Cerebrospinal Fluid Proteome Changes in Older Non-Cardiac Surgical Patients with Postoperative Cognitive Dysfunction

Abstract

Background: Postoperative cognitive dysfunction (POCD), a syndrome of cognitive deficits occurring 1-12 months after surgery primarily in older patients, is associated with poor postoperative outcomes. POCD is hypothesized to result from neuroinflammation; however, the pathways involved remain unclear. Unbiased proteomic analyses have been used to identify neuroinflammatory pathways in multiple neurologic diseases and syndromes but have not yet been applied to POCD.

Objective: To utilize unbiased mass spectrometry-based proteomics to identify potential neuroinflammatory pathways underlying POCD.

Methods: Unbiased LC-MS/MS proteomics was performed on immunodepleted cerebrospinal fluid (CSF) samples obtained before, 24 hours after, and 6 weeks after major non-cardiac surgery in older adults who did (n = 8) or did not develop POCD (n = 6). Linear mixed models were used to select peptides and proteins with intensity differences for pathway analysis.

Results: Mass spectrometry quantified 8,258 peptides from 1,222 proteins in > 50%of patient samples at all three time points. Twelve peptides from 11 proteins showed differences in expression over time between patients with versus withoutPOCD (q < 0.05), including proteins previously implicated in neurodegenerative disease pathophysiology. Additionally, 283 peptides from 182 proteins were identified with trend-level differences (q < 0.25) in expression over time between these groups. Among these, pathway analysis revealed that 50 were from 17 proteins mapping to complement and coagulation pathways (q = 2.44*10-13).

Conclusion: These data demonstrate the feasibility of performing unbiased mass spectrometry on perioperative CSF samples to identify pathways associated with POCD. Additionally, they provide hypothesis-generating evidence for CSF complement and coagulation pathway changes in patients with POCD.

Keywords: Inflammation; mass spectrometry; neurocognitive disorders; postoperative cognitive dysfunction; proteomics.

Fig.1

Complement C5 peptide locations and intensity trends. A) A map of complement C5 showing the locations of its 11 peptides with (q < 0.25) in the linear mixed models. Peptides 1–3 are located on the beta subunit, and 4–11 are located on the alpha subunit. B-L) Graphs comparing median C5 peptide intensities between POCD and non-POCD groups across all three time points. Vertical bars represent interquartile range.

Fig. 2

Complement C6 peptide locations and intensity trends. A) A map of complement C6 showing the locations of its five peptides with q < 0.25 in the linear mixed models. B-F) Graphs comparing median C6 peptide intensities between POCD and non-POCD groups across all three time points. Vertical bars represent interquartile range.

Fig. 3

Complement C8b peptide locations and intensity trends. A) A map of complement C8b showing the locations of its three peptides with q < 0.25 in the linear mixed model. B-D) Graphs comparing median C8b peptide intensities between POCD and non-POCD groups across all three time points. Vertical bars represent interquartile range.

Fig. 4

Complement factor B peptide locations and intensity trends. A) A map of complement factor B showing the locations of its eight peptides with q < 0.25 in the linear mixed model. Seven of the eight peptides represent portions of its Bb fragment. B-I) Graphs comparing median factor b peptide intensities between POCD and non-POCD groups across all three time points. Vertical bars represent interquartile range. Post-translational modifications: ^*Deamidation, ^**Carbamidomethylation, ^***Oxidation.