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 轻度认知功能障碍（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）是一种在睡眠过程中反复出现上呼吸道阻塞的疾病， 睡眠导致夜间缺氧和认知功能障碍，存在于58.7%的MCI患者中，然而， 很少被诊断或治疗。持续气道正压通气可有效治疗阻塞性睡眠呼吸暂停 （CPAP），一种在睡眠期间佩戴的加压鼻罩，但关于其在这方面的功效的信息很少。 人口，从而限制了收养。因此，该提案的主要目标是评估治疗是否 CPAP治疗遗忘型MCI（aMCI）患者的OSA可延缓认知功能下降并维持日常功能。 研究人员成功完成了NIA阿尔茨海默病先导R 01临床试验 （“记忆”）使用准实验设计，提供了宝贵的初步和可行性数据（一个- 2年随访，2个研究中心，n=68）。分为3组：1）CPAP依从性干预组; 两个对照组2a）CPAP非粘附性和2b）无OSA。结果表明：（1） CPAP可降低认知功能障碍; 2）在海马和海马区观察到基线MRI差异， 内侧颞叶亚区，其中几个在CPAP依从性患者中得到改善。虽然临床上 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不显著（p=0.125或更高）。 目前建议的具体目标是在一个更大的四个地点的研究中确认和扩大这些发现 （n=460）使用研究小组以前成功实施的方法。目标1将评估 假设一年记忆/处理速度（数字符号编码测试）的下降在 CPAP依从性（n=200）vs CPAP非依从性（n=160）aMCI。目标2将评估脑部MRI， 以下假设：1）在初步研究中，基线时观察到的右侧海马肥大是一种 OSA的标志-该研究将比较OSA+（n=360）与OSA-（n=100）参与者的脑MRI;以及2）在 一年的随访，CPAP依从参与者的萎缩减少，部分恢复正常。 与CPAP非依从参与者相比，在基线时观察到右侧海马区肥大。 目的3将是一项探索性脑脊液（CSF）子研究，以评价AB 42、总tau蛋白、磷酸化 tau，以及途径生物标志物F2-异前列烷（氧化应激），缺氧诱导因子-1a（OSA相关 间歇性缺氧）和血管内皮生长因子（神经保护性）。持续气道正压通气依从性可以是 使用传感器精确测量，确定使用小时数，并使用倾向评分分析， 有效控制与分组和结局相关的混杂变量。 这项大规模研究的结果具有足够的临床和统计学显著性， 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， 来减轻认知能力逐渐下降的破坏性后果。