention for patients.


Assuntos
Córtex Cerebral , Imagem por Ressonância Magnética , Transtornos Psicóticos , Esquizofrenia , Córtex Cerebral/diagnóstico por imagem , Humanos , Transtornos Psicóticos/diagnóstico por imagem , Transtornos Psicóticos/terapia , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/patologia , Lobo Temporal/diagnóstico por imagem , Fatores de Tempo
4.
Curr Top Behav Neurosci ; 44: 141-159, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-30895532

RESUMO

An immunologic component to schizophrenia has been increasingly recognized, where infections and chronic inflammatory diseases as atopic disorders and autoimmune diseases could be involved in the pathogenesis of schizophrenia. Psychotic symptoms can be directly triggered by infections reaching the CNS, or be secondary to systemic inflammation indirectly affecting the brain through immune components, such as brain-reactive antibodies and cytokines. Large-scale epidemiological studies have consistently displayed that infections, autoimmune diseases, and atopic disorders are associated with increased risk of schizophrenia and that schizophrenia is associated with increased levels of immune markers at diagnosis. However, since there is also an increased risk of immune-related diseases after the diagnosis with schizophrenia and in family members of individuals with schizophrenia, parts of the association could also be due to heritable factors. Shared genetic factor might account for some of this increased prevalence of immune-related diseases among individuals with schizophrenia, and indeed the most pronounced genetic association with schizophrenia lies within the HLA region, which is one of the most important regions for the immune system. However, genetic studies have shown that the common genetic variants associated with schizophrenia do not seem to increase the susceptibility for acquiring infections. Nonetheless, shared genes with the susceptibility for acquiring infections not captured by the polygenic risk score for schizophrenia could still influence the association.


Assuntos
Doenças Autoimunes , Autoimunidade , Esquizofrenia , Humanos , Sistema Imunitário , Esquizofrenia/imunologia , Esquizofrenia/patologia
5.
Curr Top Behav Neurosci ; 44: 49-66, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31115797

RESUMO

In this article, we review current evidence linking immune dysfunction in schizophrenia and related psychotic disorders focusing particularly on circulating cytokines, oxidative stress and cellular markers of inflammation in various stages on illness from drug-naïve first episode psychosis to chronic schizophrenia. Acute psychotic episode is associated with low-grade systemic inflammation in some patients, as reflected by increased concentrations of cytokines and other inflammatory markers in peripheral blood. Evidence from general population-based longitudinal cohort studies reporting an association between elevated inflammatory markers in childhood/adolescence and risk of schizophrenia and related psychosis subsequently in adulthood suggest that inflammation could be a causal risk factor for psychosis rather than simply be a consequence of illness. Mendelian randomization studies also suggest that associations between IL-6, CRP and schizophrenia are likely to be causal. In addition, we discuss evidence for disruptions in oxidative stress markers and CSF cytokine levels in schizophrenia, and potential reasons for reported trans-diagnostic associations for inflammatory cytokines including role of early-life adversity/maltreatment. We argue that low-grade inflammation is a clinically useful feature, because it is associated with poor response to antipsychotic medication in first episode psychosis. We discuss clinical implications for immunological understanding of schizophrenia including scope for clinical trials of anti-inflammatory agents and notable gaps in current knowledge, and offer suggestions for future research.


Assuntos
Citocinas , Inflamação , Estresse Oxidativo , Esquizofrenia , Adolescente , Adulto , Criança , Humanos , Estudos Longitudinais , Esquizofrenia/imunologia , Esquizofrenia/patologia
6.
Curr Top Behav Neurosci ; 44: 161-205, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-30828767

