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

Neurology. 2021 Aug 31;97(9):e902-e912. doi: 10.1212/WNL.0000000000012404. Epub 2021 Jun 25.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Comment

MeSH terms

  • Adult
  • Anemia, Sickle Cell* / complications
  • Anemia, Sickle Cell* / diagnostic imaging
  • Cerebral Infarction
  • Cerebrovascular Circulation
  • Humans
  • Magnetic Resonance Imaging
  • Oxygen
  • Oxygen Consumption
  • Stress, Physiological
  • White Matter* / diagnostic imaging


  • Oxygen