Background: A blood test that quantified the extent of brain damage following ischaemic stroke might be a useful surrogate outcome measure in trials of acute stroke treatments. Measures of neuronal and glial damage, such as neuron-specific enolase (NSE), glial fibrillary acidic protein, tau-protein, myelin-basic protein and S100-β are potential candidate biomarkers. Aim: We systematically reviewed the relevant literature to find studies that correlated blood levels of neuronal and glial damage markers with imaging measures of infarct volume. Methods: We identified studies with a comprehensive search of databases and the reference lists of relevant studies. We included studies that: (1) measured the highest level, or area under the curve (AUC) over time of markers of cerebral damage, (2) calculated infarct volume, and (3) correlated the two measures. Results: Seventeen studies met the criteria for the systematic review. There were sufficient data to provide summary estimates for S100-β and NSE. The peak level and AUC over time of both markers correlated with subacute infarct volume. Measurements of S100-β later than 24 h after stroke were better correlated with subacute infarct size than earlier measurements. However, scan times varied, and none was later than 8 days after stroke. Conclusion: Peak and AUC levels of NSE and S100-β levels correlated with subacute infarct volume. Correlations of S100-β with infarct volume were stronger when measured after 24 h than closer to admission. Exploratory studies within clinical trials are necessary before blood markers of cerebral tissue damage can be recommended as surrogate endpoints.

Keywords:
Ischaemic stroke, Blood biomarkers, Infarct volume
1.
Atkinson AJ, Colburn WA, DeGruttola VG, et al: Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther 2001;69:89–95.
2.
Dassan P, Keir G, Brown MM: Criteria for a clinically informative serum biomarker in acute ischaemic stroke: a review of S100B. Cerebrovasc Dis 2009;27:295–302.
3.
Whiteley W, Chong WL, Sengupta A, Sandercock P: Blood markers for the prognosis of ischemic stroke: a systematic review. Stroke 2009;40:e380–e389.
4.
Kirkwood BR, Sterne JAC: Essential Medical Statistics. Oxford, Blackwell, 2003.
5.
Field AP: Meta-analysis of correlation coefficients: a Monte Carlo comparison of fixed- and random-effects methods. Psychol Methods 2001;6:161–180.
6.
Foerch C, du Mesnil de RR, Singer O, et al: S100B as a surrogate marker for successful clot lysis in hyperacute middle cerebral artery occlusion. J Neurol Neurosurg Psychiatry 2003;74:322–325.
7.
Foerch C, Otto B, Singer OC, et al: Serum S100B predicts a malignant course of infarction in patients with acute middle cerebral artery occlusion. Stroke 2004;35:2160–2164.
8.
Foerch C, Singer OC, Neumann-Haefelin T, du Mesnil de RR, Steinmetz H, Sitzer M: Evaluation of serum S100B as a surrogate marker for long-term outcome and infarct volume in acute middle cerebral artery infarction. Arch Neurol 2005;62:1130–1134.
9.
Geiger S, Holdenrieder S, Stieber P, et al: Nucleosomes as a new prognostic marker in early cerebral stroke. J Neurol 2007;254:623.
10.
Herrmann M, Vos P, Wunderlich MT, de Bruijn CHMM, Lamers KJB: Release of glial tissue-specific proteins after acute stroke: a comparative analysis of serum concentrations of protein S-100B and glial fibrillary acidic protein. Stroke 2000;31:2670–2677.
11.
Wunderlich MT, Ebert AD, Kratz T, Goertler M, Jost S, Herrmann M: Early neurobehavioral outcome after stroke is related to release of neurobiochemical markers of brain damage. Stroke 1999;30:1190–1195.
12.
Cunningham RT, Watt M, Winder J, et al: Serum neurone-specific enolase as an indicator of stroke volume. Eur J Clin Invest 1996;26:298–303.
13.
Rivers CS, Wardlaw JM: What has diffusion imaging in animals told us about diffusion imaging in patients with ischaemic stroke? Cerebrovasc Dis 2005;19:328–336.
