Characterizing Blood-Brain Barrier Breakdown in Sleep Apnea and Postoperative Delirium

MICHAEL DEVINNEY, MD, PHD

AIM 1: Determine the extent to which OSA severity is associated with preoperative BBB breakdown.

HYPOTHESIS:

Higher preoperative AHI values are associated with increased preoperative Qalbumin.

AIM 2:

Determine the extent to which BBB breakdown is associated with postoperative delirium severity.

HYPOTHESIS:

Increased 24-hour postoperative Qalbumin is associated with higher delirium severity scores. Up to 40 percent of the more than 19 million older Americans who undergo surgery each year will develop postoperative delirium, a fluctuating disturbance in attention and consciousness associated with increased one-year postoperative mortality, decreased quality of life, and increased long-term risk for Alzheimer’s disease (AD) and related dementias. Despite this substantial morbidity and mortality associated with postoperative delirium, there are few if any FDA-approved drugs to prevent it, largely because we still know very little about the underlying pathophysiology of delirium.

Postoperative delirium may be caused in part by blood brain barrier (BBB) breakdown since 1) anesthesia/surgery are associated with BBB breakdown and 2) BBB breakdown has been associated with neuroinflammation,which has been linked to delirium after hip fracture and may underlie postoperative delirium. The BBB normally restricts diffusion of peripheral toxins and inflammatory mediators into the brain and cerebrospinal fluid (CSF). Postoperative BBB breakdown could allow these peripheral mediators to enter the brain, which could disrupt the neural connectivity necessary for normal

cognitive function and thereby contribute to delirium risk. Indeed, BBB breakdown occurs more often in patients with increased AD risk and is associated with increased AD neuropathology and accelerated cognitive decline. BBB permeability can be assessed by determining the CSF-to-serum ratio of large molecules like albumin (Qalbumin) that normally cannot cross the BBB and enter the brain. No prior study has determined whether postoperative BBB breakdown (i.e., increased Qalbumin) is associated with postoperative delirium. BBB breakdown in older surgical patients (who are at risk of postoperative delirium) could also occur secondary to obstructive sleep apnea (OSA), a frequently undiagnosed disorder of repeated breathing interruptions (apneas and hypopneas) during sleep. OSA prevalence

sharply increases with age, occurring

Conceptual model of relationships in about 50 percent between obstructive sleep apnea, of older adults.OSA increased blood brain barrier breakdown can be diagnosed with (BBB), and postoperative delirium. home sleep apnea tests,

Obstructive sleep apnea could increase which determine the

BBB breakdown to predispose patients apnea-hypopnea index to postoperative delirium. Anesthesia/ (AHI), a measure of surgery also can cause BBB breakdown to OSA severity. OSA precipitate postoperative delirium. may contribute to postoperative delirium via BBB breakdown because 1) animal and in vitro models of OSA show BBB breakdown, and 2) patients with OSA have increased systemic inflammation, which can disrupt the capillary endothelial tight junctions necessary to maintain BBB integrity. Further, older OSA patients exhibit increased brain

Devinney MJ, VanDusen KW, Kfouri JM, Avasarala P, Spector AR, Mathew JP, Berger M. The potential link between obstructive sleep apnea and postoperative neurocognitive disorders: current knowledge and possible mechanisms. Can J Anaesth. In Press.

parenchymal water, which could be caused by BBB breakdown. OSA has also been associated with increased risk of mild cognitive impairment, dementia due to AD and accelerated AD neuropathologic progression. These findings suggest that OSA-related BBB breakdown before and/or after surgery could play a role in causing delirium. However, no prior studies have determined whether patients with OSA actually have BBB breakdown (i.e., increased Qalbumin).

To test whether OSA patients exhibit BBB breakdown, and whether BBB breakdown is associated with postoperative delirium severity, Dr. Michael Devinney will measure Qalbumin in 201 non-cardiac surgery patients age ≥60 that completed an NIAfunded study, “Investigating NeuroinflammaTion Underlying postoperative brain connectIviTy changes (INTUIT).” These patients have already undergone pre- and postoperative blood/CSF sampling, cognitive testing and delirium severity assessments. Additionally, 101 patients completed home sleep apnea testing in Devinney’s FAER-funded sub-study, “Sleep Apnea, Neuroinflammation, & cognitive Dysfunction Manifesting After Non-cardiac surgery (SANDMAN),” which aims to determine the extent that OSA is associated with neuroinflammation and postoperative cognitive dysfunction.

The completion of these studies will advance the understanding of the role of BBB breakdown (as measured by Qalbumin) in postoperative delirium. Further, Devinney will determine the extent that BBB breakdown occurs in OSA patients, which has implications for OSA-related cognitive dysfunction such as mild cognitive impairment and Alzheimer’s disease outside of surgery, and perioperatively for delirium and postoperative cognitive dysfunction. These findings could clarify overall mechanisms of OSA-related neurocognitive dysfunction and could help lead to the development of therapies to promote BBB integrity and prevent cognitive dysfunction and delirium in patients with OSA. BP

Potential mechanisms underlying perioperative neurocognitive disorders in sleep apnea patients.

FUNDING AWARDED: $372,000, 2-YEAR COMBINED GRANT

Funding Sources:National Institute of Aging, Foundation for Anesthesia Education and Research