Publications

  • [Show abstract] [Hide abstract]
    ABSTRACT: The distribution of dynamic contrast-enhanced MRI (DCE-MRI) parametric estimates in a rat U251 glioma model was analyzed. Using Magnevist as contrast agent (CA), 17 nude rats implanted with U251 cerebral glioma were studied by DCE-MRI twice in a 24 h interval. A data-driven analysis selected one of three models to estimate either (1) plasma volume (vp), (2) vp and forward volume transfer constant (Ktrans) or (3) vp, Ktrans and interstitial volume fraction (ve), constituting Models 1, 2 and 3, respectively. CA distribution volume (VD) was estimated in Model 3 regions by Logan plots. Regions of interest (ROIs) were selected by model. In the Model 3 ROI, descriptors of parameter distributions – mean, median, variance and skewness – were calculated and compared between the two time points for repeatability. All distributions of parametric estimates in Model 3 ROIs were positively skewed. Test–retest differences between population summaries for any parameter were not significant (p ≥ 0.10; Wilcoxon signed-rank and paired t tests). These and similar measures of parametric distribution and test–retest variance from other tumor models can be used to inform the choice of biomarkers that best summarize tumor status and treatment effects. Copyright © 2014 John Wiley & Sons, Ltd.
    NMR in Biomedicine 08/2014; · 3.45 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in a rat glioma model, and nested model selection (NMS), to compare estimates of the pharmacokinetic parameters vp , K(trans) , and ve for two different contrast agents (CAs)-gadofosveset, which reversibly binds to human serum albumin, and gadopentetate dimeglumine, which does not. DCE-MRI studies were performed on nine Fisher 344 rats inoculated intracerebrally with 9L gliosarcoma cells using both gadofosveset and gadopentetate. The parameters vp , K(trans) , and ve were estimated using NMS. K(trans) estimates using gadofosveset, compared to gadopentetate, differed in their means (gadofosveset 0.025 ± 0.008 min(-1) vs. gadopentetate 0.046 ± 0.011 min(-1) ; P = 0.0039). This difference notwithstanding, the intraclass correlation coefficient (ICC) for the two estimates of K(trans) showed nearly perfect linear dependence (ICC = 0.8479 by Pearson's r). Other estimates, ve (gadofosveset 22.7 ± 4.7% vs. gadopentetate 23.6 ± 5.6%; P = 0.4258) and vp (gadofosveset 1.5 ± 0.5% vs. gadopentetate 1.6 ± 0.4%; P = 0.25), were not different in their means between the two CAs, and there was almost perfect agreement for ve (ICC = 0.8798) and substantial agreement for vp (ICC = 0.7981) between the two CAs. Estimates of K(trans) were statistically different using gadofosveset and gadopentetate, whereas ve and vp were similar with two CAs. NMS produced robust estimates of pharmacokinetic parameters using DCE-MRI that show promise as important measures of tumor physiology and microenvironment.J. Magn. Reson. Imaging 2014;. © 2014 Wiley Periodicals, Inc.
    Journal of Magnetic Resonance Imaging 01/2014; · 2.57 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Limiting expansion of the ischemic core lesion by reinstating blood flow and protecting the penumbral cells is a priority in acute stroke treatment. However, at present, methods are not available for effective drug delivery to the ischemic penumbra. To address these issues this study compared the extravasation and subsequent interstitial spread of a magnetic resonance contrast agent (MRCA) beyond the ischemic core into the surrounding brain in a rat model of ischemia-reperfusion for bolus injection and step-down infusion (SDI) protocols.
    Fluids and barriers of the CNS. 01/2014; 11:21.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The aim of the study was to determine the antiangiogenic efficacy of vatalanib, sunitinib, and AMD3100 in an animal model of human glioblastoma (GBM) by using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and tumor protein expression analysis. Orthotopic GBM-bearing animals were randomly assigned either to control group or vatalanib, sunitinib, and AMD3100 treatment groups. Following 2 weeks of drug treatment, tumor growth and vascular parameters were measured using DCE-MRI. Expression of different angiogenic factors in tumor extracts was measured using a membrane-based human antibody array kit. Tumor angiogenesis and invasion were determined by immunohistochemistry. DCE-MRI showed a significant increase in tumor size after vatalanib treatment. AMD3100-treated group showed a significant decrease in a number of vascular parameters determined by DCE-MRI. AMD3100 significantly decreased the expression of different angiogenic factors compared to sunitinib or vatalanib; however, there were no significant changes in vascular density among the groups. Sunitinib-treated animals showed significantly higher migration of the invasive cells, whereas in both vatalanib- and AMD3100-treated animals the invasive cell migration distance was significantly lower compared to that of control. Vatalanib and sunitinib resulted in suboptimal therapeutic effect, but AMD3100 treatment resulted in a significant reduction in tumor growth, permeability, interstitial space volume, and invasion of tumor cells in an animal model of GBM.
