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Contains fulltext : 249480.pdf (Publisher’s version ) (Open Access) PURPOSE: Until now, (1) H MRSI of the prostate has been performed with suppression of the large water signal to avoid distortions of metabolite signals. However, this signal can be used for absolute quantification and spectral corrections. We investigated the feasibility of water-unsuppressed MRSI in patients with prostate cancer for water signal-mediated spectral quality improvement and determination of absolute tissue levels of choline. METHODS: Eight prostate cancer patients scheduled for radical prostatectomy underwent multi-parametric MRI at 3 T, including 3D water-unsuppressed semi-LASER MRSI. A postprocessing algorithm was developed to remove the water signal and its artifacts and use the extracted water signal as intravoxel reference for phase and frequency correction of metabolite signals and for absolute metabolite quantification. RESULTS: Water-unsuppressed MRSI with dedicated postprocessing produced water signal and artifact-free MR spectra throughout the prostate. In all patients, the absolute choline tissue concentration was significantly higher in tumorous than in benign tissue areas (mean +/- SD: 7.2 +/- 1.4 vs 3.8 +/- 0.7 mM), facilitating tumor localization by choline mapping. Tumor tissue levels of choline correlated better with the commonly used (choline + spermine + creatine)/citrate ratio (r = 0.78 +/- 0.1) than that of citrate (r = 0.21 +/- 0.06). The highest maximum choline concentrations occurred in high-risk cancer foci. CONCLUSION: This report presents the first successful water-unsuppressed MRSI of the whole prostate. The water signal enabled amelioration of spectral quality and absolute metabolite quantification. In this way, choline tissue levels were identified as tumor biomarker. Choline mapping may serve as a tool in prostate cancer localization and risk scoring in multi-parametric MRI for diagnosis and biopsy procedures.

PURPOSE To introduce and validate a pulse scheme that uses low duty cycle trains of π-pulses to achieve saturation that is relatively insensitive to exchange rate yet linearly dependent on labile proton concentration. METHODS Simulations were performed to explore the exchange rate sensitivity of π-pulse trains and continuous wave chemical exchange saturation transfer (CEST) signals. Creatine phantoms with varying pH and varying concentrations were imaged to demonstrate pH insensitivity and concentration dependence of low duty cycle π-pulse saturation. RESULTS Simulations show decreasing the duty cycle of π-pulse saturation decreases peak sensitivity to exchange rate, and this range of insensitivity can be tuned to different exchange rates through average B1 power. The range of insensitivity is unaffected by changes in relaxation and magnetization transfer, while the sensitivity of CEST signal maintains linear dependence on labile proton concentration. Under B1,avg = 0.48 μT, 30 mM creatine with pHs ranging between 6.36 and 8.21 exhibited CEST contrast ranging between ~6 and 11% under continuous wave and ~4% across all pHs using 10% duty cycle π-pulses. Imaging these phantoms using duty cycles of 5, 10, 25, and 50% showed decreasing pH sensitivity with decreased duty cycle. Creatine phantoms with varied concentrations and pHs reveal that π-pulse train saturation exhibited stricter correlation to concentration at lower DCs. CONCLUSION Low DC π-pulse train is an easy-to-implement way of providing labile proton concentration-dependent CEST MRI signal that is insensitive to exchange rate. This approach can be useful in studies where a change of chemical exchange rate may interfere with accurate assessments of physiology or pathology.

