Stroke Biomarkers Research Articles

Identification of Serum Biomarkers of Ischemic Stroke in a Hypertensive Population Based on Metabolomics and Lipidomics.

Hypertensive individuals are at a high risk of stroke, and thus, prevention of stroke in hypertensive patients is essential. Metabolomics and lipidomics can be used to identify diagnostic biomarkers and conduct early assessments of stroke risk in hypertensive populations. In this study, serum samples were collected from 30 hypertensive ischemic stroke (IS), 30 matched hypertensive and 30 matched healthy participants. Metabolomics and lipidomics analyses were conducted via liquid chromatography-tandem mass spectrometry, and the data were analyzed using multivariate and univariate statistical methods. A random forest algorithm and binary logistic regression were used to screen the biomarkers and establish diagnostic model. We detected 21 differential metabolites and 38 differential lipids between the hypertensive IS and healthy group. Moreover, we found 18 differential metabolites and 31 differential lipids between the hypertensive IS and hypertension group. In particular, the following seven metabolites or lipids distinguished the hypertensive IS from the healthy group: 4-hydroxyphenylpyruvic acid, cafestol, phosphatidylethanolamine (PE) (18:0p/18:2), PE (16:0e/20:4), (O-acyI)-1-hydroxy fatty acid (36:3), PE (16:0p/20:3) and PE (18:1p/18:2) (rep). The following seven biomarkers distinguished the hypertensive IS from the hypertension group: diglyceride (DG) (20:1/18:2), PE (18:0p/18:2), PE (16:0e/22:5), phosphatidylcholine (40:7), dimethylphosphatidylethanolamine (50:3), DG (18:1/18:2), and 4-hydroxyphenylpyruvic acid. The aforementioned panels had good diagnostic and predictive ability for hypertensive IS. Our study determines the metabolomic and lipidomic profiles of hypertensive IS patients and thereby identifies potential biomarkers of the presence of IS in hypertensive populations.

Multifractal foundations of biomarker discovery for heart disease and stroke

Any reliable biomarker has to be specific, generalizable, and reproducible across individuals and contexts. The exact values of such a biomarker must represent similar health states in different individuals and at different times within the same individual to result in the minimum possible false-positive and false-negative rates. The application of standard cut-off points and risk scores across populations hinges upon the assumption of such generalizability. Such generalizability, in turn, hinges upon this condition that the phenomenon investigated by current statistical methods is ergodic, i.e., its statistical measures converge over individuals and time within the finite limit of observations. However, emerging evidence indicates that biological processes abound with nonergodicity, threatening this generalizability. Here, we present a solution for how to make generalizable inferences by deriving ergodic descriptions of nonergodic phenomena. For this aim, we proposed capturing the origin of ergodicity-breaking in many biological processes: cascade dynamics. To assess our hypotheses, we embraced the challenge of identifying reliable biomarkers for heart disease and stroke, which, despite being the leading cause of death worldwide and decades of research, lacks reliable biomarkers and risk stratification tools. We showed that raw R-R interval data and its common descriptors based on mean and variance are nonergodic and non-specific. On the other hand, the cascade-dynamical descriptors, the Hurst exponent encoding linear temporal correlations, and multifractal nonlinearity encoding nonlinear interactions across scales described the nonergodic heart rate variability more ergodically and were specific. This study inaugurates applying the critical concept of ergodicity in discovering and applying digital biomarkers of health and disease.

The Diagnostic Model of Ligusticum Chuanxiong Hort. Against Cerebral Stroke Using Network Pharmacology and Transcriptomics Analyses.

Cerebral stroke is a leading cause of death and disability worldwide. Ligusticum Chuanxiong Hort. (LCH), a well-known Chinese herb, is widely used for the treatment of cerebral stroke. This study aimed to investigate the underlying mechanisms of LCH in cerebral stroke and develop a diagnostic model. We employed network pharmacology analyses to identify the active compounds, targets, and underlying mechanisms of LCH for treating cerebral stroke. Molecular docking was performed to visualize the binding site between the core active compounds and hub targets. Furthermore, a diagnostic model for cerebral stroke was constructed based on transcriptomic analysis. Our findings revealed that LCH contains multiple active ingredients, including oleic acid and caffeic acid. Protein-protein interaction network analysis identified IL1B, CCL2, MAPK3, PTGS2, JUN, MMP9, TLR4, HIF1A, PPARA, FOS, PTEN, NFE2L2, TLR2, TIMP1, and SOD2 as the top 15 hub genes. Kyoto Encyclopedia of Genes and Genomes pathway analysis highlighted the enrichment of TNF and IL-17 signaling pathways. Molecular docking analysis demonstrated binding sites between oleic acid, caffeic acid, and MMP9, PPARP, PTEN, and TIMP1. The diagnostic model indicated that FOS, MMP9, PPARA, PTEN, TIMP1, and TLR2 serve as blood biomarkers for cerebral stroke. This study demonstrates that LCH alleviates the symptoms following cerebral stroke through interactions with the TNF and IL-17 signaling pathways. The findings contribute to a better understanding of the therapeutic mechanisms of LCH and offer insights into the development of a diagnostic model for cerebral stroke.

