Hari Hariharan

Magnetic resonance imaging of glutamate

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.

Fast spin echo sequences with very long echo trains: design of variable refocusing flip angle schedules and generation of clinical T2 contrast.

Reducing and continuously varying the flip angle of the refocusing RF pulses in a rapid acquisition with relaxation enhancement (RARE; fast/turbo spin echo) sequence is a useful means of addressing high RF power deposition and modulation transfer function (MTF) distortion due to relaxation. This work presents a streamlined technique to generate a sequence of refocusing flip angles on a per‐prescription basis that produces relatively high SNR and limits blurring in a wide range of materials encountered in vivo. Since the “effective TE” (traditionally defined as the time at which the center of k‐space is sampled) no longer corresponds to the expected amount of spin‐echo T2 contrast due to the mixing of stimulated and spin echoes, a “contrast‐equivalent” TE is defined and experimentally demonstrated that allows annotation of a more accurate effective TE that matches the contrast produced by 180° refocusing. Furthermore, contrast is shown to be manipulable by the addition of magnetization preparation pulse sequence segments, such as T2‐prep, to produce clinically desirable contrast for routine head and body imaging. Magn Reson Med, 2006.

T2 quantitation of articular cartilage at 1.5 T.

To evaluate sources of error when using a multiecho sequence for quantitative T2 mapping of articular cartilage at 1.5 T.

In vivo mapping of brain myo-inositol.

Myo-Inositol (MI) is one of the most abundant metabolites in the human brain located mainly in glial cells and functions as an osmolyte. The concentration of MI is altered in many brain disorders including Alzheimers disease and brain tumors. Currently available magnetic resonance spectroscopy (MRS) methods for measuring MI are limited to low spatial resolution. Here, we demonstrate that the hydroxyl protons on MI exhibit chemical exchange with bulk water and saturation of these protons leads to reduction in bulk water signal through a mechanism known as chemical exchange saturation transfer (CEST). The hydroxyl proton exchange rate (k=600 s(-1)) is determined to be in the slow to intermediate exchange regime on the NMR time scale (chemical shift (∆ω)>k), suggesting that the CEST effect of MI (MICEST) can be imaged at high fields such as 7 T (∆ω=1.2×10(3)rad/s) and 9.4 T (∆ω=1.6×10(3) rad/s). Using optimized imaging parameters, concentration dependent broad CEST asymmetry between ~0.2 and 1.5 ppm with a peak at ~0.6 ppm from bulk water was observed. Further, it is demonstrated that MICEST detection is feasible in the human brain at ultra high fields (7 T) without exceeding the allowed limits on radiofrequency specific absorption rate. Results from healthy human volunteers (N=5) showed significantly higher (p=0.03) MICEST effect from white matter (5.2±0.5%) compared to gray matter (4.3±0.5%). The mean coefficient of variations for intra-subject MICEST contrast in WM and GM were 0.49 and 0.58 respectively. Potential overlap of CEST signals from other brain metabolites with the observed MICEST map is discussed. This noninvasive approach potentially opens the way to image MI in vivo and to monitor its alteration in many disease conditions.

Chemical Exchange Saturation Transfer Magnetic Resonance Imaging of Human Knee Cartilage at 3 T and 7 T

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 B0 inhomogeneity (∼0.6 ppm) were >20%. After B0 inhomogeneity correction, calculated gagCEST values were negligible at 3 T and ∼6% at 7 T. These results suggest that accurate B0 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. Magn Reson Med, 2012.

Method for high-resolution imaging of creatine in vivo using chemical exchange saturation transfer

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.

Exchange rates of creatine kinase metabolites: feasibility of imaging creatine by chemical exchange saturation transfer MRI

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. Copyright

CEST signal at 2ppm (CEST@2ppm) from Z-spectral fitting correlates with creatine distribution in brain tumor.

In general, multiple components such as water direct saturation, magnetization transfer (MT), chemical exchange saturation transfer (CEST) and aliphatic nuclear Overhauser effect (NOE) contribute to the Z‐spectrum. The conventional CEST quantification method based on asymmetrical analysis may lead to quantification errors due to the semi‐solid MT asymmetry and the aliphatic NOE located on a single side of the Z‐spectrum. Fitting individual contributors to the Z‐spectrum may improve the quantification of each component. In this study, we aim to characterize the multiple exchangeable components from an intracranial tumor model using a simplified Z‐spectral fitting method. In this method, the Z‐spectrum acquired at low saturation RF amplitude (50 Hz) was modeled as the summation of five Lorentzian functions that correspond to NOE, MT effect, bulk water, amide proton transfer (APT) effect and a CEST peak located at +2 ppm, called CEST@2ppm. With the pixel‐wise fitting, the regional variations of these five components in the brain tumor and the normal brain tissue were quantified and summarized. Increased APT effect, decreased NOE and reduced CEST@2ppm were observed in the brain tumor compared with the normal brain tissue. Additionally, CEST@2ppm decreased with tumor progression. CEST@2ppm was found to correlate with the creatine concentration quantified with proton MRS. Based on the correlation curve, the creatine contribution to CEST@2ppm was quantified. The CEST@2ppm signal could be a novel imaging surrogate for in vivo creatine, the important bioenergetics marker. Given its noninvasive nature, this CEST MRI method may have broad applications in cancer bioenergetics. Copyright

A technique for in vivo mapping of myocardial creatine kinase metabolism

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 1H magnetic resonance spectroscopy. Results of CrEST studies from ex vivo myocardial tissue strongly correlate with results from 1H and 31P 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.

Imaging of glutamate neurotransmitter alterations in Alzheimer's disease.

Glutamate (Glu) is a major excitatory neurotransmitter in the brain and has been shown to decrease in the early stages of Alzheimers 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 1H MRS. A positive correlation was observed between GluCEST contrast and 1H 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