Purpose Two-dimensional creatine CEST (2D-CrCEST), with a slice thickness of 10-20 mm and temporal resolution (τRes ) of about 30 seconds, has previously been shown to capture the creatine-recovery kinetics in healthy controls and in patients with abnormal creatine-kinase kinetics following the mild plantar flexion exercise. Since the distribution of disease burden may vary across the muscle length for many musculoskeletal disorders, there is a need to increase coverage in the slice-encoding direction. Here, we demonstrate the feasibility of 3D-CrCEST with τRes of about 30 seconds, and propose an improved voxel-wise B 1 + -calibration approach for CrCEST. Methods The current 7T study with enrollment of 5 volunteers involved collecting the baseline CrCEST imaging for the first 2 minutes, followed by 2 minutes of plantar flexion exercise and then 8 minutes of postexercise CrCEST imaging, to detect the temporal evolution of creatine concentration following exercise. Results Very good repeatability of 3D-CrCEST findings for activated muscle groups on an intraday and interday basis was established, with coefficient of variance of creatine recovery constants (τCr ) being 7%-15.7%, 7.5%, and 5.8% for lateral gastrocnemius, medial gastrocnemius, and peroneus longus, respectively. We also established a good intraday and interday scan repeatability for 3D-CrCEST and also showed good correspondence between τCr measurements using 2D-CrCEST and 3D-CrCEST acquisitions. Conclusion In this study, we demonstrated for the first time the feasibility and the repeatability of the 3D-CrCEST method in calf muscle with improved B 1 + correction to measure creatine-recovery kinetics within a large 3D volume of calf muscle.

PURPOSE An L2-regularization based postprocessing method is proposed and tested for removal of residual or unsuppressed water signals in proton MR spectroscopic imaging (MRSI) data recorded from the human brain at 3T. METHODS Water signals are removed by implementation of the L2 regularization using a synthesized water-basis matrix that is orthogonal to metabolite signals of interest in the spectral dimension. Simulated spectra with variable water amplitude and in vivo brain MRSI datasets were used to demonstrate the proposed method. Results were compared with two commonly-used postprocessing methods for removing water signals. RESULTS The L2 method yielded metabolite signals that were close to true values for the simulated spectra. Residual/unsuppressed water signals in human brain short- and long-echo time MRSI datasets were efficiently removed by the proposed method allowing good quality metabolite maps to be reconstructed with minimized contamination from water signals. Significant differences of the creatine signal were observed between brain long-echo time MRSI without and with water saturation, attributable to the previously described magnetization transfer effect. CONCLUSIONS With usage of a synthesized water matrix generated based on reasonable prior knowledge about water and metabolite resonances, the L2 method is shown to be an effective way to remove water signals from MRSI of the human brain.

Purpose To develop a robust method for brain metabolite quantification in proton magnetic resonance spectroscopy (1 H-MRS) using a convolutional neural network (CNN) that maps in vivo brain spectra that are typically degraded by low SNR, line broadening, and spectral baseline into noise-free, line-narrowed, baseline-removed intact metabolite spectra. Methods A CNN was trained (n = 40 000) and tested (n = 5000) on simulated brain spectra with wide ranges of SNR (6.90-20.74) and linewidth (10-20 Hz). The CNN was further tested on in vivo spectra (n = 40) from five healthy volunteers with substantially different SNR, and the results were compared with those from the LCModel analysis. A Student t test was performed for the comparison. Results Using the proposed method the mean-absolute-percent-errors (MAPEs) in the estimated metabolite concentrations were 12.49% ± 4.35% for aspartate, creatine (Cr), γ-aminobutyric acid (GABA), glucose, glutamine, glutamate, glutathione (GSH), myo-Inositol (mI), N-acetylaspartate, phosphocreatine (PCr), phosphorylethanolamine, and taurine over the whole simulated spectra in the test set. The metabolite concentrations estimated from in vivo spectra were close to the reported ranges for the proposed method and the LCModel analysis except mI, GSH, and especially Cr/PCr for the LCModel analysis, and phosphorylcholine to glycerophosphorylcholine ratio (PC/GPC) for both methods. The metabolite concentrations estimated across the in vivo spectra with different SNR were less variable with the proposed method (~10% or less) than with the LCModel analysis. Conclusion The robust performance of the proposed method against low SNR may allow a subminute 1 H-MRS of human brain, which is an important technical development for clinical studies.