    Translational oncology 12/2013; 6(6):660-9. · 3.40 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Endothelial progenitor cells (EPCs) hold enormous therapeutic potential for ischemic vascular diseases. Previous studies have indicated that stem/progenitor cells derived from human umbilical cord blood (hUCB) improve functional recovery in stroke models. Here, we examined the effect of hUCB AC133+ EPCs on stroke development and resolution in a middle cerebral artery occlusion (MCAo) rat model. Since the success of cell therapies strongly depends on the ability to monitor in vivo the migration of transplanted cells, we also assessed the capacity of magnetic resonance imaging (MRI) to track in vivo the magnetically labeled cells that were administered. Animals were subjected to transient MCAo and 24 hours later injected intravenously with 10(7) hUCB AC133+ EPCs. MRI performed at days 1, 7, and 14 after the insult showed accumulation of transplanted cells in stroke-affected hemispheres and revealed that stroke volume decreased at a significantly higher rate in cell-treated animals. Immunohistochemistry analysis of brain tissues localized the administered cells in the stroke-affected hemispheres only and indicated that these cells may have significantly affected the magnitude of endogenous proliferation, angiogenesis, and neurogenesis. We conclude that transplanted cells selectively migrated to the ischemic brain parenchyma, where they exerted a therapeutic effect on the extent of tissue damage, regeneration, and time course of stroke resolution.
    STEM CELLS TRANSLATIONAL MEDICINE 08/2013; · 3.60 Impact Factor
  • Source
    James Ewing, Hanzhang Lu
    [Show abstract] [Hide abstract]
    ABSTRACT: Watch a video introduction to this special issue.
    NMR in Biomedicine 08/2013; 26(8):885-6. · 3.45 Impact Factor
  • Source
    James R Ewing, Hassan Bagher-Ebadian
    [Show abstract] [Hide abstract]
    ABSTRACT: A review of the selection of models in dynamic contrast-enhanced MRI (DCE-MRI) is conducted, with emphasis on the balance between the bias and variance required to produce stable and accurate estimates of vascular parameters. The vascular parameters considered as a first-order model are the forward volume transfer constant K(trans) , the plasma volume fraction vp and the interstitial volume fraction ve . To illustrate the critical issues in model selection, a data-driven selection of models in an animal model of cerebral glioma is followed. Systematic errors and extended models are considered. Studies with nested and non-nested pharmacokinetic models are reviewed; models considering water exchange are considered. Copyright © 2013 John Wiley & Sons, Ltd.
    NMR in Biomedicine 08/2013; 26(8):1028-41. · 3.45 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: To test the hypothesis that a noninvasive dynamic contrast enhanced MRI (DCE-MRI) derived interstitial volume fraction (ve ) and/or distribution volume (VD ) were correlated with tumor cellularity in cerebral tumor. T1 -weighted DCE-MRI studies were performed in 18 athymic rats implanted with U251 xenografts. After DCE-MRI, sectioned brain tissues were stained with Hematoxylin and Eosin for cell counting. Using a Standard Model analysis and Logan graphical plot, DCE-MRI image sets during and after the injection of a gadolinium contrast agent were used to estimate the parameters plasma volume (vp ), forward transfer constant (K(trans) ), ve , and VD . Parameter values in regions where the standard model was selected as the best model were: (mean ± S.D.): vp = (0.81 ± 0.40)%, K(trans) = (2.09 ± 0.65) × 10(-2) min(-1) , ve = (6.65 ± 1.86)%, and VD = (7.21 ± 1.98)%. The Logan-estimated VD was strongly correlated with the standard model's vp + ve (r = 0.91, P < 0.001). The parameters, ve and/or VD , were significantly correlated with tumor cellularity (r ≥ -0.75, P < 0.001 for both). These data suggest that tumor cellularity can be estimated noninvasively by DCE-MRI, thus supporting its utility in assessing tumor pathophysiology. Magn Reson Med, 2013. © 2013 Wiley Periodicals, Inc.
