Hari Hariharan | University of Pennsylvania (original) (raw)

Papers by Hari Hariharan

Research paper thumbnail of A technique for in vivo mapping of myocardial creatine kinase metabolism

Nature Medicine, 2014

ATP derived from the conversion of phosphocreatine to creatine by creatine kinase provides an ess... more 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.

Research paper thumbnail of Glutamate imaging (GluCEST) lateralizes epileptic foci in nonlesional temporal lobe epilepsy

Science translational medicine, Jan 14, 2015

When neuroimaging reveals a brain lesion, drug-resistant epilepsy patients show better outcomes a... more When neuroimaging reveals a brain lesion, drug-resistant epilepsy patients show better outcomes after resective surgery than do the one-third of drug-resistant epilepsy patients who have normal brain magnetic resonance imaging (MRI). We applied a glutamate imaging method, GluCEST (glutamate chemical exchange saturation transfer), to patients with nonlesional temporal lobe epilepsy based on conventional MRI. GluCEST correctly lateralized the temporal lobe seizure focus on visual and quantitative analyses in all patients. MR spectra, available for a subset of patients and controls, corroborated the GluCEST findings. Hippocampal volumes were not significantly different between hemispheres. GluCEST allowed high-resolution functional imaging of brain glutamate and has potential to identify the epileptic focus in patients previously deemed nonlesional. This method may lead to improved clinical outcomes for temporal lobe epilepsy as well as other localization-related epilepsies.

Research paper thumbnail of T1ρ MRI of healthy and fibrotic human livers at 1.5 T

Journal of Translational Medicine, 2015

Liver fibrosis is a public health problem worldwide. There is a need of noninvasive imaging based... more Liver fibrosis is a public health problem worldwide. There is a need of noninvasive imaging based methods for better diagnosis of this disease. In the current study, we aim to evaluate the potential of T1ρ MRI technique in detecting and characterizing different grades of liver fibrosis in vivo in humans. Healthy subjects and patients with liver fibrosis were prospectively recruited for T1ρ MRI of liver on a 1.5 T MR scanner. Single slice T1ρ weighted images were acquired at different spin lock duration (0, 10, 20 and 30 ms) with spin lock amplitude of 500 Hz in a single breath-hold. Additionally, liver's T1ρ images were acquired from five healthy subjects on the same day (n = 2) and different day (n = 2) sessions for test-retest study. Liver biopsy samples from patients were obtained and used to calculate the METAVIR score to define the stage of fibrosis and inflammation grade. T1ρ maps were generated followed by computation of mean and standard deviation (SD) values. Coefficient of variation (COV) of T1ρ values between two MRI scans was computed to determine reproducibility in liver. T test was used to compare T1ρ values between healthy and fibrotic liver. Pearson correlation was performed between stages of liver fibrosis and T1ρ values. The mean (SD) T1ρ value among subject with healthy liver was 51.04 (3.06) ms. The COV of T1ρ values between two repetitions in the same day session was 0.83 ± 0.8% and in different day session was 5.4 ± 2.7%. T1ρ values in fibrotic liver were significantly higher compared to those of healthy liver (p < 0.05). A statically significant correlation between stages of fibrosis and T1ρ values was observed (r = 0.99, p < 0.05). Inflammation score for one patient was 2 and for remaining patients it was 1. Proposed T1ρ pulse sequence design and protocol enabled acquisition of a single slice T1ρ weighted images in a single breath-hold and hence mitigated breathing motion related artifacts. Preliminary results have shown the sensitivity of T1ρ values to changes induced by liver fibrosis, and may potentially be used as a clinical biomarker to delineate the stages of liver fibrosis. Further, studies on a large number of subjects are required to validate the observations of the current study. Nevertheless, T1ρ imaging can be easily setup on a clinical scanner to monitor the progression of liver fibrosis and to the evaluate efficacy of anti-fibrotic drugs.

Research paper thumbnail of Chemical Exchange Saturation Transfer (CEST) Imaging: Description of Technique and Potential Clinical Applications

Chemical exchange saturation transfer (CEST) is a magnetic resonance imaging (MRI) contrast enhan... more 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.

