Improving Sleep and AD Biomarkers: A Pilot RCT of Citicoline

改善睡眠和 AD 生物标志物：胞二磷胆碱的试点随机对照试验

• 批准号: 10585583
• 负责人: Victoria M Pak
• 金额: $ 44.06万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10585583
• 关键词: Acetylcholine; Age; Age-associated memory impairment; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-42; Animal Model; Beds; Biological; Biological Markers; Caregivers; Cerebral cortex; Characteristics; Choline; Cognition; Controlled Clinical Trials; Cytidine; Cytidine Diphosphate Choline; Data; Dementia; Development; Devices; Dietary Supplementation; Disease; Double-Blind Method; Drowsiness; Elderly; Episodic memory; Female; Health; Home; Impaired cognition; Impairment; Individual; Inflammation; Inflammatory; Institutionalization; Interleukin-6; Intervention; Measures; Mediator; Memory; National Institute on Aging; Neurobiology; Neurotransmitters; Outcome; Participant; Patient Recruitments; Patients; Performance; Personal Satisfaction; Persons; Phospholipids; Pilot Projects; Placebo Control; Placebos; Plasma; Play; Population; Process; Production; Proteins; Quality of life; Questionnaires; REM Sleep; Randomized; Regulation; Reporting; Research; Research Personnel; Role; Sampling; Sirtuins; Sleep; Sleep disturbances; Supplementation; System; TNF gene; Testing; Threonine; Time; United States National Institutes of Health; Woman; Work; Wrist; actigraphy; basal forebrain; cholinergic; cholinergic neuron; cognitive function; cohort; dietary; double-blind placebo controlled trial; effective therapy; experience; fluorodeoxyglucose positron emission tomography; follow up assessment; follow-up; high risk; hippocampal atrophy; improved; improvement on sleep; inclusion criteria; interest; male; men; mild cognitive impairment; nerve supply; neuroinflammation; neurotransmission; oral supplementation; placebo group; poor sleep; prodromal Alzheimer' s disease; randomized, clinical trials; secondary outcome; sleep quality; tau Proteins; tau-1; therapeutic target; trial comparing; Acetylcholine; Age; Age-associated memory impairment; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-42; Animal Model; Beds; Biological; Biological Markers; Caregivers; Cerebral cortex; Characteristics; Choline; Cognition; Controlled Clinical Trials; Cytidine; Cytidine Diphosphate Choline; Data; Dementia; Development; Devices; Dietary Supplementation; Disease; Double-Blind Method; Drowsiness; Elderly; Episodic memory; Female; Health; Home; Impaired cognition; Impairment; Individual; Inflammation; Inflammatory; Institutionalization; Interleukin-6; Intervention; Measures; Mediator; Memory; National Institute on Aging; Neurobiology; Neurotransmitters; Outcome; Participant; Patient Recruitments; Patients; Performance; Personal Satisfaction; Persons; Phospholipids; Pilot Projects; Placebo Control; Placebos; Plasma; Play; Population; Process; Production; Proteins; Quality of life; Questionnaires; REM Sleep; Randomized; Regulation; Reporting; Research; Research Personnel; Role; Sampling; Sirtuins; Sleep; Sleep disturbances; Supplementation; System; TNF gene; Testing; Threonine; Time; United States National Institutes of Health; Woman; Work; Wrist; actigraphy; basal forebrain; cholinergic; cholinergic neuron; cognitive function; cohort; dietary; double-blind placebo controlled trial; effective therapy; experience; fluorodeoxyglucose positron emission tomography; follow up assessment; follow-up; high risk; hippocampal atrophy; improved; improvement on sleep; inclusion criteria; interest; male; men; mild cognitive impairment; nerve supply; neuroinflammation; neurotransmission; oral supplementation; placebo group; poor sleep; prodromal Alzheimer' s disease; randomized, clinical trials; secondary outcome; sleep quality; tau Proteins; tau-1; therapeutic target; trial comparing

