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Abstract

Backgrounds

Post-stroke cognitive dysfunction (PSCI), a set of illnesses ranging from moderate cognitive impairment to dementia, which is one of the most prevalent consequences following a stroke. Homocysteine (Hcy) has been related to a number of neurological and systemic diseases. It’s also a known risk factor for cardiovascular disease and systemic atherosclerosis (CVD). The link between Hcy and PSCI, on the other hand, is unknown.

Methods

Our hospital evaluated 325 patients with acute cerebral infarction between January 1, 2018 and December 1, 2021. There are biological markers and baseline data available. Patients were divided into two groups based on the results of the Montreal Cognitive Assessment (MoCA). The researchers performed logistic regression analysis to find variables that may be linked to PSCI.

Results

HCY levels were significantly higher in PSCI patients than in non-PSCI patients. Age, education, seizure manifestation, and income level were all shown to be independent risk variables for PSCI in a multivariate logistic analysis. Hcy levels in PSCI patients differed considerably between the high and low groups. The high and low Hcy levels groups had significantly varied hypertension histories and urine levels. Hcy levels in PSCI patients differed considerably between the high and low groups. The high and low Hcy levels groups had significantly varied hypertension histories and urine levels.

Conclusion

Serum Hcy levels have been linked to PSCI in post-stroke patients, and researchers believe that serum Hcy levels will diminish PSCI.

Keywords

homocysteine cognitive impairment post-stroke risk factors

Introduction

One of the most common sequelae following a stroke is post-stroke cognitive impairment (PSCI), which refers to a variety of disorders ranging from moderate cognitive dysfunction to dementia.¹ The incidence of post-stroke cognitive impairment ranges from 20% to 80%, and varies from country to country, ethnicity, and diagnostic criteria used. Post-stroke cognitive impairment is linked to both demographic and vascular factors, such as age, education, and profession.² Etiology of PSD is multifactorial and includes vascular disease, Alzheimer’s disease, post-stroke dementia, and prior vascular disease, which are also major risk factors.³ In addition, manifestations of cerebral small vessel disease, such as covert brain infarcts, white matter lesions, microbleeds, and cortical microinfarcts, are also common in patients with stroke and likewise contribute to cognitive outcomes.² Although studies of PSCI historically varied in the approach to timing and methods of diagnosis, most of them demonstrate that older age, lower educational status, socioeconomic disparities, premorbid cognitive or functional decline, life-course exposure to vascular risk factors, and a history of prior stroke increase risk of PSCI.⁴ Besides, a large number of biomarkers for PSD, including indicators for genetic polymorphisms, biomarkers in the cerebrospinal fluid and in the serum, inflammatory mediators, and peripheral microRNA profiles have been proposed.^1,5-7 Neuropsychological tests are commonly used to diagnose and prognosis PSCI, however, their results are subjective and incorrect, making them insufficient for diagnosis and prognosis. Changes in the expression of biomarkers such as C-reactive protein (CRP), interleukin 6 (IL-6), and IL-10 in blood, urine, and other body fluids have been linked to cognitive loss following a stroke in a growing number of studies in recent years.^8-10 As a result, detecting biomarkers in blood serum and plasma may help with diagnosis and prognosis in PSCI.¹

Homocysteine (Hcy) is a non-proteinogenic sulfhydryl-containing amino acid produced from methionine and is a cysteine homologue. Remethylation back to methionine or transsulfuration to cysteine with concomitant generation of hydrogen sulfide (H2S) is the two main mechanisms that control homocysteine levels.¹¹ Hcy has been connected to a variety of systemic and neurological diseases, is well-known as a risk factor for systemic atherosclerosis and cardiovascular disease (CVD), and has been linked to several ocular ailments, including diabetic retinopathy (DR) and age-related macular degeneration.^12-14 Furthermore, high levels of Hcy act as a neurotoxin, causing neurodegeneration through apoptosis caused by DNA breakage.^15-17 As a consequence, we hypothesize that variations in Hcy levels might be separate risk factors for PSCI. However, the link between cognitive performance and Hcy in individuals who have had an ischemic stroke is yet unknown.

