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PURPOSE: A non-invasive magnetization transfer indirect spin labeling (MISL) MRI method is developed to quantify the water exchange between cerebrospinal fluid (CSF) and other tissues in the brain and to examine the age-dependence of water exchange. METHOD: In the pulsed MISL, we implemented a short selective pulse followed by a post-labeling delay before an MRI acquisition with a long echo time; in the continuous MISL, a train of saturation pulses was applied. MISL signal (ΔZ) was obtained by the subtraction of the label MRI at −3.5 ppm from the control MRI at 200 ppm. CSF was extracted from the mouse ventricles for the MISL optimization and validation. Comparison between wild-type (WT) and aquaporin-4 knockout (AQP4(−/−)) mice was performed to examine the contributions of CSF water exchange, while its age-dependence was investigated by comparing the adult and young WT mice. RESULTS: The pulsed MISL method observed that the MISL signal reached the maximum at 1.5 s. The continuous MISL method showed the highest MISL signal in the fourth ventricle (ΔZ =13.5±1.4%), while the third ventricle and the lateral ventricles had similar MISL ΔZ values (ΔZ =12.0±1.8 %). Additionally, significantly lower ΔZ (9.3–18.7% reduction) was found in all ventricles for the adult mice than those of the young mice (p

PURPOSE To optimize and apply deep neural network based CEST (deepCEST) and apparent exchange dependent-relaxation (deepAREX) for imaging the mouse brain with Alzheimer's disease (AD) at 3T MRI. METHODS CEST and T1 data of central and anterior brain slices of 10 AD mice and 10 age-matched wild type (WT) mice were acquired at a 3T animal MRI scanner. The networks of deepCEST/deepAREX were optimized and trained on the WT data. The CEST/AREX contrasts of AD and WT mice predicted by the networks were analyzed and further validated by immunohistochemistry. RESULTS After optimization and training on CEST data of WT mice, deepCEST/deepAREX could rapidly (~1 s) generate precise CEST and AREX results for unseen CEST data of AD mice, indicating the accuracy and generalization of the networks. Significant lower amide weighted (3.5 ppm) signal related to amyloid β-peptide (Aβ) plaque depositions, which was validated by immunohistochemistry results, was detected in both central and anterior brain slices of AD mice compared to WT mice. Decreased magnetization transfer (MT) signal was also found in AD mice especially in the anterior slice. CONCLUSION DeepCEST/deepAREX could rapidly generate accurate CEST/AREX contrasts in animal study. The well-optimized deepCEST/deepAREX have potential for AD differentiation at 3T MRI.

To extract guanidinium (Guan) and amide CEST on the human brain at 3 T MRI with the high spectral resolution (HSR) CEST combined with the polynomial Lorentzian line-shape fitting (PLOF).Continuous wave (cw) turbo spin-echo (TSE) CEST was implemented to obtain the optimum saturation parameters. Both Guan and amide CEST peaks were extracted and quantified using the PLOF method. The NMR spectra on the egg white phantoms were acquired to reveal the fitting range and the contributions to the amide and GuanCEST. Two types of CEST approaches, including cw gradient- and spin-echo (cwGRASE) and steady state EPI (ssEPI), were implemented to acquire multi-slice HSR-CEST.GuanCEST can be extracted with the PLOF method at 3 T, and the optimummml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"mml:semanticsmml:mrowmml:msubmml:miB/mml:mimml:mn1/mml:mn/mml:msubmml:mo=/mml:momml:mn0.6/mml:mnmml:mspace/mml:miμ/mml:mimml:miT/mml:mi/mml:mrowmml:annotation$$ {\mathrm{B}}_1=0.6\kern0.2em \upmu \mathrm{T} $$/mml:annotation/mml:semantics/mml:mathwas determined for GuanCEST in white matter (WM) and 1.0 μT in gray matter (GM). The optimum Bsub1/sub = 0.8-1 μT was found for amideCEST. AmideCEST is lower in both WM and GM collected with ssEPI compared to those by cwGRASE (ssEPI = [1.27-1.63]%; cwGRASE = [2.19-2.25]%). The coefficients of variation (COV) of the amide and Guan CEST in both WM and GM for ssEPI (COV: 28.6-33.4%) are significantly higher than those of cwGRASE (COV: 8.6-18.8%). Completely different WM/GM contrasts for Guan and amide CEST were observed between ssEPI and cwGRASE. The amideCEST was found to have originated from the unstructured amide protons as suggested by the NMR spectrum of the unfolded proteins in egg white.Guan and amide CEST mapping can be achieved by the HSR-CEST at 3 T combing with the PLOF method.

