Effects of Successful OSA TreatmENT on Memory and AD BIomarkers in Older AduLts (ESSENTIAL)

阿尔茨海默病(AD)的患病率很高，预计还会增加。此外，流行病学数据 这表明大约15%的AD风险可能归因于睡眠问题。阻塞性睡眠呼吸暂停(OSA)也是 在老年人中很常见(30%-55%)，我们之前的工作已经确定，认知正常的老年女性 患有阻塞性睡眠呼吸暂停综合症的人患轻度认知障碍(MCI)或痴呆症的5年风险几乎是前者的两倍。 此外，我们还发现：1.接受正压通气(PAP)治疗的阻塞性睡眠呼吸暂停综合征患者 夜间血浆神经丝光(NFL)升高，这是神经损伤的标志，AD- 停药后特异性生物标志物(Aβ40和Tau)；OSA预测AD纵向增加 生物标志物；在报告的阻塞性睡眠呼吸暂停患者中，PAP治疗延迟了MCI的发生。因此，有 强有力的证据表明，OSA治疗可能是AD的重要预防策略。然而， 治疗阻塞性睡眠呼吸暂停综合征以减缓认知功能衰退和进展为阿尔茨海默病的试验面临许多挑战。第一, 最有效的疗法(PAP)依从性差。第二个挑战是确定目标人群： 先前的试验针对患有MCI/AD的阻塞性睡眠呼吸暂停患者，他们有更晚期的疾病，可能更不容易服从 去接受治疗。第三个挑战是确定对睡眠干扰敏感的认知测试，并与 增加AD风险。(要捕捉OSA对脱机处理阶段的影响，需要依赖睡眠 记忆范式，在这种范式中，信息的编码和回忆被一段睡眠时间隔开 使用/不使用OSA)。最后，一项为期足够长的随机试验，以测试阻塞性睡眠呼吸暂停综合征的治疗效果 突发AD的风险是不可行的。我们建议的试验，成功的阻塞性睡眠呼吸暂停治疗对记忆和 老年人的AD生物标记物(基本)，解决了这些挑战。Essential是一项为期5年的研究 认知正常的老年人，新诊断为阻塞性睡眠呼吸暂停综合征，年龄55-75岁，从4个成熟的睡眠中招募 诊所。阻塞性睡眠呼吸暂停综合症患者(n=200)将被随机分为：i)通过下列任何组合进行为期3个月的阻塞性睡眠呼吸暂停治疗 PAP、燕麦片和体位疗法可有效改善呼吸暂停低通气指数 (Ahi)；ii)在3个月干预期结束时接受治疗的等待名单对照组。 接受有效治疗的个人(~150人)和未接受治疗的人(~100人)将接受长达24个月的跟踪调查 比较AHI的持续改善是否与更好的认知功能和AD相关 与未经治疗的对照组相比，生物标记物的变化情况。参与者将接受PSG，动作描记， 认知测试，以及基线、3个月和24个月的抽血。我们的目标是：1)比较3个月的变化 在随机接受阻塞性睡眠呼吸暂停治疗和等待名单对照组之间的血浆AD生物标志物(NFL、p-tau、Aβ) 2)比较OSA治疗组和候补对照组3个月认知功能的变化； 3)检查接受有效治疗的参与者是否在24个月内持续降低AHI与 未经治疗的对照组与AD生物标记物和认知的更好的24个月变化相关。

The prevalence of Alzheimer disease (AD) is high and projected to increase. Further, epidemiological data suggests that ~15% of AD risk may be attributed to sleep problems. Obstructive sleep apnea (OSA) is also common among the elderly (30-55%), and our prior work has established that cognitively normal older women with OSA have nearly double the 5-year risk of developing mild cognitive impairment (MCI) or dementia. Further, we showed that: i. OSA patients treated with positive airway pressure (PAP) experienced significant overnight increases in plasma neurofilament light (NfL), a marker of neural injury, with strong trends for AD- specific biomarkers (i.e. Aβ40 and Tau) after PAP withdrawal; ii. OSA predicted longitudinal increases in AD biomarkers; and, iii. PAP treatment delayed the onset of MCI in subjects with reported OSA. There is therefore strong evidence suggesting that OSA treatment could be an important prevention strategy for AD. However, trials for treatment of OSA to slow cognitive decline and progression to AD face a number of challenges. First, the most effective therapy (PAP) has poor adherence. A second challenge is defining the target population: prior trials targeted OSA patients with MCI/AD, who have more advanced disease and could be less amenable to treatment. A third challenge is identifying cognitive testing that is sensitive to sleep disruption, and linked to increased AD risk. (To capture effects of OSA on the offline processing phase requires sleep-dependent memory paradigms, in which the encoding and recall of information are separated by a period of sleep with/without OSA). Finally, a randomized trial of sufficient duration to test the effects of treatment of OSA on risk of incident AD is not feasible. Our proposed trial, Effects of Successful OSA TreatmENT on Memory and AD BIomarkers in Older AduLts (ESSENTIAL), addresses these challenges. ESSENTIAL is a 5-year study of cognitively normal older adults with newly diagnosed OSA, ages 55-75, recruited from 4 well-established sleep clinics. OSA patients (n=200) will be randomized to either: i) a 3-month OSA treatment by any combination of PAP, OAT, and positional therapy that results in an “effective” improvement in the apnea-hypopnea index (AHI); ii) a waitlist control group to receive treatment at the conclusion of the 3-month intervention period. Effectively treated individuals (~150) and untreated individuals (~100) will then be followed for up to 24 months to compare whether sustained improvements in AHI are associated with better cognitive function and AD biomarker change profiles as compared to untreated controls. Participants will undergo PSG, actigraphy, cognitive tests, and blood draws at baseline, 3 and 24 months. Our aims are: 1) To compare 3-month change in plasma AD biomarkers (NfL, p-tau, Aβ) between those randomized to OSA treatment and wait-list control groups; 2) To compare 3-month change in cognition between the OSA treatment and wait-list control groups; 3) To examine if sustained reduction in AHI over 24 months among effectively treated participants versus untreated controls is associated with better 24-month change profiles for AD biomarkers and cognition.