Modular 31 P wideband inversion transfer for integrative analysis of adenosine triphosphate metabolism, T1 relaxation and molecular dynamics in skeletal muscle at 7T.

PURPOSE: For efficient and integrative analysis of de novo adenosine triphosphate (ATP) synthesis, creatine-kinase-mediated ATP synthesis, T1 relaxation time, and ATP molecular motion dynamics in human skeletal muscle at rest. METHODS: Four inversion-transfer modules differing in center inversion frequency were combined to generate amplified magnetization transfer (MT) effects in targeted MT pathways, including Pi ↔ γ-ATP, PCr ↔ γ-ATP, and 31 Pγ(α)ATP ↔ 31 PßATP . MT effects from both forward and reverse exchange kinetic pathways were acquired to reduce potential bias and confounding factors in integrated data analysis. RESULTS: Kinetic data collected using 4 wideband inversion modules (8 minutes each) yielded the forward exchange rate constants, kPCr→γATP = 0.31 ± 0.05 s-1 and kPi→γATP = 0.064 ± 0.012 s-1 , and the reverse exchange rate constants, kγATP→Pi = 0.034 ± 0.006 s-1 and kγATP→PCr = 1.37 ± 0.22 s-1 , respectively. The cross-relaxation rate constant, σγ(α) ↔ ßATP was -0.20 ± 0.03 s-1 , corresponding to ATP rotational correlation time τc of 0.8 ± 0.1 × 10-7 seconds. The intrinsic T1 relaxation times were Pi (9.2 ± 1.4 seconds), PCr (6.2 ± 0.4 seconds), γ-ATP (1.8 ± 0.1 seconds), α-ATP (1.4 ± 0.1 seconds), and ß-ATP (1.1 ± 0.1 seconds). Muscle ATP T1 values were found to be significantly longer than those previously measured in the brain using a similar method. CONCLUSION: A combination of multiple inversion transfer modules provides a comprehensive and integrated analysis of ATP metabolism and molecular motion dynamics. This relatively fast technique could be potentially useful for studying metabolic disorders in skeletal muscle.

The pH heterogeneity in human calf muscle during neuromuscular electrical stimulation.

PURPOSE: The aim of the study was to examine pH heterogeneity during fatigue induced by neuromuscular electrical stimulation (NMES) using phosphorus magnetic resonance spectroscopy (31 P-MRS). It is hypothesized that three pH components would occur in the 31 P-MRS during fatigue, representing three fiber types. METHODS: The medial gastrocnemius of eight subjects was stimulated within a 3-Tesla whole body MRI scanner. The maximal force during stimulation (Fstim ) was examined by a pressure sensor. Phosphocreatine (PCr), adenosintriphosphate, inorganic phosphate (Pi), and the corresponding pH were estimated by a nonvolume-selective 31 P-MRS using a small loop coil at rest and during fatigue. RESULTS: During fatigue, Fstim and PCr decreased to 27% and 33% of their initial levels, respectively. In all cases, the Pi peak increased when NMES was started and split into three different peaks. Based on the single Pi peaks during fatigue, an alkaline (6.76 ± 0.08), a medium (6.40 ± 0.06), and an acidic (6.09 ± 0.05) pH component were observed compared to the pH (7.02 ± 0.02) at rest. CONCLUSION: It is suggested that NMES is able to induce pH heterogeneity in the medial gastrocnemius, and that the single Pi peaks represent the different muscle fiber types of the skeletal muscle. Magn Reson Med 77:2097-2106, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Band inversion amplifies 31 P-31 P nuclear overhauser effects: Relaxation mechanism and dynamic behavior of ATP in the human brain by 31 P MRS at 7 T.

