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

项目概要/摘要 脑瘫是儿童最常见的身体残疾。几乎一半的新CP诊断是 在早产儿中产生的。虽然CP的结果是异常发展或损伤的 在胎儿或新生儿时期，CP儿童通常直到2岁才得到诊断。 年龄这头2年对神经可塑性至关重要，当被证明的预防性干预可以恢复 运动功能我们强有力的初步数据表明，CP的早期和准确的个体化预测是 在足月校正年龄（CA）时使用高级脑MRI生物标志物的组合是可能的。我们有 开发了使用扩散测量新生儿结构和功能连接的可靠方法 MRI（dMRI）和功能连接MRI（fcMRI）。这些方法可以灵敏地诊断 神经元连接性降低，即使是在结构MRI（sMRI）表现正常的婴儿中， CP.我们发现，3种感觉运动网络生物标志物的组合正确分类了98%的 有或无CP的早产儿。本提案的总体目标是确定大脑的价值 连接性生物标志物，单独和组合，以准确诊断出生3个月内的CP。 我们建议在极早产儿（胎龄≤31周）中进行一项大型多中心前瞻性队列研究， 使用先进的MRI在定期CA和发展测试在1年和2年CA。我们的核心假设是 CP是一种感觉运动网络连接减少的疾病， 在晚期CA使用先进的MRI进行连接将导致CP的早期和准确的预测。CP的诊断 出生后不久，将指导处方和细化早期，以证据为基础的感觉运动干预 和新型神经保护疗法，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）区分区域和全球的结构和功能连通性 与未发生CP的婴儿相比，sMRI正常的婴儿在足月CA时发生CP;（2）定义 在CA期，结构连接性生物标志物的独立和组合的预后测试特性 多变量模型，并确定模型，最准确地使个性化的预测CP在非常 早产儿在第一个目标下，我们将对6条感觉运动束进行dMRI纤维束成像， 区域和全球的大脑连接使用图论措施。对于第二个目标，我们将评估 有前途的连接性生物标志物，以确定最重要的多变量模型， CP预测这种方法是创新的，因为它将整合神经成像的进步， 建立了流行病学原则，以阐明病理生理学，并在3个月内准确预测CP 大量早产儿的出生。这项研究意义重大，因为它将减少 CP的诊断时间提前2年，以便早期干预资源和生物学治疗可以 在最佳神经可塑性时期针对风险最高的婴儿，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.