Stroke biomarkers in clinical practice: A critical appraisal

https://doi.org/10.1016/j.neuint.2017.01.005Get rights and content

Highlights

  • Biomarkers provide mechanistic insights to key biologic processes during stroke.

  • Biomarkers can aid in clinical decision-making during stroke management.

  • Prognostic significance of stroke biomarkers could be further examined.

Abstract

Biomarkers provide critical mechanistic insights to key biologic processes that occur during cerebral ischemia which, when carefully applied, can improve clinical decision-making in acute stroke management. The translation of a blood-based biomarker in ischemic stroke to clinical practice is challenging, in part, due to the complexity of ischemic stroke pathogenesis and the presence of a blood-brain barrier that restricts the release of brain-specific markers into the circulation. The pathologic and clinical aspects of ischemic stroke are described in this review, where a non-exhaustive list of biomarkers that interrogate different aspects of ischemic stroke such as oxidative damage, inflammation, thrombus formation, cardiac function and brain injury are described. The potential roles of these biomarkers are further examined under different clinical scenarios aimed at (1) averting the risk of hemorrhagic transformation, (2) identifying individuals at risk of early neurologic deterioration and malignant infarction, (3) aiding in the diagnosis of ischemic stroke and its differentiation from other stroke mimics, (4) guiding the search for stroke etiology, and (5) assessing stroke risk within the community. Researchers should explore the roles of stroke biomarkers to enhance clinical decision-making that is presently largely based on intuition and subjective reasoning.

Introduction

By 2050, more than 1.5 billion people in the world will be aged 65 years and older, and a silent epidemic of stroke is imminent (Feigin et al., 2014). Stroke represents the second leading cause of death for people older than 60 years, the most important cause of permanent disability, and uses approximately 3-7% of the total healthcare expenditure in high-income countries (Feigin et al., 2014).

The pathophysiology of cerebral ischemia has played a key role in guiding biomarker research in ischemic stroke. Substantial data indicate that atherosclerosis is a life course disease that begins insidiously with the evolution of risk factors, giving rise to a subtle subclinical disease that culminates in overt cerebrovascular illnesses (Kuller et al., 1995, Psaty et al., 1999). Ischemic stroke is a consequence of atherosclerosis that affects the large intra- and extracranial arteries and small vessels, as well as a result of an embolic phenomenon of blood thrombus from the heart or aorta, resulting in an interruption and severe reduction of blood flow within the cerebral circulation (Lo et al., 2005). Depending on the degree of hypoperfusion, an area with complete absence of flow can result, namely the infarct core, where neuronal death occurs within a few minutes, and a surrounding area called the penumbra which suffers from a moderate reduction of blood flow and contains functionally impaired but semi-viable brain tissues (Astrup et al., 1981). In the ischemic core region, brain cells undergo necrotic cell death producing an area that is electrically, metabolically and functionally inactive. By contrast, neurons in the ischemic penumbra are thought to be metabolically active, but electrically and functionally compromised. The penumbra has a variable outcome. If blood flow is not restored within a relatively short time, the penumbra undergoes the same destiny as the core region (Lo et al., 2005).

Central to the acute treatment of ischemic stroke are arterial recanalization and reperfusion by means of intravenous recombinant tissue plasminogen activator (TPA) (NINDS rt-PA Stroke Study Group, 1995) and endovascular treatment (through device-driven retrieval or aspiration of blood thrombus) (Powers et al., 2015). Early reperfusion can potentially salvage ischemic brain tissues and, in clinical trials, is associated with a 5-fold increase in the likelihood of a good functional recovery (Powers et al., 2015). Upon reoxygenation, reactive oxygen species (ROS) and early inflammatory cells are rapidly recruited and numerous non-enzymatic oxidation reactions take place in the cytosol and/or cellular organelles (Khatri et al., 2012). The ischemic cascade is characterized by the following biochemical events - bioenergetics failure, ionic imbalance, acidosis, excitotoxicity, oxidative stress and inflammation, before culminating in cell death via necrosis or apoptosis (Khatri et al., 2012). In practice, the benefits of arterial recanalization and reperfusion are weighed against the dreaded risk of intracranial hemorrhage that is associated with early neurologic deterioration, malignant infarction and a high mortality (Seet and Rabinstein, 2012).

The ability to identify high-risk stroke patients is desirable for clinicians to accurately triage patients to specialized stroke units for closer monitoring, individualize treatment in anticipation of stroke-related complications, and accurately inform long-term prognosis. Current methods to identify such high-risk individuals depend largely on clinical intuition that is derived from an assessment of neurologic and neuroimaging features, and initial treatment response. The use of biological signatures of cerebral ischemia that takes into account the complex biology of stroke is appealing to clinicians as this facilitates an objective assessment of benefits and risks under different clinical scenarios.

