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1.  Evaluation of the dependence of CEST-EPI measurement on repetition time, RF irradiation duty cycle and imaging flip angle for enhanced pH sensitivity 
Physics in medicine and biology  2013;58(17):10.1088/0031-9155/58/17/N229.
Chemical exchange saturation transfer (CEST) is an MRI contrast mechanism that can detect dilute CEST agents and microenvironmental properties, with a host of promising applications. Experimental measurement of the CEST effect is complex, and depends on not only CEST agent concentration and exchange rate, but also experimental parameters such as RF irradiation amplitude and scheme. Although echo planar imaging (EPI) has been increasingly used for CEST MRI, the relationship between CEST effect and repetition time (TR), RF irradiation duty cycle (DC) and EPI flip angle (α) has not been fully evaluated and optimized to enhance CEST MRI sensitivity. In addition, our study evaluated gradient echo CEST-EPI by quantifying the CEST effect and its signal-to-noise ratio per unit time (SNRput) as functions of TR, duty cycle and α. We found that CEST effect increased with TR and duty cycle but decreased with α. Importantly, we found that SNRput peaked at intermediate TRs of about twice the T1 and α, at approximately 75°, and increased with RF duty cycle. The simulation results were validated using a dual-pH creatine-gel CEST phantom. In summary, our study provides a useful framework for optimizing CEST MRI experiments.
doi:10.1088/0031-9155/58/17/N229
PMCID: PMC3811139  PMID: 23939228
Chemical Exchange Saturation Transfer (CEST); Magnetic Resonance Imaging (MRI)
2.  Simultaneous determination of labile proton fraction ratio and exchange rate with irradiation radio frequency (RF) power dependent quantitative CEST MRI analysis 
Chemical exchange saturation transfer (CEST) imaging is sensitive to dilute proteins/peptides and microenvironmental properties, and has been increasingly evaluated for molecular imaging and in vivo applications. However, the experimentally measured CEST effect depends on the CEST agent concentration, exchange rate and relaxation time. In addition, there may be non-negligible direct radio-frequency (RF) saturation effects, particularly severe for diamagnetic CEST (DIACEST) agents due to their relatively small chemical shift difference from that of the bulk water resonance. As such, the commonly used asymmetry analysis only provides CEST-weighted information. Recently, it has been shown with numerical simulation that both labile proton concentration and exchange rate can be determined by evaluating the RF power dependence of DIACEST effect. To validate the simulation results, we prepared and imaged two CEST phantoms: a pH phantom of serially titrated pH at a fixed creatine concentration and a concentration phantom of serially varied creatine concentration titrated to the same pH, and solved the labile proton fraction ratio and exchange rate per-pixel. For the concentration phantom, we showed that the labile proton fraction ratio is proportional to the CEST agent concentration with negligible change in the exchange rate. Additionally, we found the exchange rate of the pH phantom is dominantly base-catalyzed with little difference in the labile proton fraction ratio. In summary, our study demonstrated quantitative DIACEST MRI, which remains promising to augment the conventional CEST-weighted MRI analysis.
doi:10.1002/cmmi.1524
PMCID: PMC4034529  PMID: 23606428
amide proton transfer (APT); chemical exchange saturation transfer (CEST); pH
3.  Stratification of heterogeneous diffusion MRI ischemic lesion with kurtosis imaging – Evaluation of mean diffusion and kurtosis MRI mismatch in an animal model of transient focal ischemia 
Background and Purpose
Ischemic tissue damage is heterogeneous, resulting in complex patterns in the widely used diffusion-weighted MRI (DWI). Our study examined the spatiotemporal characteristics of diffusion kurtosis imaging (DKI) in an animal model of transient middle cerebral artery occlusion (MCAO).
Methods
Adult male Wistar rats (N = 18) were subjected to 90min MCAO. Multi-parametric MRI were obtained during MCAO and 20 min after reperfusion, with DWI obtained using eight b-values from 250 to 3000 s/mm2 in six diffusion gradient directions. Diffusion and kurtosis lesions were outlined in shuffled images by two investigators independently. T2 MRI was obtained 24 hr after MCAO to evaluate stroke outcome.
Results
Mean diffusion (MD) lesion (23.5±8.1%, percentage of the brain slice) was significantly larger than mean kurtosis (MK) lesion (13.2±2.0%) during MCAO. MD lesion decreased significantly after reperfusion (13.8±4.3%) while MK lesion showed little change (13.0±2.5%), with their lesion size difference being insignificant.
