Blood Biomarkers In Ischemic Stroke Research Articles

Identification of Blood Biomarkers in Ischemic Stroke by Integrated Analysis of Metabolomics and Proteomics.

We aimed to uncover the pathological mechanism of ischemic stroke (IS) using a combined analysis of untargeted metabolomics and proteomics. The serum samples from a discovery set of 44 IS patients and 44 matched controls were analyzed using a specific detection method. The same method was then used to validate metabolites and proteins in the two validation sets: one with 30 IS patients and 30 matched controls, and the other with 50 IS patients and 50 matched controls. A total of 105 and 221 differentially expressed metabolites or proteins were identified, and the association between the two omics was determined in the discovery set. Enrichment analysis of the top 25 metabolites and 25 proteins in the two-way orthogonal partial least-squares with discriminant analysis, which was employed to identify highly correlated biomarkers, highlighted 15 pathways relevant to the pathological process. One metabolite and seven proteins exhibited differences between groups in the validation set. The binary logistic regression model, which included metabolite 2-hydroxyhippuric acid and proteins APOM_O95445, MASP2_O00187, and PRTN3_D6CHE9, achieved an area under the curve of 0.985 (95% CI: 0.966-1) in the discovery set. This study elucidated alterations and potential coregulatory influences of metabolites and proteins in the blood of IS patients.

The bioinformatic identification of proteins with varying levels of post-translational modifications in experimental ischemic stroke in mice

The experimental data obtained by Simats A. et al. (Molecular and Cellular Proteomics, 2020, 19(12), 1921-1936) was analysed using a bioinformatic approach. Original experimental results available in the ProteomeXchange database were obtained using a comprehensive multidomain approach to identify potential blood biomarkers in ischemic stroke in mice. The identification of peptides with post-translational modification (PTM) was performed by us using the raw data (accession code PXD016538). Only phosphorylation and deamination were considered as PTMs. Different combinations of data sets (ischemic tissue with intact tissue, ischemic tissue with control taken from mice after sham surgery, etc.) were compared both in terms of the ratio of abundance for the modified peptide to the unmodified variant and in terms of absolute values of abundance. The most likely change in precisely PTM levels was shown for 27 proteins, which include dynamin, glycogen phosphorylase and 70 kDa heat shock protein.

A Mouse Brain-based Multi-omics Integrative Approach Reveals Potential Blood Biomarkers for Ischemic Stroke

Stroke remains a leading cause of death and disability worldwide. Despite continuous advances, the identification of key molecular signatures in the hyper-acute phase of ischemic stroke is still a primary interest for translational research on stroke diagnosis, prognosis, and treatment. Data integration from high-throughput -omics techniques has become crucial to unraveling key interactions among different molecular elements in complex biological contexts, such as ischemic stroke. Thus, we used advanced data integration methods for a multi-level joint analysis of transcriptomics and proteomics data sets obtained from mouse brains at 2 h after cerebral ischemia. By modeling net-like correlation structures, we identified an integrated network of genes and proteins that are differentially expressed at a very early stage after stroke. We validated 10 of these deregulated elements in acute stroke, and changes in their expression pattern over time after cerebral ischemia were described. Of these, CLDN20, GADD45G, RGS2, BAG5, and CTNND2 were next evaluated as blood biomarkers of cerebral ischemia in mice and human blood samples, which were obtained from stroke patients and patients presenting stroke-mimicking conditions. Our findings indicate that CTNND2 levels in blood might potentially be useful for distinguishing ischemic strokes from stroke-mimicking conditions in the hyper-acute phase of the disease. Furthermore, circulating GADD45G content within the first 6 h after stroke could also play a key role in predicting poor outcomes in stroke patients. For the first time, we have used an integrative biostatistical approach to elucidate key molecules in the initial stages of stroke pathophysiology and highlight new notable molecules that might be further considered as blood biomarkers of ischemic stroke.

Diagnosis of ischemic stroke using circulating levels of brain-specific proteins measured via high-sensitivity digital ELISA

Limited lower detection ranges associated with traditional immunoassay techniques have prevented the use of brain-specific proteins as blood biomarkers of stroke in the acute phase of care, as these proteins are often only present in circulation at low concentrations. Digital ELISA is a newly developed technique with allows for quantification of proteins in biofluids with up to 1000 times greater sensitivity than conventional ELISA techniques. The purpose of this study was to determine whether the extended lower limits of detection associated with digital ELISA could enable the use of brain-specific proteins as blood biomarkers of ischemic stroke during triage. Blood was sampled from ischemic stroke patients (n = 14) at emergency department admission, as well as from neurologically normal controls matched in terms of risk factors for cardiovascular disease (n = 33). Plasma levels of two brain-specific axonal proteins, neurofilament light chain (NfL) and tau, were measured via digital ELISA, and receiver-operating characteristic analysis was used to determine their ability to discriminate between groups. Plasma levels of NfL and tau were both significantly elevated in stroke patients versus controls, and could respectively discriminate between groups with 92.9% sensitivity / 84.9% specificity, and 85.7% sensitivity / 54.6% specificity. Furthermore, adjustment of measured NfL and Tau levels according to the lower-limits of detection associated with commercially-available conventional ELISA assays resulted in a dramatic and statistically significant decrease in diagnostic performance. Collectively, our results suggest that the increased analytical sensitivity of digital ELISA could enable the use of brain-specific proteins as blood biomarkers of ischemic stroke during triage.

