MRI Based Presymptomatic Prediction of ASD

基于 MRI 的 ASD 症状前预测

• 批准号: 9981943
• 负责人: Joseph Piven
• 金额: $ 84.79万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9981943
• 关键词: Affect; Age; Age-Months; Amygdaloid structure; Anisotropy; Anterior; Area; Axon; Behavior; Behavioral; Biological Markers; Brain; Brain imaging; Budgets; Cell model; Cerebrospinal Fluid; Characteristics; Clinical; Corpus Callosum; Data; Development; Diagnosis; Diagnostic; Diffuse; Diffusion; Diffusion Magnetic Resonance Imaging; Disease; Down Syndrome; Fiber; Functional Imaging; Funding; General Population; Goals; Growth; Impairment; Infant; Infant Development; Language; Life; Longitudinal Studies; MRI Scans; Magnetic Resonance Imaging; Maps; Measures; Motor; National Institute of Mental Health; Outcome; Outcome Assessment; Participant; Pattern; Predictive Value; Process; Property; Prospective cohort; Protocols documentation; Publishing; Radial; Reporting; Research; Research Personnel; Resources; Risk; Sampling; Scanning; Schedule; Siblings; Structure; Subgroup; Surface; Symptoms; Testing; Time; Work; autism spectrum disorder; base; behavior change; behavioral study; brain behavior; brain tissue; brain volume; cerebrospinal fluid flow; clinical research site; clinically actionable; cohort; density; drug development; high risk; imaging study; indexing; infancy; insight; joint attention; multimodality; nerve stem cell; outcome prediction; parent project; predictive test; prospective; rate of change; repetitive behavior; social deficits; therapeutic target; time interval; white matter

ABSTRACT This is an application for a 4 year competitive supplement to add a multimodal MRI scan, at 24 months of age, to a newly funded study that aims to replicate and extend our findings predicting autism spectrum disorder (ASD) in high familial risk (HR) infants using MRI scans in the first year of life. HR infants (who have an older affected sibling) have approximately a 12-fold increase in their risk (1/5 vs 1/59) to develop ASD. In HR infants who develop ASD, the first year of life is a period that is relatively free of the defining behavioral characteristics of the disorder, which then consolidate into full diagnosis over the second year of life and beyond. Longitudinal studies involving structural, diffusion, and functional imaging from the Infant Brain Imaging Study (IBIS) Network (https://www.ibis-network.org/) have produced new and fundamental insights into early brain and behavior changes across 6-24 months of age in infants who later meet criteria for ASD. The IBIS Network received funding in April 2019 to replicate and extend findings showing that structural and functional connectivity (fcMRI) MRI scans at 6 and 12 months of age can accurately (positive predictive values greater than 80%) predict ASD diagnosis at 24 months of age. This new study (IBIS-Early Prediction or “IBIS-EP”) seeks to advance the field toward a clinically actionable, predictive test for ASD in HR infants. The NIMH- approved budget for IBIS-EP, however, does not include support for a 24 month scan of HR infants. Without a 24 month scan, it will not be possible to replicate or extend IBIS’ critical findings about brain development [1-8], that are temporally specific and require the 24-month scan for characterization of the precise timing of brain changes. This competitive supplement would allow us to acquire, process, and analyze 24 month multimodal MRI scans for the 250 HR infants participating in the IBIS-EP study (who are already scheduled to return for 24 month diagnostic assessment). This time sensitive opportunity to leverage resources from IBIS-EP, and data from two parallel studies by IBIS co-investigators involving 80 low-risk (LR) infants, would allow us (Aim 1) to attempt to replicate our previous reports of age-specific, structural, diffusion, and functional connectivity MRI brain changes at 6-12 and 24 months; and (Aim 2) to investigate potential mechanisms underlying previously reported MRI findings in a new, prospective cohort, scanned through 24 months. Studies will examine the development of increased cerebrospinal fluid and aberrant white matter microstructure in ASD vs. HR-negative and LR groups, and test ASD outcome group-based differences in brain functional connectivity. The addition of a 24 month scan would, therefore, dramatically increase the impact of the parent project by: 1) identifying specific developmental windows (i.e., time intervals with significant group differences in change rate of brain features that correspond to later clinical outcomes); 2) identifying biomarkers of homogenous subgroups and symptom progression; and 3) identifying therapeutic targets, e.g., brain volume expansion as a marker of over- proliferation of neural progenitor cells, for study in cross-species and cellular models to aid drug development.

抽象的 这是一份 4 年竞争性补充申请，以在 24 个月大时添加多模式 MRI 扫描， 一项新资助的研究旨在复制和扩展我们预测自闭症谱系障碍的发现 在高家族风险 (HR) 婴儿出生后第一年使用 MRI 扫描发现自闭症谱系障碍 (ASD)。 HR 婴儿（年龄较大的 受影响的兄弟姐妹）患 ASD 的风险大约增加 12 倍（1/5 vs 1/59）。在 HR 婴儿中 对于患有自闭症谱系障碍 (ASD) 的人来说，生命的第一年是相对没有定义行为特征的时期 然后在生命的第二年及以后巩固为全面诊断。纵向 婴儿脑成像研究 (IBIS) 涉及结构、扩散和功能成像的研究 Network (https://www.ibis-network.org/) 对早期大脑和 婴儿在 6 至 24 个月大期间的行为会发生变化，随后符合自闭症谱系障碍 (ASD) 标准。 IBIS 网络 于 2019 年 4 月获得资金来复制和扩展研究结果，表明结构和功能 连接 (fcMRI) MRI 扫描在 6 个月和 12 个月大时可以准确地进行（阳性预测值更大） 超过 80%）可预测 24 个月大时诊断为自闭症谱系障碍 (ASD)。这项新研究（IBIS-早期预测或“IBIS-EP”） 旨在推动该领域朝着临床上可操作的 HR 婴儿 ASD 预测测试方向发展。 NIMH- 然而，批准的 IBIS-EP 预算不包括对 HR 婴儿 24 个月扫描的支持。没有一个 24 个月的扫描，将不可能复制或扩展 IBIS 关于大脑发育的重要发现 [1-8]， 具有时间特异性，需要 24 个月的扫描来表征大脑的精确时间 变化。这种有竞争力的补充将使我们能够获取、处理和分析 24 个月的多式联运 参加 IBIS-EP 研究的 250 名 HR 婴儿（已计划返回 24 个月）的 MRI 扫描 月诊断评估）。这是利用 IBIS-EP 资源和数据的时间敏感机会 IBIS 联合研究者对 80 名低风险 (LR) 婴儿进行的两项平行研究得出的结果将使我们（目标 1）能够 尝试复制我们之前关于特定年龄、结构、扩散和功能连接 MRI 的报告 6-12 个月和 24 个月时大脑发生变化； （目标 2）研究先前潜在的机制 报告了一个新的前瞻性队列的 MRI 结果，该队列扫描了 24 个月。研究将检验 自闭症谱系障碍 (ASD) 与 HR 阴性患者相比，脑脊液增多，白质微观结构异常 和 LR 组，并测试基于 ASD 结果组的大脑功能连接差异。添加的 因此，24 个月的扫描将通过以下方式显着增加父项目的影响：1) 识别 特定的发育窗口（即大脑变化率具有显着群体差异的时间间隔） 与后来的临床结果相对应的特征）； 2) 识别同质亚组的生物标志物和 症状进展； 3）确定治疗目标，例如，脑容量扩张作为过度的标志 神经祖细胞的增殖，用于跨物种和细胞模型的研究以帮助药物开发。