Meng Gu

Quantification of in vivo metabolic kinetics of hyperpolarized pyruvate in rat kidneys using dynamic 13C MRSI.

With signal‐to‐noise ratio enhancements on the order of 10,000‐fold, hyperpolarized MRSI of metabolically active substrates allows the study of both the injected substrate and downstream metabolic products in vivo. Although hyperpolarized [1‐13C]pyruvate, in particular, has been used to demonstrate metabolic activities in various animal models, robust quantification and metabolic modeling remain important areas of investigation. Enzyme saturation effects are routinely seen with commonly used doses of hyperpolarized [1‐13C]pyruvate; however, most metrics proposed to date, including metabolite ratios, time‐to‐peak of metabolic products and single exchange rate constants, fail to capture these saturation effects. In addition, the widely used small‐flip‐angle excitation approach does not correctly model the inflow of fresh downstream metabolites generated proximal to the target slice, which is often a significant factor in vivo. In this work, we developed an efficient quantification framework employing a spiral‐based dynamic spectroscopic imaging approach. The approach overcomes the aforementioned limitations and demonstrates that the in vivo 13C labeling of lactate and alanine after a bolus injection of [1‐13C]pyruvate is well approximated by saturatable kinetics, which can be mathematically modeled using a Michaelis–Menten‐like formulation, with the resulting estimated apparent maximal reaction velocity Vmax and apparent Michaelis constant KM being unbiased with respect to critical experimental parameters, including the substrate dose, bolus shape and duration. Although the proposed saturatable model has a similar mathematical formulation to the original Michaelis–Menten kinetics, it is conceptually different. In this study, we focus on the 13C labeling of lactate and alanine and do not differentiate the labeling mechanism (net flux or isotopic exchange) or the respective contribution of various factors (organ perfusion rate, substrate transport kinetics, enzyme activities and the size of the unlabeled lactate and alanine pools) to the labeling process. Copyright

In vivo glutamate measured with magnetic resonance spectroscopy: behavioral correlates in aging.

Altered availability of the brain biochemical glutamate might contribute to the neural mechanisms underlying age-related changes in cognitive and motor functions. To investigate the contribution of regional glutamate levels to behavior in the aging brain, we used an in vivo magnetic resonance spectroscopy protocol optimized for glutamate detection in 3 brain regions targeted by cortical glutamatergic efferents-striatum, cerebellum, and pons. Data from 61 healthy men and women ranging in age from 20 to 86 years were used. Older age was associated with lower glutamate levels in the striatum, but not cerebellum or pons. Older age was also predictive of poorer performance on tests of visuomotor skills and balance. Low striatal glutamate levels were associated with high systolic blood pressure and worse performance on a complex visuomotor task, the Grooved Pegboard. These findings suggest that low brain glutamate levels are related to high blood pressure and that changes in brain glutamate levels might mediate the behavioral changes noted in normal aging.

Reproducibility study of whole-brain 1H spectroscopic imaging with automated quantification.

A reproducibility study of proton MR spectroscopic imaging (1H‐MRSI) of the human brain was conducted to evaluate the reliability of an automated 3D in vivo spectroscopic imaging acquisition and associated quantification algorithm. A PRESS‐based pulse sequence was implemented using dualband spectral‐spatial RF pulses designed to fully excite the singlet resonances of choline (Cho), creatine (Cre), and N‐acetyl aspartate (NAA) while simultaneously suppressing water and lipids; 1% of the water signal was left to be used as a reference signal for robust data processing, and additional lipid suppression was obtained using adiabatic inversion recovery. Spiral k‐space trajectories were used for fast spectral and spatial encoding yielding high‐quality spectra from 1 cc voxels throughout the brain with a 13‐min acquisition time. Data were acquired with an 8‐channel phased‐array coil and optimal signal‐to‐noise ratio (SNR) for the combined signals was achieved using a weighting based on the residual water signal. Automated quantification of the spectrum of each voxel was performed using LCModel. The complete study consisted of eight healthy adult subjects to assess intersubject variations and two subjects scanned six times each to assess intrasubject variations. The results demonstrate that reproducible whole‐brain 1H‐MRSI data can be robustly obtained with the proposed methods. Magn Reson Med 60:542–547, 2008.

