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

Objective: To evaluate the effect of non-cardiac/non-neurologic surgery on the CSF proteome, and the effect of the APOE mimetic peptide CN-105 on postoperative CSF proteome changes. Methods: We performed mass spectrometry-based proteomics on preoperative and 24 hour postoperative cerebrospinal fluid (CSF) samples from 137 patients (age>60) in the MARBLE trial (ct.gov identifier: <ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="clintrialgov" xlink:href="NCT03802396">NCT03802396</ext-link>), who were randomized to receive APOE mimetic peptide CN-105 (or placebo), and in an independent replication cohort. Linear regression was used to evaluate postoperative changes in CSF protein levels and pathway scores (measured by single-sample gene set enrichment analysis [ssGSEA]), with false discovery rate (FDR)-based multiple comparison correction. Results: Among 2,086 proteins, 881 (42.2%) showed a change after surgery (p-FDR<0.05), of which 57 proteins (6.4%) showed a log2 fold change >0.5 or <-0.5, and postoperative changes occurred in 1,001 (54.0%) of 1854 pathways (p-FDR<0.05). Similar temporal effects were seen in the majority of these proteins and pathways in the replication cohort. The 5 most significantly upregulated CSF pathways involved smooth muscle cell migration (and its regulation) or apoptotic signaling and regulation (including within endothelial cells). The 5 most significantly downregulated CSF pathways included non-canonical NF-kB signal transduction regulation, leukocyte apoptotic process (and negative regulation of it), 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). Conclusions: Significant postoperative changes occurred in over 40% of proteins and over 50% of pathways in the CSF, most significantly in smooth muscle, endothelial, leukocyte, and apoptosis pathways.