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Proteomic Analysis of Preoperative CSF Reveals Risk Biomarkers of Postoperative Delirium.

ABSTRACT: 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).

SUBMITTER: Han Y

PROVIDER: S-EPMC7064445 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Proteomic Analysis of Preoperative CSF Reveals Risk Biomarkers of Postoperative Delirium.

Han Yongzheng Y Chen Wei W Song Yanan Y Yuan Yi Y Li Zhengqian Z Zhou Yang Y Liu Taotao T Han Dengyang D Mi Xinning X Li Min M Wang Geng G Zhong Lijun L Zhou Juntuo J Guo Xiangyang X

Frontiers in psychiatry 20200304

<b>Objective:</b> To analyze the proteome of preoperative cerebrospinal fluid (CSF) in older orthopedic patients with or without postoperative delirium (POD) using untargeted proteomics. <b>Methods:</b> 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 M ...[more]

PMID: 32194463

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Project description:Delirium is a common postoperative complication among older patients with many adverse outcomes. Due to 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 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, 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 identifies 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.

Project description:ObjectiveTo investigate dysregulated molecules in preoperative cerebrospinal fluid (CSF) of elderly hip fracture patients with postoperative delirium (POD), in order to identify potential pathological mechanisms and biomarkers for pre-stage POD.Materials and methodsThis nested case control study used untargeted metabolomic and lipidomic analysis to profile the preoperative CSF of patients (n = 40) who developed POD undergone hip fracture surgery (n = 10) and those who did not (n = 30). Thirty Non-POD patients were matched to 10 POD patients by age (± 2 years) and Mini Mental State Examination score (± 2 points). CSF was collected after successful spinal anesthesia and banked for subsequent analysis. On the first two postoperative days, patients were assessed twice daily using the Confusion Assessment Method-Chinese Revision. CSF samples from the two groups were analyzed to investigate possible relevant pathological mechanisms and identify candidate biomarkers.ResultsDemographic characteristics of the groups were matched. Eighteen metabolites and thirty-three lipids were dysregulated in the preoperative CSF of POD patients. Pathway enrichment analysis revealed perturbations in D-glutamine and D-glutamate metabolism; glycerophospholipid metabolism; alanine, aspartate and glutamate metabolism; sphingolipid metabolism; histidine metabolism; and arginine biosynthesis at the pre-delirium stage. Receiver operating characteristic curve analysis indicated that phosphatidylethanolamine (PE, 40:7e), with an area under the curve value of 0.92, is a potential biomarker for POD.ConclusionMultiple pathological mechanisms in the POD group were involved before surgery, including neuroinflammation, oxidative stress, and energy metabolism disorders induced by hypoxia, as well as neurotransmitter imbalances such as increased dopamine and glutamate, and decreased glutamine. These metabolic abnormalities potentially increase the fragility of the brain, thus contributing to POD. PE (40:7e) might be a potential biomarker for POD. Not only do our results provide potential biomarkers for POD, but also provide information for deep pathological research.Clinical trial registrationwww.ClinicalTrials.gov, identifier ChiCTR1900021533.

Project description:BackgroundBoth frailty and postoperative delirium (POD) are common in elective surgical patients 65 years of age and older. However, the association between preoperative frailty and POD remains difficult to characterize owing to the large number of frailty and POD assessment tools used in the literature, only a few of which are validated. Furthermore, some validated frailty tools fail to provide clear score cutoffs for distinguishing frail and nonfrail patients. We performed a meta-analysis to estimate the relationship between preoperative frailty and POD.MethodsWe searched several major databases for articles that investigated the relationship between preoperative frailty and POD in patients with mean age ≥65 years who were undergoing elective, nonemergent inpatient surgery. Inclusion criteria included articles published in English no earlier than 1999. Both preoperative frailty and POD must have been measured with validated tools using clear cutoff scores for frailty and delirium. Articles were selected and data extracted independently by 2 researchers. Risk of bias (ROBINS-I) and presence of confounders were summarized. Odds ratios (ORs) for POD associated with frailty relative to nonfrailty were computed with adjusted ORs when available. Original estimates were pooled by random effects analysis. Statistical significance was set at 2-sided P < .05.ResultsNine studies qualified for meta-analysis. The Fried score or a modified version of it was used in 5 studies. Frailty prevalence ranged from 18.6% to 56%. Delirium was assessed with the Confusion Assessment Method (CAM) or Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) in 7 studies, Delirium Observation Scale in 1 study, and Intensive Care Delirium Screening Checklist in 1 study. The incidence of POD ranged from 7% to 56%. ROBINS-I risk of bias was low in 1 study, moderate in 4 studies, serious in 3 studies, and critical in 1 study. Random effects analysis (n = 794) of the OR for POD in frail versus nonfrail patients based on adjusted OR estimates was significant with an OR of 2.14 and a 95% confidence interval of 1.43-3.19. The I2 value was in the low range at 5.5, suggesting small variability from random effects. Funnel-plot analysis did not definitively support either the presence or absence of publication bias.ConclusionsThis meta-analysis provides evidence for a significant association between preoperative frailty and POD in elective surgical patients age 65 years or older.