To develop a quantitative MRI method to estimate cerebrovascular reactivity (CVR) in mice.We described an MRI procedure to measure cerebral vasodilatory response to acetazolamide (ACZ), a vasoactive agent previously used in human clinical imaging. Vascular response was determined by cerebral blood flow (CBF) measured with phase-contrast or pseudo-continuous arterial spin labeling MRI. Vasodilatory input intensity was determined by plasma ACZ level using high-performance liquid chromatography. We verified the source of the CVR MRI signal by comparing ACZ injection to phosphate-buffered saline injection and noninjection experiments. Dose dependence and feasibility of regional CVR measurement were also investigated.Cerebral blood flow revealed an exponential increase following intravenous ACZ injection, with a time constant of 1.62 min. In contrast, phosphate-buffered saline or noninjection exhibited a slow linear CBF increase, consistent with a gradual accumulation of anesthetic agent, isoflurane, used in this study. When comparing different ACZ doses, injections of 30, 60, 120, and 180 mg/kg yielded a linear increase in plasma ACZ concentration (p 0.0001). On the other hand, CBF changes under these doses were not different from each other (p = 0.50). The pseudo-continuous arterial spin labeling MRI with multiple postlabeling delays revealed similar vascular responses at different postlabeling delay values. There was a regional difference in CVR (p = 0.005), with isocortex (0.81 ± 0.17%/[μg/ml]) showing higher CVR than deep-brain regions. Mice receiving multiple ACZ injections lived for a minimum of 6 months after the study without noticeable aberrant behavior or appearance.We demonstrated the proof-of-principle of a new quantitative CVR mapping technique in mice.

PURPOSE: Chemical exchange saturation transfer (CEST) MRI experiments of mobile macromolecules, e.g. proteins, carbohydrates and phospholipids, often show signals due to saturation transfer from aliphatic protons to water. Currently, the mechanism of this nuclear Overhauser effect (NOE) based transfer pathway is not completely understood and could be due either to NOEs directly to bound water or NOEs relayed intramolecularly via exchangeable protons. We used glycogen as a model system to investigate this saturation transfer pathway in sugar polymer solution. THEORY AND METHODS: To determine whether proton exchange affected saturation transfer, saturation spectra (Z-spectra) were measured for glycogen solutions of different pH, D(2)O/H(2)O ratio, and glycogen particle size. A theoretical model was derived to analytically describe the NOE-based signals in these spectra. Numerical simulations were performed to verify this theory, which was further tested by fitting experimental data for different exchange regimes. RESULTS: Signal intensities of aliphatic NOEs in Z-spectra of glycogen (glycoNOEs) in D(2)O solution were influenced by hydroxyl proton exchange rates, while those in H(2)O were not. This indicates that the primary transfer pathway is an exchange-relayed NOE (rNOE) from these aliphatic protons to neighboring hydroxyl protons, followed by the exchange to water protons. Experimental data for glycogen solutions in D(2)O and H(2)O could be analyzed successfully using an analytical theory derived for such rNOE transfer, which was further validated using numerical simulations with the Bloch equations. CONCLUSIONS: The predominant mechanism underlying aliphatic signals in Z-spectra of mobile carbohydrate polymers is intramolecular relayed NOE (rNOE) transfer followed by proton exchange.

Purpose To develop a pulsed CEST magnetization-transfer method for rapidly acquiring relayed nuclear Overhauser enhancement (rNOE)-weighted images with magnetic transfer contrast (MTC) suppression at clinical field strength (3 T). Methods Using a pulsed CEST magnetization-transfer method with low saturation powers (B1 ) and long mixing time (tmix ) to suppress contributions due to strong MTC from solid-like macromolecules, a low B1 also minimized direct water saturation. These MTC contributions were further reduced by subtracting the Z-spectral signals at two or three offsets by assuming that the residual MTC is a linear function between -3.5 ppm and -12.5 ppm. Results Phantom studies of a lactic acid (Lac) solution mixed with cross-linked bovine serum albumin show that strong MTC interference has a significant impact on the optimum B1 for detecting rNOEs, due to lactate binding. The MTC could be effectively suppressed using a pulse train with a B1 of 0.8 μT, a pulse duration (tp ) of 40 ms, a tmix of 60 ms, and a pulse number (N) of 30, while rNOE signal was well maintained. As a proof of concept, we applied the method in mouse brain with injected hydrogel and a cell-hydrogel phantom. Results showed that rNOE-weighted images could provide good contrast between brain/cell and hydrogel. Conclusion The developed pulsed CEST magnetization-transfer method can achieve MTC suppression while preserving most of the rNOE signal at 3 T, which indicates the potential for translation of this technique to clinical applications related to mobile proteins/lipids change.

