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

Abstract

Objectives-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.Materials and Methods-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, 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.Results-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 μ in diameter, although differences in tumor vessel size did not consistently account for differences in visualization of microvascularity.Conclusions-USPIO administration significantly enhanced visualization of tumor microvascularity on gradient echo 8 T MRI and significantly improved visualization of tumor microvascularity. Microvascularity identified on pre-contrast images is suspected to be partly associated with hypoxia. Keywords NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptImproved signal-to-noise ratio with ultra high field (UHF) 8 T magnetic resonance imaging (MRI) allows acquisition of high-resolution (HR) images of the central nervous system. One major advantage of UHF MRI has been its ability to delineate cortical vascular anatomy. 1 MRI (8 T) can resolve microvessels with a diameter as small as 100 μm, using gradient echo (GRE) sequences with an in-plane resolution of 196 μm in normal human brain 2-4 and in glial tumors. 5,6 This 100-micron dimension is smaller than the voxel size used in acquisition, although the paramagnetic properties of deoxyhemoglobin, combined with increasing magnetic susceptibility effects at high field, allow microvessels to be resolved on T2*-weighted images. 3,7 Ultra-small superparamagnetic particles of iron oxide (USPIO) are intravascular magnetic resonance (MR) contrast a...

Tumor blood vessel visualization

“…Its paramagnetic effects are leading to an enhanced visualization of microvessels in absence of contrast agents (Kobayashi et al, 1980) and therefore deoxyhemoglobin can serve as a surrogate marker for hypoxia. Immunohistochemical analysis supported the hypothesis that enhanced microvessel visualization correlated well with hypoxic areas within glioblastomas (Christoforidis et al, 2009). The feasibility of MRI to characterize features of tumor angiogenesis in vivo such as vessel size, vessel density, vessel size index (Troprès et al, 2004;Kiselev et al, 2005), vessel permeability, oxygen level, and hypoxic areas makes this technique highly applicable to monitor and evaluate antiangiogenic treatment.…”

“…In combination with ultrasmall superparamagnetic iron oxide (USPIO) blood pool contrast agents which remain intravascular for a long period of time (Weissleder et al, 1990;Tombach et al, 2004), an improved capability of data in terms of resolution can be achieved. In a study of Christoforides et al, (Christoforidis et al, 2009) not only vessels with diameters of 20 mm were identified after USPIO administration in an UHF MRI approach but also the state of hypoxia within the tumor was determined. A feature of hypoxia is the accumulation of deoxyhemoglobin.…”

“Tumoral Pseudoblush” Identified within Gliomas at High-Spatial-Resolution Ultrahigh-Field-Strength Gradient-Echo MR Imaging Corresponds to Microvascularity at Stereotactic Biopsy

“…This allows for identification of vessels smaller than the in-plane resolution of the image. There is some evidence to suggest that signal intensity loss adjacent to areas of increased microvascular visibility may correspond to foci of hypoxia attributable to deoxyhemoglobin and vasodilatation (8). Unlike most dynamic imaging methods assessing microvascularity, ultrahigh-field-strength high-resolution GRE MR imaging does not require intravenous contrast material.…”

“…World Health Organization (WHO) classification grades were used and included the following: WHO grade I, six biopsy samples in four enlargement of draining veins, and adjacent signal intensity loss suggest increased microvascular proliferation within a tumor bed (3,4). Visibility of microvascularity identified at highresolution GRE MR imaging in a nude mouse glioma model at 4.7-T MR imaging and in a Fischer rat F98 glioma model at 8 T has been shown to correlate with histopathologically identified increased microvascular density and hypoxia within the tumor bed (7,8). It should therefore be expected that ultrahigh-field-strength high-resolution GRE MR imaging can be used to help visualize foci with increased microvascularity within human brain tumors.…”

“…barrier for the first 30 minutes after administration and has been shown to improve microvascular visibility in a glioma model (8). Currently, the United States Food and Drug Administration considers imaging at ultrahigh field strengths (7 T and higher) investigational, without substantial risk up to 8 T, and has yet to approve it for clinical use.…”