The goal of this study was to look at the relationships between cognitive function and serum Hcy levels in individuals who had an ischemic stroke, which might lead to the discovery of possible PSCI biomarkers.

Materials and Methods

This study is a single-center, controlled study. This study was authorized by our hospital’s ethical committee as well as the institutional review board (IRB) (NDTS206155). All patients were given information and asked to sign an informed consent form. These studies, according to the CONSORT standards, also comply with the Helsinki Declaration.

Subject

Between January 1, 2018, and December 1, 2021, 325 patients were diagnosed with acute cerebral infarction at our hospital. Previous research was used to examine the diagnostic criteria for acute cerebral infarction.¹⁸ All cases that have been chosen are told, and an informed consent form is signed. Patients who had an acute ischemic stroke within 7 days of admission meet the inclusion criteria. Individuals using nootropic or xanthine drugs before stroke diagnosis, or those with any central nervous system disease, such as pre-stroke dementia or severe cognitive impairment, Parkinson’s disease, severe aphasia or dysarthria, visual or auditory impairment, or acute or chronic inflammatory diseases, are excluded. The patients were categorized into PSCI and non-PSCI groups based on the diagnostic criteria of the Montreal Cognitive Assessment (MoCA) scale.¹⁹ Among these, 201 were assigned to the PSCI group, while 124 were assigned to the non-PSCI group. Patients with PSCI have had a stroke and have aberrant cognitive impairment. Non-PSCI patients present with a stroke but no cognitive damage.

Data Collection

The baseline data of all patients is measured on admission. Levels of UA, homocysteine (Hcy), folic acid (FOA), vitamin B12 (VB12), triglycerides (TG), low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and cholinesterase (CHE) were determined from blood samples. Primary symptoms were summarized as hemorrhage and seizure. Cranial magnetic resonance imaging (MRI) and head computed tomography (CT) were performed to exclude non-stroke patients. The MoCA was administered 1 week after the onset of stroke to avoid bias caused by possible short-term impact on cognitive function following a stroke. The

Montreal Cognitive Assessment

MoCA is managed according to recommended standards. Patients with a MoCA score <26 were considered cognitively impaired and those with a MoCA score ≥26 were considered cognitively normal, with a +1 score correction for those with education ≤12 years.

Stroke Subtype

Stroke was subtyped by the Oxfordshire Community Stroke Project Classification.²⁰ Briefly, patients with large anterior circulation infarcts with both cortical and subcortical involvement were classified as total anterior circulation infarcts (TACI). Those with infarcts clearly associated with the vertebrobasilar arterial territory were grouped under posterior circulation infarcts (POCI) while those with more restricted and predominantly cortical infarcts in the territory of the anterior circulation came under the group of partial anterior circulation infarcts (PACI). Lacunar infarcts (LACI) refers to the group that had infarcts localized to the territory of deep perforating arteries.

Statistical Analysis

All statistical analyses were performed using SPSS 18.0 (IBM Corporation, Armonk, NY, USA). Measurement data are expressed as mean ± standard deviation (SD). Logistic regression analysis was used to examine factors that increase the risk of PSCI. As described above, PSCI subjects were divided into high-hcy and low-hcy groups. A t-test was then performed to examine the relationship between the population with higher serum Hcy levels and the baseline characteristics of PSCI patients. Pearson correlation analysis was used to test the correlation of other clinical parameters with serum Hcy levels. Differences with P < .05 were considered to be statistically significant.

