Stroke Biomarkers Research Articles

Associations of Tissue and Soluble LOX-1 with Human Abdominal Aortic Aneurysm.

Background Indication for prophylactic surgical abdominal aortic aneurysm (AAA) repair depends on the maximal aortic diameter. The lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is the major receptor for uptake of oxidized low-density lipoprotein cholesterol and is implicated in atherosclerosis. A soluble form of LOX-1 (sLOX-1) has been discussed as a novel biomarker in coronary artery disease and stroke. Herein, we assessed the regulation of aortic LOX-1 as well as the diagnostic and risk stratification potential of sLOX-1 in patients with AAA. Methods and Results Serum sLOX-1 was assessed in a case-control study in AAA (n=104) and peripheral artery disease (n=104). sLOX-1 was not statistically different between AAA and peripheral artery disease but was higher in AAA (β=1.28, P=0.04) after adjusting for age, atherosclerosis, type 2 diabetes, prescription of statins, β-blockers, ACE inhibitors, and therapeutic anticoagulation. sLOX-1 was not associated with the aortic diameter, AAA volume, or the thickness of the intraluminal thrombus. Aortic LOX-1 mRNA expression tended to be higher in AAA when compared with disease, and expression was positively associated with cleaved caspase-3, smooth muscle actin, collagen, and macrophage content. Conclusions In AAA, sLOX-1 was differently affected by age, cardiometabolic diseases, and corresponding medical therapies. Comparison with nonatherosclerotic disease would be beneficial to further elucidate the diagnostic potential of sLOX-1, although it was not useful for risk stratification. Aneurysmal LOX-1 mRNA expression was increased and positively associated with smooth muscle cells and collagen content, suggesting that LOX-1 is eventually not deleterious in human AAA and could counteract AAA rupture.

Identification of key biomarkers in ischemic stroke: single-cell sequencing and weighted co-expression network analysis.

At present, there is a lack of accurate early diagnostic markers for ischemic stroke. By using dimensionality reduction cluster analysis, differential expression analysis, weighted co-expression network analysis, protein-protein interaction network analysis, cell heterogeneity and key pathogenic genes were identified in ischemic stroke. Immunomicroenvironment analysis was used to explore the immune landscape and immune associations of key genes in ischemic stroke. The analysis platform we use is R software (version 4.0.5). PCR experiments were used to verify the expression of key genes. Single cell sequencing data in ischemic stroke can be annotated as fibroblast cells, pre-B cell CD34, neutrophils cells, bone marrow (BM), keratinocytes, macrophage, neurons and mesenchymal stem cells (MSC). By the intersection of differential expression analysis and WGCNA analysis, 385 genes were obtained. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that these genes were highly correlated with multiple functions and pathways. Protein-protein interaction network analysis revealed that MRPS11 and MRPS12 were key genes, both of which were down-regulated in ischemic stroke. The Pseudo-time series analysis found that the expression of MRPS12 decreased gradually with the differentiation of pre-B cell CD34 cells in ischemic stroke, suggesting that the downregulation of MRPS12 expression may play an important role in ischemic stroke. At last, PCR showed that MRPS11 and MRPS12 were significantly down-regulated in peripheral blood of patients with ischemic stroke. Our study provides a reference for the study of pathogenesis and key targets of ischemic stroke.

The identification of sex-specific biomarkers in peripheral blood mononuclear cells from elderly individuals with ischemic stroke.

The aim of this study was to identify sex-specific biomarkers for ischemic stroke (IS) prophylaxis in elderly individuals. The GSE22255 dataset for elderly individuals with IS was retrieved from the gene expression omnibus database. Thereafter, gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed, as well as gene set enrichment analysis (GSEA). Furthermore, protein-protein interactions (PPIs) were explored using the STRING database, and to screen central genes from the Cytoscape PPI network, corresponding to peripheral blood samples from elderly individuals, we used the molecular complex detection plug-in and cytoHubba. Moreover, a Venn diagram was used to visualize the key genes common among elderly women and men with IS. Statistical analysis was also performed, and receiver operating characteristic (ROC) curves were constructed to evaluate the specificity and sensitivity of the prediction of IS in the elderly. Compared with the healthy controls, in elderly women with IS, 511 biological process (BP) terms, 16 molecular function (MF) terms, and 34 KEGG terms were significantly enriched, whereas in the elderly men with IS, 681 BP terms, 12 MF terms, and 44 KEGG terms were enriched. The GSEA revealed 99 and 140 significantly enriched gene sets in elderly women and men with IS, respectively. Furthermore, in the PPI network, 10 hub genes for each sex with high specificity and sensitivity were identified using ROC curves. Ten genes for each sex with significant differential expression were also identified in individuals with IS. The novel sex-specific gene targets may be promising diagnostic or prognostic markers and potential therapeutic targets for IS in the elderly.

