Beyond Baby Siblings: Early Developmental Trajectories and Biomarkers of Risk for ASD

超越婴儿兄弟姐妹：早期发育轨迹和自闭症谱系障碍风险生物标志物

• 批准号: 10228037
• 负责人: Shafali Spurling Jeste
• 金额: $ 30.14万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-06 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10228037
• 关键词: 22q11; 22q11.2; Address; Adolescence; Age; Area; Attenuated; Auditory; Base of the Brain; Behavior; Behavioral; Behavioral Assay; Biological; Biological Assay; Biological Markers; Brain; Clinical; Cognition; Copy Number Polymorphism; Data; Data Collection; Development; Developmental Diagnostic; DiGeorge Syndrome; Diagnostic; Diagnostic tests; Early Intervention; Electrophysiology (science); Equilibrium; Etiology; Frequencies; Functional Magnetic Resonance Imaging; Gene Mutation; Genetic; Genetic Risk; Heterogeneity; Image; Impairment; Infant; Intervention Studies; Investigation; Language; Leadership; Life; Light; Magnetic Resonance Imaging; Measures; Mendelian disorder; Methods; Motor Skills; Neurobiology; Neurosciences; Outcome; Participant; Pathway interactions; Pattern; Phenotype; Population; Process; Regulation; Research; Research Priority; Rest; Risk; Risk Factors; Risk Marker; Sensory; Siblings; Signal Transduction; Sleep; Standardization; Structure; Subgroup; Symptoms; Synapses; Syndrome; Time; Tuberous sclerosis protein complex; United States National Institutes of Health; auditory processing; autism spectrum disorder; autistic children; base; clinical heterogeneity; clinically relevant; genetic disorder diagnosis; genetic variant; high risk infant; high risk population; indexing; infancy; innovation; language processing; neuroimaging; neurophysiology; outcome prediction; predictive marker; predictive modeling; prevent; protective factors; relating to nervous system; response; saliva sample; social communication; synergism; treatment response; visual processing

PROJECT SUMMARY Identification of the earliest markers of risk for ASD holds tremendous clinical relevance, as it informs the implementation of early interventions that may attenuate symptoms and even prevent the development of ASD. Historically, infant siblings of children with ASD have constituted the primary focus of research in early markers. However, other high risk groups based on genetic diagnosis have been identified over the past several years. Studying infants at heightened genetic risk for ASD affords us a valuable opportunity to examine both distinct and shared neurobiological pathways to the core features that define autism symptoms. Such investigations not only shed light on mechanisms underlying atypical development in high-risk infants, but they can also clarify the ideal timing and target of early interventions that may modulate developmental trajectories. Here, we take a genetics-first approach and investigate biomarkers of risk for ASD and predictors of outcome in early infancy in three genetically defined groups with elevated risk: infants with an older sibling with ASD (familial risk), infants with Tuberous Sclerosis Complex (TSC), and infants with 22q11.2 deletion syndrome (22q11). We select these groups both because of our unique ability to study these populations at UCLA and because they allow us to examine ASD as it emerges in the context of three genetic pathways: polygenic risk (familial risk), single gene mutations (TSC), and copy number variation (22q11.2 deletion). We combine electrophysiology (EEG) with magnetic resonance imaging (MRI) to examine neurodevelopmental processes in the first year of life that may underlie the impairments that define ASD: (1) resting state/baseline neural synchrony and connectivity, (2) low level sensory processing and (3) brain activity and connectivity in language and salience networks. We study infants at 1.5, 3, 6, 9, 12 months with MRI (1.5 and 9 months), EEG (3-12 months), and behavioral (3-12 months) assays and then perform standardized assessments of cognition and autism symptoms at 12, 24 and 36 months. The project has synergy with the other ACE projects. Infants demonstrating early signs of ASD in this project will be referred to the infant intervention study in Project II (PI: Kasari). With Project III (PI: Dapretto), we share leadership and employ common measures of brain activity and connectivity. This project also will rely on the Diagnostic and Phenotyping Core (PI: McCracken, Co-PI Gulsrud) for developmental and diagnostic testing. We also will integrate with the Biomarkers Core (PI: Geschwind, Co-PI Jeste), with data collection performed in the Jeste and Dapretto labs and imaging/EEG data combined with data from the other projects for larger scale analyses of heterogeneity from infancy to adolescence. Saliva samples for genetics will be gathered at baseline from all participants for analysis of CNV's and polygenic risk. Each aim of this project is grounded in the overarching hypotheses that we will: (1) identify distinct behavioral and brain based trajectories and areas of convergence across these risk groups in early development and (2) quantify predictive markers of atypical development and ASD across groups before age 12 months. !

项目概要 识别 ASD 风险的最早标志物具有巨大的临床意义，因为它可以告知 实施早期干预措施可能会减轻症状，甚至预防 ASD 的发展。 从历史上看，自闭症儿童的婴儿兄弟姐妹一直是早期研究的主要焦点。 标记。然而，过去根据基因诊断还发现了其他高危人群 几年。研究自闭症谱系障碍遗传风险较高的婴儿为我们提供了一个宝贵的机会来检查 定义自闭症症状的核心特征的独特和共同的神经生物学途径。这样的 研究不仅揭示了高危婴儿非典型发育的机制，而且 还可以阐明可能调节发育轨迹的早期干预的理想时机和目标。 在这里，我们采用遗传学优先的方法，研究 ASD 风险的生物标志物和结果预测因素 在婴儿早期，三个基因定义的风险较高的群体中：有一个患有自闭症谱系障碍（ASD）的年长兄弟姐妹的婴儿 （家族风险）、患有结节性硬化症 (TSC) 的婴儿以及患有 22q11.2 缺失综合征的婴儿 (22q11)。我们选择这些群体不仅是因为我们在加州大学洛杉矶分校研究这些人群的独特能力，而且 因为它们使我们能够在三种遗传途径的背景下检查 ASD 的出现： 多基因风险 （家族风险）、单基因突变 (TSC) 和拷贝数变异（22q11.2 缺失）。我们结合 电生理学 (EEG) 与磁共振成像 (MRI) 一起检查神经发育过程 生命的第一年，可能是自闭症谱系障碍的基础：(1) 静息状态/基线神经 同步性和连通性，(2) 低级感觉处理和 (3) 大脑活动和语言连通性 和显着网络。我们通过 MRI（1.5 和 9 个月）、EEG（3-12 个月）研究 1.5、3、6、9、12 个月的婴儿 月）和行为（3-12 个月）测定，然后对认知和行为进行标准化评估 12、24 和 36 个月时的自闭症症状。该项目与其他 ACE 项目具有协同作用。婴儿 本项目中展示自闭症谱系障碍（ASD）早期症状的研究将参考项目II中的婴儿干预研究（PI： 卡萨里）。通过项目 III（PI：Dapretto），我们共享领导力并采用通用的大脑活动测量方法 和连接性。该项目还将依赖于诊断和表型核心（PI：McCracken，Co-PI Gulsrud）用于发育和诊断测试。我们还将与生物标记核心（PI： Geschwind，联合 PI Jeste），在 Jeste 和 Dapretto 实验室进行数据收集以及成像/脑电图数据 结合其他项目的数据，对从婴儿期到婴儿期的异质性进行更大规模的分析 青春期。将在基线时从所有参与者收集唾液样本进行遗传学分析 CNV 和多基因风险。该项目的每个目标都基于以下总体假设：(1) 确定这些风险群体的不同行为和基于大脑的轨迹以及趋同领域 早期发育和 (2) 量化之前各组的非典型发育和自闭症谱系障碍 (ASD) 的预测标记 年龄 12 个月。 ！