    Magnetic Resonance in Medicine 07/2013; · 3.27 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Increased efficacy of radiotherapy (RT) 4-8 h after Cilengitide treatment has been reported. We hypothesized that the effects of Cilengitide on tumor transvascular transfer parameters might underlie, and thus predict, this potentiation. Athymic rats with orthotopic U251 glioma were studied at ~21 days after implantation using dynamic contrast-enhanced (DCE)-MRI. Vascular parameters, viz: plasma volume fraction (v p ), forward volume transfer constant (K (trans) ) and interstitial volume fraction (v e ) of a contrast agent, were determined in tumor vasculature once before, and again in cohorts 2, 4, 8, 12 and 24 h after Cilengitide administration (4 mg/kg; N = 31; 6-7 per cohort). Perfusion-fixed brain sections were stained for von Willebrand factor to visualize vascular segments. A comparison of pre- and post-treatment parameters showed that the differences between MR indices before and after Cilengitide treatment pivoted around the 8 h time point, with 2 and 4 h groups showing increases, 12 and 24 h groups showing decreases, and values at the 8 h time point close to the baseline. The vascular parameter differences between group of 2 and 4 h and group of 12 and 24 h were significant for K (trans) (p = 0.0001 and v e (p = 0,0271). Vascular staining showed little variation with time after Cilengitide. The vascular normalization occurring 8 h after Cilengitide treatment coincided with similar previous reports of increased treatment efficacy when RT followed Cilengitide by 8 h. Pharmacological normalization of vasculature has the potential to increase sensitivity to RT. Evaluating acute temporal responses of tumor vasculature to putative anti-angiogenic drugs may help in optimizing their combination with other treatment modalities.
    PLoS ONE 01/2013; 8(12):e84493. · 3.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Aim: The authors have investigated the usefulness of in vivo chemical exchange saturation transfer MRI for detecting gliomas using a dual-modality imaging contrast agent. Materials & methods: A paramagnetic chemical exchange saturation transfer MRI contrast agent, Eu-1,4,7,10-tetraazacclododecane-1,4,7,10-tetraacetic acid-Gly(4) and a fluorescent agent, DyLight(®) 680, were conjugated to a generation 5 polyamidoamine dendrimer to create the dual-modality, nano-sized imaging contrast agent. Results: The agent was detected with in vivo chemical exchange saturation transfer MRI in an U87 glioma model. These results were validated using in vivo and ex vivo fluorescence imaging. Conclusion: This study demonstrated the merits of using a nano-sized imaging contrast agent for detecting gliomas and using a dual-modality agent for detecting gliomas at different spatial scales. Original submitted 9 January 2012; Revised submitted 18 April 2012.
    Nanomedicine 08/2012; · 5.26 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Malignant gliomas are often very heterogeneous tumors with complex vasculature, fre-quently exhibiting angiogenesis and increased vascular permeability. In vivo measurement of the tumor vessel permeability can serve as a potential imaging biomarker to assess tumor grade and aggressiveness. It can also be used to study the response of tumors to various therapies, especially antiangiogenic therapy. Central to the concept of permeability is a thorough knowledge of the BBB and its role in brain tumors and angiogenesis. Much work has been done in the past to understand the structural/molecular composition of the BBB and the role it plays in various pathologic processes, including brain tumors. Various imag-ing techniques have also been used to evaluate BBB leakiness in brain tumors because higher tumor vascular leakiness is known to be associated with higher grade and malignant potential of the tumor and hence poor patient prognosis. These imaging techniques range from routine postcontrast T1-weighted images to measurement of vascular permeability using various quantitative or semiquantitative indices based on multicompartment pharma-cokinetic models. The purpose of this article is to discuss BBB anatomy; various clinically available imaging techniques to evaluate tumor vascular leakiness (perfusion imaging), including their advantages and limitations; as well as a brief discussion of the clinical utility of measuring vascular permeability in brain tumors. We will also discuss the various perme-ability-related indices along with the pharmacokinetic models to simplify the "nomenclature soup."
    Neurographics. 06/2012; 2:48-59.
  • Quan Jiang, James R Ewing, Michael Chopp
    [Show abstract] [Hide abstract]
    ABSTRACT: Quantitative measurement of blood-brain barrier (BBB) permeability using MRI and its application to cerebral ischemia are reviewed. Measurement of BBB permeability using MRI has been employed to evaluate ischemic damage during acute and subacute phases of stroke and to predict hemorrhagic transformation. There is also an emerging interest on the development and use of MRI to monitor vascular structural changes and angiogenesis during stroke recovery. In this review, we describe MRI BBB permeability and susceptibility-weighted MRI measurements and its applications to evaluate ischemic damage during the acute and subacute phases of stroke and vascular remodeling during stroke recovery.
