MRI STUDIES OF EARLY BRAIN DEVELOPMENT IN AUTISM

自闭症早期大脑发育的 MRI 研究

• 批准号: 7681642
• 负责人: ERIC COURCHESNE
• 金额: $ 36.21万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7681642
• 关键词: 4 year old; Affect; Age; Age-Months; Age-Years; Amygdaloid structure; Anatomy; Anisotropy; Apoptosis; Area; Autistic Disorder; Basic Science; Behavior; Behavioral; Behavioral Symptoms; Bioinformatics; Biological; Biological Markers; Biology; Biometry; Biostatistics Core; Birth; Brain; Brain region; Cell model; Cerebellum; Cerebrum; Clinical; Cognitive; Collaborations; Development; Developmental Delay Disorders; Diagnostic; Disease; Disruption; Emotional; Evaluation; Fingerprint; Functional disorder; Genes; Genetic; Goals; Gray unit of radiation dose; Growth; Head circumference; Heterogeneity; Histocompatibility Testing; Infant; Investigation; Knowledge; Language; Life; Limbic System; MRI Scans; Magnetic Resonance Imaging; Maps; Measurement; Measures; Mediating; Methods; Multivariate Analysis; Neurophysiology - biologic function; Outcome; Pathway interactions; Phenotype; Procedures; Process; Prospective Studies; Protocols documentation; Publishing; Rate; Reporting; Retrospective Studies; Risk; Severities; Signal Transduction; Staging; Stem cells; Structure; Susceptibility Gene; Temporal Lobe; Therapeutic; Thick; Time; Variant; Work; age related; autistic behaviour; base; brain size; clinical phenotype; cognitive function; concept; deviant; endophenotype; genetic analysis; genetic association; gray matter; insight; interest; member; neural circuit; neurogenesis; novel; prospective; relating to nervous system; social; tool; white matter

Early brain overgrowth is a recently identified, but not yet directly measured, phenomenon in autism. Direct MRI measurement of the young autistic brain comes from five studies that found brain overgrowth at mean study ages of 2.7 to 3.9 yrs. Affected brain regions mediate higher-order social, emotional, language and cognitive functions that characterize autism. MRI studies of early brain growth in autism are absent. Indirect evidence of brain growth in autism comes from retrospective analyses of head circumference (HC). In the first study to examine the question, we reported that HC was normal average to slightly smaller than normal at birth in those who later manifested autism, but by about 12 months HC was abnormally large. Inferring brain growth rates from age-related changes in HC and placing that with the five MRI brain size studies of 2 to 4 year olds led us to the hypothesis that autism may involve a brief and agedelimited period of abnormal brain overgrowth during the first two years of life. According to the only two existent prospective studies of autism, 12 months is also approximately the first age at which autistic behavioral abnormalities first become detectable. The formation of neural circuitry is at its most exuberant and vulnerable stage during this period of development. Aberrant connectivity and neural dysfunction resulting from disruptions to this process may be key to the development of autistic behaviors. Thus, the first years of life in autism offer a unique chance to track the simultaneous emerging expression of the autistic anatomical and clinical phenotype and establish their relationship to each other and to underlying causal mechanisms, such as genes and genetic pathways that affect brain growth. We will identify early brain growth biomarkers in ASD by longitudinally MRI scanning infants at-risk for ASD, infants at-risk for developmental delay and typical infants at 12 and 24 months. We will obtain region-specific measures of volume, area, cortical thickness, fractional anisotropy and apparent diffusivity coefficient and developmental change values. Detailed anatomic maps of each region will be derived for each infant at each age. At age 36 months, a final best estimate diagnostic evaluation will identify which atrisk infants are ASD, DD or other. MRI results from these ASD and DD infants and typical infants will be statistically compared and early ASD brain growth abnormalities identified. Anatomical measures will be identified that characterize and predict the early developmental clinical phenotype of ASD that Cores B and C in collaboration with the Integrated Biostatistics Core D will identify. We will work with Project 4 and the Integrated Biostatistics Core D to use the brain growth biomarkers to discover overgrowth susceptibility genes and pathways. With Core D, we will identify separate clusters of distinctly different brain maldevelopment phenotypes among the ASD infants.

早期大脑过度生长是最近发现的一种自闭症现象，但尚未直接测量到。 对年轻自闭症患者大脑的直接MRI测量来自五项研究，这些研究发现 平均研究年龄为2.7岁至3.9岁。受影响的大脑区域调节更高层次的社交、情感、语言 以及自闭症特有的认知功能。关于自闭症患者早期大脑发育的核磁共振研究尚未见报道。 自闭症患者大脑发育的间接证据来自对头部的回顾分析 周长(Hc)。在研究这个问题的第一个研究中，我们报告说，HC是正常的平均水平 后来表现出自闭症的人出生时略低于正常，但大约12个月时HC 大得不寻常。根据HC的年龄相关变化推断脑生长速度，并将其与五个 对2至4岁儿童的核磁共振脑大小研究引导我们得出这样的假设，即自闭症可能与短暂的和年龄受限的 在生命的头两年中，大脑过度生长的时期。 根据仅存的两项关于自闭症的前瞻性研究，12个月也大约是 自闭症行为异常第一次被发现的年龄。神经回路的形成 在这个发展时期，它正处于最旺盛和最脆弱的阶段。异常的连接性和 这一过程的中断导致的神经功能障碍可能是自闭症发展的关键 行为。因此，自闭症的头几年提供了一个独特的机会来追踪同时出现的 自闭症解剖和临床表型的表达，并建立它们之间的关系和 与潜在的因果机制有关，例如影响大脑发育的基因和遗传途径。 我们将通过纵向MRI扫描高危婴儿来确定ASD的早期脑生长生物标记物 对于自闭症，有发育迟缓风险的婴儿和12个月和24个月的典型婴儿。我们将获得 体积、面积、皮质厚度、各向异性分数和表观扩散系数的区域特定测量 系数和发展变化值。将为每个区域绘制详细的解剖图 每个年龄段的每个婴儿。在36个月大时，最终的最佳估计诊断评估将确定哪些风险 婴儿为ASD、DD或其他。这些ASD和DD婴儿以及典型婴儿的MRI结果将是 统计比较与ASD早期脑发育异常的鉴别。解剖措施将是 确定以B和B为核心的ASD的早期发育临床表型的特征和预测 C将与综合生物统计核心D合作，确定。我们将与项目4和 集成生物统计学核心D使用脑生长生物标记物发现过度生长易感性 基因和途径。对于核心D，我们将识别明显不同的大脑的单独簇 自闭症患儿的发育不良表型。