PASADENA hyperpolarization of 13C biomolecules: equipment design and installation

Object  The PASADENA method has achieved hyperpolarization of 16–20% (exceeding 40,000-fold signal enhancement at 4.7 T), in liquid samples of biological molecules relevant to in vivo MRI and MRS. However, there exists no commercial apparatus to perform this experiment conveniently and reproducibly on the routine basis necessary for translation of PASADENA to questions of biomedical importance. The present paper describes equipment designed for rapid production of six to eight liquid samples per hour with high reproducibility of hyperpolarization. Materials and methods  Drawing on an earlier, but unpublished, prototype, we provide diagrams of a delivery circuit, a laminar-flow reaction chamber within a low field NMR contained in a compact, movable housing. Assembly instructions are provided from which a computer driven, semi-automated PASADENA polarizer can be constructed. Results  Together with an available parahydrogen generator, the polarizer, which can be operated by a single investigator, completes one cycle of hyperpolarization each 52 s. Evidence of efficacy is presented. In contrast to competing, commercially available devices for dynamic nuclear polarization which characteristically require 90 min per cycle, PASADENA provides a low-cost alternative for high throughput. Conclusions  This equipment is suited to investigators who have an established small animal NMR and wish to explore the potential of heteronuclear (¹³ C and ¹⁵ N) MRI, MRS, which harnesses the enormous sensitivity gain offered by hyperpolarization.     

Ultra-fast three dimensional imaging of hyperpolarized 13C in vivo

Objective: PASADENA, a chemical method of enhancing nuclear spin polarization has demonstrated ¹³C polarizations of order unity for the nascent products of molecular addition by parahydrogen. The extreme brevity of signal enhancement obtained by hyperpolarization requires improved ¹³C MR in vivo imaging techniques for their optimum utility. Materials and Methods: ¹³C imaging sequences, including ¹³C 3D FIESTA, were compiled for a GE LX 1.5 T clinical MR scanner. Two water soluble ¹³C imaging agents were hyperpolarized utilizing parahydrogen and an automated polarizer. ¹³C polarization was quantified in flow phantoms and in rats with jugular vein catheters. Results: Fast 3D FIESTA ¹³C MR imaging technique acquired sequential 3D images (3.66 s/acquisition) with superior SNR. Hyperpolarized ¹³C solutions and vascular phantoms achieved a maximum signal of 26,624±593. In vivo ¹³C MR images of the cardiopulmonary circulation showed maximum ¹³C signal of 2,402±158. ¹³C images acquired within 3.66 s showed signal enhancement over 10,000 compared to equilibrium polarization. Conclusion: 3D-FIESTA was effective for sub-second in vivo imaging of hyperpolarized ¹³C reagents produced in a custom-built parahydrogen polarizer. Application to ¹³C hyperpolarized by parahydrogen is demonstrated in vitro and in vivo     

Fast multiecho balanced SSFP metabolite mapping of 1H and hyperpolarized 13C compounds

Object  To investigate the feasibility of multiecho balanced steady-state free precession (bSSFP)-based fast chemical shift mapping hyperpolarized ¹³C metabolites. The overall goal was to reduce total imaging time and to increase spatial resolution compared to common chemical shift imaging (CSI). Materials and methods  A multiecho bSSFP sequence in combination with an iterative reconstruction algorithm was implemented. ¹H experiments were performed on phantoms and on a human volunteer in order to investigate the feasibility of the method on a system with metabolite maps that are known beforehand. ¹³C experiments were performed in vivo on pigs, where CSI images were acquired also for comparison. Results  Chemical shift images of three and four distinct ¹H resonance frequencies as well as chemical shift images of up to five hyperpolarized ¹³C metabolites were successfully obtained. Conclusion  Fast metabolite mapping based on multiecho balanced SSFP in combination with an iterative reconstruction approach could successfully separate several ¹H resonances and hyperpolarized ¹³C metabolites.     