RESUMO

Clinical and pre-clinical studies have demonstrated an important role of neuroinflammation in the etiology of schizophrenia. While the underlying mechanisms remain poorly understood, there are some studies demonstrating an association between maternal immune activation and behavioral changes in adult offspring and identifying early life infection as a trigger for schizophrenia; in addition, inflammatory markers were found to be increased in the schizophrenic post-mortem brain. During maternal immune activation, pro-inflammatory mediators such as cytokines, chemokines, antibodies, and acute-phase proteins are released in the maternal bloodstream, thus increasing the permeability of the placental barrier and the fetal blood-brain barrier, allowing the inflammatory mediators to enter the fetal brain. In the central nervous system (CNS), these pro-inflammatory mediators are able to activate microglial cells that can release pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin (IL)-1ß, and IL-6. As a consequence, circulating immune cells may infiltrate the brain, increasing cytokine levels and releasing antibodies that aggravate the neuroinflammation. Neuroinflammation may affect processes that are pivotal for normal brain maturation such as myelination, synaptic pruning, and neuronal remodeling. Microglial cell activation and pro-inflammatory mediators have been extensively studied in schizophrenic post-mortem brain samples. Some results of these investigations demonstrated an increase in microglial activation markers, cytokines, and chemokines in post-mortem brain samples from individuals with schizophrenia. In contrast, there are studies that have demonstrated low levels of microglial activation makers in the schizophrenic post-mortem brain. Thus, based on the important role of neuroinflammation as a trigger in the development of schizophrenia, this chapter aims (1) to enumerate evidence of neuroinflammation and microglial activation from pre-clinical schizophrenia models, (2) to show links between schizophrenia and neuroinflammation in clinical studies, and (3) to identify mechanisms by which microglial activation may influence in the development of schizophrenia.


Assuntos
Microglia , Transtornos Psicóticos , Esquizofrenia , Encéfalo/imunologia , Encéfalo/patologia , Citocinas , Feminino , Humanos , Microglia/imunologia , Gravidez , Transtornos Psicóticos/imunologia , Transtornos Psicóticos/patologia , Esquizofrenia/imunologia , Esquizofrenia/patologia
7.
Hum Genet ; 139(2): 185-198, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31813014

RESUMO

Major psychiatric traits are genetically inter-correlated with one another, but it not well known which genes play pleiotropic effects across different traits. We curated and compared genes identified from large-scale genome-wide association studies for seven psychiatric traits, including depression, bipolar disorder, schizophrenia, autism spectrum disorder, attention-deficit/hyperactivity disorder, anxiety and neuroticism. We then explored biological functions of the top pleiotropic genes. A total of 243 cross-trait genes were identified for the seven traits. Except for autism spectrum disorder, there was significant enrichment of overlapped genes across these psychiatric traits. Chromosome 5q14.3, 11q23.2, and 7p22.3 are the three genomic regions conferring highest pleiotropic effects for these psychiatric traits. The long non-coding gene LINC00461 showed the highest pleiotropic effects on five psychiatric traits. In silico and functional studies with mice support the vital role of LINC00461 in neurodevelopment. In sum, our study provides insights into the shared genetic liability among major psychiatric traits.


Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Transtornos Mentais/genética , Herança Multifatorial/genética , Polimorfismo de Nucleotídeo Único , Animais , Transtorno Autístico/genética , Transtorno Autístico/patologia , Transtorno Bipolar/genética , Transtorno Bipolar/patologia , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/patologia , Hipocampo/metabolismo , Humanos , Transtornos Mentais/patologia , Camundongos , Fenótipo , RNA Longo não Codificante/genética , Fatores de Risco , Esquizofrenia/genética , Esquizofrenia/patologia
8.
Hum Genet ; 139(2): 199-213, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31844974

RESUMO

Transcriptome-wide association studies (TWAS) have been recently applied to successfully identify many novel genes associated with complex traits. While appealing, TWAS tend to identify multiple significant genes per locus, and many of them may not be causal due to confounding through linkage disequilibrium (LD) among SNPs. Here we introduce a powerful fine-mapping method that prioritizes putative causal genes by accounting for local LD. We apply a weighted adaptive test with eQTL-derived weights to maintain high power across various scenarios. Through simulations, we show that our new approach yielded a well-controlled Type I error rate while achieving higher power and AUC than competing methods. We applied our approach to a schizophrenia GWAS summary dataset and successfully prioritized some well-known schizophrenia-related genes, such as C4A. Importantly, our approach identified some putative causal genes (e.g., B3GAT1 and RGS6) that were missed by competing methods and TWAS. Our results suggest that our approach is a useful tool to prioritize putative causal genes, gaining insights into the mechanisms of complex traits.