A typology of cerebral small vessel disease based on imaging markers

BackgroundLacunes, microbleeds, enlarged perivascular spaces (EPVS), and white matter hyperintensities (WMH) are brain imaging features of cerebral small vessel disease (SVD). Based on these imaging markers, we aimed to identify subtypes of SVD and to evaluate the validity of these markers as part of clinical ratings and as biomarkers for stroke outcome.MethodsIn a cross-sectional study, we examined 1207 first-ever anterior circulation ischemic stroke patients (mean age 69.1 ± 15.4 years; mean NIHSS 5.3 ± 6.8). On acute stroke MRI, we assessed the numbers of lacunes and microbleeds and rated EPVS and deep and periventricular WMH. We used unsupervised learning to cluster patients based on these variables.ResultsWe identified five clusters, of which the last three appeared to represent distinct late stages of SVD. The two largest clusters had no to only mild or moderate WMH and EPVS, respectively, and favorable stroke outcome. The third cluster was characterized by the largest number of lacunes and a likewise favorable outcome. The fourth cluster had the highest age, most pronounced WMH, and poor outcome. Showing the worst outcome, the fifth cluster presented pronounced microbleeds and the most severe SVD burden.ConclusionThe study confirmed the existence of different SVD types with different relationships to stroke outcome. EPVS and WMH were identified as imaging features of presumably early progression. The number of microbleeds and WMH severity appear to be promising biomarkers for distinguishing clinical subgroups. Further understanding of SVD progression might require consideration of refined SVD features, e.g., for EPVS and type of lacunes.

Identification of a potential prognostic plasma biomarker of acute ischemic stroke via untargeted LC-MS metabolomics.

Strokeisthesuddendeathofbraincellsinalocalized areaduetoan inadequatebloodflow or blood vessel rupture, and it seriously affects the quality of life. The metabolite biomarkers are needed for predicting the functional outcome of acute ischemic stroke (AIS). To identify biomarkers for AIS, untargeted LC/MS metabolomics was performed on plasma samples from subjects with favorable prognosis (mRS ≤ 2) and unfavorable prognosis (mRS>2). The identified markers were further absolutely quantified by a targeted MRM approach. There were 10 upregulated and 26 downregulated markers. Among these candidates, one was successfully identified as glycocholic acid and then absolutely quantified in plasma samples. Glycocholic acid could discriminate between subjects with favorable and unfavorable prognosis with an area under the curve (AUC) of 0.68 and odds ratio of 5.88. Glycocholic acid was identified as a potential plasma metabolite marker of non-progressive outcomes after ischemic stroke and could serve as predictive prognostic markers for clinical acute stroke outcomes.

The expression levels of circulating miR-140-3p, miR-130a-3p, and miR-320b as diagnostic biomarkers in acute ischemic stroke.

