Towards the identification of blood biomarkers for acute stroke in humans: a comprehensive systematic review
Authors: Hasan Nazeeha , McColgan Peter , Bentley Paul , Edwards Robert J. , Sharma Pankaj 
Published: February 2012

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

Stroke is the largest single cause of disability in the UK. While tests based upon biomarkers have been around for decades, interest in the applications of biomarkers has increased greatly in recent years. Biomarkers released into the bloodstream following a stroke are useful not only for understanding the pathogenesis of stroke, but also play a significant role in the development of personalised medicine. The efficacy of current clinical models and imaging techniques for the diagnosis and prognosis of acute stroke could be improved when used in conjunction with blood biomarkers. While several studies have proposed a number of biomarkers associated with acute stroke in humans, there is conflicting information about the significance of implicated markers, and their clinical relevance is unclear.

WHAT THIS STUDY ADDS

In an attempt to consolidate the plethora of data in this field, we have conducted a comprehensive systematic review and meta‐analysis of proteomic and metabolomic blood biomarkers associated with acute stroke. Our meta‐analysis has found eight biomarkers that are significantly associated with the diagnosis and prognosis of acute stroke. Interestingly we also found that CRP, a protein commonly implicated as a strong biomarker of inflammation and stroke, may not have sufficient sensitivity and specificity to be of clinical value, Thus while the biomarkers identified through our study are likely to be biologically informative about the mechanisms of vascular disease, their clinical potential for a blood‐based test warrants further investigation.

AIMS Identification of biomarkers for stroke will aid our understanding of its aetiology, provide diagnostic and prognostic indicators for patient selection and stratification, and play a significant role in developing personalized medicine. We undertook the largest systematic review conducted to date in an attempt to characterize diagnostic and prognostic biomarkers in acute ischaemic and haemorrhagic stroke and those likely to predict complications following thrombolysis.

METHODS A comprehensive literature search was carried out to identify diagnostic and prognostic stroke blood biomarkers. Mean differences (MDs) and 95% confidence intervals (CIs) were calculated for each biomarker.

RESULTS We identified a total of 141 relevant studies, interrogating 136 different biomarkers. Three biomarkers (C‐reactive protein, P‐selectin and homocysteine) significantly differentiated between ischaemic stroke and healthy control subjects. Furthermore, glial fibrillary acidic protein levels were significantly different between haemorrhagic stroke and ischaemic stroke patients (MD 224.58 ng l−1; 95% CI 25.84, 423.32; P= 0.03), high levels of admission glucose were a strong predictor of poor prognosis after ischaemic stroke and symptomatic intracerebral haemorrhage post‐thrombolysis, glutamate was found to be an indicator of progressive (unstable) stroke (MD 172.65 µmol l−1, 95% CI 130.54, 214.75; P= 0.00001), D‐dimer predicted in‐hospital death (MD 0.67 µg ml−1, 95% CI 0.35, 1.00; P= 0.0001), and high fibrinogen levels were associated with poor outcome at 3 months (MD 47.90 mg l−1, 95% CI 14.88, 80.93; P= 0.004) following ischaemic stroke.

CONCLUSIONS Few biomarkers currently investigated have meaningful clinical value. Admission glucose may be a strong marker of poor prognosis following acute thrombolytic treatment. However, molecules released in the bloodstream before, during or after stroke may have potential to be translated into sensitive blood‐based tests.