In vivo 13C chemical shift imaging of the human liver

Chemical shift imaging (CSI) was applied to measure natural abundance proton-decoupled¹³C-NMR spectra of the human liver. Large surface coils were designed for¹³C spectra acquisition (16-cm-diameter circular coil) as well as for proton imaging and decoupling (21×20-cm butterfly coil). Such sizes allowed deep observations of the abdomen. A space matrix of 8×4 voxels (4×8 cm each) was defined using 32 phase-encoding steps. Magnetic field gradients were adjusted on multicompartment phantoms to limit contamination between voxels. Spectral maps containing {¹H}-¹³C spectra of liver from healthy volunteers with an acceptable signal-to-noise ratio were recorded within 20 min. Liver spectra exhibited well-defined resonances corresponding to fatty acyl chains, carbonyl groups, and sugars. The (C-l)-glycogen resonance was also detected under such conditions. Such a technique would be of interest in the development of metabolic investigations on the human liverin vivo.     

Contribution of various substrates to total citric acid cycle flux and ]anaplerosis as determined by13C isotopomer analysis and O2 consumption in the heart

A simple relationship between parameters derived from a¹³C NMR isotopomer analysis and O₂ consumption is presented that allows measurement of the absolute rate of acetyl-CoA oxidation and anaplerotic flux in tissues oxidizing a mixture of four substrates. The method was first applied in a study of the effects of work state and -adrenergic stimulation on net acetate oxidation and anaplerosis in the isolated working rat heart. The results demonstrate that the anticipated ratio of 2 between O₂ consumption and TCA cycle flux for hearts oxidizing only acetate holds at low workload when anaplerosis is low, but deviates toward a factor of 3 under high workload conditions when anaplerosis is increased. This analysis was also extended to hearts that oxidize a more physiological mixture of substrates including long-chain fatty acids, acetoacetate, lactate, pyruvate, and glucose. We show that the contribution each substrate makes to total TCA cycle flux can be determined by combined¹³C NMR and O₂ consumption measurements. The present study also demonstrates that stimulation of anaplerosis (by addition of propionate) can significantly alter the relative contribution each substrate makes to total TCA cycle flux. We conclude that if¹³C labeling patterns are selected appropriately, a comprehensive picture of flux through all major metabolic pathways feeding the cycle can be determined in a single experiment even when complex physiological mixtures of substrates are provided.     

Functional and metabolic evaluation of the hypertrophied heart using MRI and31P-MRS

4. Conclusions Diastolic LV function and myocardial HEP metabolism are impaired only when LVH is caused by permanent pressure or volume overload, and not by a temporary increase in cardiac workload during part of the day as in elite athletes. Therefore, training-induced and pressure/volume-overload-induced LVH seem to represent different phenotypes of LVH, possibly related to genetic reprogramming which only occurs during permanent cardiac overload [17]. Moreover, there is an association between impaired LV diastolic function and altered myocardial HEP metabolism in patients with hypertension and in patients with aortic valve disease. Finally we did not find a correlation between myocardial HEP metabolism and LV mass in any of the groups studied. The latter indicates that LVH should be regarded as an epiphenomenon to cardiac overload, and not as a primary factor causing abnormal HEP metabolism.     

The effect of decalcification on the microstructure of articular cartilage assessed by 2H double quantum filtered spectroscopic MRI

²H quadrupolar splitting of deuterated water molecules is a sensitive measure of the order and density of the collagen fibers in articular cartilage. In the calcified zone, near the bone, two pairs of quadrupolar split satellites were previously observed. To examine whether the large splitting observed originates from the presence of calcium ions and hydroxyapatite, one-dimensional ²H single and double quantum filtered spectroscopic imaging were performed on articular cartilage-bone plugs before and after decalcification. After decalcification, the magnitude splitting of the two pairs of satellites did not change and orientation dependency was kept. However, the intensity of the large splitting was greatly enhanced. According to these results the two pairs of satellites do not stem from the presence of calcium ions and hydroxyapatite but originate from the presence of two groups of collagen fibers with different degrees of hydration. The enhanced intensity of the large splitting is attributed to an increased amount of water molecules that fill the void, resulting from the removal of hydroxyapatite, which resides near the fibers responsible for the large splitting. The quadrupolar splitting observed in the trabecular bone was not orientation-dependent, indicating a random orientation of the collagen fibers in that tissue.     

Dual resonant birdcage coils for1H detected13C microscopic imaging at 11.7 T

Liquid state, rotating frame cross polarisation experiments are very sensitive to RF field inhomogeneity. In this work, we present an easily fabricated, co-resident high- and low-pass linear birdcage resonator, optimised to perform liquid state rotating frame polarisation transfer at¹H and¹³C frequencies. Both the RF fields have been experimentally mapped, and used to validate the spatial signal dependence of a proton detected,¹³C image. The predicted performance was then confirmed using PRAWN-based, cyclic J-cross polarisation (CYCLCROP) imaging. A novel variant of a B₁-field mapping approach is also presented, using the signal enhancement of the CYCLCROP sequence to generate proton detected,¹³C field maps.     