Plasma miRNAs can characterize several diseases, including acute ischemic stroke (AIS), which is noninvasive and currently affordable in most laboratories worldwide. We aimed to demonstrate plasma miR-140-3p, miR-130a-3p, and miR-320b as diagnostic biomarkers in AIS.GSE110993 and GSE86291 datasets were analyzed to obtain plasma differentially expressed miRNAs between AIS and healthy control subjects (HCs). We further applied RT-qPCR for the validation in 85 AIS patients and 85 HCs. Receiver operating characteristic (ROC) curve were conducted to evaluate their diagnostic utility in AIS. Correlation was analyzed between DEmiRNAs and clinical and laboratory parameters, as well as inflammatory markers. The plasma levels of miR-140-3p, miR-130a-3p, and miR-320b were found to be consistently altered in both GSE110993 and GSE86291 datasets. In comparison to HCs, AIS patients at admission exhibited lower levels of miR-140-3p and miR-320b and higher level of miR-130a-3p in their plasma. The ROC analysis revealed that plasma miR-140-3p, miR-130a-3p, and miR-320b had area under the curve values of 0.790, 0.831, and 0.907, respectively. When combined, these miRNAs showed superior discriminatory power with a sensitivity of 91.76% and specificity of 95.29%. Plasma miR-140-3p and miR-320b negatively correlated glucose levels and inflammatory markers (IL-6, MMP-2, MMP-9, and VEGF) in AIS patients. Conversely, plasma miR-130a-3p levels were positively associated with glucose levels and these markers. Plasma miR-140-3p, miR-130a-3p, and miR-320b levels varied significantly among AIS patients with different NIHSS scores. Plasma miR-140-3p, miR-130a-3p, and miR-320b had high diagnostic value in AIS patients, which were correlated with inflammation and severity in stroke.

The potential role of micro-RNA 125b-5p level in predicting outcome from thrombolytic therapy in patients with acute ischemic stroke

Several studies highlighted a significant role of specific miRNA as diagnostic and prognostic biomarkers for acute ischemic stroke. The aim of this work was to study micro-RNA 125b-5p level in patients with acute ischemic stroke in relation to stroke etiology, risk factors, severity and outcome. This case–control study was conducted on 40 patients with acute ischemic stroke eligible for receiving rt-PA and 40 age and sex matched healthy controls, Patients were submitted to neurological and radiological assessment. Functional outcome after 3 months was assessed using the modified Rankin Scale (mRS). Plasma micro-RNA 125b-5p levels were measured for both patients and control groups by quantitative real time PCR. MiRNA-125b-5p was extracted from the plasma samples then Real-time quantitative reversed transcription PCR (RT-qPCR) analysis was done. To analyze miRNA-125b-5p expression in plasma, the ∆Cq value of miRNA-125b-5p was calculated by subtracting Cq of miRNA-125b-5p from the average Cq of MiRNA RNU6B. Stroke patients had significantly higher circulating micro-RNA 125b-5p levels in comparison to healthy controls (P value = 0.01). The circulating levels of micro-RNA 125b-5p were positively correlated with stroke severity assessed by National Institutes of Health Stroke Scale (NIHSS) and infarction size. Stroke patients with poor outcome had significantly higher circulating levels of micro-RNA 125b-5p in comparison to those with good outcome (P value ≤ 0.001). The circulating levels of micro-RNA 125b-5p were significantly higher in patients who developed complications after receiving rt-PA (P value ≤ 0.001). Logistic regression model revealed that each unit increase in micro-RNA125b-5p decreased the odds of good outcome by 0.095 (95% CI 0.016–0.58, P value = 0.011). Plasma micro-RNA 125b-5p is significantly elevated is ischemic stroke patients. It is positively correlated with stroke severity and strongly associated with poor outcome and complications after thrombolytic therapy.

EEG Microstates as a Signature of Hemispheric Lateralization in Stroke

Stroke recovery trajectories vary substantially. The need for tracking and prognostic biomarkers in stroke is utmost for prognostic and rehabilitative goals: electroencephalography (EEG) advanced signal analysis may provide useful tools toward this aim. EEG microstates quantify changes in configuration of neuronal generators of short-lasting periods of coordinated synchronized communication within large-scale brain networks: this feature is expected to be impaired in stroke. To characterize the spatio-temporal signatures of EEG microstates in stroke survivors in the acute/subacute phase, EEG microstate analysis was performed in 51 first-ever ischemic stroke survivors [(28–82) years, 24 with right hemisphere (RH) lesion] who underwent a resting-state EEG recording in the acute and subacute phase (from 48 h up to 42 days after the event). Microstates were characterized based on 4 parameters: global explained variance (GEV), mean duration, occurrences per second, and percentage of coverage. Wilcoxon Rank Sum tests were performed to compare features of each microstate across the two groups [i.e., left hemisphere (LH) and right hemisphere (RH) stroke survivors]. The canonical microstate map D, characterized by a mostly frontal topography, displayed greater GEV, occurrence per second, and percentage of coverage in LH than in RH stroke survivors (p < 0.05). The EEG microstate map B, with a left-frontal to right-posterior topography, and F, with an occipital-to-frontal topography, exhibited a greater GEV in RH than in LH stroke survivors (p = 0.015). EEG microstates identified specific topographic maps which characterize stroke survivors’ lesioned hemisphere in the acute and early subacute phase. Microstate features offer an additional tool to identify different neural reorganization.