Assuntos
Marcadores Genéticos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Esquizofrenia/genética , Transcriptoma , Estudos de Casos e Controles , Humanos , Desequilíbrio de Ligação , Modelos Genéticos , Locos de Características Quantitativas , Esquizofrenia/patologia
9.
Nat Commun ; 10(1): 4493, 2019 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-31582737

RESUMO

Negative symptoms, such as amotivation and anhedonia, are a major cause of functional impairment in schizophrenia. There are currently no licensed treatments for negative symptoms, highlighting the need to understand the molecular mechanisms underlying them. Mu-opioid receptors (MOR) in the striatum play a key role in hedonic processing and reward function and are reduced post-mortem in schizophrenia. However, it is unknown if mu-opioid receptor availability is altered in-vivo or related to negative symptoms in schizophrenia. Using [11 C]-carfentanil positron emission tomography (PET) scans in 19 schizophrenia patients and 20 age-matched healthy controls, here we show a significantly lower MOR availability in patients with schizophrenia in the striatum (Cohen's d = 0.7), and the hedonic network. In addition, we report a marked global increase in inter-regional covariance of MOR availability in schizophrenia, largely due to increased cortical-subcortical covariance.


Assuntos
Encéfalo/patologia , Receptores Opioides mu/metabolismo , Esquizofrenia/patologia , Adulto , Analgésicos Opioides/administração & dosagem , Encéfalo/diagnóstico por imagem , Radioisótopos de Carbono , Estudos de Casos e Controles , Feminino , Fentanila/administração & dosagem , Fentanila/análogos & derivados , Voluntários Saudáveis , Humanos , Masculino , Tomografia por Emissão de Pósitrons/métodos , Traçadores Radioativos , Esquizofrenia/diagnóstico por imagem
10.
Nat Neurosci ; 22(10): 1617-1623, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31551603

RESUMO

Common risk factors for psychiatric and other brain disorders are likely to converge on biological pathways influencing the development and maintenance of brain structure and function across life. Using structural MRI data from 45,615 individuals aged 3-96 years, we demonstrate distinct patterns of apparent brain aging in several brain disorders and reveal genetic pleiotropy between apparent brain aging in healthy individuals and common brain disorders.


Assuntos
Envelhecimento/genética , Envelhecimento/patologia , Encefalopatias/diagnóstico por imagem , Encefalopatias/genética , Encéfalo/crescimento & desenvolvimento , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Encéfalo/diagnóstico por imagem , Criança , Pré-Escolar , Feminino , Estudo de Associação Genômica Ampla , Humanos , Lactente , Imagem por Ressonância Magnética , Masculino , Transtornos Mentais/diagnóstico por imagem , Transtornos Mentais/genética , Pessoa de Meia-Idade , Testes Neuropsicológicos , Esquizofrenia/genética , Esquizofrenia/patologia , Caracteres Sexuais , Adulto Jovem
11.
Nat Genet ; 51(10): 1475-1485, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31548722

RESUMO

The mechanisms by which common risk variants of small effect interact to contribute to complex genetic disorders are unclear. Here, we apply a genetic approach, using isogenic human induced pluripotent stem cells, to evaluate the effects of schizophrenia (SZ)-associated common variants predicted to function as SZ expression quantitative trait loci (eQTLs). By integrating CRISPR-mediated gene editing, activation and repression technologies to study one putative SZ eQTL (FURIN rs4702) and four top-ranked SZ eQTL genes (FURIN, SNAP91, TSNARE1 and CLCN3), our platform resolves pre- and postsynaptic neuronal deficits, recapitulates genotype-dependent gene expression differences and identifies convergence downstream of SZ eQTL gene perturbations. Our observations highlight the cell-type-specific effects of common variants and demonstrate a synergistic effect between SZ eQTL genes that converges on synaptic function. We propose that the links between rare and common variants implicated in psychiatric disease risk constitute a potentially generalizable phenomenon occurring more widely in complex genetic disorders.