MicroRNAs as Potential Biomarkers of Post-Traumatic Epileptogenesis: A Systematic Review.

Structural or post-traumatic epilepsy often develops after brain tissue damage caused by traumatic brain injury, stroke, infectious diseases of the brain, etc. Most often, between the initiating event and epilepsy, there is a period without seizures-a latent period. At this time, the process of restructuring of neural networks begins, leading to the formation of epileptiform activity, called epileptogenesis. The prediction of the development of the epileptogenic process is currently an urgent and difficult task. MicroRNAs are inexpensive and minimally invasive biomarkers of biological and pathological processes. The aim of this study is to evaluate the predictive ability of microRNAs to detect the risk of epileptogenesis. In this study, we conducted a systematic search on the MDPI, PubMed, ScienceDirect, and Web of Science platforms. We analyzed publications that studied the aberrant expression of circulating microRNAs in epilepsy, traumatic brain injury, and ischemic stroke in order to search for microRNAs-potential biomarkers for predicting epileptogenesis. Thus, 31 manuscripts examining biomarkers of epilepsy, 19 manuscripts examining biomarkers of traumatic brain injury, and 48 manuscripts examining biomarkers of ischemic stroke based on circulating miRNAs were analyzed. Three miRNAs were studied: miR-21, miR-181a, and miR-155. The findings showed that miR-21 and miR-155 are associated with cell proliferation and apoptosis, and miR-181a is associated with protein modifications. These miRNAs are not strictly specific, but they are involved in processes that may be indirectly associated with epileptogenesis. Also, these microRNAs may be of interest when they are studied in a cohort with each other and with other microRNAs. To further study the microRNA-based biomarkers of epileptogenesis, many factors must be taken into account: the time of sampling, the type of biological fluid, and other nuances. Currently, there is a need for more in-depth and prolonged studies of epileptogenesis.

Integration of 16S rRNA gene sequencing and LC/MS-based metabolomic analysis of early biomarkers of acute ischaemic stroke in Tibetan miniature pigs

Acute ischaemic stroke (AIS) is a complex, systemic, pathological, and physiological process. Systemic inflammatory responses and disorders of the gut microbiome contribute to increased mortality and disability following AIS. We conducted 16S high-throughput sequencing and ultra-performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry-based non-targeted metabolomic analyses of the plasma from a Tibetan miniature pig middle cerebral artery occlusion (MCAO) model. A significant decrease in the abundance of Firmicutes and a significant increase in the abundance of Actinobacteria were observed after the onset of AIS. Among the plasma metabolites, the levels of phospholipids and amino acids were considerably altered. Loading values and differential metabolite–bacterial group association analyses of the metabolome and microbiome indicated a correlation between the microbiome and metabolome of Tibetan miniature pigs after MCAO. Furthermore, significant changes were observed in the ABC transporter pathway and purine metabolism in the gut microbiome–plasma metabolome during the early stage of AIS. Kyoto Encyclopaedia of Genes and Genomes enrichment analysis showed that arginine, proline, and cyanoamino acid metabolism was upregulated while ABC transporter metabolism pathway and carbohydrate digestion and absorption were substantially downregulated. The results of this study suggest that AIS affects the gut microbiota and plasma metabolites in Tibetan miniature pigs and that faecal microbiota transplantation could be a potential therapeutic approach for AIS.

Measures of Aging Biology in Saliva and Blood as Novel Biomarkers for Stroke and Heart Disease in Older Adults.