Results

Baseline Characteristic

Table 1 summarizes the main clinical data of the patients selected for this study, which show a good balance between the two datasets. A total of 354 stroke patients were enrolled, 124 without PSCI and 201 with PSCI. There were no significant differences in the history of diabetes, smoking, or drinking between PSCI patients and non-PSCI patients. However, there were statistical differences in pathological selection between the two groups in terms of FOA, VB12, TG, CHO, HDL, and LDL. Serum UA and Hcy levels in the PSCI group were significantly higher than those in the PSCI group (P < .05). In addition, MoCA score in TACI/PACI, POCI, LACI group are 22.92 ± 2.11, 26.03 ± 3.52 and 27.32 ± 2.94 and mean Hcy level in TACI/PACI, POCI, LACI group are 14.89 ± 3.55 mmol/L, 14.23 ± 1.22 mmol/L and 14.92 ± 2.93 mmol/L.

Table 1.

Comparison of Baseline Characteristic of Study Subjects Between the PSCI Group and the Non-PSCI Group.

Characteristic	Non-PSCI (n = 124)	PSCI (n = 201)	t/χ²	P value
Sex (male, %)	72 (58.06)	114 (56.72)	3.52	.04
Age,mean (SD)	65.02 ± 10.25	64.14 ± 9.85	4.82	.04
Education year, mean (SD)	2.52 ± 1.02	1.12 ± .51	8.25	.25
Hypertension history, n (%)	63 (50.81)	104 (51.74)	2.51	.01
Diabetes history, n (%)	35 (28.22)	62 (30.85)	4.52	.85
Smoking history, n (%)	38 (30.64)	56 (27.86)	1.25	.62
Drinking history, n (%)	28 (22.58)	42 (21.00)	3.61	.15
Seizure, n (%)	27 (21.77)	40 (19.90)	2.68	.58
CD history, n (%)	14 (11.24)	20 (9.95)	2.51	.36
MoCA, mean (SD)	26.85 ± 2.51	19.62 ± 3.61	5.62	.01
FOA (ng/mL), mean (SD)	9.15 ± 2.115	9.58 ± 2.85	1.35	.35
VB12 (Pg/mL), mean (SD)	578.02 ± 125.62	503.42 ± 153.62	4.62	.85
UA (mmol/L), mean (SD)	342.61 ± 42.62	328.23 ± 3.62	3.61	.03
Hcy (mmol/L), mean (SD)	10.15 ± 2.62	21.87 ± 1.62	1.85	.02
TG (mmol/L), mean (SD)	1.58 ± .61	1.57 ± .15	5.62	.25
CHO (mmol/L), mean (SD)	4.85 ± 1.15	4.39 ± 1.03	1.57	.31
HDL (mmol/L), mean (SD)	1.18 ± .15	1.08 ± .15	2.39	.85
LDL (mmol/L), mean (SD)	1.25 ± .25	1.45 ± .54	1.95	.94

Logistic Regression Analysis

To select independent variables, we used multivariate logistic regression and developed a multivariate model to investigate risk factors for cognitive impairment in stroke. In the first step, a simple logistic regression model included all clinically relevant variables in Table 1, such as gender, age, history of hypertension, diabetes history, academic history, UA, and Hcy levels (Table 2). The results showed that even after adjusting for common risk factors such as age, sex, history of hypertension, diabetes, years of education, and uric acid levels, patients with higher serum Hcy levels had a significantly increased risk of developing PSCI (P < .05), Hcy may be an independent risk factor for PSCI.

Table 2.

Logistic Regression Analysis.

Factor	B	S.E.	Wald	df	Sig	Exp (B)
Sex	.582	.36	1.58	1	.15	1.85
Age	.082	.0018	9.88	1	.05	2.68
Hypertension history	.625	.15	1.58	1	.05	3.61
Diabetes history	5.62	.51	2.61	1	.06	3.15
Education year	−1.982	.251	42.61	1	.01	3.69
UA	.08	.001	8.61	1	.32	1.08
Hcy	.058	.0031	1.18	1	.01	1.05

Correlations Between Serum Homocysteine Level and Baseline Characteristics of Post-Stroke Cognitive Dysfunction Patients