14.
Guzel A, Er U, Tatli M, et al: Serum neuron-specific enolase as a predictor of short-term outcome and its correlation with Glasgow Coma Scale in traumatic brain injury. Neurosurg Rev 2008;31:439–444.
15.
Meric E, Gunduz A, Turedi S, Cakir E, Yandi M: The prognostic value of neuron-specific enolase in head trauma patients. J Emerg Med 2010;38:297–301.
16.
Vos PE, Jacobs B, Andriessen TM, et al: GFAP and S100B are biomarkers of traumatic brain injury: an observational cohort study. Neurology 2010;75:1786–1793.
17.
Egger M, Smith GD: Bias in location and selection of studies. BMJ 1998;316:61–66.
18.
Jauch EC, Lindsell C, Broderick J, et al: Association of serial biochemical markers with acute ischemic stroke: the National Institute of Neurological Disorders and Stroke recombinant tissue plasminogen activator Stroke Study. Stroke 2006;37:2508–2513.
19.
Saver JL, Johnston KC, Homer D, et al: Infarct volume as a surrogate or auxiliary outcome measure in ischemic stroke clinical trials. Stroke 1999;30:293–298.
20.
Hand PJ, Wardlaw JM, Rivers CS, et al: MR diffusion-weighted imaging and outcome prediction after ischemic stroke. Neurology 2006;66:1159–1163.
21.
Johnston KC, Barrett KM, Ding YH, Wagner DP; for the ASAP Investigators: Clinical and imaging data at 5 days as a surrogate for 90-day outcome in ischemic stroke. Stroke 2009;40:1332–1333.
22.
Wardlaw JM: Surrogate outcomes: a cautionary note. Stroke 2009;40:1029–1031.
23.
Brea D, Sobrino T, Blanco M, et al: Temporal profile and clinical significance of serum neuron-specific enolase and S100 in ischemic and hemorrhagic stroke. Clin Chem Lab Med 2009;47:1513–1518.
24.
Oh SH, Lee JG, Na SJ, Park JH, Choi YC, Kim WJ: Prediction of early clinical severity and extent of neuronal damage in anterior-circulation infarction using the initial serum neuron-specific enolase level. Arch Neurol 2003;60:37–41.
25.
Wunderlich MT, Lins H, Skalej M, Wallesch CW, Goertler M: 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. Clin Neurol Neurosurg 2006;108:558–563.
26.
Wunderlich MT, Wallesch CW, Goertler M: Release of glial fibrillary acidic protein is related to the neurovascular status in acute ischemic stroke. Eur J Neurol 2006;13:1118–1123.
27.
Missler U, Wiesmann M, Friedrich C, Kaps M: S-100 protein and neuron-specific enolase concentrations in blood as indicators of infarction volume and prognosis in acute ischemic stroke. Stroke 1997;28:1956–1960.
28.
Wu YC, Zhao YB, Lu CZ, Qiao J, Tan YJ: Correlation between serum level of neuron-specific enolase and long-term functional outcome after acute cerebral infarction: prospective study. Hong Kong Med J 2004;10:251–254.
29.
Wunderlich MT, Wallesch CW, Goertler M: Release of neurobiochemical markers of brain damage is related to the neurovascular status on admission and the site of arterial occlusion in acute ischemic stroke. J Neurol Sci 2004;227:49–53.
30.
Bitsch A, Horn C, Kemmling Y, et al: Serum tau protein level as a marker of axonal damage in acute ischemic stroke. Eur Neurol 2002;47:45–51.
31.
Cunningham RT, Young IS, Winder J, O’Kane MJ, McKinstry S, Johnston CF, Dolan OM, Hawkins SA, Buchanan KD: Serum neurone specific enolase (NSE) as an indicator of neuronal damage in patients with cerebral infarction. Eur J Clin Invest 1991;21:497–500.
© 2011 S. Karger AG, Basel
2011
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.