The role of aging biology as a novel risk factor and biomarker for vascular outcomes in different accessible body tissues such as saliva and blood remain unclear. We aimed to (1) assess the role of aging biology as a risk factor of stroke and heart disease among individuals of same chronologic age and sex and (2) compare aging biology biomarkers measured in different accessible body tissues as novel biomarkers for stroke and heart disease in older adults. This study included individuals who consented for blood and saliva draw in the Venous Blood Substudy and Telomere Length Study of the Health and Retirement Study (HRS). The HRS is a population-based, nationally representative longitudinal survey of individuals aged 50 years and older in the United States. Saliva-based measures included telomere length. Blood-based measures included DNA methylation and physiology biomarkers. Propensity scores-matched analyses and Cox regression models were conducted. This study included individuals aged 50 years and older, who consented for blood (N = 9,934) and saliva (N = 5,808) draw in the HRS. Blood-based biomarkers of aging biology showed strong associations with incident stroke as follows: compared with the lowest tertile of blood-based biomarkers of aging, biologically older individuals had significantly higher risk of stroke based on DNA methylation Grim Age clock (adjusted hazard ratio [aHR] = 2.64, 95% CI 1.90-3.66, p < 0.001) and Physiology-based Phenotypic Age clock (aHR = 1.75, 95% CI 1.27-2.42, p < 0.001). In secondary analysis, biologically older individuals had increased risk of heart disease as follows: DNA methylation Grim Age clock (aHR = 1.77, 95% CI 1.49-2.11, p < 0.001) and Physiology-based Phenotypic Age clock (aHR = 1.61, 95% CI 1.36-1.90, p < 0.001). Compared with saliva-based telomere length, blood-based aging physiology and some DNA methylation biomarkers are strongly associated with vascular disorders including stroke and are more precise and sensitive biomarkers of aging. Saliva-based telomere length and blood-based DNA methylation and physiology biomarkers likely represent different aspects of biological aging and accordingly vary in their precision as novel biomarkers for optimal vascular health.

TMT and PRM Based Quantitative Proteomics to Explore the Protective Role and Mechanism of Iristectorin B in Stroke.

Stroke is a serious disease caused by the rupture or blockage of the cerebrovascular system. Its pathogenesis is complex and involves multiple mechanisms. Iristectorin B is a natural isoflavone that has certain anti stroke effects. In this study, an in vitro stroke injury model of glyoxylate deprivation was established using PC12 cells, which was used to evaluate the anti-stroke activity of Iristectorin B in ejecta stem. The results showed that Iristectorin B, a natural isoflavone derived from Dried Shoot, significantly reduced the damage to PC12 cells caused by oxygen glucose deprivation/reoxygenation, decreased apoptosis, enhanced cell survival and reduced Ca2+, LDH and ROS levels. The results showed that Iristectorin B had a significant protective effect on Na2S2O4-injured PC12 cells, and the mechanism may be related to the protective effect of neurons in the brain. After protein extraction and various analyses were performed, a series of cutting-edge technologies were organically combined to study the quantitative proteome of each group. Differential proteins were then analyzed. According to the protein screening principle, ferroptosis-related proteins were most closely associated with stroke. The differential proteins associated with ferroptosis screened were SLC3A2, TFR1 and HMOX1, with HMOX1 being the most significantly elevated and reduced via dosing. Iristectorin B may act as a protective agent against stroke by regulating ferroptosis, and SLC3A2, TFR1 and HMOX1 may serve as potential diagnostic biomarkers for stroke, providing additional evidence to support the importance of ferroptosis in stroke.

Prognostic Neuroimaging Biomarkers in Acute Vascular Brain Injury and Traumatic Brain Injury.

Prognostic imaging biomarkers after acute brain injury inform treatment decisions, track the progression of intracranial injury, and can be used in shared decision-making processes with families. Herein, key established biomarkers and prognostic scoring systems are surveyed in the literature, and their applications in clinical practice and clinical trials are discussed. Biomarkers in acute ischemic stroke include computed tomography (CT) hypodensity scoring, diffusion-weighted lesion volume, and core infarct size on perfusion imaging. Intracerebral hemorrhage biomarkers include hemorrhage volume, expansion, and location. Aneurysmal subarachnoid biomarkers include hemorrhage grading, presence of diffusion-restricting lesions, and acute hydrocephalus. Traumatic brain injury CT scoring systems, contusion expansion, and diffuse axonal injury grading are reviewed. Emerging biomarkers including white matter disease scoring, diffusion tensor imaging, and the automated calculation of scoring systems and volumetrics are discussed.

Targeting Neutrophil Extracellular Traps for Stroke Prognosis: A Promising Path.

