Determinants of resting cerebral blood flow in sickle cell disease

Abstract

Stroke is common in children with sickle cell disease and results from an imbalance in oxygen supply and demand. Cerebral blood flow (CBF) is increased in patients with sickle cell disease to compensate for their anemia, but adequacy of their oxygen delivery has not been systematically demonstrated. This study examined the physiological determinants of CBF in 37 patients with sickle cell disease, 38 ethnicity matched control subjects and 16 patients with anemia of non-sickle origin. Cerebral blood flow was measured using phase contrast MRI of the carotid and vertebral arteries. CBF increased inversely to oxygen content (r(2) = 0.69, P < 0.0001). Brain oxygen delivery, the product of CBF and oxygen content, was normal in all groups. Brain composition, specifically the relative amounts of grey and white matter, was the next strongest CBF predictor, presumably by influencing cerebral metabolic rate. Grey matter/white matter ratio and CBF declined monotonically until the age of 25 in all subjects, consistent with known maturational changes in brain composition. Further CBF reductions were observed with age in subjects older than 35 years of age, likely reflecting microvascular aging. On multivariate regression, CBF was independent of disease state, hemoglobin S, hemoglobin F, reticulocyte count and cell free hemoglobin, suggesting that it is regulated similarly in patients and control subjects. In conclusion, sickle cell disease patients had sufficient oxygen delivery at rest, but accomplish this only by marked increases in their resting CBF, potentially limiting their ability to further augment flow in response to stress. Am. J. Hematol. 91:912-917, 2016. © 2016 Wiley Periodicals, Inc.

Figure 1. Plot of cerebral blood flow (CBF) versus blood oxygen content for control subjects (solid dots), non-sickle anemia control subjects (x symbols), and sickle cell disease(SCD, open circles)

The solid line is the best linear fit to the log transformed data. The light grey lines are the 95% confidence intervals calculated from a historical cohort of older, nonhemoglobinopathy patients who had a diverse range of hematocrits in whom CBF was measured by Xenon scintigraphy.

Figure 2A and 2B. Ratio of grey matter to white matter volume (2A) and relative cerebral blow flow as a function of age (2B) in control (CTL), anemic control (ACTL), and sickle cell disease (SCD) patients

The relative proportion of grey matter falls sharply during the second decade of life as synapses are pruned during normal maturation; this process continues until around 25 years of age. Brain composition is relatively stable during young adulthood and middle age but further grey matter loss occurs in senescence. The y-axis represents the ratio of observed CBF compared with the CBF predicted by oxygen content along (the solid line from Figure 1). During adolescence and young adulthood, CBF is significantly higher than predicted by oxygen content alone (depicted by the horizontal dashed line at 100%). This increased flow parallels the higher proportion of grey matter observed in Figure 2. As the brain matures to an adult composition, less CBF is needed to feed the metabolically demanding grey matter. CBF also declines in middle aged subjects, disproportionally to changes in brain composition. Other groups have attributed this decline to vascular aging.