Faculty Bibliography

High-resolution imaging of human autopsy tissues may improve our understanding of in vivo MRI findings, but interpretation is complicated because samples are obtained by immersion fixation following a postmortem interval (PMI). This study tested the hypotheses that immersion fixation and PMI's from 0-24 h would alter the water relaxation and diffusion properties in rat cortical slice and spinal cord models of human nervous tissue. Diffusion data collected from rat cortical slices at multiple diffusion times (10-60 ms) and b-values (7-15,000 s/mm(2)) were analyzed using a two-compartment model with exchange. Rat spinal cords were characterized with standard diffusion tensor imaging (21 directions, b=1250 s/mm(2)). Switching from perfusion- to immersion-fixation at 0 h PMI altered most MRI properties of rat cortical slices and spinal cords, including a 22% decrease in fractional anisotropy (P<0.001). After 4 h PMI, cortical slice T(1) and T(2) increased 22% and 65% respectively (P<0.001), transmembrane water exchange decreased 23% (P<0.001) and intracellular proton fraction increased 25% (P=0.002). After 6 h PMI, spinal cord white matter fractional anisotropy had decreased 38% (P<0.001). MRI property changes were observed for PMIs up to 24 h. The MRI changes correlated with protease activity and histopathological signs of autolysis. Thus, immersion fixation and/or even short PMIs (4-6 h) altered the MRI properties of rat nervous tissue. This suggests comparisons between in vivo clinical MRI and MRI data from human autopsy tissues should be interpreted with caution.

Herein we report investigations into the p38alpha MAP kinase activity of trisubstituted imidazoles that led to the identification of compounds possessing highly potent in vivo activity. The SAR of a novel series of imidazopyridines is demonstrated as well, resulting in compounds possessing cellular potency and enhanced in vivo activity in the rat collagen-induced arthritis model of chronic inflammation.

In this paper, we present novel algorithms for statistically robust interpolation and approximation of diffusion tensors-which are symmetric positive definite (SPD) matrices-and use them in developing a significant extension to an existing probabilistic algorithm for scalar field segmentation, in order to segment diffusion tensor magnetic resonance imaging (DT-MRI) datasets. Using the Riemannian metric on the space of SPD matrices, we present a novel and robust higher order (cubic) continuous tensor product of B-splines algorithm to approximate the SPD diffusion tensor fields. The resulting approximations are appropriately dubbed tensor splines. Next, we segment the diffusion tensor field by jointly estimating the label (assigned to each voxel) field, which is modeled by a Gauss Markov measure field (GMMF) and the parameters of each smooth tensor spline model representing the labeled regions. Results of interpolation, approximation, and segmentation are presented for synthetic data and real diffusion tensor fields from an isolated rat hippocampus, along with validation. We also present comparisons of our algorithms with existing methods and show significantly improved results in the presence of noise as well as outliers.

BACKGROUND AND PURPOSE/OBJECTIVE:Observing changes to water diffusivity and fractional anisotropy (FA) for particular hippocampal regions may improve the sensitivity and specificity of diffusion tensor MR imaging for hippocampal pathologies like Alzheimer disease and mesial temporal sclerosis. As a first step toward this goal, this study characterized the cytoarchitectural features underlying diffusion anisotropy in human hippocampus autopsy specimens at 60-microm in-plane resolution. MATERIALS AND METHODS/METHODS:Eight-millimeter coronal segments of the hippocampal body were dissected from 5 autopsy specimens (mean = 55.6 +/- 6.2 years of age) with short postmortem intervals to fixation (21.2 +/- 5.7 hours) and no histologic evidence of neuropathology. Diffusion tensor microscopy data were collected from hippocampal specimens by using a 14.1T magnet with a protocol that included 21 unique diffusion gradient orientations (diffusion time = 17 ms, b = 1250 s/mm(2)). The resulting images were used to determine the mean diffusivity, FA, and principal fiber orientation for manually segmented hippocampal regions that included the stratum oriens, stratum radiatum, stratum pyramidale (CA1 and CA3), stratum lacunosum-molecular, hilus, molecular layer, granule cell layer, fimbria, and subiculum. RESULTS:Diffusion-weighted images had high signal-to-noise ratios (31.1 +/- 13.0) and delineated hippocampal anatomy well. Water diffusivity ranged from 1.21 +/- 0.22 x 10(-4) mm(2)/s in the fimbria to 3.48 +/- 0.72 x 10(-4) mm(2)/s in granule cells (analysis of variance, P<.001). Color fiber-orientation maps indicated the underlying microstructures responsible for diffusion anisotropy in the hippocampal lamina. CONCLUSION/CONCLUSIONS:Diffusion tensor microscopy provided novel microstructural information about the different lamina of the human hippocampus. These ex vivo data obtained at high-magnetic-field strengths can be used to study injury-specific diffusion changes to susceptible hippocampal regions and may lead to more specific MR imaging surrogate markers for Alzheimer disease or epilepsy.