Proteomic Signatures of Delirium and Longterm Cognitive Decline in Older Cardiac Surgical Patients - Project Summary Postoperative delirium following cardiac surgery is characterized by sudden onset confusion and inattention. It incurs substantial costs and can lead to long-term cognitive decline, including Alzheimer’s disease and Related Dementias (AD/ADRD). Enhancing our ability to identify at-risk patients before surgery and implementing targeted interventions based on underling pathophysiology is important. In our DexAcet trial, which demonstrated the effectiveness of intravenous acetaminophen in reducing postoperative delirium after cardiac surgery (JAMA 2019), we conducted a systematic analysis of plasma samples collected at baseline and on postoperative day 2. Utilizing the SomaScan platform v 3.2 to analyze 1305 proteins, we developed a multivariable risk model for predicting preoperative delirium, identifying three novel proteins (TIMP1, ANGPT2, and CCL5), and highlighting older age and female gender as additional risk factors. These proteins indicate disruptions in immune function, inflammatory response, and neovascularization regulation. Furthermore, insights from proteomics research in the Sages I & II cohorts suggest, a systemic pre-inflammatory state predisposes to a hyperactive inflammatory response to major surgery, resulting in delirium in those with vulnerable brains. The DexAcet trail led to a successful NIA funded PANDORA trial to examine the impact of scheduled 6-hourly intravenous acetaminophen over 48 hours in 900 cardiac surgical patients (760 recruited, May 2024 from 12 centers). Leveraging on the banked plasma specimens from this ongoing trial, we will use a state-of-the-art SomaScan v5.0 proteomics platform that measures 11,000 proteins to derive (N=300, placebo group) and validate (N=remaining 150 placebo group patients) a delirium protein signature for cardiac surgery (Aim 1a). The SomaScan-derived top 10 proteins will be independently validated with standard antibody-based methods (Ella) in all 450 placebo group patients (Aim1c). This model will then be probed with the acetaminophen group (N=450, Aim1b). We will combine proteins from the AD/ADRD and aging proteomic signatures, along with additional proteins from the 11,000 protein SomaScan v5.0 covering many biological pathways, for a deep etiopathological characterization of the plasma proteome for delirium and 12-month cognitive decline in the Pandora cohort (Aim 2). Furthermore, leveraging data from the NIA-funded Sages I (N=560) & II (N=420) cohorts, we will independently validate the risk model developed in Aim 1 (Aim 3a) and explore similarities and differences in delirium mechanisms between cardiac and non-cardiac surgeries (Aim 3b). This comprehensive approach aims to provide new insights into the molecular mechanisms underlying delirium risk, pathogenesis, and its association with 12-month cognitive decline. Ultimately, the project seeks to develop accurate blood-based biomarkers for preoperative delirium risk prediction, prognostication of cognitive decline following delirium, and lay the groundwork for targeted interventions to improve outcomes in older adults at risk of delirium following cardiac surgery.