Conclusions
We demonstrated that MD/MK mismatch recovered reasonably well upon reperfusion while regions with concurrent MD and MK deficits showed poor recovery. DKI may help stratify heterogeneous DWI lesion for enhanced characterization of ischemic tissue injury.
doi:10.1161/STROKEAHA.112.661926
PMCID: PMC3412055  PMID: 22773558
acute ischemia; diffusion; kurtosis
4.  Fast radio-frequency enforced steady state (FRESS) spin echo MRI for quantitative T2 mapping: minimizing the apparent repetition time (TR) dependence for fast T2 measurement 
NMR in biomedicine  2011;25(2):189-194.
Transverse relaxation time (T2) is a basic but very informative MRI parameter, widely used in imaging to examine a host of diseases, including multiple sclerosis, stroke, and tumor. However, short repetition time (TR) is often used to minimize scan time, which may introduce non-negligible errors in T2 measurement. Specifically, due to the use of refocusing pulse, the steady state magnetization depends not only on TR but also on the TE. Hence, if the TE dependence is not properly accounted for, it may be mistaken as T2-induced signal attenuation, leading to non-negligible T2 underestimation. Our study proposed a fast radio-frequency enforced steady state (FRESS) spin echo (SE) MRI sequence, which saturates the magnetization after the echo and ensures a TE-independent steady state. The proposed FRESS-SE MRI was evaluated with numerical simulation, implemented with echo planar imaging readout, and validated by both phantom and in vivo experiments. In summary, FRESS-SE T2 MRI technique was developed for fast and accurate T2 imaging, suitable for in vivo applications.
doi:10.1002/nbm.1729
PMCID: PMC3712835  PMID: 21755552
MRI; spin echo; stroke; T2
5.  Improved measurement of labile proton concentration-weighted chemical exchange rate (kws) with experimental factor-compensated and T1-normalized quantitative chemical exchange saturation transfer (CEST) MRI 
Chemical exchange saturation transfer (CEST) MRI enables measurement of dilute CEST agents and microenvironment properties such as pH and temperature, holding great promise for in vivo applications. However, because of confounding concomitant RF irradiation and relaxation effects, the CEST-weighted MRI contrast may not fully characterize the underlying CEST phenomenon. We postulated that the accuracy of quantitative CEST MRI could be improved if the experimental factors (labeling efficiency and RF spillover effect) were estimated and taken into account. Specifically, the experimental factor was evaluated as a function of exchange rate and CEST agent concentration ratio, which remained relatively constant for intermediate RF irradiation power levels. Hence, the experimental factors can be calculated based on the reasonably estimated exchange rate and labile proton concentration ratio, which significantly improved quantification. The simulation was confirmed with Creatine phantoms of serially varied concentration titrated to the same pH, whose reverse exchange rate (kws) was found to be linearly correlated with the concentration. In summary, the proposed solution provides simplified yet reasonably accurate quantification of the underlying CEST system, which may help guide the ongoing development of quantitative CEST MRI.
doi:10.1002/cmmi.505
PMCID: PMC3415239  PMID: 22649044
Amide proton transfer (APT); Chemical exchange saturation transfer (CEST); MRI
6.  Simplified quantification of labile proton concentration-weighted chemical exchange rate (kws) with RF saturation time dependent ratiometric analysis (QUESTRA) - Normalization of relaxation and RF irradiation spillover effects for improved quantitative chemical exchange saturation transfer (CEST) MRI 
Chemical exchange saturation transfer (CEST) MRI is an emerging imaging technique capable of detecting dilute proteins/peptides and microenvironmental properties, with promising in vivo applications. However, CEST MRI contrast is complex, varying not only with the labile proton concentration and exchange rate, but also with experimental conditions such as field strength and RF irradiation scheme. Furthermore, the optimal RF irradiation power depends on the exchange rate, which must be estimated in order to optimize the CEST MRI experiments. Although methods including numerical fitting with modified Bloch-McConnell equations, quantification of exchange rate with RF saturation time and power (QUEST and QUESP), have been proposed to address this relationship, they require multiple-parameter non-linear fitting and accurate relaxation measurement. Our work here extended the QUEST algorithm with ratiometric analysis (QUESTRA) that normalizes the magnetization transfer ratio (MTR) at labile and reference frequencies, which effectively eliminates the confounding relaxation and RF spillover effects. Specifically, the QUESTRA contrast approaches its steady state mono-exponentially at a rate determined by the reverse exchange rate (kws), with little dependence on bulk water T1, T2, RF power and chemical shift. The proposed algorithm was confirmed numerically, and validated experimentally using a tissue-like phantom of serially titrated pH compartments.
doi:10.1002/mrm.23068
PMCID: PMC3417060  PMID: 21842497
MRI; amide proton transfer (APT); chemical exchange saturation transfer (CEST); quantification of exchange saturation rate with RF saturation time (QUEST); RF irradiation spillover effects
7.  Imaging acute ischemic tissue acidosis with pH-sensitive endogenous amide proton transfer (APT) MRI - Correction of tissue relaxation and concomitant RF irradiation effects toward mapping quantitative cerebral tissue pH 
Neuroimage  2011;60(1):1-6.