Assuntos
Regulação da Expressão Gênica , Predisposição Genética para Doença , Células-Tronco Pluripotentes Induzidas/patologia , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Esquizofrenia/genética , Esquizofrenia/patologia , Sistemas CRISPR-Cas , Canais de Cloreto/antagonistas & inibidores , Canais de Cloreto/genética , Canais de Cloreto/metabolismo , Feminino , Furina/antagonistas & inibidores , Furina/genética , Furina/metabolismo , Edição de Genes , Estudo de Associação Genômica Ampla , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Masculino , Proteínas Monoméricas de Montagem de Clatrina/antagonistas & inibidores , Proteínas Monoméricas de Montagem de Clatrina/genética , Proteínas Monoméricas de Montagem de Clatrina/metabolismo , Proteínas SNARE/antagonistas & inibidores , Proteínas SNARE/genética , Proteínas SNARE/metabolismo
12.
Psychiatr Danub ; 31(Suppl 3): 517-519, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31488783

RESUMO

BACKGROUND: In the literature we can find evidence that sex hormones are involved the alterations of cognition in schizophrenic patients. Another factor, which may have an impact on cognitive domains in this clinical group inflammatory processes. The objective of this review was to explore studies, in which the role of both immunological factors and sex hormones on cognitive functions in schizophrenia are analyzed. METHODS: The search of papers covering this topic in PubMed and Google Scholar was performed. RESULTS: Endocrine factors like: testosteron, estrogen, as well as immunomodulatory are observed to play a role in cognitive functioning in schizophrenia. CONCLUSIONS: More studies are necessary to confirm these possible co-relations.


Assuntos
Transtornos Cognitivos , Cognição , Hormônios Esteroides Gonadais , Inflamação , Esquizofrenia , Psicologia do Esquizofrênico , Transtornos Cognitivos/complicações , Transtornos Cognitivos/metabolismo , Transtornos Cognitivos/patologia , Hormônios Esteroides Gonadais/metabolismo , Humanos , Inflamação/metabolismo , Esquizofrenia/complicações , Esquizofrenia/metabolismo , Esquizofrenia/patologia
13.
Biochim Biophys Acta Gene Regul Mech ; 1862(9): 194413, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31382054

RESUMO

The RNA-binding protein TDP-43, associated to amyotrophic lateral sclerosis and frontotemporal dementia, regulates the alternative splicing of several genes, including the skipping of TNIK exon 15. TNIK, a genetic risk factor for schizophrenia and causative for intellectual disability, encodes for a Ser/Thr kinase regulating negatively F-actin dynamics. Here we show that in the human adult nervous system TNIK exon 15 is mostly included compared to the other tissues and that, during neuronal differentiation of human induced pluripotent stem cells and of human neuroblastoma cells, TNIK exon 15 inclusion increases independently of TDP-43 protein content. By studying the possible molecular interplay of TDP-43 with brain-specific splicing factors, we found that the neuronal NOVA-1 protein competitively inhibits both TDP-43 and hnRNPA2/B1 skipping activity on TNIK by means of a RNA-dependent interaction and that this competitive mechanism is common to other TDP-43 RNA targets. We also show that the TNIK protein isoforms including/excluding exon 15 differently regulate cell spreading in non-neuronal cells and neuritogenesis in primary cortical neurons. Our data suggest a complex regulation between the ubiquitous TDP-43 and the neuron-specific NOVA-1 splicing factors in the brain that may help better understand the pathobiology of both neurodegenerative diseases and schizophrenia.