PURPOSE: To develop an improved method to measure the 31 P nuclear Overhauser effect (NOE) for evaluation of adenosine triphosphate (ATP) dynamics in terms of correlation time (τc ), and contribution of dipole-dipole (DD) and chemical shift anisotropy (CSA) mechanisms to T1 relaxation of ATP in human brain. METHODS: The NOE of ATP in human brain was evaluated by monitoring changes in magnetization in the ß-ATP signal following a band inversion of all downfield 31 P resonances. The magnetization changes observed were analyzed using the Bloch-McConnell-Solomon formulation to evaluate the relaxation and motion dynamic parameters that describe interactions of ATP with cellular solids in human brain tissue. RESULTS: The maximal transient NOE, observed as a reduction in the ß-ATP signal, was 24 ± 2% upon band inversion of γ- and α-ATP, which is 2-3-fold higher than achievable by frequency-selective inversion of either γ- or α-ATP. The rate of 31 P-31 P cross relaxation (0.21 ± 0.02 s-1 ) led to a τc value of (9.1 ± 0.8) × 10-8 s for ATP in human brain. The T1 relaxation of ß-ATP is dominated by CSA over the DD mechanism (60%: 40%). CONCLUSIONS: The band inversion method proved effective in amplifying 31 P NOE, and thus facilitating ATP τc and relaxation measurements. This technique renders ATP a potentially useful reporter molecule for cellular environments. Magn Reson Med 77:1409-1418, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Interleaved multivoxel 31 P MR spectroscopy.

PURPOSE: Separate measurements are required when investigating multiple exercising muscles with singlevoxel-localized dynamic 31 P-MRS. With multivoxel spectroscopy, 31 P-MRS time-series spectra are acquired from multiple independent regions during one exercise-recovery experiment with the same time resolution as for singlevoxel measurements. METHODS: Multiple independently selected volumes were localized using temporally interleaved semi-LASER excitations at 7T. Signal loss caused by mutual saturation from shared excitation or refocusing slices was quantified at partial and full overlap, and potential contamination was investigated in phantom measurements. During an exercise-recovery experiment both gastrocnemius medialis and soleus of two healthy volunteers were measured using multivoxel acquisitions with a total TR of 6 s, while avoiding overlap of excitation slices. RESULTS: Signal reduction by shared adiabatic refocusing slices selected 1 s after the preceding voxel was between 10% (full overlap) and 20% (half overlap), in a phantom measurement. In vivo data were acquired from both muscles within the same exercise experiment, with 13-18% signal reduction. Spectra show phosphocreatine, inorganic phosphate, adenosine-triposphate, phosphomonoesters, and phosphodiesters. CONCLUSION: Signal decrease was relatively low compared to the 2-fold increase in information. The approach could help to improve the understanding in metabolic research and is applicable to other organs and nuclei. Magn Reson Med 77:921-927, 2017. © 2016 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Dynamic 31 P-MRSI using spiral spectroscopic imaging can map mitochondrial capacity in muscles of the human calf during plantar flexion exercise at 7 T.

Phosphorus MRSI (31 P-MRSI) using a spiral-trajectory readout at 7 T was developed for high temporal resolution mapping of the mitochondrial capacity of exercising human skeletal muscle. The sensitivity and localization accuracy of the method was investigated in phantoms. In vivo performance was assessed in 12 volunteers, who performed a plantar flexion exercise inside a whole-body 7 T MR scanner using an MR-compatible ergometer and a surface coil. In five volunteers the knee was flexed (~60°) to shift the major workload from the gastrocnemii to the soleus muscle. Spiral-encoded MRSI provided 16-25 times faster mapping with a better point spread function than elliptical phase-encoded MRSI with the same matrix size. The inevitable trade-off for the increased temporal resolution was a reduced signal-to-noise ratio, but this was acceptable. The phosphocreatine (PCr) depletion caused by exercise at 0° knee angulation was significantly higher in both gastrocnemii than in the soleus (i.e. 64.8 ± 19.6% and 65.9 ± 23.6% in gastrocnemius lateralis and medialis versus 15.3 ± 8.4% in the soleus). Spiral-encoded 31 P-MRSI is a powerful tool for dynamic mapping of exercising muscle oxidative metabolism, including localized assessment of PCr concentrations, pH and maximal oxidative flux with high temporal and spatial resolution.

The reproducibility of different metabolic markers for muscle fiber type distributions investigated by functional 31P-MRS during dynamic exercise.

