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

项目总结 ASD风险的最早标志物的识别具有巨大的临床意义，因为它告知 实施早期干预，可能会减轻症状，甚至阻止ASD的发展。 从历史上看，自闭症儿童的婴儿兄弟姐妹是早期研究的主要焦点。 记号笔。然而，过去也发现了其他基于基因诊断的高危人群 好几年了。研究ASD的高遗传风险婴儿为我们提供了一个宝贵的机会来检查 对于定义自闭症症状的核心特征，既有不同的神经生物学途径，也有共同的神经生物学途径。是这样的 研究不仅揭示了高危婴儿非典型发育的潜在机制，而且他们 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，我们采取遗传学优先的方法，研究自闭症风险的生物标记物和预后预测因素。 在早期婴儿期，有三个基因定义的高风险组：患有自闭症的哥哥姐姐的婴儿 (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，既是因为我们在加州大学洛杉矶分校研究这些群体的独特能力，也是因为我们对这些群体的研究 因为它们允许我们在ASD出现时在三种遗传途径的背景下进行检查：多基因风险 (家族性风险)、单基因突变(TSC)和拷贝数变异(22q11.2缺失)。我们结合了 用磁共振成像(MRI)检查神经发育过程的电生理(EEG) 生活的第一年可能是定义ASD的损害的基础：(1)休息状态/基线神经 同步性和连接性，(2)低水平的感觉处理和(3)大脑活动和语言的连接性 和显著网络。我们对1.5个月、3个月、6个月、9个月、12个月的婴儿进行MRI(1.5个月和9个月)、EEG(3-12个月)的研究 月)和行为(3-12个月)分析，然后执行标准化的认知评估和 12个月、24个月和36个月时出现自闭症症状。该项目与ACE的其他项目具有协同效应。婴儿 在本项目中显示ASD的早期迹象将参考项目II中的婴儿干预研究(PI： 卡萨里)。在项目III(PI：Dapretto)中，我们分享领导力，并采用共同的大脑活动衡量标准 和连通性。该项目还将依赖诊断和表型分析核心(PI：McCracken，Co-PI Gulsrud)用于发育和诊断测试。我们还将与Biomarkers Core(PI： Just和Dapretto实验室进行的数据收集和成像/脑电数据 结合其他项目的数据进行更大规模的异质性分析，从婴儿到 青春期。遗传学的唾液样本将在基线上收集所有参与者的唾液样本进行分析 CNV的风险和多基因风险。这个项目的每个目标都基于我们将：(1) 确定不同的行为和基于大脑的轨迹以及跨这些风险组的趋同区域 早期发育和(2)量化不典型发育和ASD的跨组预测标记物 12个月大。 好了！

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. !