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1.
Nat Commun ; 15(1): 5524, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38951485

RESUMO

The three-dimensional genome structure organized by CTCF is required for development. Clinically identified mutations in CTCF have been linked to adverse developmental outcomes. Nevertheless, the underlying mechanism remains elusive. In this investigation, we explore the regulatory roles of a clinically relevant R567W point mutation, located within the 11th zinc finger of CTCF, by introducing this mutation into both murine models and human embryonic stem cell-derived cortical organoid models. Mice with homozygous CTCFR567W mutation exhibit growth impediments, resulting in postnatal mortality, and deviations in brain, heart, and lung development at the pathological and single-cell transcriptome levels. This mutation induces premature stem-like cell exhaustion, accelerates the maturation of GABAergic neurons, and disrupts neurodevelopmental and synaptic pathways. Additionally, it specifically hinders CTCF binding to peripheral motifs upstream to the core consensus site, causing alterations in local chromatin structure and gene expression, particularly at the clustered protocadherin locus. Comparative analysis using human cortical organoids mirrors the consequences induced by this mutation. In summary, this study elucidates the influence of the CTCFR567W mutation on human neurodevelopmental disorders, paving the way for potential therapeutic interventions.


Assuntos
Fator de Ligação a CCCTC , Transtornos do Neurodesenvolvimento , Organoides , Fator de Ligação a CCCTC/metabolismo , Fator de Ligação a CCCTC/genética , Humanos , Animais , Camundongos , Transtornos do Neurodesenvolvimento/genética , Organoides/metabolismo , Mutação , Neurônios GABAérgicos/metabolismo , Neurônios GABAérgicos/patologia , Masculino , Cromatina/metabolismo , Cromatina/genética , Feminino , Encéfalo/metabolismo , Encéfalo/patologia , Mutação Puntual , Células-Tronco Embrionárias Humanas/metabolismo
2.
Semin Immunopathol ; 46(1-2): 1, 2024 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-38990389

RESUMO

Activation of the maternal immune system during gestation has been associated with an increased risk for neurodevelopmental disorders in the offspring, particularly schizophrenia and autism spectrum disorder. Microglia, the tissue-resident macrophages of the central nervous system, are implicated as potential mediators of this increased risk. Early in development, microglia start populating the embryonic central nervous system and in addition to their traditional role as immune responders under homeostatic conditions, microglia are also intricately involved in various early neurodevelopmental processes. The timing of immune activation may interfere with microglia functioning during early neurodevelopment, potentially leading to long-term consequences in postnatal life. In this review we will discuss the involvement of microglia in brain development during the prenatal and early postnatal stages of life, while also examining the effects of maternal immune activation on microglia and neurodevelopmental processes. Additionally, we discuss recent single cell RNA-sequencing studies focusing on microglia during prenatal development, and hypothesize how early life microglial priming, potentially through epigenetic reprogramming, may be related to neurodevelopmental disorders.


Assuntos
Microglia , Transtornos do Neurodesenvolvimento , Efeitos Tardios da Exposição Pré-Natal , Microglia/imunologia , Microglia/metabolismo , Humanos , Gravidez , Animais , Transtornos do Neurodesenvolvimento/etiologia , Transtornos do Neurodesenvolvimento/imunologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Feminino , Encéfalo/imunologia , Encéfalo/metabolismo , Encéfalo/embriologia , Epigênese Genética , Suscetibilidade a Doenças
3.
Sci Rep ; 14(1): 16455, 2024 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-39014184

RESUMO

Diffusion Kurtosis Imaging (DKI)-derived metrics are recognized as indicators of maturation in neonates with low-grade germinal matrix and intraventricular hemorrhage (GMH-IVH). However, it is not yet known if these factors are associated with neurodevelopmental outcomes. The objective of this study was to acquire DKI-derived metrics in neonates with low-grade GMH-IVH, and to demonstrate their association with later neurodevelopmental outcomes. In this prospective study, neonates with low-grade GMH-IVH and control neonates were recruited, and DKI were performed between January 2020 and March 2021. These neonates underwent the Bayley Scales of Infant Development test at 18 months of age. Mean kurtosis (MK), radial kurtosis (RK) and gray matter values were measured. Spearman correlation analyses were conducted for the measured values and neurodevelopmental outcome scores. Forty controls (18 males, average gestational age (GA) 30 weeks ± 1.3, corrected GA at MRI scan 38 weeks ± 1) and thirty neonates with low-grade GMH-IVH (13 males, average GA 30 weeks ± 1.5, corrected GA at MRI scan 38 weeks ± 1). Neonates with low-grade GMH-IVH exhibited lower MK and RK values in the PLIC and the thalamus (P < 0.05). The MK value in the thalamus was associated with Mental Development Index (MDI) (r = 0.810, 95% CI 0.695-0.13; P < 0.001) and Psychomotor Development Index (PDI) (r = 0.852, 95% CI 0.722-0.912; P < 0.001) scores. RK value in the caudate nucleus significantly and positively correlated with MDI (r = 0.496, 95% CI 0.657-0.933; P < 0.001) and PDI (r = 0.545, 95% CI 0.712-0.942; P < 0.001) scores. The area under the curve (AUC) were used to assess diagnostic performance of MK and RK in thalamus (AUC = 0.866, 0.787) and caudate nucleus (AUC = 0.833, 0.671) for predicting neurodevelopmental outcomes. As quantitative neuroimaging markers, MK in thalamus and RK in caudate nucleus may help predict neurodevelopmental outcomes in neonates with low-grade GMH-IVH.


