The pathology of sickle cell disease results from vasoocclusion caused by blockage of the microcirculation by non-deformable red cells filled with polymers of deoxy-hemoglobin S. The disease is characterized by chronic vasocclusive injury to several organs and acute events that include painful crises (which largely involves marrow infarct), acute chest syndrome, acute splenic sequestration, acute sickle liver, cerebral infarcts, renal papillary necrosis, femoral and humeral head necrosis, acute retinal vasoocclusion, and other manifestations. Finding objective criteria to evaluate risk factors and treatment protocols for sickle cell disease is a long-standing goal. To date, MRI of painful crisis has yielded results which are intriguing but difficult to evaluate. Detection of hypoxia in regions with acute pain may yield a useable marker. These experiments were designed to detect regions of hypoxia which may occur under ambient conditions in patients with sickle cell disease. The image intensity in T2 and T2* weighted images is influenced by the presence of deoxygenated hemoglobin because deoxygenated hemoglobin has a different magnetic susceptibility than oxygenated hemoglobin or tissue. The difference in magnetic susceptibility between the red cells and plasma and between the intra- and extravascular spaces results in more rapid loss of water proton transverse magnetization and ultimately results in reduced image intensity in spin-echo or gradient echo pulse sequences. The change in oxygen saturation in sickle cell patients in brain and bone marrow was investigated while the patient was breathing room air or high oxygen through a face mask and comparing the signal intensity changes in T2 or T2*-weighted images. These results were contrasted to results for normal human controls. A goal of these studies is to separate acute, ongoing events from the results of previous episodes of ischemia and fibrosis or expansion of hematopoietic tissue. Using magnetic resonance imaging (MRI) which is blood oxygenation level dependent (BOLD), we found that transgenic mice with human `- and S- globin have higher levels of deoxyHb in brain, liver, and kidney (areas with pathology) than control mice. We used this technique to examine the level of deoxyHb in the brain and bone marrow of sickle cell patients. In the brain, we found a mean global change in signal intensity with an increase of 3.7% in SS patients in contrast to a 0.98% increase in normal controls. Signal increases in SS patients were localized to the gray matter and were of a different extent and magnitude for each patient. A high percent deoxyHb under ambient conditions may not imply that the brain is hypoxic because SS RBCs have low oxygen affinity. In bone marrow, we examined two patients who reported chronic pain in the femur and hips. A large difference signal was found on the painful side which was diminished or absent when a second set of images was recorded during a pain-free period. Conventional images recorded at the same time were not found to be informative by a radiologist. The presence of a high percent deoxyHb in SS patients suggests an elevated risk of vasoocclusion. This method and new methods capable of simultaneous measurement of blood flow and BOLD effects may be useful for evaluating sickle cell patients for the risk of vasoocclusion and monitoring treatment protocols in brain and other tissues.
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