Method for high-resolution imaging of creatine in vivo using chemical exchange saturation transfer.
Magnetic resonance in medicine
2014; 71 (1): 164-172
Imaging of glutamate in the spinal cord using GluCEST
2013; 77: 262-267
To develop a chemical exchange saturation transfer (CEST)-based technique to measure free creatine (Cr) and to validate the technique by measuring the distribution of Cr in muscle with high spatial resolution before and after exercise.Phantom studies were performed to determine contributions from other Cr kinase metabolites to the CEST effect from Cr (CrCEST). CEST, T2 , magnetization transfer ratio and (31) P magnetic resonance spectroscopy acquisitions of the lower leg were performed before and after plantar flexion exercise on a 7T whole-body magnetic resonance scanner on healthy volunteers.Phantom studies demonstrated that while Cr exhibited significant CEST effect there were no appreciable contributions from other metabolites. In healthy human subjects, following mild plantar flexion exercise, increases in the CEST effect from Cr were observed, which recovered exponentially back to baseline. This technique exhibited good spatial resolution and was able to differentiate differences in muscle utilization among subjects. The CEST effect from Cr results were compared with (31) P magnetic resonance spectroscopy results showing good agreement in the Cr and phosphocreatine recovery kinetics.Demonstrated a CEST-based technique to measure free Cr changes in in vivo muscle. The CEST effect from Cr imaging can spatially map changes in Cr concentration in muscle following mild exercise. This may serve as a tool for the diagnosis and treatment of various disorders affecting muscle. Magn Reson Med 71:164-172, 2014. © 2013 Wiley Periodicals, Inc.
View details for DOI 10.1002/mrm.24641
View details for PubMedID 23412909
Investigation of chemical exchange at intermediate exchange rates using a combination of chemical exchange saturation transfer (CEST) and spin-locking methods (CESTrho)
MAGNETIC RESONANCE IN MEDICINE
2012; 68 (1): 107-119
Glutamate (Glu) is the most abundant excitatory neurotransmitter in the brain and spinal cord. The concentration of Glu is altered in a range of neurologic disorders that affect the spinal cord including multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) and spinal cord injury. Currently available magnetic resonance spectroscopy (MRS) methods for measuring Glu are limited to low spatial resolution, which makes it difficult to measure differences in gray and white matter glutamate. Recently, it has been shown that Glu exhibits a concentration dependent chemical exchange saturation transfer (CEST) effect between its amine (-NH2) group protons and bulk water protons (GluCEST). Here, we demonstrate the feasibility of imaging glutamate in the spinal cord at 7T using the GluCEST technique. Results from healthy human volunteers (N=7) showed a significantly higher (p<0.001) GluCESTasym from gray matter (6.6±0.3%) compared to white matter (4.8±0.4%). Potential overlap of CEST signals from other spinal cord metabolites with the observed GluCESTasym is discussed. This noninvasive approach potentially opens the way to image Glu in vivo in the spinal cord and to monitor its alteration in many disease conditions.
View details for DOI 10.1016/j.neuroimage.2013.03.072
View details for Web of Science ID 000320073900026
View details for PubMedID 23583425
Magnetic resonance imaging of glutamate
2012; 18 (2): 302-306
Proton exchange imaging is important as it allows for visualization and quantification of the distribution of specific metabolites with conventional MRI. Current exchange mediated MRI methods suffer from poor contrast as well as confounding factors that influence exchange rates. In this study we developed a new method to measure proton exchange which combines chemical exchange saturation transfer and T(1)(ρ) magnetization preparation methods (CESTrho). We demonstrated that this new CESTrho sequence can detect proton exchange in the slow to intermediate exchange regimes. It has a linear dependence on proton concentration which allows it to be used to quantitatively measure changes in metabolite concentration. Additionally, the magnetization scheme of this new method can be customized to make it insensitive to changes in exchange rate while retaining its dependency on solute concentration. Finally, we showed the feasibility of using CESTrho in vivo. This sequence is able to detect proton exchange at intermediate exchange rates and is unaffected by the confounding factors that influence proton exchange rates thus making it ideal for the measurement of metabolites with exchangeable protons in this exchange regime.
