Sleep Impairment: A Mechanism Explaining Neuropsychiatric Symptoms in Alzheimer's

项目摘要/摘要：阿尔茨海默病（AD）及其相关的神经病理学与一组 神经精神症状（neuropsychiatric symptoms，简称neuropsychiatric symptoms，简称neuropsychiatric symptoms）伴随着显著的临床、个人和现实生活负担。然而，在这方面， 神经系统疾病的潜在神经机制定义不清，阻碍了新的治疗方法。核心 其中包括：1）睡眠障碍，和2）焦虑。此外，睡眠障碍和焦虑 独立地与更快的纵向认知下降率相关，加强了特定的 专注于它们的重叠。然而，AD病理损害非快速眼球运动的可能性 （NREM）睡眠和焦虑的睡眠特征实际上是相互关联的，代表了一种新的大脑 解释为什么Aβ与焦虑增加有关的机制尚未研究。在这里，我们寻求 为了验证一个核心机制假设：Aβ负荷对焦虑的影响是通过β- 淀粉样蛋白（Aβ）相关的NREM慢波睡眠损害，反过来又会放大第二天的焦虑 通过受损的mPFC-杏仁核情绪大脑调节。如果支持，这些研究将（i） 推进我们对AD相关病理学如何机械地影响 通过NREM睡眠障碍焦虑，（ii）建立睡眠改善作为一种新的可改变的 治疗干预目标，可以减轻与AD疾病状态相关的焦虑， 纵向疾病/认知能力下降的比率。

Project Summary/Abstract: Alzheimer’s disease (AD) and its related neuropathology are linked to a set of neuropsychiatric symptoms (NPS) that come with marked clinical, personal and real-life burden. However, the underlying neural mechanisms of NPS are poorly defined, hindering novel treatment approaches. Core among these NPS are: 1) sleep disturbance, and 2) anxiety. Moreover, both sleep impairment and anxiety are independently associated with a faster rate of longitudinal cognitive decline, reinforcing a particular focus on their overlap. However, the possibility that AD pathology, impaired non-rapid eye movement (NREM) sleep and the NPS feature of anxiety are actually inter-related, representing a novel brain mechanism explaining why Aβ is associated with increased anxiety, has not been examined. Here, we seek to test a core mechanistic hypothesis: The impact of Aβ burden on anxiety is orchestrated through beta- amyloid (Aβ)-related impairment of NREM slow-wave sleep, which in turn, amplifies next-day anxiety through impaired mPFC-amygdala emotional brain regulation. If supportive, these studies would (i) advance our basic understanding of how AD-related pathology mechanistically impacts the NPS feature of anxiety through impairment of NREM sleep, and (ii) establish sleep improvement as a novel modifiable therapeutic intervention target that may de-escalate anxiety linked with the AD disease state, and potentially the rate of longitudinal disease/cognitive decline.