Saturation transfer MRI has previously been used to probe molecular binding interactions with signal enhancement via the water signal. Here, we detail the relayed nuclear overhauser effect (rNOE) based mechanisms of this signal enhancement, develop a strategy of quantifying molecular binding affinity, i.e., the dissociation constant (The signal enhancement mechanism was quantitatively described by a three-step magnetization transfer model, and numerical simulations were performed to verify this theory. The binding equilibria of arginine, choline, and acetyl-choline to anionic resin were studied as a function of ligand concentration, pH, and salt content. Equilibrium dissociation constants (The numerical simulations indicate that the signal enhancement is sufficient to detect the molecular binding of sub-millimolar (∼100 μM) concentration ligands to low micromolar levels of molecular targets. The measured rNOE signals from arginine, choline, and acetyl-choline binding experiments show that several magnetization transfer pathways (intra-ligand rNOEs and intermolecular rNOEs) can contribute. The rNOEs that arise from molecular ionic binding were influenced by pH and salt concentration. The molecular binding strengths in terms ofThe capability to use MRI to detect the transient binding of small substrates paves a pathway towards the detection of micromolar level receptor-substrate binding in vivo.

PURPOSE: Vascular disrupting therapy of cancer has become a promising approach not only to regress tumor growth directly but also to boost the delivery of chemotherapeutics in the tumor. An imaging approach to monitor the changes in tumor vascular permeability, therefore, has important applications for monitoring of vascular disrupting therapies. METHODS: Mice bearing CT26 subcutaneous colon tumors were injected intravenously with 150 kD dextran (Dex150, diameter, d~ 20 nm, 375 mg/kg), tumor necrosis factor-alpha (TNF-α; 1 μg per mouse), or both (n = 3 in each group). The Z-spectra were acquired before and 2 h after the injection, and the chemical exchange saturation transfer (CEST) signals in the tumors as quantified by asymmetric magnetization transfer ratio (MTR(asym)) at 1 ppm were compared. RESULTS: The results showed a significantly stronger CEST contrast enhancement at 1 ppm (ΔMTR(asym) = 0.042 ± 0.002) in the TNF-α-treated tumors than those by Dex150 alone (ΔMTR(asym) = 0.000 ± 0.005, P = 0.0229) or TNF-α alone (ΔMTR(asym) = 0.002 ± 0.004, P = 0.0264), indicating that the TNF-α treatment strongly augmented the tumor uptake of 150 kD dextran. The MRI findings were verified by fluorescence imaging and immunofluorescence microscopy. CONCLUSIONS: High molecular weight dextrans can be used as safe and sensitive CEST MRI contrast agents for monitoring tumor response to vascular disrupting therapy and, potentially, for developing dextran-based theranostic drug delivery systems.

Purpose: The mammalian target of rapamycin is an enzyme that regulates cell metabolism and proliferation. It is up-regulated in aggressive tumors, such as glioblastoma, leading to increased glucose uptake and consumption. It has been suggested that glucose CEST signals reflect the delivery and tumor uptake of glucose. The inhibitor rapamycin (sirolimus) has been applied as a glucose deprivation treatment; thus, glucose CEST MRI could potentially be useful for monitoring the tumor responses to inhibitor treatment. Methods: A human U87-EGFRvIII xenograft model in mice was studied. The mice were treated with a mammalian target of Rapamycin inhibitor, rapamycin. The effect of the treatment was evaluated in vivo with dynamic glucose CEST MRI. Results: Rapamycin treatment led to significant increases (P < 0.001) in dynamic glucose-enhanced signal in both the tumor and contralateral brain as compared to the no-treatment group, namely a maximum enhancement of 3.7% ± 2.3% (tumor, treatment) versus 1.9% ± 0.4% (tumor, no-treatment), 1.7% ± 1.1% (contralateral, treatment), and 1.0% ± 0.4% (contralateral, no treatment). Dynamic glucose-enhanced contrast remained consistently higher in treatment versus no-treatment groups for the duration of the experiment (17 min). This was confirmed with area-under-curve analysis. Conclusion: Increased glucose CEST signal was found after mammalian target of Rapamycin inhibition treatment, indicating potential for dynamic glucose-enhanced MRI to study tumor response to glucose deprivation treatment. (Less)

