Relationships of serum VILIP-1,NSE,and ADP levels with postoperative cognitive dysfunction in elderly patients undergoing general anesthesia: a retrospective,observational study

Abstract

Objective

To investigate the relationships of serum visinin-like protein-1 (VILIP-1), neuron-specific enolase (NSE), and adiponectin (ADP) levels with postoperative cognitive dysfunction (POCD) in elderly patients undergoing general anesthesia and provide a reference for the prevention and treatment of POCD.

Methods

In this retrospective, observational study, 162 elderly patients who underwent general anesthesia were divided into POCD and non-POCD groups according to whether POCD occurred with 24 hours after surgery. Serum VILIP-1, NSE, and ADP levels were measured.

Results

Immediately after and 24 hours after surgery, serum VILIP-1 and NSE levels were significantly higher in the POCD group than in the non-POCD group, whereas serum ADP levels were significantly lower in the POCD group. Mini-mental state examination (MMSE) scores significantly differed between the two groups. At 24 hours after surgery, serum VILIP-1 and NSE levels were negatively correlated with MMSE scores in the POCD group, whereas serum ADP levels were positively correlated with MMSE scores in this group.

Conclusion

Increased serum VILIP-1 and NSE levels and decreased serum ADP levels could be involved in the pathophysiology of POCD in elderly patients after general anesthesia. These serum markers could be used as indicators of POCD in elderly patients undergoing general anesthesia.

Keywords

Elderly patient general anesthesia visinin-like protein-1 neuron-specific enolase adiponectin postoperative cognitive dysfunction

Introduction

Postoperative cognitive dysfunction (POCD) is a common complication in elderly patients after anesthesia that manifests as memory impairment occurring a few days to weeks after surgery, decreased ability to learn and recall information, reduced concentration, disordered comprehension of language, and diminished decision-making and social adaptation.¹ Some studies suggested that age, hypoxia, hypotension, anesthesia, and surgical trauma can induce POCD.²^,³ Some studies also indicated that the inflammatory reaction induced by surgery might influence the occurrence of POCD and that suppressing the inflammatory reaction could reduce the incidence and severity of POCD.⁴^,⁵

POCD both affects the postoperative recovery of patients and hinders their ability to work. In addition, POCD results in mental and economic burdens to the family and society. It is particularly important to accurately predict and diagnose POCD, which might facilitate the treatment of affected patients.

In recent years, hematologic biomarkers have been widely used in cognitive evaluation. With the continuous improvement of testing instruments, the acquisition method is more direct and simpler with lower costs and requirements for basic medical equipment, making it more suitable for clinical application.

Visinin-like protein-1 (VILIP-1) is a member of the neuronal troponin family, and it is mainly expressed in brain nerve cells.⁶ VILIP-1 regulates the signal waterfall and participates in the transmission of calcium-dependent signals in neurons.⁷^,⁸ It has been reported that serum VILIP-1 levels are related to cognitive impairment after ischemic stroke, and a high serum VILIP-1 level is an independent risk factor for cognitive impairment after ischemic stroke.⁹

Neuron-specific enolase (NSE) is a functional enzyme involved in glucose metabolism that is specifically located in neurons, and it might be related to the occurrence of POCD.¹⁰ NSE can leak from damaged neurons, enter blood vessels, and accumulate in cerebrospinal fluid and blood circulation through the damaged blood–cerebrospinal fluid barrier following anesthesia. Therefore, serum NSE levels increase dramatically following neuronal injury, and the extent of the increase is positively correlated with the degree of injury.¹¹

Adiponectin (ADP) is an important marker reflecting central nervous system injury, and it is closely related to a persistent inflammatory response.¹² The secretion and expression of serum ADP are related to early POCD.¹³

General anesthesia is commonly used in surgery. With technological advances, it has been found that general anesthetics affect the central nervous system function and lead to POCD.¹⁴ The objectives of this study were to investigate the relationships of serum VILIP-1, NSE, and ADP levels with POCD in elderly patients undergoing general anesthesia and provide a reference for the prevention and treatment of POCD.

