Brain Structure and Function in Adolescents after the Fontan Operation

描述（申请人提供）：单心室病变占所有先天性心脏病（CHD）的10-15%，但消耗冠心病医疗资源的25%。通过分阶段姑息治疗，最终进行Fontan手术（“Fontan患者”），单脑室患者的生存率显著提高，这表明这一人群具有较高的神经和发育异常患病率。此外，大多数接受Fontan治疗的患者现在都能活到成年，届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名13至17岁的Fontan患者，与50名年龄和性别相似的青少年进行比较。在Aim 1中，Fontan组和对照组将在脑结构的磁共振成像（MRI）测量上进行比较。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。次要结果将包括其他分割容积：皮质和皮质下灰质、白质、脑脊液（CSF）、总颅内容积（皮质灰质+皮质下灰质+白质+脑脊液）和分割的区域脑容积。使用扩散张量MRI成像，主要结果将是区域白质微观结构，由分数各向异性测量。次要结果将是区域表观扩散系数。目的2将比较Fontan组和对照组在脑功能MRI测量上的差异。执行功能和视觉空间功能的主要结果将分别由Stroop范式和视觉关闭范式产生的区域功能性MRI （fMRI）激活。目的3将评估脑MRI测量与学业成绩、认知和行为的关系。主要的神经认知结果将是韦氏个人成就测试ii的综合总分。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感功能，以及特定的精神诊断，包括情绪、焦虑、注意力缺陷/破坏性行为和精神障碍。目的4将探讨脑MRI测量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，进行染色体微阵列检查，并有机会为DNA生物库提供样本。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。我们将通过相互作用模型探讨这些因素是否会改变MRI结果与认知之间的关系。这些研究将以更清晰和特异性的方式确定Fontan姑息治疗后单脑室患者神经发育后遗症的性质和基础。公共卫生相关性：接受过Fontan手术的单心室患者患神经、发育和行为障碍的风险很高，这些障碍是学习和发展的重要障碍；妨碍学业、职业和社交技能的习得；并对成人适应产生负面影响。拟议的评估提供了一个机会来解决关于大脑结构和功能测量与神经发育的关系以及它们与遗传和医学因素的关联的广泛生物学意义的重要问题。对这些相互关系的更好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，从而在不断增长的丰坦后人口中最大限度地发挥成人神经心理功能。

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.