Abstract
Biomarkers are objective indicators used to assess normal or pathological processes, evaluate responses to treatment and predict outcomes. Many blood biomarkers already guide decision-making in clinical practice. In stroke, the number of candidate biomarkers is constantly increasing. These biomarkers include proteins, ribonucleic acids, lipids or metabolites. Although biomarkers have the potential to improve the diagnosis and the management of patients with stroke, there is currently no marker that has demonstrated sufficient sensitivity, specificity, rapidity, precision, and cost-effectiveness to be used in the routine management of stroke, thus highlighting the need for additional work. A better standardization of clinical, laboratory and statistical procedures between centers is indispensable to optimize biomarker performance. This review focuses on blood biomarkers that have shown promise for translation into clinical practice and describes some newly reported markers that could add to routine stroke care. Avenues for the discovery of new stroke biomarkers and future research are discussed. The description of the biomarkers is organized according to their expected application in clinical practice: diagnosis, treatment decision, and outcome prediction.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Abbreviations
- aHR :
-
Adjusted hazard ratio
- aOR :
-
Adjusted odds ratio
- ADAMTS13 :
-
A disintegrin and metalloproteinase with thrombospondin type-1 motif, member 13
- ANP :
-
Atrial natriuretic peptide
- APOA1-UP :
-
Apolipoprotein A1 unique peptide
- BNP :
-
B-type natriuretic peptide
- CDM :
-
Clinical diffusion mismatch
- c-Fn :
-
Cellular fibronectin
- CRP :
-
C-reactive protein
- CT :
-
Computerized tomography
- DHC :
-
Decompressive hemicraniectomy
- END :
-
Early neurological deterioration
- EVT :
-
Endovascular thrombectomy
- FC :
-
Fold change
- GFAP :
-
Glial fibrillary acid protein
- HbA1c :
-
Glycated hemoglobin
- HFABP :
-
Heart-type fatty acid-binding protein
- HR :
-
Hazard ratio
- HT :
-
Hemorrhagic transformation
- ICAM :
-
Intercellular adhesion molecule
- ICH :
-
Intracerebral hemorrhage
- IL-10 :
-
Interleukin 10
- IL-6 :
-
Interleukin-6
- IS :
-
Ischemic stroke
- LAA :
-
Large artery atherosclerosis
- lncRNA :
-
Long non-coding RNA
- Lp-PLA2 :
-
Lipoprotein-associated phospholipase A2
- MCA :
-
Middle cerebral artery
- MBL :
-
Mannose-binding lectin
- MMP9 :
-
Matrix metalloproteinase 9
- MiRNA :
-
MicroRNA
- MR-proANP :
-
Mid-regional pro-atrial natriuretic peptide
- MRI :
-
Magnetic resonance imaging
- mRS :
-
Modified Rankin Scale
- MS :
-
Mass spectrometry
- N/A :
-
Not applicable or not available
- NDKA :
-
Nucleoside diphosphate kinase A
- NfL :
-
Neurofilament light
- NMDA :
-
N-methyl-d-aspartate
- NIHSS :
-
National Institutes of Health Stroke Scale
- NSE :
-
Neuron-specific enolase
- NT-proBNP :
-
N-terminal pro-B-type natriuretic peptide
- OR :
-
Odds ratio
- PAI-1 :
-
Plasminogen activator inhibitor 1
- PARK7 :
-
Parkinson disease protein 7
- PBP :
-
Platelet basic protein
- RBP4 :
-
Retinol-binding protein 4
- RNA :
-
Ribonucleic acid
- S100B :
-
Serum calcium-binding protein
- Se :
-
Sensitivity
- Sp :
-
Specificity
- TAFI :
-
Thrombin-activatable fibrinolysis inhibitor
- TIA :
-
Transient ischemic attack
- TNF-α :
-
Tumor necrosis factor α
- tPA :
-
Tissue plasminogen activator
- VCAM :
-
Vascular cell adhesion molecule
- VEGF :
-
Vascular endothelial growth factor
- vWF :
-
von Willebrand factor
- ZFAS1 :
-
Zinc finger antisense 1
References
Adams, H. P. Jr., Bendixen, B. H., Kappelle, L. J., Biller, J., Love, B. B., Gordon, D. L., et al. (1993). Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in acute stroke treatment. Stroke, 24(1), 35–41.
Albers, G. W., Marks, M. P., Kemp, S., Christensen, S., Tsai, J. P., Ortega-Gutierrez, S., et al. (2018). Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging. The New England Journal of Medicine, 378(8), 708–718. https://doi.org/10.1056/NEJMoa1713973.
Allard, L., Burkhard, P. R., Lescuyer, P., Burgess, J. A., Walter, N., Hochstrasser, D. F., et al. (2005). PARK7 and nucleoside diphosphate kinase A as plasma markers for the early diagnosis of stroke. Clinical Chemistry, 51(11), 2043–2051. https://doi.org/10.1373/clinchem.2005.053942.
Alvarez-Perez, F. J., Castelo-Branco, M., & Alvarez-Sabin, J. (2011). Usefulness of measurement of fibrinogen, D-dimer, D-dimer/fibrinogen ratio, C reactive protein and erythrocyte sedimentation rate to assess the pathophysiology and mechanism of ischaemic stroke. Journal of Neurology, Neurosurgery, and Psychiatry, 82(9), 986–992. https://doi.org/10.1136/jnnp.2010.230870.
Anand, N., & Stead, L. G. (2005). Neuron-specific enolase as a marker for acute ischemic stroke: A systematic review. Cerebrovascular Diseases, 20(4), 213–219. https://doi.org/10.1159/000087701.
Anderson, C. S., Selim, M. H., Molina, C. A., & Qureshi, A. I. (2017). Intensive blood pressure lowering in intracerebral hemorrhage. Stroke, 48(7), 2034–2037. https://doi.org/10.1161/STROKEAHA.117.016185.
Arenillas, J. F., Alvarez-Sabin, J., Molina, C. A., Chacon, P., Fernandez-Cadenas, I., Ribo, M., et al. (2008). Progression of symptomatic intracranial large artery atherosclerosis is associated with a proinflammatory state and impaired fibrinolysis. Stroke, 39(5), 1456–1463. https://doi.org/10.1161/STROKEAHA.107.498600.
Ariesen, M. J., Claus, S. P., Rinkel, G. J., & Algra, A. (2003). Risk factors for intracerebral hemorrhage in the general population: A systematic review. Stroke, 34(8), 2060–2065. https://doi.org/10.1161/01.STR.0000080678.09344.8D.
Atkinson, A. J., Colburn, W. A., DeGruttola, A. G., DeMets, D. L., Downing, G. J., Hoth, J. F., et al. (2001). Biomarkers and surrogate endpoints: Preferred definitions and conceptual framework. Clinical Pharmacology & Therapeutics, 69(3), 89–95. https://doi.org/10.1067/mcp.2001.113989.
Bai, J., Sun, H., Xie, L., Zhu, Y., & Feng, Y. (2018). Detection of cardioembolic stroke with B-type natriuretic peptide or N-terminal pro-BNP: A comparative diagnostic meta-analysis. International Journal of Neuroscience. https://doi.org/10.1080/00207454.2017.1408612.
Balami, J. S., Chen, R. L., Grunwald, I. Q., & Buchan, A. M. (2011). Neurological complications of acute ischaemic stroke. The Lancet Neurology, 10(4), 357–371. https://doi.org/10.1016/S1474-4422(10)70313-6.
Balami, J. S., Hadley, G., Sutherland, B. A., Karbalai, H., & Buchan, A. M. (2013). The exact science of stroke thrombolysis and the quiet art of patient selection. Brain, 136(Pt 12), 3528–3553. https://doi.org/10.1093/brain/awt201.
Bang, O. Y. (2017). Advances in biomarker for stroke patients: From marker to regulator. Precision and Future Medicine, 1(1), 32–42. https://doi.org/10.23838/pfm.2017.00052.
Bang, O. Y., Saver, J. L., Ovbiagele, B., Choi, Y. J., Yoon, S. R., & Lee, K. H. (2007). Adiponectin levels in patients with intracranial atherosclerosis. Neurology, 68(22), 1931–1937. https://doi.org/10.1212/01.wnl.0000263186.20988.9f.
Bhatia, R., Hill, M. D., Shobha, N., Menon, B., Bal, S., Kochar, P., et al. (2010). Low rates of acute recanalization with intravenous recombinant tissue plasminogen activator in ischemic stroke: Real-world experience and a call for action. Stroke, 41(10), 2254–2258. https://doi.org/10.1161/STROKEAHA.110.592535.