PURPOSE: The circulation of cerebrospinal fluid (CSF) is closely associated with many aspects of brain physiology. When gadolinium(Gd)-based contrast is administered intravenously, pre- and post-contrast MR signal changes can often be observed in the CSF at certain locations within the intra-cranial space, mainly due to the lack of a blood-brain barrier in the dural blood vessels. This study aims to develop and systemically optimize MRI sequences that can detect dynamic signal changes in the CSF after Gd administration with a sub-millimeter spatial resolution, a temporal resolution of

Purpose 3-O-Methyl-D-glucose (3-OMG) is a nonmetabolizable structural analog of glucose that offers potential to be used as a CEST-contrast agent for tumor detection. Here, we explore it for CEST-detection of malignant brain tumors and compare it with D-glucose. Methods Glioma xenografts of a U87-MG cell line were implanted in five mice. Dynamic 3-OMG weighted images were collected using CEST-MRI at 11.7 T at a single offset of 1.2 ppm, showing the effect of accumulation of the contrast agent in the tumor, following an intravenous injection of 3-OMG (3 g/kg). Results Tumor regions showed higher enhancement as compared to contralateral brain. The CEST contrast enhancement in the tumor region ranged from 2.5-5.0%, while it was 1.5-3.5% in contralateral brain. Previous D-glucose studies of the same tumor model showed an enhancement of 1.5-3.0% and 0.5-1.5% in tumor and contralateral brain, respectively. The signal gradually stabilized to a value that persisted for the length of the scan. Conclusions 3-OMG shows a CEST contrast enhancement that is approximately twice as much as that of D-glucose for a similar tumor line. In view of its suggested low toxicity and transport properties across the BBB, 3-OMG provides an option to be used as a nonmetallic contrast agent for evaluating brain tumors.

Chemical exchange saturation transfer (CEST), arterial spin labeling (ASL), and magnetization transfer contrast (MTC) methods generate different contrasts for MRI. However, they share many similarities in terms of pulse sequences and mechanistic principles. They all use RF pulse preparation schemes to label the longitudinal magnetization of certain proton pools and follow the delivery and transfer of this magnetic label to a water proton pool in a tissue region of interest, where it accumulates and can be detected using any imaging sequence. Due to the versatility of MRI, differences in spectral, spatial or motional selectivity of these schemes can be exploited to achieve pool specificity, such as for arterial water protons in ASL, protons on solute molecules in CEST, and protons on semi-solid cell structures in MTC. Timing of these sequences can be used to optimize for the rate of a particular delivery and/or exchange transfer process, for instance, between different tissue compartments (ASL) or between tissue molecules (CEST/MTC). In this review, magnetic labeling strategies for ASL and the corresponding CEST and MTC pulse sequences are compared, including continuous labeling, single-pulse labeling, and multi-pulse labeling. Insight into the similarities and differences among these techniques is important not only to comprehend the mechanisms and confounds of the contrasts they generate, but also to stimulate the development of new MRI techniques to improve these contrasts or to reduce their interference. This, in turn, should benefit many possible applications in the fields of physiological and molecular imaging and spectroscopy.

PURPOSE To develop a non-contrast-agent MRI technique to quantify cerebral venous T2 in mice. METHODS We implemented and optimized a T2 -relaxation-under-spin-tagging (TRUST) sequence on an 11.7 Tesla animal imaging system. A flow-sensitive-alternating-inversion-recovery (FAIR) module was used to generate control and label images, pair-wise subtraction of which yielded blood signals. Then, a T2 -preparation module was applied to produce T2 -weighted images, from which blood T2 was quantified. We conducted a series of technical studies to optimize the imaging slice position, inversion slab thickness, post-labeling delay (PLD), and repetition time. We also performed three physiological studies to examine the venous T2 dependence on hyperoxia (N = 4), anesthesia (N = 3), and brain aging (N = 5). RESULTS Our technical studies suggested that, for efficient data acquisition with minimal bias in estimated T2 , a preferred TRUST protocol was to place the imaging slice at the confluence of sagittal sinuses with an inversion-slab thickness of 2.5-mm, a PLD of 1000 ms and a repetition time of 3.5 s. Venous T2 values under normoxia and hyperoxia (inhaling pure oxygen) were 26.9 ± 1.7 and 32.3 ± 2.2 ms, respectively. Moreover, standard isoflurane anesthesia resulted in a higher venous T2 compared with dexmedetomidine anesthesia (N = 3; P = 0.01) which is more commonly used in animal functional MRI studies to preserve brain function. Venous T2 exhibited a decrease with age (N = 5; P