View details for DOI 10.1002/mrm.23213
View details for Web of Science ID 000305119100011
View details for PubMedID 22009759
Imaging Strategies for Assessing Cartilage Composition in Osteoarthritis
CURRENT RHEUMATOLOGY REPORTS
2014; 16 (11)
In Vivo Chemical Exchange Saturation Transfer Imaging of Creatine (CrCEST) in Skeletal Muscle at 3T
JOURNAL OF MAGNETIC RESONANCE IMAGING
2014; 40 (3): 596-602
Glutamate, a major neurotransmitter in the brain, shows a pH- and concentration-dependent chemical exchange saturation transfer effect (GluCEST) between its amine group and bulk water, with potential for in vivo imaging by nuclear magnetic resonance. GluCEST asymmetry is observed ∼3 p.p.m. downfield from bulk water. Middle cerebral artery occlusion in the rat brain resulted in an ∼100% elevation of GluCEST in the ipsilateral side compared with the contralateral side, predominantly owing to pH changes. In a rat brain tumor model with blood-brain barrier disruption, intravenous glutamate injection resulted in a clear elevation of GluCEST and a similar increase in the proton magnetic resonance spectroscopy signal of glutamate. GluCEST maps from healthy human brain were also obtained. These results demonstrate the feasibility of using GluCEST for mapping relative changes in glutamate concentration, as well as pH, in vivo. Contributions from other brain metabolites to the GluCEST effect are also discussed.
View details for Web of Science ID 000300140300047
View details for PubMedID 22270722
In vivo Magnetic Resonance Imaging of Tumor Protease Activity
To characterize the chemical exchange saturation transfer (CEST)-based technique to measure free creatine (Cr), a key component of muscle energy metabolism, distribution in skeletal muscle with high spatial resolution before and after exercise at 3T.CrCEST saturation parameters were empirically optimized for 3T. CEST, T2 , magnetization transfer ratio (MTR), and (31) P magnetic resonance spectroscopy (MRS) acquisitions of the lower leg were performed before and after mild plantar flexion exercise on a 3T whole-body MR scanner on six healthy volunteers.The feasibility of imaging Cr changes in skeletal muscle following plantar flexion exercise using CrCEST was demonstrated at 3T. This technique exhibited good spatial resolution and was able to differentiate differences in muscle use among subjects. The CrCEST results were compared with (31) P MRS results, showing good agreement in the Cr and PCr recovery kinetics. A relationship of 0.45% CrCESTasym /mM Cr was observed across all subjects.It is demonstrated that the CrCEST technique could be applied at 3T to measure dynamic changes in creatine in muscle in vivo. The widespread availability and clinical applicability of 3T scanners has the potential to clinically advance this method.
View details for DOI 10.1002/jmri.24412
View details for Web of Science ID 000340538200011
View details for PubMedID 24925857
High Resolution T1 rho Mapping of In Vivo Human Knee Cartilage at 7T
2014; 9 (5)
Increased expression of cathepsins has diagnostic as well as prognostic value in several types of cancer. Here, we demonstrate a novel magnetic resonance imaging (MRI) method, which uses poly-L-glutamate (PLG) as an MRI probe to map cathepsin expression in vivo, in a rat brain tumor model. This noninvasive, high-resolution and non-radioactive method exploits the differences in the CEST signals of PLG in the native form and cathepsin mediated cleaved form. The method was validated in phantoms with known physiological concentrations, in tumor cells and in an animal model of brain tumor along with immunohistochemical analysis. Potential applications in tumor diagnosis and evaluation of therapeutic response are outlined.
View details for DOI 10.1038/srep06081
View details for Web of Science ID 000340711400001
View details for PubMedID 25124082
A technique for in vivo mapping of myocardial creatine kinase metabolism.
Spin lattice relaxation time in rotating frame (T1ρ) mapping of human knee cartilage has shown promise in detecting biochemical changes during osteoarthritis. Due to higher field strength, MRI at 7T has advantages in term of SNR compared to clinical MR scanners and this can be used to increase in image resolution. Objective of current study was to evaluate the feasibility of high resolution T1ρ mapping of in vivo human knee cartilage at 7T MR scanner.In this study we have used a T1ρ prepared GRE pulse sequence for obtaining high resolution (in plan resolution = 0.2 mm2) T1ρ MRI of human knee cartilage at 7T. The effect of a global and localized reference frequency and reference voltage setting on B0, B1 and T1ρ maps in cartilage was evaluated. Test-retest reliability results of T1ρ values from asymptomatic subjects as well as T1ρ maps from abnormal cartilage of two human subjects are presented. These results are compared with T1ρ MRI data obtained from 3T.Our approach enabled acquisition of 3D-T1ρ data within allowed SAR limits at 7T. SNR of cartilage on T1ρ weighted images was greater than 90. Off-resonance effects present in the cartilage B0, B1 and T1ρ maps obtained using global shim and reference frequency and voltage setting, were reduced by the proposed localized reference frequency and voltage setting. T1ρ values of cartilage obtained with the localized approach were reproducible. Abnormal knee cartilage showed elevated T1ρ values in affected regions. T1ρ values at 7T were significantly lower (p<0.05) compared to those obtained at 3T.In summary, by using proposed localized frequency and voltage setting approach, high-resolution 3D-T1ρ maps of in vivo human knee cartilage can be obtained in clinically acceptable scan times (<30 min) and SAR constraints, which provides the ability to characterize cartilage molecular integrity.