Bitsch, A., Klene, W., Murtada, L., Prange, H., & Rieckmann, P. (1998). A longitudinal prospective study of soluble adhesion molecules in acute stroke. Stroke, 29(10), 2129–2135.
Bozkurt, S., Kaya, E. B., Okutucu, S., Aytemir, K., Coskun, F., & Oto, A. (2011). The diagnostic and prognostic value of first hour glycogen phosphorylase isoenzyme BB level in acute coronary syndrome. Cardiology Journal, 18(5), 496–502.
Briard, J. N., Zewude, R. T., Kate, M. P., Rowe, B. H., Buck, B., Butcher, K., et al. (2018). Stroke mimics transported by emergency medical services to a comprehensive stroke center: The magnitude of the problem. Journal of Stroke and Cerebrovascular Diseases, 27(10), 2738–2745. https://doi.org/10.1016/j.jstrokecerebrovasdis.2018.05.046.
Brott, T. G., Lyden, P., Grotta, J. C., Kwiatkowski, T. G., Levine, S. R., Frankel, M. R., et al. (1997). Intracerebral hemorrhage after intravenous t-PA therapy for ischemic stroke. The NINDS t-PA Stroke Study Group. Stroke, 28(11), 2109–2118.
Brunkhorst, R., Pfeilschifter, W., & Foerch, C. (2010). Astroglial proteins as diagnostic markers of acute intracerebral hemorrhage-pathophysiological background and clinical findings. Translational Stroke Research, 1(4), 246–251. https://doi.org/10.1007/s12975-010-0040-6.
Bruns, A. H., Oosterheert, J. J., Hak, E., & Hoepelman, A. I. (2008). Usefulness of consecutive C-reactive protein measurements in follow-up of severe community-acquired pneumonia. European Respiratory Journal, 32(3), 726–732. https://doi.org/10.1183/09031936.00003608.
Bustamante, A., Lopez-Cancio, E., Pich, S., Penalba, A., Giralt, D., Garcia-Berrocoso, T., et al. (2017a). Blood biomarkers for the early diagnosis of stroke: The stroke-chip study. Stroke, 48(9), 2419–2425. https://doi.org/10.1161/STROKEAHA.117.017076.
Bustamante, A., Ning, M., Garcia-Berrocoso, T., Penalba, A., Boada, C., Simats, A., et al. (2018). Usefulness of ADAMTS13 to predict response to recanalization therapies in acute ischemic stroke. Neurology, 90(12), e995–e1004. https://doi.org/10.1212/WNL.0000000000005162.
Bustamante, A., Vilar-Bergua, A., Guettier, S., Sanchez-Poblet, J., Garcia-Berrocoso, T., Giralt, D., et al. (2017b). C-reactive protein in the detection of post-stroke infections: Systematic review and individual participant data analysis. Journal of Neurochemistry, 141(2), 305–314. https://doi.org/10.1111/jnc.13973.
Cabral, N. L., Muller, M., Franco, S. C., Longo, A., Moro, C., Nagel, V., et al. (2015). Three-year survival and recurrence after first-ever stroke: The Joinville stroke registry. BMC Neurology, 15, 70. https://doi.org/10.1186/s12883-015-0317-1.
Campbell, B. C. V., Mitchell, P. J., Churilov, L., Yassi, N., Kleinig, T. J., Dowling, R. J., et al. (2018). Tenecteplase versus alteplase before thrombectomy for ischemic stroke. The New England Journal of Medicine, 378(17), 1573–1582. https://doi.org/10.1056/NEJMoa1716405.
Carbone, F., Burger, F., Roversi, G., Tamborino, C., Casetta, I., Seraceni, S., et al. (2015). Leptin/adiponectin ratio predicts poststroke neurological outcome. European Journal of Clinical Investigation, 45(11), 1184–1191. https://doi.org/10.1111/eci.12538.
Castellanos, M., Castillo, J., Garcia, M. M., Leira, R., Serena, J., Chamorro, A., et al. (2002). Inflammation-mediated damage in progressing lacunar infarctions: A potential therapeutic target. Stroke, 33(4), 982–987.
Castellanos, M., Leira, R., Serena, J., Blanco, M., Pedraza, S., Castillo, J., et al. (2004). Plasma cellular-fibronectin concentration predicts hemorrhagic transformation after thrombolytic therapy in acute ischemic stroke. Stroke, 35(7), 1671–1676. https://doi.org/10.1161/01.STR.0000131656.47979.39.
Castellanos, M., Leira, R., Serena, J., Pumar, J. M., Lizasoain, I., Castillo, J., et al. (2003). Plasma metalloproteinase-9 concentration predicts hemorrhagic transformation in acute ischemic stroke. Stroke, 34(1), 40–46.
Castellanos, M., Sobrino, T., & Castillo, J. (2006). Evolving paradigms for neuroprotection: Molecular identification of ischemic penumbra. Cerebrovascular Diseases, 21(Suppl 2), 71–79. https://doi.org/10.1159/000091706.
Castellanos, M., Sobrino, T., Millan, M., Garcia, M., Arenillas, J., Nombela, F., et al. (2007). Serum cellular fibronectin and matrix metalloproteinase-9 as screening biomarkers for the prediction of parenchymal hematoma after thrombolytic therapy in acute ischemic stroke: A multicenter confirmatory study. Stroke, 38(6), 1855–1859. https://doi.org/10.1161/STROKEAHA.106.481556.
Castellanos, M., Sobrino, T., Pedraza, S., Moldes, O., Pumar, J. M., Silva, Y., et al. (2008). High plasma glutamate concentrations are associated with infarct growth in acute ischemic stroke. Neurology, 71(23), 1862–1868. https://doi.org/10.1212/01.wnl.0000326064.42186.7e.
Castillo, J., Rama, R., & Davalos, A. (2000). Nitric oxide-related brain damage in acute ischemic stroke. Stroke, 31(4), 852–857.
Chaturvedi, S., & Bhattacharya, P. (2014). Large artery atherosclerosis: Carotid stenosis, vertebral artery disease, and intracranial atherosclerosis. Continuum (Minneap Minn), 20(2 Cerebrovascular Disease), 323–334. https://doi.org/10.1212/01.CON.0000446104.90043.a5.
Chen, X. L., Li, Q., Huang, W. S., Lin, Y. S., Xue, J., Wang, B., et al. (2017). Serum YKL-40, a prognostic marker in patients with large-artery atherosclerotic stroke. Acta Neurologica Scandinavica, 136(2), 97–102. https://doi.org/10.1111/ane.12688.
Choi, J. Y., Kim, J. S., Kim, J. H., Oh, K., Koh, S. B., & Seo, W. K. (2014). High free fatty acid level is associated with recurrent stroke in cardioembolic stroke patients. Neurology, 82(13), 1142–1148. https://doi.org/10.1212/WNL.0000000000000264.
Crawford, F., Andras, A., Welch, K., Sheares, K., Keeling, D., & Chappell, F. M. (2016). D-dimer test for excluding the diagnosis of pulmonary embolism. Cochrane Library: Cochrane Review, 8, CD010864. https://doi.org/10.1002/14651858.CD010864.pub2.
Dambinova, S. A., Khounteev, G. A., Izykenova, G. A., Zavolokov, I. G., Ilyukhina, A. Y., & Skoromets, A. A. (2003). Blood test detecting autoantibodies to N-methyl-D-aspartate neuroreceptors for evaluation of patients with transient ischemic attack and stroke. Clinical Chemistry, 49(10), 1752–1762.
Dasenbrock, H. H., Robertson, F. C., Vaitkevicius, H., Aziz-Sultan, M. A., Guttieres, D., Dunn, I. F., et al. (2017). Timing of decompressive hemicraniectomy for stroke: A nationwide inpatient sample analysis. Stroke, 48(3), 704–711. https://doi.org/10.1161/STROKEAHA.116.014727.
Dastur, C. K., & Yu, W. (2017). Current management of spontaneous intracerebral haemorrhage. Stroke and Vascular Neurology, 2(1), 21–29. https://doi.org/10.1136/svn-2016-000047.
Davalos, A., Castillo, J., Marrugat, J., Fernandez-Real, J. M., Armengou, A., Cacabelos, P., et al. (2000). Body iron stores and early neurologic deterioration in acute cerebral infarction. Neurology, 54(8), 1568–1574.
De Marchis, G. M., Katan, M., Weck, A., Fluri, F., Foerch, C., Findling, O., et al. (2013). Copeptin adds prognostic information after ischemic stroke: Results from the CoRisk study. Neurology, 80(14), 1278–1286. https://doi.org/10.1212/WNL.0b013e3182887944.