Stroke has become the first cause of functional disability and one of the leading causes of mortality worldwide. Therefore, it is of crucial importance to develop accurate biomarkers to assess stroke risk and prognosis. Emerging evidence suggests that neutrophil extracellular trap (NET) levels may serve as a valuable biomarker to predict stroke occurrence and functional outcome. NETs are known to create a procoagulant state by serving as a scaffold for tissue factor (TF) and platelets inducing thrombosis by activating coagulation pathways and endothelium. A literature search was conducted in two databases (MEDLINE and Scopus) to trace all relevant studies published between 1 January 2016 and 31 December 2022, addressing the potential utility of NETs as a stroke biomarker. Only full-text articles in English were included. The current review includes thirty-three papers. Elevated NET levels in plasma and thrombi seem to be associated with increased mortality and worse functional outcomes in stroke, with all acute ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage included. Additionally, higher NET levels seem to correlate with worse outcomes after recanalization therapies and are more frequently found in strokes of cardioembolic or cryptogenic origin. Additionally, total neutrophil count in plasma seems also to correlate with stroke severity. Overall, NETs may be a promising predictive tool to assess stroke severity, functional outcome, and response to recanalization therapies.

Reperfusion Therapies in Acute Ischemic Stroke Beyond the Conventional Time Window: A Narrative Review.

Stroke is the second most common cause of death worldwide, with 50% of survivors experiencing long-term disability. For more than two decades, treatment with intravenous thrombolysis (IVT) and mechanical endovascular thrombectomy (MET), the only approved stroke reperfusion therapies, was restricted to patients within the 4.5-6 hour time window, respectively. Therefore, patients who presented with acute ischemic stroke (AIS) beyond the conventionaltime window were excluded from reperfusion treatment. This narrative review aims to review the scientific literature on the possibilities of reperfusion therapies for patients who present with an unknown time of stroke onset, and those with stroke onset beyond the conventional 4.5-6 hour time window. Beyond the conventional time window, the eligibility of patients for IVT or MET, the two main therapeutic procedures, is decided based on the concept of penumbral imaging. Penumbral imaging identifies patients with hypoperfused but viable brain tissue, who could benefit from reperfusion. On the other hand, clock-based DWI-fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) can detect stroke that has occurred within 4.5 hours in patients with an unknown time of onset, including patients who awaken with stroke. The introduction of penumbral imaging and MRI-based tissue clocking as imaging biomarkers for stroke has revolutionized stroke therapy, potentially allowing for personalized treatment of eligible stroke patients.

Elevated Calcium after Acute Ischemic Stroke Predicts Severity and Prognosis.

The aim of this study is to investigate whether there is a correlation between serum calcium levels and clinical severity or functional outcome at discharge in Chinese patients with acute ischemic stroke. Data from 339 patients admitted to our hospital between July 2020 and July 2021 were analyzed. Baseline demographic and clinical information was collected within 24h of admission, including serum calcium levels, stroke severity (measured by the National Institutes of Health Stroke Scale [NIHSS] score), and lesion volumes. The modified Rankin Scale [mRS] assessed functional outcomes at discharge. Our analysis showed that the median age of patients included in the study was 65 years (interquartile range [IQR], 60-70), and 60.8% were men. We found a positive correlation between serum calcium levels and stroke severity (r[spearman] = 0.266, P < 0.001), with calcium levels increasing as stroke severity increased. In a subgroup of 188 patients with available MRI data, serum calcium concentrations positively correlated with infarct size. Furthermore, in multivariate analysis, a calcium serum level in the highest quartile was associated with a higher risk of unfavorable outcome (odds ratios [OR] = 3.27; 95% confidence intervals [CI] = 1.91-5.59; P < 0.001). In conclusion, our study indicates that higher calcium serum levels are associated with stroke severity and early neurologic outcome after acute ischemic stroke, indicating that calcium may serve as a prognostic biomarker for stroke in Chinese patients.

Inflammation biomarkers in acute ischemic stroke according to different etiologies.

