Mechanistic Insights Into Postoperative Delirium Using Untargeted High-Throughput Proteomics in Elderly Patients - A Case-Control Study

Background

Postoperative delirium (POD) in elderly patients is a common and serious complication after surgery with an unclear pathogenesis at the molecular level. Perioperative untargeted high-throughput proteomic profiling may provide insights into underlying mechanistic molecular patterns and help identify patients at high risk, guiding preventative and therapeutic measures.

Methods

This study is a monocentric substudy of the European BioCog project, a prospective multicentre observational study involving elderly patients aged ≥65 undergoing elective surgery. Patients with preexisting cognitive impairment (Mini-Mental State Examination score ≤23) were excluded. POD was assessed twice daily for up to seven days using the Nursing Delirium Screening Scale (Nu-DESC) and the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU), along with patient chart reviews. Proteomic profiling was conducted using high-throughput liquid chromatography mass spectrometry on sequential pre- and postoperative plasma samples. Data were analysed using a matched case-control design, employing both cross-sectional and longitudinal approaches, along with pathway enrichment analysis as a functional approach.

Results

A total of 226 highly abundant proteins were investigated in 168 patients (50% POD incidence). Multiple pathways, particularly those involved in the activation of the innate immune response and the complement system, were associated with POD in both cross-sectional and longitudinal analyses. Butyrylcholinesterase showed the most robust regulation, with preoperative downregulation and postoperative upregulation in patients with POD, while further downregulated in those without POD. Enzyme activity showed significant decrease in both groups. Additionally, a set of eight preoperative proteins distinguished between patients with and without POD with 86% sensitivity and 79% specificity.

Conclusion

Untargeted high-throughput proteomics is a feasible approach to characterize pathways involved in POD pathogenesis. This case-control study identified a protein signature associated with POD, emphasizing the need for larger cohorts to confirm these observations and improve the mechanistic understanding of POD.

Highlights

• The complex pathophysiology of postoperative delirium is poorly understood

• High-throughput proteomics uncovered distinct regulated features in delirium patients

• Enrichment analysis showed differential regulation of pathways in multiple domains

• Logistic regression separates delirium patients using 8 proteins with 86% sensitivity