Effects of Non-Cardiac/Non-neurologic Surgery and Anaesthesia on the CSF Proteome, and Modulation by the APOE Mimetic Peptide CN-105

BackgroundNeuroinflammation is thought to contribute to postoperative central nervous system (CNS)-related complications, and the apolipoprotein E (APOE)-mimetic peptide CN-105 blocks neuroinflammation in animal models. Thus, here we examined postoperative cerebrospinal fluid (CSF) proteome changes and their modulation by CN-105. ObjectiveTo evaluate postoperative changes in the CSF proteome, and their modulation by the APOE mimetic peptide CN-105. MethodsWe performed mass spectrometry-based proteomics on preoperative and 24-hour postoperative CSF samples from 137 non-cardiac/non-neurologic surgery MARBLE trial patients (age>60; ct.gov identifier: NCT03802396), who were randomized to receive APOE mimetic peptide CN-105 (or placebo), and in an independent replication cohort. Linear regression evaluated postoperative changes in CSF protein and pathway scores (quantified by singe set gene set enrichment assay [ssGSEA] pathway scores), with false discovery rate (FDR)-based multiple comparison correction. Results24-hour postoperative changes were observed in 881 of 2,086 proteins (57 of which showed a log2 fold change >0.5 or <-0.5) and in 1001 of 1854 pathways (p-FDR<0.05). Similar magnitude temporal effects were seen in these proteins and pathways in a replication cohort. The most significantly upregulated CSF pathways involved smooth muscle cell migration/regulation or apoptotic signaling/regulation; the 5 most significantly downregulated CSF pathways included NF-{kappa}B signal transduction regulation, leukocyte apoptotic process, and sulfur and proteoglycan metabolic processes. There was no significant CN-105 effect on 24-hour postoperative changes in CSF protein levels or ssGSEA pathway scores (p-FDR>0.05 for all). ConclusionsSignificant postoperative changes occurred in over 40% of proteins and over 50% of pathways in the CSF, particularly in smooth muscle, endothelial, leukocyte, and apoptosis pathways.