Aptamer-Based Proteomics Measuring Preoperative Cerebrospinal Fluid Protein Alterations Associated with Postoperative Delirium

Abstract

Delirium is a common postoperative complication among older patients with many adverse outcomes. Due to a lack of validated biomarkers, prediction and monitoring of delirium by biological testing is not currently feasible. Circulating proteins in cerebrospinal fluid (CSF) may reflect biological processes causing delirium. Our goal was to discover and investigate candidate protein biomarkers in preoperative CSF that were associated with the development of postoperative delirium in older surgical patients. We employed a nested case–control study design coupled with high multiplex affinity proteomics analysis to measure 1305 proteins in preoperative CSF. Twenty-four matched delirium cases and non-delirium controls were selected from the Healthier Postoperative Recovery (HiPOR) cohort, and the associations between preoperative protein levels and postoperative delirium were assessed using t-test statistics with further analysis by systems biology to elucidate delirium pathophysiology. Proteomics analysis identified 32 proteins in preoperative CSF that significantly associate with delirium (t-test p < 0.05). Due to the limited sample size, these proteins did not remain significant by multiple hypothesis testing using the Benjamini–Hochberg correction and q-value method. Three algorithms were applied to separate delirium cases from non-delirium controls. Hierarchical clustering classified 40/48 case–control samples correctly, and principal components analysis separated 43/48. The receiver operating characteristic curve yielded an area under the curve [95% confidence interval] of 0.91 [0.80–0.97]. Systems biology analysis identified several key pathways associated with risk of delirium: inflammation, immune cell migration, apoptosis, angiogenesis, synaptic depression and neuronal cell death. Proteomics analysis of preoperative CSF identified 32 proteins that might discriminate individuals who subsequently develop postoperative delirium from matched control samples. These proteins are potential candidate biomarkers for delirium and may play a role in its pathophysiology.

Discovery of Delirium Biomarkers through Minimally Invasive Serum Molecular Fingerprinting

“…Also, Han et al [ 80 ], based on proteomic analysis, identified 63 dysregulated proteins in the cerebrospinal fluid of post-operative delirium patients, which are associated with several nervous system-related pathways. Various observations underscore the importance of neuroinflammatory processes in the development of delirium, emphasizing the crucial connection between protein dynamics and the mechanisms of the disease [ 37 , 81 , 82 , 83 ]. Indeed, a recent systematic review highlighted the significance of neuroinflammatory processes in delirium, identifying 370 peri-operative protein biomarkers implicated in immune system activation, inflammatory responses, and the coagulation cascade [ 73 ].…”

Preoperative plasma bilirubin may be associated with postoperative delirium in old patients undergoing knee/hip arthroplasty: the PNDRFAP study and the PNDABLE study

“…At present, several risk factors have been suggested for postoperative delirium, including amyloid β 42 (Aβ42), total tau (T-tau), and phospho-tau (P-tau) [6,7] T-tau plays an important role in neuronal plasticity by binding tubulin to maintain microtubule stability and induce microtubule formation. Abnormally phosphorylated T-tau protein is deposited in cells, forming neuronal ber tangles that lead to cognitive dysfunction [8].…”