Assuntos
Proteínas de Ligação a DNA/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas de Ligação a RNA/genética , Esquizofrenia/genética , Processamento Alternativo/genética , Linhagem Celular , Proteínas de Ligação a DNA/química , Éxons/genética , Humanos , Neurônios/metabolismo , Neurônios/patologia , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Proteínas Serina-Treonina Quinases/química , RNA Mensageiro/genética , Proteínas de Ligação a RNA/química , Esquizofrenia/patologia
14.
DNA Cell Biol ; 38(10): 1030-1039, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31368785

RESUMO

Both endogenous and exogenous factors can cause DNA damage that compromises genomic integrity and cell viability. A proper DNA damage response (DDR) plays a role in maintaining genome stability and preventing tumorigenesis. DNA double-strand breaks (DSBs) are the most toxic DNA lesion, whose response is dominated by the ataxia-telangiectasia mutated (ATM) protein kinase. After being activated by the sensor Mre11-Rad50-Nbs1 (MRN) complex or acetyltransferase Tip60, ATM rapidly phosphorylates downstream targets to launch DDR signaling when DNA is damaged. However, the exact mechanism of DDR is complex and ambiguous. Ufmylation, one type of ubiquitin-like modification, proceeds mainly through a three-step enzymatic reaction to help ubiquitin-fold modifier 1 (Ufm1), attach to substrates with ubiquitin-like modifier-activating enzyme 5 (Uba5), Ufm1-conjugating enzyme 1 (Ufc1) and Ufm1-specific ligase 1 (Ufl1). Although ubiquitination is essential to the DSBs response, the potential function of ufmylation in DDR is largely unknown. Herein, we review the relationship between ufmylation and DDR to elucidate the function and mechanism of ufmylation in DDR, which would reveal the pathogenesis of some diseases and provide new guidance to create a therapeutic method.


Assuntos
Doenças Cardiovasculares/metabolismo , Quebras de DNA de Cadeia Dupla , Neoplasias/metabolismo , Processamento de Proteína Pós-Traducional , Proteínas/metabolismo , Esquizofrenia/metabolismo , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/patologia , Reparo do DNA , Genoma Humano , Instabilidade Genômica , Humanos , Neoplasias/genética , Neoplasias/patologia , Ligação Proteica , Proteínas/genética , Esquizofrenia/genética , Esquizofrenia/patologia , Transdução de Sinais , Enzimas Ativadoras de Ubiquitina/genética , Enzimas Ativadoras de Ubiquitina/metabolismo , Enzimas de Conjugação de Ubiquitina/genética , Enzimas de Conjugação de Ubiquitina/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação
15.
Nat Commun ; 10(1): 3355, 2019 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-31399567

RESUMO

Schizophrenia is associated with disrupted cognitive control and sleep-wake cycles. Here we identify diurnal rhythms in gene expression in the human dorsolateral prefrontal cortex (dlPFC), in schizophrenia and control subjects. We find significant diurnal (24 h) rhythms in control subjects, however, most of these transcripts are not rhythmic in subjects with schizophrenia. Instead, subjects with schizophrenia have a different set of rhythmic transcripts. The top pathways identified in transcripts rhythmic only in subjects with schizophrenia are associated with mitochondrial function. Importantly, these rhythms drive differential expression patterns of these and several other genes that have long been implicated in schizophrenia (including BDNF and GABAergic-related transcripts). Indeed, differential expression of these transcripts is only seen in subjects that died during the night, with no change in subjects that died during the day. These data provide insights into a potential mechanism that underlies changes in gene expression in the dlPFC with schizophrenia.