PSCI patients were divided into low hcy group and high hcy group. As can be seen from Table 3, the low-hcy group and the high-hcy group were significantly different in gender, age, years of education, hyperlipidemia, hypertension, smoking, drinking, history of cerebrovascular disease, FOA, VB12, TG, CHO, HDL, LDL There were significant differences in other aspects, but no significant differences in other aspects (all P > .05). Compared with the low-hcy group, the high-hcy group had higher UC values and a higher risk of diabetes (P = .02). Pearson correlation coefficient analysis showed that serum Hcy levels were significantly correlated with a history of cerebrovascular disease (P > .05). In addition, although there was a correlation between Hcy and the history of diabetes and UA (P < .05), the correlation was weak and the effect on Hcy was negligible. This further suggests that Hcy is an independent factor in PSCI patients (Table 4).

Table 3.

Comparison of Serum Hcy Levels with Baseline Characteristic of the PSCI Group.

Characteristic	Low Hcy (n = 152)	High HcyI (n = 49)	t/χ²	P value
Sex (male, %)	82 (52.95)	25 (51.02)	.85	.86
Age, mean (SD)	71.25 ± 10.52	72.42 ± 11.51	1.58	.95
Education year, mean (SD)	1.07 ± .61	1.05 ± .31	5.62	.82
Hypertension history, n (%)	109 (71.71)	43 (87.75)	6.99	.02
Diabetes history, n (%)	36 (23.68)	13 (26.53)	.05	.88
Smoking history, n (%)	51 (33.55)	14 (28.57)	.04	.21
Drinking history, n (%)	36 (23.68)	13 (26.53)	.18	.61
CD history, n (%)	36 (23.68)	14 (28.57)	3.35	.85
MoCA, mean (SD)	26.51 ± 2.61	26.35 ± 1.86	1.89	.24
FOA (ng/mL), mean (SD)	9.85 ± .84	8.05 ± 1.06	1.52	.62
VB12 (Pg/mL), mean (SD)	548.95 ± 124.85	428.62 ± 108.62	2.05	.42
UA (mmol/L), mean (SD)	325.62 ± 58.62	375.61 ± 85.95	1.39	.02
TG (mmol/L), mean (SD)	1.56 ± .48	1.68 ± .95	.68	.21
CHO (mmol/L), mean (SD)	4.85 ± 1.06	4.59 ± .88	1.35	.18
HDL (mmol/L), mean (SD)	1.09 ± .15	.99 ± .24	1.17	.11
LDL (mmol/L), mean (SD)	2.85 ± .86	2.95 ± .58	1.95	.85

Table 4.

The Correlations of Serum Hcy Level With Other Clinical Indicators and Cognitive Performances in Stroke with Cognitive Impairment.

	Hcy
	r	P value
Diabete history	.625	.01
Cerebrovascular disease history	−.36	.15
UA	.24	.03
Seizure	.18	.02
MoCA	.85	.56

Discussion

Our study found that serum Hcy levels were higher in PSCI patients. In PSCI patients, age, diabetes and Hcy levels were closely associated with cognitive impairment. Multiple logistic regression models also showed that high serum Hcy levels were an independent risk predictor for PSCI.

Hcy is a sulfur-containing amino acid derived from the essential amino acid methionine (Met), produced by mutations in genes encoding Hcy-metabolizing enzymes.^21,22 Hcy is associated with a role in cognitive function, consistent with data from neuroimaging studies suggesting an association between temporal lobe atrophy and HHcy in AD patients.²³ Song et al. Hcy levels were found to be associated with cognitive decline in Parkinson’s disease patients.²⁴ Hyperhomocysteinemia (increased homocysteine levels) is considered cytotoxic and is a biomarker of vascular disease.²⁵ High Hcy levels are associated with mental status in patients with Alzheimer’s disease.²⁶ There was a positive trend in cognitive decline and elevated plasma Hcy concentrations in the general population and patients with cognitive impairment.²⁷ Therefore, Hcy levels may play an important role in the development of a cognitive function.

