Anemia Increases Oxygen Extraction Fraction in Deep Brain Structures but Not in the Cerebral Cortex

Abstract

Sickle cell disease (SCD) is caused by a single amino acid mutation in hemoglobin, causing chronic anemia and neurovascular complications. However, the effects of chronic anemia on oxygen extraction fraction (OEF), especially in deep brain structures, are less well understood. Conflicting OEF values have been reported in SCD patients, but have largely attributed to different measurement techniques, faulty calibration, and different locations of measurement. Thus, in this study, we investigated the reliability and agreement of two susceptibility-based methods, quantitative susceptibility mapping (QSM) and complex image summation around a spherical or a cylindrical object (CISSCO), for OEF measurements in internal cerebral vein (ICV), reflecting oxygen saturation in deep brain structures. Both methods revealed that SCD patients and non-sickle anemia patients (ACTL) have increased OEF in ICV (42.6% ± 5.6% and 30.5% ± 3.6% in SCD by CISSCO and QSM respectively, 37.0% ± 4.1% and 28.5% ± 2.3% in ACTL) compared with controls (33.0% ± 2.3% and 26.8% ± 1.8%). OEF in ICV varied reciprocally with hematocrit (r ² = 0.92, 0.53) and oxygen content (r ² = 0.86, 0.53) respectively. However, an opposite relationship was observed for OEF measurements in sagittal sinus (SS) with the widely used T₂-based oximetry, T₂-Relaxation-Under-Spin-Tagging (TRUST), in the same cohorts (31.2% ± 6.6% in SCD, 33.3% ± 5.9% in ACTL and 36.8% ± 5.6% in CTL). Importantly, we demonstrated that hemoglobin F and other fast moving hemoglobins decreased OEF by TRUST and explained group differences in sagittal sinus OEF between anemic and control subjects. These data demonstrate that anemia causes deep brain hypoxia in anemia subjects with concomitant preservation of cortical oxygenation, as well as the key interaction of the hemoglobin dissociation curve and cortical oxygen extraction.

Keywords: CISSCO; QSM; internal cerebral vein; oxygen extraction fraction; sickle cell anemia; susceptibility; trust.

FIGURE 1

Representative image and region of the internal cerebral vein (ICV, highlight by red rectangle). (A) Magnitude in axial view. (B) Magnitude in coronal view. (C) Axial view, and (D) Sagittal view of ROI in the max intensity projection of a representative susceptibility map.

FIGURE 2

Group differences for OEF measurements by CISSCO, QSM and TRUST. (A) Boxplot for OEF-QSM in internal cerebral vein for SCD, ACTL and CTL. (B) Boxplot for OEF-CISSCO in internal cerebral vein for SCD, ACTL and CTL. (C) Boxplot for OEF-TRUST in sagittal sinus for SCD, ACTL and CTL. (* denoted statistically significant p < 0.05; NS denoted no significant difference).

FIGURE 3

(A) Scatter plot of OEF-CISSCO and OEF-QSM with linear correlation line (solid) and identity line (dashed) (r ² = 0.72, p < 0.001). (B) Bland-Altman plot for OEF-CISSCO and OEF-QSM. The linear correlation line (solid) is shown (r ² = 0.61, p < 0.001).

FIGURE 4

Relationship between OEF and O₂ content in SCD, ACTL and CTL. (A) Scatterplot between OEF-CISSCO and O₂ content. The fitting reciprocal line is shown in black with r ² = 0.86, p < 0.001. (B) Scatterplot between OEF-QSM and O₂ content. The fitting reciprocal line is shown in black with r ² = 0.48, p < 0.001.

FIGURE 5

(A) Relationship between OEF-TRUST with left shifted hemoglobin. Linear correlations are shown in blue line (r ² = 0.46, p = 0.0027) for ACTL and red line (r ² = 0.35, p = 0.0018) for SCD. The control group is shown as 36.8 ± 5.5 (mean ± std) in green. (B) Relationship between corrected OEF-TRUST with O₂ content.