Clinical Application of Circular RNAs as Biomarkers in Acute Ischemic Stroke.

Despite the substantial improvement in diagnosis and treatment within the last decades, ischemic stroke still represents a challenge, responsible still for a high burden of morbidity and mortality. Among the unmet clinical needs are the difficulties in identifying those subjects with the greatest risk of developing a stroke, the challenges in obtaining a timely diagnosis, the prompt recognition of the different clinical forms of stroke, the assessment of the response to treatments and the prognostic assessment. All these issues might be improved with appropriate smart biomarkers that could better inform clinical management. The present article offers an overview of the potential role of circular RNAs as disease biomarkers in stroke. A systematic approach was adopted to gather all potentially relevant information in order to provide a panoramic view on this class of promising molecules.

The burden of suspected strokes in uMgungundlovu - Can biomarkers aid prognostication?

The burden of stroke is increasing worldwide. The hierarchical healthcare referral system in South Africa (SA) poses unique challenges to clinicians when caring for people with suspected strokes (PsS). To improve health outcomes, novel strategies are required to provide adequate care, including prognostication, in SA. To determine the subjective burden of and challenges posed by suspected stroke cases and the potential usefulness of biomarkers in prognostication. This study was conducted in the uMgungundlovu Health District (UHD), KwaZulu-Natal, SA. An online questionnaire was distributed to doctors within the UHD. Demographic data and answers to a series of 5-point-Likert-type statements were collected. Seventy-seven responses were analysed. A third of doctors worked in primary healthcare facilities (PHCare) and saw ≥ 2.15 suspected strokes-per-doctor-per-week, compared to ≥ 1.38 seen by doctors working in higher levels of healthcare. Neuroimaging was relied upon by > 85% of doctors, with nearly half of PHCare doctors having to refer patients to facilities 5 km - 20 km away, with resultant delays. Knowledge about prognostic biomarkers in strokes was poor, yet most doctors believed that a biomarker would assist in the prognostication process and they would use it routinely. Doctors in this study faced a significant burden of strokes and rely on neuroimaging to guide their management; however, many challenges exist in obtaining such imaging, especially in the PHCare setting. The need for prognostic biomarkers was clear. This research lays the platform for further studies to investigate prognostic biomarkers in stroke in our clinical setting.

Quantitative analysis of cell-free plasma DNA as a prognostic biomarker in acute ischemic stroke patients

BackgroundStroke has become a leading cause of death and disability worldwide, and despite the introduction of new screening programs, therapies, and monitoring technologies, there is still a need to develop more useful biochemical tests to monitor treatment response and inform clinical decision-making. Cell-free DNA released from damaged neurons in stroke patients may be useful in assessing stroke prognosis. The purpose of this study was to evaluate the role of cell-free DNA and a highly sensitive blood biomarker in acute ischemic stroke. 188 patients with acute ischemic stroke were recruited for the study. The level of cell-free DNA in plasma was estimated using a real-time PCR assay for the β-globin gene (Qiagen-Rotor-Gene Q MDX, Germany). Clinical assessment was performed with the National Institutes of Health Stroke Scale (NIHSS) at the time of admission. After a period of three months from the onset of stroke, (mRS) scores were estimated using the modified Rankin scale.ResultsElevated levels of cell-free DNA were found in patients with higher NIHSS admission scores and mRS 3-month scores (p < 0.05). The regression analysis revealed that the markers are associated with an unfavorable outcome in comparison to other stroke risk factors (R2 = 0.224). Stroke outcome was relatively better in patients with a cell-free DNA level < 10,000 kilogenome equivalents/L (p < 0.05).ConclusionsMeasurement of total cell-free DNA levels is a simpler and less-expensive biomarker suggesting potential clinical application of blood-based test. Cell-free DNA can contribute to the clinical evaluation and optimal management of ischemic stroke patients. This biomarker seems to have the potential to predict the long-term prognosis of acute ischemic stroke.

