Spina Bifida: Cognitive and Neurobiological Variability

描述(由申请者提供)：该项目的目标是确定遗传、中枢神经系统和环境的变异源，以解释与脊柱裂脑膜脊髓膨出(SB)相关的神经行为结果的变化，SB是北美最常见的严重致残出生缺陷。在过去的五年中，研究小组确定了几个与临床标记(例如，病变程度)和种族相关的潜在候选基因。这些临床标记物解释了遗传和神经变异性，并与结果有关。他们确定了跨越认知和运动功能领域(例如，计时)的过程，并将它们与大脑变形学联系起来。在这项延续申请中，研究人员建议在两个主要数据收集地点的四个项目和三个核心项目中评估450名SB儿童和成人、20名导水管狭窄患者和277名对照人员：德克萨斯大学休斯顿分校和多伦多患病儿童医院。项目I(遗传学；诺斯罗普，PI)在2000多名西班牙裔和高加索人参与者的样本中评估了与SB和相关神经管缺陷相关的遗传因素。不同的统计模型将被用来测试遗传连锁/关联的候选基因，并评估与SB遗传力相关的环境因素。项目II(早期学习；Landry，PI)继续对85名出生时发现患有SB和73名对照组的婴儿进行纵向研究，跟踪他们到7.5、8.5和9.5岁。这项研究探讨了SB的核心神经认知缺陷的早期发展与产生学龄期结果的环境因素(SES、父母教养)的关系。项目III(神经认知；丹尼斯，PI)评估了与患有SB的儿童和成人的脑变形相关的核心神经认知过程，将这项研究扩展到整个生命周期。项目IV(磁源成像；Papanicolaou，PI)利用磁源成像来评估SB和AS儿童运动、躯体感觉、语言和认知技能的重组，这是第一批先天性脑损伤儿童的功能神经成像研究之一。这四个项目得到行政事务核心(A；Fletcher，PI)、科目征聘和评价核心(B；Fletcher，PI)以及数据库和统计核心(C；Francis，P.I.)的支持。这一综合性计划项目将促进对SB的综合、多学科的了解，并为其他具有遗传异质性、脑畸形和可变神经行为结果的神经发育障碍提供一个模型。

DESCRIPTION (provided by applicant): The objective of this program project is to identify genetic, CNS, and environmental sources of variability that explain the variations in neurobehavioral outcomes associated with spina bifida meningomyelocele (SB), the most common severely disabling birth defect in North America. In the previous five years, the investigative team identified several potential candidate genes that were associated with clinical markers (e.g., lesion level) and ethnicity. These clinical markers accounted for genetic and neurological variability and were linked to outcomes. They identified processes that cross domains of cognitive and motor function (e.g., timing) and related them to brain dysmorphology. In this continuation application, the investigators propose to evaluate 450 children and adults with SB, 20 with aqueductal stenosis, and 277 controls in four projects and three cores at two primary data collection sites: the University of Texas-Houston, and The Hospital for Sick Children, Toronto. Project I (Genetics; Northrup, PI) evaluates genetic factors associated with SB and related neural tube defects in a sample of over 2,000 Hispanic and Caucasian participants. Different statistical models will be used to test candidate genes for genetic linkage/associations and to evaluate environmental factors related to the heritability of SB. Project II (Early Learning; Landry, PI) continues a longitudinal study of 85 infants with SB and 73 controls identified at birth, following them to 7.5, 8.5, and 9.5 years of age. This study addresses the early development of core neurocognitive deficits in SB in relation to environmental factors (SES, parenting) that produce school age outcomes. Project III (Neurocognitive; Dennis, PI) evaluates core neurocognitive processes in relation to brain dysmorphology in children and adults with SB, extending the study across the life span. Project IV (Magnetic Source Imaging; Papanicolaou, PI) utilizes magnetic source imaging to evaluate the reorganization of motor, somatosensory, language, and cognitive skills in children with SB and AS, representing one of the first functional neuroimaging studies of children with congenital brain injury. These four projects are supported by an Administrative Services Core (A; Fletcher, PI), Subject Recruitment and Evaluation Core (B; Fletcher, PI), and Database and Statistics Core (C; Francis, P.I.). This comprehensive program project will facilitate an integrated, multidisciplinary understanding of SB and provides a model for other neurodevelopmental disorders with genetic heterogeneity, brain dysmorphologies, and variable neurobehavioral outcomes.