High throughput technologies provide new opportunities to further investigate the pathophysiology of ischemic strokes. The present cross-sectional study aimed to evaluate potential associations between the etiologic subtypes of ischemic stroke and blood-based proteins. We investigated the associations between ischemic stroke subtypes and a panel of circulating inflammation biomarkers in 364 patients included in the Stroke Cohort Augsburg (SCHANA). Stroke etiologies were categorized according to the TOAST (Trial of Org 10172 in Acute Stroke Treatment) classification. Serum concentrations of 52 biomarkers were measured using the Bio-Plex Pro™ Human Cytokine Screening Panel, ICAM-1 set and VCAM-1 set, plus the Pro™ Human TH17 cytokine sCD40L set and IL31 set (all Bio-Rad, USA). Multivariable linear regression models were used to examine associations. Point estimates were calculated as the mean difference in -standardized cytokine levels on the log2 -scale. Stromal-cell-derived-factor 1 alpha (SDF-1a) showed significantly higher serum levels in cardioembolic compared with large vessel atherosclerotic stroke (β = 0.48; 95% CI 0.22; 0.75; Padj = 0.036). Significantly lower levels of interleukin-6 (IL-6) (β = -0.53; 95% CI -0.84; -0.23; Padj = 0.036) and macrophage migration inhibitory factor (MIF) (β = -0.52; 95% CI -0.84; -0.21; Padj = 0.043) were found in the small vessel versus large vessel stroke subtype. Immune dysregulations observed in different stroke subtypes might help uncover pathophysiological mechanisms of the disease. Further studies are needed to validate identified biomarkers in diverse study populations before they can potentially be used in clinical practice to further improve stroke management and patient outcomes.

Homoarginine Associates with Carotid Intima-Media Thickness and Atrial Fibrillation and Predicts Adverse Events after Stroke.

Homoarginine is associated with cardio- and cerebrovascular morbidity and mortality. However, the underlying pathomechanisms remain elusive. Here, we evaluated the association of homoarginine with adverse events (i.e., death, stroke, and myocardial infarction) and carotid intima-media thickness (cIMT) in stroke patients. In the prospective bioMARKers in STROKE (MARK-STROKE) cohort, patients with acute ischemic stroke or transient ischemic attack (TIA) were enrolled. Plasma homoarginine concentrations were analyzed and associated with clinical phenotypes in cross-sectional (374 patients) and prospective (273 patients) analyses. Adjustments for possible confounders were evaluated. A two-fold increase in homoarginine was inversely associated with the National Institutes of Health Stroke Scale (NIHSS) score at admission, cIMT, and prevalent atrial fibrillation (mean factor -0.68 [95% confidence interval (CI): -1.30, -0.07], -0.14 [95% CI: -0.22, -0.05]; and odds ratio 0.57 [95% CI: 0.33, 0.96], respectively). During the follow-up (median 284 [25th, 75th percentile: 198, 431] days), individuals with homoarginine levels in the highest tertile had fewer incident events compared with patients in the lowest homoarginine tertile independent of traditional risk factors (hazard ratio 0.22 [95% CI: 0.08, 0.63]). A lower prevalence of atrial fibrillation and a reduced cIMT pinpointed potential underlying pathomechanisms.

Neutrophil-to-lymphocyte ratio and its changes predict the 3-month outcome and mortality in acute ischemic stroke patients after intravenous thrombolysis.

The neutrophil-to-lymphocyte ratio (NLR) has been demonstrated as a prognostic inflammatory biomarker in ischemic stroke. The study aimed to investigate the association of NLR and its dynamic change with long-term outcome and mortality in acute ischemic stroke (AIS) patients who received intravenous thrombolysis (IVT). From a prospective cohort, AIS patients receiving IVT (alteplase, 0.9mg/kg) with complete NLR data were retrospectively screened. Based on 3-month modified Rankin scale score (mRS), patients were classified into good group (mRS 0-1) and poor outcome group (mRS 2-6), or survival group (mRS 0-5) and death group (mRS 6). Multivariate logistic regression analysis and receiver operating curve were used to identify prognostic factors and their predictive powers. A total of 259 eligible patients were enrolled in our study. Logistic regression analysis showed that NLR at 24h (adjusted odds ratio [aOR] 1.182), 12 days (aOR 1.218) after IVT was independent predictors of 3-month outcome with the AUC of 0.815, 0.820, respectively, whereas NLR at 24h (aOR 1.17), 12 days (aOR 1.252) after IVT and percentage changes of NLR between admission and 24h after IVT (aOR 1.214), and between admission and 12 days after IVT (aOR 1.233) were independent predictors of 3-month mortality with the AUCs of 0.86, 0.902, 0.814, and 0.855, respectively. The comprehensive report suggests that NLR and its dynamic changes are associated with 3-month outcome and mortality in AIS patients after IVT with good predictive powers.

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.