There are two stroke subtypes: ischaemic and hemorrhagic. Ischaemic strokes occur due to lack of blood flow to brain tissue because a clot or other obstruction such as atherosclerosis. Caused by a ruptured blood vessel, or abnormal vascular structure, hemorrhagic strokes are the most deadly (36%), however they are also less prevalent. (1) Strokes from blood blockages represent 87% of all strokes, resulting in an 8- to 12-percent death rate at 30 days.
Making a differential diagnosis between the two forms as early as possible is critical to directing treatment regimens.(2) Clinicians typically treat ischaemic stroke with a tissue plasminogen activator (tPA) or other thrombolytic agent designed to dissolve clots, thereby restoring blood flow. However, applying this treatment to hemorrhagic stroke patients can result in death because blood thinners can promote further internal bleeding.
Clinical practice today uses magnetic resonance imaging (MRI) to scan the brain to decide which form of stroke has occurred. MRIs take time to schedule, cost a lot, and patients are not always mobile or able to comply with instructions. As a result, researchers have begun looking for biomarkers in both urine and blood that might accurately distinguish stroke subtype. The goal is to produce a low-cost bedside test that would provide a rapid, accurate diagnosis. A research review reveals some early contenders, but none are definitive without further confirmation.
Biomarker candidates include a model developed using CE-mass spectrometry to look at proteome polypeptide signatures in stroke patient urine. This study showed that urine does contain biomarkers capable of detecting stroke subtype in patients. Peptides in the biomarker include the FXYD domain-containing ion transport regulator 4 (FXYD-4), inter-alpha-trypsin inhibitor heavy chain H4, uromodulin, polymeric-immunoglobulin receptor, and collagen fragments. This study also showed that the higher the number of biomarkers, the higher the specificity and accuracy. The authors argue that since urine is more chemically stable than blood plasma, it is a better candidate for use in subtyping.(3)
Another study also used a multi-plexed mass spectrometry-based assay combined with a multi-marker receiver operating characteristic (ROC) algorithm to separate false positives from true positives to find potential diagnostic biomarkers in blood. The team used an optimized
SRM-assay to investigate plasma samples obtained from patients with both kinds of stroke. The ROC analyses confirmed that several single proteins that bind lipids, notably apoC-III and apoC-I were associated with ischaemic stroke. After applying a further multi-marker ROC algorithm, researchers found the ischaemic versus hemorrhagic groups were best differentiated by a combination of apoC-III and apoA-I.(4)
A study of blood taken within 3 to 6 hours of symptom onset from more than 900 stroke patients investigated a wide panel of suspected blood-based biomarkers to find markers that might distinguish stroke type. Immunoassays and ROC analyses identified high S100B and low sRAGE levels in hemorrhagic patients when compared to ischaemic patients. The study found this difference in as little time as 3 hours after onset, which suggests it as a candidate to meeting the rapidity test.(5)
Stroke is a complex disease, and these three studies illustrate some of the potentially many chemical changes that may be linked to stroke subtype. Over time, researchers and drug developers will need to sort and rank the diverse range of biomarker candidates for highest efficacy to find the best in terms of clinical application.
1. Dawson, J., et al. (2012) ‘Urinary proteomics to support diagnosis of stroke‘, PLoS One 7 (5), e35879
2. Hirano, K. (2012) ‘Study of hemostatic biomarkers in acute ischemic stroke by clinical subtype‘, Journal of Stroke and Cerebrovascular Diseases, 21 (5), (pp. 404-410)
3. Jaroslav, P., et al. (2012) ‘Increased risk of stroke’ International Journal of Vascular Medicine, published online 2012. doi:10.1155/2012/906954
4. Lopez. M., et al. (2012) ‘Discrimination of ischemic and hemorrhagic strokes using a multiplexed, mass spectrometry-based assay for serum apolipoproteins coupled to multi-marker ROC algorithm‘, Proteomics Clinical Applications, 6 (3-4), (pp. 190-200)
5. Montaner, J., et al. (2012), ‘Differentiating ischemic from hemorrhagic stroke using plasma biomarkers: The S100B/RAGE pathway‘, Journal of Proteomics, published online February 11, 2012. doi:10.1016/j.prot.2012.01.033