Nighttime Agitation and Restless Legs Syndrome in People with Alzheimer's Disease

项目概要/摘要。夜间激越，定义为出现或加重的行为 在下午和/或晚上的干扰，如徘徊和攻击，是一种普遍的症状， 老年痴呆症患者的生活质量下降，生活环境受到限制。有效 缺乏治疗。过去治疗失败的一个主要原因是治疗所有 夜间躁动一样。与过去的干预措施不同，我们的精准医疗方法 一种特殊的睡眠障碍，不宁腿综合征（RLS）的干预。RLS发生在10-14%的老年人中 阿尔茨海默病患者很可能患有RLS，因为它很常见，但很少发生 因为诊断依赖于患者回答有关其症状的复杂问题。 RLS引起与不舒服和不愉快的腿部感觉相关的移动冲动。促使移动 腿部不适只在夜间发生或加重，通过运动缓解。我们假设RLS可能 是夜间激越的病因，因为：1）夜间激越和RLS症状的昼夜节律模式 几乎相同; 2）未缓解的RLS不适可能会引发尖叫和请求等行为 寻求帮助，移动的冲动可能会导致徘徊，踱步和不安; 3）常见的因素， 老年痴呆症患者的制度化治疗，如贫血、长期卧床和抗抑郁药， 触发或恶化RLS。我们的初步工作支持了我们的假设，并提供了初步证据， RLS可能是夜间激越的一种不明病因。在59例痴呆患者中， 我们发现，几乎1/4的患者患有RLS，并且RLS是 与夜间躁动相关（r = 0.31，p 0.01）。我们现在提出一个试点临床试验，以确定是否RLS 治疗减少夜间躁动，改善睡眠，减少抗精神病药物，其机制 对于这些影响。我们选择加巴喷丁enacarbil（GEn）作为治疗，因为它是FDA批准的 RLS并具有良好的安全性。我们建议进行一项为期8周的双盲安慰剂对照随机 在136名患有中度至重度阿尔茨海默病的疗养院居民中进行了GEn与安慰剂的初步试验， 夜间激越和RLS，随后进行为期8周的抗精神病药物使用试验后评价。的 具体的目的是：1）确定GEn与安慰剂相比对夜间激越的影响（主要是 终点）; 2）描述GEn与安慰剂相比在该人群中的安全性特征; 3）估计效应 GEn与安慰剂相比在夜间睡眠、RLS行为和抗精神病药物方面的大小; 4）探索 RLS行为频率是否介导GEn对夜间激越行为的影响。结果 这项研究和未来的确定性试验可能会改变和改善夜间睡眠的治疗标准。 激动;减少私奔，侵略和其他夜间激动行为;改善睡眠。

Project Summary/Abstract. Nighttime agitation, defined as the appearance or exacerbation of behavioral disturbances, such as wandering and aggression, in the afternoon and/or evening, is a prevalent symptom in persons with Alzheimer’s disease that reduces their quality of life and restricts their environments. Effective treatments are lacking. One major cause for past failure of treatments has been the approach of treating all nighttime agitation alike. Unlike interventions in the past, our precision medicine approach tailors the intervention to a specific sleep disorder, restless legs syndrome (RLS). RLS occurs in 10-14% of older adults and it is likely that persons with Alzheimer’s disease have RLS, since it is quite common, but it is infrequently identified because diagnosis is dependent on patients answering complex questions about their symptoms. RLS causes an urge to move associated with uncomfortable and unpleasant leg sensations. The urge to move and leg discomfort only occur or worsen at night, and relief is by movement. We hypothesized that RLS might be an etiology for nighttime agitation because: 1) circadian patterns of nighttime agitation and RLS symptoms are almost identical; 2) unrelieved RLS discomfort may precipitate behaviors such as screaming and requests for help, and the urge to move may cause wandering, pacing, and restlessness; and 3) factors common in institutionalized persons with Alzheimer’s disease, such as anemia, prolonged bed rest, and antidepressants, trigger or worsen RLS. Our preliminary work supports our hypothesis, and provides beginning evidence that RLS may be an unidentified etiology for nighttime agitation. In 59 persons with dementia and nighttime agitation, and RLS diagnosed using objective measures, we found that almost ¼ had RLS and that RLS was associated with nighttime agitation (r = 0.31, p .01). We now propose a pilot clinical trial to determine if RLS treatment reduces nighttime agitation, improves sleep, reduces antipsychotic medications, and the mechanism for these effects. We have chosen gabapentin enacarbil (GEn) as the treatment because it is FDA approved for RLS and has a favorable safety profile. We propose an 8-week, double-blind placebo-controlled randomized pilot trial of GEn versus placebo in 136 nursing home residents with moderate to severe Alzheimer’s disease, nighttime agitation, and RLS, followed by an 8-week post-trial evaluation of antipsychotic medication use. The specific aims are to: 1) Determine the effect of GEn, compared to placebo on nighttime agitation (primary endpoint); 2) Describe the safety profile of GEn compared to placebo in this population; 3) Estimate the effect size of GEn compared to placebo on nighttime sleep, RLS behaviors, and antipsychotic medications; 4) Explore whether frequency of RLS behaviors mediates the effect of GEn on nighttime agitation behaviors. The results of this study and future definitive trials may shift and improve standards of care for treatment of nighttime agitation; reduce elopement, aggression, and other nighttime agitation behaviors; and improve sleep.