Early Prediction of Cerebral Palsy in Premature Infants using Advanced MRI Biomarkers

项目摘要/摘要 -- 脑性瘫痪(CP)是儿童最常见的肢体残疾。几乎一半的新CP诊断是 在早产儿身上制造的。尽管慢性阻塞性肺疾病是由于大脑发育异常或损伤所致 在胎儿期或新生儿期，患有脑瘫的儿童通常直到两岁后才会得到诊断 年龄。这头两年是神经可塑性的关键，经过证明的康复干预可以恢复 运动功能。我们强有力的初步数据表明，早期准确的CP个体化预测是 在足月矫正年龄(CA)使用高级脑MRI生物标记物的组合是可能的。我们有 开发了使用弥散技术测量新生儿结构和功能连通性的可靠方法 磁共振成像(DMRI)和功能连接磁共振成像(FcMRI)。这些方法可以灵敏地诊断 神经元连接性降低，即使是结构磁共振成像(SMRI)外观正常的婴儿也是如此 CP。我们发现，3种感觉运动网络生物标记物的组合正确地将98%的 有或无CP的早产儿。这项提议的总体目标是确定大脑的价值 连接性生物标志物，单独或联合使用，可在出生后3个月内准确诊断CP。 我们提出了一项针对极早产儿(≤31周胎龄)的大型多中心前瞻性队列研究。 在CA期间使用先进的MRI，并在CA 1和2年时进行发育测试。我们的中心假设是 CP是一种感觉运动网络连接性降低的障碍，并对此作出敏感的诊断 在CA期使用高级MRI的连通性将导致对CP的早期和准确预测。脑瘫的诊断 出生后不久将指导早期循证感觉运动干预的处方和改进 以及新的神经保护疗法，以改善CP儿童的预后。两个具体目标 检验中心假设的方法是：(1)区分区域和全球结构和功能的连通性 在CA期，sMRI正常的婴儿与未发生CP的婴儿进行比较；(2)定义 结构连接性生物标记物在CA期独立和组合时的预后测试特性 多变量模型，并确定最准确地实现CP个性化预测的模型 早产儿。在第一个目标下，我们将对6个感觉运动束进行dmri成像，并评估 使用图论测量区域和全球大脑连通性。对于第二个目标，我们将评估 有希望的连接性生物标记物识别个性化最重要的多变量模型 CP的预测。这种方法是创新的，因为它将神经成像方面的进步与 建立流行病学原则，以阐明病理生理并在3个月内准确预测CP 在大量极早产儿中出生。这项拟议的研究意义重大，因为它将减少 将CP的诊断时间缩短2年，以便早期干预资源和基于生物的治疗方法能够 在最佳神经可塑性期间针对最高风险婴儿，以减少未来的损伤。

Project Summary/Abstract   Cerebral palsy (CP) is the most common physical disability in children. Almost half of all new CP diagnoses are made in children who were born preterm. Although CP results from abnormal development or injury of the brain during the fetal or neonatal period, children with CP typically do not receive a diagnosis until 2 years of age. These first 2 years are critical for neuroplasticity, when proven habilitative interventions could restore motor function. Our strong preliminary data suggest that early and accurate individualized prediction of CP is possible by using a combination of advanced brain MRI biomarkers at term corrected age (CA). We have developed reliable methods for measuring structural and functional connectivity in neonates using diffusion MRI (dMRI) and functional connectivity MRI (fcMRI), respectively. These methods can sensitively diagnose reduced neuronal connectivity, even in infants with a normal-appearing structural MRI (sMRI) that later develop CP. We have found that a combination of 3 sensorimotor network biomarkers correctly classified 98% of preterm infants with or without CP. The overall objective of this proposal is to determine the value of brain connectivity biomarkers, individually and in combination, to accurately diagnose CP within 3 months of birth. We propose a large multicenter prospective cohort study in very preterm infants (≤31 weeks gestational age), using advanced MRI at term CA and developmental testing at 1 and 2 years CA. Our central hypothesis is that CP is a disorder of reduced sensorimotor network connectivity, and sensitive diagnosis of this reduced connectivity using advanced MRI at term CA will result in early and accurate prediction of CP. Diagnosis of CP soon after birth will guide the prescription and refinement of early, evidence-based sensorimotor interventions and novel neuroprotective therapies to enable improved outcomes in children with CP. The two specific aims to test the central hypothesis are: (1) To differentiate regional and global structural and functional connectivity at term CA in infants with a normal sMRI who develop CP, compared to infants who do not; (2) To define the prognostic test properties of structural connectivity biomarkers at term CA, independently and in combined multivariable models, and identify the model that most accurately enables personalized prediction of CP in very preterm infants. Under the first aim, we will perform dMRI tractography of 6 sensorimotor tracts and evaluate regional and global brain connectivity using graph theory measures. For the second aim, we will evaluate promising connectivity biomarkers to identify the most significant multivariable model for individualized prediction of CP. The approach is innovative because it will integrate advances in neuroimaging with established epidemiologic principles to elucidate pathophysiology and accurately predict CP within 3 months of birth in a large population of very preterm infants. The proposed research is significant because it will reduce the time to diagnosis of CP by 2 years so that early intervention resources and biologically based therapies can be targeted to the highest risk infants during a period of optimal neuroplasticity for reducing future impairments.