Assuntos
Imagem de Tensor de Difusão , Humanos , Masculino , Recém-Nascido , Feminino , Imagem de Tensor de Difusão/métodos , Estudos Prospectivos , Hemorragia Cerebral/diagnóstico por imagem , Transtornos do Neurodesenvolvimento/diagnóstico por imagem , Transtornos do Neurodesenvolvimento/etiologia , Lactente , Hemorragia Cerebral Intraventricular/diagnóstico por imagem , Idade Gestacional , Desenvolvimento Infantil , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/patologia
4.
J Neurodev Disord ; 16(1): 37, 2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-38970057

RESUMO

BACKGROUND: A sizeable proportion of pathogenic genetic variants identified in young children tested for congenital differences are associated with neurodevelopmental psychiatric disorders (NPD). In this growing group, a genetic diagnosis often precedes the emergence of diagnosable developmental concerns. Here, we describe DAGSY (Developmental Assessment of Genetically Susceptible Youth), a novel interdisciplinary 'genetic-diagnosis-first' clinic integrating psychiatric, psychological and genetic expertise, and report our first observations and feedback from families and referring clinicians. METHODS: We retrieved data on referral sources and indications, genetic and NPD diagnoses and recommendations for children seen at DAGSY between 2018 and 2022. Through a survey, we obtained feedback from twenty families and eleven referring clinicians. RESULTS: 159 children (mean age 10.2 years, 57.2% males) completed an interdisciplinary (psychiatry, psychology, genetic counselling) DAGSY assessment during this period. Of these, 69.8% had a pathogenic microdeletion or microduplication, 21.5% a sequence-level variant, 4.4% a chromosomal disorder, and 4.4% a variant of unknown significance with emerging evidence of pathogenicity. One in four children did not have a prior NPD diagnosis, and referral to DAGSY was motivated by their genetic vulnerability alone. Following assessment, 76.7% received at least one new NPD diagnosis, most frequently intellectual disability (24.5%), anxiety (20.7%), autism spectrum (18.9%) and specific learning (16.4%) disorder. Both families and clinicians responding to our survey expressed satisfaction, but also highlighted some areas for potential improvement. CONCLUSIONS: DAGSY addresses an unmet clinical need for children identified with genetic variants that confer increased vulnerability for NPD and provides a crucial platform for research in this area. DAGSY can serve as a model for interdisciplinary clinics integrating child psychiatry, psychology and genetics, addressing both clinical and research needs for this emerging population.


Assuntos
Transtornos Mentais , Transtornos do Neurodesenvolvimento , Humanos , Criança , Transtornos do Neurodesenvolvimento/genética , Feminino , Masculino , Transtornos Mentais/genética , Predisposição Genética para Doença , Adolescente
5.
BMC Med ; 22(1): 284, 2024 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-38972993

RESUMO

BACKGROUND: Infant neurodevelopment in the first years after birth is determined by multiple factors, including parental care and maternal mental wellbeing. In this study, we aim to assess the impact of persistent maternal depressive symptoms during the first 3 months postpartum on infant neurodevelopment at 6 months. METHODS: Using a longitudinal cohort design, 1253 mother-infant pairs were followed up at 7, 45, and 90 days to assess postpartum depressive symptoms using the Edinburgh Postnatal Depression Scale (EPDS); infants were followed up at 6 months to assess neuro-developmental status using the WHO's Infant and Young Child Development (IYCD) tool. A generalized linear regression model was used to assess the association between persistent postpartum depressive symptoms and infant neurodevelopmental delay at 6 months. A generalized linear mixed model (GLMM) with a hospital as a random intercept was used to assess the persistent postpartum depressive symptoms with an IYCD score. Linear regression was used to compare the IYCD scores between exposure groups. RESULTS: In the study population, 7.5% of mothers had persistent depressive symptoms, and 7.5% of infants had neurodevelopmental delay. Infants born to mothers with persistent depressive symptoms had a higher proportion of neurodevelopmental delay than infants born to women without persistent symptoms (48.6% vs 5.1%; p < 0.001). In the adjusted regression model, infants whose mothers had persistent depressive symptoms at 7, 45, and 90 days had a 5.21-fold increased risk of neurodevelopmental delay (aRR, 5.21; 95% CI, 3.17, 8.55). Mean scores in the motor domain (12.7 vs 15.2; p < 0.001) and language domain (6.4 vs 8.5; p < 0.001) were significant when a mother had persistent depression vs. no depression. Mean scores in the general behavioral domain (5.9 vs 10.4, p < 0.001) and the socio-emotional domain (15.4 vs 17.7; p < 0.001) were significantly different when a mother had persistent depression vs no persistent depression. CONCLUSIONS: Our results suggest that 6-month-old infants are at higher risk for neurodevelopment delays if their mother reports persistent symptoms of depression from 7 to 90 days postpartum. The neurodevelopmental delay can be observed in all functional domains. Preventive intervention to reduce maternal postpartum depression may reduce the impact on infant developmental delay.