Circulating Extracellular-Vesicle-Incorporated MicroRNAs as Potential Biomarkers for Ischemic Stroke in Patients With Cancer.

This study aimed to evaluate whether extracellular-vesicle-incorporated microRNAs (miRNAs) are potential biomarkers for cancer-related stroke. This cohort study compared patients with active cancer who had embolic stroke of unknown sources (cancer-stroke group) with patients with only cancer, patients with only stroke, and healthy individuals (control groups). The expression profiles of miRNAs encapsulated in plasma exosomes and microvesicles were evaluated using microarray and validated using quantitative real-time polymerase chain reaction. The XENO-QTM miRNA assay technology was used to determine the absolute copy numbers of individual miRNAs in an external validation cohort. This study recruited 220 patients, of which 45 had cancer-stroke, 76 were healthy controls, 39 were cancer controls, and 60 were stroke controls. Three miRNAs (miR-205-5p, miR-645, and miR-646) were specifically incorporated into microvesicles in patients with cancer-related stroke, cancer controls, and stroke controls. The area under the receiver operating characteristic curves of these three miRNAs were 0.7692-0.8510 for the differentiation of patients with cancer-stroke from cancer-controls and 0.8077-0.8846 for the differentiation of patients with cancer-stroke from stroke controls. The levels of several miRNAs were elevated in the plasma exosomes of patients with cancer, but were lower than those in plasma microvesicles. An in vivo study showed that systemic injection of miR-205-5p promoted the development of arterial thrombosis and elevation of D-dimer levels. Stroke due to cancer-related coagulopathy was associated with deregulated expression of miRNAs, particularly microvesicle-incorporated miR-205-5p, miR-645, and miR-646. Further prospective studies of extracellular-vesicle-incorporated miRNAs are required to confirm the diagnostic role of miRNAs in patients with stroke and to screen the roles of miRNAs in patients with cancer.

Association between PAI-1 Polymorphisms and Ischemic Stroke in a South Korean Case-Control Cohort.

Stroke is the second leading cause of death in the world. Approximately 80% of strokes are ischemic in origin. Many risk factors have been linked to stroke, including an increased level of plasminogen activator inhibitor-1 (PAI-1). PAI-1 levels increase and remain elevated in blood during the acute phase of ischemic stroke, which can impair fibrinolytic activity, leading to coronary artery disease and arterial thrombotic disorders. Here, we present a case-control study of 574 stroke patients and 425 controls seen for routine health examination or treatment for nonspecific dizziness, nonorganic headache, or anxiety for positive family history of stroke at the Bundang Medical Center in South Korea. Polymorphisms in PAI-1 were identified by polymerase chain reaction/restriction fragment length polymorphism analysis using genomic DNA. Specifically, three variations (-675 4G>5G, 10692T>C, and 12068G>A) were linked to a higher overall prevalence of stroke as well as a higher prevalence of certain stroke subtypes. Haplotype analyses also revealed combinations of these variations (-844G>A, -675 4G>5G, 43G>A, 9785A>G, 10692T>C, 11053T>G, and 12068G>A) that were significantly associated with a higher prevalence of ischemic stroke. To the best of our knowledge, this is the first strong evidence that polymorphic sites in PAI-1 promoter and 3'-UTR regions are associated with higher ischemic stroke risk. Furthermore, the PAI-1 genotypes and haplotypes identified here have potential as clinical biomarkers of ischemic stroke and could improve the prognosis and future management of stroke patients.

Circular RNA as biomarkers for acute ischemic stroke: Asystematic review and meta-analysis.