De Marchis, G. M., Weck, A., Audebert, H., Benik, S., Foerch, C., Buhl, D., et al. (2014). Copeptin for the prediction of recurrent cerebrovascular events after transient ischemic attack: Results from the CoRisk study. Stroke, 45(10), 2918–2923. https://doi.org/10.1161/STROKEAHA.114.005584.
de Oliveira Manoel, A. L., Goffi, A., Zampieri, F. G., Turkel-Parrella, D., Duggal, A., Marotta, T. R., et al. (2016). The critical care management of spontaneous intracranial hemorrhage: A contemporary review. Critical Care, 20, 272. https://doi.org/10.1186/s13054-016-1432-0.
DeGraba, T. J., Siren, A. L., Penix, L., McCarron, R. M., Hargraves, R., Sood, S., et al. (1998). Increased endothelial expression of intercellular adhesion molecule-1 in symptomatic versus asymptomatic human carotid atherosclerotic plaque. Stroke, 29(7), 1405–1410.
del Zoppo, G. J., Levy, D. E., Wasiewski, W. W., Pancioli, A. M., Demchuk, A. M., Trammel, J., et al. (2009). Hyperfibrinogenemia and functional outcome from acute ischemic stroke. Stroke, 40(5), 1687–1691. https://doi.org/10.1161/STROKEAHA.108.527804.
Delgado, P., Chacon, P., Penalba, A., Pelegri, D., Garcia-Berrocoso, T., Giralt, D., et al. (2012). Lipoprotein-associated phospholipase A(2) activity is associated with large-artery atherosclerotic etiology and recurrent stroke in TIA patients. Cerebrovascular Diseases, 33(2), 150–158. https://doi.org/10.1159/000334193.
Denorme, F., Langhauser, F., Desender, L., Vandenbulcke, A., Rottensteiner, H., Plaimauer, B., et al. (2016). ADAMTS13-mediated thrombolysis of t-PA-resistant occlusions in ischemic stroke in mice. Blood, 127(19), 2337–2345. https://doi.org/10.1182/blood-2015-08-662650.
Dieplinger, B., Bocksrucker, C., Egger, M., Eggers, C., Haltmayer, M., & Mueller, T. (2017). Prognostic value of inflammatory and cardiovascular biomarkers for prediction of 90-day all-cause mortality after acute ischemic stroke-results from the linz stroke unit study. Clinical Chemistry, 63(6), 1101–1109. https://doi.org/10.1373/clinchem.2016.269969.
Dolz, S., Gorriz, D., Tembl, J. I., Sanchez, D., Fortea, G., Parkhutik, V., et al. (2017). Circulating MicroRNAs as novel biomarkers of stenosis progression in asymptomatic carotid stenosis. Stroke, 48(1), 10–16. https://doi.org/10.1161/STROKEAHA.116.013650.
Dykstra-Aiello, C., Jickling, G. C., Ander, B. P., Shroff, N., Zhan, X., Liu, D., et al. (2016). Altered expression of long noncoding RNAs in blood after ischemic stroke and proximity to putative stroke risk loci. Stroke, 47(12), 2896–2903. https://doi.org/10.1161/STROKEAHA.116.013869.
Efstathiou, S. P., Tsioulos, D. I., Tsiakou, A. G., Gratsias, Y. E., Pefanis, A. V., & Mountokalakis, T. D. (2005). Plasma adiponectin levels and five-year survival after first-ever ischemic stroke. Stroke, 36(9), 1915–1919. https://doi.org/10.1161/01.STR.0000177874.29849.f0.
El Husseini, N., & Laskowitz, D. T. (2010). Clinical application of blood biomarkers in cerebrovascular disease. Expert Review of Neurotherapeutics, 10(2), 189–203. https://doi.org/10.1586/ern.09.151.
Elkind, M. S., Luna, J. M., McClure, L. A., Zhang, Y., Coffey, C. S., Roldan, A., et al. (2014). C-reactive protein as a prognostic marker after lacunar stroke: Levels of inflammatory markers in the treatment of stroke study. Stroke, 45(3), 707–716. https://doi.org/10.1161/STROKEAHA.113.004562.
Elkind, M. S., Tai, W., Coates, K., Paik, M. C., & Sacco, R. L. (2009). Lipoprotein-associated phospholipase A2 activity and risk of recurrent stroke. Cerebrovascular Diseases, 27(1), 42–50. https://doi.org/10.1159/000172633.
Eng, L. F., Ghirnikar, R. S., & Lee, Y. L. (2000). Glial fibrillary acidic protein: GFAP-thirty-one years (1969–2000). Neurochemical Research, 25(9–10), 1439–1451.
Feinberg, M. W., & Moore, K. J. (2016). MicroRNA regulation of atherosclerosis. Circulation Research, 118(4), 703–720. https://doi.org/10.1161/CIRCRESAHA.115.306300.
Foerch, C., Montaner, J., Furie, K. L., Ning, M. M., & Lo, E. H. (2009). Invited article: Searching for oracles? Blood biomarkers in acute stroke. Neurology, 73(5), 393–399. https://doi.org/10.1212/WNL.0b013e3181b05ef9.
Foerch, C., Niessner, M., Back, T., Bauerle, M., De Marchis, G. M., Ferbert, A., et al. (2012). Diagnostic accuracy of plasma glial fibrillary acidic protein for differentiating intracerebral hemorrhage and cerebral ischemia in patients with symptoms of acute stroke. Clinical Chemistry, 58(1), 237–245. https://doi.org/10.1373/clinchem.2011.172676.
Foerch, C., Otto, B., Singer, O. C., Neumann-Haefelin, T., Yan, B., Berkefeld, J., et al. (2004). Serum S100B predicts a malignant course of infarction in patients with acute middle cerebral artery occlusion. Stroke, 35(9), 2160–2164. https://doi.org/10.1161/01.STR.0000138730.03264.ac.
Foerch, C., Wunderlich, M. T., Dvorak, F., Humpich, M., Kahles, T., Goertler, M., et al. (2007). Elevated serum S100B levels indicate a higher risk of hemorrhagic transformation after thrombolytic therapy in acute stroke. Stroke, 38(9), 2491–2495. https://doi.org/10.1161/STROKEAHA.106.480111.
Ganz, P., Amarenco, P., Goldstein, L. B., Sillesen, H., Bao, W., Preston, G. M., et al. (2017). Association of osteopontin, neopterin, and myeloperoxidase with stroke risk in patients with prior stroke or transient ischemic attacks: Results of an analysis of 13 biomarkers from the stroke prevention by aggressive reduction in cholesterol levels trial. Stroke, 48(12), 3223–3231. https://doi.org/10.1161/STROKEAHA.117.017965.
George, P. M., Mlynash, M., Adams, C. M., Kuo, C. J., Albers, G. W., & Olivot, J. M. (2015). Novel TIA biomarkers identified by mass spectrometry-based proteomics. International Journal of Stroke, 10(8), 1204–1211. https://doi.org/10.1111/ijs.12603.
Giles, M. F., & Rothwell, P. M. (2007). Risk of stroke early after transient ischaemic attack: A systematic review and meta-analysis. The Lancet Neurology, 6(12), 1063–1072. https://doi.org/10.1016/S1474-4422(07)70274-0.
Glushakova, O. Y., Glushakov, A. V., Miller, E. R., Valadka, A. B., & Hayes, R. L. (2016). Biomarkers for acute diagnosis and management of stroke in neurointensive care units. Brain Circulation, 2(1), 28–47. https://doi.org/10.4103/2394-8108.178546.
Haapaniemi, E., & Tatlisumak, T. (2009). Is D-dimer helpful in evaluating stroke patients? A systematic review. Acta Neurol Scand, 119(3), 141–150. https://doi.org/10.1111/j.1600-0404.2008.01081.x.
Hacke, W., Kaste, M., Bluhmki, E., Brozman, M., Davalos, A., Guidetti, D., et al. (2008). Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. The New England Journal of Medicine, 359(13), 1317–1329. https://doi.org/10.1056/NEJMoa0804656.
Hart, R. G., Diener, H. C., Coutts, S. B., Easton, J. D., Granger, C. B., O’Donnell, M. J., et al. (2014). Embolic strokes of undetermined source: The case for a new clinical construct. The Lancet Neurology, 13(4), 429–438. https://doi.org/10.1016/S1474-4422(13)70310-7.
Hart, R. G., Sharma, M., Mundl, H., Kasner, S. E., Bangdiwala, S. I., Berkowitz, S. D., et al. (2018). Rivaroxaban for stroke prevention after embolic stroke of undetermined source. The New England Journal of Medicine, 378(23), 2191–2201. https://doi.org/10.1056/NEJMoa1802686.
Hassan, A., Hunt, B. J., O’Sullivan, M., Parmar, K., Bamford, J. M., Briley, D., et al. (2003). Markers of endothelial dysfunction in lacunar infarction and ischaemic leukoaraiosis. Brain, 126(Pt 2), 424–432.
