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

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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