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 without POCD (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.

Postoperative changes in cognition and cerebrospinal fluid neurodegenerative disease biomarkers

“…Second, these data do not show a correlation between AD‐related CSF biomarker change and cognitive change from before to 6 weeks after surgery, a time interval during which cognitive deficits have been detected after anesthesia and surgery in numerous prior studies 10–12,16,17,40,53–70 . Yet, this does not exclude the possibility that such a correlation exists over a longer postoperative follow‐up period.…”

“…Second, these data do not show a correlation between AD-related CSF biomarker change and cognitive change from before to 6 weeks after surgery, a time interval during which cognitive deficits have been detected after anesthesia and surgery in numerous prior studies. [10][11][12]16,17,40,[53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70] Yet, this does not exclude the possibility that such a correlation exists over a longer postoperative follow-up period. However, with longer time intervals postsurgery, it becomes less clear that any changes in CSF biomarkers or cognition are directly related to the surgery; this is partly why the perioperative neurocognitive disorders nomenclature 11 does not use the modifier "perioperative" for cognitive dysfunction occurring >1-year postsurgery.…”

Successful aging after elective surgery II: Study design and methods

“…We acknowledge that there are many recent studies examining biomarkers for delirium and postoperative cognitive decline. [19][20][21][22][23] The major advantage of the SAGES study is the large sample size, long followup with serial neuropsychologic testing and functional assessments, and the multicomponent nature of risk factors and biomarkers being examined.…”

Serum proteomics study on cognitive impairment after cardiac valve replacement surgery: a prospective observational study

“…Present research illustrates that PND’s pathogenesis is multifaceted, including encompassing oxidative stress ( Netto et al, 2018 ), neuroinflammatory responses ( Luo et al, 2019 ), mitochondrial dysfunction ( Rivero-Segura et al, 2019 ; Salminen et al, 2012 ), blood–brain barrier injury ( Marungruang et al, 2018 ) and synaptic damage ( Xiao et al, 2018 ). Given this complexity, it is insufficient to rely solely on low concentrations of beta-amyloid proteins in the cerebrospinal fluid and elevated levels of phosphorylated tau proteins for diagnosis and treatment ( VanDusen et al, 2021 ). Studies are needed to identify and utilize more proteins to enhance diagnostic precision and therapeutic effectiveness.…”