Materials and methods

In this retrospective, observational study, elderly patients who underwent general anesthesia from December 2019 to August 2022 in Qinghai Red Cross Hospital (Xining City, China) were included. All patient were de-identified. Ethical approval of the research work was obtained from the Research Ethical Committee of Qinghai Red Cross Hospital (No. 20193012). The reporting of this study conforms to STROBE guidelines.¹⁵

Patients older than 65 years old undergoing elective surgery under general anesthesia were included, and other inclusion criteria were as follows: educational level of junior high school or higher; American Association of Anesthesiologists (ASA) grade I or II; normal cognitive function and an ability to complete cognitive function tests; and provision of written consent by patients or their families.

The exclusion criteria were as follows: preoperative Mini-mental state examination (MMSE) score lower than 24 points; inability to understand the text in the cognitive function test form; severe preoperative respiratory and circulatory system diseases, liver and kidney dysfunction, or a history of psychoneurological disorders; preoperative diabetes mellitus; use of antipsychotics, sedatives, and narcotic analgesic within 2 years before enrollment; history of alcohol abuse or drug dependence; severe visual acuity, hearing impairment, or other reasons leading to communication difficulty with the visitors; intraoperative blood pressure fluctuating by more than 20% versus the basal blood pressure or the use of hyperensort twice during the operation; operative time shorter than 2 hours or more than 4 hours; and intraoperative blood loss exceeding 800 mL.

The patients were divided into POCD and non-POCD groups according to whether POCD occurred within 24 hours after surgery. The diagnosis of POCD was based on a comparison of MMSE scores between 1 day before and 1 day after surgery. Patients whose MMSE scores decreased by at least 2 points between 1 day before surgery and 1 day after surgery were judged to have POCD.¹⁶

Anesthesia method

All patients underwent general anesthesia induced via an intramuscular injection of 0.3 mg of hyoscine 30 minutes before surgery, followed by an intravenous injection of sufentanil (1.0 μg/kg), propofol (1.8 mg/kg), 0.2 mg/kg cisatracurium, and 0.3 mg/kg etomidate. Anesthesia was maintained via sevoflurane inhalation and intermittent intravenous injections of cisatracurium. The patients were sent to the anesthetic recovery room after surgery.¹⁶

Measurement of biomarkers

Venous blood samples were collected from all patients before surgery, after the completion of operation, and 24 hours after operation. Serum VILIP-1, NSE, and ADP levels were measured by enzyme-linked immunosorbent assay (Shanghai Keshun Biotechnology Co., Ltd., Shanghai, China).

Statistical analysis

Sample size was calculated using G power software (https://www.psychologie.hhu.de/arbeitsgruppen/allgemeine-psychologie-und-arbeitspsychologie/gpower). SPSS 25 statistical software (IBM Corp., Armonk, NY, USA) was used for analysis. Normally distributed data were expressed as the mean ± standard deviation. Intra-group comparisons were performed using repeated-measures analysis of variance, and pairwise comparisons were performed using Tukey’s test. A paired t-test was used for comparisons between the groups. Numerical data are expressed as n (%), and the chi-squared test was used for analysis. Pearson’s method was used to analyze the correlations of serum VILIP-1, NSE, and ADP levels with MMSE scores. P < 0.05 indicated statistical significance.

Results

Comparison of general data between the two groups

Of the 162 patients, 45 had POCD within 24 hours after surgery (27.78%). There were no significant differences in the sex ratio, age, body mass index, proportions of patients with ASA grade I or II, anesthesia time, operative time, intraoperative bleeding volume, and MMSE score 1 day before surgery between the two groups, as presented in Table 1. A flowchart of this study is presented in Figure 1.

Table 1.

Comparison of general data between the two groups.