Assuntos
Depressão Pós-Parto , Humanos , Feminino , Depressão Pós-Parto/epidemiologia , Estudos Longitudinais , Lactente , Adulto , Nepal/epidemiologia , Adulto Jovem , Masculino , Desenvolvimento Infantil/fisiologia , Transtornos do Neurodesenvolvimento/epidemiologia , Estudos de Coortes , Recém-Nascido
6.
JAMA Netw Open ; 7(7): e2420382, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38967923

RESUMO

Importance: Preeclampsia has direct influences on a developing fetus and may impact postnatal health, and fetal growth restriction (FGR) is often seen co-occurring with preeclampsia. The development of children born very preterm after preeclampsia diagnosis with and without FGR is not well characterized. Objective: To examine the associations of preeclampsia and FGR with developmental and/or behavioral outcomes in a cohort of very preterm infants. Design, Setting, and Participants: In this cohort study, infants in the prospective Neonatal Neurobehavior and Outcomes in Very Preterm Infants study were enrolled between April 2014 and June 2016 from 9 US university-affiliated neonatal intensive care units (NICUs). Eligible infants were born before 30 weeks' gestation. Infants were excluded for any major congenital anomalies and for maternal age younger than 18 years or cognitive impairment impacting the ability to provide informed consent. Data analysis was performed from November 2023 to January 2024. Exposure: Maternal preeclampsia and FGR in very preterm infants. Main Outcomes and Measures: The Bayley-III cognition, motor, and language scores less than 85 (-1 SD) indicated developmental delay. Child Behavior Checklist/Preschool 1.5-5 T-scores greater than or equal to 64 for internalizing, externalizing, or total problems indicated clinical importance. Results: Of 704 infants enrolled, 529 (mean [SD] gestational age, 27.0 [1.9] weeks; 287 male [54.3%]) were studied at 24-month follow-up. A total of 94 infants' mothers had preeclampsia (23.2%), and 46 infants (8.7%) had FGR. In adjusted models, preeclampsia was not associated with Bayley-III (cognitive, B = 3.43 [95% CI, -0.19 to 6.66]; language, B = 3.92 [95% CI, 0.44 to 7.39]; motor, B = 1.86 [95% CI, -1.74 to 5.47]) or Child Behavior Checklist/Preschool 1.5-5 (internalizing, B = -0.08 [95% CI, -2.58 to 2.73]; externalizing, B = 0.69 [95% CI, -1.76 to 3.15]; total, B = 0.21 [95% CI, -2.48 to 2.91]) outcomes. FGR was associated with significantly lower Bayley-III scores (cognitive, B = -8.61 [95% CI, -13.33 to -3.89]; language, B = -8.29 [95% CI, -12.95 to -3.63]; motor, B = -7.60 [95% CI, -12.40 to -2.66]), regardless of preeclampsia status. Conclusions and Relevance: In this cohort study of preterm infants, preeclampsia was not associated with developmental and/or behavioral outcomes, but infants with FGR may be prone to developmental delays. These findings suggest future areas of research for understanding the roles of preeclampsia and FGR separately and together in early child development for preterm infants.


Assuntos
Retardo do Crescimento Fetal , Pré-Eclâmpsia , Humanos , Feminino , Pré-Eclâmpsia/epidemiologia , Gravidez , Retardo do Crescimento Fetal/epidemiologia , Masculino , Recém-Nascido , Estudos Prospectivos , Adulto , Desenvolvimento Infantil/fisiologia , Pré-Escolar , Lactente Extremamente Prematuro , Deficiências do Desenvolvimento/epidemiologia , Deficiências do Desenvolvimento/etiologia , Lactente , Recém-Nascido Prematuro , Transtornos do Neurodesenvolvimento/epidemiologia , Transtornos do Neurodesenvolvimento/etiologia , Estudos de Coortes
7.
Sci Adv ; 10(28): eadk5462, 2024 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-38985877

RESUMO

Adherens junction-associated protein 1 (AJAP1) has been implicated in brain diseases; however, a pathogenic mechanism has not been identified. AJAP1 is widely expressed in neurons and binds to γ-aminobutyric acid type B receptors (GBRs), which inhibit neurotransmitter release at most synapses in the brain. Here, we show that AJAP1 is selectively expressed in dendrites and trans-synaptically recruits GBRs to presynaptic sites of neurons expressing AJAP1. We have identified several monoallelic AJAP1 variants in individuals with epilepsy and/or neurodevelopmental disorders. Specifically, we show that the variant p.(W183C) lacks binding to GBRs, resulting in the inability to recruit them. Ultrastructural analysis revealed significantly decreased presynaptic GBR levels in Ajap1-/- and Ajap1W183C/+ mice. Consequently, these mice exhibited reduced GBR-mediated presynaptic inhibition at excitatory and inhibitory synapses, along with impaired synaptic plasticity. Our study reveals that AJAP1 enables the postsynaptic neuron to regulate the level of presynaptic GBR-mediated inhibition, supporting the clinical relevance of loss-of-function AJAP1 variants.


