Cerebral Oxygen Metabolic Stress, Microstructural Injury, and Infarction in Adults With Sickle Cell Disease

Abstract

Objective: To determine the patient- and tissue-based relationships between cerebral hemodynamic and oxygen metabolic stress, microstructural injury, and infarct location in adults with sickle cell disease (SCD).

Methods: Control participants and patients with SCD underwent brain MRI to quantify cerebral blood flow (CBF), oxygen extraction fraction (OEF), mean diffusivity (MD), and fractional anisotropy (FA) within normal-appearing white matter (NAWM) and infarcts on fluid-attenuated inversion recovery. Multivariable linear regression examined the patient- and voxel-based associations between hemodynamic and metabolic stress (defined as elevated CBF and OEF, respectively), white matter microstructure, and infarct location.

Results: Of 83 control participants and patients with SCD, adults with SCD demonstrated increased CBF (50.9 vs 38.8 mL/min/100 g, p < 0.001), increased OEF (0.35 vs 0.25, p < 0.001), increased MD (0.76 vs 0.72 × 10^-3 mm²s^-1, p = 0.005), and decreased FA (0.40 vs 0.42, p = 0.021) within NAWM compared to controls. In multivariable analysis, increased OEF (β = 0.19, p = 0.035), but not CBF (β = 0.00, p = 0.340), independently predicted increased MD in the SCD cohort; neither were predictors in controls. On voxel-wise regression, the SCD cohort demonstrated widespread OEF elevation, encompassing deep white matter regions of elevated MD and reduced FA, which spatially extended beyond high-density infarct locations from the SCD cohort.

Conclusion: Elevated OEF, a putative index of cerebral oxygen metabolic stress, may provide a metric of ischemic vulnerability that could enable individualization of therapeutic strategies in SCD. The patient- and tissue-based relationships between elevated OEF, elevated MD, and cerebral infarcts suggest that oxygen metabolic stress may underlie microstructural injury prior to the development of cerebral infarcts in SCD.

Figure 1. White Matter Oxygen Extraction Fraction (OEF) is Associated With White Matter Microstructural Injury in Participants With Sickle Cell Disease (SCD)

Relationships between normal-appearing white matter (NAWM) OEF/cerebral blood flow (CBF) vs NAWM mean diffusivity (MD)/fractional anisotropy (FA) are shown after performing linear mixed-model regressions adjusted for age, participants with multiple MRI scans, and scanner type. All effect plots were calculated at the median cohort age of 29.0 years and the most prevalent scanner type as the reference scanner. In participants with SCD, NAWM OEF was associated with MD (A) and nonsignificantly associated with FA (B), while no association was found between OEF and diffusion tensor imaging metrics in controls. NAWM CBF was not associated with MD (C) or FA (D) in either cohort. 95% Confidence intervals for the control cohort were excluded for simplicity.

Figure 2. Adults With Sickle Cell Disease (SCD) Demonstrate Widespread Oxygen Metabolic Stress and Microstructural Injury in Deep White Matter Regions

Voxel-wise nonparametric statistical comparisons between the SCD and control cohorts were performed with corrections for multiple voxel-wise comparisons using threshold-free cluster enhancement and adjusted for age and scanner type. Voxels with statistically significant differences in oxygen extraction fraction (OEF), mean diffusivity (MD), and fractional anisotropy (FA) between SCD and control cohorts at p < 0.05 are displayed. (A) OEF was elevated throughout the white matter of adults with SCD, with significance lost in the juxtacortical regions and adjacent to the lateral ventricles. In addition, the SCD cohort demonstrated increased MD (B) and decreased FA (C) relative to controls, predominately in the deep white matter.

Figure 3. Spatial Relationship Between Oxygen Metabolic Stress, White Matter Microstructural Injury, and Cerebral Infarcts

(A) Infarct density map was calculated from fluid-attenuated inversion recovery lesion maps in the sickle cell disease (SCD) cohort, defined as number of participants with infarcts in the voxel, divided by total number of participants, thresholded to include at least 2 participants with infarcts in the voxel. (B) To determine the spatial relationship between impairment in white matter microstructure and oxygen metabolic stress, the map of voxels with elevated mean diffusivity (MD) was overlaid onto the map of voxels with elevated oxygen extraction fraction (OEF). Regions of significant OEF elevation colocalized with and extended beyond regions of significant microstructural impairment. (C) To determine the spatial relationship between infarct location and white matter microstructural injury, the infarct density map was overlaid onto the map of voxels with elevated MD. The region of elevated MD surrounded and extended beyond the borders of the cerebral infarcts, suggesting that microstructural injury in normal-appearing white matter may be a precursor to infarct development in SCD.