Physiological constraints on changes in pH and phosphorus metabolite concentrations in ischemically exercising muscle: implications for metabolic control and for the interpretation of31P-magnetic resonance spectroscopic studies

Relationships between pH and the concentrations of phosphocreatine (PCr), inorganic phosphate (Pi), and lactate during ischemic exercise depend on passive buffering, proton consumption as a consequence of net PCr breakdown, the control of glycogenolysis, (particularly in relation to the concentration of Pi, a substrate of glycogen phosphorylase that is produced by net PCr breakdown), and the creatine kinase equilibrium. The author analyzes the implications of these relationships for the interpretation of³¹P-magnetic resonance spectroscopic data and for the control of glycogenolysis. For realistic adenosine diphosphate (ADP) concentrations, given the constraints of the creatine kinase equilibrium, the pH must be near-linear with lactate, with an apparent buffer capacity (i.e., the ratio of lactate accumulation to pH change) that is nearly twice the true buffer capacity (i.e., the ratio of net proton loading to pH change). The implications for glycogenolytic control depend on adenosine triphosphate (ATP) turnover, but an upper limit of activation of glycogen phosphorylase (i.e., the amount of thea form) that would permit no increase in ADP concentration can be calculated. Phosphorylase activation during ischemic exercise seems approximately proportional to the power output, consistent with calcium stimulation of phosphorylaseb kinase. In simulations, ADP concentration is highly sensitive to this proportionality, as (unlike in purely oxidative exercise) ADP concentration is not known to participate in any closed feedback loops in ischemic exercise.     

Data disturb characteristics of 1T2C ferroelectric memory array

Abstract

The data disturb characteristics of a newly proposed 1T2C-type ferroelectric memory with an array structure were investigated, in which one ferroelectric capacitor C_fa was used for storing data and the other capacitor C_fb was used for reading out the data. It was found that the data disturb problem in write operation was much improved by using a lower write voltage and a compensation pulse. It was also demonstrated that the use of a thicker film in C_fa was a very effective approach for realizing reliable disturb-free read-out operation.     

The role of relaxation time corrections for the evaluation of long and short echo time <Superscript>1</Superscript>H MR spectra of the hippocampus by NUMARIS and LCModel techniques

1H MR spectroscopy is routinely used for lateralization of epileptogenic lesions. The present study deals with the role of relaxation time corrections for the quantitative evaluation of long (TE=135 ms) and short echo time (TE=10 ms) 1H MR spectra of the hippocampus using two methods (operator-guided NUMARIS and LCModel programs). Spectra of left and right hippocampi of 14 volunteers and 14 patients with epilepsy were obtained by PRESS (TR/TE=5000/135 ms) and STEAM (TR/TE=5000/10 ms) sequences with a 1.5-T imager. Evaluation was carried out using Siemens NUMARIS software and the results were compared with data from LCModel processing software. No significant differences between the two methods of processing spectra with TE=135 ms were found. The range of relaxation corrections was determined. Metabolite concentrations in hippocampi calculated from spectra with TE=135 ms and 10 ms after application of correction coefficients did not differ in the range of errors and agreed with published data (135 ms/10 ms: NAA=10.2±0.6/10.4±1.3 mM, Cho=2.4±0.1/2.7±0.3 mM, Cr=12.2±1.3/11.3±1.3 mM). When relaxation time corrections were applied, quantitative results from short and long echo time evaluation with LCModel were in agreement. Signal intensity ratios obtained from long echo time spectra by NUMARIS operator-guided processing also agreed with the LCModel results.     