Research paper thumbnail of Glutaminase catalyzes reaction of glutamate to GABA

Biochemical and biophysical research communications, Jan 13, 2014

Here, for the first time, we report an NMR spectroscopy study of l-Glutamine (Gln) conversion by ... more Here, for the first time, we report an NMR spectroscopy study of l-Glutamine (Gln) conversion by Glutaminase (Glnase), which shows that the reaction involves two distinct steps. In the first step, Glnase rapidly hydrolyzes Gln to Glutamate (Glu) (∼16.87 μmol of Gln/min/mg of Glnase) and in the second step, Glu generated in the first step is decarboxylated into gamma-amino butyric acid (GABA) with a much slower rate (∼0.185 μmol/min/mg). When Glnase was added to the sample containing l-Glu alone, it was also converted to GABA, at a similar rate as in the second step mentioned above. The rate of Glu decarboxylation into GABA by Glnase is about an order of magnitude lower than that by commonly known enzyme, Glutamate decarboxylase. Potential impact of these findings, on the mechanistic aspects of Gln-Glu shuttle in neuroscience and glutaminolysis in tumors, is discussed.

Research paper thumbnail of High resolution T1ρ mapping of in vivo human knee cartilage at 7T

PloS one, 2014

Spin lattice relaxation time in rotating frame (T1ρ) mapping of human knee cartilage has shown pr... more 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 acq...

Research paper thumbnail of In vivo measurement of glutamate loss is associated with synapse loss in a mouse model of tauopathy

NeuroImage, 2014

Glutamate is the primary excitatory neurotransmitter in the brain, and is implicated in neurodege... more Glutamate is the primary excitatory neurotransmitter in the brain, and is implicated in neurodegenerative diseases such as Alzheimer's disease (AD) and several other tauopathies. The current method for measuring glutamate in vivo is proton magnetic resonance spectroscopy ((1)H MRS), although it has poor spatial resolution and weak sensitivity to glutamate changes. In this study, we sought to measure the effect of tau pathology on glutamate levels throughout the brain of a mouse model of tauopathy using a novel magnetic resonance imaging (MRI) technique. We employed glutamate chemical exchange saturation transfer (GluCEST) imaging, which has been previously validated as a complimentary method for measuring glutamate levels with several important advantages over conventional (1)H MRS. We hypothesized that the regional changes in glutamate levels would correlate with histological measurements of pathology including pathological tau, synapse and neuron loss. Imaging and spectroscopy...

Research paper thumbnail of High resolution mapping of modafinil induced changes in glutamate level in rat brain

PloS one, 2014

Modafinil is marketed in the United States for the treatment of narcolepsy and daytime somnolence... more Modafinil is marketed in the United States for the treatment of narcolepsy and daytime somnolence due to shift-work or sleep apnea. Investigations of this drug in the treatment of cocaine and nicotine dependence in addition to disorders of executive function are also underway. Modafinil has been known to increase glutamate levels in rat brain models. Proton magnetic resonance spectroscopy (1HMRS) has been commonly used to detect the glutamate (Glu) changes in vivo. In this study, we used a recently described glutamate chemical exchange saturation transfer (GluCEST) imaging technique to measure Modafinil induced regional Glu changes in rat brain and compared the results with Glu concentration measured by single voxel 1HMRS. No increases in either GluCEST maps or 1HMRS were observed after Modafinil injection over a period of 5 hours. However, a significant increase in GluCEST (19 ± 4.4%) was observed 24 hours post Modafinil administration, which is consistent with results from previou...

Research paper thumbnail of In vivo Magnetic Resonance Imaging of Tumor Protease Activity

Scientific Reports, 2014

Increased expression of cathepsins has diagnostic as well as prognostic value in several types of... more 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.

Research paper thumbnail of In vivo mapping of brain myo-inositol

NeuroImage, 2011

Myo-Inositol (MI) is one of the most abundant metabolites in the human brain located mainly in gl... more 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 Alzheimer's 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 Hz) is determined to be in the slow to intermediate exchange regime on the NMR time scale (chemical shift (Δω)>k), suggesting that the CEST effect of MI (MICEST) can be imaged at high fields such as 7T (Δω=1.2×10 3 rad/s) and 9.4T (Δω=1.6×10 3 rad/s). Using optimized imaging parameters, concentration dependent broad CEST asymmetry between ~0.2 to 1.5ppm with a peak at ~0.6ppm from bulk water was observed. Further, it is demonstrated that MICEST detection is feasible in the human brain at ultra high fields (7T) 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.