Assuntos
Neurotransmissores , Sinapses , Transmissão Sináptica , Animais , Humanos , Neurotransmissores/metabolismo , Camundongos , Sinapses/metabolismo , Masculino , Alelos , Feminino , Neurônios/metabolismo , Mutação com Perda de Função , Epilepsia/metabolismo , Epilepsia/genética , Epilepsia/patologia , Camundongos Knockout , Plasticidade Neuronal , Transtornos do Neurodesenvolvimento/metabolismo , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/patologia
8.
Int J Mol Sci ; 25(13)2024 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-38999997

RESUMO

In recent decades, emerging evidence has identified endocrine and neurologic health concerns related to exposure to endocrine-disrupting chemicals (EDCs), including bisphenol A (BPA), certain per- and polyfluoroalkyl compounds (PFASs), and phthalates. This has resulted in consumer pressure to remove these chemicals from the market, especially in food-contact materials and personal care products, driving their replacement with structurally or functionally similar substitutes. However, these "new-generation" chemicals may be just as or more harmful than their predecessors and some have not received adequate testing. This review discusses the research on early-life exposures to new-generation bisphenols, PFASs, and phthalates and their links to neurodevelopmental and behavioral alterations in zebrafish, rodents, and humans. As a whole, the evidence suggests that BPA alternatives, especially BPAF, and newer PFASs, such as GenX, can have significant effects on neurodevelopment. The need for further research, especially regarding phthalate replacements and bio-based alternatives, is briefly discussed.


Assuntos
Compostos Benzidrílicos , Encéfalo , Disruptores Endócrinos , Fenóis , Ácidos Ftálicos , Animais , Ácidos Ftálicos/toxicidade , Fenóis/toxicidade , Compostos Benzidrílicos/toxicidade , Humanos , Disruptores Endócrinos/toxicidade , Encéfalo/efeitos dos fármacos , Encéfalo/crescimento & desenvolvimento , Transtornos do Neurodesenvolvimento/induzido quimicamente , Modelos Animais , Peixe-Zebra , Fluorocarbonos/toxicidade
9.
Int J Mol Sci ; 25(13)2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-39000367

RESUMO

Homotypic Fusion and Protein Sorting (HOPS) and Class C-core Vacuole/Endosome Tethering (CORVET) complexes regulate the correct fusion of endolysosomal bodies. Mutations in core proteins (VPS11, VPS16, VPS18, and VPS33) have been linked with multiple neurological disorders, including mucopolysaccharidosis (MPS), genetic leukoencephalopathy (gLE), and dystonia. Mutations in human Vacuolar Protein Sorting 16 (VPS16) have been associated with MPS and dystonia. In this study, we generated and characterized a zebrafish vps16(-/-) mutant line using immunohistochemical and behavioral approaches. The loss of Vps16 function caused multiple systemic defects, hypomyelination, and increased neuronal cell death. Behavioral analysis showed a progressive loss of visuomotor response and reduced motor response and habituation to acoustic/tap stimuli in mutants. Finally, using a novel multiple-round acoustic/tap stimuli test, mutants showed intermediate memory deficits. Together, these data demonstrate that zebrafish vps16(-/-) mutants show systemic defects, neurological and motor system pathologies, and cognitive impairment. This is the first study to report behavior abnormalities and memory deficiencies in a zebrafish vps16(-/-) mutant line. Finally, we conclude that the deficits observed in vps16(-/-) zebrafish mutants do not mimic pathologies associated with dystonia, but more align to abnormalities associated with MPS and gLE.


Assuntos
Proteínas de Transporte Vesicular , Proteínas de Peixe-Zebra , Peixe-Zebra , Animais , Peixe-Zebra/genética , Proteínas de Transporte Vesicular/genética , Proteínas de Transporte Vesicular/metabolismo , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo , Mutação , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/metabolismo , Modelos Animais de Doenças , Bainha de Mielina/metabolismo , Comportamento Animal
10.
BMJ Open ; 14(6): e081082, 2024 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-38885994