    Translational stroke research. 03/2012; 3(1):56-64.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Dynamic contrast enhanced T(1)-weighted MRI using the contrast agent gadopentetate dimeglumine (Gd-DTPA) was performed on 10 patients with glioblastoma. Nested models with as many as three parameters were used to estimate plasma volume or plasma volume and forward vascular transfer constant (K(trans)) and the reverse vascular transfer constant (k(ep)). These constituted models 1, 2, and 3, respectively. Model 1 predominated in normal nonleaky brain tissue, showing little or no leakage of contrast agent. Model 3 predominated in regions associated with aggressive portions of the tumor, and model 2 bordered model 3 regions, showing leakage at reduced rates. In the patient sample, v(p) was about four times that of white matter in the enhancing part of the tumor. K(trans) varied by a factor of 10 between the model 2 (1.9 ↔ 10(-3) min(-1)) and model 3 regions (1.9 ↔ 10(-2) min(-1)). The mean calculated interstitial space (model 3) was 5.5%. In model 3 regions, excellent curve fits were obtained to summarize concentration-time data (mean R(2) = 0.99). We conclude that the three parameters of the standard model are sufficient to fit dynamic contrast enhanced T(1) data in glioblastoma under the conditions of the experiment.
    Magnetic Resonance in Medicine 11/2011; 68(1):241-51. · 3.27 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Sildenafil provides restorative therapeutic benefits in the treatment of experimental stroke. The majority of experimental studies on treatment of stroke have been performed in young animals; however, stroke is primarily a disease of the aged. Thus, using MRI, we evaluated the effects of sildenafil treatment of embolic stroke in aged animals. Aged male Wistar rats (18 months) were subjected to embolic stroke and treated daily with saline (n=10) or with sildenafil (n=10) initiated at 24 hours and subsequently for 7 days after onset of ischemia. MRI measurements were performed at 24 hours and weekly to 6 weeks after embolization. MRI and histological measurements demonstrated that sildenafil treatment of aged rats significantly enhanced angiogenesis and axonal remodeling after stroke compared to saline-treated aged rats. Local cerebral blood flow in the angiogenic area was elevated and expansion of the ipsilateral ventricle and, consequently, brain atrophy was significantly reduced in the sildenafil-treated rats. Treatment of embolic stroke in aged rats with sildenafil significantly augments angiogenesis and axonal remodeling, which increased local blood flow and reduced expansion of the ipsilateral ventricle 6 weeks after stroke compared to control aged rats. MRI can be used to investigate brain repair after stroke in aged rats.
    Stroke 09/2011; 42(12):3537-41. · 6.16 Impact Factor
  • Stroke 09/2011; 42(10):e568. · 6.16 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Tumor interstitial fluid pressure (TIFP) has the potential to predict tumor response to nonsurgical cancer treatments, including radiation therapy. At present the only quantitative measures available are of limited use, since they are invasive and yield only point measurements. We present the mathematical framework for a quantitative, noninvasive measure of TIFP. The model describes the distribution of interstitial fluid pressure in three distinct tumor regions: vascularized tumor rim, central tumor region, and normal tissue. A relationship between the TIFP and the fluid flow velocity at the periphery of a tumor is presented. This model suggests that a measure of fluid flow rate from a tumor into normal tissue reflects TIFP. We demonstrate that the acquisition of serial images of a tumor after the injection of a contrast agent can provide a noninvasive and potentially quantitative measure of TIFP.
