What biomarkers are used in the diagnosis and prognosis of central nervous system (CNS) stroke?

Biomarkers for CNS Stroke Diagnosis and Prognosis

Several neuroimaging and blood-based biomarkers are valuable for the diagnosis and prognosis of central nervous system stroke, with structural and functional neuroimaging biomarkers currently having the strongest evidence for clinical application.

Neuroimaging Biomarkers

Structural Neuroimaging

• Diffusion Tensor Imaging (DTI) of the corticospinal tract (CST) has demonstrated moderate to strong relationships with motor impairment outcomes and recovery across all phases post-stroke 1
• CST lesion load measured in the acute stage has predictive value for poor motor outcomes and can improve prediction beyond baseline clinical assessment, age, or infarct volume 1
• Fractional anisotropy (FA) of the ipsilesional and contralesional CST at the acute stage is higher in individuals who achieve better motor recovery 1
• Lesion location, particularly in critical areas, may be more important than lesion volume for predicting recovery and treatment response 1

Functional Neuroimaging

• Transcranial Magnetic Stimulation (TMS) with Motor Evoked Potentials (MEP+/-) status strongly predicts upper limb motor recovery up to the late subacute phase 1
• Resting-state functional connectivity (rsFC) shows promise for understanding and predicting recovery across multiple domains including motor, cognitive, and language functions 1
• In the language domain, functional MRI (fMRI) shows potential at the early subacute stage for significantly improving prediction of outcome 1
• Perfusion-weighted MRI in the hyperacute period shows that word comprehension deficits correlate with blood flow within Wernicke's area 1

Blood-Based Biomarkers

Glial Cell Markers

• S100B protein is a sensitive marker that reflects CNS injury and can be measured in serum 2
• S100B levels correlate with stroke severity, infarct size, and functional outcomes 2, 3
• S100B concentrations above 1.03 μg/L at 24 hours are associated with large infarction 1
• Glial Fibrillary Acidic Protein (GFAP) is more specific for CNS injury than S100B and has minimal extracranial sources 2, 4
• Cellular fibronectin elevations >16.6 μg/mL predict edema with 90% sensitivity and 100% specificity 1

Neuronal Cell Markers

• Neuron-Specific Enolase (NSE) is specific for neuronal damage and correlates with stroke severity 5, 4
• Myelin Basic Protein (MBP) shows elevation 48-72 hours after injury and correlates with lesion volumes 5
• Higher peak concentrations of MBP and S100B are associated with larger CT lesion volumes 5
• Tau protein measured with single-molecule array (Simoa) method correlates with infarct size and functional outcomes 3

Blood-Brain Barrier Markers

• Matrix Metalloproteinase-9 (MMP-9) is associated with edema development, with concentrations ≥140 ng/mL having 64% sensitivity and 88% specificity for predicting infarction 1
• MMP-9 is also associated with increased risk of hemorrhagic conversion 1

Clinical Application of Biomarkers

Diagnosis

• Blood biomarkers including S100B, GFAP, and NSE can aid in confirming the presence of CNS injury in patients with suspected stroke 2, 4
• A normal S100B level reliably predicts the absence of significant CNS injury 2
• Combined use of multiple biomarkers (S100B, GFAP, NSE) improves diagnostic accuracy 2

Prognosis and Outcome Prediction

• CST integrity measured by DTI and TMS (MEP+/-) status are ready to be used in clinical trials for stratification and outcome prediction 1
• S100B and tau concentrations correlate with functional outcome at three months (modified Rankin Scale) 3
• Patients with favorable outcomes have smaller changes in MBP and S100B concentrations in the first 24 hours 5

Treatment Selection and Monitoring

• Biomarkers can help identify treatment responders from non-responders 1
• In the Everest trial, patients with preserved motor evoked responses upon cortical stimulation had better outcomes (67%) compared to those lacking a response (27%) 1
• S100B levels may rise hours to days before changes in intracranial pressure, neurological examinations, and neuroimaging tests, potentially allowing earlier intervention 2

Limitations and Future Directions

• Blood biomarkers currently lack sufficient evidence for routine clinical use and remain a developmental priority 1
• Most biomarker studies are cross-sectional rather than longitudinal, limiting their predictive value 1
• Extracranial injuries can elevate some biomarkers (particularly S100B), reducing specificity 2
• Future research should focus on combining multiple biomarkers and integrating them with clinical and imaging data for improved accuracy 1, 4
• Prospective validation in independent cohorts and development of rapid, reliable testing methodologies are needed 1