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Serum Biomarkers of a Pro-Neuroinflammatory State May Define the Pre-Operative Risk for Postoperative Delirium in Spine Surgery.

ABSTRACT: Advances in spine surgery enable technically safe interventions in older patients with disabling spine disease, yet postoperative delirium (POD) poses a serious risk for postoperative recovery. This study investigates biomarkers of pro-neuroinflammatory states that may help objectively define the pre-operative risk for POD. This study enrolled patients aged ≥60 scheduled for elective spine surgery under general anesthesia. Biomarkers for a pro-neuroinflammatory state included S100 calcium-binding protein β (S100β), brain-derived neurotrophic factor (BDNF), Gasdermin D, and the soluble ectodomain of the triggering receptor expressed on myeloid cells 2 (sTREM2). Postoperative changes of Interleukin-6 (IL-6), Interleukin-1β (IL-1β), and C-reactive protein (CRP) were assessed as markers of systemic inflammation preoperatively, intraoperatively, and early postoperatively (up to 48 h). Patients with POD (n = 19, 75.7 ± 5.8 years) had higher pre-operative levels of sTREM2 (128.2 ± 69.4 pg/mL vs. 97.2 ± 52.0 pg/mL, p = 0.049) and Gasdermin D (2.9 ± 1.6 pg/mL vs. 2.1 ± 1.4 pg/mL, p = 0.29) than those without POD (n = 25, 75.6 ± 5.1 years). STREM2 was additionally a predictor for POD (OR = 1.01/(pg/mL) [1.00-1.03], p = 0.05), moderated by IL-6 (Wald-χ² = 4.06, p = 0.04). Patients with POD additionally showed a significant increase in IL-6, IL-1β, and S100β levels on the first postoperative day. This study identified higher levels of sTREM2 and Gasdermin D as potential markers of a pro-neuroinflammatory state that predisposes to the development of POD. Future studies should confirm these results in a larger cohort and determine their potential as an objective biomarker to inform delirium prevention strategies.

SUBMITTER: Ruhnau J

PROVIDER: S-EPMC10298968 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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Serum Biomarkers of a Pro-Neuroinflammatory State May Define the Pre-Operative Risk for Postoperative Delirium in Spine Surgery.

Ruhnau Johanna J Müller Jonas J Nowak Stephan S Strack Sarah S Sperlich Denise D Pohl Anna A Dilz Jasmin J Saar Angelika A Veser Yannick Y Behr Frederik F Rehberg Sebastian S Usichenko Taras T Hahnenkamp Klaus K Ehler Johannes J Flöel Agnes A Schroeder Henry W S HWS Müller Jan-Uwe JU Fleischmann Robert R Vogelgesang Antje A

International journal of molecular sciences 20230619 12

Advances in spine surgery enable technically safe interventions in older patients with disabling spine disease, yet postoperative delirium (POD) poses a serious risk for postoperative recovery. This study investigates biomarkers of pro-neuroinflammatory states that may help objectively define the pre-operative risk for POD. This study enrolled patients aged ≥60 scheduled for elective spine surgery under general anesthesia. Biomarkers for a pro-neuroinflammatory state included S100 calcium-bindin ...[more]

PMID: 37373482

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Project description:BackgroundPostoperative delirium (POD) is an acute altered mental state commonly encountered after cardiac surgery. The pathophysiological mechanisms underlying POD remain unclear. We aimed to identify circulating proteins significantly altered after major cardiac surgery with cardiopulmonary bypass (CPB). We also aimed to enable inferences on associations with POD.MethodsSerum and whole blood samples were collected before CPB (n = 16 patients; n = 8 with POD) and again from the same patients on postoperative day 1. All patients were clinically evaluated for POD on postoperative days 1-3. An aptamer-based proteomics platform (SOMAscan) was used to quantify serum protein abundance in patients with POD compared with non-POD controls. We also performed a lipopolysaccharide (LPS)-based in vitro functional analysis (TruCulture) on whole blood samples from patients with POD and non-POD controls to approximate surgical stress. Cytokine levels were determined using a Luminex immunoassay.ResultsCardiac surgery with CPB resulted in a significant (p adj < 0.01) change in 48.8% (637 out of 1,305) of proteins detected by SOMAscan. Gene set enrichment showed that the most impacted biological processes involved myeloid cell activation. Specifically, activation and degranulation of neutrophils were the top five highest-scoring processes. Pathway analyses with the Kyoto Encyclopedia of Genes and Genomes (KEGG) showed that metabolic enzymes, particularly those of glycolysis, were elevated in serum concentration after surgery. Several proteins were significantly increased postoperatively in patients diagnosed with POD relative to the non-POD controls, with interleukin-6 (IL-6) showing the greatest fold-change. LPS stimulation of whole blood samples confirmed these findings. Linear regression analysis showed a highly significant correlation between Confusion Assessment Method (CAM) scores and CPB-mediated changes in cGMP-inhibited 3',5'-cyclic phosphodiesterase A (PDE3A).ConclusionsCardiac surgery with CPB resulted in inflammasome changes accompanied by unexpected increases in metabolic pathways. In exploratory analyses, we found that POD was associated with changes in the expression level of various proteins, most notably IL-6 and PDE3A. This study and ongoing protein biomarker studies will likely help quantify risk or confirm the diagnosis for POD and increase understanding of its pathophysiological mechanisms.