PURPOSE The aim of this study was to investigate potential effects of acute caffeine intake on J-difference-edited MRS measures of the primary inhibitory neurotransmitter γ-aminobutyric acid (GABA). METHODS J-difference-edited Mescher-Garwood PRESS (MEGA-PRESS) and conventional PRESS data were acquired at 3T from voxels in the anterior cingulate and occipital area of the brain in 15 healthy subjects, before and after oral intake of a 200-mg caffeine dose. MEGA-PRESS data were analyzed with the MATLAB-based Gannet tool to estimate GABA+ macromolecule (GABA+) levels, while PRESS data were analyzed with LCModel to estimate levels of glutamate, glutamate+glutamine, N-acetylaspartate, and myo-inositol. All metabolites were quantified with respect to the internal reference compounds creatine and tissue water, and compared between the pre- and post-caffeine intake condition. RESULTS For both MRS voxels, mean GABA+ estimates did not differ before and after caffeine intake. Slightly lower estimates of myo-inositol were observed after caffeine intake in both voxels. N-acetylaspartate, glutamate, and glutamate+glutamine did not show significant differences between conditions. CONCLUSION Mean GABA+ estimates from J-difference-edited MRS in two different brain regions are not altered by acute oral administration of caffeine. These findings may increase subject recruitment efficiency for MRS studies.

Purpose Chemical exchange saturation transfer effects at 2 ppm (CEST@2ppm) in brain have previously been interpreted as originating from creatine. However, protein guanidino amine protons may also contribute to CEST@2ppm. This study aims to investigate the molecular origins and specificity of CEST@2ppm in brain. Methods Two experiments were performed: (i) samples containing egg white albumin and creatine were dialyzed using a semipermeable membrane to demonstrate that proteins and creatine can be separated by this method; and (ii) tissue homogenates of rat brain with and without dialysis to remove creatine were studied to measure the relative contributions of proteins and creatine to CEST@2ppm. Results The experiments indicate that dialysis can successfully remove creatine from proteins. Measurements on tissue homogenates show that, with the removal of creatine via dialysis, CEST@2ppm decreases to approximately 34% of its value before dialysis, which indicates that proteins and creatine have comparable contribution to the CEST@2ppm in brain. However, considering the contribution from peptides and amino acids to CEST@2ppm, creatine may have much less contribution to CEST@2ppm. Conclusions The contribution of proteins, peptides, and amino acids to CEST@2ppm cannot be neglected. The CEST@2ppm measurements of creatine in rat brain should be interpreted with caution. Magn Reson Med, 2017. © 2017 International Society for Magnetic Resonance in Medicine.

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.

To improve the detection of peritumoral changes in GBM patients by exploring the relation between MRSI information and the distance to the solid tumor volume (STV) defined using structural MRI (sMRI).Twenty-three MRSI studies (PRESS, TE 135 ms) acquired from different patients with untreated GBM were used in this study. For each MRSI examination, the STV was identified by segmenting the corresponding sMRI images using BraTumIA, an automatic segmentation method. The relation between different metabolite ratios and the distance to STV was analyzed. A regression forest was trained to predict the distance from each voxel to STV based on 14 metabolite ratios. Then, the trained model was used to determine the expected distance to tumor (EDT) for each voxel of the MRSI test data. EDT maps were compared against sMRI segmentation.The features showing abnormal values at the longest distances to the tumor were: %NAA, Glx/NAA, Cho/NAA, and Cho/Cr. These four features were also the most important for the prediction of the distances to STV. Each EDT value was associated with a specific metabolic pattern, ranging from normal brain tissue to actively proliferating tumor and necrosis. Low EDT values were highly associated with malignant features such as elevated Cho/NAA and Cho/Cr.The proposed method enables the automatic detection of metabolic patterns associated with different distances to the STV border and may assist tumor delineation of infiltrative brain tumors such as GBM.