Purpose To investigate the use of natural dextrans as nano-sized chemical exchange saturation transfer (CEST) MRI probes for characterizing size-dependent tumor vascular permeability. Methods Dextrans of different molecular weight (10, 70, 150, and 2000 kD) were characterized for their CEST contrast. Mice (N = 5) bearing CT26 subcutaneous colon tumors were injected intravenously with 10 kD (D10, 6 nm) and 70 kD (D70, 12 nm) dextran at a dose of 375 mg/kg. The CEST-MRI signal in the tumors was assessed before and approximately 40 min after each injection using a dynamic CEST imaging scheme. Results All dextrans of different molecular weights have a strong CEST signal with an apparent maximum of approximately 0.9 ppm. The detectability and effects of pH and saturation conditions (B1 and Tsat ) were investigated. When applied to CT26 tumors, the injection of D10 could produce a significant "dexCEST" enhancement in the majority of the tumor area, whereas the injection of D70 only resulted in an increase in the tumor periphery. Quantitative analysis revealed the differential permeability of CT26 tumors to different size particles, which was validated by fluorescence imaging and immunohistochemistry. Conclusions As a first application, we used 10- and 70-kD dextrans to visualize the spatially variable, size-dependent permeability in the tumor, indicating that nano-sized dextrans can be used for characterizing tumor vascular permeability with dexCEST MRI and, potentially, for developing dextran-based theranostic drug delivery systems. Magn Reson Med 79:1001-1009, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Purpose To optimize phase-contrast (PC) MRI for the measurement of global cerebral blood flow (CBF) in the mouse at 11.7T. Methods We determined proper velocity encoding (VENC) for internal carotid arteries (ICAs) and vertebral arteries (VAs). Next, we optimized spatial resolution of the sequence. To shorten scan time without compromising data quality, we further optimized repetition time and developed a reduced field-of-view (FOV) scheme for ICA and VA PC MRI. Whole-brain volume was determined with T2 -weighted image to obtain unit-volume CBF. Results Peak flow velocities were 13.8 ± 1.7, 14.4 ± 0.6, 6.5 ± 1.7, and 6.7 ± 1.3 cm/s for left ICA, right ICA, left VA, and right VA, respectively. Thus, VENC values of 20 and 10 cm/s were chosen for ICA and VA PC MRI, respectively. An in-plane spatial resolution of 50 × 50 μm2 was found to provide a reasonable trade-off between reducing partial-volume effects and maintaining signal-to-noise ratio. Because of the fact that saturated spins in the imaging slice are rapidly replaced by fresh spins, TR of the sequence can be decreased to as short as 15 ms without reducing signal intensity, thereby substantially lowering scan time. Moreover, reduced FOV along the phase-encoding direction was able to shorten scan time by 33.3% while maintaining measurement accuracy. With these optimizations, it took 96 seconds to evaluate CBF with a test-retest variability of approximately 5% and an inter-rater correlation of >0.95. Global unit-volume CBF was found to be 279.5 ± 11.1 mL of blood/100 ml of tissue/min. Conclusion We have optimized PC MRI for noninvasive quantification of blood flow in mice at 11.7T.

PURPOSE: To obtain high-resolution creatine (Cr) and phosphocreatine (PCr) maps of mouse skeletal muscle using a Polynomial and Lorentzian Line-shape Fitting (PLOF) CEST method. METHODS: Wild type (WT) mice and Guanidinoacetate N-Methyltransferase deficient (GAMT−/−) mice that have low Cr and PCr concentrations in muscle were used to assign the Cr and PCr peaks in the Z-spectrum at 11.7 T. A PLOF method was proposed to simultaneously extract and quantify the Cr and PCr by assuming a polynomial function for the background and two Lorentzian functions for the CEST peaks at 1.95 ppm and 2.5 ppm. RESULTS: The Z-spectra of phantoms revealed that PCr has two CEST peaks (2 ppm and 2.5 ppm), while Cr only showed one peak at 2 ppm. Comparison of the Z-spectra of WT and GAMT−/− mice indicated that, contrary to brain, there was no visible protein guanidinium peak in the skeletal muscle Z-spectrum, which allowed us to extract clean PCr and Cr CEST signals. High-resolution PCr and Cr concentration maps of mouse skeletal muscle were obtained by the PLOF CEST method after calibration with in vivo MRS. CONCLUSIONS: he PLOF method provides an efficient way to map Cr and PCr concentrations simultaneously in the skeletal muscle at high MRI field.