Amide proton transfer (APT) MRI is sensitive to ischemic tissue acidosis and has been increasingly used as a research tool to investigate disrupted tissue metabolism during acute stroke. However, magnetization transfer asymmetry (MTRasym) analysis is often used for calculating APT contrast, which only provides pH-weighted images. In addition to pH- dependent APT contrast, in vivo MTRasym is subject to a baseline shift (ΔMTR′asym) attributable to the slightly asymmetric magnetization transfer (MT) effect. Additionally, APT contrast approximately scales with T1 relaxation time. Tissue relaxation time may also affect the experimentally obtainable APT contrast via saturation efficiency and RF spillover effects. In this study, we acquired perfusion, diffusion, relaxation and pH-weighted APT MRI data, and spectroscopy (MRS) in an animal model of acute ischemic stroke. We modeled in vivo MTRasym as a superposition of pH-dependent APT contrast and a baseline shift ΔMTR′asym (i.e., MTRasym=APTR(pH) + ΔMTR′asym), and quantified tissue pH. We found pH of the contralateral normal tissue to be 7.03 ± 0.05 and the ipsilateral ischemic tissue pH was 6.44 ± 0.24, which correlated with tissue perfusion and diffusion rates. In summary, our study established an endogenous and quantitative pH imaging technique for improved characterization of ischemic tissue acidification and metabolism disruption.
doi:10.1016/j.neuroimage.2011.11.091
PMCID: PMC3288866  PMID: 22178815
acute stroke; amide proton transfer (APT); chemical exchange saturation transfer (CEST); MRI; pH; tissue acidosis
8.  Simulation and optimization of pulsed radio frequency (RF) irradiation scheme for chemical exchange saturation transfer (CEST) MRI – demonstration of pH-weighted pulsed-amide proton CEST MRI in an animal model of acute cerebral ischemia 
Chemical exchange saturation transfer (CEST) MRI is capable of measuring dilute labile protons and microenvironment properties; however, the CEST contrast is also dependent upon experimental conditions, particularly, the RF irradiation scheme. Although continuous-wave (CW) RF irradiation has been conventionally utilized, the RF pulse duration or duty cycle are limited on most clinical systems, for which pulsed RF irradiation must be chosen. Here, conventional numerical simulation was extended to describe pulsed-CEST MRI contrast as a function of RF pulse parameters (i.e., RF pulse duration and flip angle) and labile proton properties (i.e., exchange rate and chemical shift). For diamagnetic CEST agents undergoing slow/intermediate chemical exchange, our simulation showed a linear regression relationship between the optimal mean RF power for pulsed-CEST MRI and that of CW-CEST MRI. Worth noting, the optimized pulsed-CEST contrast was approximately equal to that of CW-CEST MRI for exchange rates below 50 s−1, as confirmed experimentally using a multi-compartment pH phantom. Moreover, acute stroke animals were imaged with both pulsed- and CW- amide protons CEST MRI, which showed similar contrast. In summary, our study elucidated the RF irradiation dependence of pulsed-CEST MRI contrast, providing useful insights to guide its experimental optimization and quantification.
doi:10.1002/mrm.22894
PMCID: PMC3135736  PMID: 21437977
amide proton transfer (APT); chemical exchange saturation transfer (CEST); pH; radio frequency (RF); stroke
9.  Simplified and scalable numerical solution for describing multi-pool chemical exchange saturation transfer (CEST) MRI contrast 
Chemical exchange saturation transfer (CEST) imaging is sensitive to dilute labile proton and microenvironment properties such as pH and temperature, and provides vital information complementary to the conventional MRI methods. Whereas the Bloch equations coupled by exchange terms (i.e., Bloch-McConnell equations) have been utilized to quantify 2-pool CEST contrast, it is tedious to extend the Bloch-McConnell equations to describe CEST contrast beyond 4 saturation transfer sites. Hence, it is necessary to develop a scalable yet reasonably accurate numerical solution to describe the complex multi-pool CEST contrast. It is postulated here that the multi-pool CEST contrast can be quantified by modifying the classic 2-pool model. Although the direct exchange among labile proton groups is often negligible, labile protons may be coupled indirectly through their interaction with bulk water protons, which has to be quantified. The coupling term was solved empirically, and the proposed simplified solution was shown in good agreement with the conventional simulation. Moreover, the proposed solution is scalable, and can be easily extended to describe multi-pool CEST contrast. In sum, our study established a simplified and scalable, yet reasonably accurate numerical solution, suitable for quantitatively describing multi-pool CEST contrast.
