The Association of Blood-Brain Barrier Breakdown with Sleep Apnea and Postoperative Delirium

摘要 老年患者在麻醉/手术后会出现血脑屏障(BBB)的破坏，并可能 增加术后精神错乱的风险。血脑屏障受损可能在术后精神错乱中起作用 因为1)麻醉/手术与血脑屏障破裂有关，而2)血脑屏障破裂是 与神经炎有关，后者与精神错乱和阿尔茨海默病(AD)有关。 血脑屏障通常会限制大分子扩散到中枢神经系统，但它可以 通过测量脑脊液中的大分子，如白蛋白进行评估。BBB故障 结果脑脊液/血清白蛋白比值升高。增加的QAlb与 神经炎症，增加阿尔茨海默病的风险，并加速认知能力下降。虽然BBB 精神崩溃被理论认为与术后精神错乱有关，目前还没有研究确定是否 术后神志不清与血脑屏障受损(即血清白蛋白升高)有关。 BBB崩溃的一个潜在的可改变的危险因素是阻塞性睡眠呼吸暂停(OSA)， 以睡眠中呼吸反复中断为特征的，与术后有关 精神错乱，轻度认知障碍，以及加速的AD病理。由于OSA是一种经常 未确诊的高度流行(约50%的老年人)障碍，OSA可能代表着一种普遍存在的 因此，我们还将确定阻塞性睡眠呼吸暂停综合征患者是否患有 术前血脑屏障分解增加(即QAlb)，这可能会导致OSA 患者术后出现精神错乱。 这项研究的总体目标是测量血脑屏障(Bbb)的破坏程度。 在接受非心脏手术的老年人中，并确定血脑屏障崩溃的程度 与阻塞性睡眠呼吸暂停和术后精神错乱有关。为了检验这些假设，我将前瞻性地 从我正在进行的基金会资助的研究中对200名60岁以上的非心脏手术患者进行研究：睡眠 非心脏手术后出现的呼吸暂停、神经炎症和认知功能障碍 (Sandman)，以及我导师更大的NIA K76资助的研究。这些患者已经接受了 术前OSA检测，术前、术后采血/脑脊液，以及精神错乱评估。 利用这一独特的、现有的队列和脑脊液样本进行这些拟议的研究 这是可行的，因为所有样本都将在预期的赠款期限前收集完毕。我们的发现将 帮助我们了解阻塞性睡眠呼吸暂停综合征相关神经认知功能障碍的机制，并最终告知 为1600万老年人减少术后精神错乱和帮助预防AD的治疗方法的开发 每年接受手术的美国人

ABSTRACT Blood-brain barrier (BBB) breakdown occurs in older patients after anesthesia/surgery, and could increase risk for postoperative delirium. BBB breakdown could play a role in postoperative delirium because 1) anesthesia/surgery are associated with BBB breakdown and 2) BBB breakdown is associated with neuroinflammation, which has been linked to delirium and Alzheimer’s disease (AD). The BBB, which normally restricts diffusion of large molecules into the central nervous system, can be assessed by measuring large molecules, such as albumin, in the cerebrospinal (CSF). BBB breakdown results in an increased CSF-to-serum ratio of albumin (Qalbumin). Increased Qalbumin is associated with neuroinflammation, increased AD risk, and accelerated cognitive decline. Although BBB breakdown is theorized to play a role in postoperative delirium, no studies have yet determined whether postoperative delirium is associated with BBB breakdown (ie, increased Qalbumin). One potentially modifiable risk factor for BBB breakdown is obstructive sleep apnea (OSA), characterized by repeated interruptions in breathing during sleep, that is associated with postoperative delirium, mild cognitive impairment, and accelerated AD pathology. Since OSA is a frequently undiagnosed, highly prevalent (~50% of older adults) disorder, OSA could represent a pervasive, yet treatable, risk factor for BBB breakdown.Thus, we will also determine whether OSA patients have increased preoperative BBB breakdown (ie, Qalbumin), which could potentially predispose OSA patients to postoperative delirium. The overall aim of this study is to measure the magnitude of blood-brain barrier (BBB) breakdown in older adults undergoing non-cardiac surgery, and determine the extent that BBB breakdown is associated with OSA and postoperative delirium severity. To test these hypotheses, I will prospectively study 200 non-cardiac surgery patients over age 60 from my ongoing foundation-funded study: Sleep Apnea, Neuroinflammation, and cognitive Dysfunction Manifesting After Non-cardiac surgery (SANDMAN), and my mentor’s larger NIA K76-funded study. These patients already undergo preoperative OSA testing, pre- and postoperative blood/CSF sampling, and delirium assessment. Leveraging this unique, existing cohort and cerebrospinal fluid samples makes these proposed studies feasible as all the samples will already be collected by the anticipated grant period. Our findings will help us understand mechanisms of OSA-related neurocognitive dysfunction, and eventually inform the development of therapies to reduce postoperative delirium and to help prevent AD for >16 million older Americans who undergo surgery every year