Androgen effect on brain structure/function in Klinefelter syndrome

描述(由申请人提供)：本提案是一个补充，旨在扩大我们正在进行的第二阶段安慰剂对照临床试验(NS050597，“雄激素对Klinefelter综合征运动/认知结果的影响”[KS])。我们目前正在调查雄激素替代治疗24个月对4-12岁KS男孩运动功能和认知方面的影响。本附录的主要目的是在一项独特的正在进行的临床试验的背景下，调查雄激素替代疗法如何影响雄激素缺乏人群--患有KS的男孩--的大脑结构和功能。这项拟议的研究将调查患有KS的男孩(8-12岁)和年龄匹配的对照组男孩之间的大脑结构和功能差异，并将纵向检查KS患者与雄激素替代相关的脑形态和功能。KS是一种遗传性疾病，发生在1/500-1000的男性中，由核型47，XXY定义。KS神经认知表型包括运动功能受损、基于语言的学习困难和执行功能(注意力/工作记忆)缺陷。正在进行的随机、安慰剂对照临床试验试图通过雄激素(氧雄酮)治疗2年来恢复4-12岁KS男孩的正常睾酮水平。具体目标1(正在进行的临床试验)预测，与安慰剂治疗的KS男孩相比，接受雄激素治疗的KS男孩在运动功能的几个方面都有改善。特定目标2(正在进行的临床试验)预测，与安慰剂治疗的KS男孩相比，接受雄激素治疗的男孩在认知的特定方面，特别是在语言和执行功能方面的表现有所改善。与对照组男孩相比，患有KS的男孩在与语言、记忆提取和工作记忆相关的区域以及运动功能方面的脑体积较小，包括额顶区(与工作记忆有关)、额叶、顶颞区(与语言有关)和运动区(与运动功能有关)。这些特定区域的结构和功能已被证明随着雄激素替代的反应而改变。最重要的是，这些区域的变化与认知功能的变化有关，我们假设在正在进行的第二阶段临床试验中，雄激素替代将改善认知功能。在本补充资料中，我们将使用结构和功能磁共振成像(FMRI)方案来1)比较患有KS的男孩和年龄匹配的对照组男孩的大脑结构和功能，以及2)研究雄激素替代对接受雄激素治疗和安慰剂治疗的KS男孩大脑结构和功能的影响(正在进行的临床试验)。这一补充代表了一个独特的机会，可以纵向评估KS大脑在雄激素替代期间的变化，并通过增加我们对KS大脑结构和功能的了解，增加正在进行的临床试验的意义。我们的目标是将KS雄激素缺乏和替代的结构和功能神经影像表现联系起来，以扩大我们对雄激素影响认知的机制的理解。公共卫生相关性：本附录中的结构和功能脑成像将提供有关雄激素在男性大脑发育中的作用的独特见解，并将显著扩大正在进行的临床试验(“Klinefelter综合征中雄激素对运动/认知结果的影响”)。我们的目标是1)帮助确定Klinefelter综合征男孩与对照组男孩在大脑结构和功能上的差异，以及2)提供与雄激素治疗KS受试者认知功能改善相关的大脑变化的见解。我们的目标是将KS雄激素缺乏和替代的结构和功能神经影像表现联系起来，以扩大我们对雄激素影响认知的机制的理解。

DESCRIPTION (provided by applicant): This proposal is a supplement designed to expand our ongoing, Phase II, placebo-controlled clinical trial (NS050597, "Androgen effect on motor/cognitive outcome in Klinefelter syndrome" [KS]). We are currently investigating the impact of androgen replacement for 24 months on motor function and aspects of cognition in boys with KS ages 4-12 years. The Primary aim of this supplement is to investigate how androgen replacement therapy affects brain structure and function in an androgen-deficient population, boys with KS, in the context of a unique ongoing clinical trial. This proposed study will investigate the structural and functional brain differences between boys with KS (8-12 years) and age-matched control boys and will longitudinally examine brain morphometry and function associated with androgen replacement in KS. KS is a genetic disorder that occurs in 1/500-1000 males and is defined by the karyotype 47,XXY. The KS neurocognitive phenotype includes impaired motor function, language-based learning difficulties, and executive function (attention/working memory) deficits. The ongoing randomized, placebo-controlled clinical trial attempts to restore normal testosterone levels in boys with KS, ages 4-12 years, through treatment with androgen (oxandrolone) for 2 years. Specific Aim #1 (in the ongoing clinical trial) predicts improved performance in androgen-treated compared to placebo-treated boys with KS in several aspects of motor function. Specific Aim #2 (in the ongoing clinical trial) predicts improved performance in androgen-treated compared to placebo-treated boys with KS in selected aspects of cognition, specifically in language and executive function. Boys with KS have smaller brain volumes in regions related to language, memory retrieval and working memory, and motor function including the fronto-parietal regions (related to working memory), frontal, parieto-temporal regions (related to language) and motor regions (related to motor function), compared to control boys. Structure and function in these specific areas have been shown to change in response to androgen replacement. Most importantly, changes in these regions have been associated with changes in the cognitive functions that we have hypothesized will improve with androgen replacement in the ongoing Phase II clinical trial. In this supplement, we will use structural and functional MRI (fMRI) protocols to 1) compare brain structure and function in boys with KS with age-matched control boys and 2) study the effects of androgen replacement on brain structure and function in androgen- versus placebo-treated boys with KS (ongoing clinical trial). This supplement represents a unique opportunity to assess changes in the KS brain longitudinally during this interval of androgen replacement and will add to the significance of the ongoing clinical trial by increasing our knowledge of brain structure and function in KS. We aim to link the structural and functional neuroimaging findings of androgen deficiency and replacement in KS, in order to expand our understanding of mechanisms underlying androgen impact on cognition. PUBLIC HEALTH RELEVANCE: The structural and functional brain imaging in this supplement will provide unique insight into the role of androgen in male brain development and will significantly expand the ongoing clinical trial ("Androgen effect on motor/cognitive outcome in Klinefelter syndrome"). Our goals are to 1) help define the differences in brain structure and function that distinguish boys with Klinefelter syndrome from control boys and 2) provide insights into the brain changes associated with improved cognitive function in androgen-treated KS subjects. We aim to link the structural and functional neuroimaging findings of androgen deficiency and replacement in KS, in order to expand our understanding of mechanisms underlying androgen impact on cognition.