Purpose To use the variable delay multipulse (VDMP) chemical exchange saturation transfer (CEST) approach to obtain clean amide proton transfer (APT) and relayed Nuclear Overhauser enhancement (rNOE) CEST images in the human brain by suppressing the conventional magnetization transfer contrast (MTC) and reducing the direct water saturation contribution. Methods The VDMP CEST scheme consists of a train of RF pulses with a specific mixing time. The CEST signal with respect to the mixing time shows distinguishable characteristics for protons with different exchange rates. Exchange rate filtered CEST images are generated by subtracting images acquired at two mixing times at which the MTC signals are equal, while the APT and rNOE-CEST signals differ. Because the subtraction is performed at the same frequency offset for each voxel and the CEST signals are broad, no B0 correction is needed. Results MTC-suppressed APT and rNOE-CEST images of human brain were obtained using the VDMP method. The APT-CEST data show hyperintensity in gray matter versus white matter, whereas the rNOE-CEST images show negligible contrast between gray and white matter. Conclusion The VDMP approach provides a simple and rapid way of recording MTC-suppressed APT-CEST and rNOE-CEST images without the need for B0 field correction. Magn Reson Med 75:88–96, 2016. © 2015 Wiley Periodicals, Inc.

Recently, natural d-glucose was suggested as a potential biodegradable contrast agent. The feasibility of using d-glucose for dynamic perfusion imaging was explored to detect malignant brain tumors based on blood brain barrier breakdown.

Purpose: A steady pulsed imaging and labeling (SPIL) scheme is proposed to obtain high-resolution multislice perfusion images of mice brain using standard preclinical MRI equipment. Theory and Methods: The SPIL scheme repeats a pulsed arterial spin labeling (PASL) module together with a short mixing time to extend the temporal duration of the generated PASL bolus to the total experimental time. Multislice image acquisition takes place during the mixing times. The mixing time is also used for magnetization recovery following image acquisition. The new scheme is able to yield multislice perfusion images rapidly. The perfusion kinetic curve can be measured by a multipulsed imaging and labeling (MPIL) scheme, i.e., acquiring single-slice ASL signals before reaching steady-state in the SPIL sequence. Results: When applying the SPIL method to normal mice, and to mice with unilateral ischemia, high-resolution multislice (five slices) CBF images could be obtained in 8 min. Perfusion data from ischemic mice showed clear CBF reductions in ischemic regions. The SPIL method was also applied to postmortem mice, showing that the method is free from magnetization transfer confounds. Conclusion: The new SPIL scheme provides for robust measurement of CBF with multislice imaging capability in small animals. Magn Reson Med, 2015. © 2015 Wiley Periodicals, Inc.

PURPOSE: To develop a non-contrast-agent MRI technique to quantify cerebral venous T(2) in mice. METHODS: We implemented and optimized a T(2)-Relaxation-Under-Spin-Tagging (TRUST) sequence on an 11.7 Tesla animal imaging system. A flow-sensitive-alternating-inversion-recovery (FAIR) module was used to generate control and label images, pair-wise subtraction of which yielded blood signals. Then, a T(2)-preparation module was applied to produce T(2)-weighted images, from which blood T(2) was quantified. We conducted a series of technical studies to optimize the imaging slice position, inversion slab thickness, post-labeling delay, and repetition time. We also performed three physiological studies to examine the venous T(2) dependence on hyperoxia (N=4), anesthesia (N=3), and brain aging (N=5). RESULTS: Our technical studies suggested that, for efficient data acquisition with minimal bias in estimated T(2), a preferred TRUST protocol was to place the imaging slice at the confluence of sagittal sinuses with an inversion-slab thickness of 2.5mm, a post-labeling delay of 1000ms and a TR of 3.5s. Venous T(2) values under normoxia and hyperoxia (inhaling pure oxygen) were 26.9±1.7 and 32.3±2.2 ms, respectively. Moreover, standard isoflurane anesthesia resulted in a higher venous T(2) compared to dexmedetomidine anesthesia (N=3, p=0.01) which is more commonly used in animal fMRI studies to preserve brain function. Venous T(2) exhibited a decrease with age (N=5, p