doi:10.1016/j.jmr.2010.05.004
PMCID: PMC2902598  PMID: 20570196
amide proton transfer (APT); chemical exchange saturation transfer (CEST); numerical solution
10.  Simultaneous determination of labile proton concentration and exchange rate utilizing optimal RF power: radio frequency power (RFP) dependence of chemical exchange saturation transfer (CEST) MRI 
Chemical exchange saturation transfer (CEST) MRI is increasingly used to probe mobile proteins and microenvironment properties, and shows great promise for tumor and stroke diagnosis. However, CEST MRI contrast mechanism is complex, depending not only on the CEST agent concentration, exchange and relaxation properties, but also varying with experimental conditions such as magnetic field strength and RF power. Hence, it remains somewhat difficult to quantify apparent CEST MRI contrast for properties such as pH, temperature and protein content. In particular, CEST MRI is susceptible to RF spillover effects in that RF irradiation may directly saturate the bulk water MR signal, leading to an optimal RF power at which the CEST contrast is maximal. Whereas RF spillover is generally considered an adverse effect, it is noted here that the optimal RF power strongly varies with exchange rate, although with negligible dependence on labile proton concentration. An empirical solution suggested that optimal RF power may serve as a sensitive parameter for simultaneously determining the labile proton content and exchange rate, hence, allowing improved characterization of the CEST system. The empirical solution was confirmed by numerical simulation, and experimental validation is needed to further evaluate the proposed technique.
doi:10.1016/j.jmr.2009.10.012
PMCID: PMC2818407  PMID: 19926319
amide proton transfer (APT); chemical exchange saturation transfer (CEST)
11.  Improved Diffusion Measurement in Heterogeneous Systems Using the Magic Asymmetric Gradient Stimulated Echo (MAGSTE) Technique 
A magic asymmetric gradient stimulated echo (MAGSTE) sequence was recently proposed to improve molecular diffusion measurements in the presence of spatially varying background gradients. Its effectiveness has been demonstrated previously with simulated background gradients and in phantoms that contain bulk susceptibility differences. In this study, we investigated the MAGSTE technique in microscopically heterogeneous systems, and compared it with the conventional bipolar pulsed gradient stimulated echo (bPGSTE) sequence. We demonstrated that the MASGTE measurements, compared to the bPGSTE method, varied significantly less when the diffusion encoding/decoding interval (δ) was changed. In addition, the MAGSTE technique provided good characterization of the surface area-to-volume ratio for heterogeneous systems investigated in this study. In sum, this study showed that the MAGSTE technique provided diffusion measurements superior to those of the bPGSTE sequence, especially in the presence of severe heterogeneous background gradients.
doi:10.1016/j.jmr.2007.04.011
PMCID: PMC2075361  PMID: 17500019
background gradient; bPGSTE; diffusion; inhomogeneity; MAGSTE; porous media; pulsed field gradient
12.  Association between pH-weighted endogenous amide proton chemical exchange saturation transfer MRI and tissue lactic acidosis during acute ischemic stroke 
The ischemic tissue becomes acidic after initiation of anaerobic respiration, which may result in impaired tissue metabolism and, ultimately, in severe tissue damage. Although changes in the major cerebral metabolites can be studied using magnetic resonance (MR) spectroscopy (MRS)-based techniques, their spatiotemporal resolution is often not sufficient for routine examination of fast-evolving and heterogeneous acute stroke lesions. Recently, pH-weighted MR imaging (MRI) has been proposed as a means to assess tissue acidosis by probing the pH-dependent chemical exchange of amide protons from endogenous proteins and peptides. In this study, we characterized acute ischemic tissue damage using localized proton MRS and multiparametric imaging techniques that included perfusion, diffusion, pH, and relaxation MRI. Our study showed that pH-weighted MRI can detect ischemic lesions and strongly correlates with tissue lactate content measured by 1H MRS, indicating lactic acidosis. Our results also confirmed the correlation between apparent diffusion coefficient and lactate; however, no significant relationship was found for perfusion, T1, and T2. In summary, our study showed that optimized endogenous pH-weighted MRI, by sensitizing to local tissue pH, remains a promising tool for providing a surrogate imaging marker of lactic acidosis and altered tissue metabolism, and augments conventional techniques for stroke diagnosis.