Research paper thumbnail of Chemical exchange saturation transfer magnetic resonance imaging of human knee cartilage at 3 T and 7 T

Magnetic Resonance in Medicine, 2012

The sensitivity of chemical exchange saturation transfer (CEST) on glycosaminoglycans (GAGs) in h... more 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.

Research paper thumbnail of Fast spin echo sequences with very long echo trains: Design of variable refocusing flip angle schedules and generation of clinicalT2 contrast

Magnetic Resonance in Medicine, 2006

Reducing and continuously varying the flip angle of the refocusing RF pulses in a rapid acquisiti... more 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 degrees 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.

Research paper thumbnail of On B 1 inhomogeneity correction of in vivo human brain glutamate chemical exchange saturation transfer contrast at 7T

Magnetic Resonance in Medicine, 2013

The effects of radio frequency field (B(1)) inhomogeneity on measured in vivo human brain glutama... more The effects of radio frequency field (B(1)) inhomogeneity on measured in vivo human brain glutamate chemical exchange saturation transfer contrast maps are normally confounded with contributions from chemical exchange saturation transfer, direct saturation and magnetization transfer effects. Consequently, the chemical exchange saturation transfer effect variation with B(1) follows a complicated function and depends on the tissue types as well. In this work, we developed and tested a novel approach for B(1) inhomogeneity correction based on acquiring calibration data at a coarsely sampled B(1) values in conjunction with the measured B(1) maps. With this approach, different calibration curves are derived for gray matter and white matter instead of a simple linear scaling based on local B(1) values. Potential extensions of this approach to study chemical exchange saturation transfer contrast from other metabolites and tissue types are discussed.

Research paper thumbnail of Implementation of two-dimensional L-COSY at 7 tesla: An investigation of reproducibility in human brain

Journal of Magnetic Resonance Imaging, 2013

To evaluate the utility of two-dimensional (2D) Localized Correlated Spectroscopy (L-COSY) in met... more To evaluate the utility of two-dimensional (2D) Localized Correlated Spectroscopy (L-COSY) in metabolic profiling of the human brain at 7 Tesla (T). The 2D L-COSY sequence was implemented at 7 T and its reliability was assessed by test-retest studies of a metabolite phantom and a healthy volunteer. L-COSY data were acquired from the occipital lobe of healthy subjects (n = 6; all male; age, 30-72 years) to assess intersubject variability. Additionally, two subjects underwent scans from the parieto-occipital region, basal ganglia, frontal lobe or dorsolateral prefrontal cortex to test the versatility of L-COSY in studying differing anatomy. Integral/volume measurements of L-COSY spectra were used to estimate normalized metabolite-to-creatine concentrations. Phantom test-retest studies revealed coefficients of variation (CVs) of 3-20% for most metabolites. Human 2D L-COSY spectra permitted detection of several metabolite resonances from multiple locations and inter-subject variation studies demonstrated CVs of 4-26%. Cross-peaks from gamma-aminobutyric acid (GABA), isoleucine (Ile), lysine (Lys) and Ethanolamine (Eth) were quantified, which are not readily resolvable with conventional one-dimensional (1D) MR spectroscopy. 2D L-COSY at 7 T demonstrated improved sensitivity in detecting additional metabolites with reliability comparable to established techniques at lower fields, which may aid in the metabolic assessment of diseased states.

Research paper thumbnail of T2 quantitation of articular cartilage at 1.5 T

Journal of Magnetic Resonance Imaging, 2003

To evaluate sources of error when using a multiecho sequence for quantitative T2 mapping of artic... more To evaluate sources of error when using a multiecho sequence for quantitative T2 mapping of articular cartilage at 1.5 T. Phantom measurements were used to assess the contribution of stimulated echoes to inaccuracy of T2 measurements in cartilage using a multiecho sequence. Five volunteer studies compared in vivo single-echo spin echo results to multiecho, single-slice and multiecho, multislice acquisitions for assessment of both the stimulated echo and magnetization transfer contrast (MTC) contributions to T2 measurement inaccuracy. Phantom experiments demonstrated that substantial inaccuracy (10%-13% longer T2 values) is introduced from stimulated echoes with a multiecho sequence with slice-selective refocusing pulses. The in vivo volunteer studies also demonstrated increases in measured T2 by up to 48% with a multiecho sequence. Use of the multiecho sequence in the multislice mode resulted in T2 values closer to the single-echo standards for the volunteer studies. However, this apparent increased accuracy should be regarded as circumstantial, as it only occurs because the error due to MTC has the opposite sign compared to the error due to the stimulated echo contribution. Use of a multiecho, multislice sequence for cartilage T2 measurements should be undertaken with the caution that substantial inaccuracy is introduced from stimulated echoes and MTC.