    Physical Review E 08/2011; 84(2 Pt 1):021919. · 2.31 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: In previous studies on a rat model of transient cerebral ischemia, the blood and brain concentrations of gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) following intravenous bolus injection were repeatedly assessed by dynamic contrast-enhanced (DCE)-MRI, and blood-to-brain influx rate constants (K(i)) were calculated from Patlak plots of the data in areas with blood-brain barrier (BBB) opening. For concurrent validation of these findings, after completing the DCE-MRI study, radiolabeled sucrose or α-aminoisobutyric acid was injected intravenously, and the brain disposition and K(i) values were calculated by quantitative autoradiography (QAR) assay employing the single-time equation. To overcome two of the shortcomings of this comparison, the present experiments were carried out with a radiotracer virtually identical to Gd-DTPA, Gd-[(14)C]DTPA, and K(i) was calculated from both sets of data by the single-time equation. The protocol included 3 h of middle cerebral artery occlusion and 2.5 h of reperfusion in male Wistar rats (n = 15) preceding the DCE-MRI Gd-DTPA and QAR Gd-[(14)C]DTPA measurements. In addition to K(i) , the tissue-to-blood concentration ratios, or volumes of distribution (V(R) ), were calculated. The regions of BBB opening were similar on the MRI maps and autoradiograms. Within them, V(R) was nearly identical for Gd-DTPA and Gd-[(14)C]DTPA, and K(i) was slightly, but not significantly, higher for Gd-DTPA than for Gd-[(14)C]DTPA. The K(i) values were well correlated (r = 0.67; p = 0.001). When the arterial concentration-time curve of Gd-DTPA was adjusted to match that of Gd-[(14)C]DTPA, the two sets of K(i) values were equal and statistically comparable with those obtained previously by Patlak plots (the preferred, less model-dependent, approach) of the same data (p = 0.2-0.5). These findings demonstrate that this DCE-MRI technique accurately measures the Gd-DTPA concentration in blood and brain, and that K(i) estimates based on such data are good quantitative indicators of BBB injury.
    NMR in Biomedicine 06/2011; 24(5):547-58. · 3.45 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: This paper models the behavior of the longitudinal relaxation rate of the protons of tissue water R(1) (R(1) = 1/T(1) ), measured in a Look-Locker experiment at 7 Tesla after administration of a paramagnetic contrast agent (CA). It solves the Bloch-McConnell equations for the longitudinal magnetization of the protons of water in a three-site two-exchange (3S2X) model with boundary conditions appropriate to repeated sampling of magnetization. The extent to which equilibrium intercompartmental water exchange kinetics affect monoexponential estimates of R(1) after administration of a CA in dynamic contrast enhanced experiment is described. The relation between R(1) and tissue CA concentration was calculated for CA restricted to the intravascular, or to the intravascular and extracellular compartments, by varying model parameters to mimic experimental data acquired in a rat model of cerebral tumor. The model described a nearly linear relationship between R(1) and tissue concentration of CA, but demonstrated that the apparent longitudinal relaxivity of CA depends upon tissue type. The practical consequence of this finding is that the extended Patlak plot linearizes the ΔR(1) data in tissue with leaky microvessels, accurately determines the influx rate of the CA across these microvessels, but underestimates the volume of intravascular blood water.
    Magnetic Resonance in Medicine 05/2011; 66(5):1432-44. · 3.27 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The apparent forward transfer constant, K transa, for albumin was measured in 9L cerebral tumors in 15 rats. An MRI study using gadolinium-labeled bovine serum albumin was followed by terminal quantitative autoradiography (QAR) using radioiodinated serum albumin. Look-Locker MRI estimates of T(1) followed gadolinium-labeled bovine serum albumin blood and tissue concentration. QAR and MRI maps of K transa were coregistered, a region of interest (ROI) that included the tumor and its surround was selected, and the two estimates of K transa from the ROI on QAR and MRI maps were compared by either mean per animal ROI or on pixel-by-pixel data using a generalized estimating equation. An ROI analysis showed a moderate correlation between the two measures (r = 0.57, P = 0.026); pixel-by-pixel generalized estimating equation analysis concurred (r = 0.54, P < 0.0001). The estimates of QAR with MRI of last time points (e.g., 25 min) showed a moderate correlation (ROI r = 0.55, P < 0.035; generalized estimating equation r = 0.58, P < 0.0001). Differences between the QAR and MRI estimates of K transa did not differ from zero, but the MRI 25-min estimate was significantly lower than the QAR estimate. Thus, noninvasive MRI estimates of vascular permeability can serve as a surrogate for QAR measures.
    Magnetic Resonance in Medicine 05/2011; 66(5):1422-31. · 3.27 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The longitudinal relaxivity on the protons of water of a Gd-chelate-albumin compound was measured at 7 T as a function of the macromolecular content of a cross-linked matrix. In agreement with previous works, the results demonstrate that the effect of gadolinium on water proton relaxivity is not constant, rising moderately with increase in the concentration of bovine serum albumin (BSA). About 35% variation in relaxivity was observed over a 0%-25% range of BSA concentrations (ℜ = 3.893 + 0.0502 × BSA [%], SE = 0.0119 and 0.1740, t = 4.215 and 22.383, p < 0.014 and 0.001).
    NeuroImage 01/2011; 54 Suppl 1:S176-9. · 6.25 Impact Factor

27 Following View all

54 Followers View all