Changing the Trajectory of Mild Cognitive Impairment with CPAP Treatment of Obstructive Sleep Apnea

通过 CPAP 治疗阻塞性睡眠呼吸暂停改变轻度认知障碍的轨迹

• 批准号: 9308618
• 负责人: Nalaka S Gooneratne
• 金额: $ 251.47万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9308618
• 关键词: Accelerometer; Adherence; Adoption; Alzheimer' s Disease; Amyloid; Apnea; Area; Atrophic; Attenuated; Authorization documentation; Biological Markers; Brain; Breathing; Caring; Cells; Cerebrospinal Fluid; Cerebrovascular Circulation; Cerebrovascular Disorders; Clinical; Clinical Trials; Clinical dementia rating scale; Code; Cognitive; Confounding Factors (Epidemiology); Continuous Positive Airway Pressure; Control Groups; Data; Diagnosis; Diagnostic; Diagnostic radiologic examination; Digit structure; Direct Costs; Elderly; Evaluation; Experimental Designs; F2-Isoprostanes; Follow-Up Studies; Goals; Grant; Health Personnel; Health system; Hippocampus (Brain); Hour; Hypertrophy; Hypoxia; Hypoxia Inducible Factor; Impaired cognition; Inflammation; Link; MRI Scans; Magnetic Resonance Imaging; Masks; Measurable; Measures; Medial; Medical; Memory; Nose; Obstructive Sleep Apnea; Outcome; Oxidative Stress; Participant; Pathology; Pathway interactions; Patients; Physiological; Pilot Projects; Population; Positron-Emission Tomography; Prevalence; Recurrence; Research; Research Personnel; Risk; Risk Factors; Sample Size; Sampling Studies; Seminal; Severities; Site; Sleep; Sleep Apnea Syndromes; Study models; Temporal Lobe; Testing; Up-Regulation; Vascular Endothelial Growth Factors; Work; airway obstruction; amnestic mild cognitive impairment; base; cognitive function; cognitive testing; cohort; design; experience; face mask; follow-up; group intervention; improved; innovation; ischemic lesion; memory process; mild cognitive impairment; neuroimaging; neuroimaging marker; normal aging; patient subsets; permissiveness; pilot trial; pressure; primary outcome; processing speed; prospective; research study; sensor; tau Proteins; tau aggregation; tau-1

Project Summary Mild cognitive impairment (MCI) can be a transitional stage between normal aging and Alzheimer's Disease (AD). Obstructive sleep apnea (OSA), a condition in which there is recurrent upper airway obstruction during sleep leading to nocturnal hypoxia and cognitive dysfunction, is present in 58.7% of MCI patients, yet it is rarely diagnosed or treated. OSA can be effectively managed with continuous positive airway pressure (CPAP), a pressurized nasal mask worn during sleep, but there is little information on its efficacy in this population, thus limiting adoption. The primary goal of this proposal is therefore to evaluate whether treatment of OSA in amnestic MCI (aMCI) with CPAP delays cognitive decline and preserves everyday function. The study investigators have successfully completed an NIA Alzheimer's Disease Pilot R01 Clinical Trial (“Memories”) using a quasi-experimental design that provided valuable preliminary and feasibility data (one- year follow-up, two sites, n=68). It consisted of three aMCI groups: 1) CPAP adherent intervention group; and two control groups 2a) CPAP non-adherent and 2b) No OSA. They demonstrated that 1) progression of cognitive impairment was reduced with CPAP; and 2) baseline MRI differences were noted in hippocampal and medial temporal lobe subregions, several of which improved in CPAP adherent patients. While clinically compelling, these findings were not statistically significant (p=0.125 and higher) due to the study sample size. The specific aims of the current proposal are to confirm and expand these findings in a larger four-site study (n=460) using the approach the study team has successfully implemented previously. Aim 1 will evaluate the hypothesis that declines in one-year memory/processing speed (Digit Symbol-Coding test) are attenuated in CPAP adherent (n=200) vs CPAP non-adherent (n=160) aMCI. Aim 2 will evaluate brain MRIs to test the following hypotheses: 1) Right hippocampal hypertrophy noted at baseline in the preliminary study is a hallmark of OSA--the study will compare brain MRIs in OSA+ (n=360) to OSA- (n=100) participants; and 2) At one-year follow-up, CPAP adherent participants will have reductions in atrophy, with partial normalization of the right hippocampal area hypertrophy noted at baseline when compared to CPAP non-adherent participants. Aim 3 will be an exploratory cerebrospinal fluid (CSF) sub-study to evaluate AB42, total tau, phosphorylated tau, as well as pathway biomarkers F2-isoprostane (oxidative stress), hypoxia-inducible factor-1a (OSA-related intermittent hypoxia), and vascular endothelial growth factor (neuroprotective). CPAP adherence can be measured precisely with a sensor that determines hours of use and propensity score analysis will be used to effectively control for confounding variables related to group allocation and outcome. The findings from this large-scale study, adequately powered for clinical and statistical significance based on successful prior trial results, have the potential to change the care of millions of MCI patients as they seek to mitigate the devastating consequences of progressive cognitive decline.

