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系列 神经精神症状(NPS)，伴随着明显的临床、个人和现实生活负担。然而， NPS的潜在神经机制尚不明确，阻碍了新的治疗方法。堆芯 这些NPS包括：1)睡眠障碍，2)焦虑。此外，睡眠障碍和焦虑 独立地与更快的纵向认知衰退速度相关，强化了特定的 把重点放在它们的重叠上。然而，AD病理可能损害了非快速眼动 (NREM)睡眠和焦虑的NPS特征实际上是相互关联的，代表了一个新的大脑 解释为什么Aβ与焦虑增加有关的机制还没有被研究过。在这里，我们寻求 为了检验一个核心机制假说：β负担对焦虑的影响是通过Beta- 淀粉样蛋白(Aβ)相关的非快速眼动慢波睡眠障碍，进而放大第二天的焦虑 通过受损的mPFC-杏仁核情绪脑调节。如果支持，这些研究将(I) 促进我们对AD相关病理如何机械地影响NPS特征的基本理解 通过损害NREM睡眠引起的焦虑，以及(Ii)将改善睡眠确立为一种新的可修改的 治疗干预目标，可能降低与AD疾病状态相关的焦虑，并可能 纵向疾病/认知功能减退的比率。

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.