View details for DOI 10.1371/journal.pone.0097486
View details for Web of Science ID 000336789500067
View details for PubMedID 24830386
T2 Relaxation time quantitation differs between pulse sequences in articular cartilage.
Journal of magnetic resonance imaging : JMRI
ATP derived from the conversion of phosphocreatine to creatine by creatine kinase provides an essential chemical energy source that governs myocardial contraction. Here, we demonstrate that the exchange of amine protons from creatine with protons in bulk water can be exploited to image creatine through chemical exchange saturation transfer (CrEST) in myocardial tissue. We show that CrEST provides about two orders of magnitude higher sensitivity compared to (1)H magnetic resonance spectroscopy. Results of CrEST studies from ex vivo myocardial tissue strongly correlate with results from (1)H and (31)P magnetic resonance spectroscopy and biochemical analysis. We demonstrate the feasibility of CrEST measurement in healthy and infarcted myocardium in animal models in vivo on a 3-T clinical scanner. As proof of principle, we show the conversion of phosphocreatine to creatine by spatiotemporal mapping of creatine changes in the exercised human calf muscle. We also discuss the potential utility of CrEST in studying myocardial disorders.
View details for DOI 10.1038/nm.3436
View details for PubMedID 24412924
MICEST: A potential tool for non-invasive detection of molecular changes in Alzheimer's disease
JOURNAL OF NEUROSCIENCE METHODS
2013; 212 (1): 87-93
To compare T2 relaxation time measurements between MR pulse sequences at 3 Tesla in agar phantoms and in vivo patellar, femoral, and tibial articular cartilage.T2 relaxation times were quantified in phantoms and knee articular cartilage of eight healthy individuals using a single echo spin echo (SE) as a reference standard and five other pulse sequences: multi-echo SE (MESE), fast SE (2D-FSE), magnetization-prepared spoiled gradient echo (3D-MAPSS), three-dimensional (3D) 3D-FSE with variable refocusing flip angle schedules (3D vfl-FSE), and quantitative double echo steady state (qDESS). Cartilage was manually segmented and average regional T2 relaxation times were obtained for each sequence. A regression analysis was carried out between each sequence and the reference standard, and root-mean-square error (RMSE) was calculated.Phantom measurements from all sequences demonstrated strong fits (R(2) > 0.8; P < 0.05). For in vivo cartilage measurements, R(2) values, slope, and RMSE were: MESE: 0.25/0.42/5.0 ms, 2D-FSE: 0.64/1.31/9.3 ms, 3D-MAPSS: 0.51/0.66/3.8 ms, 3D vfl-FSE: 0.30/0.414.2 ms, qDESS: 0.60/0.90/4.6 ms.2D-FSE, qDESS, and 3D-MAPSS demonstrated the best fits with SE measurements as well as the greatest dynamic ranges. The 3D-MAPSS, 3D vfl-FSE, and qDESS demonstrated the closest average measurements to SE. Discrepancies in T2 relaxation time quantitation between sequences suggest that care should be taken when comparing results between studies.J. Magn. Reson. Imaging 2014. © 2014 Wiley Periodicals, Inc.
View details for DOI 10.1002/jmri.24757
View details for PubMedID 25244647
Chemical Exchange Saturation Transfer (CEST) Imaging: Description of Technique and Potential Clinical Applications.
Current radiology reports
2013; 1 (2): 102-114
Myo-inositol (mIns) is a marker of glial cells proliferation and has been shown to increase in early Alzheimer's disease (AD) pathology. mIns exhibits a concentration dependent chemical-exchange-saturation-transfer (CEST) effect (MICEST) between its hydroxyl groups and bulk water protons. Using the endogenous MICEST technique brain mIns concentration and glial cells proliferation can be mapped at high spatial resolution. The high resolution mapping of mIns was performed using MICEST technique on ∼20 months old APP-PS1 transgenic mouse model of AD as well as on age matched wild type (WT) control (n=5). The APP-PS1 mice show ∼50% higher MICEST contrast than WT control with concomitant increase in mIns concentration as measured through proton spectroscopy. Immunostaining against glial-fibric-acidic protein also depicts proliferative glial cells in larger extent in APP-PS1 than WT mice, which correspond to the higher mIns concentration. Potential significance of MICEST in early detection of AD pathology is discussed in detail.
