Sleep Spindle Dynamics as a Clinical Biomarker of Aging, Alzheimer's Disease, and Trisomy 21

睡眠纺锤体动力学作为衰老、阿尔茨海默病和 21 三体症的临床生物标志物

• 批准号: 10733629
• 负责人: Uri Tzvi Eden
• 金额: $ 257.69万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10733629
• 关键词: Age; Aging; Alzheimer' s Disease; Alzheimer’s disease biomarker; Biological Markers; Brain; Brain region; Clinical; Complex; Coupling; Data; Databases; Detection; Disease; Down Syndrome; Electroencephalography; Event; Functional disorder; General Population; Generations; Heterogeneity; Individual; Legal patent; Link; Mathematics; Mental disorders; Methods; Modeling; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neurologic; Pathologic; Pathologic Processes; Pathology; Patients; Phase; Phenotype; Play; Polysomnography; Population; Process; Property; Recording of previous events; Research; Role; Schizophrenia; Sleep; Sleep Disorders; Specificity; Stage II Sleep; Symptoms; Time; Variant; Waxes; Work; autism spectrum disorder; biomarker development; biomarker identification; clinical biomarkers; cohort; comparison group; developmental disease; insight; memory consolidation; mild cognitive impairment; multi-ethnic; neurophysiology; non rapid eye movement; novel marker; novel strategies; older patient; sleep spindle; theories; trait

PROJECT SUMMARY Nearly every psychiatric, neurodegenerative, and neurodevelopmental disorder has sleep dysfunction as a symptom. However, the specificity of biomarkers of sleep dysfunction for a given disease process is poorly un- derstood, due to the extreme heterogeneity observed within healthy populations and clinical cohorts. Of particular importance to neurological biomarker identification are sleep spindles—waxing-waning EEG waveforms of ~15Hz oscillatory activity that define NREM Stage 2 (N2) sleep. Spindle activity has been linked to memory consolidation during sleep and associated with numerous psychiatric, neurodegenerative, and neurodevelop- mental diseases, including Alzheimer's disease, trisomy 21, schizophrenia, and autism, as well as with natural aging. Recent work has shown that spindles have trait-like intrasubject stability, but also vast intersubject heter- ogeneity—the extent of which has yet to be characterized. Without characterizing spindle variability, we cannot understand the specificity of sleep EEG biomarkers. In this study, we develop a robust mathematical framework for understanding spindle temporal dynamics. Using this framework, we will characterize the variability in spindle activity across a multi-ethnic, heterogenous population of thousands of subjects across a wide age range. We will then use these normative distributions to evaluate the specificity of established and novel biomarkers of spindle dysfunction in trisomy 21 and Alzheimer's disease and mild cognitive impairment cohorts. In doing so, we fill an important gap essential to Alzheimer's disease biomarker development, providing a context and spec- ificity lacking in current approaches.

项目摘要 几乎每种精神病，神经退行性和神经发育障碍都有睡眠功能障碍 症状。然而，睡眠功能障碍在给定疾病过程中的生物标志物的特异性尚无 由于在健康的人群和临床队列中观察到的极端异质性，因此很难。特别 对神经系统生物标志物识别的重要性是睡眠纺锤 〜定义NREM阶段2（N2）睡眠的15Hz振荡活性。主轴活动已链接到内存 睡眠期间的巩固，并与许多精神病，神经退行性和神经发育有关 精神疾病，包括阿尔茨海默氏病，三体疾病，精神分裂症和自闭症以及自然疾病 老化。最近的工作表明，纺锤具有类似特质的主体内稳定性，但也具有巨大的主体间异质 - 有性 - 尚未表征的程度。没有表征主轴变异性，我们就无法 了解睡眠脑电图生物标志物的特异性。在这项研究中，我们开发了一个强大的数学框架 使用此框架，我们将表征主轴的变异性 在广泛年龄范围内的数千名受试者的多种族异基人群中的活动。我们 然后，将使用这些正常分布来评估已建立和新型生物标志物的特异性 三体疾病的主轴功能障碍以及阿尔茨海默氏病和轻度认知障碍队列。这样做， 我们填补了对阿尔茨海默氏病生物标志物发展至关重要的重要差距，提供了背景和规范 当前方法缺乏验证。