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

项目概要/摘要 背景：一些独立的证据表明，睡眠障碍可能直接导致 与神经精神症状（ESTA）的产生和维持有关，包括焦虑、抑郁、激动， 易怒和冷漠通过额叶边缘脑网络调节情绪，特别是在大脑皮层的区域， 前额皮质（PFC）和边缘区（杏仁核）。然而，睡眠障碍的模型有助于 通过额叶边缘系统功能受损而增加的焦虑尚未在参与者样本中得到测试 患有或处于发展阿尔茨海默病（AD）的高风险中。目的：我们的目标是在患者中测试该模型 通过描述睡眠中断、 额边缘功能，同时调节情绪，并在基线和实验操纵睡眠， 确定睡眠的变化是否会导致额边缘功能和睡眠的下游改变。 设计/方法：我们的假设将在150例2组随机对照机制试验中进行检验。 患有MCI和轻度AD的睡眠障碍患者，他们还经历了情绪困扰 和其他行为症状参与者将以1：1的比例随机接受睡眠操作 （认知行为治疗失眠; CBT-I）或可靠的对照治疗失眠组。 这两种干预措施将在八周内进行六次会议。CBT-I是一种有效的 行为干预，特别针对改善睡眠模式，通过结合睡眠， 限制，刺激控制，针对睡眠功能障碍信念的认知疗法，以及睡眠卫生 教育在基线和睡眠后的操作中，我们将检测每个参与者的额叶边缘系统功能 在调节情绪（杏仁核反应性和PFC-杏仁核连接）时，使用神经精神病学 清单（NPI），和睡眠效率使用高密度脑电图收集夜间睡眠期间。具体目标 1）表征睡眠障碍、情绪调节脑功能之间的基线关联，以及 在睡眠操作之前，2）测试睡眠诱导的额边缘脑功能改善介导 睡眠改善和睡眠减少之间的关联，以及3）确定睡眠改善和睡眠减少的基线预测因子。 改进了。新颖性和影响：在机械试验中使用多方法学方法 通过因果操纵睡眠的框架，我们将揭示跨多个单位的潜在睡眠机制。 分析（脑回路，生理，行为和自我报告）。我们的研究结果将推进一种 了解睡眠障碍和额叶边缘系统在调节情绪时的功能， 在早期AD患者中的抑郁症的情绪痛苦和经济相关问题的基础。这些 研究结果将是发展以睡眠为基础、以机制为重点的预防性药物的必要的第一步。 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.