Behavioral and Neurobiological Phenotyping of ASD with Megalencephaly

项目2--摘要 非典型的、早期迅速的脑增大是一种独特的神经表型，在15%的自闭症男性中可以观察到。 谱系障碍(ASD)。这种表型被标记为“伴有不成比例的巨脑畸形的自闭症”。 (ASD-DM)，因为头部和大脑的发育与身高不成比例。来自加州大学戴维斯分校的证据 研究所的自闭症现象学项目表明，患有自闭症-糖尿病的儿童中有更高比例的儿童语言能力较弱 在3岁的时候。到5岁时，这种表型的孩子在智商上的进步比他们的 大脑大小正常的自闭症患者。在学龄期，ASD-DM中智商较高的比例较高 智力残疾的范围。该项目的短期目标是确认ASD-DM预后较差 比其他患有自闭症的儿童要高。长期目标是充分了解认知过程和神经 这些缺陷背后的系统，以便可以开发有针对性的干预措施来改善脑血管疾病的预后 有这种表型的儿童。为了实现这些目标，新的2-3.5岁儿童队列将是 在招聘和留用核心部门的协助下招聘。4组，ASD正常脑大小(ASD-N)组， 伴有不成比例巨脑的ASD(ASD-DM)和发育正常或增大的典型发育(TD) 将对大脑大小进行评估。儿童将在两个时间点进行纵向评估，一次是在研究开始时(2- 3.5岁)，两年后(4-5.5岁)进行随访。在第一个目标中，全面 包括标准化评估和经过良好验证的眼球跟踪任务的行为评估 将进行注意力、记忆和语言的特定认知过程测试。眼球跟踪任务 预计对细微的表型差异比标准化指标更敏感，并可以指导 制定有针对性的干预措施。在第二和第三个目标中，进一步评估神经 将进行不成比例的巨脑表型的基础研究。结构和功能 MRI和听觉事件相关电位将被用来询问损伤的神经基础 在这一表型中观察到的，重点是涉及注意力、语言和记忆的神经系统。 识别与行为缺陷有关的神经系统将不仅为潜在的 病因，但也将提供神经靶点，可用作衡量治疗反应的生物标记物 在未来的研究中。项目2的参与者将被邀请参与项目3，该项目旨在生成诱导 多能干细胞(IPSCs)，以研究ASD巨脑形成的细胞机制。 数据管理和统计核心将管理两个项目的数据，并将促进项目间 分析。实现这些目标将使研究团队能够为此制定有针对性的干预措施 临床上有意义的表型，出现在发育早期，并很容易在 生活。

PROJECT 2 – SUMMARY Atypical, rapid early brain enlargement is a distinct neurophenotype that is observed in 15% of males with autism spectrum disorder (ASD). This phenotype has been labeled “autism with disproportionate megalencephaly” (ASD-DM) because head and brain growth is disproportionate to height. Evidence from the UC Davis MIND Institute Autism Phenome Project suggests that a higher proportion of children with ASD-DM are minimally verbal at 3 years of age. By 5 years of age, children with this phenotype have made fewer gains in IQ than their counterparts with ASD and normal brain size. At school age, a higher proportion of ASD-DM have IQs in the range of intellectual disability. A short-term goal of this project is to confirm that ASD-DM have a poorer prognosis than other children with ASD. The long-term objective is to fully understand the cognitive processes and neural systems underlying these deficits so that targeted interventions can be developed to improve the prognosis of children with this phenotype. To accomplish these objectives, a new cohort of 2-3.5-year old children will be recruited with aid from the Recruitment and Retention Core. Four groups, ASD with normal brain size (ASD-N), ASD with disproportionate megalencephaly (ASD-DM) and typical development (TD) with normal or enlarged brain sizes will be evaluated. Children will be assessed longitudinally at two time points, once at study entry (2- 3.5 years of age) with a follow up visit two years later (4-5.5 years of age). In the first aim, a comprehensive behavioral evaluation that includes both standardized assessments and well-validated eye-tracking tasks that test specific cognitive processes of attention, memory, and language will be conducted. The eye-tracking tasks are expected to be more sensitive to subtle phenotypic differences than standardized measures and could guide development of targeted interventions. In the second and third aims, further evaluation of the neural underpinnings of the disproportionate megalencephaly phenotype will be carried out. Structural and functional MRI and auditory event-related potentials will be utilized to interrogate the neural basis of the impairments observed in this phenotype with emphasis on neural systems involved in attention, language, and memory. Identifying the neural systems that are involved in the behavioral deficits will provide clues not only to underlying etiologies, but will also provide neural targets that could be used as biomarkers for measuring treatment response in future studies. Participants in Project 2 will be invited to participate in Project 3, which aims to generate induced pluripotent stem cells (iPSCs) in order to investigate cellular mechanisms underlying megalencephaly in ASD. The Data Management and Statistics Core will manage data from both projects and will facilitate inter-project analyses. Accomplishing these aims will enable the research team to develop targeted interventions for this clinically meaningful phenotype that is present early in development and is easily identifiable in the first years of life.