Biochemical markers in the diagnosis of acute ischaemic stroke

M arkers of Strokeas published in CLI November 2004imaging modalities may be unavailable, such a test could contribute to a physician'sconfidence in administering thrombolytic therapy or assist in the decisionto transport patients with suspected cerebral ischaemia to a hospital with astroke unit for further evaluation. Without such a test, the diagnosis of strokeremains one that is made solely on clinical grounds in most hospitals.Table 2. Biochemical markers significantly correlated with the presence of ischaemic stroke inpatients presenting within six hours, and from 6 to 24 hours after onset of symptoms [4].The study of biochemical markers involved in the ischaemic cascade has providedimportant information regarding the pathogenesis of stroke and has identifiedpotential targets for therapeutic intervention. However, these surrogatemarkers for cerebral ischaemia are useful as a diagnostic modality only ifpatients with ischaemic stroke can be identified with high sensitivity and specificity.A recent report of a diagnostic panel of biochemical markers [5] suggeststhat this novel approach may serve as a useful diagnostic test for ischaemicstroke during the acute period.and higher levels at baseline are associated with an increased incidence of stroke.Various growth factors have been implicated in facilitating recovery after stroke,some by stimulating angiogenesis in regions of infarction. In post-mortemanalyses of brain specimens, increased expression of transforming growth factor-β(TGF- β) and platelet-derived growth factor (PDGF) were found ininfarcted areas and border zones. The measurement of vascular endothelialgrowth factor (VEGF) in the blood of ischaemic stroke patients revealed elevatedlevels on the day of admission, persisting for two weeks. Conversely, apoptosisleads to continued necrosis after cerebral ischaemia, particularly in theischaemic penumbra. Immunochemical staining of brain specimens frompatients with symptomatic cerebral ischaemia demonstrated upregulation ofcaspase-3 in selectively vulnerable areas of the brain.The acute time-windowAlthough the number of studies of biochemical markers in ischaemic strokepatients has increased dramatically over the past few years, very few have includedmeasurements made during the first few hours after symptom onset - a criticalperiod for therapeutic decision-making. Recently, plasma levels of 26 differentbiochemical markers have been evaluated in patients presenting acutely withcerebral ischaemia, and compared with healthy controls [4]. These markers -many of which were examined in relation to ischaemic stroke for the first time -included inflammatory mediators, growth factors, and markers of glial activation,cellular injury, myelin breakdown, thrombosis, and apoptosis. The clinicaloutcome of ischaemic stroke was defined as a neurological deficit lasting longerthan 24 hours resulting from cerebral ischaemia, confirmed either radiographicallyor through the exclusion of other aetiologies.Significant correlations between many of the biochemical markers and the presenceof ischaemic stroke were demonstrated in patients with blood drawn bothbefore 6 hours and between 6 and 24 hours after symptom onset [Table 2].Although many of the individual correlations were excellent - as with previousstudies examining biochemical markers - no single marker possessed the requisitepredictive capacity for it to serve as a clinically useful diagnostic test.A panel approach for the diagnosis of ischaemic strokeTo optimise diagnostic accuracy, the biochemical markers that best correlatedwith ischaemic stroke were entered into a predictive multivariate model and athree-marker panel was developed that included matrix metalloproteinase-9(MMP-9), vascular cell adhesion molecule (VCAM), and vWF [4]. This panelwas able to distinguish ischaemic stroke patients presenting within 6 hours ofsymptom onset from controls with a sensitivity and specificity of over 90%[Figure 1]. Another panel, which included S100β rather than MMP-9, was ableto distinguish stroke patients presenting between 6 and 24 hours after symptomonset from controls with a similar sensitivity and specificity. Abnormalities inthese markers reflect glial activation and derangements in the coagulation systemand inflammatory processes - events that occur early in the ischaemic cascade.A point-of-care test that measures biochemical markers of cerebral ischaemiacould be cost- and time-saving in comparison with expensive neuroimagingtechniques currently being investigated. In the community setting, where theseFigure 1. Received operating characteristics (ROC) curve demonstrating predictive capacityof biomarker panel: sensitivity vs 1-specificity [4].References1. Barber PA, Demchuk AM, Hirt L, et al. Biochemistry of ischemic stroke. Adv Neurol2003; 92: 151 - 164.2. Pantoni L, Sarti C and Inzitari D. Cytokines and cell adhesion molecules in cerebralischaemia: experimental bases and therapeutic perspectives. Arterioscler Throm VascBiol 1998; 18: 503 - 513.3. Price CJS, Warburton EA and Menon DK. Human cellular inflamation in the pathologyof acute ischemia. J Neurol Neurosurg Psychiatry 2003; 74: 1476 - 1484.4. Lynch JR, Blessing R, White WD, et al. Novel diagnostic test for acute stroke. Stroke2004; 35: 57 - 63.5. Reynolds MA, Kirchick HJ, Dahlen JR, Anderberg JM, McPherson PH, Nakamura KK,Laskowitz DT, Valkirs GE and Buechler KF. Early Biomarkers of Stroke. ClinicalChemistry 2003; 49: 1733 - 1739.For a full list of references contact the corresponding author.The authorsJames S. Floyd, BSDuke University School of MedicineDaniel T. Laskowitz, MD, MHSAssociate ProfessorDepartments of Medicine (Neurology) and AnesthesiologyDuke University Medical CenterDurham, NC 27707U.S.A.Corresponding authorDaniel T. Laskowitz. MD, MHSBox 2900, Duke University Medical CenterDurham, NC 27710, USA.Fax +1 919 684 6514Email: danl@neuro.duke.edu