PURPOSE: To investigate potential effects of acute caffeine intake on J-difference edited MR spectroscopy (MRS) measures of the primary inhibitory neurotransmitter γ-aminobutyric acid (GABA). METHODS: J-difference-edited MEGA-PRESS and conventional PRESS data were acquired at 3T from voxels in the anterior cingulate (ACC) and occipital area (OCC) of the brain in 15 healthy subjects, prior to and after oral intake of a 200-mg caffeine dose. MEGA-PRESS data were analysed with the MATLAB-based Gannet tool to estimate GABA + macromolecule (GABA+) levels, while PRESS data were analysed with LCModel to estimate levels of glutamate (Glu), glutamate+glutamine (Glx), N-acetylaspartate (NAA), and myo-inositol (mI). All metabolites were quantified with respect to the internal reference compounds creatine (Cr) and tissue water, and compared between the pre- and post-caffeine intake condition. RESULTS: For both MRS voxels, mean GABA+ estimates did not differ before and after caffeine intake. Slightly lower estimates of mI were observed after caffeine intake in both voxels. NAA, Glu and Glx did not show significant differences between conditions. CONCLUSION: Mean GABA+ estimates from J-difference edited MRS in two different brain regions are not altered by acute oral administration of caffeine. These findings may increase subject recruitment efficiency for MRS studies.

Purpose MR spectroscopic imaging (SI) of glycine (Gly) in the human brain is challenging due to the interference of the abundant neighboring J-coupled resonances. Our aim is to accomplish reliable imaging of Gly in healthy brain and brain tumors using an optimized MR sequence scheme at 3 tesla. Methods Two-dimensional 1H SI was performed with a point-resolved spectroscopy scheme. An echo time of 160 ms was used for separation between Gly and myo-inositol signals. Data were collected from eight healthy volunteers and 14 subjects with gliomas. Spectra were analyzed with the linear combination model using numerically calculated basis spectra. Metabolite concentrations were estimated with reference to creatine in white matter (WM) regions at 6.4 molar concentrations (mM). Results From a linear regression analysis with respect to the fractional gray matter (GM) content, the Gly concentrations in pure GM and WM in healthy brains were estimated to be 1.1 and 0.3 mM, respectively. Gly was significantly elevated in tumors. The tumor-to-contralateral Gly concentration ratio was more extensive with higher grades, showing ∼10-fold elevation of Gly in glioblastomas. Conclusion The Gly level is significantly different between GM and WM in healthy brains. Our data indicate that SI of Gly may provide a biomarker of brain tumor malignancy. Magn Reson Med, 2015. © 2015 Wiley Periodicals, Inc.

Purpose To develop an in vivo 1H short-echo-time semi-LASER spectroscopy protocol at 7 Tesla (T) incorporating subject-specific macromolecule removal. Methods T1 constants of the major metabolites were measured with little macromolecule contribution in seven healthy volunteers and used to optimize double inversion metabolite nulling. Spectra were acquired from parietal–occipital cortex of five healthy volunteers. Metabolite-nulled macromolecule spectra were subtracted from the metabolite spectra before fitting in the time domain with prior-knowledge templates. Absolute metabolite concentrations were determined by referencing to the water signal, following partial volume and relaxation corrections. Results The average signal to noise ratio, N-acetylaspartate peak height divided by the baseline noise standard deviation, was 48 ± 6. T1 constants for N-acetylaspartate, glutamate, creatine, and choline were 1.71 ± 0.15 s, 1.68 ± 0.19 s, 1.63 ± 0.10 s, and 1.41 ± 0.09 s, respectively. The optimal double inversion times for metabolite suppression were TI1 = 2.09 s and TI2 = 0.52 s. The coefficient of variation was less than 10% for N-acetylaspartate, creatine, choline, and myo-inositol, and less than 20% for glutamate and glutamine. Conclusion Short echo-time 1H semi-LASER spectroscopy at 7T incorporating subject-specific macromolecule removal yielded reproducible brain metabolite concentrations ideal for applications in disease conditions where macromolecule contributions may deviate from the norm. Magn Reson Med 74:4–12, 2015. © 2014 Wiley Periodicals, Inc.

