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PURPOSE - To investigate the influence of transcytolemmal water exchange on estimates of tissue microstructural parameters derived from diffusion MRI using conventional PGSE and IMPULSED methods.
METHODS - Computer simulations were performed to incorporate a broad range of intracellular water life times τ (50-∞ ms), cell diameters d (5-15 μm), and intrinsic diffusion coefficient D (0.6-2 μm /ms) for different values of signal-to-noise ratio (SNR) (10 to 50). For experiments, murine erythroleukemia (MEL) cancer cells were cultured and treated with saponin to selectively change cell membrane permeability. All fitted microstructural parameters from simulations and experiments in vitro were compared with ground-truth values.
RESULTS - Simulations showed that, for both PGSE and IMPULSED methods, cell diameter d can be reliably fit with sufficient SNR (≥ 50), whereas intracellular volume fraction f is intrinsically underestimated due to transcytolemmal water exchange. D can be reliably fit only with sufficient SNR and using the IMPULSED method with short diffusion times. These results were confirmed with those obtained in the cell culture experiments in vitro.
CONCLUSION - For the sequences and models considered in this study, transcytolemmal water exchange has minor effects on the fittings of d and D with physiologically relevant membrane permeabilities if the SNR is sufficient (> 50), but f is intrinsically underestimated. Magn Reson Med 77:2239-2249, 2017. © 2016 International Society for Magnetic Resonance in Medicine.
© 2016 International Society for Magnetic Resonance in Medicine.
Sphingolipids serve important structural and functional roles in cellular membranes and myelin sheaths. Plasma sphingolipids have been shown to predict cognitive decline and Alzheimer's disease. However, the association between plasma sphingolipid levels and brain white matter (WM) microstructure has not been examined. We investigated whether plasma sphingolipids (ceramides and sphingomyelins) were associated with magnetic resonance imaging-based diffusion measures, fractional anisotropy (FA), and mean diffusivity, 10.5 years later in 17 WM regions of 150 cognitively normal adults (mean age 67.2). Elevated ceramide species (C20:0, C22:0, C22:1, and C24:1) were associated with lower FA in multiple WM regions, including total cerebral WM, anterior corona radiata, and the cingulum of the cingulate gyrus. Higher sphingomyelins (C18:1 and C20:1) were associated with lower FA in regions such as the anterior corona radiata and body of the corpus callosum. Furthermore, lower sphingomyelin to ceramide ratios (C22:0, C24:0, and C24:1) were associated with lower FA or higher mean diffusivity in regions including the superior and posterior corona radiata. However, although these associations were significant at the a priori p < 0.05, only associations with some regional diffusion measures for ceramide C22:0 and sphingomyelin C18:1 survived correction for multiple comparisons. These findings suggest plasma sphingolipids are associated with variation in WM microstructure in cognitively normal aging.
Copyright © 2016 Elsevier Inc. All rights reserved.
BACKGROUND AND PURPOSE - This single institution phase I trial determined the maximum tolerated dose (MTD) of concurrent vorinostat and capecitabine with radiation in non-metastatic pancreatic cancer.
MATERIAL AND METHODS - Twenty-one patients received escalating doses of vorinostat (100-400mg daily) during radiation. Capecitabine was given 1000mg q12 on the days of radiation. Radiation consisted of 30Gy in 10 fractions. Vorinostat dose escalation followed the standard 3+3 design. No dose escalation beyond 400mg vorinostat was planned. Diffusion-weighted (DW)-MRI pre- and post-treatment was used to evaluate in vivo tumor cellularity.
RESULTS - The MTD of vorinostat was 400mg. Dose limiting toxicities occurred in one patient each at dose levels 100mg, 300mg, and 400mg: 2 gastrointestinal toxicities and one thrombocytopenia. The most common adverse events were lymphopenia (76%) and nausea (14%). The apparent diffusion coefficient (ADC) increased in most tumors. Nineteen (90%) patients had stable disease, and two (10%) had progressive disease at time of surgery. Eleven patients underwent surgical exploration with four R0 resections and one R1 resection. Median overall survival was 1.1years (95% confidence interval 0.78-1.35).
CONCLUSIONS - The combination of vorinostat 400mg daily M-F and capecitabine 1000mg q12 M-F with radiation (30Gy in 10 fractions) was well tolerated with encouraging median overall survival.
Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.