Hu, L., Dong, M. X., Zhao, H., Xu, G. H., & Qin, X. Y. (2016). Fibulin-5: A novel biomarker for evaluating severity and predicting prognosis in patients with acute intracerebral haemorrhage. European Journal of Neurology, 23(7), 1195–1201. https://doi.org/10.1111/ene.13013.
Huang, Y. Q., Li, J., Huang, C., & Feng, Y. Q. (2018). Plasma MicroRNA-29c levels are associated with carotid intima-media thickness and is a potential biomarker for the early detection of atherosclerosis. Cellular Physiology and Biochemistry, 50(2), 452–459. https://doi.org/10.1159/000494158.
Im, H. I., & Kenny, P. J. (2012). MicroRNAs in neuronal function and dysfunction. Trends in Neurosciences, 35(5), 325–334. https://doi.org/10.1016/j.tins.2012.01.004.
Jaillard, A., Cornu, C., Durieux, A., Moulin, T., Boutitie, F., Lees, K. R., et al. (1999). Hemorrhagic transformation in acute ischemic stroke. The MAST-E study. MAST-E group. Stroke, 30(7), 1326–1332.
Jauch, E. C., Lindsell, C., Broderick, J., Fagan, S. C., Tilley, B. C., Levine, S. R., et al. (2006). Association of serial biochemical markers with acute ischemic stroke: The National Institute of Neurological Disorders and Stroke recombinant tissue plasminogen activator Stroke Study. Stroke, 37(10), 2508–2513. https://doi.org/10.1161/01.STR.0000242290.01174.9e.
Jickling, G. C., Ander, B. P., Shroff, N., Orantia, M., Stamova, B., Dykstra-Aiello, C., et al. (2016). Leukocyte response is regulated by microRNA let7i in patients with acute ischemic stroke. Neurology, 87(21), 2198–2205. https://doi.org/10.1212/WNL.0000000000003354.
Jickling, G. C., Ander, B. P., Stamova, B., Zhan, X., Liu, D., Rothstein, L., et al. (2013). RNA in blood is altered prior to hemorrhagic transformation in ischemic stroke. Annals of Neurology, 74(2), 232–240. https://doi.org/10.1002/ana.23883.
Jickling, G. C., Ander, B. P., Zhan, X., Noblett, D., Stamova, B., & Liu, D. (2014a). microRNA expression in peripheral blood cells following acute ischemic stroke and their predicted gene targets. PLoS ONE, 9(6), e99283. https://doi.org/10.1371/journal.pone.0099283.
Jickling, G. C., Liu, D., Stamova, B., Ander, B. P., Zhan, X., Lu, A., et al. (2014b). Hemorrhagic transformation after ischemic stroke in animals and humans. Journal of Cerebral Blood Flow & Metabolism, 34(2), 185–199. https://doi.org/10.1038/jcbfm.2013.203.
Jickling, G. C., & Sharp, F. R. (2011). Blood biomarkers of ischemic stroke. Neurotherapeutics, 8(3), 349–360. https://doi.org/10.1007/s13311-011-0050-4.
Jickling, G. C., & Sharp, F. R. (2015). Biomarker panels in ischemic stroke. Stroke, 46(3), 915–920. https://doi.org/10.1161/STROKEAHA.114.005604.
Jickling, G. C., Stamova, B., Ander, B. P., Zhan, X., Tian, Y., Liu, D., et al. (2011). Profiles of lacunar and nonlacunar stroke. Annals of Neurology, 70(3), 477–485. https://doi.org/10.1002/ana.22497.
Jickling, G. C., Xu, H., Stamova, B., Ander, B. P., Zhan, X., Tian, Y., et al. (2010). Signatures of cardioembolic and large-vessel ischemic stroke. Annals of Neurology, 68(5), 681–692. https://doi.org/10.1002/ana.22187.
Jickling, G. C., Zhan, X., Stamova, B., Ander, B. P., Tian, Y., Liu, D., et al. (2012). Ischemic transient neurological events identified by immune response to cerebral ischemia. Stroke, 43(4), 1006–1012. https://doi.org/10.1161/STROKEAHA.111.638577.
Jove, M., Mauri-Capdevila, G., Suarez, I., Cambray, S., Sanahuja, J., Quilez, A., et al. (2015). Metabolomics predicts stroke recurrence after transient ischemic attack. Neurology, 84(1), 36–45. https://doi.org/10.1212/WNL.0000000000001093.
Kamel, H., Longstreth, W. T. Jr., Tirschwell, D. L., Kronmal, R. A., Broderick, J. P., Palesch, Y. Y., et al. (2018). The AtRial cardiopathy and antithrombotic drugs in prevention after cryptogenic stroke randomized trial: Rationale and methods. International Journal of Stroke. https://doi.org/10.1177/1747493018799981.
Katan, M., & Elkind, M. S. V. (2018). The potential role of blood biomarkers in patients with ischemic stroke: An expert opinion. Clinical and Translational Neuroscience, 2(1), 1–7. https://doi.org/10.1177/2514183X18768050.
Katan, M., Fluri, F., Morgenthaler, N. G., Schuetz, P., Zweifel, C., Bingisser, R., et al. (2009). Copeptin: A novel, independent prognostic marker in patients with ischemic stroke. Annals of Neurology, 66(6), 799–808. https://doi.org/10.1002/ana.21783.
Katan, M., Fluri, F., Schuetz, P., Morgenthaler, N. G., Zweifel, C., Bingisser, R., et al. (2010). Midregional pro-atrial natriuretic peptide and outcome in patients with acute ischemic stroke. Journal of the American College of Cardiology, 56(13), 1045–1053. https://doi.org/10.1016/j.jacc.2010.02.071.
Katan, M., Moon, Y. P., Paik, M. C., Mueller, B., Huber, A., Sacco, R. L., et al. (2016). Procalcitonin and midregional proatrial natriuretic peptide as markers of ischemic stroke: The Northern Manhattan Study. Stroke, 47(7), 1714–1719. https://doi.org/10.1161/STROKEAHA.115.011392.
Katan, M., Moon, Y. P., Paik, M. C., Wolfert, R. L., Sacco, R. L., & Elkind, M. S. (2014). Lipoprotein-associated phospholipase A2 is associated with atherosclerotic stroke risk: The Northern Manhattan Study. PLoS ONE, 9(1), e83393. https://doi.org/10.1371/journal.pone.0083393.
Katan, M., Nigro, N., Fluri, F., Schuetz, P., Morgenthaler, N. G., Jax, F., et al. (2011). Stress hormones predict cerebrovascular re-events after transient ischemic attacks. Neurology, 76(6), 563–566. https://doi.org/10.1212/WNL.0b013e31820b75e6.
Katsanos, A. H., Makris, K., Stefani, D., Koniari, K., Gialouri, E., Lelekis, M., et al. (2017). Plasma glial fibrillary acidic protein in the differential diagnosis of intracerebral hemorrhage. Stroke, 48(9), 2586–2588. https://doi.org/10.1161/STROKEAHA.117.018409.
Kazmierski, R., Michalak, S., Wencel-Warot, A., & Nowinski, W. L. (2012). Serum tight-junction proteins predict hemorrhagic transformation in ischemic stroke patients. Neurology, 79(16), 1677–1685. https://doi.org/10.1212/WNL.0b013e31826e9a83.
Kelly, P. J., Albers, G. W., Chatzikonstantinou, A., De Marchis, G. M., Ferrari, J., George, P., et al. (2016). Validation and comparison of imaging-based scores for prediction of early stroke risk after transient ischaemic attack: A pooled analysis of individual-patient data from cohort studies. The Lancet Neurology, 15(12), 1238–1247. https://doi.org/10.1016/S1474-4422(16)30236-8.
Kernagis, D. N., & Laskowitz, D. T. (2012). Evolving role of biomarkers in acute cerebrovascular disease. Annals of Neurology, 71(3), 289–303. https://doi.org/10.1002/ana.22553.
Kernan, W. N., Viscoli, C. M., Brass, L. M., Makuch, R. W., Sarrel, P. M., Roberts, R. S., et al. (2000). The stroke prognosis instrument II (SPI-II): A clinical prediction instrument for patients with transient ischemia and nondisabling ischemic stroke. Stroke, 31(2), 456–462.
Keyt, B. A., Paoni, N. F., Refino, C. J., Berleau, L., Nguyen, H., Chow, A., et al. (1994). A faster-acting and more potent form of tissue plasminogen activator. Proceedings of the National Academy of Sciences of the United States of America, 91(9), 3670–3674.