PURPOSE: The objective of the study was to investigate the reproducibility of exercise induced pH-heterogeneity by splitting of the inorganic phosphate (Pi) signal in the corresponding 31P-MRS spectra and to compare results of this approach with other fiber-type related markers, like phosphocreatine/adenosine triphosphate (PCr/ATP) ratio, and PCr-recovery parameters. MATERIAL AND METHODS: Subjects (N=3) with different sportive background were tested in 10 test sessions separated by at least 3 days. A MR-compatible pedal ergometer was used to perform the exercise and to induce a pH-based splitting of the Pi-signal in 31P-MR spectra of the medial gastrocnemius muscle. The PCr recovery was analyzed using a non-negative least square algorithm (NNLS) and multi-exponential regression analysis to estimate the number of non-exponential components as well as their amplitude and time constant. The reproducibility of the estimated metabolic marker and the resulting fiber-type distributions between the 10 test sessions were compared. RESULTS: The reproducibility (standard deviation between measurements) based on (1) Pi components varied from 2% to 4%, (2) PCr recovery time components varied from 10% to 12% and (3) phosphate concentrations at rest varied from 8% to 11% between test sessions. Due to the sportive activity differences between the 3 subjects were expected in view of fiber type distribution. All estimated markers indicate the highest type I percentage for volunteer 3 medium for volunteer 2 and the lowest for volunteer 1. CONCLUSIONS: The relative high reproducibility of pH dependent Pi components during exercise indicates a high potential of this method to estimate muscle fiber-type distributions in vivo. To make this method usable not only to detect differences in muscle fiber distributions but also to determine individual fiber-type volume contents it is therefore recommended to validate this marker by histological methods and to reveal the effects of muscle fiber recruitments and fiber-type specific Pi concentrations on the intensity ratios between the splitted Pi-components.

In vivo (31) P MRS assessment of intracellular NAD metabolites and NAD(+) /NADH redox state in human brain at 4 T.

NAD(+) and NADH play key roles in cellular respiration. Intracellular redox state defined by the NAD(+) /NADH ratio (RX) reflects the cellular metabolic and physiopathological status. By taking advantage of high/ultrahigh magnetic field strengths, we have recently established a novel in vivo (31) P MRS-based NAD assay for noninvasive and quantitative measurements of intracellular NAD concentrations and redox state in animal and human brains at 16.4 T, 9.4 T and 7 T. To explore its potential for clinical application, in this study we investigated the feasibility of assessing the NAD metabolism and redox state in human brain at a lower field of 4 T by incorporating the (1) H-decoupling technique with the in vivo (31) P NAD assay. The use of (1) H decoupling significantly narrowed the linewidths of NAD and α-ATP resonances, resulting in higher sensitivity and better spectral resolution as compared with the (1) H-coupled (31) P spectrum. These improvements made it possible to reliably quantify cerebral NAD concentrations and RX, consistent with previously reported results obtained from similar age human subjects at 7 T. In summary, this work demonstrates the capability and utility of the (1) H-decoupled (31) P MRS-based NAD assay at lower field strength; thus, it opens new opportunities for studying intracellular NAD metabolism and redox state in human brain at clinical settings. This conclusion is supported by the simulation results, indicating that similar performance and reliability as observed at 4T can be achieved at 3 T with the same signal-to-noise ratio. Copyright © 2016 John Wiley & Sons, Ltd.

Whole-body radiofrequency coil for (31) P MRSI at 7 T.

Widespread use of ultrahigh-field (31) P MRSI in clinical studies is hindered by the limited field of view and non-uniform radiofrequency (RF) field obtained from surface transceivers. The non-uniform RF field necessitates the use of high specific absorption rate (SAR)-demanding adiabatic RF pulses, limiting the signal-to-noise ratio (SNR) per unit of time. Here, we demonstrate the feasibility of using a body-sized volume RF coil at 7 T, which enables uniform excitation and ultrafast power calibration by pick-up probes. The performance of the body coil is examined by bench tests, and phantom and in vivo measurements in a 7-T MRI scanner. The accuracy of power calibration with pick-up probes is analyzed at a clinical 3-T MR system with a close to identical (1) H body coil integrated at the MR system. Finally, we demonstrate high-quality three-dimensional (31) P MRSI of the human body at 7 T within 5 min of data acquisition that includes RF power calibration. Copyright © 2016 John Wiley & Sons, Ltd.

Performance and Limitations of Phosphate Quantification: Guidelines for Plant Biologists.

Phosphate (Pi) is a macronutrient that is essential for plant life. Several regulatory components involved in Pi homeostasis have been identified, revealing a very high complexity at the cellular and subcellular levels. Determining the Pi content in plants is crucial to understanding this regulation, and short real-time(33)Pi uptake imaging experiments have shown Pi movement to be highly dynamic. Furthermore, gene modulation by Pi is finely controlled by localization of this ion at the tissue as well as the cellular and subcellular levels. Deciphering these regulations requires access to and quantification of the Pi pool in the various plant compartments. This review presents the different techniques available to measure, visualize and trace Pi in plants, with a discussion of the future prospects.