Research paper thumbnail of T 2 and T2* quantification using optimal B 1 image reconstruction for multicoil arrays

Journal of Magnetic Resonance Imaging, 2008

To investigate the accuracy of low signal-to-noise ratio (SNR) T(2) and T(2)* measurements using ... more To investigate the accuracy of low signal-to-noise ratio (SNR) T(2) and T(2)* measurements using array coils and optimal B(1) image reconstruction (OBR) compared to the standard root sum of squares (RSS) reconstruction. Calibrated gels were used for the in vitro study of T(2). T(2) and T(2)* measurements were obtained from a volunteer's knee and liver, respectively. T(2) and T(2)* measurements were performed using multiecho spin echo and multiecho gradient echo sequences, respectively. SNR was deliberately kept low. The same raw data were used for both reconstructions. For the in vivo studies the effect of signal averaging was also investigated. The optimal reconstructions demonstrated a lower mean background noise level than RSS. In vitro, the T(2) measurements made with OBR images agreed better with a reference high SNR measurement than measurements made from RSS images; the RSS image results overestimated the T(2.) In vivo, increasing the signal averages decreased the difference between the measurements obtained using the OBR and RSS methods, with RSS resulting in longer relaxation times. This work demonstrates improvements to the accuracy of T(2) and T(2)* measurements obtained when OBR is used compared to RSS, particularly in the case of low SNR.

Research paper thumbnail of A technique for in vivo mapping of myocardial creatine kinase metabolism

Nature Medicine, 2014

ATP derived from the conversion of phosphocreatine to creatine by creatine kinase provides an ess... more 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.

Research paper thumbnail of A technique for in vivo mapping of myocardial creatine kinase metabolism

Nature Medicine, 2014

ATP derived from the conversion of phosphocreatine to creatine by creatine kinase provides an ess... more 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.

Research paper thumbnail of Glutamate imaging (GluCEST) lateralizes epileptic foci in nonlesional temporal lobe epilepsy

Science translational medicine, Jan 14, 2015

When neuroimaging reveals a brain lesion, drug-resistant epilepsy patients show better outcomes a... more When neuroimaging reveals a brain lesion, drug-resistant epilepsy patients show better outcomes after resective surgery than do the one-third of drug-resistant epilepsy patients who have normal brain magnetic resonance imaging (MRI). We applied a glutamate imaging method, GluCEST (glutamate chemical exchange saturation transfer), to patients with nonlesional temporal lobe epilepsy based on conventional MRI. GluCEST correctly lateralized the temporal lobe seizure focus on visual and quantitative analyses in all patients. MR spectra, available for a subset of patients and controls, corroborated the GluCEST findings. Hippocampal volumes were not significantly different between hemispheres. GluCEST allowed high-resolution functional imaging of brain glutamate and has potential to identify the epileptic focus in patients previously deemed nonlesional. This method may lead to improved clinical outcomes for temporal lobe epilepsy as well as other localization-related epilepsies.

Research paper thumbnail of T1ρ MRI of healthy and fibrotic human livers at 1.5 T

