Brain and Behavior during Puberty in Klinefelter Syndrome

克兰费尔特综合征青春期的大脑和行为

• 批准号: 10197985
• 负责人: Allan L Reiss
• 金额: $ 61.14万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-17 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10197985
• 关键词: Address; Adolescent; Affect; Affective; Age; Amygdaloid structure; Anterior; Anxiety; Attention; Attention deficit hyperactivity disorder; Awareness; Base of the Brain; Behavior; Behavioral; Birth; Brain; Characteristics; Child; Childhood; Clinical; Clinical Management; Cognition; Cognitive; Collaborations; Coupled; Development; Diagnosis; Diffusion Magnetic Resonance Imaging; Dose; Emotional; Emotions; Endocrinologist; Executive Dysfunction; Exhibits; Failure; Functional Magnetic Resonance Imaging; Genetic Diseases; Goals; Gonadal Steroid Hormones; Gynecomastia; Home; Hormonal; Hormones; Impairment; Individual; Inferior frontal gyrus; Insula of Reil; Interdisciplinary Study; Investigation; Klinefelter' s Syndrome; Knowledge; Language; Language Development; Lead; Learning Disabilities; Literature; Mental Depression; Moods; Multimodal Imaging; Neurophysiology - biologic function; Outcome; Parents; Pattern; Phenotype; Principal Investigator; Psyche structure; Psychosocial Assessment and Care; Puberty; Reporting; Research; Research Personnel; Sampling; Schools; Severities; Social Functioning; Spermatogenesis; Structure; Supplementation; Symptoms; Syndrome; Testing; Testosterone; Time; Variant; X Chromosome; anxiety symptoms; base; behavior measurement; boys; brain behavior; cingulate cortex; cognitive ability; cognitive development; cognitive testing; comparison group; depressive symptoms; emotional functioning; emotional symptom; executive function; experience; flexibility; improved; male; neural circuit; novel; peripubertal period; physical symptom; prepuberty; prospective; recruit; relating to nervous system; secondary analysis; sex chromosome aneuploidy; social; social skills; standard care; testosterone replacement therapy

Klinefelter syndrome (KS) is a highly prevalent sex chromosome aneuploidy syndrome that is characterized by an increased number of X chromosomes (47,XXY) in phenotypic males. Despite its frequent occurrence (up to 1 in 500 male births), clinicians often have relatively little awareness about diagnosis or management of cognitive-behavioral and social-emotional problems in boys with KS. These problems can include significant language-based learning disability, executive function deficits and ADHD symptoms, impaired social skills, depression and anxiety. Parents of children with KS often report greater concerns about these brain-based disturbances relative to commonly observed physical symptoms in KS such as tall stature and testicular failure, since they have the potential to affect everyday function at home and school, and long- term social and vocational outcome. Most boys with KS experience testicular insufficiency (i.e., deficiency in testosterone and/or hypogonadal symptoms) starting in mid-puberty. For this reason, pediatric endocrinologists typically prescribe testosterone replacement therapy (TRT) starting in the pubertal period. However, there remain large gaps in knowledge and fundamental questions about the effects of TRT on brain development and function in KS. Indeed, a wide body of literature indicates that the rise in testosterone at puberty in typically developing boys influences a wave of neural remodeling, and that these changes in neural circuitry are tightly coupled with changes in cognition, behavior and mood. The prospective, longitudinal, multi-time point research proposed here would be the first to assess the effects of TRT on brain development and function in adolescents with KS using multiple levels of analysis (cognitive-behavioral and social-emotional functioning, multi-modal imaging, pubertal status, hormone levels). Sixty boys with KS and a comparison group of 60 age- and IQ-matched neurotypical boys between the ages of 9 and 13 years will be recruited and followed annually for up to four years. Three specific aims will be addressed: (1) to examine the effects of TRT on executive function and social-emotional symptoms in KS (2) to evaluate the effects of TRT on brain structure and function in KS and, (3) to elucidate brain-behavior associations in KS (exploratory). We will also examine severity of testicular insufficiency as a modifier of brain and behavioral measures in secondary analyses. The multidisciplinary research we propose offers a first-of-its-kind opportunity to provide an increased understanding of how TRT exerts its beneficial effect on cognition, behavior and mood in boys with KS during the peripubertal period. The results of this study are intended to lead to the development of improved clinical management of cognitive-behavioral and social-emotional symptoms in boys with KS while advancing our general knowledge of neural changes underlying cognition, behavior and mood during male puberty.

克兰费尔特综合征 (KS) 是一种高度流行的性染色体非整倍体综合征， 其特征是表型男性的 X 染色体 (47,XXY) 数量增加。尽管其频繁 发生率（每 500 名男性新生儿中就有 1 名），临床医生通常对诊断或了解相对较少。 KS 男孩认知行为和社会情感问题的管理。这些问题可以 包括严重的语言学习障碍、执行功能缺陷和多动症症状， 社交能力受损、抑郁和焦虑。患有 KS 的儿童的父母经常报告更多的担忧 这些基于大脑的紊乱与 KS 中常见的身体症状（例如身材高大）有关 和睾丸衰竭，因为它们有可能影响家庭和学校的日常功能，并且长期 术语“社会和职业成果”。 大多数患有 KS 的男孩都会出现睾丸功能不全（即睾酮缺乏和/或性腺功能减退） 症状）从青春期中期开始。因此，儿科内分泌科医生通常会开睾酮 替代疗法（TRT）从青春期开始。但在知识和知识方面仍存在很大差距 关于 TRT 对 KS 大脑发育和功能影响的基本问题。确实宽体 大量文献表明，典型发育男孩青春期睾酮水平的升高会影响一波 神经重塑，并且神经回路的这些变化与认知的变化紧密相关， 行为和情绪。 这里提出的前瞻性、纵向、多时间点研究将是第一个评估 使用多层次分析研究 TRT 对 KS 青少年大脑发育和功能的影响 （认知行为和社会情感功能、多模式成像、青春期状态、激素水平）。 60 名患有 KS 的男孩和由 60 名年龄和智商匹配的神经典型男孩组成的对照组 每年都会招募 9 岁和 13 岁的学生，并进行为期四年的随访。将实现三个具体目标 解决：（1）检查 TRT 对 KS 执行功能和社会情绪症状的影响（2） 评估 TRT 对 KS 大脑结构和功能的影响，以及 (3) 阐明大脑行为 KS 中的关联（探索性）。我们还将检查睾丸功能不全的严重程度作为大脑的调节剂 和二次分析中的行为测量。 我们提出的多学科研究提供了前所未有的机会，以提供更多 了解 TRT 如何在 KS 男孩的认知、行为和情绪方面发挥有益作用 青春期前后。这项研究的结果旨在促进临床改进的发展 管理 KS 男孩的认知行为和社会情感症状，同时推进我们的研究 关于男性青春期期间认知、行为和情绪的神经变化的一般知识。