Multivendor implementation and comparison of volumetric whole-brain echo-planar MR spectroscopic imaging

To assess volumetric proton MR spectroscopic imaging (MRSI) of the human brain on multivendor MRI instruments.

Parallel Spectroscopic Imaging Reconstruction with Arbitrary Trajectories Using k-Space Sparse Matrices

Parallel imaging reconstruction has been successfully applied to magnetic resonance spectroscopic imaging (MRSI) to reduce scan times. For undersampled k‐space data on a Cartesian grid, the reconstruction can be achieved in image domain using a sensitivity encoding (SENSE) algorithm for each spectral data point. Alternative methods for reconstruction with undersampled Cartesian k‐space data are the SMASH and GRAPPA algorithms that do the reconstruction in the k‐space domain. To reconstruct undersampled MRSI data with arbitrary k‐space trajectories, image‐domain‐based iterative SENSE algorithm has been applied at the cost of long computing times. In this paper, a new k‐space domain‐based parallel spectroscopic imaging reconstruction with arbitrary k‐space trajectories using k‐space sparse matrices is applied to MRSI with spiral k‐space trajectories. The algorithm achieves MRSI reconstruction with reduced memory requirements and computing times. The results are demonstrated in both phantom and in vivo studies. Spectroscopic images very similar to that reconstructed with fully sampled spiral k‐space data are obtained at different reduction factors. Magn Reson Med 61:267–272, 2009.

B1 and T1 insensitive water and lipid suppression using optimized multiple frequency‐selective preparation pulses for whole‐brain 1H spectroscopic imaging at 3T

A new method for the simultaneous suppression of water and lipid resonances using a series of dual‐band frequency‐selective radiofrequency (RF) pulses with associated dephasing gradients is presented. By optimizing the nutation angles of the individual pulses, the water and lipid suppression is made insensitive to a range of both T1‐relaxation times and B1 inhomogeneities. The method consists only of preparatory RF pulses and thus can be combined with a wide variety of MRSI schemes including both long and short TE studies. Simulations yield suppression factors, in the presence of ±20% B1 inhomogeneity, on the order of 100 for lipid peaks with three different T1s (300 ms, 310 ms, and 360 ms), and water peaks with T1s ranging from 0.8 s to 4 s. Excellent in vivo study performance is demonstrated using a 3 Tesla volumetric proton spectroscopic imaging (1H‐MRSI) sequence for measuring the primary brain metabolites peaks of choline (Cho), creatine (Cr), and N‐acetyl aspartate (NAA). Magn Reson Med 61:462–466, 2009.

Association of Metabolite Concentrations and Water Diffusivity in Normal Appearing Brain Tissue with Glioma Grade

Studies of brain tumors have identified altered tissue metabolism and water diffusion in MRI normal appearing tissue regions. In this retrospective study the relationship of these imaging measures with tumor grade in gliomas was investigated.

Quantification of glutamate and glutamine using constant-time point-resolved spectroscopy at 3 T

Separate quantification of glutamate (Glu) and glutamine (Gln) using conventional MRS on clinical scanners is challenging. In previous work, constant‐time point‐resolved spectroscopy (CT‐PRESS) was optimized at 3 T to detect Glu, but did not resolve Gln. To quantify Glu and Gln, a time‐domain basis set was constructed taking into account metabolite T2 relaxation times and dephasing from B0 inhomogeneity. Metabolite concentrations were estimated by fitting the basis one‐dimensional CT‐PRESS diagonal magnitude spectra to the measured spectrum. This method was first validated using seven custom‐built phantoms containing variable metabolite concentrations, and then applied to in vivo data acquired in rats exposed to vaporized ethanol and controls. Separate metabolite quantification revealed increased Gln after 16 weeks and increased Glu after 24 weeks of vaporized ethanol exposure in ethanol‐treated compared with control rats. Without separate quantification, the signal from the combined resonances of Glu and Gln (Glx) showed an increase at both 16 and 24 weeks in ethanol‐exposed rats, precluding the determination of the independent and differential contribution of each metabolite at each time. Copyright