Project description:BackgroundPost-operative delirium (POD) is a common complication in elderly patients undergoing surgery, but the underpinning causes are not clear. We hypothesized that inflammaging, the subclinical low and chronic grade inflammation characteristic of old people, can contribute to POD onset. Accordingly, we investigated the association of pre-operative and circulating cytokines in elderly patients (>65 years), admitted for elective and emergency surgery.MethodsThis is a secondary analysis of a sub-cohort of patients belonging to a previous large case-control study, where 351 patients were clinically and cognitively thoroughly characterized, together with the assessment of POD (47 patients) by confusion assessment method and delirium rating scale. Seventy-four pre-operative plasma samples were selected from a larger bio-bank and they included 37 subjects with POD and 37 without POD. Inflammaging related cytokines, i.e., IL-1β, IL-2, IL-6, IL-8, IL-10, and TNF-α, were assayed by ELISA in pre-operative blood samples; univariate and multivariable analyses have been applied to identify cytokines independently associated to POD. Associations of cytokine levels with functional status, cognitive decline, intra-hospital mortality, and comorbidity were also analyzed independently of POD onset.ResultsHigh IL-6 and low-IL-2 levels were significantly associated with POD. After adjustment for potential confounders in multivariate analysis, high level of pre-operative IL-6 was confirmed to be significantly associated with risk of POD onset. High level of IL-6 was also associated with several baseline features (including poor functional status, cognitive impairment, emergency admission, and higher comorbidity burden) and intra-hospital mortality.ConclusionPre-operative, high-plasma level of IL-6 (≥9 pg/mL) was significantly associated with POD onset. We propose IL-6 as an additional risk factor of POD onset together with the previously identified factors. Discovery of all risk factors contributing to POD onset will permit to improve hospitalized patient management and the decrease of healthcare cost.

Project description:Objective: To analyze the proteome of preoperative cerebrospinal fluid (CSF) in older orthopedic patients with or without postoperative delirium (POD) using untargeted proteomics. Methods: A prospective cohort study was conducted. Eighty hip fracture patients aged ≥65 years were recruited. After successful spinal anesthesia, CSF was collected. The patients were divided into POD and No-POD groups based on the Confusion Assessment Method, and patients with POD were graded using the Memorial Delirium Assessment Scale (MDAS). Thirty No-POD patients were matched to 10 POD patients by age (±2 years) and Mini-Mental State Examination score (±2 scores). Label-free proteomic analysis was performed using a liquid chromatography coupled to mass spectrometry (LC-MS) workflow. Validation was performed using mass-spectrometry-based parallel reaction monitoring (PRM) for the 30 No-POD and 10 POD patients, as well as for an additional 5 POD patients. Bioinformatics were used to investigate possible relevant pathological mechanisms. Results: The incidence of POD in older orthopedic patients was 18.8% in our cohort of 80 patients. Proteomics results revealed 63 dysregulated CSF proteins, and PRM analysis validated these results. The preoperative CSF levels of both V-set and transmembrane domain-containing protein 2B (VSTM2B) and coagulation factor V (FA5) were positively correlated with MDAS scores on postoperative day 1 (r > 0.8, p < 0.05). Bioinformatic analysis revealed that several nervous-system-related pathways are relevant to POD development. Conclusion: We identified and validated several novel CSF proteins that are dysregulated in POD, and revealed several pathways that are relevant to POD development. Our results not only provide risk biomarkers for POD, but also give clues for further investigations into the pathological mechanisms of delirium. Clinical trial registration: This study was registered in the Chinese Clinical Trial Registry (ChiCTR1900021533).

Project description:IntroductionThe interaction between delirium and dementia is complex. We examined if Alzheimer's disease (AD) biomarkers in patients without clinical dementia are associated with increased risk of postoperative delirium, and whether AD biomarkers demonstrate a graded association with delirium severity.MethodsParticipants (n = 59) were free of clinical dementia, age ≥ 70 years, and scheduled for elective total knee or hip arthroplasties. Cerebrospinal fluid (CSF) was collected at the time of induction for spinal anesthesia. CSF AD biomarkers were measured by enzyme-linked immunosorbent assay (ELISA) (ADX/Euroimmun); cut points for amyloid, tau, and neurodegeneration (ATN) biomarker status were A = amyloid beta (Aβ)42 <175 pg/mL or Aβ42/40 ratio <0.07; T = p-tau >80 pg/mL; and N = t-tau >700 pg/mL. Confusion Assessment Method (CAM) and CAM-Severity (CAM-S) were rated daily post-operatively for delirium and delirium severity, respectively.ResultsAβ42, tau, and p-tau mean pg/mL (SD) were 361.5 (326.1), 618.3 (237.1), and 97.1 (66.1), respectively, for those with delirium, and 550.4 (291.6), 518.3 (213.5), and 54.6 (34.5), respectively, for those without delirium. Thirteen participants (22%) were ATN positive. Delirium severity by peak CAM-S [mean difference (95% confidence interval)] was 1.48 points higher (0.29-2.67), P = 0.02 among the ATN positive. Delirium in the ATN-positive group trended toward but did not reach statistical significance (23% vs. 7%, p = 0.10). Peak CAM-S [mean (SD)] in the delirium group was 7 (2.8) compared to no delirium group 2.5 (1.3), but when groups were further classified by ATN status, an incremental effect on delirium severity was observed, such that patients who were both ATN and delirium negative had the lowest mean (SD) peak CAM-S scores of 2.5 (1.3) points, whereas those who were ATN and delirium positive had CAM-S scores of 8.7 (2.3) points; other groups (either ATN or delirium positive) had intermediate CAM-S scores.DiscussionThe presence of AD biomarkers adds important information in predicting delirium severity. Future studies are needed to confirm this relationship and to better understand the role of AD biomarkers, even in pre-clinical phase, in delirium.

Dataset Information

Serum Biomarkers of a Pro-Neuroinflammatory State May Define the Pre-Operative Risk for Postoperative Delirium in Spine Surgery.

Publications

Serum Biomarkers of a Pro-Neuroinflammatory State May Define the Pre-Operative Risk for Postoperative Delirium in Spine Surgery.

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