Correlation Between Cystatin-C and Interleukin-34 Expression Detection and Post-Stroke Cognitive Impairment

By Xinlei Wang, Weina Guo, Jinye Zhao, Jing Zhao, Jing Wei

Affiliations

1. 1st Department of Internal Medicine-Neurology, Baoding No.1 Central Hospital, Hebei, China

doi: 10.29271/jcpsp.2025.08.1065

ABSTRACT
The aim of this study was to explore the relationship between the expression levels of Cystatin-C (Cys-C) and Interleukin-34 (IL-34) and cognitive impairment following a stroke. It was a retrospective study carried out from May 2022 to May 2024. Stroke patients were selected as research subjects; 109 patients had cognitive impairment (PSCI group), while 191 patients did not have cognitive impairment (non-PSCI group). The differences in Cys-C and IL-34 levels between the two groups and the correlation between Cys-C, IL-34, and post-stroke cognitive impairment were compared. There was a statistically significant difference in the levels of Cys-C and IL-34 between the two groups. The correlation analysis showed a significant correlation between Cys-C (r = 0.192, p = 0.001) and IL-34 (r = 0.393, p <0.001) levels and cognitive dysfunction. Multivariate analysis showed that Cys-C (OR = 6.768, p = 0.016) and IL-34 (OR = 0.049, p = 0.002) were risk factors for cognitive dysfunction in patients. Cys-C and IL-34 expressions are significantly correlated with post-stroke cognitive impairment.

Key Words: Cystatin-C, Interleukin-34, Stroke, Cognitive impairment.

Post-stroke cognitive impairment (PSCI) is prevalent worldwide, with a reported prevalence ranging from 30 to 70%.¹ The severity and type of stroke significantly influence the likelihood and extent of cognitive impairment. Large-scale cerebral infarctions or recurrent strokes are associated with more severe cognitive impairment. Research indicates a correlation between Cystatin-C (Cys-C) and PSCI, suggesting that Cys-C may contribute to PSCI development through mechanisms such as antioxidant stress reduction, anti-inflammatory actions, promotion of cerebrovascular remodelling and neuro-repair, and immune response regulation.² Interleukin-34 (IL-34) is implicated in PSCI through mechanisms such as enhancing neuroregeneration, suppressing inflammatory responses, modulating neurotransmitter release and synaptic plasticity, and interacting with genetic factors.³

The aim of this study was to explore the correlation between the expression levels of Cys-C and IL-34 and PSCI, providing  scientific  evidence  to  guide  clinical  treatment.
 

This retrospective study was carried out at the 1^st Department of Internal Medicine Neurology, Baoding No. 1 Central Hospital, Hebei, China, from May 2022 to May 2024. The study was conducted after taking approval from the Hospital’s Ethical Committee. Patients who met the diagnostic criteria for stroke and were able to complete the survey scales were included.⁴ Patients with a history of cerebrovascular disease, hereditary metabolic disorders, cognitive impairment due to other neurological conditions, aphasia or right limb paralysis, and communication barriers were excluded. Based on whether the patient experienced cognitive impairment within 6 months after admission for treatment, they were divided into the cognitive impairment group (PSCI group) and the non-cognitive impairment group (non-PSCI group). Among them, there were 109 patients in the PSCI group and 191 patients in the non-PSCI group. Cognitive impairment was evaluated using the Mini State Examination (MMSE), with scores of 27-30 indicating no cognitive impairment and scores below 27 indicating cognitive impairment. Scores of 21-26 indicated mild cognitive impairment, scores of 10-20 indicated moderate cognitive impairment, and scores below 10 indicated severe cognitive impairment. There were 39 patients in the mild group, 31 patients in the moderate group, and 39 patients in the severe group in the PSCI group.

Clinical data included gender, age, alcohol consumption history, smoking history, education status, chronic disease status, blood pressure, blood lipids, and National Institutes of Health Stroke Scale (NIHSS) scores.

Table   I:   Correlation   of   cognitive   impairment.

