This article is mentioned in:

Introduction

In recent years, intracranial tumors have an increasing incidence rate (1) and high disability rate worldwide, becoming an important challenge threatening the life and health of humans. Moreover, the mortality rate is 2.16% among all malignant tumors, and it is the 9th leading cause of death from malignant tumors (2). With the improvements in neurosurgery techniques and adjuvant therapy technologies such as radiotherapy and chemotherapy, the survival rate has gradually increased, and the survival time is 5–15 years (3). Most patients with brain tumors often have manifestations such as cognitive impairment memory loss and language dysfunction (4). In clinical practice, the cognitive function of patients is comprehensively assessed via the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). The mechanism of cognitive impairment in intracranial tumors is complex, and no definitive conclusion is made clinically. Theoretically, cognitive function is correlated with the brain tumors, related neurological complications and cerebral cortical structural basis. Some scholars analyzed the brain structure network to investigate the relationship between cognitive function and the tumors (5). Moreover, it is reported that cognitive impairment is closely related to tumor-related inflammatory responses (6). Inflammatory factors including tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) directly damage neuronal cells, resulting in cognitive impairment. In case of ischemia and hypoxia of the central nervous system due to various factors, serum neuron-specific enolase (NSE) and S100β protein are highly expressed in neuronal cells and glial cells, respectively. These two indexes can specifically reflect the damage to nerve cells and are considered to be the most sensitive indicators for brain tissue damage (7,8). This study detected the changes in serum NSE level, S100β protein concentration and inflammatory factor levels and their relationships with cognitive impairment in MMSE and MoCA scores of intracranial tumor patients with cognitive impairment to provide certain practical basis for the early diagnosis and treatment of cognitive impairment in intracranial tumors.

Patients and methods

Clinical data

A total of 70 patients diagnosed with intracranial tumors based on clinical symptoms and computed tomography (CT) images and who underwent surgical resection in Shiyan Taihe Hospital from January 2018 to December 2018 were selected and divided into non-cognitive impairment group (MoCA scores ≥26 points, n=44) and cognitive impairment group (MoCA scores <26 points, n=26) according to the comprehensive evaluation scores for cognitive function. Exclusion criteria: Patients treated with chemoradiotherapy or biologics 1 month prior to the evaluation, those unable to tolerate surgery due to serious disease of other organs, or those complicated by other cognitive impairments. The age, gender and education level of patients were comparable between the two groups (P>0.05).

The study was approved by the Ethics Committee of Shiyan Taihe Hospital (Shiyan, China) and signed informed consents were obtained by the patients and/or guardians.

Study methods

After admission, serum samples were collected to determine the NSE level, S100β protein concentration and inflammatory factor levels. On the same day, the comprehensive cognitive function evaluation was conducted by professionals using MMSE and MoCA scores, the age and education year of patients were recorded, and the neuropsychology of the patients was evaluated. The evaluation time was 5–10 min. The MMSE consists of 7 items: Time orientation, location orientation, delayed memory, immediate memory, attention and calculation capacity, linguistic competence and visuo-spatial structure, with a total score of 0–30 points. The MoCA includes visuo-spatial execution capability, attention, language fluency, naming ability, abstract thinking, orientation and delayed recall. Since the MoCA is affected by different education levels, cultural correction is necessary, and 1 point is added to the total score if the period of education is ≤12 years. The comprehensive cognitive function evaluation score <26 points suggested cognitive impairment (9,10).

Detection indicators

Fasting venous blood (3–5 ml) was collected from all the patients the next day after admission and centrifuged at 3,000 × g and 4°C for 10 min, and then the supernatant was collected and stored at −80°C for later detection.

The expression levels of serum NSE and S100β protein were measured using a CobasE411 automatic electrochemiluminescence analyzer.

A Sunrise automatic microplate reader (Decon) was used to detect the levels of serum IL-6, IL-8 and TNF-α.

The cognitive function of patients was scored according to the items in the scales.

Statistical analysis

SPSS 20.0 software was used to analyze the data. Measurement data were expressed as mean ± standard deviation (mean ± SD), and LSD test was employed for comparison between two groups. Pearsons correlation analysis was employed to analyze the correlation of serum S100β, NSE and inflammatory factor level changes with MMSE and MoCA. P<0.05 was considered to indicate a statistically significant.

