High Resolution Ultra High Field Magnetic Resonance Imaging of Glioma Microvascularity and Hypoxia Using Ultra-Small Particles of Iron Oxide

Abstract

This study assessed whether ultra-small particles of iron oxide (USPIO) intravascular contrast agent could enhance visualization of tumor microvascularity in F98 glioma bearing rats by means of ultra high field (UHF) high-resolution gradient echo (GRE) magnetic resonance imaging (MRI). In an effort to explain differences in visualization of microvascularity before and after USPIO administration, hypoxia and vessel diameters were assessed on corresponding histopathologic sections. F98 glioma cells were implanted stereotactically into the brains of syngeneic Fischer rats. Based on clinical criteria, rats were imaged 1 to 2 days before their death with and without USPIO contrast on an 8 Tesla MRI. To identify hypoxic regions of the brain tumor by immunohistochemical staining, a subset of animals also received a nitroimidazole-based hypoxia marker, EF5, before euthanasia. These sections then were compared with noncontrast enhanced MR images. The relative caliber of tumor microvasculature, compared with that of normal brain, was analyzed in a third group of animals. After USPIO administration, UHF high-resolution GRE MRI consistently predicted increased microvascular density relative to normal gray matter when correlated with histopathology. The in-plane visibility of glioma microvascularity in 22 rats increased by an average of 115% and signal intensity within the tumor decreased by 13% relative to normal brain. Tumor microvascularity identified on noncontrast MR images matched hypoxic regions identified by immunohistochemical staining with a sensitivity of 83% and specificity of 89%. UHF GRE MRI was able to resolve microvessels less than 20 micro in diameter, although differences in tumor vessel size did not consistently account for differences in visualization of microvascularity. USPIO administration significantly enhanced visualization of tumor microvascularity on gradient echo 8 T MRI and significantly improved visualization of tumor microvascularity. Microvascularity identified on precontrast images is suspected to be partly associated with hypoxia.