Experience with diffusion-weighted imaging (DWI) shows that signal attenuation is consistent with a multicompartmental theory of water diffusion in the brain. The source of this so-called nonexponential behavior is a topic of debate, because the cerebral cortex contains considerable microscopic heterogeneity and is therefore difficult to model. To account for this heterogeneity and understand its implications for current models of diffusion, a stretched-exponential function was developed to describe diffusion-related signal decay as a continuous distribution of sources decaying at different rates, with no assumptions made about the number of participating sources. DWI experiments were performed using a spin-echo diffusionweighted pulse sequence with b-values of 500 -6500 s/mm 2 in six rats. Signal attenuation curves were fit to a stretched-exponential function, and 20% of the voxels were better fit to the stretched-exponential model than to a biexponential model, even though the latter model had one more adjustable parameter. Based on the calculated intravoxel heterogeneity measure, the cerebral cortex contains considerable heterogeneity in diffusion. The use of a distributed diffusion coefficient (DDC) is suggested to measure mean intravoxel diffusion rates in the presence of such heterogeneity.Magn Two types of heterogeneity can be defined in MRI diffusion experiments: intravoxel and intervoxel. The goal of this work was to understand how intravoxel heterogeneity affects measurements of diffusion in the cerebral cortex using diffusion-weighted imaging (DWI). A stretched-exponential model was used to study the heterogeneity in DWI data.The motivation for understanding the biophysical basis of DWI lies partially in the potential of the technique for noninvasively detecting microscopic changes in tissue due to cerebral infarction and stroke (1). In addition, DWI studies of the changes in restrictions to intra-and extracellular water diffusion that occur with neoplastic invasion may lead to improved understanding and treatment of tumors (2,3). Finally, it has been shown that a reduction in the apparent diffusion coefficient (ADC) may occur during functional stimulation, which suggests the use of DWI as a functional contrast technique to study brain activation (4).Mathematical models of DWI have been tested in humans, animals, and cell cultures, but the controversy surrounding the identification of specific proton pools contributing to nonexponential behavior of the neural DWI signal remains (5-11). In vitro models, such as erythrocyte ghosts (10), have done much to establish the sensitivity of multiexponential models to cellular density, volume fractions, and exchange rates. However, the direct correspondence of these models to the results of brain imaging must still be established.The biexponential model of water diffusion assumes that there are two distinct proton pools inside each voxel, and that these proton pools have different diffusion rates that result in signal relaxation with b that is biexponential, whe...
The goal of this work was to nondestructively measure glomerular (and thereby nephron) number in the whole kidney. Variations in the number and size of glomeruli have been linked to many renal and systemic diseases. Here, we develop a robust magnetic resonance imaging (MRI) technique based on injection of cationic ferritin (CF) to produce an accurate measurement of number and size of individual glomeruli. High-field (19 Tesla) gradient-echo MR images of perfused rat kidneys after in vivo intravenous injection of CF showed specific labeling of individual glomeruli with CF throughout the kidney. We developed a three-dimensional image-processing algorithm to count every labeled glomerulus. MRI-based counts yielded 33,786 Ϯ 3,753 labeled glomeruli (n ϭ 5 kidneys). Acid maceration counting of contralateral kidneys yielded an estimate of 30,585 Ϯ 2,053 glomeruli (n ϭ 6 kidneys). Disector/fractionator stereology counting yielded an estimate of 34,963 glomeruli (n ϭ 2). MRI-based measurement of apparent glomerular volume of labeled glomeruli was 4.89 ϫ 10 Ϫ4 mm 3 (n ϭ 5) compared with the average stereological measurement of 4.99 ϫ 10 Ϫ4 mm 3 (n ϭ 2). The MRI-based technique also yielded the intrarenal distribution of apparent glomerular volume, a measurement previously unobtainable in histology. This work makes it possible to nondestructively measure whole-kidney glomerular number and apparent glomerular volumes to study susceptibility to renal diseases and opens the door to similar in vivo measurements in animals and humans. stereology; nephron; glomerulus count; nanoparticles; magnetic resonance imaging THE PURPOSE OF THIS WORK WAS to measure the number and size of all glomeruli in the entire, intact kidney using magnetic resonance imaging (MRI). Changes in the number and size of glomeruli have been linked to a number of renal and systemic diseases (5, 7). However, current techniques for counting and measuring glomeruli, such as acid maceration (4) and the dissector/fractionator stereology technique (3), require the destruction of the entire kidney. Furthermore, conventional histological techniques extrapolate the total number and size of glomeruli from a selected number of histological sections or isolated glomeruli. Current techniques are thus estimates rather than direct measurements and do not allow for localization of identified functioning glomeruli to specific parts of the kidney. A method for directly and nondestructively measuring the number and size of all glomeruli in the kidney would serve as a useful tool in animal studies and potentially in the clinic.Recently we demonstrated that intravenous injections of the iron-binding protein ferritin, functionalized with cationic amine groups (6), can be used to detect individual glomeruli both in vivo and ex vivo with MRI (1). This method is based on the electrostatic binding of cationic ferritin (CF) to the anionic macromolecules of the glomerular basement membrane (GBM) and subsequent perturbation of the magnetic field around the labeled GBM by ferritin, result...
The integrity of the basement membrane is essential for tissue cellular growth and is often altered in disease. In this work a method for noninvasively detecting the structural integrity of the basement membrane, based on the delivery of cationic iron-oxide nanoparticles, was developed. Cationic particles accumulate due to the highly negative charge of proteoglycans in the basement membrane. The kidney was used to test this technique because of its highly fenestrated endothelia and wellestablished disease models to manipulate the basement membrane charge barrier.
The ␣ diffusion-weighted imaging (DWI) method was developed to study heterogeneous water diffusion in the human brain using magnetic resonance imaging (MRI). An advantage of this model is that it does not require an assumption about the shape of the intravoxel distribution of apparent diffusion rates, and it has a calculable relationship to this distribution. The ␣-DWI technique is useful for detecting microstructural tissue changes associated with brain tumor invasion, and may be useful for directing therapy to invading tumor cells. In previous work, ␣-DWI was performed with magnetic field gradients applied along a single direction in order to avoid artificially introducing a source of heterogeneity to the decay. However, it is known that restricted diffusion is anisotropic in the brain, and the ␣-DWI method must take this into account to be complete. In this work the relationship between the applied magnetic field gradients and the fitted stretched-exponential model parameters was studied in the human brain. It was found the distributed diffusion coefficient (DDC) varies with the direction of applied gradients, while the heterogeneity index ␣ is relatively direction-insensitive. It is proposed that in clinical use, maps of ␣ can be created using diffusion-weighting gradients applied in a single direction that reflect the tissue heterogeneity. Diffusion-weighted imaging (DWI) is an MRI method that is sensitive to the ensemble motion of water molecules (1,2). The signal attenuation measured by DWI is a function of the average distance traveled by water molecules, and is used to characterize water motion that occurs over distances smaller than a typical imaging voxel. The time over which this motion occurs is determined by the timing of the DWI pulse sequence. External magnetic field gradients are applied, and random water diffusion through the gradients results in a loss of phase coherence, causing a detectable decrease in signal intensity.
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