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

项目摘要 几乎每一种精神病、神经退行性疾病和神经发育障碍都有睡眠功能障碍， 症状.然而，睡眠功能障碍的生物标志物对于给定疾病过程的特异性很差， 这是由于在健康人群和临床队列中观察到的极端异质性。特别 神经学生物标记识别重要性是睡眠纺锤波-渐增-渐减EEG波形， ~ 15 Hz振荡活动，定义NREM阶段2（N2）睡眠。纺锤体的活动与记忆有关 睡眠期间的巩固，与许多精神病，神经退行性疾病和神经发育有关- 精神疾病，包括阿尔茨海默病，21三体，精神分裂症和自闭症，以及与自然 衰老最近的研究表明，纺锤体具有像特质一样的主体内稳定性，但也具有巨大的主体间异质性。 遗传性--其程度尚待确定。如果不描述纺锤体的变异性， 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， 来理解纺锤体的时间动力学使用这个框架，我们将表征主轴的可变性 活动在一个多种族，异质人群的数千名受试者在广泛的年龄范围。我们 然后将使用这些标准分布来评估已建立的和新的生物标志物的特异性， 21三体综合征、阿尔茨海默病和轻度认知障碍队列中纺锤体功能障碍在这样做时， 我们填补了阿尔茨海默病生物标志物开发的一个重要空白，提供了一个背景和规范， 目前的方法缺乏灵活性。

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.