Behavioral and Neurobiological Phenotyping of ASD with Megalencephaly

自闭症谱系障碍（ASD）伴巨脑畸形的行为和神经生物学表型

• 批准号: 10238007
• 负责人: Christine Wu Nordahl
• 金额: $ 54.63万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-07 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10238007
• 关键词: 3 year old; 5 year old; Affect; Age; Attention; Auditory; Behavior assessment; Behavioral; Biological Markers; Body Size; Brain; Child; Child Development; Clinical; Cognitive; Data; Dependence; Detection; Development; Emotions; Enrollment; Etiology; Evaluation; Event-Related Potentials; Evoked Potentials; Exhibits; Functional Magnetic Resonance Imaging; Future; Goals; Growth; Head; Height; Impaired cognition; Impairment; Institutes; Intellectual functioning disability; Intervention; Investigation; Label; Language; Language Development; Life; Loudness; Magnetic Resonance Imaging; Measures; Medical; Megalencephaly; Memory; Neurobiology; Neurodevelopmental Disorder; Participant; Pattern; Performance; Phenotype; Process; Prognosis; Research; Resources; Rest; Sampling; Scalp structure; School-Age Population; Sensory; Standardization; Stimulus; Structure; Subgroup; Surface; System; Testing; Time; Visit; Visual; Visual attention; Vocabulary; auditory stimulus; autism spectrum disorder; autistic children; base; boys; brain overgrowth; brain size; brain volume; clinically significant; cognitive function; cognitive process; cognitive testing; cohort; data management; electric field; follow-up; improved; induced pluripotent stem cell; information processing; male; memory recognition; neural patterning; neuropathology; phenome; recruit; relating to nervous system; response; selective attention; standardize measure; statistics; targeted treatment; treatment response; visual tracking; white matter

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.

项目2 - 摘要 非典型，快速的早期大脑扩张是一种独特的神经表现型，在15％的自闭症男性中观察到 频谱障碍（ASD）。这种表型被标记为“自闭症的大脑畸形” （ASD-DM）因为头部和大脑的生长与高度不成比例。加州大学戴维斯分校的证据 Institute自闭症现象项目表明，ASD-DM的儿童比例较高 在3岁。到5岁时，患有这种表型的儿童在智商中的收益少于他们 ASD和正常脑大小的对应物。在学龄前，ASD-DM的比例较高 智力残疾范围。该项目的短期目标是确认ASD-DM的预后较差 比其他ASD的孩子。长期目标是充分了解认知过程和中立 这些定义基础的系统，以便可以开发出靶向干预措施以改善 患有这种表型的孩子。为了实现这些目标，将有一个新的2-3.5岁孩子的队列 在招聘和保留核心的帮助下招募。四组，脑大小正常（ASD-N）， ASD不成比例的大脑（ASD-DM）和典型开发（TD），正常或扩大 将评估脑大小。一旦在研究进入时，将在两个时间点进行纵向评估儿童（2- 3.5岁）两年后（4-5.5岁）进行随访。在第一个目标中，全面 行为评估包括标准化评估和精心验证的眼神追踪任务 将进行特定的注意力，记忆和语言的认知过程。眼神追踪任务 预计比标准化措施对细微的表型差异更敏感，并且可以指导 制定目标干预措施。在第二和第三目标中，进一步评估中性 将执行不成比例的大脑表型的基础。结构和功能 MRI和听觉事件相关的电位将用于询问损害的神经基础 在这种表型中观察到，重点是涉及注意力，语言和记忆的神经系统。 确定行为定义中涉及的神经系统不仅可以为基础提供线索 病因，但还将提供可以用作测量治疗反应的生物标志物的神经靶标 在未来的研究中。项目2的参与者将被邀请参加项目3，该项目旨在产生诱发 多能干细胞（IPSC）为了研究ASD中脑脑的基础机制。 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开发针对性的干预措施 临床意义有意义的表型，在开发早期出现，在最初几年中很容易识别 生活。