RESUMO

INTRODUCTION: Due to a change in diagnostic prerequisites and the inclusion of novel diagnostic entities, the implementation of the 11th revision of the International Classification of Diseases (ICD-11) will presumably change prevalence rates of specific mental, behavioural or neurodevelopmental disorders and result in an altered prevalence rate for this grouping overall. This scoping review aims to summarise the characteristics of primary studies examining the prevalence of mental, behavioural or neurodevelopmental disorders based on ICD-11 criteria. The knowledge attained through this review will primarily characterise the methodological approaches of this research field and additionally assist in deciding which psychiatric diagnoses are-given the current literature-most relevant for subsequent systematic reviews and meta-analyses intended to approximate the magnitude of prevalence rates while providing a first glimpse of the range of expected (differences in) prevalence rates in these conditions. METHODS AND ANALYSIS: MEDLINE, Embase, Web of Science and PsycINFO will be searched from 2011 to present without any language filters. This scoping review will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Review guidelines.We will consider (a) cross-sectional and longitudinal studies (b) focusing on the prevalence rates of mental, behavioural or neurodevelopmental disorders (c) using ICD-11 criteria for inclusion. The omission of (a) case numbers and sample size, (b) study period and period of data collection or (c) diagnostic procedures on full-text level is considered an exclusion criterion.This screening will be conducted by two reviewers independently from one another and a third reviewer will be consulted with disagreements. Data extraction and synthesis will focus on outlining methodological aspects. ETHICS AND DISSEMINATION: We intend to publish our review in a scientific journal. As the primary data are publicly available, we do not require research ethics approval.


Assuntos
Classificação Internacional de Doenças , Transtornos Mentais , Transtornos do Neurodesenvolvimento , Humanos , Transtornos do Neurodesenvolvimento/epidemiologia , Transtornos do Neurodesenvolvimento/diagnóstico , Prevalência , Transtornos Mentais/epidemiologia , Transtornos Mentais/diagnóstico , Projetos de Pesquisa
12.
Sci Rep ; 14(1): 13993, 2024 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-38886474

RESUMO

Neurodevelopmental disorders (NDD) in offspring are associated with a complex combination of pre-and postnatal factors. This study uses machine learning and population data to evaluate the association between prepregnancy or perinatal risk factors and the NDD of offspring. Population-based retrospective cohort data were obtained from Korea National Health Insurance Service claims data for 209,424 singleton offspring and their mothers who gave birth for the first time in 2007. The dependent variables were motor development disorder (MDD), cognitive development disorder (CDD) and combined overall neurodevelopmental disorder (NDD) from offspring. Seventeen independent variables from 2002 to 2007 were included. Random forest variable importance and Shapley Additive Explanation (SHAP) values were calculated to analyze the directions of its associations with the predictors. The random forest with oversampling registered much higher areas under the receiver-operating-characteristic curves than the logistic regression of interaction and non-linearity terms, 79% versus 50% (MDD), 82% versus 52% (CDD) and 74% versus 50% (NDD). Based on random forest variable importance, low socioeconomic status and age at birth were highly ranked. In SHAP values, there was a positive association between NDD and pre- or perinatal outcomes, especially, fetal male sex with growth restriction associated the development of NDD in offspring.


Assuntos
Aprendizado de Máquina , Transtornos do Neurodesenvolvimento , Humanos , Feminino , Fatores de Risco , Masculino , Gravidez , Transtornos do Neurodesenvolvimento/epidemiologia , Transtornos do Neurodesenvolvimento/etiologia , Adulto , República da Coreia/epidemiologia , Estudos Retrospectivos , Recém-Nascido , Pré-Escolar , Criança
13.
Int J Mol Sci ; 25(11)2024 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-38891827

RESUMO

In this Special Issue, we focus on the complex mechanisms underlying neurodevelopmental disorders (as delineated in the DSM-5), which are a group of neurological disorders that begin in childhood but significantly impact adult life [...].


Assuntos
Epigênese Genética , Transtornos do Neurodesenvolvimento , Humanos , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/terapia
14.
BMJ Paediatr Open ; 8(1)2024 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-38823798

RESUMO

OBJECTIVE: To compare the neurodevelopmental outcomes of preterm infants before and during the COVID-19 pandemic. DESIGN: Premature infants born in 2018 were assigned to the pre-pandemic group, while those born in 2019 were assigned to the during-pandemic group. SETTING: Nationwide cohort study. PATIENTS: Very low birthweight premature infants registered in the Taiwan Premature Infant Follow-up Network database. INTERVENTIONS: Anti-epidemic measures, including quarantine and isolation protocols, social distancing, the closure of public spaces and restrictions on travel and gatherings during COVID-19 pandemic. MAIN OUTCOME MEASURES: Outcomes were measured by Bayley Scales of Infant and Toddler Development Third Edition at corrected ages of 6, 12 and 24 months old. Generalised estimating equation (GEE) was applied to incorporate all measurements into a single model. RESULTS: Among the 1939 premature infants who were enrolled, 985 developed before the pandemic, while 954 developed during the pandemic. Premature infants whose development occurred during the pandemic exhibited better cognitive composite at the corrected age of 6 months (beta=2.358; 95% CI, 1.07 to 3.65; p<0.001), and motor composite at corrected ages of 12 months (beta=1.680; 95% CI, 0.34 to 3.02; p=0.014). GEE analysis showed that infants who had grown during the pandemic achieved higher scores in cognitive composite (beta=1.416; 95% CI, 0.36 to 2.48; p=0.009). CONCLUSION: Premature infants in Taiwan who developed during the pandemic showed better neurodevelopment compared with those born before the pandemic.