Indicators	r	p-values*
Diabetes	0.252	<0.001
FBG	0.174	0.002
Glycosylated haemoglobin	0.219	<0.001
Fasting C-peptide	0.291	<0.001
Diastolic blood pressure	0.528	<0.001
Systolic blood pressure	0.789	<0.001
Low-density lipoprotein	0.258	<0.001
High-density lipoprotein	0.447	<0.001
Triglycerides	0.197	0.001
Cholesterol	0.395	<0.001
Cys-C	0.192	0.001
TyG	0.814	<0.001
Tau protein	0.704	<0.001
IL-34	0.393	<0.001
NIHSS	0.983	<0.001
Alcohol consumption	0.219	<0.001
Smoking	0.217	<0.001
Lacunar infarcts	0.563	<0.001
White matter lesions	0.436	<0.001
Cerebral microbleeds	0.364	<0.001
Enlarged perivascular spaces	0.352	<0.001
Note: Pearson’s correlation analysis, *p <0.05.

Fasting blood glucose (FBG) and triglyceride glucose index (TyG) were measured using the chemiluminescence method, while Cys-C, Tau protein, and IL-34 were detected using the enzyme-linked immunosorbent assay (ELISA). Imaging examination were also performed. All patients underwent magnetic resonance imaging (MRI) to analyse their lacunar ischaemic lesions, white matter lesions, cerebral microbleeds, and vascular gap enlargement. All measurement data conformed to a normal distribution. Collected data were analysed using Pearson’s correlation analysis, and logistic regression analysis was adopted to investigate the relationships between Cys-C, IL-34, and post-stroke cognitive impairment. The analysis was performed using the Statistical Package for Social Sciences (SPSS) version 26.0. A p-value of less than 0.05 was considered significant.

The 300 patients included 135 males and 165 females. Median age of the patients was 67 years. In the non-PSCI group, the PSCI group, and patients with mild, moderate, and severe cognitive impairment within the PSCI group, statistically significant differences were observed between diabetes, fasting blood glucose, glycosylated haemoglobin, fasting C-foetoprotein, diastolic and systolic pressure, low-density lipoprotein, high- density lipoprotein, triglyceride, cholesterol, Cys-C, TyG, Tau protein, IL-34, NIHSS, alcohol consumption, and smoking (p <0.005). There are statistically significant differences in imaging features between the non-PSCI and PSCI groups, as well as among patients with mild, moderate, and severe cognitive impairment within the PSCI group, including lacunar infarcts, white matter lesions, cerebral microbleeds, and enlarged perivascular spaces (p <0.001).

The results of Pearson’s correlation analysis showed that diabetes (p <0.001), FBG (p = 0.002), glycosylated haemoglobin (p <0.001), fasting C-peptide (p <0.001), diastolic blood pressure (p <0.001), systolic blood pressure (p <0.001), low- density lipoprotein (p <0.001), high- density lipoprotein (p <0.001), triglycerides (p = 0.001), cholesterol (p <0.001), Cys-C (p = 0.001), TyG (p <0.001), Tau protein (p <0.001), IL-34 (p <0.001), NIHSS score (p <0.001), alcohol consumption (p <0.001), smoking (p <0.001), lacunar infarcts (p <0.001), white matter lesions (p <0.001), cerebral microbleeds (p <0.001), and enlarged perivascular spaces (p <0.001) showed a significant correlation with cognitive dysfunction, as shown in Table Ⅰ. Logistic regression analysis showed that FBG (p = 0.025), glycosylated haemoglobin (p <0.001), fasting C-peptide (p = 0.015), high-density lipoprotein (p = 0.034), triglycerides (p = 0.012), Cys-C (p = 0.016), IL-34 (p = 0.002), and smoking (p = 0.037) were all risk factors for cognitive dysfunction in patients, as shown in Table II.

Research data show that about 30 to 70% of post-stroke patients experience varying degrees of cognitive impairment, with approximately 10 to 30% developing significant PSCI.1 As the age increases, the risk of PSCI in stroke patients also gradually increases.