Mapping axon diameter is of interest for the potential diagnosis and monitoring of various neuronal pathologies. Advanced diffusion-weighted MRI methods have been developed to measure mean axon diameters non-invasively, but suffer major drawbacks that prevent their direct translation into clinical practice, such as complex non-linear data fitting and, more importantly, long scanning times that are usually not tolerable for most human subjects. In the current study, temporal diffusion spectroscopy using oscillating diffusion gradients was used to measure mean axon diameters with high sensitivity to small axons in the central nervous system. Axon diameters have been found to be correlated with a novel metric, DDR⊥ (the rate of dispersion of the perpendicular diffusion coefficient with gradient frequency), which is a model-free quantity that does not require complex data analyses and can be obtained from two diffusion coefficient measurements in clinically relevant times with conventional MRI machines. A comprehensive investigation including computer simulations and animal experiments ex vivo showed that measurements of DDR⊥ agree closely with histological data. In humans in vivo, DDR⊥ was also found to correlate well with reported mean axon diameters in human corpus callosum, and the total scan time was only about 8 min. In conclusion, DDR⊥ may have potential to serve as a fast, simple and model-free approach to map the mean axon diameter of white matter in clinics for assessing axon diameter changes.
Copyright © 2016 John Wiley & Sons, Ltd.
BACKGROUND - Lower integrity of cerebral gray matter is associated with higher gait variability. It is not known whether gray matter integrity is associated with higher lap time variation (LTV), a clinically accessible measure of gait variability, high levels of which have been associated with mortality. This study examines the cross-sectional association between gray matter mean diffusivity (MD) and LTV in community-dwelling older adults.
METHODS - Study participants consisted of 449 high-functioning adults aged 50 and older (56.8% female) in the Baltimore Longitudinal Study of Aging, free of overt neurological disease. The magnitude of MD in the gray matter, a measure of impaired tissue integrity, was assessed by diffusion tensor imaging in 16 regions of interest (ROIs) involved with executive function, sensorimotor function, and memory. LTV was assessed as variability in lap time based on individual trajectories over ten 40-m laps. Age, sex, height, and weight were covariates. The model additionally adjusted for mean lap time and health conditions that may affect LTV.
RESULTS - Higher levels of average MD across 16 ROIs were significantly associated with higher LTV after adjustment for covariates. Specifically, higher MD in the precuneus and the anterior and middle cingulate cortices was strongly associated with higher LTV, as compared to other ROIs. The association persisted after adjustment for mean lap time, hypertension, and diabetes.
CONCLUSIONS - Lower gray matter integrity in selected areas may underlie greater LTV in high-functioning community-dwelling older adults. Longitudinal studies are warranted to examine whether changes in gray matter integrity precede more variable gait.
Published by Elsevier Inc.
The ability of diffusion MRI (dMRI) fiber tractography to non-invasively map three-dimensional (3D) anatomical networks in the human brain has made it a valuable tool in both clinical and research settings. However, there are many assumptions inherent to any tractography algorithm that can limit the accuracy of the reconstructed fiber tracts. Among them is the assumption that the diffusion-weighted images accurately reflect the underlying fiber orientation distribution (FOD) in the MRI voxel. Consequently, validating dMRI's ability to assess the underlying fiber orientation in each voxel is critical for its use as a biomedical tool. Here, using post-mortem histology and confocal microscopy, we present a method to perform histological validation of orientation functions in 3D, which has previously been limited to two-dimensional analysis of tissue sections. We demonstrate the ability to extract the 3D FOD from confocal z-stacks, and quantify the agreement between the MRI estimates of orientation information obtained using constrained spherical deconvolution (CSD) and the true geometry of the fibers. We find an orientation error of approximately 6° in voxels containing nearly parallel fibers, and 10-11° in crossing fiber regions, and note that CSD was unable to resolve fibers crossing at angles below 60° in our dataset. This is the first time that the 3D white matter orientation distribution is calculated from histology and compared to dMRI. Thus, this technique serves as a gold standard for dMRI validation studies - providing the ability to determine the extent to which the dMRI signal is consistent with the histological FOD, and to establish how well different dMRI models can predict the ground truth FOD.
Copyright © 2016 Elsevier Inc. All rights reserved.