In (1)H MR spectroscopic imaging ((1)H-MRSI) of the prostate the spatial distribution of the signal levels of the metabolites choline, creatine, polyamines, and citrate are assessed. The ratio of choline (plus spermine as the main polyamine) plus creatine over citrate [(Cho+(Spm+)Cr)/Cit] is derived from these metabolites and is used as a marker for the presence of prostate cancer. In this review, the factors that are of importance for the metabolite ratio are discussed. This is relevant, because the appearance of the metabolites in the spectrum depends not only on the underlying anatomy, metabolism, and physiology of the tissue, but also on acquisition parameters. These parameters influence especially the spectral shapes of citrate and spermine resonances, and consequently, the (Cho+(Spm+)Cr)/Cit ratio. Both qualitative and quantitative approaches can be used for the evaluation of (1)H-MRSI spectra of the prostate. For the quantitative approach, the (Cho+(Spm+)Cr)/Cit ratio can be determined by integration or by a fit based on model signals. Using the latter, the influence of the acquisition parameters on citrate can be taken into account. The strong overlap between the choline, creatine, and spermine resonances complicates fitting of the individual metabolites. This overlap and (unknown, possibly tissue-related) variations in T1, T2, and J-modulation hamper the application of corrections needed for a "normalized" (Cho+(Spm+)Cr)/Cit ratio that would enable comparison of spectra measured with different prostate MR spectroscopy protocols. Quantitative (Cho+(Spm+)Cr)/Cit thresholds for the evaluation of prostate cancer are therefore commonly established per institution or per protocol. However, if the same acquisition and postprocessing protocol were used, the ratio and the thresholds would be institution-independent, promoting the clinical usability of prostate (1)H-MRSI.

PURPOSE: A semi-LASER sequence was optimized for in vivo lactate detection in the prostate. METHODS: The ethical committee waived the need for informed consent to measure 17 patients with high grade prostate cancer on a 3T system. A semi-LASER sequence was used with an echo time of 144 ms and optimized interpulse timing for a spectral citrate shape with high signal intensity. An LCModel basis set was developed for fitting choline, creatine, spermine, citrate, and lactate and was used to fit all spectra in tumor-containing voxels. For patients without detectable lactate, the minimal detectable lactate concentration was determined by adding in all spectra of tumor tissue a simulated lactate signal. The amplitude of the simulated lactate signal was iteratively decreased until its fit reached a Cramer Rao lower bound >20\%, which was then set as the patient-specific detection limit. RESULTS: In none of the patients a convincing lactate signal was found. We estimated that on average the lactate levels in high grade prostate cancer are below 1.5 mM (range 0.9-3.5 mM), Interestingly, in one patient with extensive necrosis in the tumor biopsy samples (Gleason score 5+5), large lipid resonances were observed, which originated from the tumor. CONCLUSION: The minimal detectable lactate concentration of 1.5 mM in high grade prostate cancer indicates that if lactate is increased it remains at low concentrations. Magn Reson Med, 2013. © 2013 Wiley Periodicals, Inc.

Purpose 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.

Purpose Amide-proton transfer (APT) and amine–water proton exchange (APEX) MRI can be viable to map pH-decreasing ischemic regions. However, their exact contributions are unclear. Methods We measured APEX- and APT-weighted magnetization transfer ratio asymmetry (denoted as APEXw and APTw), apparent diffusion coefficient, T2, and T1 images and localized proton spectra in rats with permanent middle cerebral artery occlusion at 9.4 T. Phantoms and theoretical studies were also performed. Results Within 1-h postocclusion, APEXw and APTw maps showed hyperintensity (3.1% of M0) and hypointensity (−1.8%), respectively, in regions with decreased apparent diffusion coefficient. Ischemia increased lactate and gamma aminobutyric acid concentrations, but decreased glutamate and taurine concentrations. Over time, the APEXw contrast decreased with glutamate, taurine, and creatine, whereas the APTw contrast and lactate level were similar. Phantom and theoretical studies suggest that the source of APEXw signal is mainly from proteins at normal pH, whereas at decreased pH, gamma aminobutyric acid and glutamate contributions increase, inducing the positive APEXw contrast in ischemic regions. The APTw contrast is sensitive to lactate concentration and pH, but contaminated from contributions of the faster APEX processes. Conclusion Positive APEXw contrast is more sensitive to ischemia than negative APTw contrast. They may provide complementary tissue metabolic information. Magn Reson Med 71:118–132, 2014. © 2013 Wiley Periodicals, Inc.

