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

摘要 老年患者在麻醉/手术后发生血脑屏障（BBB）破坏， 增加术后谵妄风险。血脑屏障破坏可能在术后谵妄中起作用 因为1）麻醉/手术与BBB破坏相关，2）BBB破坏是 与神经炎症有关，神经炎症与谵妄和阿尔茨海默病（AD）有关。 通常限制大分子扩散到中枢神经系统中的BBB，可以是 通过测量脑脊液（CSF）中的大分子（如白蛋白）进行评估。BBB破坏 导致CSF与血清白蛋白比率（Qalbumin）增加。Q白蛋白增加与 神经炎症，增加AD风险，加速认知能力下降。虽然BBB 理论上，精神崩溃在术后谵妄中起作用，但还没有研究确定是否 术后谵妄与血脑屏障破坏（即，Q白蛋白增加）有关。 一个潜在的可改变的BBB破坏的风险因素是阻塞性睡眠呼吸暂停（OSA）， 特征在于睡眠期间呼吸反复中断，这与术后 谵妄、轻度认知障碍和加速AD病理。由于OSA是一个经常 未确诊的高度流行（约50%的老年人）疾病，OSA可能代表一种普遍的，但 因此，我们还将确定OSA患者是否有 术前BBB分解（即，Q白蛋白）增加，可能导致OSA 患者术后谵妄。 本研究的总体目的是测量血脑屏障（BBB）破坏的程度 在接受非心脏手术的老年人中，并确定BBB破裂的程度， 与OSA和术后谵妄严重程度相关。为了验证这些假设，我将前瞻性地 研究200名60岁以上的非心脏手术患者，来自我正在进行的基金会资助的研究：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 （桑德曼），和我的导师的更大的NIA K76资助的研究。这些患者已经经历了 术前OSA测试、术前和术后血液/CSF采样以及谵妄评估。 利用这种独特的现有队列和脑脊液样本， 由于在预计的资助期内，所有样本均已收集完毕，因此有关建议并不可行。我们的发现将 帮助我们了解OSA相关的神经认知功能障碍的机制，并最终告知 开发减少术后谵妄的治疗方法，并帮助> 1600万老年人预防AD 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