LONGITUDINAL OUTCOMES & NEUROIMAGING OF FRAGILE X SYND

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 研究中心，而研究中心不一定是研究者所在的机构。 脆性X综合征（fraX）是遗传性精神障碍最常见的已知原因，在美国有超过10万人受到影响。FMR 1基因突变引起临床表型，包括异常认知，行为和情感功能的风险增加。本申请中提出的5年研究的主要重点是对当前资助期内完成的工作进行前瞻性、纵向扩展，在此期间，从美国和加拿大的120个家庭收集了关键的认知、行为、神经内分泌、遗传和环境数据，每个家庭都有一个受fraX影响的儿童先证者和一个典型的发育中的兄弟姐妹。据我们所知，这项研究将是第一次纵向调查的一个大的，学龄fraX队列中的生物和环境因素有助于临床结果进行了评估的前瞻性基础上。我们还建议使用先进的脑成像技术扩展我们对这种疾病的神经生物学的研究。具体而言，纵向成像研究将用于阐明与关键对照组相比，fraX儿童的大脑结构和功能的发育轨迹。具体目标：1）采用纵向、前瞻性实验设计（用“时间1”和“时间2”评估）阐明fraX先证者与其同性同胞相比的认知、行为和情感发展的发展轨迹; 2）详细说明fraX先证者下丘脑-垂体-肾上腺（HPA）功能的纵向轨迹和FMR 1基因表达的测量; 3）利用神经成像技术来确定fraX儿童与特定年龄、性别、利手、SES和智商匹配的对照组相比的脑结构和功能的轨迹。尽管在过去的20年里，对患有fraX的儿童和成人的认知、行为和大脑的了解有了相当大的增长，但来自患有这种疾病的学龄儿童的纵向数据是有限的。迄今为止，横断面研究结果和有限的纵向数据支持这一假设，即在fraX学龄儿童中，标准化认知和适应行为评分出现与年龄相关的下降。然而，关于这种现象，特别是与程度，时间和神经基础有关的许多问题仍然没有答案。这些未回答的问题提供了一个令人信服的理由进行纵向研究的一大群学龄男孩和女孩与fraX在本申请中提出的。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Fragile X syndrome (fraX) is the most common known cause of inherited mental impairment with well over 100,000 individuals affected in the U.S. Mutations in the FMR1 gene give rise to a clinical phenotype that includes increased risk for aberrant cognitive, behavioral and emotional function. The major emphasis of the 5-year study proposed in this application is a prospective, longitudinal extension of the work completed during the current grant period, during which key cognitive, behavioral, neuroendocrinological, genetic and environmental data were collected from 120 families across the U.S. and Canada, each having a child proband affected with fraX and a typically developing sibling. To the best of our knowledge, this study would be the first longitudinal investigation of a large, school-age fraX cohort in which both biological and environmental factors contributing to clinical outcome were assessed on a prospective basis. We also propose to extend our investigation into the neurobiology of this disorder using advanced brain imaging techniques. Specifically, longitudinal imaging studies will be used to explicate the developmental trajectory of brain structure and function in children with fraX as compared to key control groups. Specific Aims: 1) To use a longitudinal, prospective experimental design (with "Time 1" and "Time 2" assessments) to elucidate the developmental trajectory of cognitive, behavioral and emotional development in probands with fraX compared to their like-gender siblings; 2)to specify the longitudinal trajectory of hypothalamic-pituitary-adrenal (HPA) function and measures of FMR1 gene expression in probands with fraX; and 3)to utilize neuromaging techniques to specify the trajectory of brain structure and function in children with fraX compared to specific age-, gender-, handedness-, SES- and IQ-matched control groups. Although knowledge of cognition, behavior and the brain in children and adults with fraX has grown considerably over the past 20 years, longitudinal data from school-age children with this condition are limited. Cross-sectional findings and limited longitudinal data to date support the hypothesis that an age-related decline in standardized cognitive and adaptive behavioral scores occurs among school-age children with fraX. However, many questions remain unanswered regarding this phenomenon, in particular as related to extent, timing and neural basis. These unanswered questions offer a compelling rationale for conducting a longitudinal study of a large group of school-age boys and girls with fraX as proposed in this application.