I guess not, no protocols were written or distributed.
Acute Stroke Biomarkers: Are We There Yet?
Marie Dagonnier1,2*, 
Geoffrey A. Donnan1,3, 
Stephen M. Davis3, Helen M. Dewey1,4 and 
David W. Howells1,5- 1Stroke Division, Melbourne Brain Centre, The Florey Institute of Neuroscience and Mental Health, Melbourne, VIC, Australia
- 2Department of Neurology, Ambroise Paré Hospital, Mons, Belgium
- 3Melbourne Brain Centre at the Royal Melbourne Hospital and University of Melbourne, Melbourne, VIC, Australia
- 4Eastern Health Clinical School, Monash University, Melbourne, VIC, Australia
- 5Faculty of Health, School of Medicine, University of Tasmania, Hobart, TAS, Australia
Background: Distinguishing between stroke subtypes and knowing the time of stroke onset are critical in clinical practice. Thrombolysis and thrombectomy are very effective treatments in selected patients with acute ischemic stroke. Neuroimaging helps decide who should be treated and how they should be treated but is expensive, not always available and can have contraindications. These limitations contribute to the under use of these reperfusion therapies.
Aim: An alternative approach in acute stroke diagnosis is to identify blood biomarkers which reflect the body's response to the damage caused by the different types of stroke. Specific blood biomarkers capable of differentiating ischemic from hemorrhagic stroke and mimics, identifying large vessel occlusion and capable of predicting stroke onset time would expedite diagnosis and increase eligibility for reperfusion therapies.
Summary of Review: To date, measurements of candidate biomarkers have usually occurred beyond the time window for thrombolysis. Nevertheless, some candidate markers of brain tissue damage, particularly the highly abundant glial structural proteins like GFAP and S100β and the matrix protein MMP-9 offer promising results. Grouping of biomarkers in panels can offer additional specificity and sensitivity for ischemic stroke diagnosis. Unbiased “omics” approaches have great potential for biomarker identification because of greater gene, protein, and metabolite coverage but seem unlikely to be the detection methodology of choice because of their inherent cost.
Conclusion: To date, despite the evolution of the techniques used in their evaluation, no individual candidate or multimarker panel has proven to have adequate performance for use in an acute clinical setting where decisions about an individual patient are being made. Timing of biomarker measurement, particularly early when decision making is most important, requires urgent and systematic study.
Biomarkers
Use of the term “biomarker” describes measures of biological function was first seen in Medline is 1977 and has exploded in the last decade (1). A US National Institutes of Health working group defined a biomarker as: “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention” (2). While the term “biomarker” can include clinical or imaging measurements, it is usually reserved for describing molecules found in bodily fluids (1).
Biomarkers such as cardiac troponin, creatine kinase, or D-dimer are used in practice in the emergency department for the diagnosis and early management of the life-threatening conditions including myocardial infarction or pulmonary embolism. Indeed, D-dimer measurements are used for the exclusion of a diagnosis of pulmonary embolism with a sensitivity of 96%. A negative D-dimer test will virtually rule out thromboembolism (3). Cardiac troponin (and especially the I isoform) is used routinely to diagnose myocardial infarction with a sensitivity of more than 90% for a cut off value of 0.04 ng/ml (4).
Other biomarkers are used as tools for disease stating (e.g., carcinoembryonic antigen-125 for cancers), for classification of disease severity (e.g., blood prostate-specific antigen concentration to indicate prostate cancer growth and metastasis), to assess disease prognosis (e.g., measurement of tumor shrinkage) or to aid therapeutic monitoring (e.g., blood cholesterol concentrations during therapy to reduce the risk of heart disease) (2).
The Need For Acute Stroke Biomarkers
Five interventions improve outcome in patients with ischemic stroke. These are thrombolysis with recombinant tissue plasminogen activator (rt-PA) (5), aspirin given within 48 h (6), management of the patients within a dedicated stroke unit (7), hemicraniectomy (8), and more recently endovascular clot retrieval (9).
Thrombolysis is currently recommended for IS patients that present within 4.5 h of stroke onset. Advanced neuroimaging allows extension of this time window up to 9 h and inclusion of patients that wake up with stroke symptoms if salvageable brain tissue can be identified (10, 11). Nevertheless, thrombolysis is disappointingly infrequent in patients with acute ischemic stroke. Indeed, <10% of ischemic stroke patients receive this therapy in most centers and no more than a third in the best performing centers (12–16). The main reasons for this underuse are uncertainty about stroke type, how long the ischemia has been present diagnosis and the associated risks of cerebral bleeding (17–21).
Thrombectomy is currently recommended in IS patients (after or independently from rt-PA) with evidence of large vessel proximal anterior circulation occlusion and within 6 (or 24 h with advanced imaging selection) of symptoms onset (9, 22–24). This revolutionary treatment is unfortunately not in more widespread use than thrombolysis as it is estimated that fewer than 10% of acute IS patients would meet the eligibility criteria and not all stroke centers have sufficient resources and expertise to deliver this therapy (25, 26).
Brain imaging currently plays a critical biomarker role in acute stroke management as it is the only proven way to differentiate ischemic from hemorrhagic stroke. Advanced perfusion imaging can also be used to help select patients that might benefit from rt-PA or thrombectomy under specific circumstances (10, 11, 23, 24). Nevertheless, imaging cost, availability, contraindications, as well as the level of expertise required to interpret advanced imaging results, restricts the global use of reperfusion therapies.
Other less expensive more and accessible stroke biomarkers detected in the blood would be an important addition to the stroke clinician's armory.
An ideal stroke biomarker(s) should be able, with high specificity and sensitivity, to differentiate hemorrhagic and ischemic stroke (and clearly distinguish them from stroke mimics). They should predict stroke prognosis, facilitate therapeutic stratification and therapeutic monitoring, for example by indicating risk of hemorrhagic transformation after stroke or after rt-PA treatment. Moreover, if repeated measures can be made in a clinically useful time frame, specific stroke biomarkers could act as a “stroke clock” to aid in assessing time of stroke onset to increase the number of IS able to benefit from treatment with rt-PA, especially those who wake-up with stroke.
With the advent of mechanical thrombectomy, brain imaging with vascular sequences has become a de facto standard in the management of an acute stroke. Nevertheless, a biomarker that provides the same information would facilitate and fasten the access to therapies. It would have the potential to aid early identification and pre-hospital stratification of ischemic stroke patients. Indeed, biomarker stratification of the different classes of stroke patients in a pre-hospital setting would facilitate directing them to a hospital where thrombectomy is performed without losing crucial time by performing brain imaging in the nearest hospital and then transferring the patient to the comprehensive stroke center. It is known that substantial delays of 110–128 min are associated with secondary transfer vs. the direct approach (27).
Over 150 candidate stroke biomarkers have been studied for roles ranging from diagnosis to long term prognosis (28–35).
The following literature review highlights those biomarkers with the potential to have an impact in the acute clinical setting, especially with regard to reperfusion therapy. Moreover, in this acute context, the review has been focused on studies using blood as a substrate for biomarker research because of the ease with which this biological fluid can be accessed in the emergency setting. Table 1 summarizes the most relevant results of this review. Table 2 highlights the main clinical uses ascribed to the potential biomarkers and Figure 1 illustrates the sources of the major candidate biomarkers.
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