Skeletal muscle dysfunction in the db/db mouse model of type 2 diabetes.

INTRODUCTION: In this study we examined the mechanisms of motor dysfunction in type 2 diabetes. METHODS: Contractile force was measured in isolated nerve-muscle preparations of db/db mice using various protocols for electrical stimulation. Sarcoplasmic reticulum Ca(2+) adenosine triphosphatase protein (SERCA) was quantified by comparing Ca(2+) -dependent and non-specific phosphorylation. RESULTS: Compared with controls, the muscle-nerve preparations of db/db mice displayed muscle atrophy, reduced axonal excitability, and force deficit when stimulated via the nerve. Muscle relaxation after contraction was slowed, and SERCA content was reduced. In contrast, the sensitivity of the neuromuscular junction to tubocurarine and muscle fiber excitability were not affected. CONCLUSIONS: The force deficit in db/db muscles was caused by atrophy and failure of neuromuscular signal transmission related to motor nerve axonal dysfunction. The slowed relaxation rate generally observed in diabetic muscles can, to a large extent, be explained by decreased SERCA pump content. Muscle Nerve 54: 460-468, 2016.

Simultaneous and interleaved acquisition of NMR signals from different nuclei with a clinical MRI scanner.

PURPOSE: Modification of a clinical MRI scanner to enable simultaneous or rapid interleaved acquisition of signals from two different nuclei. METHODS: A device was developed to modify the local oscillator signal fed to the receive channel(s) of an MRI console. This enables external modification of the frequency at which the receiver is sensitive and rapid switching between different frequencies. Use of the device was demonstrated with interleaved and simultaneous 31 P and 1 H spectroscopic acquisitions, and with interleaved 31 P and 1 H imaging. RESULTS: Signal amplitudes and signal-to-noise ratios were found to be unchanged for the modified system, compared with data acquired with the MRI system in the standard configuration. CONCLUSION: Interleaved and simultaneous 1 H and 31 P signal acquisition was successfully demonstrated with a clinical MRI scanner, with only minor modification of the RF architecture. While demonstrated with 31 P, the modification is applicable to any detectable nucleus without further modification, enabling a wide range of simultaneous and interleaved experiments to be performed within a clinical setting. Magn Reson Med 76:1636-1641, 2016. © 2015 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

2D AMESING multi-echo (31)P-MRSI of the liver at 7T allows transverse relaxation assessment and T2-weighted averaging for improved SNR.

PURPOSE: Liver diseases are a major global health concern often requiring invasive assessment by needle biopsy. (31)P magnetic resonance spectroscopic imaging (MRSI) allows non-invasive probing of important liver metabolites. Recently, the adiabatic multi-echo spectroscopic imaging sequence with spherical k-space sampling (AMESING) was introduced at 7T, enabling acquisition of T2 information. T2-weighed averaging of the multiple echoes improves signal-to-noise ratio (SNR). The purpose of our study was to implement AMESING MRSI of the liver at 3T and 7T, derive localized T2 information and compare T2-weighted average spectra in terms of SNR. METHODS: Ten male volunteers underwent 2D AMESING MRSI at 3T and 7T after a minimum four-hour fast. SNR was calculated for PC, PE, Pi, GPE, GPC and α-ATP using maximum peak amplitudes and the SD of the noise. Metabolite peak ratios were calculated after fitting in jMRUI. SNR values and peak ratios were compared with the Wilcoxon signed-rank test. RESULTS: For the first time liver metabolites' T2 values at 7T were measured: PE (55.6±3.5 ms), PC (51.2±2.3 ms), Pi (46.4±1.1 ms), GPE (44.0±0.8 ms), GPC (50.4±0.8 ms) and α-ATP (18.2±0.4 ms). SNR gain using T2-weighted averaging at 7T resulted in a 1.2× SNR gain. In conjunction with higher field strength and improved coil set-up T2-weighted averaging at 7T allowed a total 3.2× SNR gain compared to 3T FID-only. CONCLUSION: AMESING 2D MRSI of the liver at 7T provides T2 values that allow T2-weighted averaging of data from multiple echoes resulting in improved SNR.

Proton observed phosphorus editing (POPE) for in vivo detection of phospholipid metabolites.