Aberrant basal ganglia metabolism in fragile X syndrome: a magnetic resonance spectroscopy study

BackgroundThe profile of cognitive and behavioral variation observed in individuals with fragile X syndrome (FXS), the most common known cause of inherited intellectual impairment, suggests aberrant functioning of specific brain systems. Research investigating animal models of FXS, characterized by limited or lack of fragile X mental retardation protein, (FMRP), has linked brain dysfunction to deficits in the cholinergic and glutamatergic systems. Thus, we sought to examine in vivo levels of neurometabolites related to cholinergic and glutamatergic functioning in males and females with FXS.MethodsThe study participants included 18 adolescents and young adults with FXS, and a comparison group of 18 individuals without FXS matched for age, sex and general intellectual functioning. Proton magnetic resonance spectroscopy (MRS) was used to assess neurometabolite levels in the caudate nucleus, a region known to be greatly enlarged and involved in abnormal brain circuitry in individuals with FXS. A general linear model framework was used to compare group differences in metabolite concentration.ResultsWe observed a decrease in choline (P = 0.027) and in glutamate + glutamine (P = 0.032) in the caudate nucleus of individuals with FXS, relative to individuals in the comparison group.ConclusionsThis study provides evidence of metabolite differences in the caudate nucleus, a brain region of potential importance to our understanding of the neural deficits underlying FXS. These metabolic differences may be related to aberrant receptor signaling seen in animal models. Furthermore, identification of the specific neurometabolites involved in FXS dysfunction could provide critical biomarkers for the design and efficacy tracking of disease-specific pharmacological treatments.

A proton MR spectroscopy study of the thalamus in twins with autism spectrum disorder

&NA; Multiple lines of research have reported thalamic abnormalities in individuals with autism spectrum disorder (ASD) that are associated with social communication impairments (SCI), restricted and repetitive behaviors (RRB), or sensory processing abnormalities (SPA). Thus, the thalamus may represent a common neurobiological structure that is shared across symptom domains in ASD. Same‐sex monozygotic (MZ) and dizygotic (DZ) twin pairs with and without ASD underwent cognitive/behavioral evaluation and magnetic resonance imaging to assess the thalamus. Neurometabolites were measured with 1H magnetic resonance spectroscopy (MRS) utilizing a multi‐voxel PRESS sequence and were referenced to creatine + phosphocreatine (tCr). N‐acetyl aspartate (NAA), a marker of neuronal integrity, was reduced in twins with ASD (n = 47) compared to typically‐developing (TD) controls (n = 33), and this finding was confirmed in a sub‐sample of co‐twins discordant for ASD (n = 11). NAA in the thalamus was correlated to a similar extent with SCI, RRB, and SPA, such that reduced neuronal integrity was associated with greater symptom severity. Glutamate + glutamine (Glx) was also reduced in affected versus unaffected co‐twins. Additionally, NAA and Glx appeared to be primarily genetically‐mediated, based on comparisons between MZ and DZ twin pairs. Thus, thalamic abnormalities may be influenced by genetic susceptibility for ASD but are likely not domain‐specific. HighlightsTwins with ASD had thalamic abnormalities relative to controls/unaffected co‐twins.Thalamic neurometabolite levels were correlated with multiple symptom domains.Comparing twin pairs, neurometabolite levels were primarily genetically‐mediated.Thalamic abnormalities in ASD are influenced by genetics but not domain‐specific.