Despite its importance in energy metabolism, lactate in human skeletal muscle has been difficult to detect by noninvasive 1H-magnetic resonance spectroscopy mainly due to interference from large water and lipid signals. Long echo-time acquisitions at 7 T effectively attenuates the water and lipid signals in forearm muscle allowing direct observation of both lactate resonances, the methine at 4.09 ppm and the methyl at 1.31 ppm. Using this approach, we were able to monitor lactate dynamics at a temporal resolution of 32 s. While lactate was not detectable at rest, immediately after an acute period of exercise to fatigue the forearm muscle, lactate rose to a level comparable to that of creatine (∼30 mmol/kg wet weight). In a typical 1H-magnetic resonance spectrum collected using a echo-time of 140 ms, the lactate methine and methyl resonances both appear as doublets with an unusually large splitting of ∼20 Hz due to residual dipolar coupling. During muscle recovery following exercise, the lactate signals decay rapidly with a time constant of t½ = 2.0 ± 0.6 min (n = 12 subjects). This fast and simple lactate detection method may prove valuable for monitoring lactate metabolism in cancer and in sports medicine applications. Magn Reson Med 70:610–619, 2013. © 2012 Wiley Periodicals, Inc.

Many metabolites in the proton magnetic resonance spectrum undergo magnetization exchange with water, such as those in the downfield region (6.0-8.5 ppm) and the upfield peaks of creatine, which can be measured to reveal additional information about the molecular environment. In addition, these resonances are attenuated by conventional water suppression techniques complicating detection and quantification. To characterize these metabolites in human skeletal muscle in vivo at 3 T, metabolite cycled non-water-suppressed spectroscopy was used to conduct a water inversion transfer experiment in both the soleus and tibialis anterior muscles. Resulting median exchange-independent T1 times for the creatine methylene resonances were 1.26 and 1.15 s, and for the methyl resonances were 1.57 and 1.74 s, for soleus and tibialis anterior muscles, respectively. Magnetization transfer rates from water to the creatine methylene resonances were 0.56 and 0.28 s(-1), and for the methyl resonances were 0.39 and 0.30 s(-1), with the soleus exhibiting faster transfer rates for both resonances, allowing speculation about possible influences of either muscle fibre orientation or muscle composition on the magnetization transfer process. These water magnetization transfer rates observed without water suppression are in good agreement with earlier reports that used either postexcitation water suppression in rats, or short CHESS sequences in human brain and skeletal muscle.

