Electrophysiological biomarkers of sleep and cognition in Dup15q syndrome

Dup15q 综合征睡眠和认知的电生理生物标志物

• 批准号: 9810069
• 负责人: Shafali Spurling Jeste
• 金额: $ 22.46万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-05 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9810069
• 关键词: Adult; Age; Area; Attenuated; Behavior; Behavior Therapy; Biological Factors; Biological Markers; Brain; Child; Clinical; Clinical Trials; Cognition; Cognitive; Country; Data; Development; Disease; Electroencephalography; Electrophysiology (science); Epilepsy; Etiology; Future; GABA-A Receptor; Genes; Genetic Diseases; Goals; Impaired cognition; Infant; Intellectual functioning disability; Investigation; Light; Link; Mental Retardation and Developmental Disabilities Research Centers; National Institute of Child Health and Human Development; Neurodevelopmental Disorder; Pharmacology; Phenotype; Physiological; Property; Protein Biosynthesis; Receptor Gene; Research Priority; Sleep; Sleep disturbances; Slow-Wave Sleep; Surrogate Endpoint; Synapses; Syndrome; UBE3A gene; autism spectrum disorder; behavior measurement; cognitive development; cohort; comparison group; density; improved; infancy; interest; neurodevelopment; neurotransmission; patient advocacy group; protein degradation; repository; signal processing; skills; sleep abnormalities; sleep physiology; sleep quality; sleep spindle

Project Abstract Duplications of 15q11.3-21.1 (Dup15q syndrome) are highly penetrant for intellectual disability (ID), autism spectrum disorder (ASD) and epilepsy (Finucane et al., 2016). Several genes in the region, particularly UBE3A and a cluster of GABAA receptor genes, are critical for neural development, disrupting synaptic protein synthesis and degradation as well as inhibitory neurotransmission. In a previous study, we identified an electrophysiological biomarker of this syndrome defined by increased beta band oscillations that likely reflect aberrant GABAergic neurotransmission (Frohlich et al., 2016). As we further explored properties of this biomarker, we discovered that the sleep physiology in these children is profoundly abnormal, with grossly attenuated slow wave sleep and reduced sleep spindle density. Healthy sleep physiology is necessary for robust cognitive development, from early infancy through adulthood, (den Bakker et al., 2018; Fogel & Smith, 2011; Hahn et al., 2018; Tham, Schneider, & Broekman, 2017), and there is extensive evidence of physiological sleep impairment in neurodevelopmental disorders (Gruber & Wise, 2016; Kose, Yilmaz, Ocakoglu, & Ozbaran, 2017; Tessier et al., 2015). We hypothesize that abnormal sleep physiology directly undermines cognitive development in Dup15q syndrome and may serve as a quantifiable and modifiable target for pharmacological or even behavioral interventions. Through a partnership with the Dup15q Alliance (patient advocacy group) and our UCLA Intellectual and Developmental Disabilities Research Center (IDDRC), we propose a comprehensive study of sleep electrophysiology and cognition in Dup15q syndrome. We will collect previously recorded overnight clinical EEG’s from children with Dup15q syndrome across the country and compare these EEG’s to those of children with nonsyndromic ID and typical development. We will ask whether sleep physiology, specifically (1) spindle density, (2) percent slow wave sleep, (3) percent spikes in slow wave sleep and (4) absolute beta power in stage 1 and 2 of sleep differentiates Dup15q syndrome from these comparison groups and whether these variables relate to cognition and adaptive skills. The field of neurodevelopmental disorders has sorely lacked quantifiable electrophysiological biomarkers that relate to disease mechanisms, and sleep EEG may represent a robust biomarker that sheds light on the etiology of cognitive impairment while also serving as a surrogate endpoint in clinical trials, particularly for Dup15q syndrome. Moreover, the pipeline that we have developed, from building a remote clinical EEG repository to performing semi-automated sleep EEG signal processing can inform other biomarker studies in syndromic and nonsyndromic forms of ID.

项目摘要 15q11.3-21.1的重复（Dup 15 q综合征）是智力残疾（ID）、自闭症 谱系障碍（ASD）和癫痫（Finucane等人，2016年）。该地区的几个基因，特别是UBE 3A 和一组GABAA受体基因，对神经发育至关重要， 合成和降解以及抑制性神经传递。在之前的一项研究中，我们发现了一种 这种综合征的电生理生物标志物由增加的β带振荡定义，可能反映了 异常GABA能神经传递（Frohlich等，2016年）。随着我们进一步探索这种 生物标志物，我们发现这些儿童的睡眠生理学非常不正常， 减弱慢波睡眠和降低睡眠梭形密度。健康的睡眠生理是必要的， 从早期婴儿期到成年期的稳健的认知发展，（denBakker等人，2018; Fogel & Smith， 2011; Hahn等人，2018; Tham，Schneider和Broekman，2017），并且有大量证据表明 神经发育障碍中的生理性睡眠障碍（Gruber & Wise，2016; Kose，Yilmaz， Ocakoglu，& Ozbaran，2017; Tessier et al.，2015年）。我们假设异常的睡眠生理 破坏Dup 15 q综合征的认知发展，并可能作为一种可量化和可修改的 药物甚至行为干预的目标。通过与Dup 15 q联盟的合作， （患者倡导小组）和我们的加州大学洛杉矶分校智力和发育障碍研究中心（IDDRC）， 我们建议对Dup 15 q综合征患者的睡眠电生理和认知功能进行全面的研究。我们将 从全国各地患有Dup 15 q综合征的儿童中收集先前记录的夜间临床EEG 并将这些脑电图与非综合征型ID和典型发育儿童的脑电图进行比较。我们会要求 睡眠生理学，特别是（1）纺锤体密度，（2）慢波睡眠百分比，（3） 慢波睡眠和（4）睡眠阶段1和2的绝对β功率区分Dup 15 q综合征和 这些比较组以及这些变量是否与认知和适应技能有关。领域 神经发育障碍严重缺乏可量化的电生理学生物标志物， 疾病机制，睡眠脑电图可能是一个强大的生物标志物，揭示了病因， 认知障碍，同时也作为临床试验的替代终点，特别是对于Dup 15 q 综合征此外，我们已经开发的管道，从建立一个远程临床脑电图储存库， 进行半自动睡眠EEG信号处理可以为综合征和 非综合征型ID