Results

Comparison of serum NSE and S100β expression levels between the two groups

The experimental results showed that the NSE and S100β levels were 22.69±9.49 and 1.22±0.46 ng•l−1 in non-cognitive impairment group and 36.81±10.75 and 1.85±0.51 ng•l−1 in cognitive impairment group, respectively. The expression levels of NSE and S100β protein were notably higher in cognitive impairment group than those in non-cognitive impairment group (P<0.05), implying that monitoring the changes in the expression of the two indicators is conducive to early intervention treatment (Table I).

Table I. Comparison of serum NSE and S100β between the two groups (ng/l).

Table I.

Comparison of serum NSE and S100β between the two groups (ng/l).

Group	n	NSE	S100β
Non-cognitive impairment group	44	22.69±9.49	1.22±0.46
Cognitive impairment group	26	36.81±10.75	1.85±0.51
t value		6.876	5.257
P-value		<0.01	<0.01

[i] NSE, neuron-specific enolase.

Comparison of inflammatory factor levels between the two groups

The levels of IL-6, IL-8 and TNF-α were 13.36±3.44, 25.12±6.53 and 1.88±0.55 pg•ml−1 in non-cognitive impairment group and 28.58±5.02, 38.77±7.95 and 5.59±1.16 pg•ml−1 in cognitive impairment group, suggesting that inflammatory factors are involved in the development of cognitive impairment (Table II).

Table II. Comparison of inflammatory factor levels between the two groups (pg/ml).

Table II.

Comparison of inflammatory factor levels between the two groups (pg/ml).

Group	n	IL-6	IL-8	TNF-α
Non-cognitive impairment group	44	13.36±3.44	25.12±6.53	1.88±0.55
Cognitive impairment group	22	28.58±5.02	38.77±7.95	5.59±1.16
t value		3.145	3.876	2.778
P-value		<0.05	<0.05	<0.05

[i] IL, interleukin; TNF-α, tumor necrosis factor-α.

Comparison of MoCA and MMSE scores between the two groups

The comparison of MoCA and MMSE scores (Table III) revealed that both MoCA and MMSE scores in non-cognitive impairment group were higher than those in cognitive impairment group (26.71±0.82 vs. 18.22±1.70 points and 25.47±1.32 vs. 20.18±1.86 points, P<0.05), indicating that both MoCA and MMSE can directly reflect the severity of cognitive impairment in patients with intracranial tumors.

Table III. Comparison of MoCA and MMSE scores between the two groups.

Table III.

Comparison of MoCA and MMSE scores between the two groups.

Group	n	MoCA	MMSE
Non-cognitive impairment group	44	26.71±0.82	25.47±1.32
Cognitive impairment group	26	18.22±1.70	20.18±1.86
t value		6.133	3.256
P-value		<0.01	<0.05

[i] MoCA, Montreal Cognitive Assessment; MMSE, Mini-Mental State Examination.

Correlation of various indicators with cognitive impairment scores

The correlation analysis of cognitive impairment scores with indicators such as inflammatory mediators, NSE and S100β protein showed that the levels of serum inflammatory factors (IL-6, IL-8 and TNF-α), NSE and S100β were negatively correlated with MoCA score in patients with cognitive impairment (r=−0.4401, −0.5292, −0.6070, −0.272 and −0.5089, P<0.001), proving that the increased expression of NSE and S100β protein in vivo indicate cognitive impairment, and the abnormal expression of immune inflammatory factors in vivo is directly related to the development of cognitive impairment in patients (Figs. 1–5).

Figure 1. Correlation analysis of NSE and MoCA score (r=−0.6272). NSE, neuron-specific enolase; MoCA, Montreal Cognitive Assessment.

Figure 5. Correlation analysis of TNF-α and MoCA score (r=−0.6070). TNF-α, tumor necrosis factor-α; MoCA, Montreal Cognitive Assessment.