The purpose of this article was to compare the sensitivity of proton observed phosphorus editing (POPE) with direct (31) P MRS with Ernst angle excitation for (1) H-(31) P coupled metabolites at 7 T. POPE sequences were developed for detecting phosphocholine (PC), phosphoethanolamine (PE), glycerophosphocholine (GPC), and glycerophosphoethanolamine (GPE) on the (1) H channel, thereby using the enhanced sensitivity of the (1) H nuclei over (31) P detection. Five healthy volunteers were examined with POPE and (31) P-MRS. POPE editing showed a more than doubled sensitivity in an ideal phantom experiment as compared with direct (31) P MRS with Ernst angle excitation. In vivo, despite increased relaxation losses, significant gains in signal-to-noise ratio (SNR) of 30-40% were shown for PE and GPE + PC levels in the human brain. The SNR of GPC was lower in the POPE measurement compared with the (31) P-MRS measurement. Furthermore, selective narrowband editing on the (31) P channel showed the ability to separate the overlapping GPE and PE signals in the (1) H spectrum. POPE can be used for enhanced detection of (1) H-(31) P coupled metabolites in vivo. Copyright © 2015 John Wiley & Sons, Ltd.

A simple approach to evaluate the kinetic rate constant for ATP synthesis in resting human skeletal muscle at 7 T.

Inversion transfer (IT) is a well-established technique with multiple attractive features for analysis of kinetics. However, its application in measurement of ATP synthesis rate in vivo has lagged behind the more common saturation transfer (ST) techniques. One well-recognized issue with IT is the complexity of data analysis in comparison with much simpler analysis by ST. This complexity arises, in part, because the γ-ATP spin is involved in multiple chemical reactions and magnetization exchanges, whereas Pi is involved in a single reaction, Pi → γ-ATP. By considering the reactions involving γ-ATP only as a lumped constant, the rate constant for the reaction of physiological interest, kPi→γATP , can be determined. Here, we present a new IT data analysis method to evaluate kPi→γATP using data collected from resting human skeletal muscle at 7 T. The method is based on the basic Bloch-McConnell equation, which relates kPi→γATP to m˙Pi, the rate of Pi magnetization change. The kPi→γATP value is accessed from m˙Pi data by more familiar linear correlation approaches. For a group of human subjects (n = 15), the kPi→γATP value derived for resting calf muscle was 0.066 ± 0.017 s(-1) , in agreement with literature-reported values. In this study we also explored possible time-saving strategies to speed up data acquisition for kPi→γATP evaluation using simulations. The analysis indicates that it is feasible to carry out a (31) P IT experiment in about 10 min or less at 7 T with reasonable outcome in kPi→γATP variance for measurement of ATP synthesis in resting human skeletal muscle. We believe that this new IT data analysis approach will facilitate the wide acceptance of IT to evaluate ATP synthesis rate in vivo. Copyright © 2015 John Wiley & Sons, Ltd.

Bloch-Siegert B1+-mapping for human cardiac (31) P-MRS at 7 Tesla.

PURPOSE: Phosphorus MR spectroscopy ((31) P-MRS) is a powerful tool for investigating tissue energetics in vivo. Cardiac (31) P-MRS is typically performed using surface coils that create an inhomogeneous excitation field across the myocardium. Accurate measurements of B1+ (and hence flip angle) are necessary for quantitative analysis of (31) P-MR spectra. We demonstrate a Bloch-Siegert B1+-mapping method for this purpose. THEORY AND METHODS: We compare acquisition strategies for Bloch-Siegert B1+-mapping when there are several spectral peaks. We optimize a Bloch-Siegert sensitizing (Fermi) pulse for cardiac (31) P-MRS at 7 Tesla (T) and apply it in a three-dimensional (3D) chemical shift imaging sequence. We validate this in phantoms and skeletal muscle (against a dual-TR method) and present the first cardiac (31) P B1+-maps at 7T. RESULTS: The Bloch-Siegert method correlates strongly (Pearson's r = 0.90 and 0.84) and has bias <25 Hz compared with a multi-TR method in phantoms and dual-TR method in muscle. Cardiac 3D B1+-maps were measured in five normal volunteers. B1+ maps based on phosphocreatine and alpha-adenosine-triphosphate correlated strongly (r = 0.62), confirming that the method is T1 insensitive. CONCLUSION: The 3D (31) P Bloch-Siegert B1+-mapping is consistent with reference methods in phantoms and skeletal muscle. It is the first method appropriate for (31) P B1+-mapping in the human heart at 7T. Magn Reson Med 76:1047-1058, 2016. © 2015 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Spectral improvement by fourier thresholding of in vivo dynamic spectroscopy data.

