Variation in early motor function in autism, cerebellar injury and normal twins

自闭症、小脑损伤和正常双胞胎早期运动功能的变化

• 批准号: 10391519
• 负责人: Catherine Lang
• 金额: $ 72.74万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10391519
• 关键词: Accelerometer; Age; Age-Months; Animal Model; Attention deficit hyperactivity disorder; Attentional deficit; Basal Ganglia; Bilateral; Brain; Cerebellar Diseases; Cerebellum; Child; Clinical; Data Collection; Development; Developmental Therapeutics Program; Diagnosis; Early Intervention; Family; First Degree Relative; Future; General Population; Genes; Genetic; Genetic Risk; Goals; Heritability; Hyperactivity; Image; Impairment; Individual; Infant; Inherited; Injury; Intervention; Intervention Studies; Joints; Life; Measurable; Measurement; Measures; Mediating; Methodology; Methods; Modeling; Motor; Motor Cortex; Movement; Outcome; Parents; Performance; Phenotype; Population; Premature Infant; Prevalence; Publishing; Recurrence; Reporting; Research; Rest; Risk; Risk Factors; Sampling; Schools; Social Behavior; Social outcome; Specific qualifier value; Structure; Syndrome; Testing; Time; Toddler; Transgenic Animals; Twin Multiple Birth; Upper Extremity; Variant; Visual; Work; Wrist; aged; autism spectrum disorder; autistic; autistic children; base; behavioral outcome; behavioral phenotyping; child battery; cohort; comorbidity; data analysis pipeline; de novo mutation; developmental disease; early childhood; endophenotype; high risk; indexing; infancy; insight; motor behavior; motor deficit; neuroimaging; novel; personalized intervention; premature; programs; screening; secondary analysis; sensor; social; trait; visual tracking; wearable sensor technology

Project Summary Autism spectrum disorder (ASD) is one of the most common and highly inherited of all developmental disorders, with heritability exceeding 0.80. Although remarkable advances in genetics have identified rare de novo mutations in select brain genes, by definition, none of these relate to the pronounced heritability of autism relevant to the vast proportion of cases in the population. Given that heritability has been shown to be a function of additive genetic risk, inferring an impractically large number of genetic targets for intervention, an important strategy is to identify convergent mechanisms of polygenic risk factors by elucidating intermediate phenotypes (i.e., endophenotypes) through which they exert their causal influence. Our group has identified two such candidates that appear highly contributory but not sufficient for ASD: (i) the social behavioral phenotype indexed by quantitative (subclinical) autistic traits in parents (QAT-p); and (ii) variation in social visual engagement (SVE), an eye-tracking measure based on viewing of dynamic social scenes. Both can be ascertained in the first year of life using rapid acquisition methods of less than 20 minutes. Our team’s prior work strongly supports a developmental model in which autism arises from joint additive genetic effects of these and other neurodevelopmental liabilities, suggesting that targeting a discrete group of early-contributing liabilities before autism develops offers the greatest opportunity for high-impact, personalized intervention for children at risk for common, polygenic forms of ASD. The primary objective of this research program is to validate wearable-sensor methodology (bilateral, wrist-worn accelerometers) for quantifying two additional endophenotypes: hyperactivity (HYP, as an early marker of liability to Attention Deficit Hyperactivity Disorder, which is strongly comorbid with autism) and impairment in motor coordination (MOT). We will examine HYP and MOT in three distinct samples. Aim I will study 120 pairs of infant twins first assessed at 6 months of age and then followed at ages 18 and 36 months to evaluate early associations between HYP, MOT, QAT, and SVE, as well as their heritability and ability to predict quantitative variation in autistic traits among the twins. Aim II will study a cohort of 50 toddlers diagnosed with idiopathic ASD to determine whether novel sensor-based metrics of HYP and MOT show differences between the twins and children with ASD. Aim III will study a legacy cohort of 120 infants at elevated risk for autism due to prematurity and/or cerebellar injury, in whom we will explore relationships between cerebellar structure and function in the first year of life and a) sensor-based indices of HYP and MOT, b) quantitative autistic traits, and c) performance-based indices of motor ability at age three years. This project is expected to yield a rich, comprehensive understanding of motor endophenotypes in infants and children and their contributions to autism, with the eventual goal of providing a launching point for future screening and early intervention studies in high-risk children.

项目摘要 自闭症谱系障碍（ASD）是所有发育障碍中最常见和高度遗传的一种， 遗传力超过0.80。虽然遗传学的显著进步已经确定了罕见的新生 根据定义，选择大脑基因的突变，没有一个与自闭症的明显遗传性有关。 与人口中的大部分病例有关。考虑到遗传力是一个函数 加性遗传风险，推断不切实际的大量遗传干预目标，一个重要的 策略是通过阐明中间表型来确定多基因风险因子的会聚机制 (i.e.,内在表型），通过这些表型发挥其因果影响。我们的小组已经确定了两个这样的 出现高度贡献但不足以ASD的候选人：（i）社会行为表型指数 通过父母的定量（亚临床）自闭症特征（QAT-p）;和（ii）社交视觉参与（SVE）的变化， 一种基于观看动态社交场景的眼动跟踪测量。两者都可以在第一年确定 使用不到20分钟的快速采集方法。我们团队先前的工作有力地支持了 自闭症是由这些因素和其他因素的联合加性遗传效应引起的发展模型。 神经发育的责任，这表明，针对一个离散的群体早期贡献的责任之前， 自闭症的发展为有自闭症风险的儿童提供了高影响力、个性化干预的最大机会 常见的多基因型自闭症 该研究计划的主要目标是验证可穿戴传感器方法（双侧、腕戴式 加速度计）用于定量两种额外的内表型：多动（HYP，作为 易患注意缺陷多动障碍，与自闭症密切相关）， 运动协调障碍（MOT）。我们将在三个不同的样本中检查HYP和MOT。AIM I 将对120对婴儿双胞胎进行研究，首先在6个月大时进行评估，然后在18个月和36个月大时进行随访 评估HYP，MOT，QAT和SVE之间的早期关联，以及它们的遗传力和能力， 预测双胞胎自闭症特征的数量变化。Aim II将研究一组50名被诊断为 以确定HYP和MOT的新的基于传感器的指标是否显示差异 双胞胎和自闭症儿童之间的关系目标III将研究120名婴儿的遗留队列， 自闭症由于早产和/或小脑损伤，我们将探讨小脑之间的关系， 结构和功能在第一年的生活和a）基于传感器的指标HYP和MOT，B）定量自闭症 特征，和c）在三岁时的运动能力的基于性能的指数。该项目预计将产生一个 对婴儿和儿童的运动内表型及其对 自闭症，最终目标是为未来的筛查和早期干预研究提供一个起点 高危儿童。