Assuntos
COVID-19 , Recém-Nascido Prematuro , Humanos , COVID-19/epidemiologia , COVID-19/prevenção & controle , Taiwan/epidemiologia , Recém-Nascido Prematuro/crescimento & desenvolvimento , Masculino , Feminino , Recém-Nascido , Lactente , Estudos Retrospectivos , Desenvolvimento Infantil/fisiologia , SARS-CoV-2 , Transtornos do Neurodesenvolvimento/epidemiologia , Recém-Nascido de muito Baixo Peso/crescimento & desenvolvimento , Pandemias , Estudos de Coortes
15.
JAMA Netw Open ; 7(6): e2416760, 2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38869906

RESUMO

Importance: The use of evidence-based standardized outcome measures is increasingly recognized as key to guiding clinical decision-making in mental health. Implementation of these measures into clinical practice has been hampered by lack of clarity on what to measure and how to do this in a reliable and standardized way. Objective: To develop a core set of outcome measures for specific neurodevelopmental disorders (NDDs), such as attention-deficit/hyperactivity disorder (ADHD), communication disorders, specific learning disorders, and motor disorders, that may be used across a range of geographic and cultural settings. Evidence Review: An international working group composed of clinical and research experts and service users (n = 27) was convened to develop a standard core set of accessible, valid, and reliable outcome measures for children and adolescents with NDDs. The working group participated in 9 video conference calls and 8 surveys between March 1, 2021, and June 30, 2022. A modified Delphi approach defined the scope, outcomes, included measures, case-mix variables, and measurement time points. After development, the NDD set was distributed to professionals and service users for open review, feedback, and external validation. Findings: The final set recommends measuring 12 outcomes across 3 key domains: (1) core symptoms related to the diagnosis; (2) impact, functioning, and quality of life; and (3) common coexisting problems. The following 14 measures should be administered at least every 6 months to monitor these outcomes: ADHD Rating Scale 5, Vanderbilt ADHD Diagnostic Rating Scale, or Swanson, Nolan, and Pelham Rating Scale IV; Affective Reactivity Index; Children's Communication Checklist 2; Colorado Learning Disabilities Questionnaire; Children's Sleep Habits Questionnaire; Developmental-Disability Children's Global Assessment Scale; Developmental Coordination Disorder Questionnaire; Family Strain Index; Intelligibility in Context Scale; Vineland Adaptive Behavior Scale or Repetitive Behavior Scale-Revised and Social Responsiveness Scale; Revised Child Anxiety and Depression Scales; and Yale Global Tic Severity Scale. The external review survey was completed by 32 professionals and 40 service users. The NDD set items were endorsed by more than 70% of professionals and service users in the open review survey. Conclusions and Relevance: The NDD set covers outcomes of most concern to patients and caregivers. Use of the NDD set has the potential to improve clinical practice and research.


Assuntos
Consenso , Transtornos do Neurodesenvolvimento , Avaliação de Resultados em Cuidados de Saúde , Humanos , Transtornos do Neurodesenvolvimento/diagnóstico , Criança , Adolescente , Técnica Delphi , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Feminino
16.
J Neuroimmune Pharmacol ; 19(1): 29, 2024 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-38874861

RESUMO

The opioid epidemic has received considerable attention, but the impact on perinatal opioid-exposed (POE) offspring remains underexplored. This study addresses the emerging public health challenge of understanding and treating POE children. We examined two scenarios using preclinical models: offspring exposed to oxycodone (OXY) in utero (IUO) and acute postnatal OXY (PNO). We hypothesized exposure to OXY during pregnancy primes offspring for neurodevelopmental deficits and severity of deficits is dependent on timing of exposure. Notable findings include reduced head size and brain weight in offspring. Molecular analyses revealed significantly lower levels of inflammasome-specific genes in the prefrontal cortex (PFC). Gene Set Enrichment Analysis (GSEA) and Ingenuity Pathway Analysis (IPA) highlighted the enrichment of genes associated with mitochondrial and synapse dysfunction in POE offspring. Western blot analysis validated IPA predictions of mitochondrial dysfunction in PFC-derived synaptosomes. Behavioral studies identified significant social deficits in POE offspring. This study presents the first comparative analysis of acute PNO- and IUO-offspring during early adolescence finding acute PNO-offspring have considerably greater deficits. The striking difference in deficit severity in acute PNO-offspring suggests that exposure to opioids in late pregnancy pose the greatest risk for offspring well-being.