Journal of Translational Medicine, 2015

Liver fibrosis is a public health problem worldwide. There is a need of noninvasive imaging based... more Liver fibrosis is a public health problem worldwide. There is a need of noninvasive imaging based methods for better diagnosis of this disease. In the current study, we aim to evaluate the potential of T1ρ MRI technique in detecting and characterizing different grades of liver fibrosis in vivo in humans. Healthy subjects and patients with liver fibrosis were prospectively recruited for T1ρ MRI of liver on a 1.5 T MR scanner. Single slice T1ρ weighted images were acquired at different spin lock duration (0, 10, 20 and 30 ms) with spin lock amplitude of 500 Hz in a single breath-hold. Additionally, liver's T1ρ images were acquired from five healthy subjects on the same day (n = 2) and different day (n = 2) sessions for test-retest study. Liver biopsy samples from patients were obtained and used to calculate the METAVIR score to define the stage of fibrosis and inflammation grade. T1ρ maps were generated followed by computation of mean and standard deviation (SD) values. Coefficient of variation (COV) of T1ρ values between two MRI scans was computed to determine reproducibility in liver. T test was used to compare T1ρ values between healthy and fibrotic liver. Pearson correlation was performed between stages of liver fibrosis and T1ρ values. The mean (SD) T1ρ value among subject with healthy liver was 51.04 (3.06) ms. The COV of T1ρ values between two repetitions in the same day session was 0.83 ± 0.8% and in different day session was 5.4 ± 2.7%. T1ρ values in fibrotic liver were significantly higher compared to those of healthy liver (p < 0.05). A statically significant correlation between stages of fibrosis and T1ρ values was observed (r = 0.99, p < 0.05). Inflammation score for one patient was 2 and for remaining patients it was 1. Proposed T1ρ pulse sequence design and protocol enabled acquisition of a single slice T1ρ weighted images in a single breath-hold and hence mitigated breathing motion related artifacts. Preliminary results have shown the sensitivity of T1ρ values to changes induced by liver fibrosis, and may potentially be used as a clinical biomarker to delineate the stages of liver fibrosis. Further, studies on a large number of subjects are required to validate the observations of the current study. Nevertheless, T1ρ imaging can be easily setup on a clinical scanner to monitor the progression of liver fibrosis and to the evaluate efficacy of anti-fibrotic drugs.

Research paper thumbnail of Chemical Exchange Saturation Transfer (CEST) Imaging: Description of Technique and Potential Clinical Applications

Chemical exchange saturation transfer (CEST) is a magnetic resonance imaging (MRI) contrast enhan... more 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.

Research paper thumbnail of Glutaminase catalyzes reaction of glutamate to GABA

Biochemical and biophysical research communications, Jan 13, 2014

Here, for the first time, we report an NMR spectroscopy study of l-Glutamine (Gln) conversion by ... more Here, for the first time, we report an NMR spectroscopy study of l-Glutamine (Gln) conversion by Glutaminase (Glnase), which shows that the reaction involves two distinct steps. In the first step, Glnase rapidly hydrolyzes Gln to Glutamate (Glu) (∼16.87 μmol of Gln/min/mg of Glnase) and in the second step, Glu generated in the first step is decarboxylated into gamma-amino butyric acid (GABA) with a much slower rate (∼0.185 μmol/min/mg). When Glnase was added to the sample containing l-Glu alone, it was also converted to GABA, at a similar rate as in the second step mentioned above. The rate of Glu decarboxylation into GABA by Glnase is about an order of magnitude lower than that by commonly known enzyme, Glutamate decarboxylase. Potential impact of these findings, on the mechanistic aspects of Gln-Glu shuttle in neuroscience and glutaminolysis in tumors, is discussed.

Research paper thumbnail of High resolution T1ρ mapping of in vivo human knee cartilage at 7T

PloS one, 2014

Spin lattice relaxation time in rotating frame (T1ρ) mapping of human knee cartilage has shown pr... more 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 acq...

Research paper thumbnail of In vivo measurement of glutamate loss is associated with synapse loss in a mouse model of tauopathy

NeuroImage, 2014

Glutamate is the primary excitatory neurotransmitter in the brain, and is implicated in neurodege... more Glutamate is the primary excitatory neurotransmitter in the brain, and is implicated in neurodegenerative diseases such as Alzheimer's disease (AD) and several other tauopathies. The current method for measuring glutamate in vivo is proton magnetic resonance spectroscopy ((1)H MRS), although it has poor spatial resolution and weak sensitivity to glutamate changes. In this study, we sought to measure the effect of tau pathology on glutamate levels throughout the brain of a mouse model of tauopathy using a novel magnetic resonance imaging (MRI) technique. We employed glutamate chemical exchange saturation transfer (GluCEST) imaging, which has been previously validated as a complimentary method for measuring glutamate levels with several important advantages over conventional (1)H MRS. We hypothesized that the regional changes in glutamate levels would correlate with histological measurements of pathology including pathological tau, synapse and neuron loss. Imaging and spectroscopy...

