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

睡眠障碍：解释阿尔茨海默病神经精神症状的机制

• 批准号: 10272379
• 负责人: Matthew P Walker
• 金额: $ 83.59万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-18 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10272379
• 关键词: Address; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Amygdaloid structure; Amyloid; Amyloid beta-Protein; Anti-Anxiety Agents; Anxiety; Behavior; Behavioral; Brain; Clinical; Cognition; Cognitive; Data; Detection; Development; Disease; Elderly; Electroencephalography; Elements; Emotional; Functional Magnetic Resonance Imaging; Generations; Impaired cognition; Impairment; Individual; Life; Link; Measures; Mediation; Mental Depression; Methods; Modality; Modeling; Moods; National Institute of Mental Health; Negative Valence; Participant; Pathology; Positron-Emission Tomography; Preparation; Publishing; Regulation; Research Domain Criteria; Severities; Sleep; Sleep Deprivation; Sleep disturbances; Slow-Wave Sleep; Speed; Testing; Therapeutic Intervention; abeta accumulation; anxiety symptoms; cohort; depressive symptoms; emotion regulation; follow-up; functional MRI scan; improvement on sleep; longitudinal design; neuromechanism; neuropathology; neuropsychiatric symptom; non rapid eye movement; novel; prevent; prospective; relating to nervous system; young adult; β-amyloid burden

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.

项目摘要/摘要：阿尔茨海默氏病 (AD) 及其相关神经病理学与一组 神经精神症状（NPS）给临床、个人和现实生活带来显着的负担。然而， NPS 的潜在神经机制尚不清楚，阻碍了新的治疗方法。核 这些 NPS 包括：1) 睡眠障碍，2) 焦虑。此外，睡眠障碍和焦虑 与更快的纵向认知衰退速度独立相关，从而强化了特定的 重点关注它们的重叠部分。然而，AD 病理学、非快速眼球运动受损的可能性 （NREM）睡眠和焦虑的 NPS 特征实际上是相互关联的，代表着一种新的大脑 解释为什么 Aβ 与焦虑增加相关的机制尚未得到研究。在这里，我们寻求 测试一个核心机制假设：Aβ 负担对焦虑的影响是通过 beta- 精心策划的 淀粉样蛋白 (Aβ) 相关的 NREM 慢波睡眠受损，进而加剧第二天的焦虑 通过受损的 mPFC-杏仁核情绪脑调节。如果支持的话，这些研究将 (i) 增进我们对 AD 相关病理学如何机械地影响 NPS 特征的基本理解 通过 NREM 睡眠受损而产生焦虑，以及 (ii) 将睡眠改善确立为一种新的可改变的方法 治疗干预目标可能会降低与 AD 疾病状态相关的焦虑，并可能 纵向疾病/认知能力下降的比率。