Blood biomarkers in ischemic stroke: Role of biomarkers in differentiation of clinical phenotype

Stroke is the major cause of death and disability worldwide and ischemic stroke contributes 80% among them. Although limited number of patients display hemorrhagic stroke (HS), the disability and death rate are higher in HS. Several studies have been reported on identification of suitable markers for diagnosis of stroke, but none of them holds true worldwide. These observations direct toward identification of population-specific biomarker of stroke. In this study, we screened various blood biomarkers in a large cohort of well-characterized Chinese stroke patients and healthy controls. A total of 308 stroke patients including 262 acute ischemic stroke (AIS) patients and 42 HS patients were enrolled in the study and blood samples were collected within 6–24 h of stroke onset. In addition, 46 stroke mimic subjects were included for comparison of blood markers with stroke patients. Furthermore, healthy controls (n = 200) and patient controls (n = 125) from similar ethnic group were enrolled in the study. Biomarkers (S100 calcium-binding protein B (S100B), C-reactive protein (CRP), interleukin 6 (IL-6), plasminogen activator inhibitor-1 (PAI-1), matrix metallopeptidase 9 (MMP-9), P-selectin, intercellular adhesion molecule 1 (ICAM-1), tumor necrosis factor α (TNF-α), low-density lipoprotein (LDL) cholesterol, interleukin 10 (IL-10), nitric oxide (NO), and glial fibrillary acidic protein (GFAP)) were quantified by ELISA. Blood levels of S100B, CRP, IL-6, PAI-1, MMP-9, P-selectin, ICAM-1, and TNF-α were significantly higher in AIS and HS patients compared to healthy controls, patient controls, and stroke mimic patients. Receiver operating characteristic (ROC) curve analysis revealed CRP, IL-6, PAI-1, P-selectin, and TNF-α as possible biomarkers for AIS patients, and HS patients can be diagnosed based on S100B, IL-6, PAI-1, MMP-9, and TNF-α. Interestingly, significant area under ROC curves were observed for plasma S100B and CRP for differentiating AIS from HS. The results of this study validated certain blood parameters used for diagnosis of AIS or HS in Chinese patients. Furthermore, S100B and CRP are promising biomarkers for differentiation of AIS from HS.

Progress and potential roles blood biomarkers of ischemic stroke in clinical setting

Stroke is one of the leading causes of death and disability which involving a complex pathophysiology with multiple mechanisms. Rapid treatment is necessary to terminate the disease progression, hence minimizing CNS damage and subsequent disability. Stroke diagnostic process composed of history taking, neurological examination and supplemented with neuroimaging. Imaging modalities such as CT-scan or MRI are essential in establishing a definitive diagnosis of ischemic stroke. However, the high cost and limited number made them inaccessible for those who have low or middle income which will delay the diagnosis and treatment. On the other hand, blood biomarker has potential in either diagnostic or prognostic aspect of ischaemic stroke management. It has a promising potential to aid diagnosis, determine the subtype of stroke, predicting the outcome or early neurological deterioration, and recurrence. It also could potentially help to assess the risk of hemorrhagic transformation, treatment selection, as well as to detect salvageable ischemic penumbra. Although it could not replace neuroimaging, blood-based biomarker assessment had lower cost and faster result. However, despite its promising potential, none of the blood biomarkers is currently used in clinical practice. Therefore, further studies are needed to develop biomarkers or panels of biomarkers with better sensitivity and specificity. This review provides a highlight and summary of blood biomarkers based on their potential application in a clinical setting.

Clinical applications of blood biomarkers in ischemic stroke

Early diagnosis and timely treatment are two critical factors in reducing the cerebral damage and improving prognosis for ischemic stroke patients.The only proved effective way is to intravenously administer recombinant tissue plasminogen activator for thrombolytic therapy.However,the narrow time window restricts its application.One rapid and effective blood test,or auxiliary examinations such as computer tomography which may aid early diagnosis of ischemic stroke would contribute to treatment and intervention promptly,then take a pivotal role for the disease prognosis.Herein,the reported proteins and RNA markers are summarized and analysed in clinical application of acute ischemic stroke likewise.（Chin J Lab Med,2014,37:497-500） Key words: Brain ischemia; Stroke; Biological markers

Ischemic Stroke Biomarkers in Blood

Ischemic stroke is a leading cause of adult disability and mortality. With over 15 million strokes occurring every year in the world, methods to better identify patients at risk for stroke are needed, as are methods to improve patient diagnosis and prognosis when stroke occurs. Use of blood-based biomarkers is one method that has been evaluated to predict risk of stroke, diagnose stroke and its causes, predict stroke severity and outcome, and guide prevention therapy. Markers that have been identified include a variety of proteins, nucleic acids and lipids that relate to stroke pathophysiology. The role of blood biomarkers in ischemic stroke is still being defined, and further study is needed to develop blood biomarkers for clinical stroke use. In this review, the authors provide a summary of biomarkers that have been divided by their potential clinical application.