Rapid diagnosis of acute ischemic stroke (AIS) patients is still challenging, and reliable biomarkers are needed. Noncoding RNAs are important for many physiological activities, among which circular RNAs (circRNAs) have been proven to be more tissue-specific and conservative. Many recent studies found the potential of circRNAs as biomarkers for many diseases, including cardiovascular diseases, cancers, and ischemic stroke. This systemic review and meta-analysis aimed to identify circRNAs as potential biomarkers for AIS. This study has been prospectively registered in PROSPERO (Registration No. 11 CRD42021288033). Published literature comparing circRNA expression profiles between AIS and non-AIS in human and animal models were retrieved from the articles published by January 2023 in major databases. We descriptively summarized the included studies, conducted meta-analysis under a random effects model, and did bioinformatics analysis including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Totally 23 studies were included, reporting 18 distinctive upregulated and 20 distinctive downregulated circRNAs. Diagnostic meta-analysis indicated discriminative ability of the circRNAs. Furthermore, circRNA HECTD1, circRNA DLGAP4, circRNA CDC14A, circRNA SCMH1, and circRNA TLK1 were reported with the same regulation trend in more than one study (animal studies included). GO and KEGG enrichment analyses indicated that the target genes of these five circRNAs were enriched in regulating cell proliferation, apoptosis, and oxidative stress. This study demonstrates that circRNAs (circRNA HECTD1, circRNA DLGAP4, circRNA CDC14A, circRNA SCMH1, and circRNA TLK1) generally are promising as potential biomarkers for AIS. However, due to the limited number of studies, diagnostic value of individual circRNA could not be validated. More in vitro and in vivo functional studies are needed.

Trimethylamine-N-oxide: a potential biomarker and therapeutic target in ischemic stroke.

Ischemic stroke is by far the most common cerebrovascular disease and a major burden to the global economy and public health. Trimethylamine-N-oxide (TMAO), a small molecule compound produced by the metabolism of intestinal microorganisms, is reportedly associated with the risk of stroke, as well as the severity and prognosis of stroke; however, this conclusion remains contentious. This article reviews the production of TMAO, TMAO's relationship with different etiological types of ischemic stroke, and the possibility of reducing TMAO levels to improve the prognosis of ischemic stroke.

Total oxidant/antioxidant status, copper and zinc levels in acute ischemic stroke patients after mechanical thrombectomy

Background and purposeWe aimed to identify the relationship of total antioxidant status, total oxidant status, and copper (Cu) and zinc (Zn) situations with the short-term prognostic and stroke severity in acute ischemic stroke cases who were successfully recanalized by mechanical thrombectomy. MethodsA study of 36 acute ischemic stroke patients and 22 controls were prospectively studied. Tube samples were attained at admission and 24 h after recanalization. In patients who were successfully recanalized (thrombolysis in cerebral infarction ≥ 2b), a 3-month modified Rankin scale (mRS) score of 0–2 was considered a good prognosis, and a score of 3–6 was considered a poor prognosis. ResultsAdmission Cu levels were significantly higher in the poor prognosis group (p = 0.031). In the multivariate logistic regression analysis, Cu was not associated with poor prognosis (p = 0.357). Cu and Zn levels were lower in the patients group compared to controls (p = 0.014 and p = 0.010, respectively). There was no correlation between National Institute of Health Stroke Scale and biomarkers (p > 0.05). The temporal variation of biomarkers did not differ significantly between the good prognosis and poor prognosis groups (p interaction > 0.05). ConclusionsHigh admission Cu levels were associated with poor prognosis, but this association was limited. In addition, Cu and Zn levels were statistically lower in patients. There was no relationship between total antioxidant/oxidant status and short-term prognosis or stroke severity

Common clinical blood and urine biomarkers for ischemic stroke: an Estonian Electronic Health Records database study

BackgroundIschemic stroke (IS) is a major health risk without generally usable effective measures of primary prevention. Early warning signals that are easy to detect and widely available can save lives. Estonia has one nation-wide Electronic Health Record (EHR) database for the storage of medical information of patients from hospitals and primary care providers.MethodsWe extracted structured and unstructured data from the EHRs of participants of the Estonian Biobank (EstBB) and evaluated different formats of input data to understand how this continuously growing dataset should be prepared for best prediction. The utility of the EHR database for finding blood- and urine-based biomarkers for IS was demonstrated by applying different analytical and machine learning (ML) methods.ResultsSeveral early trends in common clinical laboratory parameter changes (set of red blood indices, lymphocyte/neutrophil ratio, etc.) were established for IS prediction. The developed ML models predicted the future occurrence of IS with very high accuracy and Random Forests was proved as the most applicable method to EHR data.ConclusionsWe conclude that the EHR database and the risk factors uncovered are valuable resources in screening the population for risk of IS as well as constructing disease risk scores and refining prediction models for IS by ML.

