Table 4.
Biomarkers for diagnostic and prognostic evaluation of AIS patients.
| Biomarker | Biomarker Function | Clinical Information | Bio-fluid Tested/Method | Ref. |
|---|---|---|---|---|
| Markers of Glial Activation | ||||
| S100B | Calcium binding protein expressed in astrocytes and oligodendrocytes | Level decreased from day 3 following AIS (p < 0.0001). The significant differences in S100B level between days 3 and 5 from AIS vs. day 10 (p < 0.001). AIS n= 56, control n=38 | Serum/ELISA | [81] |
| Glial fibrillary acidic protein (GFAP) | Expressed by astrocytes | Levels significantly higher in HS patients (P=0.0057), AIS n= 83, HS n=14 |
Plasma/ELISA | [82] |
| Myelin basic protein (MBP) | Myelin sheath protein | Patients with AIS had significantly higher levels of MBP vs. Controls (P value < 0.001), AIS n=20, control n=20 | CSF/ ELISA | [83] |
| Markers of Inflammation | ||||
| C-reactive protein (CRP) | Acute phase protein | Level in AIS patients statistically higher than in HS patient group (P<0.0001). AIS n= 32, HS n=32 | Serum/Immuno-nephelo-metry | [84] |
| IL-6 | Inflammatory cytokine | A positive correlation between IL-6, NIHSS and modified Rankin Scale of the AIS patients (P < 0.001, r = 0.6). Correlation between IL-6 level and infarction size in brain as evaluated by MRI (P < 0.001, r = 0.7). AIS n=45 | Serum/ELISA | [85] |
| TNF-alpha | Inflammatory cytokine | Significant different level in AIS vs. control. AUC: 0.99, P < 0.0001. Significantly elevated level in HS vs. control. AUC: 1.0, P < 0.0001. AIS n= 262, HS n=42, Control n=200 | Plasma/ELISA | [86] |
| ICAM-1 | Immunoglobulin super family members | Significantly elevated in AIS vs. healthy controls. P <0.05, AIS n=262, HS n= 42, Control n=200 | Plasma/ELISA | [86] |
| VCAM-1 | inflammation of adhesion molecules | Sensitivity and Specificity of 90% for discriminating AIS from non-stroke patients. AIS n=65, control n=157. | Plasma/ELISA | [87] |
| Matrix metalloproteinase-9 (MMP-9) | Biomarker of the severity of acute brain ischemia. | Elevated mRNA expression level; correlated with the size of brain infarct lesion, poor neurological outcome and hemorrhagic transformation after thrombolytic therapy. n=21 Elevated mRNA level; higher in HS patients than in AIS. Stroke n=126, Control n=9 |
Blood PBMC/qPCR | [88,89] |
| Markers of oxidative stress | ||||
| PARK-7 | Redox-sensitive molecular chaperone | Higher diagnostic potential with an AUC of 0.897, p < 0.001. AIS n=72 Control n= 78 |
Plasma/ELISA | [90] |
| Malondi-aldehyde (MDA) | Lipid peroxidation product | Non-survivors (n = 29) showed higher serum higher serum MDA levels (p = 0.004) than survivors (n = 29). | Serum | [91] |
| Oxidized low density lipoprotein | Lipid peroxidation product | Median values significantly higher in patients with ICH than in patients with AIS (P < .0001). ICH n=7, AIS n=9 | Serum/ELISA | [92] |
| Markers of neuronal injury | ||||
| Neuron specific enolase (NSE) | Neuronal glycolytic enzyme | Significantly elevated in AIS patients vs. healthy control pā¤0.05, AIS n=100, control n=101 | Serum/ELISA | [93] |
| Heart fatty acid binding protein (H-FABP) | Involved in intracellular fatty acid transport | Elevated in stroke group vs. control: P < 0.001. Levels correlated with initial NIHSS score (r=0.46, P<0.01). AIS n=111, Control n=127 |
Plasma/ELISA | [94] |
| NMDA receptor | Cytosolic protein, Excitotoxic receptor | Sensitivity of 92% specificity of 96%, AIS n=192, Control n=100 |
Plasma/ELISA | [95] |
| Markers of Hemostasis and Endothelial dysfunction | ||||
| Thrombomodulin (sTM) | Endothelial cell glycoprotein (anticoagulation properties) | Plasma levels significantly higher in AIS patients than controls (P < 0.005). AIS n=93, Control n=76 | Plasma/ELISA | [96] |
| D-dimer | Fibrin degradation product | Medians higher in patients with cardioembolic stroke than in those with other etiologies (p<0.001), AIS n=98 Control n= 0 | Plasma/ELISA | [97] |
| Von Willebrand factor (VWF) | Glycoprotein involved in platelet adhesion stabilization | Levels significantly elevated in severe AIS (based on NIHSS) P = 0.013, AIS n=131, Control n= 0 |
Plasma/Immuno-turbidimetric | [98] |
| Miscellaneous markers | ||||