Assuntos
Analgésicos Opioides , Oxicodona , Efeitos Tardios da Exposição Pré-Natal , Animais , Oxicodona/toxicidade , Gravidez , Feminino , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Masculino , Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/toxicidade , Comportamento Animal/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Transtornos do Neurodesenvolvimento/induzido quimicamente , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo
17.
Transl Psychiatry ; 14(1): 259, 2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38890284

RESUMO

A range of rare mutations involving micro-deletion or -duplication of genetic material (copy number variants (CNVs)) have been associated with high neurodevelopmental and psychiatric risk (ND-CNVs). Irritability is frequently observed in childhood neurodevelopmental conditions, yet its aetiology is largely unknown. Genetic variation may play a role, but there is a sparsity of studies investigating the presentation of irritability in young people with ND-CNVs. This study aimed to investigate whether there is a difference in irritability in young people with rare ND-CNVs compared to those without ND-CNVs, and to what extent irritability is associated with psychiatric diagnoses and cognitive ability (IQ). Irritability and broader psychopathology were assessed in 485 young people with ND-CNVs and 164 sibling controls, using the child and adolescent psychiatric assessment. Autism was assessed using the social communication questionnaire, and intelligence quotient (IQ) by the Wechsler abbreviated scale of intelligence. Fifty four percent of young people with ND-CNVs met the threshold for irritability; significantly more than controls (OR = 3.77, CI = 3.07-7.90, p = 5.31 × 10-11). When controlling for the presence of other psychiatric comorbidities, ND-CNV status was still associated with irritability. There was no evidence for a relationship between irritability and IQ. Irritability is an important aspect of the clinical picture in young people with ND-CNVs. This work shows that genetic variation is associated with irritability in young people with ND-CNVs, independent of psychiatric comorbidities or IQ impairment. Clinicians should be aware of this increased risk to inform management and interventions.


Assuntos
Variações do Número de Cópias de DNA , Humor Irritável , Transtornos do Neurodesenvolvimento , Humanos , Masculino , Feminino , Adolescente , Transtornos do Neurodesenvolvimento/genética , Criança , Inteligência/genética , Estudos de Casos e Controles , Irmãos
18.
Trials ; 25(1): 412, 2024 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-38926739

RESUMO

INTRODUCTION: Parents of children with a neurodevelopmental disorder (NDD) experience more stress than parents of typically developing children. In a cocreation process with experts and parents, a low-threshold application that uses exercises based on the principles of positive psychology and mindfulness was developed. This application, called "Adappt," aims at enhancing the ability to adapt of the parents and caregivers of children with NDDs and at supporting their mental health. This protocol describes the evaluation study of the effectiveness of Adappt, its core working mechanisms and user experiences. METHOD: A pragmatic international multicenter randomized controlled trial will compare the effectiveness of Adappt with a (delayed) waitlist control condition. At least 212 parents or primary caregivers of children younger than 18 years diagnosed with or suspected of a NDD will be randomly assigned to the intervention or waitlist control condition. Participants are excluded if they have severe anxiety or depression levels or are in treatment for mental health issues. Measures will be collected online at baseline, post-intervention (1 month after baseline), and 4 and 7 months after baseline. The primary outcome is the improvement in generic sense of ability to adapt as measured with the Generic Sense of Ability to Adapt Scale (GSAAS; (Front Psychol 14:985408, 2023)) at 4-month follow-up. Secondary outcomes are mental well-being, (parental) distress, and client satisfaction with "Adappt." DISCUSSION: Results of this study will contribute to knowledge on the effectiveness of a low-threshold application for parents of children with a NDD in multiple countries. If the application is found to be effective in improving mental health, recommendations will be made for implementation in health care. TRIAL REGISTRATION: This study is registered on clinicaltrials.gov (NCT06248762) on February 8, 2024, and the Open Science Framework ( https://osf.io/5znqv ).


Assuntos
Saúde Mental , Atenção Plena , Aplicativos Móveis , Estudos Multicêntricos como Assunto , Transtornos do Neurodesenvolvimento , Pais , Ensaios Clínicos Pragmáticos como Assunto , Humanos , Atenção Plena/métodos , Pais/psicologia , Transtornos do Neurodesenvolvimento/psicologia , Transtornos do Neurodesenvolvimento/terapia , Criança , Psicologia Positiva/métodos , Adolescente , Estresse Psicológico/terapia , Estresse Psicológico/psicologia , Resultado do Tratamento , Adaptação Psicológica , Ensaios Clínicos Controlados Aleatórios como Assunto
19.
Int J Mol Sci ; 25(12)2024 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-38928227

RESUMO

Glutamate is the main excitatory neurotransmitter in the brain wherein it controls cognitive functional domains and mood. Indeed, brain areas involved in memory formation and consolidation as well as in fear and emotional processing, such as the hippocampus, prefrontal cortex, and amygdala, are predominantly glutamatergic. To ensure the physiological activity of the brain, glutamatergic transmission is finely tuned at synaptic sites. Disruption of the mechanisms responsible for glutamate homeostasis may result in the accumulation of excessive glutamate levels, which in turn leads to increased calcium levels, mitochondrial abnormalities, oxidative stress, and eventually cell atrophy and death. This condition is known as glutamate-induced excitotoxicity and is considered as a pathogenic mechanism in several diseases of the central nervous system, including neurodevelopmental, substance abuse, and psychiatric disorders. On the other hand, these disorders share neuroplasticity impairments in glutamatergic brain areas, which are accompanied by structural remodeling of glutamatergic neurons. In the current narrative review, we will summarize the role of glutamate-induced excitotoxicity in both the pathophysiology and therapeutic interventions of neurodevelopmental and adult mental diseases with a focus on autism spectrum disorders, substance abuse, and psychiatric disorders. Indeed, glutamatergic drugs are under preclinical and clinical development for the treatment of different mental diseases that share glutamatergic neuroplasticity dysfunctions. Although clinical evidence is still limited and more studies are required, the regulation of glutamate homeostasis is attracting attention as a potential crucial target for the control of brain diseases.