Diffusion tensor imaging (DTI) measures are commonly used as imaging markers to investigate individual differences in relation to behavioral and health-related characteristics. However, the ability to detect reliable associations in cross-sectional or longitudinal studies is limited by the reliability of the diffusion measures. Several studies have examined the reliability of diffusion measures within (i.e. intra-site) and across (i.e. inter-site) scanners with mixed results. Our study compares the test-retest reliability of diffusion measures within and across scanners and field strengths in cognitively normal older adults with a follow-up interval less than 2.25 years. Intra-class correlation (ICC) and coefficient of variation (CoV) of fractional anisotropy (FA) and mean diffusivity (MD) were evaluated in sixteen white matter and twenty-six gray matter bilateral regions. The ICC for intra-site reliability (0.32 to 0.96 for FA and 0.18 to 0.95 for MD in white matter regions; 0.27 to 0.89 for MD and 0.03 to 0.79 for FA in gray matter regions) and inter-site reliability (0.28 to 0.95 for FA in white matter regions, 0.02 to 0.86 for MD in gray matter regions) with longer follow-up intervals were similar to earlier studies using shorter follow-up intervals. The reliability of across field strengths comparisons was lower than intra- and inter-site reliabilities. Within and across scanner comparisons showed that diffusion measures were more stable in larger white matter regions (>1500 mm(3)). For gray matter regions, the MD measure showed stability in specific regions and was not dependent on region size. Linear correction factor estimated from cross-sectional or longitudinal data improved the reliability across field strengths. Our findings indicate that investigations relating diffusion measures to external variables must consider variable reliability across the distinct regions of interest and that correction factors can be used to improve consistency of measurement across field strengths. An important result of this work is that inter-scanner and field strength effects can be partially mitigated with linear correction factors specific to regions of interest. These data-driven linear correction techniques can be applied in cross-sectional or longitudinal studies.
Published by Elsevier Inc.
Diffusion MRI provides a non-invasive means to characterize tissue microstructure at varying length scales. Temporal diffusion spectra reveal how the apparent diffusion coefficient (ADC) varies with frequency. When measured using oscillating gradient spin echo sequences, the manner in which ADC disperses with gradient frequency (which is related to the reciprocal of diffusion time) provides information on the characteristic dimensions of restricting structures within the medium. For example, the dispersion of ADC with oscillating gradient frequency (ΔfADC) has been shown to correlate with axon sizes in white matter and provide novel tissue contrast in images of mouse hippocampus and cerebellum. However, despite increasing interest in applying frequency-dependent ADC to derive novel information on tissue, the interpretations of ADC spectra are not always clear. In this study, the relation between ADC spectra and restricting dimensions are further elucidated and used to derive novel image contrast related to the sizes of intrinsic microstructures.
Copyright © 2015 Elsevier Inc. All rights reserved.
PURPOSE - To investigate the influence of cell membrane permeability on diffusion measurements over a broad range of diffusion times.
METHODS - Human myelogenous leukemia K562 cells were cultured and treated with saponin to selectively alter cell membrane permeability, resulting in a broad physiologically relevant range of 0.011-0.044 μm/ms. Apparent diffusion coefficient (ADC) values were acquired with the effective diffusion time (Δeff ) ranging from 0.42 to 3000 ms. Cosine-modulated oscillating gradient spin echo (OGSE) measurements were performed to achieve short Δeff from 0.42 to 5 ms, while stimulated echo acquisitions were used to achieve long Δeff from 11 to 2999 ms. Computer simulations were also performed to support the experimental results.
RESULTS - Both computer simulations and experiments in vitro showed that the influence of membrane permeability on diffusion MR measurements is highly dependent on the choice of diffusion time, and it is negligible only when the diffusion time is at least one order of magnitude smaller than the intracellular exchange lifetime.
CONCLUSION - The influence of cell membrane permeability on the measured ADCs is negligible in OGSE measurements at moderately high frequencies. By contrast, cell membrane permeability has a significant influence on ADC and quantitative diffusion measurements at low frequencies such as those sampled using conventional pulsed gradient methods.
© 2015 Wiley Periodicals, Inc.
PURPOSE - To assess the effect of anisotropic smoothing on fiber tracking measures, including pennation angle, fiber tract length, and fiber tract number in the medial gastrocnemius (MG) muscle in healthy subjects using diffusion-weighted magnetic resonance imaging (DW-MRI).
MATERIALS AND METHODS - 3T DW-MRI data were used for muscle fiber tractography in the MG of healthy subjects. Anisotropic smoothing was applied at three levels (5%, 10%, 15%), and pennation angle, tract length, fiber tract number, fractional anisotropy, and principal eigenvector orientation were quantified for each smoothing level.
RESULTS - Fiber tract length increased with pre-fiber tracking smoothing, and local heterogeneities in fiber direction were reduced. However, pennation angle was not affected by smoothing.
CONCLUSION - Modest anisotropic smoothing (10%) improved fiber-tracking results, while preserving structural features.