Parameter	Non-POCD group (n = 117)	POCD group (n = 45)	P
Male [n (%)]	69 (58.97)	28 (62.22)	0.706
Female [n (%)]	48 (41.03)	17 (37.78)	0.706
Age (years)	72.85 ± 3.95	73.36 ± 4.25	0.473
Body mass index (kg/m²)	22.17 ± 3.89	22.28 ± 3.00	0.866
ASA grade I [n (%)]	60 (51.28)	22 (48.89)	0.785
ASA grade II [n (%)]	57 (48.72)	23 (51.11)	0.785
Anesthesia time (minutes)	101.51 ± 17.81	102.04 ± 13.32	0.856
Operative time (minutes)	83.85 ± 12.38	84.12 ± 10.77	0.898
Intraoperative bleeding volume (mL)	336.22 ± 49.66	338.35 ± 43.45	0.801
MMSE score 1 day before surgery	26.81 ± 1.45	26.74 ± 1.55	0.787

ASA, American Society of Anesthesiologists; MMSE, Mini-mental state examination; POCD, postoperative cognitive dysfunction.

Figure 1.

Flowchart of this study.

There were no significant differences in serum VILIP-1, NSE, and ADP levels between the two groups before surgery. At the end of surgery and 24 hours after operation, serum VILIP-1 and NSE levels were higher in the POCD group than in the non-POCD group (all P < 0.001), whereas serum ADP levels were lower in the POCD than in in the non-POCD group (both P < 0.001), as presented in Table 2.

Table 2.

Comparison of serum markers between the two groups.

Parameter	Non-POCD group (n = 117)	POCD group (n = 45)	P
Serum VILIP-1 level before surgery (pg/mL)	525.31 ± 92.16	526.20 ± 68.67	0.950
Serum VILIP-1 level at the end of surgery (pg/mL)	596.65 ± 97.55	655.59 ± 72.88	<0.001
Serum VILIP-1 level 24 hours after surgery (pg/mL)	545.27 ± 89.71	626.65 ± 66.36	<0.001
Serum NSE level before surgery (μg/L)	5.79 ± 0.95	5.84 ± 0.62	0.726
Serum NSE level at the end of surgery (μg/L)	7.51 ± 1.24	13.70 ± 1.44	<0.001
Serum NSE level 24 hours after surgery (μg/L)	9.16 ± 1.50	10.03 ± 1.05	<0.001
Serum ADP level before surgery (g/L)	12.78 ± 2.10	12.62 ± 1.33	0.633
Serum ADP level at the end of surgery (g/L)	8.60 ± 1.41	7.05 ± 0.74	<0.001
Serum ADP level 24 hours after surgery (g/L)	7.91 ± 1.30	4.08 ± 0.43	<0.001

VILIP-1, visinin-like protein-1; NSE, neuron-specific enolase; ADP, adiponectin, POCD, postoperative cognitive dysfunction.

The MMSE scores of patients in the non-POCD and POCD groups were 25.88 ± 1.46 and 21.28 ± 1.57 at 24 hours after surgery, respectively (P < 0.001). The results of Pearson analysis revealed that serum VILIP-1 (r = −0.571, P < 0.001) and NSE levels (r = −0.528, P < 0.001) were negatively correlated with MMSE scores at 24 hours after surgery in the POCD group, whereas serum ADP levels were positively correlated with MMSE score at 24 hours after surgery in the POCD group (r = 0.609, P < 0.001).

Discussion

This study revealed that the incidence of POCD in elderly patients after general anesthesia was 27.78%, consistent with previous reports.¹⁷ The occurrence of POCD might delay patients’ recovery.

At present, the widely used neuropsychological scores mainly include MMSE, the Montreal Cognitive Scale, and the Wechsler Intelligence Scale.¹⁸^,¹⁹ However, cooperation of speech and behavior is needed in the process of scale assessment. Some patients cannot complete the assessments because of aphasia or motor dysfunction. However, hematological indicators are relatively convenient, and the detection is relatively simple, which is of great practical significance for identifying biomarkers.

