Development of a Dynamic Multi-Protein Signature of Postoperative Delirium.

Background: Delirium is common, morbid, and costly, yet its biology is poorly understood. We aimed to develop a multi-protein signature of delirium by identifying proteins associated with delirium from unbiased proteomics and combining them with delirium biomarkers identified in our prior work (interleukin [IL]-6 and IL-2).

Methods: We used the Successful Aging after Elective Surgery (SAGES) Study of adults age ≥70 undergoing major non-cardiac surgery (N=560; 24% delirium). Plasma was collected preoperatively (PREOP) and on postoperative day 2 (POD2). In a nested matched case-control study involving 12 pairs of delirium cases and no-delirium controls, isobaric tags for relative and absolute quantitation-based (iTRAQ) mass spectrometry proteomics was applied to identify the top set of delirium-related proteins. With these proteins, we then conducted enzyme-linked immunosorbent assay (ELISA) confirmation, and if confirmed, ELISA validation in 75 matched pairs. Multi-marker conditional logistic regression was used to select the 'best' PREOP and POD2 models for delirium.

Results: We identified three proteins from iTRAQ: C-reactive protein (CRP), zinc alpha-2 glycoprotein (AZGP1) and alpha-1 antichymotrypsin (SERPINA3). The 'best' multi-protein models of delirium included: PREOP: CRP and AZGP1 (Bayesian Information Criteria [BIC] 93.82, c-statistic 0.77); and POD2: IL-6, IL-2, and CRP (BIC 87.11, c-statistic 0.84).

Conclusion: The signature of postoperative delirium is dynamic, with some proteins important prior to surgery (risk markers) and others at the time of delirium (disease markers). Our dynamic, multi-protein signature for delirium improves our understanding of delirium pathophysiology and may identify patients at-risk of this devastating disorder that threatens independence of older adults.