PURPOSE: MR spectroscopy (MRS) typically requires averaging of multiple acquisitions to achieve adequate signal-to-noise ratio (SNR). In systems undergoing dynamic changes this can compromise the temporal resolution of the measurement. One such example is (31) P MRS of exercising skeletal muscle. Spectral improvement by Fourier thresholding (SIFT) offers a way of suppressing noise without averaging. In this study, we evaluate the performance of SIFT in healthy subjects and clinical cases. METHODS: (31) P MRS of the calf or thigh muscle of subjects (n = 12) was measured continuously before, during, and after exercise. The data were processed conventionally and with the addition of SIFT before quantifying peak amplitudes and frequencies. The postexercise increase in the amplitude of phosphocreatine was also characterized by fitting with an exponential function to obtain the recovery time constant. RESULTS: Substantial reductions in the uncertainty of peak fitting for phosphocreatine (73%) and inorganic phosphate (60%) were observed when using SIFT relative to conventional processing alone. SIFT also reduced the phosphocreatine recovery time constant uncertainty by 38%. CONCLUSION: SIFT considerably improves SNR, which improved quantification and parameter estimation. It is suitable for any type of time varying MRS and is both straightforward and fast to apply. Magn Reson Med 76:978-985, 2016. © 2015 Wiley Periodicals, Inc.

In vivo (1)H MRS and (31)P MRSI of the response to cyclocreatine in transgenic mouse liver expressing creatine kinase.

Hepatocyte transplantation has been explored as a therapeutic alternative to liver transplantation, but a means to monitor the success of the procedure is lacking. Published findings support the use of in vivo (31)P MRSI of creatine kinase (CK)-expressing hepatocytes to monitor proliferation of implanted hepatocytes. Phosphocreatine tissue level depends upon creatine (Cr) input to the CK enzyme reaction, but Cr measurement by (1)H MRS suffers from low signal-to-noise ratio (SNR). We examine the possibility of using the Cr analog cyclocreatine (CCr, a substrate for CK), which is quickly phosphorylated to phosphocyclocreatine (PCCr), as a higher SNR alternative to Cr. (1)H MRS and (31)P MRSI were employed to measure the effect of incremental supplementation of CCr upon PCCr, γ-ATP, pH and Pi /ATP in the liver of transgenic mice expressing the BB isoform of CK (CKBB) in hepatocytes. Water supplementation with 0.1% CCr led to a peak total PCCr level of 17.15 ± 1.07 mmol/kg wet weight by 6 weeks, while adding 1.0% CCr led to a stable PCCr liver level of 18.12 ± 3.91 mmol/kg by the fourth day of feeding. PCCr was positively correlated with CCr, and ATP concentration and pH declined with increasing PCCr. Feeding with 1% CCr in water induced an apparent saturated level of PCCr, suggesting that CCr quantization may not be necessary for quantifying expression of CK in mice. These findings support the possibility of using (31)P MRS to noninvasively monitor hepatocyte transplant success with CK-expressing hepatocytes.

Dynamic correlations between hemodynamic, metabolic, and neuronal responses to acute whole-brain ischemia.

Cerebral ischemia sets off a cascade of neuronal and metabolic responses to preserve brain viability. An understanding of the temporal evolution of these changes during and after ischemia, and their correlation with hemodynamic changes, is essential. In this study, a 12-min whole-brain ischemia based on the four-blood-vessel occlusion model was employed in rats. Using a high-temporal-resolution simultaneous (1)H-(31)P MRS acquisition sequence at 9.4 T, we investigated dynamic occlusion and reperfusion responses in cerebral lactate (Lac), phosphocreatine (PCr), adenosine triphosphate (ATP), pH, and blood oxygenation level dependence (BOLD), together with changes in neuronal field potential activity. We reveal tightly coupled dynamics between hemodynamic, metabolic, and neuronal responses to ischemia. Neuronal activity, BOLD, PCr, Lac, and pH changed immediately following occlusion, indicating reduced energy substrates and consumption, and increased glycolysis to maintain cellular ATP levels, which started to decrease 2.2 min after the onset of occlusion. ATP stores were then gradually consumed to maintain a minimum housekeeping neuronal activity level. By correlating dynamic changes of brain activity, BOLD, and energy metabolism, new insights into the brain's survival ability and mechanisms during an acute ischemic attack from the perspectives of cerebral metabolism, neuroenergetics, and neuronal activity were gained.