Assuntos
Ritmo Circadiano/genética , Córtex Pré-Frontal/metabolismo , Esquizofrenia/genética , Adulto , Antipsicóticos , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Córtex Pré-Frontal/patologia , Esquizofrenia/patologia , Análise de Sequência de RNA
16.
Expert Opin Pharmacother ; 20(16): 2033-2039, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31393186

RESUMO

Background: In this post hoc analysis in patients recently diagnosed (≤5 years) with schizophrenia, the effect on hospitalization risk after switching from oral antipsychotic to once-monthly paliperidone palmitate (PP1M) was evaluated. Research design and methods: Change in hospitalization risk following PP1M initiation among patients switching from oral antipsychotics was assessed using prescription sequence symmetry analysis. Hospitalization risk was expressed as an adjusted sequence ratio (ASR) of the number of patients hospitalized prior to PP1M initiation/post PP1M initiation. Cumulative distribution of the time to hospitalization was estimated by the Kaplan-Meier method and symmetry of distribution was assessed using log-rank test. Hazard ratio and 95% CI were calculated using the Cox proportional hazard model. Results: The number of patients hospitalized after switching to PP1M: no change, 203/300 (67.7%); increase, 18/300 (6.0%); and decrease, 79/300 (26.3%). Following PP1M initiation, ASR (95% CI) was 3.56 (2.67, 5.33) suggesting asymmetry and a significant decline in hospitalization risk. Asymmetry in distribution of hospitalization events with significant (p ≤ 0.001) delay in time to hospitalization was also observed. Conclusion: Switching to PP1M treatment from oral antipsychotics is likely to be associated with a significant reduction in hospitalization risk along with a delay in time to hospitalization and rehospitalization.


Assuntos
Antipsicóticos/uso terapêutico , Palmitato de Paliperidona/uso terapêutico , Esquizofrenia/tratamento farmacológico , Administração Oral , Adulto , Grupo com Ancestrais do Continente Asiático , Esquema de Medicação , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Modelos de Riscos Proporcionais , Risco , Esquizofrenia/patologia
17.
Transl Psychiatry ; 9(1): 179, 2019 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-31358727

RESUMO

Human induced pluripotent stem cells (hiPSC) provide an attractive tool to study disease mechanisms of neurodevelopmental disorders such as schizophrenia. A pertinent problem is the development of hiPSC-based assays to discriminate schizophrenia (SZ) from autism spectrum disorder (ASD) models. Healthy control individuals as well as patients with SZ and ASD were examined by a panel of diagnostic tests. Subsequently, skin biopsies were taken for the generation, differentiation, and testing of hiPSC-derived neurons from all individuals. SZ and ASD neurons share a reduced capacity for cortical differentiation as shown by quantitative analysis of the synaptic marker PSD95 and neurite outgrowth. By contrast, pattern analysis of calcium signals turned out to discriminate among healthy control, schizophrenia, and autism samples. Schizophrenia neurons displayed decreased peak frequency accompanied by increased peak areas, while autism neurons showed a slight decrease in peak amplitudes. For further analysis of the schizophrenia phenotype, transcriptome analyses revealed a clear discrimination among schizophrenia, autism, and healthy controls based on differentially expressed genes. However, considerable differences were still evident among schizophrenia patients under inspection. For one individual with schizophrenia, expression analysis revealed deregulation of genes associated with the major histocompatibility complex class II (MHC class II) presentation pathway. Interestingly, antipsychotic treatment of healthy control neurons also increased MHC class II expression. In conclusion, transcriptome analysis combined with pattern analysis of calcium signals appeared as a tool to discriminate between SZ and ASD phenotypes in vitro.


Assuntos
Transtorno Autístico/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Neurônios/metabolismo , Esquizofrenia/metabolismo , Transtorno Autístico/patologia , Sinalização do Cálcio/fisiologia , Diferenciação Celular/fisiologia , Humanos , Células-Tronco Pluripotentes Induzidas/patologia , Neuritos/fisiologia , Neurônios/patologia , Esquizofrenia/patologia
18.
Brain Nerve ; 71(7): 657-664, 2019 Jul.
Artigo em Japonês | MEDLINE | ID: mdl-31289240

RESUMO

This article aims at understanding the essential dynamical characteristics of the brain by modeling the brain as a simplified dynamical control system. Although the brain is a highly complex system, such a simplified model provides us insights into its essential features. Using a control system model, the first half of this article describes the dynamics of a system comprising the dorsolateral prefrontal cortex and striatum with dopaminergic modulation and argue its relevance to the functions of the brain with schizophrenia. The second half of this article introduces a model-based analysis of molecular imaging data.