项目摘要 轻度认知障碍(MCI)可能是正常衰老和阿尔茨海默病之间的过渡阶段 (Ad)。阻塞性睡眠呼吸暂停(OSA)，一种在以下情况下反复出现上呼吸道阻塞的情况 睡眠导致夜间缺氧和认知功能障碍，在58.7%的MCI患者中存在，但它是 很少被诊断或治疗。持续气道正压可有效治疗阻塞性睡眠呼吸暂停 睡眠时佩戴的加压鼻罩(CPAP)，但关于其疗效的信息很少 人口，因此限制了收养。因此，这项建议的主要目标是评估治疗 OSA在遗忘性MCI(AMCI)合并CPAP中的作用延缓了认知功能的下降并保留了日常生活功能。 研究人员已经成功地完成了NIA阿尔茨海默病试点R01临床试验 使用准实验设计，提供了有价值的初步和可行性数据(一个-- 年随访，两个部位，n=68)。包括三组aMCI：1)CPAP依从性干预组； 两个对照组2a)CPAP非粘附组和2b)无OSA组。他们证明了1)进展 使用CPAP可减轻认知损害；2)基线MRI在海马区和 内侧颞叶亚区，其中几个在CPAP依从性患者中得到改善。虽然在临床上 令人信服的是，由于研究样本量的原因，这些发现在统计学上并不显著(p=0.125或更高)。 当前提案的具体目标是在一个更大的四个站点的研究中确认和扩展这些发现 (n=460)使用研究小组以前成功实施的方法。目标1将评估 假设在一年的记忆/处理速度(数字符号编码测试)中衰减 CPAP黏附组(n=200)与非黏附组(n=160)比较。AIM 2将评估大脑核磁共振以测试 以下假设：1)在初步研究中注意到的右侧海马区肥大是一种 OSA的特点--这项研究将比较OSA+(n=360)和OSA-(n=100)参与者的大脑磁共振成像；以及2) 一年后，CPAP依从者的萎缩程度将有所减少，部分正常化 与未坚持CPAP的参与者相比，基线时注意到右侧海马区肥大。 目的3将是一项探索性的脑脊液(CSF)亚研究，以评估AB42，总tau，磷酸化 Tau，以及途径生物标志物F2-异前列腺素(氧化应激)、低氧诱导因子-1a(与OSA相关) 间歇性低氧)和血管内皮生长因子(神经保护)。CPAP遵从性可以 使用可确定使用小时数的传感器进行精确测量，并使用倾向分数分析 有效控制与群体分配和结果相关的混杂变量。 这项大规模研究的发现充分支持了临床和统计学意义 根据成功的先前试验结果，有可能改变数百万MCI患者的护理，因为他们寻求 以减轻渐进性认知衰退的破坏性后果。