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

项目摘要 ASD风险的最早标志物的识别具有巨大的临床意义，因为它告知了 实施早期干预措施，可以减轻症状，甚至预防ASD的发展。 从历史上看，ASD儿童的婴儿兄弟姐妹构成了早期研究的主要焦点。 标记。然而，在过去已经确定了基于基因诊断的其他高风险群体 几年研究ASD遗传风险高的婴儿为我们提供了一个宝贵的机会， 这两种不同的和共同的神经生物学途径的核心特征，定义自闭症症状。等 研究不仅揭示了高危婴儿非典型发育的机制， 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的预测因子 在三个具有高风险的遗传定义组中的早期婴儿期： （家族性风险），患有多发性硬化症（TSC）的婴儿，以及患有22q11.2缺失综合征的婴儿 （22q11）。我们之所以选择这些群体，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， 因为它们使我们能够在三种遗传途径的背景下检查ASD：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）。我们将联合收割机 电生理学（EEG）与磁共振成像（MRI）检查神经发育过程中， 第一年的生活，可能是基础的损害，定义ASD：（1）静息状态/基线神经 同步性和连接性，（2）低级感觉处理和（3）语言中的大脑活动和连接性 和显着性网络。对1.5、3、6、9、12个月的婴儿进行MRI（1.5和9个月）、EEG（3 - 12 月）和行为（3 - 12个月）测定，然后进行认知和 自闭症症状在12，24和36个月。该项目与其他ACE项目具有协同作用。婴儿 在本项目中表现出ASD早期体征的患者将被转介至项目II中的婴儿干预研究（PI： Kasari）。在Project III（PI：Dapretto）中，我们分享领导力，并采用共同的大脑活动测量方法 和连通性。该项目还将依赖于诊断和表型核心（PI：McCracken，Co-PI Gulsrud）进行开发和诊断测试。我们还将整合生物标志物核心（PI： Geschwind，Co-PI Jeste），在Jeste和Dapretto实验室进行数据收集，并收集成像/EEG数据 结合其他项目的数据，对从婴儿期到 青春期将在基线时从所有受试者中采集唾液样本用于遗传学分析， CNV和多基因风险。本项目的每一个目标都基于我们将：（1） 确定这些风险群体之间不同的行为和基于大脑的轨迹和趋同区域， 早期发展和（2）量化非典型发展和ASD的预测标志物， 年龄12个月。 !

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. !