Purpose The aim of this study was to develop a technique for rapid collection of chemical exchange saturation transfer images with the saturation varied to modulate signal loss transfer and enhance contrast. Methods Multi-echo Length and Offset VARied Saturation (MeLOVARS) divides the saturation pulse of length Tsat into N = 3–8 submodules, each consisting of a saturation pulse with length of Tsat/N (∼0.3–1 s), one or more low flip-angle gradient-echo readout(s) and a flip back pulse. This results in N readouts with increasing saturation time from Tsat/N to Tsat without extra scan time. Results For phantoms, eight images with Tsat incremented every 0.5 s from 0.5–4 s were collected simultaneously using MeLOVARS, which allows rapid determination of exchange rates for agent protons. For live mice bearing glioblastomas, the Z-spectra for five different Tsat values from 0.5 to 2.5 s were acquired in a time normally used for one Tsat. With the additional Tsat-dependence information, LOVARS phase maps were produced with a more clearly defined tumor boundary and an estimated 4.3-fold enhanced contrast-to-noise ratio (CNR). We also show that enhancing CNR is achievable by simply averaging the collected images or transforming them using the principal component analysis. Conclusions MeLOVARS enables collection of multiple saturation-time-weighted images without extra time, producing a LOVARS phase map with increased CNR. Magn Reson Med 73:488–496, 2015. © 2014 Wiley Periodicals, Inc.

Purpose Demonstrate applicability of natural D-glucose as a T2 MRI contrast agent. Methods D-glucose solutions were prepared at multiple concentrations and variable pH. The relaxation rate (R2 = 1/T2) was measured at 3, 7, and 11.7 T. Additional experiments were performed on blood at 11.7 T. Also, a mouse was infused with D-glucose (3.0 mmol/kg) and dynamic T2 weighted images of the abdomen acquired. Results The transverse relaxation rate depended strongly on glucose concentration and solution pH. A maximum change in R2 was observed around physiological pH (pH 6.8-7.8). The transverse relaxivities at 22°C (pH 7.3) were 0.021, 0.060, and 0.077 s−1mM−1 at 3.0, 7.0, and 11.7 T, respectively. These values showed good agreement with expected values from the Swift-Connick equation. There was no significant dependence on glucose concentration or pH for T1 and the diffusion coefficient for these solutions. The transverse relaxivity in blood at 11.7 T was 0.09 s−1mM−1. The dynamic in vivo experiment showed a 10% drop in signal intensity after glucose infusion followed by recovery of the signal intensity after about 50–100 s. Conclusion Glucose can be used as a T2 contrast agent for MRI at concentrations that are already approved for human use. Magn Reson Med 72:823–828, 2014. © 2014 Wiley Periodicals, Inc.

Purpose Chemical exchange saturation transfer (CEST) imaging is a new MRI technology allowing the detection of low concentration endogenous cellular proteins and metabolites indirectly through their exchangeable protons. A new technique, variable delay multi-pulse CEST (VDMP-CEST), is proposed to eliminate the need for recording full Z-spectra and performing asymmetry analysis to obtain CEST contrast. Methods The VDMP-CEST scheme involves acquiring images with two (or more) delays between radiofrequency saturation pulses in pulsed CEST, producing a series of CEST images sensitive to the speed of saturation transfer. Subtracting two images or fitting a time series produces CEST and relayed-nuclear Overhauser enhancement CEST maps without effects of direct water saturation and, when using low radiofrequency power, minimal magnetization transfer contrast interference. Results When applied to several model systems (bovine serum albumin, crosslinked bovine serum albumin, l-glutamic acid) and in vivo on healthy rat brain, VDMP-CEST showed sensitivity to slow to intermediate range magnetization transfer processes (rate < 100–150 Hz), such as amide proton transfer and relayed nuclear Overhauser enhancement-CEST. Images for these contrasts could be acquired in short scan times by using a single radiofrequency frequency. Conclusions VDMP-CEST provides an approach to detect CEST effect by sensitizing saturation experiments to slower exchange processes without interference of direct water saturation and without need to acquire Z-spectra and perform asymmetry analysis. Magn Reson Med 71:1798–1812, 2014. © 2013 Wiley Periodicals, Inc.

Purpose To image endogenous exchangeable proton signals in the human brain using a recently reported method called frequency labeled exchange transfer (FLEX) MRI. Methods As opposed to labeling exchangeable protons using saturation (i.e., chemical exchange saturation transfer, or CEST), FLEX labels exchangeable protons with their chemical shift evolution. The use of short high-power frequency pulses allows more efficient labeling of rapidly exchanging protons, while time domain acquisition allows removal of contamination from semi-solid magnetization transfer effects. Results FLEX-based exchangeable proton signals were detected in human brain over the 1–5 ppm frequency range from water. Conventional magnetization transfer contrast and the bulk water signal did not interfere in the FLEX spectrum. The information content of these signals differed from in vivo CEST data in that the average exchange rate of these signals was 350–400 s−1, much faster than the amide signal usually detected using direct saturation (∼30 s−1). Similarly, fast exchanging protons could be detected in egg white in the same frequency range where amide and amine protons of mobile proteins and peptides are known to resonate. Conclusions FLEX MRI in the human brain preferentially detects more rapidly exchanging amide/amine protons compared to traditional CEST experiments, thereby changing the information content of the exchangeable proton spectrum. This has the potential to open up different types of endogenous applications as well as more easy detection of rapidly exchanging protons in diaCEST agents or fast exchanging units such as water molecules in paracest agents without interference of conventional magnetization transfer contrast. Magn Reson Med 69:966–973, 2013. © 2013 Wiley Periodicals, Inc.

