Program Director/Principal Investigator (Last, First, Middle): Crosby, Gregory J Abstract Delirium, an acute confusional state, is one of the most common postoperative complications in older surgical patients and is associated with suboptimal recovery and high mortality. Yet, its cause is uncertain, therapeutic options are limited, and there are no reliable biomarkers. We hypothesize that circulating extracellular vesicles (EVs) and their cargo can identify patients at risk for or who experience postoperative delirium and carry new biomarkers for the syndrome. EVs are small (30-500 nm) bilipid particles that are shed or secreted by most cells, including those of the immune and central nervous systems, are present in blood, have surface markers of the parent cell, and carry a cargo of RNA and proteins. EVs are involved in numerous physiological and pathological processes and increasingly are being researched as biomarkers of many age-related conditions and diseases. No research, however, has investigated the relationship between delirium and circulating EVs. We will test our hypothesis that postoperative delirium is associated with changes in the concentration, size, and cargo of blood-borne EVs using biobanked plasma samples from a well-characterized cohort of older, elective spine surgery patients, and then confirm the results in a prospective replication cohort.
In Aim 1, we will sort and profile EVs in plasma using serial centrifugation, affinity columns, Nanoparticle Tracking and Nano FACS and compare EV abundance and size in preoperative and postoperative samples from patients that did or did not develop delirium postoperatively, and do the same using just the EV population derived from neurons or glia as determined by immunoaffinity methods.
In Aim 2, we will investigate the RNA and protein cargo of the total EV population and CNS-derived fraction in plasma using multiplexed RNA panels and targeted ELISAs and Western blots, focusing on pathways implicated in delirium such as inflammation, endothelial cell / blood brain barrier function, stress, and neurodegeneration. The outcome of this research will be original information about the relationship between circulating extracellular vesicles and postoperative delirium, new insights into the role of EVs and their contents in the pathogenesis of this common, highly morbid syndrome, and insight into the potential of an EV-based ?liquid biopsy? to discover novel biomarkers that could improve the care of older surgical patients at high risk for delirium. OMB No. 0925-0001/0002 (Rev. 03/16 Approved Through 10/31/2018) Page Continuation Format Page
Crosby, Gregory J Narrative Older surgical patients are at high risk for delirium after surgery but its pathobiology is unclear and biomarkers are not available. This proposal will investigate whether circulating extracellular vesicles, small RNA and protein containing particles shed by most cells, can be a biomarker for postoperative delirium and provide insight into its pathogenesis. Such a fluid biopsy may improve outcomes for older surgical patients. OMB No. 0925-0001/0002 (Rev. 03/16 Approved Through 10/31/2018) Page Continuation Format Page