Glutamatergic dysfunction linked to energy and membrane lipid metabolism in frontal and anterior cingulate cortices of never treated first-episode schizophrenia patients.

BACKGROUND: Glutamatergic dysfunction and altered membrane lipid and energy metabolism have been repeatedly demonstrated in the frontal/prefrontal and anterior cingulate cortex (ACC) in schizophrenia. Though having been already studied in animals, the presumed link between glutamatergic function and structural plasticity has not been investigated directly in the human brain yet. We measured glutamate (Glu), focal energy metabolism, and membrane phospholipid turnover to investigate main pathologies in those key brain regions of schizophrenia. METHODS: (1)H- and (31)P-Chemical Shift Imaging (CSI) was combined in a single session to assess Glu and markers of energy (PCr, ATP) and membrane lipid (PME, PDE) metabolism in 31 neuroleptic-naïve first acute onset psychosis patients and 31 matched healthy controls. Multivariate analyses of covariance were used to assess disease effects on Glu and to investigate the impact of Glu alterations on phospholipid and energy metabolites. RESULTS: Glu levels of patients were increased in the frontal and prefrontal cortex bilaterally and in the ACC. Higher Glu was associated with increased left frontal/prefrontal PME and right frontal/prefrontal PDE in patients, which was not observed in healthy controls. In contrast, higher Glu levels were associated with lower PCr or ATP values in the frontal/prefrontal cortex bilaterally and in the right ACC of controls. This was not observed in the right ACC and left frontal/prefrontal cortex of patients. CONCLUSION: Frontal glutamatergic hyperactivity is disconnected from physiologically regulated energy metabolism and is associated with increased membrane breakdown in right and increased membrane restoration in left frontal and prefrontal cortical regions. As indicated by previous findings, this pathology is likely dynamic during the course of first acute illness and possibly associated with negative symptoms and cognitive impairment. Our findings underline the importance of further research on neuroprotective treatment options during the early acute or even better for the ultra-high risk state of psychotic illness.

Multiparametric MRI With Dynamic Contrast Enhancement, Diffusion-Weighted Imaging, and 31-Phosphorus Spectroscopy at 7 T for Characterization of Breast Cancer.

OBJECTIVES: To describe and to correlate tumor characteristics on multiparametric 7 tesla (T) breast magnetic resonance imaging (MRI) with prognostic characteristics from postoperative histopathology in patients with breast cancer. MATERIALS AND METHODS: Institutional review board approval and written informed consent of 15 women (46-70 years) with 17 malignant lesions were obtained. In this prospective study (March 2013 to March 2014), women were preoperatively scanned using dynamic contrast-enhanced MRI, diffusion-weighted imaging, and 31-phosphorus spectroscopy (¹³P-MRS). The value of the protocol was assessed to quantify tumor differentiation and proliferation. Dynamic contrast-enhanced MRI was assessed according to the American College of Radiology Breast Imaging Reporting and Data System-MRI lexicon. Apparent diffusion coefficients (ADCs) were calculated from diffusion-weighted imaging. On ¹³P-MRS, at the location of the tumor, the amount of phosphorus components was obtained in a localized spectrum. In this spectrum, the height of phosphodiester (PDE) and phosphomonoester (PME) peaks was assessed to serve as a measure for metabolic activity, stratifying tumors into a PDE > PME, PDE = PME, or PDE < PME group. Tumor grade and mitotic count from resection specimen were compared with the MRI characteristics using explorative analyses. RESULTS: On dynamic contrast-enhanced MRI, the mean tumor size was 24 mm (range, 6-55 mm). An inverse trend was seen between ADC and tumor grade (P = 0.083), with mean ADC of 867 × 10⁻6 mm²/s for grade 1 (N = 4), 751 × 10⁻6 mm²/s for grade 2 (N = 6), and 659 × 10⁻6 mm²/s for grade 3 (N = 2) tumors. Between P-MR spectra and mitotic count, a relative increase of PME over PDE showed significant association with increasing mitotic counts (P = 0.02); a mean mitotic count of 6 was found in the PDE greater than PME group (N = 7), 8 in the PDE = PME group (N = 1), and 17 in the PDE < PME group (N = 3). CONCLUSIONS: Multiparametric 7 T breast MRI is feasible in clinical setting and shows association between ADC and tumor grade, and between ¹³P-MRS and mitotic count.