In this study, by analysing the risk factors of cognitive dysfunction and non-cognitive function, it was found that hypertension, diabetes, hyperlipidaemia, FBG, glycosylated haemoglobin, fasting C-foetoprotein, diastolic pressure, systolic pressure, low-density lipoprotein, high-density lipoprotein, triglyceride, cholesterol, Cys-C, TyG, Tau protein, IL-34, NIHSS, alcohol consumption, smoking, lacunar ischaemia, leucoencephalopathy, cerebral microbleeds, and vasodilation are all risk factors affecting the cognitive function in post-stroke patients. Analysis showed that vascular disease is one of the important risk factors affecting the cognitive function of patients after stroke. Hypertension, diabetes, hyperlipidaemia, and other vascular diseases will lead to an insufficient blood supply to the brain and affect cognitive function.⁵ Abnormalities such as FBG, glycated haemoglobin, and fasting C-reactive protein, may lead to brain damage and cognitive decline.

Table II: Multivariate analysis of cognitive impairment.
 

Indicators	b	S.E	χ2	p-valuee*	OR	95% CI for OR
FBG	1.149	0.513	5.013	0.025	3.156	1.154-8.633
Glycosylated haemoglobin	2.156	0.474	20.716	<0.001	8.636	3.413-21.853
Fasting C-peptide	1.007	0.416	5.862	0.015	2.737	1.211-6.184
High-density lipoprotein	1.645	0.777	4.479	0.034	0.193	0.042-0.885
Triglycerides	2.103	0.839	6.285	0.012	8.188	1.582-42.376
Cys-C	1.912	0.793	5.810	0.016	6.768	1.429-30.042
IL-34	3.017	0.985	9.371	0.002	0.049	0.007-0.338
Smoking	1.776	0.854	4.328	0.037	0.169	0.032-0.902
Note: Logistic regression analysis, *p <0.05.

Abnormal changes in diastolic and systolic blood pressure may lead to insufficient blood supply to the brain or microcirculatory disorders, resulting in cognitive decline. Abnormality of blood lipid indicators will increase the risk of atherosclerosis and affect brain blood supply and cognitive function.⁶ Abnormal Cys-C can lead to the accumulation of metabolic products in the body, damage nerve cells, and cause cognitive decline. Some studies have found that Cys-C may be involved in the pathogenesis of PSCI by regulating immune responses.⁴ Research has found that inflammatory factors such as Tau protein and IL-34 are associated with cognitive impairment in post-stroke patients.⁵ The elevated level of IL-34 in plasma is closely related to the occurrence of PSCI. Some studies have shown that IL-34 can regulate the balance of neurotransmitters such as glutamate and gamma-aminobutyric acid in the brain, affecting communi-cation between neurons and synaptic plasticity.⁶ Abnormal changes, such as lacunar ischaemia, white matter lesions, and cerebral microbleeds, may lead to neuronal damage and chain reactions, which in turn can cause cognitive decline.

However, there are still some shortcomings in this study. Fewer samples were included in this study, and the corresponding results need to be verified in a larger-scale sample size.

In summary, the expression detection of Cys-C and IL-34 is significantly correlated with PSCI and can serve as an important basis for early clinical diagnosis of cognitive dysfunction.

FUNDING:
This study is supported by the Science and Technology Projects in Baoding, China (No. 2441ZF026).

ETHICAL APPROVAL:
The study was conducted after approval from the Hospital’s Ethical Committee of Baoding No. 1 Central Hospital, Hebei, China.

COMPETING INTEREST:
The authors declared no conflict of interest.

AUTHORS’ CONTRIBUTION:
XW: Designed the study and prepared the manuscript.
WG, JZ: Collected and analysed the clinical data.
JZ, JW: Contributed to the acquisition, analysis, interpretation of data, and drafting of the manuscript.
All authors approved the final version of the manuscript to be published.

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