Sleep Disturbance and Emotion Regulation Brain Dysfunction as Mechanisms of Neuropsychiatric Symptoms in Alzheimer's Dementia

项目摘要/摘要 背景：几条独立的证据表明，睡眠障碍可能直接导致 神经精神症状(NP)的产生和维持，包括焦虑、抑郁、激越、 易怒和冷漠通过额叶-边缘大脑网络调节情绪，特别是在大脑的 前额叶皮质(PFC)和边缘区域(杏仁核)。然而，睡眠障碍的模型有助于 通过额叶边缘功能受损而增加的NPS尚未在参与者样本中进行测试 患有或处于阿尔茨海默病(AD)的高危人群。目的：我们的目标是在患者身上测试这一模型。 轻度认知障碍(MCI)和轻度阿尔茨海默病(AD)之间的关系 调节情绪时的额缘功能，以及基线时的NPS，并通过实验操纵睡眠来 确定睡眠变化是否会导致额叶边缘功能和NPS的下游变化。 设计/方法：我们的假设将在150人的双臂随机对照机械试验中得到验证。 MCI和轻度AD患者经历睡眠障碍，同时也经历情绪困扰 以及其他行为症状。参与者将按1：1的比例随机接受睡眠操作 (认知行为疗法治疗失眠症；CBT-I)或失眠症可信对照治疗组。 这两种干预措施将在八周内分六次进行。CBT-I是一种有效的 旨在通过组合睡眠改善睡眠模式的行为干预 限制、刺激控制、针对睡眠功能障碍信念的认知治疗和睡眠卫生 教育。在基线和睡后操作中，我们将测试每个参与者的额叶边缘功能 在调节情绪(杏仁核反应性和PFC-杏仁核连接)的同时，NPS使用神经精神病学 库存(NPI)，并使用夜间睡眠期间收集的高密度脑电来提高睡眠效率。具体目标 是为了1)描述睡眠障碍、情绪调节、大脑功能和 NPS在睡眠操作前，2)测试睡眠诱导的额叶边缘脑功能改善 睡眠改善和NPS减少之间的关联，以及3)确定 NPS的改进。新颖性与影响：在机械性试验中使用多方法方法 框架通过因果操作睡眠，我们将发现跨多个单位的潜在NPS机制 分析(脑回路、生理、行为和自我报告)。我们的结果将推动一种机械性的 了解睡眠障碍和额叶边缘脑在调节情绪时的功能可能 这是早期AD患者NPS的情绪痛苦和经济相关问题的基础。这些 结果将是发展以睡眠为基础、以机制为重点的预防措施的必要的第一步 针对个人的更个性化的策略和治疗。

PROJECT SUMMARY/ABSTRACT BACKGROUND: Several independent lines of evidence suggest that sleep disturbance may directly contribute to the generation and maintenance of neuropsychiatric symptoms (NPS) including anxiety, depression, agitation, irritability, and apathy through fronto-limbic brain networks that regulate emotion, particularly in regions of the prefrontal cortex (PFC) and limbic areas (amygdala). However, the model of sleep disturbance contributing to increased NPS through impairments in fronto-limbic function has not yet been tested in a sample of participants with or at high-risk for developing Alzheimer’s Disease (AD). OBJECTIVE: We aim to test this model in patients with mild cognitive impairment (MCI) and mild AD by characterizing associations between sleep disruption, fronto-limbic function while regulating emotion, and NPS at baseline and by experimentally manipulating sleep to determine whether changes in sleep cause downstream alterations in fronto-limbic functioning and NPS. DESIGN/METHODS: Our hypotheses will be tested in a 2-arm randomized controlled mechanistic trial with 150 patients with MCI and mild AD experiencing sleep disturbances who are also experiencing emotional distress and other behavioral symptoms. Participants will be randomized in a 1:1 ratio to receive a sleep manipulation (Cognitive Behavioral Therapy for Insomnia; CBT-I) or to the credible control treatment for insomnia group. Both interventions will be administered in six sessions delivered over eight weeks. CBT-I is an efficacious behavioral intervention specifically targeted at improving sleep patterns through a combination of sleep restriction, stimulus control, cognitive therapy targeting dysfunctional beliefs about sleep, and sleep hygiene education. At baseline, and post-sleep manipulation we will assay each participant’s fronto-limbic functioning while regulating emotions (amygdala reactivity and PFC-amygdala connectivity), NPS using the Neuropsychiatric Inventory (NPI), and sleep efficiency using high-density EEG collected overnight during sleep. SPECIFIC AIMS are to 1) characterize baseline associations among sleep disturbances, emotion regulation brain function, and NPS prior to a sleep manipulation, 2) test that sleep-induced fronto-limbic brain function improvement mediates the association between sleep improvement and NPS reductions, and 3) determine baseline predictors of the NPS improvement. NOVELTY & IMPACT: Using a multi-methodological approach within a mechanistic trial framework by causally manipulating sleep, we will uncover potential NPS mechanisms across multiple units of analysis (brain circuit, physiological, behavioral, and self-report). Our results will advance a mechanistic understanding of how sleep disturbances and fronto-limbic brain function while regulating emotions may underlie the emotionally distressing and economically relevant problem of NPS in early AD patients. These results would be a necessary first step in the development of sleep based, mechanism-focused preventative strategies and treatments that are more personalized for the individual.