Integration of Mendelian randomisation and systems biology models to identify novel blood-based biomarkers for stroke

Stroke is the second largest cause of mortality in the world. Genome-wide association studies (GWAS) have identified some genetic variants associated with stroke risk, but their putative functional causal genes are unknown. Hence, we aimed to identify putative functional causal gene biomarkers of stroke risk. We used a summary-based Mendelian randomisation (SMR) approach to identify the pleiotropic associations of genetically regulated traits (i.e., gene expression and DNA methylation) with stroke risk. Using SMR approach, we integrated cis-expression quantitative loci (cis-eQTLs) and cis-methylation quantitative loci (cis-mQTLs) data with GWAS summary statistics of stroke. We also utilised heterogeneity in dependent instruments (HEIDI) test to distinguish pleiotropy from linkage from the observed associations identified through SMR analysis. Our integrative SMR analyses and HEIDI test revealed 45 candidate biomarker genes (FDR < 0.05; PHEIDI > 0.01) that were pleiotropically or potentially causally associated with stroke risk. Of those candidate biomarker genes, 10 genes (HTRA1, PMF1, FBN2, C9orf84, COL4A1, BAG4, NEK6, SH2B3, SH3PXD2A, ACAD10) were differentially expressed in genome-wide blood transcriptomics data from stroke and healthy individuals (FDR < 0.05). Functional enrichment analysis of the identified candidate biomarker genes revealed gene ontologies and pathways involved in stroke, including “cell aging”, “metal ion binding” and “oxidative damage”. Based on the evidence of genetically regulated expression of genes through SMR and directly measured expression of genes in blood, our integrative analysis suggests ten genes as blood biomarkers of stroke risk. Furthermore, our study provides a better understanding of the influence of DNA methylation on the expression of genes linked to stroke risk.

Disturbed Ratios between Essential and Toxic Trace Elements as Potential Biomarkers of Acute Ischemic Stroke.

Cadmium (Cd) and lead (Pb) are known to be two of the metal contaminants that pose the greatest potential threat to human health. The purpose of this research study was to compare the levels of toxic metals (Cd, Pb) in patients with acute ischemic stroke (AIS), with a control group in Podlaskie Voivodeship, Poland. The study also aimed to assess the correlations between toxic metals and clinical data in AIS patients, and to assess the potential effect of smoking. The levels of mineral components in the collected blood samples were assessed by means of atomic absorption spectrometry (AAS). The Cd blood concentration was significantly higher in AIS patients as compared to the control group. We found that the molar ratios of Cd/Zn and Cd/Pb were significantly higher (p < 0.001; p < 0.001, respectively), when the molar ratios of Se/Pb, Se/Cd, and Cu/Cd were significantly lower (p = 0.01; p < 0.001; p < 0.001, respectively), in AIS patients as compared to control subjects. However, there were no considerable fluctuations in relation to the blood Pb concentration or molar ratios of Zn/Pb and Cu/Pb between our AIS patients and the control group. We also found that patients with internal carotid artery (ICA) atherosclerosis, particularly those with 20-50% ICA stenosis, had higher concentrations of Cd and Cd/Zn, but lower Cu/Cd and Se/Cd molar ratios. In the course of our analysis, we observed that current smokers among AIS patients had significantly higher blood-Cd concentrations, Cd/Zn and Cd/Pb molar ratios, and hemoglobin levels, but significantly lower HDL-C concentrations, Se/Cd, and Cu/Cd molar ratios. Our research has shown that the disruption of the metal balance plays a crucial role in the pathogenesis of AIS. Furthermore, our results broaden those of previous studies on the exposure to Cd and Pb as risk factors for AIS. Further investigations are necessary to examine the probable mechanisms of Cd and Pb in the onset of ischemic stroke. The Cd/Zn molar ratio may be a useful biomarker of atherosclerosis in AIS patients. An accurate assessment of changes in the molar ratios of essential and toxic trace elements could serve as a valuable indicator of the nutritional status and levels of oxidative stress in AIS patients. It is critical to investigate the potential role of exposure to metal mixtures in AIS, due to its public health implications.

CT hyperdense cerebral artery sign reflects distinct proteomic composition in acute ischemic stroke thrombus

BackgroundHyperdense cerebral artery sign (HCAS) is an imaging biomarker in acute ischemic stroke (AIS) that has been shown to be associated with various clinical outcomes and stroke etiology. While prior...