Elevated Cerebral Metabolic Oxygen Consumption in Sickle Cell Disease
Authors: Bush Adam M , Borzage Matthew , Choi Soyoung , Coates Thomas , Wood John C 
Published: October 2019

Abstract
Introduction Stroke occurs when cerebral blood flow (CBF) is inadequate to the metabolic needs of the brain. In sickle cell disease (SCD) stroke is common, however accurate quantification of basal cerebral oxygen consumption (CMRO2) has not been performed. Early PET studies suggested CMRO2 was decreased in SCD patients, but these studies lacked data regarding brain volume and gray-white matter fractions; lower CMRO2 may simply have reflected brain loss from prior stroke. In contrast, NIRS and global resting energy expenditure studies have demonstrated elevated peripheral metabolic rate in SCD patients at baseline, with further increases during painful crisis. In those studies, oxygen consumption was correlated with markers of inflammation, particularly white blood cell count, consistent with metabolic consequences of neutrophil activation. Characterizing CMRO2 in SCD provides insight into better prevention and management of stroke in the SCD population. Accordingly, we measured CBF and cerebral venous saturation (SvO2) via a recently developed magnetic resonance imaging (MRI) technique: T2 Relaxation Under Spin Tagging (TRUST). Using the Fick Principle, this allowed for quantification of oxygen extraction fraction (OEF) and the first quantitative measurements of CMRO2in SCD patients.
Methods All patients were recruited with informed consent or assent and this study was approved by the CHLA IRB. Exclusion criteria included pregnancy, previous stroke, acute chest or pain crisis hospitalization within one month. Fifteen patients with SCD and 12 healthy ethnicity matched controls (CTL) were studied. Arterial oxygen saturation (SaO2) was measured via peripheral pulse oximetery. TRUST was used to measured T2 relaxation of blood within the sagittal sinus; T2 relaxation was converted to SvO2 using established calibration curves. OEF represented the difference of SaO2 andSvO2 .Phase Contrast (PC) of the carotid and vertebral arteries was used to measure global CBF. CMRO2 was calculated as the product of CBF and OEF. High resolution, 3D, T1 weighted images were used for grey-white segmentation and brain volume calculations using BrainSuiteñ software. Relative grey matter CMRO2 and white matterCMRO2 were estimated by assuming that (gm) CMRO2 was three-fold higher than (wm) CRMRO2. Complete blood count, cell free hemoglobin, LDH, and hemoglobin electrophoresis were measured at the study visit.
Results Table 1 summarizes the results. To compensate for their chronic anemia, SCD patients had 67% greater CBF than control subjects, producing a normal SvO2 and OEF. Oxygen delivery also trended higher than for controls leading to higher total CMRO2 in the SCD patients. CMRO2 increases remained significant even after correction for differences in grey and white matter volumes. We found no correlation between WBC and CMRO2when tested by population.
Discussion Our study demonstrates elevated cerebral metabolism in SCD, mirroring increases in global resting energy expenditure and peripheral metabolic rate described by other groups. The etiology of the increased CMRO2 is unknown but could reflect neuroinflammation or energy demands from chronic injury/repair. Regardless, our observation at least partially explains the increase of CBF beyond predicted by anemia alone. By excluding patients with overt stroke and by correcting for differences in brain volume and composition, our results are the first CMRO2 measurements in SCD that are unconfounded by brain volume loss. Given the age differences between our study and control populations, we cannot exclude developmental differences in CMRO2 among patients and controls. However, in general, CMRO2 increases with age, which would tend to lessen rather than increase the CMRO2 differences seen in our study.
Table 1 Controls SCD p Age (years) 37.2 + 2.8 20.3 + 2.6 <0.05 Sex 9 F, 3 M 9 F, 6 M ns Hemoglobin (g/dl) 13.5 + 1.2 9.6 + 1.1 <0.05 WBC (103/uL) 6.1 + 2.2 11.0 + 4.2 <0.05 Sa O2 (%) 95.7 + 1.5 94.1 + 4.1 ns Sv O2 (%) 65.6 + 6.7 63.6 + 8.4 ns OEF 30.0 + 7.1 32.3 + 7.4 ns CBF (ml/100g/min) 70.0 + 4.6 116.8 + 19.1 <0.05 Cerebral O2 delivery (umol O2/100g/min) 193.0 + 44.9 239.0 + 35.7 ns Grey Matter Mass (ml) 499.6 + 72.0 528.4 + 58.1 ns White Matter Mass (ml) 444.6 + 58.2 422.9 + 59.5 ns CMRO2 (umol O2/100g/min) 193.1 + 44.9 239.0 + 35.7 <0.05 (gm)CMRO2 250.7 + 58.7 292.7 + 39.7 <0.05 (wm) CMRO2 175.5 + 41.1 204.9 + 27.8 <0.05

Disclosures
Coates: Novartis: Honoraria, Speakers Bureau; Apo Pharma: Consultancy, Honoraria; Acceleron: Consultancy, Honoraria; SHire: Consultancy, Honoraria.