Dong-Cheol Woo

β-Hydroxybutyrate attenuates NMDA-induced spasms in rats with evidence of neuronal stabilization on MR spectroscopy

BACKGROUNDnInfantile spasms (IS) is a devastating epileptic encephalopathy. The ketogenic diet (KD) has been successfully used as a treatment for IS. This study was designed to test whether beta-hydroxybutyrate (BHB), a major metabolite of the KD, is effective in an animal model of IS.nnnMETHODSnPregnant rats received betamethasone on gestational day 15. The offspring received either single [30min prior to NMDA-triggered spasms on postnatal day (P) 15] or prolonged (three per day from P12 to P15) i.p. BHB. An additional experiment used repeated bouts of spasms on P12, P13, and P15 with randomized prolonged BHB treatment initiated after the first spasms. We determined the latency to onset of spasms and the number of spasms after the NMDA injection on P15. The rats that received randomized BHB treatment were also monitored with open field, sociability, and fear-conditioning tests and underwent in vivo (1)H MR imaging on a 9.4T MR system after NMDA-induced spasms. The acquired (1)H MR spectra were quantified using LC model.nnnRESULTSnSingle-dose BHB pretreatment had no effect on spasms. In contrast, prolonged pretreatment with BHB significantly delayed the onset and decreased the frequency of spasms. In addition, randomized prolonged BHB treatment resulted in a significant reduction in number of spasms at P15. BHB treatment had no significant effect on motor activities, but significantly decreased the interactions with strangers and increased the contextual memory. On MR spectroscopic analysis of randomized prolonged BHB-treated rats at 24h after the cluster of spasms, the elevation of GABA, glutamine, glutamate, total creatine, macromolecule-plus lipids, and N-acetylaspartate levels after spasms were significantly attenuated by randomized BHB treatment (p<0.05).nnnSIGNIFICANCEnProlonged administration of BHB directly suppresses development of spasms in a rat model of IS with acute stabilization of brain metabolites. Additionally, BHB appears to decrease the interests to other rats and improve memory responses.

Dynamic contrast-enhanced MRI for oncology drug development

Dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI) is a promising tool for evaluating tumor vascularity, as it can provide vasculature‐derived, functional, and quantitative parameters. To implement DCE‐MRI parameters as biomarkers for monitoring the effect of antiangiogenic or vascular‐disrupting treatment, two crucial elements of surrogate endpoint, ie, validation and qualification, should be satisfied. Although early studies have shown the accuracy and reliability of DCE‐MRI parameters for evaluating treatment‐driven vascular alterations, there have been an increasing number of studies demonstrating the limitations of DCE‐MRI parameters as surrogate endpoints. Therefore, in order to improve the application of DCE‐MRI parameters in drug development, it is necessary to establish a standardized evaluation method and to determine the correct therapeutics‐oriented meaning of individual DCE‐MRI parameter. In this regard, this article describes the biophysical background and data acquisition/analysis techniques of DCE‐MRI while focusing on the validation and qualification issues. Specifically, the causes of disagreement and confusion encountered in the preclinical and clinical trials using DCE‐MRI are presented in detail. Finally, considering these limitations, we present potential strategies to optimize implementation of DCE‐MRI. J. Magn. Reson. Imaging 2016;44:251–264.

Simultaneous evaluation of vascular morphology, blood volume and transvascular permeability using SPION‐based, dual‐contrast MRI: imaging optimization and feasibility test

Exploiting ultrashort‐TE (UTE) MRI, T1‐weighted positive contrast can be obtained from superparamagnetic iron oxide nanoparticles (SPIONs), which are widely used as a robust T2‐weighted, negative contrast agent on conventional MR images. Our study was designed (a) to optimize the dual‐contrast MRI method using SPIONs and (b) to validate the feasibility of simultaneously evaluating the vascular morphology, blood volume and transvascular permeability using the dual‐contrast effect of SPIONs. All studies were conducted using 3u2009T MRI. According to numerical simulation, 0.15u2009mM was the optimal blood SPION concentration for visualizing the positive contrast effect using UTE MRI (TEu2009=u20090.09u2009ms), and a flip angle of 40° could provide sufficient SPION‐induced enhancement and acceptable measurement noise for UTE MR angiography. A pharmacokinetic study showed that this concentration can be steadily maintained from 30 to 360u2009min after the injection of 29u2009mg/kg of SPIONs. An in vivo study using these settings displayed image quality and CNR of SPION‐enhanced UTE MR angiography (image quality score 3.5; CNR 146) comparable to those of the conventional, Gd‐enhanced method (image quality score 3.8; CNR 148) (pu2009>u20090.05). Using dual‐contrast MR images obtained from SPION‐enhanced UTE and conventional spin‐ and gradient‐echo methods, the transvascular permeability (water exchange index 1.76–1.77), cerebral blood volume (2.58–2.60%) and vessel caliber index (3.06–3.10) could be consistently quantified (coefficient of variation less than 9.6%; Bland–Altman 95% limits of agreement 0.886–1.111) and were similar to the literature values. Therefore, using the optimized setting of combined SPION‐based MRI techniques, the vascular morphology, blood volume and transvascular permeability can be comprehensively evaluated during a single session of MR examination. Copyright