| Natriuretic peptides (ANP, BNP) | Vasoactive peptide hormones | A statistically significant difference between stroke patients group and control (p < 0.001), AIS n=40, Control n= 30 | Plasma/Immuno-assay | [99] |
| N-terminal brain natriuretic peptide (NT-proBNP) | Associated with underlying cause of brain ischemia | Independently associated with the diagnosis of AIS stroke when compared to patients with HS (P<0.001). AIS n=767, stroke mimics n=115, HS n=100, control n=23 | Plasma/ Ab-based (Search-Light) | [100] |
| Lipoprotein associated phospholipase A2 (LpPLA2-M) | Hydrolytic enzyme | LpPLA2-M levels higher compared to controls, P=0.04). Sample n=167 | Blood/ELISA | [101] |
| Calcium | Physiological ion, i.e., messenger that regulates many processes | The highest delayed Ca2+ quartile (versus lowest) was associated with lesser stroke severity and better 3-month functional and independence scale outcomes (all P<0.001). No significant outcome differences noted among early Ca2+ levels. AIS n=659, control n= 167 | Serum | [102] |
| Free hemoglobin (Hb) | Erythrocyte protein | Hb alpha-chain and beta-chain differentially expressed between stroke patients and controls. No significant correlation (p > 0.05) between Hb chains and the NIHSS, TOAST, mRS, stroke risk factors, infarct volume, infarct location and laboratory data. Sensitivity 70.2%, Specificity 85.3%, AIS n=47 Control n= 34 | Serum/MALDI-TOF, MS | [78] |
| Asymmetric dimethylarginine (ADMA) | Endogenous inhibitor of nitric oxide synthase | ADMA higher in stroke patients than in controls, elevated levels at day 3 and 7 indicative of an unfavorable clinical outcome. Specificity 75%, sensitivity 60% 3 days post stroke event. AIS n=67, control n=32 | Plasma/HPLC-MS-MS | [103] |
| Parkinsonism Associated Deglycase (PARK7) and nucleoside diphosphate kinase A (NDKA) | PARK7: RNA binding protein regulatory subunit NDKA: Elevated in neurodegenerative disease. |
Increase in concentration 3 h of stroke onset. An increase in concentration of both markers observed in each type of stroke, HS, TIA and AIS, compared with controls (P <0.001). PARK7: Sensitivities of 54%-91% and specificities of 80%-97%.NDKA: Sensitivities of 70%-90% and specificities of 90%-97%. AIS n=234, TIA n=153, HS n=235, control n=165 |
Plasma/ELISA | [67] |
| Panel of markers: insulin-like growth factor-binding protein-3 (IGFBP-3), tumor necrosis factor receptor-1 (TNF-R1), Fas ligand (FasL), S100B, Heat shock 70 kDa protein-8 (Hsc70), apolipoprotein CIII, and neuron cell adhesion molecule (NCAM) | Real stroke vs. stroke mimics: AUC= 0.742, AIS vs HS AUC=0.757. AIS n=767, stroke mimics n=115, HS n=100, control n=23 |
Plasma/ Ab-based (Search-Light) | [100] | |
| Ubiquitin C-terminal hydrolase (UCH-L1) and glial fibrillary astrocytic protein (GFAP) | GFAP: brain-specific astrocytic intermediate filament protein, UCH-L1 is a cytoplasmic deubiquitinating enzyme of neurons | UCH-L1 and GFAP levels elevated in ICH patients vs. controls (P < 0.0001). GFAP differed in ICH vs. AIS (P < 0.0001), AUC = 0.86 within 4.5hrs of symptom onset, Sensitivity = 61%, Specificity = 96%. Higher GFAP levels associated with stroke severity and history of prior stroke. ICH n=45, AIS n=79, SAH n=5, TIA n= 3, control n=57. |
Serum/ELISA | [104] |
| Copeptin | neuroendocrine marker | High level predicted unfavorable outcome P < 0.001, AUC 0.83 Concentrations along with the NIHSS better predictor of functional outcome and mortality within 90 days than the clinical scale or the biomarker alone. AIS n=783, Control n=359 | Plasma/ELISA | [105] |
| circulating cfDNA | Marker of cell death via apoptosis or necrosis. | Levels correlated with severity of stroke at the time of admission (P=0.032) and poor outcome (P=0.001). AIS n=26, control n=0 cfDNA marker added to the clinical predictive model improved AIS discrimination (p = 0.009). AIS n=54, control n=15 |
Plasma/qPCR | [106] [107] [108] |
Notes: AIS ā acute ischemic stroke, HS ā hemorrhagic stroke, ICH - Intracerebral hemorrhage, MALDI - Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, HPLC-MS/MS- high-performance liquid chromatography-tandem mass spectrometry, CNS - central nervous system, SAH- subarachnoid hemorrhage, TIA- transient ischemic attack, ELISA- enzyme-linked immunosorbent assay, qPCR- quantitative polymerase chain reaction