Transmit/receive headcoil for optimal <Superscript>1</Superscript>H MR spectroscopy of the brain in paediatric patients at 3 T

¹H magnetic resonance (MR) spectroscopy is a useful tool to obtain metabolic information from the brain in paediatric patients. To detect signals of metabolites at low concentrations or from small volumes, the signal-to-noise ratio (SNR) has to be optimized. The SNR can be increased by going to higher field strengths. However, this leads to higher spectral bandwidths, which increases the chemical shift artefact. Here we present a transmit/receive headcoil which is adapted to the dimensions of the paediatric head and enables PRESS localization with high radio-frequency (RF) bandwidths that minimize the chemical shift displacement to only 5%. In addition, since the pulse lengths are shorter with higher RF bandwidths, the echo time can be reduced to 10 ms improving SNR as well.Parts of this work have been presented at the European Society for Magnetic Resonance in Medicine and Biology in Rotterdam in 2003     

Versatile coil design and positioning of transverse-field RF surface coils for clinical 1.5-T MRI applications

Clinical MRI/MRS applications require radio frequency (RF) surface coils positioned at an arbitrary angle with respect to B₀. In these experimental conditions the standard circular loop (CL) coil, producing an axial RF field, shows a large signal loss in the central region of interest (ROI). We demonstrate that transverse-field figure-of-eight (FO8) RF surface coils design are not subject to the same amount of signal loss in the central ROI as loop coils when their orientations are changed. The 1.5-T CL and FO8 prototypes (diameter = 10 cm) were built on Plexiglas using copper strips (width = 4 mm, thickness = 100 m). The two linear elements of the FO8 coil were 1 cm apart. Axial spoiled gradient echo (SPGR) images of a phantom containing doped water were acquired with the coil plane at =0°, 45°, and 90°. As increases, the CL images show, in the central ROI, a signal that decreases from a maximum value to zero. Whereas the FO8 images show, in the same ROI, a signal that varies little from the maximum value (20%). Optimized FO8 coils can be oriented with the coil plane positioned along any direction with respect to B₀ without significant signal loss. Transverse RF coil design should be useful for clinical MRS studies and also for parallel imaging techniques where versatile RF coils disposed along arbitrary directions are required.     

Comparison of three commercially available radio frequency coils for human brain imaging at 3 Tesla

Objective To evaluate a transverse electromagnetic (TEM), a circularly polarized (CP) (birdcage), and a 12-channel phased array head coil at the clinical field strength of B ₀ = 3T in terms of signal-to-noise ratio (SNR), signal homogeneity, and maps of the effective flip angle α. Materials and methods SNR measurements were performed on low flip angle gradient echo images. In addition, flip angle maps were generated for α_nominal = 30° using the double angle method. These evaluation steps were performed on phantom and human brain data acquired with each coil. Moreover, the signal intensity variation was computed for phantom data using five different regions of interest. Results In terms of SNR, the TEM coil performs slightly better than the CP coil, but is second to the smaller 12-channel coil for human data. As expected, both the TEM and the CP coils show superior image intensity homogeneity than the 12-channel coil, and achieve larger mean effective flip angles than the combination of body and 12-channel coil with reduced radio frequency power deposition. Conclusion At 3T the benefits of TEM coil design over conventional lumped element(s) coil design start to emerge, though the phased array coil retains an advantage with respect to SNR performance.     

Application of LCModel for quality control and quantitative in vivo1H MR spectroscopy by short echo time STEAM sequence

The linear combination of model spectra (LCModel) calculation of a parameter for long-term quality control,k _T, was introduced, representing the ratio of the temporal and nominal intensities of CH₃ groups of lactate and acetate in a quality control phantom. This procedure is a part of the quality assurance of the scanner using fully automatic measurement and calculation ofk _T parameters, and utilizing Shewhart regulation control charts for continuous evaluation of the magnetic resonance (MR) scanner setting. The application of thek _T parameter for the correction of in vivo data increases the precision of molar concentration determination by about 4%. This was tested by the quantitative in vivo MR determination of the molar concentrations of 13 prominent metabolites (N-acetylaspartate (NAA),N-acetylaspartylgutamate, creatine and phosphocreatine (Cr), choline-containing compounds (Cho), myo-inositol, scyllo-inositol., γ-aminobutyric acid, glutamine, glutamate, glucose, lactate, alanine, taurine) in the white matter and hippocampus of the brain in groups of volunteers, using a short echo time stimulated echo acquisition mode sequence (echo time =10 ms) and the LCModel technique. The repeatability of the measurement of prominent metabolites such as NAA, Cr and Cho was found to be around 10% (relative standard deviation,n=6); precision in a group of volunteers (n=20 and 28, respectively) was in the range of approximately 13–20%. For other metabolites, which are measured with a lower signal-to-noise ratio, the precision can be much lower.