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

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.

摘要 睡眠障碍在高达45%的轻度认知障碍（MCI）患者中普遍存在， 阿尔茨海默病（AD）。基于越来越多的人认识到阿尔茨海默病的前驱期 (MCI由于AD）是旨在改变神经生物学和睡眠的干预措施的最佳时间， 在这一阶段通常会观察到干扰，因此睡眠干预越来越有吸引力。 治疗靶点快速眼动（REM）睡眠百分比降低是AD所致MCI的特征 患者，即使在疾病过程的早期阶段，这可能是由于胆碱能神经受损， 过渡到快速眼动睡眠所需的神经支配。胆碱能系统参与了AD的病理过程 和睡眠-觉醒调节，因此针对胆碱能功能的干预有可能改善 AD相关的睡眠中断。PI最近完成的NIH R 00研究发现， 胆碱水平和炎症增加与非AD个体的睡眠中断有关。初步 PI和其他人的工作表明，在MCI和AD患者中也观察到较低的胆碱水平。作为 睡眠障碍和认知障碍之间存在已知的双向关系，我们的团队已经 以前提出神经炎症作为一个潜在的调解人。胞磷胆碱是乙酰胆碱的内源性前体 和磷脂。虽然在最近的一项随机临床试验中发现胞磷胆碱可以改善记忆， 迄今为止，没有研究检查胞磷胆碱是否改善REM睡眠%，炎症或AD生物标志物， 因AD而患有MCI的个人。我们假设补充胞二磷胆碱会改善 % REM睡眠、炎症和AD生物标志物。我们将进行为期3个月的随机、双盲、 在100例（每组50例）MCI患者中比较胞磷胆碱与安慰剂的安慰剂对照临床试验 由于AD。第一个目的是确定胞磷胆碱组是否显示出快速眼动睡眠百分比的改善， 从基线到随访，与安慰剂组相比血浆胆碱。第二个目标是确定 胞二磷胆碱是否能减少炎症（白细胞介素-6（IL-6）和肿瘤坏死因子-α（TNF-α））， α））和AD生物标志物（CSF Aβ42/Aβ40、总tau和p-tau 181）水平与安慰剂组相比， 基线跟踪。我们将通过利用现有的阿尔茨海默氏症患者队列来验证这些假设。 疾病研究队列（ADRC）的100个人与MCI由于AD。基线和随访评估 在3个月时，将包括睡眠问卷调查，2个晚上的睡眠分析仪PSG 2家庭睡眠设备，和7个 晚上做腕关节活动记录我们团队的研究人员在生物标志物、睡眠和 老年痴呆症这个试点项目的积极成果将表明，胞磷胆碱改善睡眠， 炎症和AD生物标志物，这将使更大规模的研究能够证实 这些发现并改善老年人的健康和福祉。