Androgen effect on brain structure/function in Klinefelter syndrome

雄激素对克兰费尔特综合征脑结构/功能的影响

• 批准号: 7657022
• 负责人: Judith L Ross
• 金额: $ 20.22万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7657022
• 关键词: 12 year old; Abbreviations; Address; Affect; Age; Androgen Receptor; Androgens; Animal Model; Anterior; Area; Attention; Back; Base of the Brain; Bilateral; Body of uterus; Brain; Brain imaging; Brain region; Characteristics; Childhood; Clinical Trials; Cognition; Cognitive; Cognitive deficits; Complex; Controlled Clinical Trials; Cross-Sectional Studies; Cues; Development; Disease; Enrollment; Failure; Fingers; Functional Magnetic Resonance Imaging; Future; Generations; Globus Pallidus; Goals; Gray unit of radiation dose; Hereditary Disease; Hippocampus (Brain); Hormonal; Human; Image; Inferior; Inferior frontal gyrus; Insula of Reil; Internal Capsule; Intervention; Karyotype; Klinefelter' s Syndrome; Knowledge; Language; Lead; Learning; Left; Limb structure; Link; Lobule; Magnetic Resonance Imaging; Measurable; Memory; Memory impairment; Methods; Motor; Movement; Neurocognitive; Outcome; Oxandrolone; Parietal; Parietal Lobe; Performance; Phase; Phase II Clinical Trials; Phenotype; Placebo Control; Placebos; Population; Prefrontal Cortex; Protocols documentation; Randomized; Relative (related person); Replacement Therapy; Research; Resolution; Rest; Role; Sensorimotor functions; Short-Term Memory; Speed; Structure; Syndrome; Techniques; Temporal Lobe; Testosterone; Turner' s Syndrome; Visual; base; boys; brain behavior; brain volume; cingulate cortex; cognitive function; design; executive function; frontal lobe; gray matter; improved; insight; male; memory retrieval; morphometry; motor control; muscle strength; neuroimaging; public health relevance; regional difference; relating to nervous system; response; white matter

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.

描述（由申请人提供）：该提案是一项补充，旨在扩大我们正在进行的 II 期安慰剂对照临床试验（NS050597，“雄激素对克兰费尔特综合征运动/认知结果的影响”[KS]）。我们目前正在调查 24 个月的雄激素替代疗法对 4-12 岁 KS 男孩运动功能和认知方面的影响。该补充剂的主要目的是在一项正在进行的独特临床试验中，研究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 KS 男孩（8-12 岁）和年龄匹配的对照男孩之间的大脑结构和功能差异，并将纵向检查 KS 中与雄激素替代相关的大脑形态测量和功能。 KS 是一种遗传性疾病，发生于 1/500-1000 名男性，其核型为 47,XXY。 KS 神经认知表型包括运动功能受损、语言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（氧雄龙）治疗 2 年，使 4-12 岁 KS 男孩恢复正常睾酮水平。具体目标#1（正在进行的临床试验中）预测，与接受安慰剂治疗的 KS 男孩相比，接受雄激素治疗的男孩在运动功能的多个方面的表现有所改善。具体目标#2（正在进行的临床试验中）预测，与接受安慰剂治疗的 KS 男孩相比，接受雄激素治疗的男孩在某些认知方面（特别是语言和执行功能）的表现有所改善。患有 KS 的男孩与语言、记忆检索和工作记忆以及运动功能相关的区域的脑容量较小，包括额顶叶区（与工作记忆相关）、额叶、顶颞区（与语言相关）和运动区域。与运动功能有关），与对照组男孩相比。这些特定区域的结构和功能已被证明会随着雄激素替代而发生变化。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 II 期临床试验中，认知功能将通过雄激素替代而得到改善。在本补充材料中，我们将使用结构和功能 MRI (fMRI) 方案来 1) 比较 KS 男孩与年龄匹配的对照男孩的大脑结构和功能，以及 2) 研究雄激素替代对雄激素中大脑结构和功能的影响。与接受安慰剂治疗的 KS 男孩进行对比（正在进行的临床试验）。该补充品提供了一个独特的机会，可以在雄激素替代期间纵向评估 KS 大脑的变化，并将通过增加我们对 KS 大脑结构和功能的了解来增加正在进行的临床试验的意义。我们的目标是将 KS 中雄激素缺乏和替代的结构和功能神经影像学发现联系起来，以扩大我们对雄激素影响认知的机制的理解。公共健康相关性：该补充剂中的结构和功能脑成像将为雄激素在男性大脑发育中的作用提供独特的见解，并将显着扩大正在进行的临床试验（“雄激素对克兰费尔特综合征运动/认知结果的影响”）。我们的目标是 1) 帮助确定大脑结构和功能的差异，从而区分患有克兰费尔特综合征的男孩和对照男孩；2) 深入了解接受雄激素治疗的 KS 受试者中与认知功能改善相关的大脑变化。我们的目标是将 KS 中雄激素缺乏和替代的结构和功能神经影像学发现联系起来，以扩大我们对雄激素影响认知的机制的理解。