Khan, S. Q., Dhillon, O., Kelly, D., Squire, I. B., Struck, J., Quinn, P., et al. (2008). Plasma N-terminal B-Type natriuretic peptide as an indicator of long-term survival after acute myocardial infarction: Comparison with plasma midregional pro-atrial natriuretic peptide: The LAMP (Leicester Acute Myocardial Infarction Peptide) study. Journal of the American College of Cardiology, 51(19), 1857–1864. https://doi.org/10.1016/j.jacc.2008.01.041.
Knoflach, M., Lang, W., Seyfang, L., Fertl, E., Oberndorfer, S., Daniel, G., et al. (2016). Predictive value of ABCD2 and ABCD3-I scores in TIA and minor stroke in the stroke unit setting. Neurology, 87(9), 861–869. https://doi.org/10.1212/WNL.0000000000003033.
Kumar, S., Selim, M. H., & Caplan, L. R. (2010). Medical complications after stroke. The Lancet Neurology, 9(1), 105–118. https://doi.org/10.1016/S1474-4422(09)70266-2.
Lalive, P. H. (2011). Biomarkers in neuroimmunology. Revue Médicale Suisse, 7(291), 860–866.
Li, J., & Wang, Y. (2016). Blood biomarkers in minor stroke and transient ischemic attack. Neuroscience Bulletin, 32(5), 463–468. https://doi.org/10.1007/s12264-016-0038-5.
Li, J., Wang, Y., Wang, D., Lin, J., Wang, A., Zhao, X., et al. (2015). Glycated albumin predicts the effect of dual and single antiplatelet therapy on recurrent stroke. Neurology, 84(13), 1330–1336. https://doi.org/10.1212/WNL.0000000000001421.
Li, J., Zhao, X., Meng, X., Lin, J., Liu, L., Wang, C., et al. (2016). High-sensitive C-reactive protein predicts recurrent stroke and poor functional outcome: Subanalysis of the clopidogrel in high-risk patients with acute nondisabling cerebrovascular events trial. Stroke, 47(8), 2025–2030. https://doi.org/10.1161/STROKEAHA.116.012901.
Llombart, V., Antolin-Fontes, A., Bustamante, A., Giralt, D., Rost, N. S., Furie, K., et al. (2015). B-type natriuretic peptides help in cardioembolic stroke diagnosis: Pooled data meta-analysis. Stroke, 46(5), 1187–1195. https://doi.org/10.1161/STROKEAHA.114.008311.
Llombart, V., Garcia-Berrocoso, T., Bustamante, A., Giralt, D., Rodriguez-Luna, D., Muchada, M., et al. (2016). Plasmatic retinol-binding protein 4 and glial fibrillary acidic protein as biomarkers to differentiate ischemic stroke and intracerebral hemorrhage. Journal of Neurochemistry, 136(2), 416–424. https://doi.org/10.1111/jnc.13419.
Longstreth, W. T. Jr., Kronmal, R. A., Thompson, J. L., Christenson, R. H., Levine, S. R., Gross, R., et al. (2013). Amino terminal pro-B-type natriuretic peptide, secondary stroke prevention, and choice of antithrombotic therapy. Stroke, 44(3), 714–719. https://doi.org/10.1161/STROKEAHA.112.675942.
Lorenz, M. W., Markus, H. S., Bots, M. L., Rosvall, M., & Sitzer, M. (2007). Prediction of clinical cardiovascular events with carotid intima-media thickness: A systematic review and meta-analysis. Circulation, 115(4), 459–467. https://doi.org/10.1161/CIRCULATIONAHA.106.628875.
Luger, S., Witsch, J., Dietz, A., Hamann, G. F., Minnerup, J., Schneider, H., et al. (2017). Glial fibrillary acidic protein serum levels distinguish between intracerebral hemorrhage and cerebral ischemia in the early phase of stroke. Clinical Chemistry, 63(1), 377–385. https://doi.org/10.1373/clinchem.2016.263335.
Lynch, J. R., Blessing, R., White, W. D., Grocott, H. P., Newman, M. F., & Laskowitz, D. T. (2004). Novel diagnostic test for acute stroke. Stroke, 35(1), 57–63. https://doi.org/10.1161/01.STR.0000105927.62344.4C.
Magenta, A., Sileno, S., D’Agostino, M., Persiani, F., Beji, S., Paolini, A., et al. (2018). Atherosclerotic plaque instability in carotid arteries: miR-200c as a promising biomarker. Clinical Science(London), 132(22), 2423–2436. https://doi.org/10.1042/CS20180684.
Maitrias, P., Metzinger-Le Meuth, V., Nader, J., Reix, T., Caus, T., & Metzinger, L. (2017). The involvement of miRNA in carotid-related stroke. Arteriosclerosis, Thrombosis, and Vascular Biology, 37(9), 1608–1617. https://doi.org/10.1161/ATVBAHA.117.309233.
Makris, K., Haliassos, A., Chondrogianni, M., & Tsivgoulis, G. (2018). Blood biomarkers in ischemic stroke: Potential role and challenges in clinical practice and research. Critical Reviews in Clinical Laboratory Sciences, 55(5), 294–328. https://doi.org/10.1080/10408363.2018.1461190.
Markus, H. S., Larsson, S. C., Kuker, W., Schulz, U. G., Ford, I., Rothwell, P. M., et al. (2017). Stenting for symptomatic vertebral artery stenosis: The vertebral artery ischaemia stenting trial. Neurology, 89(12), 1229–1236. https://doi.org/10.1212/WNL.0000000000004385.
Marti-Fabregas, J., Borrell, M., Cocho, D., Belvis, R., Castellanos, M., Montaner, J., et al. (2005). Hemostatic markers of recanalization in patients with ischemic stroke treated with rt-PA. Neurology, 65(3), 366–370. https://doi.org/10.1212/01.wnl.0000171704.50395.ba.
Missler, U., Wiesmann, M., Friedrich, C., & Kaps, M. (1997). S-100 protein and neuron-specific enolase concentrations in blood as indicators of infarction volume and prognosis in acute ischemic stroke. Stroke, 28(10), 1956–1960.
Missler, U., Wiesmann, M., Wittmann, G., Magerkurth, O., & Hagenstrom, H. (1999). Measurement of glial fibrillary acidic protein in human blood: Analytical method and preliminary clinical results. Clinical Chemistry, 45(1), 138–141.
Mocco, J., Choudhri, T. F., Mack, W. J., Laufer, I., Lee, J., Kiss, S., et al. (2001). Elevation of soluble intercellular adhesion molecule-1 levels in symptomatic and asymptomatic carotid atherosclerosis. Neurosurgery, 48(4), 718–721. (discussion 721–712).
Modak, J. M., Roy-O’Reilly, M., Zhu, L., Staff, I., & McCullough, L. D. (2018). Differential microribonucleic acid expression in cardioembolic stroke. Journal of Stroke and Cerebrovascular Diseases. https://doi.org/10.1016/j.jstrokecerebrovasdis.2018.09.018.
Montaner, J., Perea-Gainza, M., Delgado, P., Ribo, M., Chacon, P., Rosell, A., et al. (2008). Etiologic diagnosis of ischemic stroke subtypes with plasma biomarkers. Stroke, 39(8), 2280–2287. https://doi.org/10.1161/STROKEAHA.107.505354.
Nash, D. L., Bellolio, M. F., & Stead, L. G. (2008). S100 as a marker of acute brain ischemia: A systematic review. Neurocritical Care, 8(2), 301–307. https://doi.org/10.1007/s12028-007-9019-x.
Ng, G. J. L., Quek, A. M. L., Cheung, C., Arumugam, T. V., & Seet, R. C. S (2017). Stroke biomarkers in clinical practice: A critical appraisal. Neurochemistry International, 107, 11–22. https://doi.org/10.1016/j.neuint.2017.01.005.
Nogueira, R. G., Jadhav, A. P., Haussen, D. C., Bonafe, A., Budzik, R. F., Bhuva, P., et al. (2018). Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct. The New England Journal of Medicine, 378(1), 11–21. https://doi.org/10.1056/NEJMoa1706442.
Olivot, J. M., Labreuche, J., Aiach, M., Amarenco, P., & Investigators, G. (2004). Soluble thrombomodulin and brain infarction: Case-control and prospective study. Stroke, 35(8), 1946–1951. https://doi.org/10.1161/01.STR.0000133340.37712.9b.
Paraskevas, K. I., Veith, F. J., & Spence, J. D. (2018). How to identify which patients with asymptomatic carotid stenosis could benefit from endarterectomy or stenting. Stroke and Vascular Neurology, 3(2), 92–100. https://doi.org/10.1136/svn-2017-000129.