To develop a novel diffusion-weighted magnetic resonance spectroscopy (DW-MRS) technique in conjunction with J-resolved spatially localized spectroscopy (JPRESS) to measure the apparent diffusion coefficients (ADCs) of brain metabolites beyond N-acetylaspartic acid (NAA), creatine (Cr), and choline (Cho) at 3T. This technique will be useful to probe tissue microstructures in vivo, as the various metabolites have different physiological characteristics.Two JPRESS spectra were collected (high b-value and low b-value), and the ADCs of 16 different metabolites were estimated. Two analysis pipelines were developed: 1) a 2D pipeline that uses ProFit software to extract ADCs from metabolites not typically accessible at 3T and 2) a 1D pipeline that uses TARQUIN software to extract the metabolite concentrations from each line in the 2D dataset, allowing for scaling as well as validation.The ADCs of 16 different metabolites were estimated from within six subjects in parietal white matter. There was excellent agreement between the results obtained from the 1D and 2D pipelines for NAA, Cr, and Cho.The proposed technique provided consistent estimates for the ADCs of NAA, Cr, Cho, glutamate + glutamine, and myo-inositol in all subjects and additionally glutathione and scyllo-inositol in all but one subject. Magn Reson Med 78:1235-1245, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Alzheimer's disease (AD) is the most common form of dementia in the elderly. Due to ongoing advances in our understanding of the underlying pathology of AD, many potential new targets for therapeutics are becoming available. Transgenic mouse models of AD have helped in furthering our understanding of AD and also provide a vehicle for preclinical testing of new, putative disease-modifying therapeutics, which may have potential for translation to use in clinical trials. To identify possible translational biomarkers, we have studied the longitudinal cerebral metabolic pattern of the TASTPM transgenic AD mouse, a double transgenic mouse overexpressing human mutant amyloid precursor protein (hAPP695swe) and presenilin-1 (M146V) by (1) H magnetic resonance spectroscopy, along with concurrent brain T(1) /T(2) mapping and behavioral testing. We found significant differences in creatine, glutamate, N-acetylaspartate, choline-containing compounds, and myo-inositol between TASTPM and wild-type mice. In the case of N-acetylaspartate and myo-inositol, there were similarities to differences detected in human AD. T(1) /T(2) values were shorter overall in TASTPM mice, indicating possible differences in water content between TASTPM and wild-type mice. In older TASTPM mice, exploratory behavior became more random, indicating a possible memory deficiency. The decrease in behavioral performance correlated in the transgenic group with higher expression of myo-inositol. Magn Reson Med, 2012. (c) 2012 Wiley Periodicals, Inc.

Different lines of evidence suggest an abnormal cerebral energy metabolism as being critical to the pathophysiology of schizophrenia. However, it is unknown as to whether levels of creatine (Cr) would be involved in these anomalies. The study involved 33 unmedicated first episode psychosis patients and 41 healthy controls. Proton magnetic resonance spectroscopy (1H-MRS) was performed at 3 T using a long TE (TE/TM/TR of 240/27/3000 ms) such that within the total phosphocreatine (PCr) plus Cr signal (tCr240), mainly Cr was detectable. The target region was an 18 cm3 prefrontal volume. A negative association was found between age of patients and tCr240 levels referenced to internal water, with 20% of the variance in tCr240 accounted for by Age. A secondary finding revealed 16% reduction of tCr240 levels in patients, solely when comparing participants older than the median age of patients. No association existed between tCr240 levels and clinical variables. These findings support previous data reporting abnormalities in brain creatine kinase isoenzymes involved with the maintenance of energy pools in schizophrenia. The implications of using a long TE are discussed in terms of the relative proportions of Cr and PCr within the tCr240 signal, and of potential group differences in T2 times. Magn Reson Med, 2013. © 2012 Wiley Periodicals, Inc.

Muscle 1H magnetic resonance spectroscopy noninvasively measures intramyocellular lipid levels, which correlate with obesity, insulin resistance, and type 2 diabetes. The appearance of muscle magnetic resonance spectra is influenced by bulk magnetic susceptibility and residual dipolar couplings which depend on the angle between the muscle fibers and the main magnetic field. This study used a 4 T magnet to examine the influence of foot orientation on the appearance and quantification of muscle magnetic resonance spectra from the soleus and the vastus lateralis. For each individual, intramyocellular lipid, extramyocellular lipid, and creatine concentrations were quantified in the soleus and the vastus lateralis during one session. Foot orientation was found to influence the appearance of muscle spectra from the soleus but not from the vastus lateralis. It was concluded that quantifying intramyocellular lipid by the standard LCModel using a water reference may be more appropriate than using a creatine reference in the presence of residual dipolar couplings. Magn Reson Med, 2012. © 2012 Wiley Periodicals, Inc.