Abstract Sleep disturbances are prevalent in up to 45% of persons with mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Based on the growing recognition that prodromal stages of Alzheimer’s disease (MCI due to AD) are the optimal time for interventions aimed at modifying neurobiology, and sleep disturbances are commonly observed during this stage, sleep interventions are an increasingly attractive therapeutic target. Reduced percentage rapid eye movement (REM) sleep is characteristic of MCI due to AD patients, even in early stages of the disease process, which is likely due to impairment of cholinergic innervation necessary for the transition to REM sleep. The cholinergic system is involved in both AD pathology and sleep-wake regulation, and thus interventions targeting cholinergic function have the potential to improve AD-associated sleep disruption. The PI’s recently completed NIH R00 study discovered that lower plasma choline levels and increased inflammation is associated with disrupted sleep in non-AD individuals. Preliminary work from the PI and others show lower choline levels are also observed in patients with both MCI and AD. As there is a known bidirectional relationship between sleep disturbances and cognitive impairment, our team has previously proposed neuroinflammation as a potential mediator. Citicoline is an endogenous precursor of ACh and phospholipids. While Citicoline has been found to improve memory in a recent randomized clinical trial, to date, no studies have examined whether Citicoline improves REM sleep %, inflammatory, or AD biomarkers in individuals with MCI due to AD. We hypothesize that supplementation of Citicoline will result in improvement in % REM sleep, inflammation, and AD biomarkers. We will conduct a 3-month randomized, double-blind, placebo-controlled clinical trial comparing Citicoline versus placebo in 100 (50 per group) individuals with MCI due to AD. The first aim is to determine whether the Citicoline group shows improvements in % REM sleep and plasma choline compared to the placebo group from baseline to follow up. The second aim is to determine whether the Citicoline has reductions in inflammation (Interleukin-6 (IL-6) and (Tumor Necrosis Factor-α (TNF- α)), and levels of AD biomarkers (CSF Aβ42/Aβ40, total tau and p-tau 181) compared to the placebo group from baseline to follow up. We will test these hypotheses by leveraging an existing cohort from the Alzheimer’s Disease Research Cohort (ADRC) of 100 individuals with MCI due to AD. Baseline and follow-up assessments at 3 months will consist of sleep questionnaires, 2 nights of the Sleep Profiler PSG2 home sleep device, and 7 nights of wrist actigraphy. Investigators on our team have extensive experience in biomarkers, sleep, and Alzheimer’s disease. Positive outcomes from this pilot project will show that Citicoline improves sleep, inflammation, and AD biomarkers in persons with MCI due to AD, which will enable larger studies to confirm these findings and improve the health and well-being of older adults.

抽象的 在高度认知障碍（MCI）和 阿尔茨海默氏病（AD）。基于人们日益认识到阿尔茨海默氏病前阶段的认识 （由于AD的MCI）是旨在修改神经生物学和睡眠的干预措施的最佳时间 在此阶段通常观察到干扰，睡眠干预措施越来越吸引人 治疗靶标。降低了快速眼动（REM）睡眠的百分比是MCI的特征 患者，即使在疾病过程的早期阶段，这也可能是由于胆碱能的损害 过渡到REM睡觉所需的神经。胆碱能系统参与了两种AD病理学 和睡眠效果调节，因此针对胆碱能功能的干预措施有可能改善 与广告相关的睡眠中断。 PI最近完成的NIH R00研究发现较低的血浆 胆碱水平和感染增加与非AD个体的睡眠破坏有关。初步的 PI和其他人的工作显示在MCI和AD患者中也观察到较低的胆碱水平。作为 睡眠障碍与认知障碍之间存在已知的双向关系，我们的团队有 先前提出的神经炎症为潜在的介体。 citicoline是ACH的内源前体 和磷脂。虽然在最近的一项随机临床试验中发现citicoline可以改善记忆力，但 日期，尚无研究检查citicoline是否改善了REM睡眠％，炎症或AD生物标志物是 由于AD而患有MCI的人。我们假设补充citicoline将改善 REM睡眠，注射和AD生物标志物％。我们将进行3个月的随机，双盲， 安慰剂对照的临床试验比较了citicoline与安慰剂的100（每组50） 由于广告。第一个目的是确定citicoline组是否显示出REM睡眠％的改善和 血浆胆碱与从基线到跟进的安慰剂组相比。第二个目的是确定 citicoline是否减少炎症（白介素6（IL-6）和（肿瘤坏死因子-α）（TNF- α））和AD生物标志物的水平（CSFAβ42/Aβ40，Total Tau和P-Tau 181）与安慰剂组相比 跟进的基线。我们将通过利用阿尔茨海默氏症现有队列来检验这些假设 疾病研究队列（ADRC）由100名MCI患者引起的AD。基线和随访评估 在3个月时，将包括睡眠问卷，2晚睡眠PSG2家庭睡眠设备和7个 手腕行为的夜晚。我们团队的调查人员在生物标志物，睡眠和 阿尔茨海默氏病。该试点项目的积极结果将表明citicoline可以改善睡眠， 由于AD而患有MCI的人的炎症和AD生物标志物，这将使大型研究能够确认 这些发现并改善了老年人的健康和福祉。