Park, S. Y., Kim, J., Kim, O. J., Kim, J. K., Song, J., Shin, D. A., et al. (2013a). Predictive value of circulating interleukin-6 and heart-type fatty acid binding protein for three months clinical outcome in acute cerebral infarction: Multiple blood markers profiling study. Critical Care, 17(2), R45. https://doi.org/10.1186/cc12564.
Park, S. Y., Kim, M. H., Kim, O. J., Ahn, H. J., Song, J. Y., Jeong, J. Y., et al. (2013b). Plasma heart-type fatty acid binding protein level in acute ischemic stroke: Comparative analysis with plasma S100B level for diagnosis of stroke and prediction of long-term clinical outcome. Clinical Neurology and Neurosurgery, 115(4), 405–410. https://doi.org/10.1016/j.clineuro.2012.06.004.
Park, K. Y., Ay, I., Avery, R., Caceres, J. A., Siket, M. S., Pontes-Neto, O. M., et al. (2018). New biomarker for acute ischaemic stroke: Plasma glycogen phosphorylase isoenzyme BB. Journal of Neurology, Neurosurgery, and Psychiatry, 89(4), 404–409. https://doi.org/10.1136/jnnp-2017-316084.
Penn, A. M., Bibok, M. B., Saly, V. K., Coutts, S. B., Lesperance, M. L., Balshaw, R. F., et al. (2018). Verification of a proteomic biomarker panel to diagnose minor stroke and transient ischaemic attack: Phase 1 of SpecTRA, a large scale translational study. Biomarkers, 23(4), 392–405. https://doi.org/10.1080/1354750X.2018.1434681.
Perry, L. A., Lucarelli, T., Penny-Dimri, J. C., McInnes, M. D., Mondello, S., Bustamante, A., et al. (2018). Glial fibrillary acidic protein for the early diagnosis of intracerebral hemorrhage: Systematic review and meta-analysis of diagnostic test accuracy. International Journal of Stroke. https://doi.org/10.1177/1747493018806167.
Poli, S., Hartig, F., Selim, M. H., Molina, C. A., & Dowlatshahi, D. (2017). Prothrombin complex concentrates use in intracerebral hemorrhage. Stroke, 48(9), 2644–2646. https://doi.org/10.1161/STROKEAHA.117.017591.
Powers, W. J., Rabinstein, A. A., Ackerson, T., Adeoye, O. M., Bambakidis, N. C., Becker, K., et al. (2018). 2018 guidelines for the early management of patients with acute ischemic stroke: A guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke, 49(3), e46–e110. https://doi.org/10.1161/STR.0000000000000158.
Ramos-Fernandez, M., Bellolio, M. F., & Stead, L. G. (2011). Matrix metalloproteinase-9 as a marker for acute ischemic stroke: A systematic review. Journal of Stroke and Cerebrovascular Diseases, 20(1), 47–54. https://doi.org/10.1016/j.jstrokecerebrovasdis.2009.10.008.
Ren, C., Kobeissy, F., Alawieh, A., Li, N., Li, N., Zibara, K., et al. (2016). Assessment of Serum UCH-L1 and GFAP in acute stroke patients. Scientific Reports, 6, 24588. https://doi.org/10.1038/srep24588.
Ribo, M., Montaner, J., Molina, C. A., Arenillas, J. F., Santamarina, E., & Alvarez-Sabin, J. (2004a). Admission fibrinolytic profile predicts clot lysis resistance in stroke patients treated with tissue plasminogen activator. Thrombosis and Haemostasis, 91(6), 1146–1151. https://doi.org/10.1160/TH04-02-0097.
Ribo, M., Montaner, J., Molina, C. A., Arenillas, J. F., Santamarina, E., Quintana, M., et al. (2004b). Admission fibrinolytic profile is associated with symptomatic hemorrhagic transformation in stroke patients treated with tissue plasminogen activator. Stroke, 35(9), 2123–2127. https://doi.org/10.1161/01.STR.0000137608.73660.4c.
Ridker, P. M., MacFadyen, J. G., Wolfert, R. L., & Koenig, W. (2012). Relationship of lipoprotein-associated phospholipase A(2) mass and activity with incident vascular events among primary prevention patients allocated to placebo or to statin therapy: An analysis from the JUPITER trial. Clinical Chemistry, 58(5), 877–886. https://doi.org/10.1373/clinchem.2011.180281.
Riedel, C. H., Zimmermann, P., Jensen-Kondering, U., Stingele, R., Deuschl, G., & Jansen, O. (2011). The importance of size: Successful recanalization by intravenous thrombolysis in acute anterior stroke depends on thrombus length. Stroke, 42(6), 1775–1777. https://doi.org/10.1161/STROKEAHA.110.609693.
Rodriguez-Yanez, M., Sobrino, T., Arias, S., Vazquez-Herrero, F., Brea, D., Blanco, M., et al. (2011). Early biomarkers of clinical-diffusion mismatch in acute ischemic stroke. Stroke, 42(10), 2813–2818. https://doi.org/10.1161/STROKEAHA.111.614503.
Rosell, A., Cuadrado, E., Alvarez-Sabin, J., Hernandez-Guillamon, M., Delgado, P., Penalba, A., et al. (2008). Caspase-3 is related to infarct growth after human ischemic stroke. Neuroscience Letters, 430(1), 1–6. https://doi.org/10.1016/j.neulet.2007.05.006.
Rothwell, P. M. (2018). Clinical innovation in stroke: Getting the simple things right. The Lancet Neurology, 17(6), 491–493. https://doi.org/10.1016/S1474-4422(18)30113-3.
Rozanski, M., & Audebert, H. J. (2018). Glial fibrillary acidic protein in acute stroke: What we know and what we need to know. AME Medical Journal. https://doi.org/10.21037/amj.2018.01.04
Rozanski, M., Waldschmidt, C., Kunz, A., Grittner, U., Ebinger, M., Wendt, M., et al. (2017). Glial fibrillary acidic protein for prehospital diagnosis of intracerebral hemorrhage. Cerebrovascular Diseases, 43(1–2), 76–81. https://doi.org/10.1159/000453460.
Sato, M., Suzuki, A., Nagata, K., & Uchiyama, S. (2006). Increased von Willebrand factor in acute stroke patients with atrial fibrillation. Journal of Stroke and Cerebrovascular Diseases, 15(1), 1–7. https://doi.org/10.1016/j.jstrokecerebrovasdis.2005.09.005.
Saver, J. L. (2016). Cryptogenic stroke. The New England Journal of Medicine, 375(11), e26. https://doi.org/10.1056/NEJMc1609156.
Seiffge, D. J., Werring, D. J., Paciaroni, M., Dawson, J., Warach, S., Milling, T. J., et al. (2018). Timing of anticoagulation after recent ischaemic stroke in patients with atrial fibrillation. The Lancet Neurology. https://doi.org/10.1016/S1474-4422(18)30356-9.
Serena, J., Blanco, M., Castellanos, M., Silva, Y., Vivancos, J., Moro, M. A., et al. (2005). The prediction of malignant cerebral infarction by molecular brain barrier disruption markers. Stroke, 36(9), 1921–1926. https://doi.org/10.1161/01.STR.0000177870.14967.94.
Sharp, F. R., & Jickling, G. C. (2013). Whole genome expression of cellular response to stroke. Stroke, 44(6 Suppl 1), S23–S25. https://doi.org/10.1161/STROKEAHA.112.679357.
Sharp, F. R., Jickling, G. C., Stamova, B., Tian, Y., Zhan, X., Liu, D., et al. (2011). Molecular markers and mechanisms of stroke: RNA studies of blood in animals and humans. Journal of Cerebral Blood Flow & Metabolism, 31(7), 1513–1531. https://doi.org/10.1038/jcbfm.2011.45.
Sharp, F. R., Lu, A., Tang, Y., & Millhorn, D. E. (2000). Multiple molecular penumbras after focal cerebral ischemia. Journal of Cerebral Blood Flow & Metabolism, 20(7), 1011–1032. https://doi.org/10.1097/00004647-200007000-00001.
Si, W., He, P., Wang, Y., Fu, Y., Li, X., Lin, X., et al. (2018). Complement complex C5b-9 levels are associated with the clinical outcomes of acute ischemic stroke and carotid plaque stability. Translational Stroke Research. https://doi.org/10.1007/s12975-018-0658-3.
Simats, A., Garcia-Berrocoso, T., & Montaner, J. (2016). Neuroinflammatory biomarkers: From stroke diagnosis and prognosis to therapy. Biochimica et Biophysica Acta, 1862(3), 411–424. https://doi.org/10.1016/j.bbadis.2015.10.025.