VILIP-1 is a potential marker of brain damage and neurodegenerative diseases.²⁰ The serum VILIP-1 level might reflect the degree of neuronal injury.²¹ The results of this study revealed that serum VILIP-1 levels were higher in the POCD group than in the non-POCD group both immediately after and 24 hours after surgery. Further analysis found a negative correlation between serum VILIP-1 levels and the MMSE score 24 hours after operation in the POCD group. The results indicated that serum VILIP-1 levels increased with increasing severity of cognitive impairment, and VILIP-1 caused cognitive impairment through direct or indirect mechanisms.

Upon neuronal damage, NSE quickly leaks from damaged neurons and enters cerebrospinal fluid and blood through the impaired blood–brain barrier. The NSE level might reflect the degree of brain injury and central nervous system injury.²²^,²³ The results of this study illustrated that serum NSE levels were higher in the POCD group than in the non-POCD group both immediately after and 24 hours after surgery. Further analysis uncovered a negative correlation between serum NSE levels and MMSE scores 24 hours after surgery in the POCD group, suggesting that serum NSE levels increased with increasing severity of cognitive impairment, and NSE caused cognitive impairment through direct or indirect mechanisms. Therefore, serum NSE might be an indicator of POCD in elderly patients after general anesthesia. The conclusions of this study are consistent with previous reports.²⁴

ADP is a hormone protein secreted by adipose tissue, and it has anti-inflammatory, hypoglycemic, and other effects that are protective for organs and tissues. ADP levels are high in plasma. ADP secretion is regulated by hormones, inflammatory factors, and other factors. Studies have confirmed that ADP is involved in the regulation of central nervous system signaling.²⁵ Increased serum ADP levels have a protective effect on cognitive function.²⁶

Correlation analysis in this study revealed a positive correlation between serum ADP levels and MMSE scores at 24 hours after surgery in the POCD group. ADP might be involved in the pathogenesis of POCD after surgery, but the detailed mechanism remains unclear. This is the limitation of this study, and further investigation is needed.

It should be noted that there is no unified standard for the diagnosis of POCD. In this study, MMSE was used to diagnose POCD. However, it is not sensitive to mild POCD, and it is also affected by the patient’s educational level. Specifically, high educational levels might lead to false-negative results. The use of the MMSE score in the diagnosis of POCD could lead to bias. This is another limitation of this study.

An additional study limitation was that cognitive testing was only performed on the first day after surgery. In addition, the patients in this study underwent different types of surgery, which differently affected the cognitive status.

Conclusion

Increased serum VILIP-1 and NSE levels and decreased serum ADP levels in elderly patients after general anesthesia could be involved in the pathophysiology of POCD. These serum markers might be useful as monitoring indicators of POCD in elderly patients undergoing general anesthesia.

Supplemental Material

sj-pdf-1-imr-10.1177_03000605231172447 - Supplemental material for Relationships of serum VILIP-1, NSE, and ADP levels with postoperative cognitive dysfunction in elderly patients undergoing general anesthesia: a retrospective, observational study

Supplemental material, sj-pdf-1-imr-10.1177_03000605231172447 for Relationships of serum VILIP-1, NSE, and ADP levels with postoperative cognitive dysfunction in elderly patients undergoing general anesthesia: a retrospective, observational study by Yuhai Xie and Zeyu Yao in Journal of International Medical Research

Footnotes

Author contributions

YX and ZY conceived the project, designed the study, and analyzed the data. YX wrote the paper. ZY critically reviewed the manuscript.

Availability of data and materials

The dataset of this article is not openly available. However, it can be accessed upon reasonable request from the corresponding author.

Declaration of conflicting interest

The authors declare that there is no conflict of interest.

Funding

This study was financially supported by the Basic Research project of Qinghai Province, China (No. 2019-2J-7085).

ORCID iD

Zeyu Yao

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