The aims of the research proposed are to develop new magnetic resonance imaging methods that measure the apparent diffusion coefficient (ADC) of water in tissues as a function of temporal frequency, and to evaluate whether so-called diffusion spectra are useful for characterizing tumors and for monitoring their response to treatment. Variations of ADC of water occur within tissues in various pathological conditions including cancer, and give rise to the image contrast depicted in diffusion-weighted magnetic resonance imaging (DWI). Diffusion measurements have proven useful in small animal imaging for characterizing the state and response of tumors, and reveal information on tissue characteristics such as cellularity not obtainable by other means. Conventional measurements of ADC reveal the effects of restrictions to free diffusion on a specific spatial scale determined by the diffusion time interval, and typically this is several microns. Variations in ADC are thus dominated by variations in the density of restricting barriers of this spacing, and no information is available from ADC measurements about structural changes that occur at a smaller scale.
We aim to develop a new approach to diffusion imaging by measuring so-called diffusion spectra using novel gradient waveforms. Measurements will thereby be obtained that are very sensitive to those structural features that affect restriction over very much shorter time scales. Images will thus be obtained in which the contrast is more sensitive to variations within cells. Oscillating gradient methods are uniquely capable of providing information on diffusion in the regime in which inferences can be drawn about the intracellular tissue structures that modify diffusion. We will further develop these methods to measure diffusion over much shorter times and finer spatial scales, and will then apply these methods to derive new information on tumors in vivo. To achieve these aims we will implement oscillating gradient spin echo (OGSE) measurements of diffusion of water at 9.4T to probe tissue structure on a scale ? 1 micron. From these data we will produce images related to the pore (cell) size, intrinsic water diffusion rates and surface to volume ratio of spaces within tissues. We will establish whether OGSE methods can detect intracellular changes in cells following pharmacological treatments and during mitosis, and what changes are detectable in tumor bearing animals before and after treatment. The MR measurements will be correlated with histological image data and immunochemistry. In addition, we will predict the results of OGSE measurements by performing computer simulations of water in compartmental systems that replicate tissue structure.
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