A prominent feature of clinical MR images of cerebral and extra-cerebral hemorrhage, regardless of etiology, are regions of altered signal intensity attributed to paramagnetic effects of iron from extravasated erythrocytes. These MR characteristics have received considerable discussion in the literature but, as yet, have not been investigated rigorously by in vivo biochemical methods. We propose to investigate iron metabolism in cerebral and extra-cerebral hemorrhage in experimental animal models using MR imaging in conjunction with correlative biochemical and pathological studies of iron. We propose to show that the evolving biochemical processes of iron metabolism can be monitored non-invasively by MR parameters based on symmetric and asymmetric spin echo images that exploit the variation in intra-voxel signal line width caused by the presence of varying concentrations of paramagnetic iron. Such iron alters the variation in the intravoxel magnetic susceptibility of the tissue. Sensitive biochemical studies using the radionuclide 59Fe to label the blood used to produce the hemorrhage will be used to study the time dependent evolution of iron-containing substances within the hematoma, including determination of biochemical form, concentration, and spatial distribution. Such basic biochemical information is not currently available but is essential for quantitative interpretations of MR images altered by endogenous paramagnetic substances. The animal model of cerebral hemorrhage is the injection of blood into the basal ganglia of rat and rabbit brain. The extra-cerebral model is injection of blood into the thigh muscles of the hind leg of rat. Injection of plasma is the control for each model as this represents changes attributable to blood components other than erythrocytes and to the mass effects exerted by the hematoma mass. The comparison of MR images and iron biochemistry for cerebral and extra-cerebral hemorrhages in the rat allows the time courses of the repair processes and iron salvage pathways to be compared in the same animal. The larger brain of the rabbit model of cerebral hemorrhage allows the time course of resolution of hematoma to be studied as a function of size of the hematoma. Spatially resolved sampling of tissue not feasible on the scale of the rat model is possible in the larger rabbit model. Model systems designed on the results of the in vivo biochemistry and histology will be used to develop quantitative MR parameters sensitive to iron metabolism. These extensive studies using the experimental rat and rabbit models will serve as the basis for preliminary MR imaging studies of human cerebral hemorrhage of varying etiology with the goal of establishing quantitative interpretations of iron metabolism in different types of human pathology in which hemorrhage occurs.
