A New Model to Identify Preterm Neonates at High-Risk for Cognitive Impairments and School Readiness

项目概要/摘要 极早产儿（VPT; <32周妊娠）面临着不成比例的神经发育负担， 损伤（NDI）。在数学、阅读和行为等子领域的障碍是最常见的 NDI，影响25-50%的VPT儿童。这些能力对入学准备和工作成功至关重要。在 在第一轮拨款中，我们收集了北美最大的VPT婴儿队列， 在足月校正年龄（CA）进行晚期脑MRI，并进行纵向神经发育评估。我们 证明了弥漫性白色物质异常（DWMA）和多种其他新型MRI的临床重要性 生物标志物，以加强预测短期NDI在2年或3年CA。在第二个融资周期中，我们的 一个独特的队列将达到5至7岁的关键早期学龄，当高阶认知能力在 数学和阅读、情绪自我调节和行为变得更加明显和可准确测试。的 如果能够在几年前准确预测这些功能，就可以进行早期干预。评估 VPT儿童NDI的动态轨迹及其可改变的环境和生物原因， 在这些关键的早期阶段， 神经可塑性正处于顶峰该提案的总体目标是绘制儿童早期发展轨迹， 大脑结构和功能的变化，并制定早期和准确的预测模型的入学准备。 我们的基本原理是阐明DWMA的长期影响，确定轨迹和介质 NDI的变化，以及强大的入学准备的预后模型将使新的早期干预试验， 针对VPT婴儿。为了实现我们的目标，我们将在年龄段进行形态测量，扩散和功能MRI 在我们的VPT儿童队列中进行了5年和7年CA的全面发育测试， 一组对照组儿童。为了推进这一极具影响力的研究领域，我们提出了以下三点建议 具体目标：（1）确定长期CA时DWMA对大脑发育和功能障碍的影响 （2）模拟NDI的个体轨迹并确定神经发育变化的介质 3 - 7年的CA;（3）发展早期预测模型的入学准备。第一个目标，我们 将客观量化的DWMA体积与大脑结构和功能连接性相关联 来自高级MRI和高阶认知功能，均为5年CA。根据目标2，我们将 绘制神经发育评分的个体轨迹，并确定轨迹变化的介质， 3年和7年CA。对于第三个目标，我们将应用丰富的临床，生物学和神经发育学知识， 从出生到3岁收集的数据，预测我们在5岁和7岁时的入学准备的三个指标 约这项研究将提供美国人群中关于长期不良神经解剖学的患病率数据。 VPT出生的功能后果，确定NDI变化的介质，并促进早期预测 学校准备，使有针对性的EI和新的随机临床试验的VPT儿童。

Project Summary/Abstract Children born very preterm (VPT; <32 weeks’ gestation) face a disproportionate burden of neurodevelopmental impairments (NDI). Impairments in the subdomains of mathematics, reading, and behavior are the most common NDI, affecting 25-50% of VPT children. These abilities are critical to school readiness and success at work. In the first cycle of this grant, we assembled the largest North American cohort of VPT infants and performed advanced brain MRI at term corrected age (CA) with longitudinal neurodevelopmental assessments. We demonstrated the clinical importance of diffuse white matter abnormality (DWMA) and multiple other novel MRI biomarkers to enhance prediction of short-term NDI at 2 or 3 years CA. During this second funding cycle, our unique cohort will reach the critical early school ages of 5 to 7 years, when higher-order cognitive abilities in math and reading, emotional self-regulation, and behavior become more apparent and accurately testable. The ability to accurately predict these functions several years earlier could enable early interventions. Assessment of the dynamic trajectories of NDI in VPT children and their modifiable environmental and biologic causes can also accelerate the development of targeted neuroprotective interventions during these critical early years when neuroplasticity is at its peak. The overall objectives of this proposal are to map the early childhood trajectory of brain structural and functional changes and develop early and accurate prognostic models of school readiness. Our rationale is that elucidation of the long-term impact of DWMA, identification of the trajectory and mediators of NDI changes, and robust prognostic models of school readiness will enable novel early intervention trials in targeted VPT infants. To achieve our goals, we will perform morphometric, diffusion, and functional MRI at age 5 and comprehensive developmental testing at 5 and 7 years CA in our cohort of VPT children and a matched group of term-control children. To advance this highly impactful area of research, we propose the following three specific aims: (1) Determine the impact of DWMA at term CA on brain development and functional impairments at age 5; (2) Model individual trajectories of NDI and identify the mediators of neurodevelopmental changes between 3 and 7 years CA; and (3) Develop early prognostic models of school readiness. For the first aim we will correlate objectively quantified DWMA volume at term CA with brain structural and functional connectivity derived from advanced MRI and with higher-order cognitive functions, both at 5 years CA. Under Aim 2, we will plot individual trajectories of neurodevelopmental scores and identify the mediators of trajectory change between 3 and 7 years CA. For the third aim, we will apply the rich collection of clinical, biologic, and neurodevelopmental data collected between birth and 3 years CA to predict our three measures of school readiness at 5 and 7 years CA. This study will provide U.S. population-based prevalence data about the long-term adverse neuroanatomic and functional consequences of VPT birth, identify mediators of NDI change, and facilitate early prediction of school readiness to enable targeted EI and novel randomized clinical trials for VPT children.