Project description:BackgroundPostoperative delirium is a common complication that hinders recovery after surgery. Intraoperative electroencephalogram suppression has been linked to postoperative delirium, but it is unknown if this relationship is causal or if electroencephalogram suppression is merely a marker of underlying cognitive abnormalities. The hypothesis of this study was that intraoperative electroencephalogram suppression mediates a nonzero portion of the effect between preoperative abnormal cognition and postoperative delirium.MethodsThis is a prespecified secondary analysis of the Electroencephalography Guidance of Anesthesia to Alleviate Geriatric Syndromes (ENGAGES) randomized trial, which enrolled patients age 60 yr or older undergoing surgery with general anesthesia at a single academic medical center between January 2015 and May 2018. Patients were randomized to electroencephalogram-guided anesthesia or usual care. Preoperative abnormal cognition was defined as a composite of previous delirium, Short Blessed Test cognitive score greater than 4 points, or Eight Item Interview to Differentiate Aging and Dementia score greater than 1 point. Duration of intraoperative electroencephalogram suppression was defined as number of minutes with suppression ratio greater than 1%. Postoperative delirium was detected via Confusion Assessment Method or chart review on postoperative days 1 to 5.ResultsAmong 1,113 patients, 430 patients showed evidence of preoperative abnormal cognition. These patients had an increased incidence of postoperative delirium (151 of 430 [35%] vs.123 of 683 [18%], P < 0.001). Of this 17.2% total effect size (99.5% CI, 9.3 to 25.1%), an absolute 2.4% (99.5% CI, 0.6 to 4.8%) was an indirect effect mediated by electroencephalogram suppression, while an absolute 14.8% (99.5% CI, 7.2 to 22.5%) was a direct effect of preoperative abnormal cognition. Randomization to electroencephalogram-guided anesthesia did not change the mediated effect size (P = 0.078 for moderation).ConclusionsA small portion of the total effect of preoperative abnormal cognition on postoperative delirium was mediated by electroencephalogram suppression. Study precision was too low to determine if the intervention changed the mediated effect.

Project description:Medications are frequently reported as both predisposing factors and inducers of delirium. This review evaluated the available evidence and determined the magnitude of risk of postoperative delirium associated with preoperative medication use.A systematic search in Medline and EMBASE was conducted using MeSH terms and keywords for postoperative delirium and medication. Studies which included patients 18 years and older who underwent major surgery were included. The methodological quality of included studies was assessed independently by two authors using the Newcastle-Ottawa quality assessment scale for cohort studies.Twenty-nine studies; 25 prospective cohort, three retrospective cohort and one post hoc analysis of RCT data were included. Only four specifically aimed to assess medicines as an independent predictor of delirium, all other studies included medicines among a number of potential predictors of delirium. Of the studies specifically testing the association with a medication class, preoperative use of beta-blockers (OR?=?2.06[1.18-3.60]) in vascular surgery and benzodiazepines RR 2.10 (1.23-3.59) prior to orthopedic surgery were significant. However, evidence is from single studies only. Where medicines were included as one possible factor among many, hypnotics had a similar risk estimate to the benzodiazepine study, with one significant and one non-significant result. Nifedipine use prior to cardiac surgery was found to be significantly associated with delirium. The non-specific grouping of psychoactive medication use preoperatively was generally higher with an associated two-to-seven-fold higher risk of postoperative delirium, while only two studies included narcotics without other agents, with one significant and one non-significant result.There was a limited number of high quality studies in the literature quantifying the direct association between preoperative medication use and postsurgical delirium. More studies are required to evaluate the association of specific preoperative medications on the risk of postoperative delirium so that comprehensive guidelines for medicine use prior to surgery can be developed to aid delirium prevention.This systematic review has been registered on PROSPERO International prospective register of systematic reviews (Registration number: CRD42016051245 ).

Project description:BackgroundPostoperative delirium (POD) is a common postoperative complication, characterized by disturbance of attention, perception, and consciousness within 1 week after surgery, and linked to cognitive decline, increased mortality, and other serious surgical outcomes. Early identification and treatment of risk factors for POD could reduce the occurrence of delirium and the related poor outcomes. Malnutrition as a possible precipitating factor, defined as the poor anthropometric, functional, and clinical outcomes of nutrient deficiency, has been investigated. However, the evidence is controversial. The goal of this systematic review and meta-analysis was to comprehensively assess the correlation between preoperative malnutrition and POD.MethodsPubMed, Embase, Cochrane Library, and Web of Science were used to search prospective cohort articles that explored the correlation between preoperative malnutrition and POD from inception until September 30, 2022. Two researchers independently conducted the literature selection and data extraction. The quality of the literature was evaluated according to the Newcastle-Ottawa scale (NOS). Odds ratios (ORs) and 95% confidence intervals (CIs) for POD associated with malnutrition relative to normal nutritional status were calculated.ResultsSeven prospective cohort studies qualified for the meta-analysis, which included 2701 patients. The pooled prevalence of preoperative malnutrition was 15.1% (408/2701), and POD occurred in 428 patients (15.8%). The NOS score was above 7 points in all 7 studies. Our results demonstrated that the pooled OR for malnutrition and POD was 2.32 (95% CI 1.62-3.32) based on a random-effects model. Our subgroup analysis suggested that the relationship between malnutrition and POD was significant in adults following noncardiac surgery (OR = 3.04, 95% CI, 1.99-4.62, P < 0.001), while there was no statistical significance in adults following cardiac surgery (OR = 1.76, 95% CI, 0.96-3.22, P = 0.07). Additionally, in the subgroup analysis based on different malnutrition assessment tools (MNA-SF versus others), a significant association was found in the MNA-SF group (OR = 3.04, 95% CI, 1.99-4.62, P < 0.001), but not in the others group (OR = 1.76, 95% CI, 0.96-3.22, P = 0.07). Other subgroup analyses showed that this association was not significantly affected by evaluation instruments for POD, location of the study, or quality of the article (all P < 0.05).ConclusionsBased on the currently available evidence, our results suggested that preoperative malnutrition was independently associated with POD in adult surgical patients.

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Proteomic Analysis of Preoperative CSF Reveals Risk Biomarkers of Postoperative Delirium.

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Proteomic Analysis of Preoperative CSF Reveals Risk Biomarkers of Postoperative Delirium.

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