Research paper thumbnail of High resolution mapping of modafinil induced changes in glutamate level in rat brain

PloS one, 2014

Modafinil is marketed in the United States for the treatment of narcolepsy and daytime somnolence... more Modafinil is marketed in the United States for the treatment of narcolepsy and daytime somnolence due to shift-work or sleep apnea. Investigations of this drug in the treatment of cocaine and nicotine dependence in addition to disorders of executive function are also underway. Modafinil has been known to increase glutamate levels in rat brain models. Proton magnetic resonance spectroscopy (1HMRS) has been commonly used to detect the glutamate (Glu) changes in vivo. In this study, we used a recently described glutamate chemical exchange saturation transfer (GluCEST) imaging technique to measure Modafinil induced regional Glu changes in rat brain and compared the results with Glu concentration measured by single voxel 1HMRS. No increases in either GluCEST maps or 1HMRS were observed after Modafinil injection over a period of 5 hours. However, a significant increase in GluCEST (19 ± 4.4%) was observed 24 hours post Modafinil administration, which is consistent with results from previou...

Research paper thumbnail of In vivo Magnetic Resonance Imaging of Tumor Protease Activity

Scientific Reports, 2014

Increased expression of cathepsins has diagnostic as well as prognostic value in several types of... more 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.

Research paper thumbnail of In vivo mapping of brain myo-inositol

NeuroImage, 2011

Myo-Inositol (MI) is one of the most abundant metabolites in the human brain located mainly in gl... more 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 Alzheimer's 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 Hz) is determined to be in the slow to intermediate exchange regime on the NMR time scale (chemical shift (Δω)>k), suggesting that the CEST effect of MI (MICEST) can be imaged at high fields such as 7T (Δω=1.2×10 3 rad/s) and 9.4T (Δω=1.6×10 3 rad/s). Using optimized imaging parameters, concentration dependent broad CEST asymmetry between ~0.2 to 1.5ppm with a peak at ~0.6ppm from bulk water was observed. Further, it is demonstrated that MICEST detection is feasible in the human brain at ultra high fields (7T) 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.

Research paper thumbnail of Chemical exchange saturation transfer magnetic resonance imaging of human knee cartilage at 3 T and 7 T

Magnetic Resonance in Medicine, 2012

The sensitivity of chemical exchange saturation transfer (CEST) on glycosaminoglycans (GAGs) in h... more 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.

Research paper thumbnail of Fast spin echo sequences with very long echo trains: Design of variable refocusing flip angle schedules and generation of clinicalT2 contrast

Magnetic Resonance in Medicine, 2006

Reducing and continuously varying the flip angle of the refocusing RF pulses in a rapid acquisiti... more 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 degrees 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.

Research paper thumbnail of On B 1 inhomogeneity correction of in vivo human brain glutamate chemical exchange saturation transfer contrast at 7T

Magnetic Resonance in Medicine, 2013

The effects of radio frequency field (B(1)) inhomogeneity on measured in vivo human brain glutama... more The effects of radio frequency field (B(1)) inhomogeneity on measured in vivo human brain glutamate chemical exchange saturation transfer contrast maps are normally confounded with contributions from chemical exchange saturation transfer, direct saturation and magnetization transfer effects. Consequently, the chemical exchange saturation transfer effect variation with B(1) follows a complicated function and depends on the tissue types as well. In this work, we developed and tested a novel approach for B(1) inhomogeneity correction based on acquiring calibration data at a coarsely sampled B(1) values in conjunction with the measured B(1) maps. With this approach, different calibration curves are derived for gray matter and white matter instead of a simple linear scaling based on local B(1) values. Potential extensions of this approach to study chemical exchange saturation transfer contrast from other metabolites and tissue types are discussed.