Assuntos
Encéfalo/fisiologia , Encéfalo/fisiopatologia , Esquizofrenia/patologia , Corpo Estriado , Dopamina , Humanos , Córtex Pré-Frontal
19.
Psychiatry Res ; 277: 70-71, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31229308

RESUMO

The Genain Quadruplets, a genetically identical group of sisters, all developed schizophrenia by their early 20s. Beginning in the 1950s, under the direction of David Rosenthal, they have been studied extensively with a number of neurobiological, neuroradiological and neurobehavioral measures at the Intramural Program of the National Institute of Mental Health (NIMH). A major focus of research interest has been the fact that they varied greatly in the severity of their illness. The present report emphasizes the important role that Monte Buchsbaum had in their evaluation, especially with respect to neuroradiology, during their second period of study at NIMH in the 1980s. It is of special interest that Buchsbaum et al. (1984) concluded "No strong relationship is shown between these (radiological) measures and illness severity or drug responsivity." The inference, therefore, is that the differences in illness severity among the sisters were not readily attributable to differences in the amount of damaged brain, at least as could be determined by the imaging methods available in the 1980s. The current report also summarizes the results of the other studies performed on the sisters in the 1980s, to which Monte Buchsbaum contributed.


Assuntos
Quadrigêmeos/história , Esquizofrenia/história , Adulto , Feminino , História do Século XX , Humanos , National Institute of Mental Health (U.S.) , Psiquiatria/história , Quadrigêmeos/psicologia , Esquizofrenia/genética , Esquizofrenia/patologia , Estados Unidos
20.
Am J Psychiatry ; 176(7): 552-563, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31164006

RESUMO

OBJECTIVE: Cortical thickness reductions in schizophrenia are irregularly distributed across multiple loci. The authors hypothesized that cortical connectivity networks would explain the distribution of cortical thickness reductions across the cortex, and, specifically, that cortico-cortical connectivity between loci with these reductions would be exceptionally strong and form an interconnected network. This hypothesis was tested in three cross-sectional schizophrenia cohorts: first-episode psychosis, chronic schizophrenia, and treatment-resistant schizophrenia. METHODS: Structural brain images were acquired for 70 patients with first-episode psychosis, 153 patients with chronic schizophrenia, and 47 patients with treatment-resistant schizophrenia and in matching healthy control groups (N=57, N=168, and N=54, respectively). Cortical thickness was compared between the patient and respective control groups at 148 regions spanning the cortex. Structural connectivity strength between pairs of cortical regions was quantified with structural covariance analysis. Connectivity strength between regions with cortical thickness reductions was compared with connectivity strength between 5,000 sets of randomly chosen regions to establish whether regions with reductions were interconnected more strongly than would be expected by chance. RESULTS: Significant (false discovery rate corrected) and widespread cortical thickness reductions were found in the chronic schizophrenia (79 regions) and treatment-resistant schizophrenia (106 regions) groups, with more circumscribed reductions in the first-episode psychosis group (34 regions). Cortical thickness reductions with the largest effect sizes were found in frontal, temporal, cingulate, and insular regions. In all cohorts, both the patient and healthy control groups showed significantly increased structural covariance between regions with cortical thickness reductions compared with randomly selected regions. CONCLUSIONS: Brain network architecture can explain the irregular topographic distribution of cortical thickness reductions in schizophrenia. This finding, replicated in three distinct schizophrenia cohorts, suggests that the effect is robust and independent of illness stage.


Assuntos
Córtex Cerebral/patologia , Rede Nervosa/patologia , Esquizofrenia/patologia , Adulto , Estudos de Casos e Controles , Córtex Cerebral/diagnóstico por imagem , Estudos Transversais , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Neuroimagem , Esquizofrenia/diagnóstico por imagem , Adulto Jovem
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