The pathophysiology of PSD is multifactorial and likely involves decreased levels of monoamines, abnormal neurotrophic response, increased inflammation with dysregulation of hypothalamic-pituitary-adrenal axis, and glutamate-mediated excitotoxicity.²⁸ To diagnose PSCI, the following is needed: complaint of a decline in cognitive function, obtained from the individual or an informant who knows the patient; the deterioration of one or more cognitive domains at a higher level than expected at the given age and education of the patient, confirmed in an objective manner by a professional through a cognitive test; independent function preserved, with no impairment in social and work abilities of the individual.^1,5,29 Although several triage tools are used to detect a decline in cognitive function, MoCA has been the most used screening instrument throughout decades.³⁰ MoCA was developed by Nasreddine and collaborators and has been shown as a tracking tool with a high ability to discriminate normal cognitive function and MCI and early onset dementia. The average time to administer the test is 10 to 15 minutes. The main advantage of MoCA is its sensitivity in detecting MCI and mild AD: 90% and 100%, respectively.^30-32 Therefore, in our study, we used the MoCA to categorize the patients into PSCI and non-PSCI groups. In addition, MoCA has been used extensively in recent studies as a criterion for assessing PSCI^33-36

A growing number of studies have demonstrated an association between elevated serum Hcy levels and an increased risk of stroke.³⁷ Hcy is not only a risk factor for stroke severity, poor prognosis, and stroke recurrence, but is also associated with stroke recurrence.^38,39 Hcy is not only a risk factor for stroke severity, poor prognosis, and stroke recurrence, but is also associated with stroke recurrence.²³ An evident increase in effect measures was observed when Hcy levels exceeded 15 µmol/L, indicating a nonlinear association between ischemic stroke and Hcy levels.⁴⁰ In vivo experiments, the studies provide evidence for the interplay and tight integration between ERK and p38 MAPK signaling mechanisms in response to the hHcy and also in the association of hHcy with ischemia/IPC challenge in the rat brain.⁴¹ Hcy may cause excessive autophagy by downregulation of both PI3K-AKT- and ERK- dependent mTOR signaling, thereby facilitating the toxicity of Hcy on NSCs in ischemic brains.⁴² Li et al also found that Elevated plasma Hcy concentrations are independently associated with the risk of the first ischemic stroke in hypertensive patients with obstructive sleep apnea and plasma Hcy concentrations ≥5 μmol/L surely increased the risk of the first ischemic stroke in hypertensive patients with obstructive sleep apnea.⁴³ Therefore, Hcy is very likely to have an impact on both the cognitive function and the prognosis of stroke. In our study, serum Hcy levels were higher in PSCI patients than in non-PSCI patients. This finding also broadly supports the work of other studies in this area linking Hcy and stroke.^44,45

Homocysteine (Hcy), as one of the risk factors, and uric acid (UA) as the most common antioxidant in serum have their roles in the processes of inflammation and atherogenesis.⁴⁶ The relationship between Hcy and UA has been investigated in a number of diseases. Among US adolescents, Hcy levels were positively correlated with serum uric acid levels and elevated serum uric acid levels, especially in boys aged ≥17 years.⁴⁷ Serum UA level was an independent risk factor for PSCI and these findings indicate that serum UA level was correlated with PSCI in post-stroke patients and is anticipated to be used in clinical practice to reduce the incidence of PSCI.⁴⁸ Serum UA is positively associated with serum Hcy and these two markers synergistically increase cerebrovascular burden and suggested that dietary intervention for sUA and sHcy would be helpful for cognitive decline with vascular lesion.⁴⁹ Takafumi et al found that hyperhomocysteinemia is one of the risk factors associated with cerebrovascular stiffness in hypertensive patients, especially elderly males.⁵⁰ Since HCY and UA participate in the atherosclerotic process and their metabolism, as well as the effects on the cardiovascular system show significant overlaps, their serum level should be analyzed synchronously with the level of CRP and NLR (indicators of the significant inflammatory process in vessels).⁵¹ Serum levels of hydroperoxides, homocysteine and advanced oxidation protein products, and uric acid in older patients with late-onset Alzheimer’s disease or vascular dementia.⁵² Therefore, Serum metabolomic patterns such as Hcy and UA were significantly different between young patients with ischemic stroke and healthy controls and is beneficial in providing a further view into the pathophysiology of young patients with ischemic stroke.⁵³