View details for DOI 10.1016/j.jneumeth.2012.09.025
View details for Web of Science ID 000313390600009
View details for PubMedID 23041110
Exchange rates of creatine kinase metabolites: feasibility of imaging creatine by chemical exchange saturation transfer MRI
NMR IN BIOMEDICINE
2012; 25 (11): 1305-1309
Chemical exchange saturation transfer (CEST) is a magnetic resonance imaging (MRI) contrast enhancement technique that enables indirect detection of metabolites with exchangeable protons. Endogenous metabolites with exchangeable protons including many endogenous proteins with amide protons, glycosaminoglycans (GAG), glycogen, myo-inositol (MI), glutamate (Glu), creatine (Cr) and several others have been identified as potential in vivo endogenous CEST agents. These endogenous CEST agents can be exploited as non-invasive and non-ionizing biomarkers of disease diagnosis and treatment monitoring. This review focuses on the recent technical developments in endogenous in vivo CEST MRI from various metabolites as well as their potential clinical applications. The basic underlying principles of CEST, its potential limitations and new techniques to mitigate them are discussed.
View details for DOI 10.1007/s40134-013-0010-3
View details for PubMedID 23730540
Chemical exchange saturation transfer magnetic resonance imaging of human knee cartilage at 3 T and 7 T
MAGNETIC RESONANCE IN MEDICINE
2012; 68 (2): 588-594
Creatine (Cr), phosphocreatine (PCr) and adenosine-5-triphosphate (ATP) are major metabolites of the enzyme creatine kinase (CK). The exchange rate of amine protons of CK metabolites at physiological conditions has been limited. In the current study, the exchange rate and logarithmic dissociation constant (pKa) of amine protons of CK metabolites were calculated. Further, the chemical exchange saturation transfer effect (CEST) of amine protons of CK metabolites with bulk water was explored. At physiological temperature and pH, the exchange rate of amine protons in Cr was found to be 7-8 times higher than PCr and ATP. A higher exchange rate in Cr was associated with lower pKa value, suggesting faster dissociation of its amine protons compared to PCr and ATP. CEST MR imaging of these metabolites in vitro in phantoms displayed predominant CEST contrast from Cr and negligible contribution from PCr and ATP with the saturation pulse parameters used in the current study. These results provide a new method to perform high-resolution proton imaging of Cr without contamination from PCr. Potential applications of these finding are discussed.
View details for DOI 10.1002/nbm.2792
View details for Web of Science ID 000310237400013
View details for PubMedID 22431193
Imaging of glutamate neurotransmitter alterations in Alzheimer's disease.
NMR in biomedicine
The sensitivity of chemical exchange saturation transfer (CEST) on glycosaminoglycans (GAGs) in human knee cartilage (gagCEST) in vivo was evaluated at 3 and 7 T field strengths. Calculated gagCEST values without accounting for B(0) inhomogeneity (~0.6 ppm) were >20%. After B(0) inhomogeneity correction, calculated gagCEST values were negligible at 3 T and ~6% at 7 T. These results suggest that accurate B(0) correction is a prerequisite for observing reliable gagCEST. Results obtained with varying saturation pulse durations and amplitudes as well as the consistency between numerical simulations and our experimental results indicate that the negligible gagCEST observed at 3 T is due to direct saturation effects and fast exchange rate. As GAG loss from cartilage is expected to result in a further reduction in gagCEST, gagCEST method is not expected to be clinically useful at 3 T. At high fields such as 7 T, this method holds promise as a viable clinical technique.
View details for DOI 10.1002/mrm.23250
View details for Web of Science ID 000306318900031
View details for PubMedID 22213239
Glutamate (Glu) is a major excitatory neurotransmitter in the brain and has been shown to decrease in the early stages of Alzheimer's disease (AD). Using a glutamate chemical (amine) exchange saturation transfer (GluCEST) method, we imaged the change in [Glu] in the APP-PS1 transgenic mouse model of AD at high spatial resolution. Compared with wild-type controls, AD mice exhibited a notable reduction in GluCEST contrast (~30%) in all areas of the brain. The change in [Glu] was further validated through (1) H MRS. A positive correlation was observed between GluCEST contrast and (1) H MRS-measured Glu/total creatine ratio. This method potentially provides a novel noninvasive biomarker for the diagnosis of the disease in preclinical stages and enables the development of disease-modifying therapies for AD. Copyright © 2012 John Wiley & Sons, Ltd.
View details for PubMedID 23045158