Assuntos
Ácido Glutâmico , Transtornos Mentais , Humanos , Ácido Glutâmico/metabolismo , Transtornos Mentais/metabolismo , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/etiologia , Animais , Transtornos do Neurodesenvolvimento/metabolismo , Transtornos do Neurodesenvolvimento/etiologia , Plasticidade Neuronal , Encéfalo/metabolismo , Encéfalo/patologia , Adulto , Transtornos Relacionados ao Uso de Substâncias/metabolismo , Transtorno do Espectro Autista/metabolismo
20.
Lancet Glob Health ; 12(7): e1129-e1138, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38876760

RESUMO

BACKGROUND: Data on long-term neurodevelopmental outcomes of normocephalic children (born with normal head circumference) exposed to Zika virus in utero are scarce. We aimed to compare neurodevelopmental outcomes in normocephalic children up to age 48 months with and without Zika virus exposure in utero. METHODS: In this prospective cohort study, we included infants from two cohorts of normocephalic children born in León and Managua, Nicaragua during the 2016 Zika epidemic. In León, all women pregnant during the two enrolment periods were eligible. In Managua, mother-child pairs were included from three districts in the municipality of Managua: all women who became pregnant before June 15, 2016, and had a due date of Sept 15, 2016 or later were eligible. Infants were serologically classified as Zika virus-exposed or Zika virus-unexposed in utero and were followed up prospectively until age 48 months. At 36 months and 48 months of age, the Mullen Scales of Early Learning (MSEL) assessment was administered. Primary outcomes were MSEL early learning composite (ELC) scores at 30-48 months in León and 36-48 months in Managua. We used an inverse probability weighting generalised estimating equations model to assess the effect of Zika virus exposure on individual MSEL cognitive domain scores and ELC scores, adjusted for maternal education and age, poverty status, and infant sex. FINDINGS: The initial enrolment period for the León cohort was between Jan 31 and April 5, 2017 and the second was between Aug 30, 2017, and Feb 22, 2018. The enrolment period for the Managua cohort was between Oct 24, 2019, and May 5, 2020. 478 mothers (482 infants) from the León cohort and 615 mothers (609 infants) from the Managua cohort were enrolled, of whom 622 children (303 from the León cohort; 319 from the Managua cohort) were included in the final analysis; four children had microcephaly at birth and thus were excluded from analyses, two from each cohort. 33 (11%) of 303 children enrolled in León and 219 (69%) of 319 children enrolled in Managua were exposed to Zika virus in utero. In both cohorts, no significant differences were identified in adjusted mean ELC scores between Zika virus-exposed and unexposed infants at 36 months (between-group difference 1·2 points [95% CI -4·2 to 6·5] in the León cohort; 2·8 [-2·4 to 8·1] in the Managua cohort) or at 48 months (-0·9 [-10·8 to 8·8] in the León cohort; 0·1 [-5·1 to 5·2] in the Managua cohort). No differences in ELC scores between Zika virus-exposed and unexposed infants exceeded 6 points at any time between 30 months and 48 months in León or between 36 months and 48 months in Managua, which was considered clinically significant in other settings. INTERPRETATION: We found no significant differences in neurodevelopmental scores between normocephalic children with in-utero Zika virus exposure and Zika virus-unexposed children at age 36 months or 48 months. These findings are promising, supporting typical neurodevelopment in Zika virus-exposed normocephalic children, although additional follow-up and research is warranted. FUNDING: National Institute of Child Health and Development, National Institute of Allergy and Infectious Diseases, and Fogarty International Center. TRANSLATION: For the Spanish translation of the abstract see Supplementary Materials section.


Assuntos
Desenvolvimento Infantil , Complicações Infecciosas na Gravidez , Efeitos Tardios da Exposição Pré-Natal , Infecção por Zika virus , Humanos , Nicarágua/epidemiologia , Infecção por Zika virus/epidemiologia , Feminino , Estudos Prospectivos , Pré-Escolar , Gravidez , Masculino , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/virologia , Lactente , Complicações Infecciosas na Gravidez/epidemiologia , Complicações Infecciosas na Gravidez/virologia , Zika virus , Adulto , Transtornos do Neurodesenvolvimento/epidemiologia , Transtornos do Neurodesenvolvimento/virologia
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