Biomarker Indicates Brain Tissue at Risk for Stroke in Sickle Cell Disease

In children with sickle cell disease (SCD), a high oxygen extraction fraction (OEF) in the deep white matter represents a signature of brain tissue with a high risk for stroke, according to study findings published in Neurology.

Investigators prospectively enrolled children with SCD and hemoglobin SS or hemoglobin S-β thalassemia null disease (n=36) and healthy sibling controls (n=20).

All participants underwent magnetic resonance imaging (MRI) to quantify voxel-based cerebral blood flow (CBF), OEF, and cerebral metabolic rate of oxygen utilization (CMRO₂), and the investigators created an infarct heat map based on an independent cohort of pediatric patients with SCD who presented with silent infarcts.

Compared with controls, participants with SCD had higher levels of whole-brain CBF (66.3 mL/100 g/min vs 99.2 mL/100 g/min, respectively; P <.001), OEF (28.8% vs 42.7%, respectively; P <.001), and CMRO2 (2.5 mL/100 g/min vs 3.7 mL/100 g/min, respectively; P <.001). In the SCD cohort, the investigators identified a region of peak OEF in the deep white matter.

In addition, whole-brain CBF correlated with CaO², an association observed even after adjustment for age (model R2 = 0.582; P <.001; CaO2: β = −5.128; 95% CI, −6.516 to −3.741; P <.001; age: β = −1.574; 95% CI, −2.793 to −0.356; P =.012). Using the infarct heat map, the investigators determined that infarct density was higher in the deep white matter and co-localized with the elevated OEF region in the independent prospective cohort. Also, with each incremental increase in the OEF ratio, the cumulative infarct density increased.

The investigators of this study were unable to determine whether elevations in CBF and OEF occurred in parallel or sequentially, primarily due to the study’s cross-sectional design. In addition, the investigators were unable to discover whether elevations in OEF in this population were due to extracranial carotid disease, due to the lack of extracranial cervical vasculature assessment.

Based on the findings, the investigators concluded that the regional OEF elevations with simultaneous “decreases in CBF and CMRO2 defines border zone physiology, supported by high coincidence with infarct density in a separate cohort of children with SCD.”

Reference

Fields ME, Guilliams KP, Ragan DK, et al. Regional oxygen extraction predicts border zone vulnerability to stroke in sickle cell disease.  Neurology. 2018;90(13):e1134-e1142.