This review provides an overview of the mechanistic basis of a non-exhaustive list of biomarkers that interrogate different aspects of stroke pathogenesis (e.g. oxidative damage, inflammation, thrombus formation, cardiac function and brain injury) and describes their potential applications to guide clinical decision-making at critical time-points in stroke management. This review focuses on biomarkers that are measurable in blood, a material that is widely accessible in human stroke. We searched medical databases such as MEDLINE, PubMed and Ovid for publications that highlight the use of blood-based biomarkers in clinical scenarios where comparisons between biomarkers are made with outcomes such as hemorrhagic transformation, early neurologic deterioration and malignant infarction (see Table 1, Table 2).

Section snippets

What is a biomarker?

Biomarkers are objectively-measured biological signatures of normal and pathologic processes that can serve a wide range of purposes such as risk stratification, therapeutic assessment strategies, clinical trial design and drug development (Biomarkers Definitions Working Group, 2001). Simply, a biomarker has good clinical acceptance if the biomarker is accurate, is acceptable to the patient, is easy to interpret by clinicians, has a high sensitivity and specificity for the outcome it is

Types of biomarkers

Following cerebral ischemia, an increase in ROS occurs, triggering an activation of downstream inflammatory responses, where recruitment of multiple immune cells such as macrophages, neutrophils and T cells to the damaged brain tissues occurs (Clark et al., 1994). These inflammatory cells release pro-inflammatory cytokines such as interleukin-6 (IL-6) that are capable of crossing the BBB into the circulation (Banks et al., 1994). Another class of proteins that is also involved in the

Applications of blood-based biomarkers in the clinical setting

Biomarkers can be classified by their intended clinical application. In ischemic stroke, studies have evaluated biomarkers to distinguish ischemic stroke from its mimics, determine stroke etiology, predict stroke severity and outcomes (e.g. early neurological deterioration and hemorrhagic complications), and identify patients who might benefit from decompressive hemicranietomy. Several studies have also examined the use of biomarkers to prognosticate patients for outcomes such as functional

Conclusions

Blood-based biomarkers provide useful insights to the pathological events leading to cerebral infarction and could add to the armamentarium of clinical tools in stroke management. Although the ischemic cascade has been extensively studied in animal stroke models, few studies have examined the prognostic significance and temporal release of circulatory biomarkers that examine the different states of oxidative damage, inflammation, hemostasis, neuronal/glial injury and cardiac dysfunction in

Acknowledgements

We would like to thank the National Medical Research Council, Singapore (NMRC/CSA-SI/0003/2015, NMRC/CNIG/1115/2014 and NMRC/MOHIAFCat1/0015/2014) for their generous support.

References (132)

  • M. Kral et al.

    Troponin T in acute ischemic stroke

    Am. J. Cardiol.

    (2013)
  • D.T. Laskowitz et al.

    Serum markers of cerebral ischemia

    J. Stroke Cerebrovasc. Dis.

    (1998)
  • N. Minamino et al.

    The presence of brain natriuretic peptide of 12,000 daltons in porcine heart

    Biochem. Biophys. Res. Commun.

    (1988)
  • I. Olmez et al.

    Reactive oxygen species and ischemic cerebrovascular disease

    Neurochem. Int.

    (2012)
  • A.A. Rabinstein et al.

    Paroxysmal atrial fibrillation in cryptogenic stroke: a case-control study

    J. Stroke Cerebrovasc. Dis.

    (2013)
  • R.S. Rosenson et al.

    Effects of lipids and lipoproteins on thrombosis and rheology

    Atherosclerosis

    (1998)
  • B.W. Schafer et al.

    The S100 family of EF-hand calcium-binding proteins: functions and pathology

    Trends Biochem. Sci.

    (1996)
  • D. Acalovschi et al.

    Multiple levels of regulation of the interleukin-6 system in stroke

    Stroke

    (2003)
  • H.P. Adams et al.

    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

    (1993)
  • W. Ageno et al.

    Plasma measurement of D-dimer levels for the early diagnosis of ischemic stroke subtypes

    Arch. Intern Med.

    (2002)
  • S.T.L.R. Akira

    signaling

    Curr. Top. Microbiol. Immunol.

    (2006)
  • S. Amaro et al.

    A pilot study of dual treatment with recombinant tissue plasminogen activator and uric acid in acute ischemic stroke

    Stroke

    (2007)
  • S. Amaro et al.

