Perfusion Magnetic Resonance Imaging to Assess Brain Tumor - Responses to New Therapies

Perfusion Magnetic Resonance Imaging to Assess Brain Tumor - Responses to New Therapies

Andreas Rimner, Andrei I Holodny, Fred H Hochberg
Published: US Neurological Disease 2006
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Neuroimaging has become a means to display both normal and abnormal brain physiology and function. Magnetic resonance imaging (MRI) techniques have been optimized to provide measures of change within and around primary and metastatic brain tumors, including peri-tumoral cerebral edema, deformation of contiguous white matter tracts, volumetric and anatomic features of inhomogeneous areas within tumors, and spectroscopic evaluations of tumor chemistry. Diffusion imaging techniques measure the diffusion characteristics of water molecules. Understanding that brain tumors contain areas of necrosis, reactive cells, cyst formation, and live tumor infiltrates, clinicians make use of advanced MRI analyses to delineate tumor as distinct from normal brain. This distinction serves as the basis for MRIguided operative intervention, MR-based provision of radiation treatment fields, and the separation of therapeutic responses and tumor necrosis, calcification, and reduced blood supply.

Recently available biological therapies mandate further refinements in MRI images. Basic to tumor growth in the brain is the recruitment of new vessels, which investigators have attempted to prevent with a plethora of angiogenesis inhibitors provided in phase I/II clinical trials.1 Similarly, conventional therapies like radiotherapy are at least partly mediated by microvascular damage.2 Of newer MRI modalities, perfusion MRI has emerged as a unique marker of tumor-induced blood vessels and their function. MRIbased perfusion measures the vascularity within a tumor, as well as its component heterogeneous parts. In this review, we will present the principles of perfusion MRI, its application in brain tumor imaging, and the areas of translational application.

Perfusion MRI
At initiation, tumors in a pre-vascular phase are supplied by oxygen and nutrients that diffuse from pre-existing normal vessels.When the tumor reaches a critical size of approximately 1-4mm diameter,3,4 the resultant ischemia leads to the secretion of angiogenic factors, which in turn leads to proliferation of new vessels. These factors, such as vascular endothelial growth factor (VEGF), recruit and maintain tumor vessels, which are characterized by a tortuous and branched structure.5,6 Both in vitro and in vivo, ‘new’ vessels (neovasculature) exhibit increased blood volume and permeability compared with normal vessels.

Vascular imaging provides a visual correlate of vessel dilatation, increased blood vessel volume, and permeability. To evaluate these changes as well as the effects of vessel-specific therapies, neuroradiologists provide research-based measures of cerebral blood volume (CBV), cerebral blood flow (CBF), the mean transit time of contrast (MTT), and transfer constants of contrast agents leaving and re-entering these blood vessels (k1, k2). Of these parameters, blood volume and permeability are commonly applied in patient studies. Blood volume measures the aggregate size of the vascular space within designated areas, while the permeability function informs about the integrity of vessels and their ‘leakiness’ to contrast agents. Each function is derived from the analysis of signal changes over time of contrast agents that are injected into the vein and subsequently reach the area of interest. If no contrast flows to the imaged areas or the molecular size of the contrast agent is extremely large, permeability estimates cannot be made. In general, measurements of vascular images assume two compartments of contrast flow:(k1) describes contrast that initially moves out of the vessel into the extravascular space and (k2) the contrast that moves from the extravascular space back into the vessel.7 The rate of change of contrast in the extravascular space is described by the following formula:

Rate of change of contrast = k1 x Cb – k2 x Ae

where Cb = contrast concentration in blood and Ae = amount of contrast in the extravascular space.

In clinical settings, two different contrast-based MRI techniques are used: T2*-weighted dynamic susceptibility MRI and T1-weighted dynamic contrastenhanced perfusion imaging. Both measure the pharmacokinetics of contrast that passes through a predefined volume. In general, T2*-weighted images,obtained during ultrafast scans, reflect contrast in the vascular bed, while T1-weighted dynamic contrast images measure the intravascular contrast and the resulting leakage from the vessels.

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