Discussion

It has been verified (11) that patients with intracranial tumors are complicated by varying degrees of cognitive impairment, with an incidence rate of 19–83% (12). Cognitive function, one of the important prognostic indicators for patients with brain tumors (13), is comprehensively evaluated using MMSE and MoCA scores, respectively. MoCA has a relatively high diagnostic sensitivity and specificity (14). In this study, the MoCA and MMSE scores were compared between the two groups, and it was found that compared with those (18.22±1.70 and 20.18±1.86 points) in cognitive impairment group, the scores of MoCA and MMSE (26.71±0.82 and 25.47±1.32 points) were increased in non-cognitive disorder group (P<0.05), implying that both MMSE and MoCA are able to directly reflect the severity of cognitive impairment in patients with intracranial tumors. During the progression of the disease, patients with intracranial tumors generally have cognitive impairment (15) that may even occur earlier than the anatomical changes indicated by CT and MRI. Therefore, cognitive function examination is beneficial for clinicians to know the progression and possible recurrence of tumors in time.

When brain neuronal cells are damaged, increased concentration of NSE and S100β is detected in the peripheral blood. NSE is a specific enzyme for cerebral ischemia-hypoxia injury, and S100β protein is associated with the degree of damage to the nervous system (7). A previous study (16) on patients with Alzheimer's disease discovered that serum S100β protein and NSE levels are related to cognition degree, i.e., the higher their expression levels are, the worse the cognitive function will be. It was found in this study that the NSE and S100β levels (22.69±9.49 and 1.22±0.46 ng•l−1) in non-cognitive impairment group were lower than those (36.81±10.75 and 1.85±0.51 ng•l−1) in cognitive impairment group (P<0.05), indicating that monitoring the changes in the expression of both indexes contributes to early intervention treatment. Researchers pay increasing attention to the role of inflammatory mediators in the development of cognitive impairment as clinical and basic studies have manifested (17). TNF-α is implicated in the physiological processes of learning and memory, and the cognitive function of mice with TNF-α gene knockout is evidently weakened. TNF-α, as a promoter of the inflammatory cascade, can induce the production of cytokines including IL-6 and IL-8 (18), damaging neuronal cells and leading to the development and progression of cognitive impairment. It was revealed in statistical regression analysis in the study of inflammatory factors and cognitive impairment that elevated plasma IL-6 level is one of the risk factors for cognitive impairment (19). In this study, the relevant results showed that the level of IL-6 was 13.36±3.44 and 28.58±5.02 pg•ml−1, that of IL-8 was 25.12±6.53 and 38.77±7.95 pg•ml−1, and that of TNF-α was 1.88±0.55 and 5.59±1.16 pg.ml−1 in non-cognitive impairment group and cognitive impairment group, respectively. The expression levels of the above inflammatory factors were higher in cognitive impairment group than those in non-cognitive impairment group (P<0.05), implying that inflammatory factors participate in the development of cognitive impairment. As to the treatment of cognitive impairment, anti-infective therapy may help suppress its progression.

The correlation analysis of cognitive impairment scores with indicators such as inflammatory mediators, NSE and S100β protein displayed that the levels of serum inflammatory factors including IL-6, IL-8 and TNF-α, NSE and S100β protein were negatively related to MoCA score in intracranial tumor patients with cognitive impairment (r=−0.4401, −0.5292, −0.6070, −0.272 and −0.5089, P<0.001), confirming that the increase in the expression of NSE and S100β protein in vivo suggests cognitive impairment, and the abnormal expression of immune inflammatory factors in vivo is directly associated with the development of cognitive impairment in patients.

In conclusion, the changes in serum NSE, S100β protein and inflammatory factors in patients with cognitive impairment reflect the severity of the disease to some extent, directly correlated with cognitive impairment. Accurately and comprehensively evaluating the cognitive function of patients and early developing effective and targeted cognitive interventions have certain clinical practical value for improving prognosis.

Acknowledgements

Not applicable

Funding

No funding was received.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Authors' contributions

DY wrote the manuscript. DY and BL collected and analyzed the general data of patients. GJ assisted with the detection of indicators. SP and HP were responsible for the statistical analysis. All authors read and approved the final manuscript.

Ethics approval and consent to participate

The study was approved by the Ethics Committee of Shiyan Taihe Hospital (Shiyan, China) and signed informed consents were obtained by the patients and/or guardians.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References