Brain Development in Adolescents with Genetic Risk Factors for Alcoholism

描述(由申请人提供)：这是一个项目的重新提交，该项目的总体目标是使用认知评估和功能和结构脑成像来评估酒精中毒对发育中的青少年大脑的遗传易感性的影响。爱荷华大学是自1989年以来参与酒精中毒遗传学合作研究(COGA)项目的几个地点之一。COGA由NIAAA(U10AA008401)资助，目标是确定酒精中毒和相关疾病的易感性的特定基因。COGA最近开始了一项前瞻性研究，从12岁开始每两年评估一次青少年。这里提出的项目将评估来自高遗传风险(HGR)家庭的青少年COGA志愿者，使用结构磁共振(MRI)测量和脑功能，通过功能磁共振(FMRI)和认知评估评估大脑结构。FMRI任务将集中在前脑奖励系统和额叶抑制功能上。在五年的时间里，我们建议招募96名13-18岁的HGR COGA受试者，他们最少使用酒精和其他娱乐药物，以及96名年龄和性别匹配的低遗传风险(LGR)对照组。两组的排除标准都将包括除品行障碍外的任何精神或神经障碍病史。由于品行障碍(CD)是青少年和成人酒精使用障碍(AUDS)最常见的共病精神障碍，我们将招募具有一系列CD症状的HGR受试者。然后将使用回归分析来评估与CD相关的因变量与酒精紊乱的遗传风险之间的独特差异。我们将评估有酒精问题遗传风险的青少年在大脑形态、功能磁共振任务的激活模式和/或已被证明与AUD或CD相关的一系列认知任务上的表现是否与正常的青少年志愿者不同。尽管符合严格纳入标准的青少年将在COGA的几个地点被招募，但神经成像和认知评估将仅在爱荷华州进行。虽然在每个站点收集成像数据是可行的，但我们与功能脑信息学研究网络(FBIRN)项目(O‘Leary博士是爱荷华州的站点PI)的经验表明，在多个站点获取兼容的成像数据需要相当大的费用和精力，增加了不统一评估的可能性，并且通常只有在需要非常大量的受试者时才值得。我们的策略是使用数量较少的青少年受试者，这些受试者的家系受到酒精中毒的密集影响，根据严格的标准进行选择，充分利用了已经收集的广泛的COGA数据库。我们建议的青少年脑成像和认知评估将提供有关大脑结构和功能的重要信息，这些信息将从现有的COGA数据库中协同受益，并增加具有基础科学和临床意义的信息。

DESCRIPTION (provided by applicant): This is a resubmission of a project whose overall aim is to assess the effects of genetic vulnerability to alcoholism on the developing adolescent brain, using cognitive assessments and functional and structural brain imaging. The University of Iowa is one of several sites that have participated in the Collaborative Studies on Genetics of Alcoholism (COGA) project since 1989. COGA is funded by NIAAA (U10AA008401) with the goal of identifying specific genes underlying vulnerability to alcoholism and related disorders. COGA recently began a prospective study, assessing adolescents every two years, beginning at age 12. The project proposed here would assess adolescent COGA volunteers from high genetic risk (HGR) families with state-of-the-art measures of brain structure, using structural magnetic resonance imaging (MRI) measures, and brain function, assessed both by functional MRI (fMRI) and cognitive assessment. The fMRI tasks will focus upon the forebrain reward system, and frontal lobe inhibitory function. Over a five-year period we propose to recruit a group of 96, 13-18 year old HGR COGA subjects, who have minimal use of alcohol and other recreational drugs, and 96 age and gender matched low genetic risk (LGR) controls. Exclusion criteria for both groups will include any history of a psychiatric or neurologic disorder other than conduct disorder. Because conduct disorder (CD) is the most frequent co-morbid psychiatric disorder in adolescents and adults with alcohol use disorders (AUDs) we will recruit HGR subjects with a range of CD symptoms. Regression analyses will then be used to assess the unique variance in the dependent variables associated with CD versus genetic risk for alcohol disorders. We will assess whether adolescents at genetic risk for developing alcohol problems differ from normal adolescent volunteers in brain morphology, activation patterns on fMRI tasks, and/or performance on a range of cognitive tasks that have been shown to be associated with AUD or CD. Although adolescents meeting the rigorous inclusion criteria will be recruited at several of the COGA sites, the neuroimaging and cognitive assessments will take place exclusively in Iowa. While it is feasible to collect imaging data at each site, our experience with the functional Brain Informatics Research Network (fBIRN) project (Dr. O'Leary is the Iowa site PI) indicates that acquiring compatible imaging data at multiple sites requires considerable expense and effort, raises the possibility of non-uniform assessment, and is typically worthwhile only when very large numbers of subjects are required. Our strategy of using a smaller number of adolescent subjects with pedigrees densely affected with alcoholism, selected according to rigorous criteria, makes good use of the extensive COGA data base that has already been collected. The brain imaging and cognitive assessments of adolescents that we propose will provide important information concerning brain structure and function that will profit synergistically from the existing COGA data base, and add information that has both basic science and clinical significance.