Difference in the intratumoral distributions of extracellular-fluid and intravascular MR contrast agents in glioblastoma growth

Contrast enhancement by an extracellular‐fluid contrast agent (CA) (Gd‐DOTA) depends primarily on the blood–brain‐barrier permeability (bp), and transverse‐relaxation change caused by intravascular T2 CA (superparamagnetic iron oxide nanoparticles, SPIONs) is closely associated with the blood volume (BV). Pharmacokinetic (PK) vascular characterization based on single‐CA‐using dynamic contrast‐enhanced MRI (DCE‐MRI) has shown significant measurement variation according to the molecular size of the CA. Based on this recognition, this study used a dual injection of Gd‐DOTA and SPIONs for tracing the changes of bp and BV in C6 glioma growth (Days 1 and 7 after the tumor volume reached 2 mL). bp was quantified according to the non‐PK parameters of Gd‐DOTA‐using DCE‐MRI (wash‐in rate, maximum enhancement ratio and initial area under the enhancement curve (IAUC)). BV was estimated by SPION‐induced ΔR2* and ΔR2. With validated measurement reliability of all the parameters (coefficients of variation ≤10%), dual‐contrast MRI demonstrated a different region‐oriented distribution between Gd‐DOTA and SPIONs within a tumor as follows: (a) the BV increased stepwise from the tumor center to the periphery; (b) the tumor periphery maintained the augmented BV to support continuous tumor expansion from Day 1 to Day 7; (c) the internal tumor area underwent significant vascular shrinkage (i.e. decreased ΔR2 and ΔR2) as the tumor increased in size; (d) the tumor center showed greater bp‐indicating parameters, i.e. wash‐in rate, maximum enhancement ratio and IAUC, than the periphery on both Days 1 and 7 and (e) the tumor center showed a greater increase of bp than the tumor periphery in tumor growth, as suggested to support tumor viability when there is insufficient blood supply. In the MRI–histologic correlation, a prominent BV increase in the tumor periphery seen in MRI was verified with increased fluorescein isothiocyanate–dextran signals and up‐regulated immunoreactivity of CD31–VEGFR. In conclusion, the spatiotemporal alterations of BV and bp in glioblastoma growth, i.e. augmented BV in the tumor periphery and increased bp in the center, can be sufficiently evaluated by MRI with dual injection of extracellular‐fluid Gd chelates and intravascular SPION.

Influence of B1-Inhomogeneity on Pharmacokinetic Modeling of Dynamic Contrast-Enhanced MRI: A Simulation Study

Objective To simulate the B1-inhomogeneity-induced variation of pharmacokinetic parameters on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Materials and Methods B1-inhomogeneity-induced flip angle (FA) variation was estimated in a phantom study. Monte Carlo simulation was performed to assess the FA-deviation-induced measurement error of the pre-contrast R1, contrast-enhancement ratio, Gd-concentration, and two-compartment pharmacokinetic parameters (Ktrans, ve, and vp). Results B1-inhomogeneity resulted in −23–5% fluctuations (95% confidence interval [CI] of % error) of FA. The 95% CIs of FA-dependent % errors in the gray matter and blood were as follows: −16.7–61.8% and −16.7–61.8% for the pre-contrast R1, −1.0–0.3% and −5.2–1.3% for the contrast-enhancement ratio, and −14.2–58.1% and −14.1–57.8% for the Gd-concentration, respectively. These resulted in −43.1–48.4% error for Ktrans, −32.3–48.6% error for the ve, and −43.2–48.6% error for vp. The pre-contrast R1 was more vulnerable to FA error than the contrast-enhancement ratio, and was therefore a significant cause of the Gd-concentration error. For example, a −10% FA error led to a 23.6% deviation in the pre-contrast R1, −0.4% in the contrast-enhancement ratio, and 23.6% in the Gd-concentration. In a simulated condition with a 3% FA error in a target lesion and a −10% FA error in a feeding vessel, the % errors of the pharmacokinetic parameters were −23.7% for Ktrans, −23.7% for ve, and −23.7% for vp. Conclusion Even a small degree of B1-inhomogeneity can cause a significant error in the measurement of pharmacokinetic parameters on DCE-MRI, while the vulnerability of the pre-contrast R1 calculations to FA deviations is a significant cause of the miscalculation.

