Introduction

Patients with thalassemia intermedia, sickle cell disease and other chronic anemias have a higher risk of cerebrovascular disease and stroke¹. We have previously demonstrated that cerebral blood flow (CBF) increases to preserve global cerebral oxygen delivery, yet the sufficiency of regional cerebral tissue oxygen (O₂) delivery has never been studied². In this study, we used pseudo continuous arterial spin labeling (PCASL) to measure cerebral blood flow (CBF) and O₂ delivery in patients with chronic, non-sickle anemia syndromes and age matched healthy controls.

Methods

The study includes 23 anemic patients (ACTL) and 25 healthy control patients (CTL) that were recruited from the Children’s Hospital Los Angeles. Brain MRI was performed on a Philips Achieva 3 Tesla scanner with an 8-channel head coil. Imaging protocol consisted to 3D T1w, 3D T2w, 3D MRA, and 3D pseudo continuous arterial spin labeling (PCASL) scans³. CBF quantification was calculated using a two-compartment kinetic quantification model reported by Wang et. al⁴. We corrected for the effect of hematocrit on blood T1, velocity and B1+ inhomogeneity on labeling efficiency, and increased cerebral blood flow on transit time as previously described³. Then CBF maps were converted into cerebral O₂ delivery maps to correct for hemoglobin and O₂ saturation in anemic group. The following equations show the relationship of hemoglobin, O₂ content and O₂ delivery⁵: Oxygen Delivery = CBF × Oxygen Content (1) Oxygen Content = 1 .34 × Hemoglobin×SpO₂ + 0.003 × pO₂ (2) where SpO₂ is the arterial oxygen saturation and pO₂ is the partial pressure of oxygen. After both CBF and oxygen delivery maps were produced, non-zero mean of the central 5 slices were used for each subject to conduct group-wise comparison. The preprocessing and registration pipeline of CBF to standard atlas was previously published in Chai et. al.⁶. Predictors of global, grey matter (GM) and white matter (WM) were identified using univariate and stepwise multivariate regression (JMP Pro, SAS, Cary NC).

Results

Patients’ demographic information is summarized in Table 1. There was no significance difference in age and sex between two groups. Fourteen of the 23 anemic subjects were receiving transfusion therapy every three weeks; these patients were studied at their hemoglobin nadir to better match non-transfused subjects. Two of the spherocytosis patients were polycythemic and were excluded from group-wise comparisons. Anemic subjects were mildly desaturated compared to CTL group and exhibited higher circulating cell-free hemoglobin due to ineffective erythropoiesis. MRA images were screened by a licensed neuroradiologist and were normal for all participants. Ten patients out of 23 patients and 5 out of 25 healthy controls were identified with white matter hyperintensities (WMHs) from T2 w images. One patient was excluded due to poor image quality. The left panel of Figure 1 compares the spatial distribution of CBF in CTL and ACTL patients and the right panel of Figure 1 compares regional O₂ maps. Group differences are not visually obvious on the color maps, but Figure 2 demonstrates that whole brain and GM CBF were significantly higher in ACTL group than healthy controls but WM CBF was not. When expressed as oxygen delivery, GM and whole brain O₂ delivery was not different between the two groups but WM O₂ delivery was 20% lower in anemic subjects. To further explore the contributions to CBF and O₂ delivery, we regressed CBF and O₂ delivery across patient demographics and blood test results. Age was inversely correlated with whole brain and GM CBF (p<0.05), and more strongly correlated with whole brain and GM O₂ delivery (p<0.01). Other strong predictors are listed in Table 2. On multivariate analysis, age and hematocrit predicted whole brain and GM CBF with combined R²=0.45 and 0.48, respectively. When O₂ delivery was examined, factors related to anemia were no longer significant. Only age was remained in multivariate model with R²=0.20.

Discussion

Similar to our prior studies using phase contrast MRI, we found that global CBF was elevated in anemic patients to compensate for decreased oxygen carrying capacity². While global and GM O₂ delivery was preserved in anemic patients, WM O₂ delivery was 20% lower in anemic subjects. This finding is consistent with the white matter volume loss, abnormal diffusion weighted imaging, silent stroke heat maps, and increased oxygen extraction fractions observed in borderzone white matter regions^7–9. However, whether the decreased WM O₂ delivery falls into a physiological steal phenomenon: cerebral compensatory mechanisms protect GM, or simply inadequate neovascularization in response to chronic hypoxia requires further investigation.

Acknowledgements

This work is supported by the National Heart Lung and Blood Institute (1RO1HL136484-A1, 1U01HL117718-01), the National Institute of Clinical Research Resources (UL1 TR001855-02) and by Research Support In Kind from Philips Healthcare.

References

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