Frequency-labeled exchange transfer is a promising MRI technique for labeling and detecting exchanging protons of low-concentration solutes through the water signal. Early frequency-labeled exchange studies have used off-resonance excitation-based labeling schemes that are well suited to study rapidly exchanging protons or molecules far from the water resonance (e.g., water in paramagnetic contrast agents) or slowly exchanging protons close to the water resonance (e.g., some amide protons). However, off-resonance labeling is not efficient for rapidly exchanging protons close to water. Here, we show that a new frequency-labeled exchange labeling scheme with excitation pulses applied on the water resonance gives much higher exchange contrast for rapidly exchanging protons resonating close to the water resonance frequency. This labeling scheme is particularly suited for studying rapidly exchanging hydroxyl, amine, and imino protons in diamagnetic chemical exchange saturation transfer agents.

Recently, natural d-glucose was suggested as a potential biodegradable contrast agent. The feasibility of using d-glucose for dynamic perfusion imaging was explored to detect malignant brain tumors based on blood brain barrier breakdown.Mice were inoculated orthotopically with human U87-EGFRvIII glioma cells. Time-resolved glucose signal changes were detected using chemical exchange saturation transfer (glucoCEST) MRI. Dynamic glucose enhanced (DGE) MRI was used to measure tissue response to an intravenous bolus of d-glucose.DGE images of mouse brains bearing human glioma showed two times higher and persistent changes in tumor compared with contralateral brain. Area-under-curve (AUC) analysis of DGE delineated blood vessels and tumor and had contrast comparable to the AUC determined using dynamic contrast enhanced (DCE) MRI with GdDTPA, both showing a significantly higher AUC in tumor than in brain (P 0.005). Both CEST and relaxation effects contribute to the signal change.DGE MRI is a feasible technique for studying brain tumor enhancement reflecting differences in tumor blood volume and permeability with respect to normal brain. We expect DGE will provide a low-risk and less expensive alternative to DCE MRI for imaging cancer in vulnerable populations, such as children and patients with renal impairment.

Demonstrate applicability of natural D-glucose as a T2 MRI contrast agent.D-glucose solutions were prepared at multiple concentrations and variable pH. The relaxation rate (R2 = 1/T2 ) was measured at 3, 7, and 11.7 T. Additional experiments were performed on blood at 11.7 T. Also, a mouse was infused with D-glucose (3.0 mmol/kg) and dynamic T2 weighted images of the abdomen acquired.The transverse relaxation rate depended strongly on glucose concentration and solution pH. A maximum change in R2 was observed around physiological pH (pH 6.8-7.8). The transverse relaxivities at 22°C (pH 7.3) were 0.021, 0.060, and 0.077 s(-1) mM(-1) at 3.0, 7.0, and 11.7 T, respectively. These values showed good agreement with expected values from the Swift-Connick equation. There was no significant dependence on glucose concentration or pH for T1 and the diffusion coefficient for these solutions. The transverse relaxivity in blood at 11.7 T was 0.09 s(-1) mM(-1) . The dynamic in vivo experiment showed a 10% drop in signal intensity after glucose infusion followed by recovery of the signal intensity after about 50-100 s.Glucose can be used as a T2 contrast agent for MRI at concentrations that are already approved for human use.

Frequency-labeled exchange transfer is a promising MRI technique for labeling and detecting exchanging protons of low-concentration solutes through the water signal. Early frequency-labeled exchange studies have used off-resonance excitation-based labeling schemes that are well suited to study rapidly exchanging protons or molecules far from the water resonance (e.g., water in paramagnetic contrast agents) or slowly exchanging protons close to the water resonance (e.g., some amide protons). However, off-resonance labeling is not efficient for rapidly exchanging protons close to water. Here, we show that a new frequency-labeled exchange labeling scheme with excitation pulses applied on the water resonance gives much higher exchange contrast for rapidly exchanging protons resonating close to the water resonance frequency. This labeling scheme is particularly suited for studying rapidly exchanging hydroxyl, amine, and imino protons in diamagnetic chemical exchange saturation transfer agents.