Sonneveld, M. A., de Maat, M. P., Portegies, M. L., Kavousi, M., Hofman, A., Turecek, P. L., et al. (2015). Low ADAMTS13 activity is associated with an increased risk of ischemic stroke. Blood, 126(25), 2739–2746. https://doi.org/10.1182/blood-2015-05-643338.
Sonneveld, M. A., Franco, O. H., Ikram, M. A., Hofman, A., Kavousi, M., de Maat, M. P., et al. (2016). Von Willebrand Factor, ADAMTS13, and the risk of mortality: The Rotterdam study. Arteriosclerosis, Thrombosis, and Vascular Biology, 36(12), 2446–2451. https://doi.org/10.1161/ATVBAHA.116.308225.
Stability Investigators, White, H. D., Held, C., Stewart, R., Tarka, E., Brown, R., et al. (2014). Darapladib for preventing ischemic events in stable coronary heart disease. The New England Journal of Medicine, 370(18), 1702–1711. https://doi.org/10.1056/NEJMoa1315878.
Stamova, B., Ander, B. P., Jickling, G., Hamade, F., Durocher, M., Zhan, X., et al. (2018). The intracerebral hemorrhage blood transcriptome in humans differs from the ischemic stroke and vascular risk factor control blood transcriptomes. Journal of Cerebral Blood Flow & Metabolism. https://doi.org/10.1177/0271678X18769513.
Stamova, B., Xu, H., Jickling, G., Bushnell, C., Tian, Y., Ander, B. P., et al. (2010). Gene expression profiling of blood for the prediction of ischemic stroke. Stroke, 41(10), 2171–2177. https://doi.org/10.1161/STROKEAHA.110.588335.
Stanca, D. M., Marginean, I. C., Soritau, O., Dragos, C., Marginean, M., Muresanu, D. F., et al. (2015). GFAP and antibodies against NMDA receptor subunit NR2 as biomarkers for acute cerebrovascular diseases. Journal of Cellular and Molecular Medicine, 19(9), 2253–2261. https://doi.org/10.1111/jcmm.12614.
Steadman, C. D., Ray, S., Ng, L. L., & McCann, G. P. (2010). Natriuretic peptides in common valvular heart disease. Journal of the American College of Cardiology, 55(19), 2034–2048. https://doi.org/10.1016/j.jacc.2010.02.021.
Suwanwela, N. C., Chutinet, A., & Phanthumchinda, K. (2006). Inflammatory markers and conventional atherosclerotic risk factors in acute ischemic stroke: Comparative study between vascular disease subtypes. Journal of the Medical Association of Thailand, 89(12), 2021–2027.
Switzer, J. A., Hess, D. C., Ergul, A., Waller, J. L., Machado, L. S., Portik-Dobos, V., et al. (2011). Matrix metalloproteinase-9 in an exploratory trial of intravenous minocycline for acute ischemic stroke. Stroke, 42(9), 2633–2635. https://doi.org/10.1161/STROKEAHA.111.618215.
Tang, Y., Lu, A., Aronow, B. J., & Sharp, F. R. (2001). Blood genomic responses differ after stroke, seizures, hypoglycemia, and hypoxia: Blood genomic fingerprints of disease. Annals of Neurology, 50(6), 699–707.
Tang, Y., Xu, H., Du, X., Lit, L., Walker, W., Lu, A., et al. (2006). Gene expression in blood changes rapidly in neutrophils and monocytes after ischemic stroke in humans: A microarray study. Journal of Cerebral Blood Flow & Metabolism, 26(8), 1089–1102. https://doi.org/10.1038/sj.jcbfm.9600264.
Tanne, D., Macko, R. F., Lin, Y., Tilley, B. C., Levine, S. R., & Group, N. r. S. S. (2006). Hemostatic activation and outcome after recombinant tissue plasminogen activator therapy for acute ischemic stroke. Stroke, 37(7), 1798–1804. https://doi.org/10.1161/01.STR.0000226897.43749.27.
Thiebaut, A. M., Gauberti, M., Ali, C., De Lizarrondo, M., Vivien, S., Yepes, D., M., et al (2018). The role of plasminogen activators in stroke treatment: Fibrinolysis and beyond. The Lancet Neurology, 17(12), 1121–1132. https://doi.org/10.1016/S1474-4422(18)30323-5.
Thomalla, G., Simonsen, C. Z., Boutitie, F., Andersen, G., Berthezene, Y., Cheng, B., et al. (2018). MRI-guided thrombolysis for stroke with unknown time of onset. The New England Journal of Medicine, 379(7), 611–622. https://doi.org/10.1056/NEJMoa1804355.
Tiedt, S., Duering, M., Barro, C., Kaya, A. G., Boeck, J., Bode, F. J., et al. (2018). Serum neurofilament light: A biomarker of neuroaxonal injury after ischemic stroke. Neurology, 91(14), e1338–e1347. https://doi.org/10.1212/WNL.0000000000006282.
Touboul, P. J., Hennerici, M. G., Meairs, S., Adams, H., Amarenco, P., Bornstein, N., et al. (2012). Mannheim carotid intima-media thickness and plaque consensus (2004-2006-2011). An update on behalf of the advisory board of the 3rd, 4th and 5th watching the risk symposia, at the 13th, 15th and 20th European Stroke Conferences, Mannheim, Germany, 2004, Brussels, Belgium, 2006, and Hamburg, Germany, 2011. Cerebrovascular Diseases, 34(4), 290–296. https://doi.org/10.1159/000343145.
Tu, L., Liu, X., Li, T., Yang, X., Ren, Y., Zhang, Q., et al. (2018). Admission serum calcium level as a prognostic marker for intracerebral hemorrhage. Neurocritical Care. https://doi.org/10.1007/s12028-018-0574-0.
Tu, W. J., Zhao, S. J., Xu, D. J., & Chen, H. (2014). Serum 25-hydroxyvitamin D predicts the short-term outcomes of Chinese patients with acute ischaemic stroke. Clinical Science (London), 126(5), 339–346. https://doi.org/10.1042/CS20130284.
Turaj, W., Slowik, A., Dziedzic, T., Pulyk, R., Adamski, M., Strojny, J., et al. (2006). Increased plasma fibrinogen predicts one-year mortality in patients with acute ischemic stroke. Journal of the Neurological Sciences, 246(1–2), 13–19. https://doi.org/10.1016/j.jns.2006.01.020.
Tuttolomondo, A., Di Sciacca, R., Di Raimondo, D., Serio, A., D’Aguanno, G., La Placa, S., et al. (2009). Plasma levels of inflammatory and thrombotic/fibrinolytic markers in acute ischemic strokes: Relationship with TOAST subtype, outcome and infarct site. Journal of Neuroimmunology, 215(1–2), 84–89. https://doi.org/10.1016/j.jneuroim.2009.06.019.
Twerenbold, R., Boeddinghaus, J., Nestelberger, T., Wildi, K., Rubini Gimenez, M., Badertscher, P., et al. (2017). Clinical use of high-sensitivity cardiac troponin in patients with suspected myocardial infarction. Journal of the American College of Cardiology, 70(8), 996–1012. https://doi.org/10.1016/j.jacc.2017.07.718.
Uno, M., Kitazato, K. T., Nishi, K., Itabe, H., & Nagahiro, S. (2003). Raised plasma oxidised LDL in acute cerebral infarction. Journal of Neurology, Neurosurgery, and Psychiatry, 74(3), 312–316.
Urbich, C., Kuehbacher, A., & Dimmeler, S. (2008). Role of microRNAs in vascular diseases, inflammation, and angiogenesis. Cardiovascular Research, 79(4), 581–588. https://doi.org/10.1093/cvr/cvn156.
Vahedi, K., Hofmeijer, J., Juettler, E., Vicaut, E., George, B., Algra, A., et al. (2007). Early decompressive surgery in malignant infarction of the middle cerebral artery: A pooled analysis of three randomised controlled trials. The Lancet Neurology, 6(3), 215–222. https://doi.org/10.1016/S1474-4422(07)70036-4.
VanGilder, R. L., Davidov, D. M., Stinehart, K. R., Huber, J. D., Turner, R. C., Wilson, K. S., et al. (2014). C-reactive protein and long-term ischemic stroke prognosis. Journal of Clinical Neuroscience, 21(4), 547–553. https://doi.org/10.1016/j.jocn.2013.06.015.
Wang, H., Cheng, Y., Chen, S., Li, X., Zhu, Z., & Zhang, W. (2018). Impact of elevated hemoglobin A1c levels on functional outcome in patients with acute ischemic stroke. Journal of Stroke and Cerebrovascular Diseases. https://doi.org/10.1016/j.jstrokecerebrovasdis.2018.10.026.