Spatiotemporal heterogeneity of tumor vasculature during tumor growth and antiangiogenic treatment: MRI assessment using permeability and blood volume parameters

Tumor heterogeneity is an important concept when assessing intratumoral variety in vascular phenotypes and responses to antiangiogenic treatment. This study explored spatiotemporal heterogeneity of vascular alterations in C6 glioma mice during tumor growth and antiangiogenic treatment on serial MR examinations (days 0, 4, and 7 from initiation of vehicle or multireceptor tyrosine kinase inhibitor administration). Transvascular permeability (TP) was quantified on dynamic‐contrast‐enhanced MRI (DCE‐MRI) using extravascular extracellular agent (Gd‐DOTA); blood volume (BV) was estimated using intravascular T2 agent (SPION). With regard to region‐dependent variability in vascular phenotypes, the control group demonstrated higher TP in the tumor center than in the periphery, and greater BV in the tumor periphery than in the center. This distribution pattern became more apparent with tumor growth. Antiangiogenic treatment effect was regionally heterogeneous: in the tumor center, treatment significantly suppressed the increase in TP and decrease in BV (ie, typical temporal change in the control group); in the tumor periphery, treatment‐induced vascular alterations were insignificant and BV remained high. On histopathological examination, the control group showed greater CD31, VEGFR2, Ki67, and NG2 expression in the tumor periphery than in the center. After treatment, CD31 and Ki67 expression was significantly suppressed only in the tumor center, whereas VEGFR2 and α‐caspase 3 expression was decreased and NG2 expression was increased in the entire tumor. These results demonstrate that MRI can reliably depict spatial heterogeneity in tumor vascular phenotypes and antiangiogenic treatment effects. Preserved angiogenic activity (high BV on MRI and high CD31) and proliferation (high Ki67) in the tumor periphery after treatment may provide insights into the mechanism of tumor resistance to antiangiogenic treatment.

Performing Gadoxetic Acid–Enhanced MRI After CT for Guiding Curative Treatment of Early-Stage Hepatocellular Carcinoma: A Cost-Effectiveness Analysis

OBJECTIVEnWe determined the cost-effectiveness of two different diagnostic imaging strategies in guiding curative treatment of early-stage hepatocellular carcinoma (HCC).nnnMATERIALS AND METHODSnWe developed a decision analytic model using as its starting point a cohort of patients aged 55 years with early-stage HCC detected at dynamic multiphasic CT and with Child-Pugh class A cirrhosis. The model compared two strategies on the initial workup: conventional CT strategy using dynamic multiphasic CT only and gadoxetic acid-enhanced MRI strategy using additional gadoxetic acid-enhanced MRI after initial CT. A Markov cohort model simulated a cohort of patients after curative or adjuvant treatment, with follow-up over the remaining life expectancy. We analyzed mean life-years gain, quality-adjusted life-years (QALYs), costs per person, and incremental cost-effectiveness ratio (ICER). To evaluate results, we performed one-way, two-way, and probabilistic sensitivity analyses.nnnRESULTSnThe life expectancies and QALY were 7.22 years and 5.08 for the conventional CT strategy and 7.79 years and 5.52 for the gadoxetic acid-enhanced MRI strategy, respectively. The expected costs were

In vivo 1H MR spectroscopy using 3 Tesla to investigate the metabolic profiles of joint fluids in different types of knee diseases.

99,770 for conventional CT and

Chemical-exchange-saturation-transfer magnetic resonance imaging to map gamma-aminobutyric acid, glutamate, myoinositol, glycine, and asparagine: Phantom experiments

105,025 for gadoxetic acid-enhanced MRI in the United States. The ICER with gadoxetic acid-enhanced MRI was

Preliminary Phantom Experiments to Map Amino Acids and Neurotransmitters Using MRI

11,957, as opposed to that with conventional CT, which was lower than the cost-effectiveness threshold of