Biomarkers in Stroke
At a glance
Biomarkers are markers in blood, body fluids, or tissues that indicate physiologic or disease states, disease risk or pharmacological response to therapy. Secondly, biomarkers are valuable for drug discovery and are a better and more complete measure of drug activity, progression of disease, or the response to particular drug therapy. In stroke, there is a growing number of candidate biomarkers that can be used as guiding tools for more effective personalized therapy.
At Ace Therapeutics, we are committed to developing stroke biomarkers to support mechanism of action, pharmacodynamic, prognostic, and predictive preclinical studies throughout all phases of stroke drug development. By integrating technology platforms such as high-throughput genomics, transcriptomics, proteomics, and metabolomics, we help our clients discover new biomarkers, including proteins, ribonucleic acids, lipids, and metabolites.
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The Need for Stroke Biomarkers
Stroke has a heterogeneous pathophysiology and mechanisms. In addition, individual characteristics of stroke patients vary even among subjects with the same stroke mechanisms. Stroke biomarkers can provide information about heterogeneity and can be a guiding tool for more effective personalized treatment of patients with ischemic cerebrovascular disease.
The main reason for the inadequacy of medications for stroke treatment is uncertainty about stroke type, duration of ischemia, and the associated risk of cerebral hemorrhage. Although biomarkers have the potential to improve the diagnosis and management of stroke patients, no marker has yet demonstrated sufficient sensitivity, specificity, rapidity, precision, and cost-effectiveness for routine stroke management.
Fig.1. Sources of the major candidate biomarkers for stroke. (Dagonnier, et al., 2021)
Role of Biomarkers in Stroke Research
While biomarkers primarily serve to diagnose stroke and predict outcomes, they can also offer insights into the risk of future strokes, potential underlying mechanisms, and responses to treatments. Additionally, biomarkers can be utilized as surrogate endpoints in clinical trials, enhancing their utility beyond initial diagnosis and prognosis.
| Roles | Description |
|---|---|
| Screening high-risk subjects | Researchers are exploring new factors that contribute to stroke risk, such as obesity, diet, sleep disorders, air pollution, and lifestyle choices. In addition to discovering these new risk factors, a range of biomarkers reflecting inflammation, hemostasis, thrombosis, endothelial function, or neurohormonal activity have been evaluated as potential tools to improve the prediction of future stroke risk and thus avoid future events. |
| Rapid stroke diagnosis | The potential of biomarkers for rapid stroke diagnosis could complement conventional neuroimaging techniques. The use of biomarker combinations rather than individual markers could enhance stroke diagnosis. |
| Detection of possible stroke mechanisms | Biomarkers can be used to detect possible stroke mechanisms. For example, molecular markers associated with neuronal death can provide information about tissues at risk for infarction. |
| Accelerating stroke drug development | Biomarkers may provide more accurate and complete information about drug performance, disease progression, or response to specific drug treatments. |
| Predicting drug response and outcome | Biomarkers can help study pharmacogenetics and predict drug response in stroke patients. |
| Surrogate endpoints in clinical trials | In the field of stroke research, several studies have begun to use biomarkers to monitor the effectiveness and safety of treatments in Phase III clinical trials. However, changes detected in surrogate markers do not always translate into clinical endpoints, and may even be contrary to clinical outcomes. |
Type of Biomarkers in Stroke Research
Stroke biomarkers include traditional protein biomarkers and novel genetic, lipids, and metabolomics-associated biomarkers.
| Types | Examples |
|---|---|
| Proteins | Serum calcium binding protein (S100B), Glial fibrillary acid protein (GFAP), Myelin basic protein (MBP), Neuron-specific enolase (NSE), Heart fatty acid-binding protein (HFABP), Anti-N-methyl-D-Aspartate (anti-NMDA) receptors antibodies, Von Willebrand Factor (vWF) and its cleaving protein ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), D-Dimer, Fibrinogen, Plasminogen activator inhibitor (PAI), Thrombomodulin, Fibronectin, Thrombin activatable fibrinolysis inhibitor, Soluble intercellular adhesion molecule (ICAM), Vascular cell adhesion molecule (VCAM), C-reactive protein (CRP), Matrix metalloproteinase 9 (MMP-9), Lipoprotein-associated phospholipase A2, Interleukins (IL-6, IL-10) and tumor necrosis factor alpha (TNF-α), Plasma ferritin, Caspase-3, Copeptin, Atrial natriuretic peptide (ANP), midregional pro-atrial natriuretic peptide (MR-proANP), B-type natriuretic peptide (BNP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), Adiponectin |
| RNAs | Messenger RNA (mRNA): 40 gene panel: ADAMTSL4, AP3S2, ARHGEF12, ARHGEF5, BANK1, C16orf68, C19orf28, CD46, CHURC1, CLEC18A, COL13A1, EBF1, ENPP2, EXT2, FCRL1, FLJ40125, GRM5, GSTK1, HLA-DOA, IRF6, LHFP, LHFP, LOC284751, LRRC37A3, OOEP, P2RX5, PIK3C2B, PTPN20A, TFDP1, TMEM19, TSKS, ZNF185, ZNF254 41 gene panel: ALS2CR11, C18orf49, CALM1, CCDC114, CCDC78, CCL2, CCL3, CHML, FAM179A, FAM70B, FLJ13773, GBP4, GTF2H2, HLA-DQA1, HLADRB4, IL8, LAG3, LAIR2, LGR6, LRRC8B, MPZL3, OASL, PDXDC1, PROCR, PRSS23, QKI, RASEF, RUNX3, SCAND2, STK4, STX7, TGFBR3, TSEN54, TTC12, UBA7, UGCG. UTS2, VAPA MicroRNAs (miRNA): miR-200c, Let-7i Long non-coding RNAs (lncRNA): Zinc Finger Antisense 1 (ZFAS1) |
| Lipids | Oxidized low-density lipoprotein, Free fatty acids, Lysophosphatidylcholine |
| Metabolites | Plasma glutamate, Nitric oxide |
Limitations of Stroke Biomarkers
The application of biomarkers in the management of stroke has some limitations, despite their evolving role.
- Changes in the brain are not sufficiently reflected by blood biomarkers due to the presence of the blood-brain barrier
- Biomarkers can change by a variety of comorbid conditions or brain damage itself (confounders and lack of specificities).
- There is no sufficiently robust single marker for stroke.
Each biomarker offers unique insights, each with its own set of advantages and limitations. Therefore, a comprehensive approach that integrates various biomarkers is essential to overcome these challenges. Furthermore, a multidisciplinary approach that includes neuroimaging biomarkers is crucial. We strongly believe that biomarkers will serve as a pivotal tool in advancing our understanding of the pathophysiology and treatment mechanisms of ischemic stroke.
- Dagonnier, M., et al. (2021). Acute stroke biomarkers: are we there yet?. Frontiers in neurology, 12, 619721.