Aim of the study was to determine distribution and depletion patterns of intramyocellular lipids (IMCL) in leg muscles before and after two types of standardized endurance exercise. ¹H-magnetic resonance spectroscopic imaging was performed (1) in the thigh of eight-trained cyclists after exercising on an ergometer for 3 h at 52 ± 8% of maximal speed and (2) in the lower leg of eight-trained runners after exercising on a treadmill for 3 h at 49 ± 3% of maximal workload. Pre-exercise IMCL contents were reduced postexercise in 11 out of 13 investigated upper and lower leg muscles (P < 0.015 for all). A strong linear correlation with a slope of ∼0.5 between pre-exercise IMCL content and IMCL depletion was found. IMCL depletion differed strongly between muscles. Absolute and also relative IMCL reduction was significantly higher in muscles with predominantly slow fibers compared to those with fast fibers. Creatine levels and fiber orientation were stable and unchanged after exercise, while trimethyl-ammonium groups increased. This is presented in the accompanying paper. In conclusion, a systematic comparison of metabolic changes in cross sections of the upper and lower leg was performed. The results imply that pre-exercise IMCL levels determine the degree of IMCL depletion after exercise.

Organophosphates are highly toxic substances, which cause severe brain damage. The hallmark of the brain injury is major convulsions. The goal of this study was to assess the spatial and temporal MR changes in the brain of paraoxon intoxicated rats. T2-weighted MRI and ¹H-MR-spectroscopy were conducted before intoxication, 3 h, 24 h, and 8 days postintoxication. T2 prolongation mainly in the thalami and cortex was evident as early as 3 h after intoxication (4-6% increase in T2 values, P 20% decrease, P 15%, P < 0.05). Animals who succumbed had extensive cortical edema, significant higher lactate levels and a significant decrease in NAA/creatine and NAA/choline levels compared to animals which survived the experiment. Organophosphates-induced brain damage is obvious on MR data already 3 h postintoxication. In vivo spectroscopic changes are more sensitive for assessing long-term injury than T2-weighted MR imaging. Early spectroscopic findings might be used as biomarkers for the severity of the intoxication and might predict early survival.

Amide proton transfer imaging, a specific form of chemical exchange saturation transfer imaging, has previously been applied to studies of acute ischemic acidosis, stroke, and cancer. However, interpreting the resulting contrast is complicated by its dependence on the exchange rate between amides and water, the amide concentration, amide and water relaxation, and macromolecular magnetization transfer. Hence, conventional chemical exchange saturation transfer contrast is not specific to changes such as reductions in pH due to tissue acidosis. In this article, a multi-angle ratiometric approach based on several pulsed-chemical exchange saturation transfer scans at different irradiation flip angles is proposed to specifically reflect exchange rates only. This separation of exchange effects in pulsed-chemical exchange saturation transfer experiments is based on isolating rotation vs. saturation contributions, and such methods form a new subclass of chemical exchange rotation transfer (CERT) experiments. Simulations and measurements of creatine/agar phantoms indicate that a newly proposed imaging metric isolates the effects of exchange rate changes, independent of other sample parameters.

The longitudinal repeatability of proton MR spectroscopy ((1) H-MRS) in the healthy human brain at high fields over long periods is not established. Therefore, we assessed the inter- and intra-subject repeatability of (1) H-MRS in an approach suited for diffuse pathologies in 10 individuals, at 3T, annually for 3 years. Spectra from 480 voxels over 360 cm(3) (∼30%) of the brain, were individually phased, frequency-aligned, and summed into one average spectrum. This dramatically increases metabolites' signal-to-noise-ratios while maintaining narrow linewidths that improve quantification precision. The resulting concentrations of the N-acetylaspartate, creatine, choline, and myo-inositol are: 8.9 ± 0.8, 5.9 ± 0.6, 1.4 ± 0.1, and 4.5 ± 0.5 mM (mean ± standard-deviation). the inter-subject coefficients of variation are 8.7%, 10.2%, 10.7%, and 11.8%; and the longitudinal (intra-subject) coefficients of variation are lower still: 6.6%, 6.8%, 6.8%, and 10%, much better than the 35%, 44%, 55%, and 62% intra-voxel coefficients of variation. The biological and nonbiological components of the summed spectra coefficients of variation had similar contributions to the overall variance.