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）可以是正常衰老和阿尔茨海默氏病之间的过渡阶段 （广告）。阻塞性睡眠呼吸暂停（OSA），在这种情况下 导致夜间缺氧和认知功能障碍的睡眠存在于58.7％的MCI患者中，但它是 很少被诊断或治疗。可以通过连续的正气道有效地管理OSA （CPAP），在睡眠期间戴着加压的鼻膜，但在此方面几乎没有信息 人口，从而限制采用。因此，该提案的主要目标是评估是否治疗 CPAP的Amnescic MCI（AMCI）中的OSA延迟认知能力下降，并保留每天的功能。 研究调查人员已成功完成了NIA Alzheimer疾病试验R01临床试验 （“记忆”）使用准实验设计，该设计提供了有价值的初步和可行性数据（一个 - 年随访，两个地点，n = 68）。它由三个AMCI组组成：1）CPAP粘附干预组；和 两个对照组2A）CPAP非粘附器和2B）无OSA。他们证明了1） CPAP降低了认知障碍。 2）在海马和 中位临时叶子区域中位数，其中一些改进了CPAP粘附患者。而诊所 引人注目的是，由于研究样本量，这些发现在统计学上没有统计学意义（p = 0.125及更高）。 当前提案的具体目的是在较大的四个站点研究中确认和扩展这些发现 （n = 460）使用该方法研究团队以前成功实施的方法。 AIM 1将评估 在一年内存/处理速度（数字符号编码测试）下下降的假设被减弱 CPAP依从剂（n = 200）与CPAP非粘附器（n = 160）AMCI。 AIM 2将评估大脑MRIS以测试 以下假设：1）初步研究基线时注意到的右海马肥大是 OSA的标志 - 该研究将将OSA+（n = 360）中的大脑MRI与OSA-（n = 100）参与者进行比较；和2） 一年的随访，CPAP依从者参与者将减少萎缩，部分正常化 与CPAP非遵守参与者相比，基线时右海马区域肥大指出。 AIM 3将是一种探索性脑脊液（CSF）子研究，以评估AB42，Total Tau，磷酸化 TAU以及途径生物标志物F2-异丙烷（氧化应激），低氧诱导因子1a（与OSA相关） 间歇性缺氧）和血管内皮生长因子（神经保护剂）。 CPAP依从性可以是 精确地使用确定使用时间和可靠性评分分析的传感器来测量 有效控制与组分配和结果有关的混杂变量。 这项大规模研究的发现，为基于临床显着性和统计显着性提供了足够的功能 在成功的先前试验结果中，有可能改变数百万MCI患者的护理 减轻渐进认知能力下降的毁灭性后果。