Liquid biopsy markers for stroke diagnosis

ABSTRACT

Introduction

There is a short time window (4.5 h) for the effective treatment of acute ischemic stroke (AIS), which uses recombinant tissue plasminogen activator (rt-PA). Unfortunately, this short therapeutic timeframe is a contributing factor to the relatively small number of patients (~7%) that receive rt-PA. While neuroimaging is the major diagnostic for AIS, more timely decisions could be made using a molecular diagnostic.

Areas covered

In this review, we survey neuroimaging techniques used to diagnose stroke and their limitations. We also highlight the potential of various molecular/cellular biomarkers, especially peripheral blood-based (i.e. liquid biopsy) biomarkers, for diagnosing stroke to allow for precision decisions on managing stroke in a timely manner. Both protein and nucleic acid molecular biomarkers are reviewed. In particular, mRNA markers are discussed for AIS and hemorrhagic stroke diagnosis sourced from both cells and extracellular vesicles.

Expert opinion

While there are a plethora of molecular markers for stroke diagnosis that have been reported, they have yet to be FDA-cleared. Possible reasons include the inability for these markers to appear in sufficient quantities for highly sensitive clinical decisions within the rt-PA therapeutic time

KEYWORDS:

• Activated leukocytes
• computed tomography
• extracellular vesicles
• hemorrhagic stroke
• acute ischemic stroke
• liquid biopsy biomarkers
• magnetic resonance imaging
• recombinant tissue plasminogen activator

Article highlights

• Eighty five% of stroke patients experience acute ischemic stroke (AIS) for which rapid diagnosis is essential to allow for thrombolytic treatment using rt-PA.

• rt-PA is contraindicated in hemorrhagic stroke patients, therefore differentiation between AIS and hemorrhagic stroke is essential.

• Short timeframe (4.5 h) for rt-PA treatment is a major contributing factor leading to the relatively small number of patients (~7%) receiving this treatment in time.

• Delay in diagnosis are due to deferral in seeking medical help, lack of specialized imaging equipment in some medical venues, or lack of around the clock medical personnel to perform the test.

• Computed tomography (CT) can rule out hemorrhagic stroke but is much less sensitive for AIS.

• Magnetic resonance imaging (MRI) provides 83% sensitivity to AIS but it is not widely used in an emergency setting.

• There is no FDA approved molecular diagnostic test for stroke diagnosis.

• Protein markers associated with AIS related to glial activation, inflammation, oxidative stress, neuronal injury, and endothelial dysfunction become elevated in blood 6-12 h after symptom onset, therefore, are not adequate to accommodate the short diagnostic timeframe for AIS.

• Leukocytes recruited to the brain injury site show gene expression differences characteristic of either AIS or hemorrhagic stroke.

• Evaluation of different leukocyte subpopulations in stroke patients and mouse models identified gene panels specific to stroke (~85% accuracy for stroke diagnosis).

• Another liquid biopsy marker, namely extracellular vesicles (EVs), can provide information on mRNA or miRNA abundance distinct to different types of stroke.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The authors thank the NIH for financial support of this work via (NIBIB P41-EB020594 and NIGMS P20-GM130423).