Brain Structure and Function in Adolescents after the Fontan Operation

描述（由申请人提供）：单心室病变占所有先天性心脏病（CHD）的10 - 15%，但消耗CHD卫生保健资源的25%。单心室患者（"Fontan患者"）的存活率显著提高，这些患者接受了以Fontan手术为高潮的分期姑息治疗，这表明该人群具有较高的神经和发育异常患病率。此外，Fontan后的大多数患者现在都能活到成年，此时神经发育障碍的后果可能会影响就业能力和心理健康。我们建议评估155例13至17岁的Fontan患者，与年龄和性别相似的普通人群中的50例青少年进行比较。在目标1中，将比较Fontan组和对照组的脑结构磁共振成像（MRI）测量值。使用定量体积MRI成像，主要结果将是总皮质灰质的分割体积。次要结局将包括其他分段体积：皮质和皮质下灰质、白色物质、脑脊液（CSF）、颅内总体积（皮质灰质+皮质下灰质+白色物质+CSF）和包裹的局部脑体积。使用扩散张量MRI成像，主要结果将是局部白色物质微结构，通过分数各向异性测量。次要结果将是区域表观扩散系数。目的2将比较Fontan组和对照组的脑功能MRI测量结果。执行功能和视觉空间功能的主要结局将分别是Stroop范式和视觉闭合范式的区域功能性MRI（fMRI）激活。目的3将评估脑MRI测量与学习成绩，认知和行为的关系。主要神经认知结局为韦氏个人成就测试-II的总综合评分。次要结果将包括能力（IQ）、学习障碍、神经心理功能（即，语言、记忆、注意力、执行功能和视觉空间/运动整合），和心理健康，包括生活质量和整体情绪功能，以及特定的精神病诊断，包括情绪、焦虑、注意力缺陷/破坏性行为和精神病。目的4探讨脑MRI测量值与遗传和医学因素的关系。Fontan患者将由临床遗传学家进行评估，接受染色体微阵列，并有机会为DNA生物储存库提供样本。我们将使用相关和回归方法来分析MRI测量与遗传和医学因素的关联。我们将探讨这些因素是否通过相互作用模型修改MRI结果和认知之间的关系。这些研究将更加清晰和特异地确定单心室患者Fontan姑息治疗后神经发育后遗症的性质和基础。公共卫生相关性：接受Fontan手术的单心室患者发生神经、发育和行为障碍的风险较高，这些障碍是学习和发育的重要障碍;干扰学术、职业和社交技能的获得;并对成人适应产生负面影响。拟议的评估提供了一个机会，以解决重要的问题，广泛的生物学意义的措施与神经发育的关系，以及它们与遗传和医学因素。对这些相互关系的进一步理解可能有助于设计和实施针对特定中枢神经系统缺陷的干预措施，从而最大限度地提高不断增长的后Fontan人群的成人神经心理功能。

DESCRIPTION (provided by applicant): Single ventricle lesions comprise 10-15% of all congenital heart disease (CHD), but consume 25% of CHD health care resources. Striking improvement in the survival of patients with single ventricle, treated with staged palliation culminating in the Fontan operation ("Fontan patients"), has revealed that this population harbors a high prevalence of neurologic and developmental abnormalities. Furthermore, most patients after Fontan now survive to adulthood, when consequences of neurodevelopmental impairment may affect employability and mental health. We propose to evaluate 155 Fontan patients at ages 13 through 17 years, compared to 50 adolescents in the general population of similar age and gender. In Aim 1, Fontan and control groups will be compared on Magnetic Resonance Imaging (MRI) measures of brain structure. Using quantitative volumetric MRI imaging, the primary outcome will be the segmented volume of total cortical gray matter. Secondary outcomes will comprise other segmented volumes: cortical and subcortical gray matter, white matter, cerebrospinal fluid (CSF), total intracranial volume (cortical gray matter + subcortical gray matter + white matter + CSF), and parcellated regional brain volumes. Using diffusion tensor MRI imaging, the primary outcome will be regional white matter microstructure, as measured by fractional anisotropy. Secondary outcomes will be regional apparent diffusion coefficients. Aim 2 will compare the Fontan and control groups on MRI measures of brain function. The primary outcomes for executive function and visual-spatial function will be regional functional MRI (fMRI) activation derived from performance of a Stroop paradigm and a visual closure paradigm, respectively. Aim 3 will evaluate the relationship of brain MRI measures to academic achievement, cognition, and behavior. The primary neurocognitive outcome will be the Total Composite score on the Wechsler Individual Achievement Test-II. Secondary outcomes will include measures of ability (IQ), learning disability, neuropsychological function (i.e., language, memory, attention, executive functions, and visual-spatial/motor integration), and mental health, including quality-of-life and global emotional functioning, as well as specific psychiatric diagnoses including mood, anxiety, attention-deficit/disruptive behavior, and psychotic disorders. Aim 4 will explore the relationship of brain MRI measures to genetic and medical factors. Fontan patients will be assessed by a clinical geneticist, undergo chromosomal microarray, and have the opportunity to provide a sample for a DNA biorepository. We will use correlation and regression methods to analyze associations of MRI measures with genetic and medical factors. We will explore whether these factors modify the relationship between MRI findings and cognition through interaction models. These studies will establish, with greater clarity and specificity, the nature and basis of neurodevelopmental sequelae of single ventricle patients following Fontan palliation. PUBLIC HEALTH RELEVANCE: Patients with single ventricle who have undergone the Fontan procedure have a high risk of neurologic, developmental, and behavioral disorders that are important barriers to learning and development; interfere with the acquisition of academic, vocational, and social skills; and negatively affect adult adjustment. The proposed assessment offers an opportunity to address important questions of broad biologic significance regarding the relationships of measures of brain structure and function with neurodevelopment, as well as their association with genetic and medical factors. Improved understanding of these interrelationships may facilitate the design and implementation of interventions to target specific central nervous system deficits and thereby maximize adult neuropsychological function in the growing post-Fontan population.