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、快速的早期大脑增大是一种独特的神经表型，在 15% 的自闭症男性中观察到 这种表型被标记为“伴有不成比例巨脑畸形的自闭症”。 （ASD-DM）因为头部和大脑的生长与身高不成比例。来自加州大学戴维斯分校 MIND 的证据。 研究所自闭症表型项目表明，患有 ASD-DM 的儿童中很少有语言能力的比例较高 到了 3 岁时，具有这种表型的儿童的智商增长幅度低于他们自己。 在学龄期，患有自闭症谱系障碍 (ASD) 且大脑大小正常的自闭症谱系障碍 (ASD-DM) 患者的智商处于正常水平。 该项目的短期目标是确认 ASD-DM 的预后较差。 与其他患有自闭症谱系障碍的儿童相比，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，以便制定有针对性的干预措施来改善预后 为了实现这些目标，将培养一批 2-3.5 岁的新儿童。 在招募和保留核心的帮助下招募的四个组，具有正常大脑大小的自闭症谱系障碍（ASD-N）， 自闭症谱系障碍 (ASD) 伴不成比例巨脑畸形 (ASD-DM) 和正常或增大的典型发育 (TD) 将在两个时间点对儿童的大脑大小进行纵向评估，一次是在研究开始时（2- 3.5 岁），两年后进行随访（4-5.5 岁） 第一个目标是全面的。 行为评估，包括标准化评估和经过充分验证的眼动追踪任务 将进行眼球追踪任务来测试注意力、记忆力和语言的特定认知过程。 预计比标准化测量对细微的表型差异更敏感，并且可以指导 在第二个和第三个目标中，制定有针对性的干预措施，进一步评估神经系统。 将进行不成比例的巨脑畸形表型的结构和功能基础。 MRI 和听觉事件相关电位将用于询问损伤的神经基础 在这种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不仅可以提供潜在的线索 病因学，但还将提供可用作测量治疗反应的生物标志物的神经靶点 在未来的研究中，项目 2 的参与者将被邀请参加项目 3，该项目旨在产生诱导效应。 多能干细胞 (iPSC)，用于研究自闭症谱系障碍 (ASD) 巨脑畸形的细胞机制。 数据管理和统计核心将管理两个项目的数据，并促进项目间的合作 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。 有临床意义的表型存在于发育早期，并且在发育的最初几年很容易识别 生活。