Wang, J., Ruan, J., Zhu, M., Yang, J., Du, S., Xu, P., et al. (2018). Predictive value of long noncoding RNA ZFAS1 in patients with ischemic stroke. Clinical and Experimental Hypertension. https://doi.org/10.1080/10641963.2018.1529774.
White, H. D., Simes, J., Stewart, R. A., Blankenberg, S., Barnes, E. H., Marschner, I. C., et al. (2013). Changes in lipoprotein-Associated phospholipase A2 activity predict coronary events and partly account for the treatment effect of pravastatin: Results from the Long-Term Intervention with Pravastatin in Ischemic Disease study. Journal of the American Heart Association, 2(5), e000360. https://doi.org/10.1161/JAHA.113.000360.
Whiteley, W., Chong, W. L., Sengupta, A., & Sandercock, P. (2009a). Blood markers for the prognosis of ischemic stroke: A systematic review. Stroke, 40(5), e380–e389. https://doi.org/10.1161/STROKEAHA.108.528752.
Whiteley, W., Jackson, C., Lewis, S., Lowe, G., Rumley, A., Sandercock, P., et al. (2009b). Inflammatory markers and poor outcome after stroke: A prospective cohort study and systematic review of interleukin-6. PLoS Medicine, 6(9), e1000145. https://doi.org/10.1371/journal.pmed.1000145.
Whiteley, W., Tian, Y., & Jickling, G. C. (2012a). Blood biomarkers in stroke: Research and clinical practice. International Journal of Stroke, 7(5), 435–439. https://doi.org/10.1111/j.1747-4949.2012.00784.x.
Whiteley, W., Tseng, M. C., & Sandercock, P. (2008). Blood biomarkers in the diagnosis of ischemic stroke: A systematic review. Stroke, 39(10), 2902–2909. https://doi.org/10.1161/STROKEAHA.107.511261.
Whiteley, W., Wardlaw, J., Dennis, M., Lowe, G., Rumley, A., Sattar, N., et al. (2012b). The use of blood biomarkers to predict poor outcome after acute transient ischemic attack or ischemic stroke. Stroke, 43(1), 86–91. https://doi.org/10.1161/STROKEAHA.111.634089.
Wiseman, S., Marlborough, F., Doubal, F., Webb, D. J., & Wardlaw, J. (2014). Blood markers of coagulation, fibrinolysis, endothelial dysfunction and inflammation in lacunar stroke versus non-lacunar stroke and non-stroke: Systematic review and meta-analysis. Cerebrovascular Diseases, 37(1), 64–75. https://doi.org/10.1159/000356789.
Wunderlich, M. T., Lins, H., Skalej, M., Wallesch, C. W., & Goertler, M. (2006). Neuron-specific enolase and tau protein as neurobiochemical markers of neuronal damage are related to early clinical course and long-term outcome in acute ischemic stroke. Clinical Neurology and Neurosurgery, 108(6), 558–563. https://doi.org/10.1016/j.clineuro.2005.12.006.
Wyseure, T., Rubio, M., Denorme, F., Martinez de Lizarrondo, S., Peeters, M., Gils, A., et al. (2015). Innovative thrombolytic strategy using a heterodimer diabody against TAFI and PAI-1 in mouse models of thrombosis and stroke. Blood, 125(8), 1325–1332. https://doi.org/10.1182/blood-2014-07-588319.
Xie, S., Lu, L., Liu, L., Bi, G., & Zheng, L. (2016). Progranulin and short-term outcome in patients with acute ischaemic stroke. European Journal of Neurology, 23(3), 648–655. https://doi.org/10.1111/ene.12920.
Xiong, L., Yang, Y., Zhang, M., & Xu, W. (2015). The use of serum glial fibrillary acidic protein test as a promising tool for intracerebral hemorrhage diagnosis in Chinese patients and prediction of the short-term functional outcomes. Neurological Sciences, 36(11), 2081–2087. https://doi.org/10.1007/s10072-015-2317-8.
Xu, Q., Tian, Y., Peng, H., & Li, H. (2017). Copeptin as a biomarker for prediction of prognosis of acute ischemic stroke and transient ischemic attack: A meta-analysis. Hypertension Research, 40(5), 465–471. https://doi.org/10.1038/hr.2016.165.
Xu, T., Zuo, P., Cao, L., Gao, Z., & Ke, K. (2018). Omentin-1 is associated with carotid plaque instability among ischemic stroke patients. Journal of Atherosclerosis and Thrombosis, 25(6), 505–511. https://doi.org/10.5551/jat.42135.
Yaghi, S., Bernstein, R. A., Passman, R., Okin, P. M., & Furie, K. L. (2017a). Cryptogenic stroke: Research and practice. Circulation Research, 120(3), 527–540. https://doi.org/10.1161/CIRCRESAHA.116.308447.
Yaghi, S., Willey, J. Z., Cucchiara, B., Goldstein, J. N., Gonzales, N. R., Khatri, P., et al. (2017b). Treatment and outcome of hemorrhagic transformation after intravenous alteplase in acute ischemic stroke: A scientific statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke, 48(12), e343–e361. https://doi.org/10.1161/STR.0000000000000152.
Yip, H. K., Lu, C. H., Yang, C. H., Chang, H. W., Hung, W. C., Cheng, C. I., et al. (2006). Levels and value of platelet activity in patients with severe internal carotid artery stenosis. Neurology, 66(6), 804–808. https://doi.org/10.1212/01.wnl.0000208220.04165.05.
Yoon, C. W., Kim, S. J., Bang, O. Y., Chung, C. S., Lee, K. H., & Kim, G. M. (2012). Premorbid warfarin use and lower D-dimer levels are associated with a spontaneous early improvement in an atrial fibrillation-related stroke. Journal of Thrombosis and Haemostasis, 10(11), 2394–2396. https://doi.org/10.1111/j.1538-7836.2012.04909.x.
Zhan, X., Jickling, G. C., Tian, Y., Stamova, B., Xu, H., Ander, B. P., et al. (2011). Transient ischemic attacks characterized by RNA profiles in blood. Neurology, 77(19), 1718–1724. https://doi.org/10.1212/WNL.0b013e318236eee6.
Zhang, Z. G., Wang, C., Wang, J., Zhang, Z., Yang, Y. L., Gao, L., et al. (2015). Prognostic value of mannose-binding lectin: 90-day outcome in patients with acute ischemic stroke. Molecular Neurobiology, 51(1), 230–239. https://doi.org/10.1007/s12035-014-8682-0.
Zhao, X., Yu, Y., Xu, W., Dong, L., Wang, Y., Gao, B., et al. (2016). Apolipoprotein A1-unique peptide as a diagnostic biomarker for acute ischemic stroke. International Journal of Molecular Sciences, 17(4), 458. https://doi.org/10.3390/ijms17040458.
Zhou, S., Bao, J., Wang, Y., & Pan, S. (2016). S100beta as a biomarker for differential diagnosis of intracerebral hemorrhage and ischemic stroke. Neurological Research, 38(4), 327–332. https://doi.org/10.1080/01616412.2016.1152675.
Zhu, Y. Y., Zhang, J. L., Liu, L., Han, Y., Ge, X., & Zhao, S. (2018). Evaluation of serum retinol-binding protein-4 levels as a biomarker of poor short-term prognosis in ischemic stroke. Bioscience Reports. https://doi.org/10.1042/BSR20180786.
Zhu, Z., Tang, W., Ge, L., Han, X., & Dong, Q. (2018). The value of plasma fibrillin-1 level in patients with spontaneous cerebral artery dissection. Neurology, 90(9), e732–e737. https://doi.org/10.1212/WNL.0000000000005027.
Zimmermann-Ivol, C. G., Burkhard, P. R., Floch-Rohr, L., Allard, L., Hochstrasser, D. F., & Sanchez, J. C. (2004). Fatty acid binding protein as a serum marker for the early diagnosis of stroke: A pilot study. Molecular & Cellular Proteomics, 3(1), 66–72. https://doi.org/10.1074/mcp.M300066-MCP200.
Funding
GCJ receives research support from the Canadian Institutes of Health Research (CIHR), the Heart and Stroke Foundation, the University Hospital Foundation, and the National Institutes of Health (NIH).
Author information
Authors and Affiliations
Contributions
JK-T did the literature search and drafted the manuscript. GCJ critically revised the initial draft and all the subsequent versions. All authors have approved the final version of the manuscript.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical Approval
This review is based solely on previously published articles from ethically approved studies. The work did not involve human or animal experiments and did not require the collection of new data. Therefore, no ethical approval or consent was required.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Kamtchum-Tatuene, J., Jickling, G.C. Blood Biomarkers for Stroke Diagnosis and Management. Neuromol Med 21, 344–368 (2019). https://doi.org/10.1007/s12017-019-08530-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12017-019-08530-0