Homocysteine (Hcy) is a sulfur-containing amino acid that is generated during methionine metabolism. Physiologic Hcy levels are determined primarily by dietary intake and vitamin status. Elevated plasma levels of Hcy can be caused by deficiency of either vitamin B12 or folate. Besides, HHcy has been considered as a risk factor for systemic atherosclerosis and cardiovascular disease (CVD) and HHcy has been reported in many neurologic disorders including cognitive impairment and stroke, independent of long-recognized factors such as hyperlipidemia, hypertension, diabetes mellitus, and smoking.⁵⁴ HHcy modulates the N-homocysteinylation process, promoting a pro-coagulative state and damage of the cellular protein integrity. This altered process could be directly involved in the altered endothelium activation, typical of SVD and protein quality, inhibiting the ubiquitin-proteasome system control.⁵⁵ Mutus et al found that homocysteine could exert its atherogenic action in healthy and diabetic subjects partly by inhibiting platelet nitric oxide production with the subsequent increased platelet activation and aggregation.⁵⁶ However, it is worthwhile that various vitamin supplements affect HCY levels and have a positive effect on the protection against neurological diseases is still debated.⁵⁷

Blood homocysteine and diabetes mellitus (DM) are related to cognitive impairments or dementia. Byeon et al. found that high blood homocysteine levels and DM synergistically aggravate brain damage independently of AD and cerebrovascular disease.⁵⁸ For gestational diabetes mellitus patients, serum homocysteine levels are not associated with HbA1c levels and fasting glycemia.⁵⁹ The present meta-analysis shows that homocysteine level is significantly elevated among women with GDM compared with women with normal glucose tolerance, and this finding persists more during the second trimester.⁶⁰ In addition, homocysteine is an independent risk factor for cognitive impairment in middle-aged T2DM populations.⁶¹ Noor et al also found that patients with diabetes mellitus and hypertension are likely to have increased levels of Hcy and, therefore, must be regularly screened for hyperhomocysteinemia.⁶² The higher levels of serum homocysteine and lower levels of serum betaine are associated with an increased risk of microangiopathy in patients with diabetes.⁶³ For type 1 diabetes, fasting plasma total homocysteine concentrations were within normal limits in children and adolescents who were without any clinical evidence of microvascular and macrovascular complications.⁶⁴ What’s more, tHcy in predicting de novo or recurrent cardiovascular events in individuals with a diabetic complications for example nephropathy.⁶⁵ Therefore, Hcy level may also play an important key role in diabetes which is consistent with our result.

Conclusion

Results of this study demonstrated an association between serum Hcy level and PSCI and that serum Hcy level may serve as a predictive factor for PSCI. Further studies with larger sample sizes are needed to confirm these findings and to identify potential biomarkers for the detection of PSCI.

Supplemental Material

Supplemental Material - The Correlations Between Serum Hcy Level and Seizures and Cognitive Function in Patients After Stroke

Supplemental Material for The Correlations Between Serum Hcy Level and Seizures and Cognitive Function in Patients After Stroke by Chen Lan, Zhiqiang Huang, Xinxin Luo, and Yongcheng Zhang in American Journal of Alzheimer's Disease & Other DementiasÂ®

Footnotes

Acknowledgments

We would like to thank all participants and our hospital.

Author Contributions

Conception and design: LC, ZQH; Acquisition, analysis, and interpretation of the data: LC, ZQH, XXL; Drafting and writing: YCZ; Final approval of the article: LC, ZQH, XXL, YCZ.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Consent for Publication

We all agree to publication.

Data Availability

The data used to support the findings of this study are included within the article.

ORCID iD

Yongcheng Zhang

Supplemental Material

Supplemental material for this article is available online.

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