doi:10.1038/jcbfm.2011.23
PMCID: PMC3170940  PMID: 21386856
acute stroke; animal studies; brain ischemia; diffusion-weighted MRI; MRI
13.  Fast multi-slice pH-weighted chemical exchange saturation transfer (CEST) MRI with uneven segmented RF irradiation 
Chemical exchange saturation transfer (CEST) MRI is a versatile imaging technique for measuring microenvironment properties via dilute CEST labile groups. Conventionally, CEST MRI is implemented with a long RF irradiation module, followed by fast image acquisition to obtain the steady state CEST contrast. Nevertheless, the sensitivity, scan time and spatial coverage of the conventional CEST MRI method may not optimal. Our study proposed a segmented RF labeling scheme that includes a long primary RF irradiation module to generate the steady state CEST contrast and repetitive short secondary RF irradiation module immediately after the image acquisition so as to maintain the steady state CEST contrast for multi-slice acquisition and signal averaging. The proposed modified CEST MRI method was validated experimentally with a tissue-like pH phantom, and optimized for the maximal contrast-to-noise ratio (CNR). In addition, the proposed sequence was evaluated for imaging ischemic acidosis via pH-weighted endogenous amide proton transfer (APT) MRI, which showed similar contrast as conventional APT MRI. In sum, a fast multi-slice relaxation self-compensated CEST MRI sequence was developed, with significantly improved sensitivity.
doi:10.1002/mrm.22628
PMCID: PMC3145541  PMID: 20872859
acute ischemia; amide proton transfer (APT); chemical exchange saturation transfer (CEST); pH; stroke
14.  Developing a multiscale, multi-resolution agent-based brain tumor model by graphics processing units 
Multiscale agent-based modeling (MABM) has been widely used to simulate Glioblastoma Multiforme (GBM) and its progression. At the intracellular level, the MABM approach employs a system of ordinary differential equations to describe quantitatively specific intracellular molecular pathways that determine phenotypic switches among cells (e.g. from migration to proliferation and vice versa). At the intercellular level, MABM describes cell-cell interactions by a discrete module. At the tissue level, partial differential equations are employed to model the diffusion of chemoattractants, which are the input factors of the intracellular molecular pathway. Moreover, multiscale analysis makes it possible to explore the molecules that play important roles in determining the cellular phenotypic switches that in turn drive the whole GBM expansion. However, owing to limited computational resources, MABM is currently a theoretical biological model that uses relatively coarse grids to simulate a few cancer cells in a small slice of brain cancer tissue. In order to improve this theoretical model to simulate and predict actual GBM cancer progression in real time, a graphics processing unit (GPU)-based parallel computing algorithm was developed and combined with the multi-resolution design to speed up the MABM. The simulated results demonstrated that the GPU-based, multi-resolution and multiscale approach can accelerate the previous MABM around 30-fold with relatively fine grids in a large extracellular matrix. Therefore, the new model has great potential for simulating and predicting real-time GBM progression, if real experimental data are incorporated.
doi:10.1186/1742-4682-8-46
PMCID: PMC3312859  PMID: 22176732
15.  Amide proton transfer imaging of 9L gliosarcoma and human glioblastoma xenografts 
NMR in biomedicine  2008;21(5):489-497.
Amide proton transfer (APT) imaging is a variant of magnetization transfer (MT) imaging, in which the contrast is determined by a change in water intensity due to chemical exchange with saturated amide protons of endogenous mobile proteins and peptides. In this study, eight Fisher 344 rats implanted with 9L gliosarcoma cells and six nude rats implanted with human glioblastoma cells were imaged at 4.7 T. There were increased signal intensities in tumors in the APT-weighted images. The contrast of APT imaging between the tumor and contralateral brain tissue was about 3.9% in water intensity (1.49% ± 0.66% versus −2.36% ± 0.19%) for the more uniformly hypercellular 9L brain tumors, and it was reduced to 1.6% (−1.18% ± 0.60% versus −2.77% ± 0.42%) for the human glioblastoma xenografts that contained hypocellular zones of necrosis. The preliminary results show that the APT technique at the protein level may provide a unique MRI contrast for the characterization of brain tumors.
doi:10.1002/nbm.1216
PMCID: PMC2943209  PMID: 17924591
magnetization transfer; amide proton transfer; APT imaging; protein; brain tumor; 9L gliosarcoma

Results 1-15 (15)