Cerebral oxygen metabolic stress is increased in children with sickle cell anemia compared to anemic controls

Abstract

Patients with sickle cell anemia (SCA) experience cerebral metabolic stress with an increase in oxygen extraction fraction (OEF) to compensate for reduced oxygen carrying capacity due to anemia. It remains unclear if anemia alone drives this metabolic stress. Using MRI, we collected voxel-wise OEF measurements to test our hypothesis that OEF would be elevated in anemic controls without SCA (AC) compared to healthy controls (HC), but OEF would be even higher in SCA compared to AC. Brain MRIs (N = 159) were obtained in 120 participants (34 HC, 27 AC, 59 SCA). While hemoglobin was lower in AC versus HC (p < 0.001), hemoglobin was not different between AC and SCA cohorts (p = 0.459). Whole brain OEF was higher in AC compared to HC (p < 0.001), but lower compared to SCA (p = 0.001). Whole brain OEF remained significantly higher in SCA compared to HC (p = 0.001) while there was no longer a difference between AC versus HC (p = 0.935) in a multivariate model controlling for age and hemoglobin. OEF peaked within the border zone regions of the brain in both SCA and AC cohorts, but the volume of white matter with regionally elevated OEF in AC was smaller (1.8%) than SCA (58.0%). While infarcts colocalized within regions of elevated OEF, more SCA participants had infarcts than AC (p < 0.001). We conclude that children with SCA experience elevated OEF compared to AC and HC after controlling for the impact of anemia, suggesting that there are other pathophysiologic factors besides anemia contributing to cerebral metabolic stress in children with SCA.

Figure 1.. OEF remains elevated in the SCA cohort after controlling for hemoglobin.

A. OEF is elevated in anemic control participants (green) compared to healthy controls (blue), but significantly lower than participants with SCA (red) in white matter (left), gray matter (middle) and whole brain (right) even though there is not a significant difference in hemoglobin between the AC and SCA cohorts (p = 0.459). B. Whole brain OEF increases as hemoglobin decreases (Spearman’s rho = −0.878, p < 0.001). Data is shown as a LOESS curve fit per cohort on the left. While controlling for age, hemoglobin, hemoglobin-squared and subject-specific effects, whole brain OEF remains significantly elevated in participants with SCA compared to HC (p = 0.001) but there is not a significant elevation in whole brain OEF in the AC participants compared to HC (p = 0.935) on the right. Figure displays hemoglobin effect plot computed at mean age of 12 years.

Figure 2.. Regions of greatest elevation in OEF in SCA and AC compared to HC.

Regions of the white matter with significantly elevated OEF in the SCA (red) and AC (green) cohorts compared to HC (p<0.05 with probabilistic threshold free cluster enhancement) fall within the border zone of the brain. While the regions of elevated OEF align in both the SCA and AC cohorts, the volume of brain with elevated OEF is greater in the SCA cohort compared to AC.

Figure 3.. Infarct Burden in Anemic Cohorts.

Infarct count from the SCA cohort (red, orange, yellow) and AC cohorts (green) are overlaid on axial slices of an atlas moving inferior (left) to superior (right). In contrast to the SCA cohort, none of the infarcts in the AC cohort overlap with each other. A greater percentage of participants with SCA (55.2%) had infarcts compared to AC (16%, p < 0.001), and the volume of infarcted brain tissue was larger in the SCA cohort (8.1 [0.0–168.4] mm³) versus the AC cohort (0.0 [0.0–0.0] mm³, p = 0.002).