RCT Targeting Cognition in Early Alzheimer's Disease by Improving Sleep with Trazodone (Rest)

通过曲唑酮（休息）改善睡眠来针对早期阿尔茨海默病认知的随机对照试验

基本信息

批准号：
10180391
负责人：
Barry David Greenberg
金额：
$ 78.56万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-15 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10180391
关键词：
Acute Affect Alleles Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer’s disease biomarker Amyloid Amyloid deposition Animal Model Animals Antidepressive Agents Attention Benign Biological Markers Brain Cerebrospinal Fluid Cognition Cognitive Cross-Over Trials Data Dementia Development Disease Disease Progression Double-Blind Method Drug Targeting Elderly FDA approved Family Caregiver Functional Magnetic Resonance Imaging Health Care Costs Hippocampus (Brain)Home Human Impaired cognition Impairment Individual Insecta Intercellular Fluid Link Measures Mediating Memory Modification Morbidity - disease rate Observational Study Outcome Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Patient Self-Report Pattern Performance Persons Pharmaceutical Preparations Phase Placebos Polysomnography Process Public Health Quality of life Randomized Research Personnel Rest Risk Rodent Safety Sleep Sleep Deprivation Sleep Fragmentations Sleep disturbances Slow-Wave Sleep Study models Surrogate Markers Testing Therapeutic Time Trazodone Wakefulness actigraphy amnestic mild cognitive impairment apolipoprotein E-4 base blood-based biomarker cognitive performance cognitive task cost disability effective therapy executive function follow-up glymphatic system hemodynamics improved informant interstitial magnetic resonance imaging biomarker mild cognitive impairment neuropsychiatric symptom off-label use phase III trial poor sleep prevent primary outcome processing speed prodromal Alzheimer&apos s disease relating to nervous system response secondary outcome side effect sleep onset symptom treatment tau Proteins tau-1 therapy development trial comparing vigilance

项目摘要

PROJECT SUMMARY It is estimated that 5.8 million people are afflicted by dementia in the US, a number projected to increase to 14 million by 2050 unless effective therapies are available that prevent or significantly slow the disease process. Sleep complaints are common throughout the AD continuum beginning with prodromal stages. In observational studies, disturbed sleep has been linked to AD pathogenesis and subsequent development of mild cognitive impairment (MCI) and dementia. Co-investigator Dr. Bakker has studied pattern separation (PS; a memory task involved with the earliest stages of encoding that is essential to formation of new memories) in a task related functional MRI (fMRI) paradigm, determining that impaired PS is associated with increased hippocampal activation in amnestic MCI (aMCI). Because poor sleep may be associated with increased hippocampal activation, improving sleep is a potential target for positively affecting cognition and disease progression in AD. Trazodone is a generic antidepressant widely used off-label to treat sleep disturbance, particularly enhancing slow wave sleep (SWS) that is evidenced to be a critical sleep phase influencing pathogenic mechanisms. While it has been demonstrated to improve sleep in AD and potentially mitigate the risk of developing MCI, its effect on sleep has not been rigorously studied in MCI. Supported by its benign safety profile, we propose a rigorous double-blind, placebo-controlled, randomized crossover trial of trazodone in 100 subjects with prodromal AD/aMCI and sleep complaints. Each treatment phase will last four weeks with a two-week washout between phases. Sleep will be measured by home sleep testing including polysomnography, actigraphy, and self-report. Hippocampal function and excitability will be assessed by task-related fMRI employing PS. The primary outcome will be to examine the association of trazodone with sleep parameters. We hypothesize that trazodone will improve total sleep time and proportion of time in SWS. Secondary outcomes include assessment of trazodone's effect on 1) PS and hippocampal activation by task-related fMRI, with the hypothesis that trazodone will improve PS performance and decrease hippocampal activation; 2) a broader range of cognitive domains, with the hypothesis that trazodone will improve performance on other memory tasks, executive function, and processing speed; 3) neuropsychiatric symptoms with the hypothesis that they will improve with trazodone treatment. We will also assess blood- based biomarkers of amyloid and tau, as exploratory outcomes to assess their association with sleep and cognitive responses to trazodone.

项目概要据估计，美国有 580 万人患有痴呆症，这一数字预计将增加到 14 人除非有有效的疗法来预防或显着减缓疾病进程，否则到 2050 年将有 100 万人死亡。从前驱阶段开始，睡眠问题在 AD 连续过程中很常见。在观察性研究表明，睡眠障碍与 AD 发病机制和后续发展有关轻度认知障碍（MCI）和痴呆。共同研究员 Bakker 博士研究了模式分离（PS；涉及编码的最早阶段的记忆任务，对于新记忆的形成至关重要）任务相关功能 MRI (fMRI) 范式，确定 PS 受损与 PS 增加相关遗忘性 MCI (aMCI) 中的海马激活。因为睡眠不佳可能与增加海马体激活、改善睡眠是积极影响认知和疾病的潜在目标 AD 的进展。曲唑酮是一种通用抗抑郁药，广泛用于标签外治疗睡眠障碍，特别是增强慢波睡眠（SWS），这被证明是影响睡眠的关键阶段致病机制。虽然它已被证明可以改善 AD 患者的睡眠并有可能减轻 AD 患者的睡眠障碍尽管存在发生 MCI 的风险，但其对睡眠的影响尚未在 MCI 中得到严格研究。其良性的支持为了安全性，我们提出了一项严格的双盲、安慰剂对照、随机交叉试验曲唑酮治疗 100 名患有前驱 AD/aMCI 和睡眠问题的受试者。每个治疗阶段将持续四个星期，各阶段之间有两周的冲洗期。睡眠将通过家庭睡眠测试来测量包括多导睡眠图、体动记录仪和自我报告。海马功能和兴奋性将通过使用 PS 的任务相关功能磁共振成像进行评估。主要结果将是检查以下关联：曲唑酮与睡眠参数。我们假设曲唑酮会改善总睡眠时间和比例在 SWS 的时间。次要结局包括评估曲唑酮对 1) PS 和海马的影响通过任务相关的功能磁共振成像激活，假设曲唑酮会提高 PS 表现并降低海马激活； 2）更广泛的认知领域，假设曲唑酮将提高其他记忆任务、执行功能和处理速度的性能； 3）神经精神科假设曲唑酮治疗会改善症状。我们还将评估血液- 基于淀粉样蛋白和 tau 的生物标志物，作为评估其与睡眠和睡眠的关系的探索性结果对曲唑酮的认知反应。