Research paper thumbnail of Implementation of two-dimensional L-COSY at 7 tesla: An investigation of reproducibility in human brain

Journal of Magnetic Resonance Imaging, 2013

To evaluate the utility of two-dimensional (2D) Localized Correlated Spectroscopy (L-COSY) in met... more To evaluate the utility of two-dimensional (2D) Localized Correlated Spectroscopy (L-COSY) in metabolic profiling of the human brain at 7 Tesla (T). The 2D L-COSY sequence was implemented at 7 T and its reliability was assessed by test-retest studies of a metabolite phantom and a healthy volunteer. L-COSY data were acquired from the occipital lobe of healthy subjects (n = 6; all male; age, 30-72 years) to assess intersubject variability. Additionally, two subjects underwent scans from the parieto-occipital region, basal ganglia, frontal lobe or dorsolateral prefrontal cortex to test the versatility of L-COSY in studying differing anatomy. Integral/volume measurements of L-COSY spectra were used to estimate normalized metabolite-to-creatine concentrations. Phantom test-retest studies revealed coefficients of variation (CVs) of 3-20% for most metabolites. Human 2D L-COSY spectra permitted detection of several metabolite resonances from multiple locations and inter-subject variation studies demonstrated CVs of 4-26%. Cross-peaks from gamma-aminobutyric acid (GABA), isoleucine (Ile), lysine (Lys) and Ethanolamine (Eth) were quantified, which are not readily resolvable with conventional one-dimensional (1D) MR spectroscopy. 2D L-COSY at 7 T demonstrated improved sensitivity in detecting additional metabolites with reliability comparable to established techniques at lower fields, which may aid in the metabolic assessment of diseased states.

Research paper thumbnail of T2 quantitation of articular cartilage at 1.5 T

Journal of Magnetic Resonance Imaging, 2003

To evaluate sources of error when using a multiecho sequence for quantitative T2 mapping of artic... more To evaluate sources of error when using a multiecho sequence for quantitative T2 mapping of articular cartilage at 1.5 T. Phantom measurements were used to assess the contribution of stimulated echoes to inaccuracy of T2 measurements in cartilage using a multiecho sequence. Five volunteer studies compared in vivo single-echo spin echo results to multiecho, single-slice and multiecho, multislice acquisitions for assessment of both the stimulated echo and magnetization transfer contrast (MTC) contributions to T2 measurement inaccuracy. Phantom experiments demonstrated that substantial inaccuracy (10%-13% longer T2 values) is introduced from stimulated echoes with a multiecho sequence with slice-selective refocusing pulses. The in vivo volunteer studies also demonstrated increases in measured T2 by up to 48% with a multiecho sequence. Use of the multiecho sequence in the multislice mode resulted in T2 values closer to the single-echo standards for the volunteer studies. However, this apparent increased accuracy should be regarded as circumstantial, as it only occurs because the error due to MTC has the opposite sign compared to the error due to the stimulated echo contribution. Use of a multiecho, multislice sequence for cartilage T2 measurements should be undertaken with the caution that substantial inaccuracy is introduced from stimulated echoes and MTC.

Research paper thumbnail of T 2 and T2* quantification using optimal B 1 image reconstruction for multicoil arrays

Journal of Magnetic Resonance Imaging, 2008

To investigate the accuracy of low signal-to-noise ratio (SNR) T(2) and T(2)* measurements using ... more To investigate the accuracy of low signal-to-noise ratio (SNR) T(2) and T(2)* measurements using array coils and optimal B(1) image reconstruction (OBR) compared to the standard root sum of squares (RSS) reconstruction. Calibrated gels were used for the in vitro study of T(2). T(2) and T(2)* measurements were obtained from a volunteer's knee and liver, respectively. T(2) and T(2)* measurements were performed using multiecho spin echo and multiecho gradient echo sequences, respectively. SNR was deliberately kept low. The same raw data were used for both reconstructions. For the in vivo studies the effect of signal averaging was also investigated. The optimal reconstructions demonstrated a lower mean background noise level than RSS. In vitro, the T(2) measurements made with OBR images agreed better with a reference high SNR measurement than measurements made from RSS images; the RSS image results overestimated the T(2.) In vivo, increasing the signal averages decreased the difference between the measurements obtained using the OBR and RSS methods, with RSS resulting in longer relaxation times. This work demonstrates improvements to the accuracy of T(2) and T(2)* measurements obtained when OBR is used compared to RSS, particularly in the case of low SNR.

Research paper thumbnail of A technique for in vivo mapping of myocardial creatine kinase metabolism

Nature Medicine, 2014

ATP derived from the conversion of phosphocreatine to creatine by creatine kinase provides an ess... more 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.