    Uric acid levels are relevant in patients with stroke treated with thrombolysis

    Stroke

    (2011)
  • B.N. Ames et al.

    Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis

    Proc. Natl. Acad. Sci. U. S. A.

    (1981)
  • J.F. Arenillas et al.

    Prediction of early neurological deterioration using diffusion- and perfusion-weighted imaging in hyperacute middle cerebral artery ischemic stroke

    Stroke

    (2002)
  • J. Astrup et al.

    Thresholds in cerebral ischemia - the ischemic penumbra

    Stroke

    (1981)
  • A. Aurell et al.

    Determination of S-100 and glial fibrillary acidic protein concentrations in cerebrospinal fluid after brain infarction

    Stroke

    (1991)
  • C.M. Ballantyne et al.

    Lipoprotein-associated phospholipase A2, high-sensitivity C-reactive protein, and risk for incident ischemic stroke in middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study

    Arch. Intern Med.

    (2005)
  • S. Bandeali et al.

    High-density lipoprotein and atherosclerosis: the role of antioxidant activity

    Curr. Atheroscler. Rep.

    (2012)
  • M. Barber et al.

    Hemostatic function and progressing ischemic stroke: D-dimer predicts early clinical progression

    Stroke

    (2004)
  • T.L. Barr et al.

    Blood-brain barrier disruption in humans is independently associated with increased matrix metalloproteinase-9

    Stroke

    (2010)
  • P.J. Barter et al.

    New insights into the role of HDL as an anti-inflammatory agent in the prevention of cardiovascular disease

    Curr. Cardiol. Rep.

    (2007)
  • Biomarkers Definitions Working Group

    Biomarkers and surrogate endpoints: preferred definitions and conceptual framework

    Clin. Pharmacol. Ther.

    (2001)
  • D. Brea et al.

    Toll-like receptors 2 and 4 in ischemic stroke: outcome and therapeutic values

    J. Cereb. Blood Flow. Metab.

    (2011)
  • T. Buttner et al.

    S-100 protein: serum marker of focal brain damage after ischemic territorial MCA infarction

    Stroke

    (1997)
  • M. Castellanos et al.

    Plasma metalloproteinase-9 concentration predicts hemorrhagic transformation in acute ischemic stroke

    Stroke

    (2003)
  • M. Castellanos et al.

    Plasma cellular-fibronectin concentration predicts hemorrhagic transformation after thrombolytic therapy in acute ischemic stroke

    Stroke

    (2004)
  • A. Chamorro et al.

    Prognostic significance of uric acid serum concentration in patients with acute ischemic stroke

    Stroke

    (2002)
  • W.A. Colburn

    Optimizing the use of biomarkers, surrogate endpoints, and clinical endpoints for more efficient drug development

    J. Clin. Pharmacol.

    (2000)
  • M. Cushman et al.

    N-terminal pro-B-type natriuretic peptide and stroke risk: the reasons for geographic and racial differences in stroke cohort

    Stroke

    (2014)
  • S.A. Dambinova et al.

    Multiple panel of biomarkers for TIA/stroke evaluation

    Stroke

    (2002)
  • S.A. Dambinova et al.

    Blood test detecting autoantibodies to N-methyl-D-aspartate neuroreceptors for evaluation of patients with transient ischemic attack and stroke

    Clin. Chem.

    (2003)
  • S.A. Dambinova et al.

    Diagnostic potential of the NMDA receptor peptide assay for acute ischemic stroke

    PLoS One

    (2012)
  • A. Davalos et al.

    The role of gama aminobutyric acid (GABA) in acute ischemic stroke

    Stroke

    (2000)
  • A. Davalos et al.

    Body iron stores and early neurologic deterioration in acute cerebral infarction

    Neurology

    (2000)
  • M. Di Napoli et al.

    C-reactive protein in ischemic stroke: an independent prognostic factor

    Stroke

    (2001)
  • M. Dobaczewski et al.

    Targeting the urine and plasma determinants of thromboxane A2 metabolism in detection of aspirin effectiveness

    Blood Coagul. Fibrinolysis

    (2008)
  • P.N. Durrington et al.

    Paraoxonase and atherosclerosis

    Arterioscler. Thromb. Vasc. Biol.

    (2001)
  • M.S. Elkind et al.

    Lipoprotein-associated phospholipase A2 activity and risk of recurrent stroke

    Cerebrovasc. Dis.

    (2009)
  • K. Fadakar et al.

    The role of Toll-like receptors (TLRs) in stroke

    Rev. Neurosci.

    (2014)
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