Relationship Between Postoperative Biomarkers of Neuronal Injury and Postoperative Cognitive Dysfunction: A Meta-Analysis

Xiaohua Wang, Xinli Chen, Fan Wu, Yingchao Liu, Yushen Yang, Weican Chen, Zhigang Pan, Weipeng Hu , Feng Zheng , Hefan He


Early biomarkers are needed to identify patients at risk of developing postoperative cognitive dysfunction (POCD). Our objective was to determine neuronal injury-related biomarkers with predictive values for this condition. Six biomarkers (S100β, neuron-specific enolase [NSE], amyloid beta [Aβ], tau, neurofilament light chain, and glial fibrillary acidic protein) were evaluated.


Postoperative cognitive dysfunction (POCD) affects direction, attention, consciousness, perception, and judgment of patients under general anesthesia [1], with an incidence of 8.9–46.1% [2]. Several factors, including neuroinflammation, oxidative stress, autophagy disorder, neuronal injury, and lack of neurotrophic support are hypothesized to contribute to POCD [3, 4]. However, the specific pathogenesis of POCD remains unclear. Currently, the diagnosis of POCD is based mainly on neuropsychological tests. However, the composition of the test batteries varies greatly [5] and they are easily affected by factors such as culture, educational level, and language [6], which leads to their limited value for diagnostic application. Recent studies have found that anesthesia and surgery can cause neuronal damage and related biomarkers may be associated with postoperative cognitive outcomes [7, 8]. Identifying the relationship between neuronal injury biomarkers and POCD may present another method of diagnosing POCD.

Materials and methods

Study selection

To be included, studies had to meet the following criteria: (1) conducted in humans; (2) assessment of at least one specific neuronal marker in blood or cerebrospinal fluid (CSF); and (3) written in English. Studies with the following characteristics were excluded: (1) no clear differentiation between POCD subtypes, (2) lack of comparison groups, (3) non-human studies, and (4) non-English articles. Two reviewers (X.W. and X.C.) independently evaluated the retrieved articles according to the title, summary, or full text, and a third independent reviewer (W.C.) resolved discrepancies.


The results of the sensitivity analysis showed that when the study by He et al. [35] was removed, there was no significant difference in S100β level between POCD patients and non-POCD patients (P = 0.25). When the study by Linstedt et al. [28] was removed, the NSE was significantly higher in patients with POCD than in those without POCD (P <0.0001). When the study by Evered et al. [31] was removed, Aβ levels were significantly higher in patients with POCD than in those without POCD (P <0.00001). This suggests that the results summarized at the first postoperative sampling should be interpreted with caution.


This meta-analysis had some limitations. Firstly, heterogeneity was high in many analyses. Heterogeneity may be due to the following reasons: (1) small sample size of each study, (2) different sources (blood or CSF), detection time, and biomarker identification methods, (3) different evaluation times and diagnostic methods of POCD, (4) different types of surgery, and (5) patients of different ages. Secondly, the number of articles included was relatively small and most of the analyses were based on a few studies, which hindered us from conducting a more in-depth analysis of patient age, surgical type, anesthesia method, and source of marker samples. Thirdly, due to the lack of available data, we could not further analyze the impact of preoperative biomarker levels on the present findings. Fourthly, due to the inconsistent diagnosis time of POCD, the predictive value of biomarkers for postoperative short- and long-term cognitive function could not be compared. Therefore, future studies should focus on these issues.


This meta-analysis identified that postoperative S100β, NSE, and Aβ levels have predictive value for POCD. The relationship between these biomarkers and POCD may be affected by sampling time. Early diagnosis and prevention of POCD are important in postoperative clinical practice, and future studies with larger sample sizes are warranted to confirm this finding.


We would like to thank Editage ( for English language editing.

Citation: Wang X, Chen X, Wu F, Liu Y, Yang Y, Chen W, et al. (2023) Relationship between postoperative biomarkers of neuronal injury and postoperative cognitive dysfunction: A meta-analysis. PLoS ONE 18(4): e0284728.

Editor: Venkatesh Shankar Madhugiri, National Institute of Mental Health and Neuro Sciences, INDIA

Received: November 16, 2022; Accepted: April 7, 2023; Published: April 25, 2023

Copyright: © 2023 Wang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the paper and Supporting Information files.

Funding: This work was supported by grants from the Natural Science Foundation of Fujian Province (2020J01227), the Medical Innovation Science and Technology Project of Fujian Province (2020CXA047), and the Doctoral Startup Fund of the Second Affiliated Hospital of Fujian Medical University (BS202205).Funders have no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Equinix accelerated medical research...The Healthcare Patient Experience & Engagement Summit 2024Healthcare Innovation & Transformation SummitHealthcare CNO SummitHealthcare CMO Summit