Dirk Mayer

Application of subsecond spiral chemical shift imaging to real-time multislice metabolic imaging of the rat in vivo after injection of hyperpolarized 13C1-pyruvate.

Dynamic nuclear polarization can create hyperpolarized compounds with MR signal‐to‐noise ratio enhancements on the order of 10,000‐fold. Both exogenous and normally occurring endogenous compounds can be polarized, and their initial concentration and downstream metabolic products can be assessed using MR spectroscopy. Given the transient nature of the hyperpolarized signal enhancement, fast imaging techniques are a critical requirement for real‐time metabolic imaging. We report on the development of an ultrafast, multislice, spiral chemical shift imaging sequence, with subsecond acquisition time, achieved on a clinical MR scanner. The technique was used for dynamic metabolic imaging in rats, with measurement of time‐resolved spatial distributions of hyperpolarized 13C1‐pyruvate and metabolic products 13C1‐lactate and 13C1‐alanine, with a temporal resolution of as fast as 1 s. Metabolic imaging revealed different signal time courses in liver from kidney. These results demonstrate the feasibility of real‐time, hyperpolarized metabolic imaging and highlight its potential in assessing organ‐specific kinetic parameters. Magn Reson Med, 2009.

Metabolic imaging in the anesthetized rat brain using hyperpolarized [1-13C] pyruvate and [1-13C] ethyl pyruvate.

Formulation, polarization, and dissolution conditions were developed to obtain a stable hyperpolarized solution of [1‐13C]‐ethyl pyruvate. A maximum tolerated concentration and injection rate were determined, and 13C spectroscopic imaging was used to compare the uptake of hyperpolarized [1‐13C]‐ethyl pyruvate relative to hyperpolarized [1‐13C]‐pyruvate into anesthetized rat brain. Hyperpolarized [1‐13C]‐ethyl pyruvate and [1‐13C]‐pyruvate metabolic imaging in normal brain is demonstrated and quantified in this feasibility and range‐finding study. Magn Reson Med 63:1137–1143, 2010.

Brain Injury and Recovery Following Binge Ethanol: Evidence from In Vivo Magnetic Resonance Spectroscopy

BACKGROUND The binge-drinking model in rodents using intragastric injections of ethanol (EtOH) for 4 days results in argyrophilic corticolimbic tissue classically interpreted as indicating irreversible neuronal degeneration. However, recent findings suggest that acquired argyrophilia can also identify injured neurons that have the potential to recover. The current in vivo magnetic resonance (MR) imaging and spectroscopy study was conducted to test the hypothesis that binge EtOH exposure would injure but not cause the death of neurons as previously ascertained postmortem. METHODS After baseline MR scanning, 11 of 19 rats received a loading dose of 5 g/kg EtOH via oral gavage, then a maximum of 3 g/kg every 8 hours for 4 days, for a total average cumulative EtOH dose of 43 +/- 1.2 g/kg and average blood alcohol levels of 258 +/- 12 mg/dL. All animals were scanned after 4 days of gavage (post-gavage scan) with EtOH (EtOH group) or dextrose (control [Con] group) and again after 7 days of abstinence from EtOH (recovery scan). RESULTS Tissue shrinkage at the post-gavage scan was reflected by significantly increased lateral ventricular volume in the EtOH group compared with the Con group. At the post-gavage scan, the EtOH group had lower dorsal hippocampal N-acetylaspartate and total creatine and higher choline-containing compounds than the Con group. At the recovery scan, neither ventricular volume nor metabolite levels differentiated the groups. CONCLUSIONS Rapid recovery of ventricular volume and metabolite levels with removal of the causative agent argues for transient rather than permanent effects of a single EtOH binge episode in rats.

Detection of glutamate in the human brain at 3 T using optimized constant time point resolved spectroscopy.

A CT‐PRESS sequence was implemented on a 3‐T MR scanner and optimized for the detection of the C4 resonance of glutamate. By simulating the sequence using the full density matrix it was found that 121 chemical shift encoding steps in t1 with an increment Δt1 = 1.6 ms were sufficient to separate the glutamate C4 resonance. The simulations also showed that the highest signal‐to‐noise ratio was achieved at an average echo time of 131 ms. When using an eightfold undersampling scheme in f1 in order to reduce the minimum total measurement time, the average echo time was 139 ms with 17 encoding steps (Δt1 = 12.8 ms). The sequence was tested on phantoms containing solutions of various brain metabolites and on healthy human volunteers. Besides resolving glutamate, other resonances detected in vivo comprised N‐acetyl aspartate, total creatine, choline containing compounds, and myo‐inositol. However, glutamine resonances could not be resolved due to severe signal overlap from glutamate and N‐acetyl aspartate. Magn Reson Med 54:439–442, 2005.

Optimization of fast spiral chemical shift imaging using least squares reconstruction: Application for hyperpolarized 13C metabolic imaging

A least‐squares–based optimization and reconstruction algorithm has been developed for rapid metabolic imaging in the context of hyperpolarized 13C. The algorithm uses a priori knowledge of resonance frequencies, J‐coupling constants, and T2* values to enable acquisition of high‐quality metabolic images with imaging times of approximately 100 ms for an 8‐cm field of view (FOV) and 0.5 cm isotropic resolution. A root‐mean‐square error (rMSE) analysis is introduced to optimize metabolic image quality by appropriate choice of pulse sequence parameters, echo times, and signal model. By performing the reconstruction in k‐space, the algorithm also allows the inclusion of the effect of chemical shift evolution during the readout period. Single‐interleaf multiecho spiral chemical shift imaging (spCSI) is analyzed in detail as an illustrative example for the use of the new reconstruction and optimization algorithm. Simulation of the in vivo spectrum following the bolus injection of hyperpolarized 13C1 pyruvate shows that single‐interleaf spiral spectroscopic imaging can achieve image quality in 100 ms, comparable to the performance of a 13‐s phase‐encoded chemical shift imaging (FIDCSI) experiment. Single‐interleaf spCSI was also tested at a 3‐T MR scanner using a phantom containing approximately 0.5‐M solutions of alanine, lactate, and a pyruvate‐pyruvate hydrate C1‐C2 ester at thermal equilibrium polarization, all enriched to 99% 13C in the C1 carbonyl positions. Upon reconstruction using the k‐space–based least‐squares technique, metabolite ratios obtained using the spCSI method were comparable to those obtained using a reference FIDCSI acquisition. Magn Reson Med 58:245–252, 2007.

Fast metabolic imaging of systems with sparse spectra: application for hyperpolarized 13C imaging.

A fast spiral chemical shift imaging (spCSI) sequence was developed for application to hyperpolarized 13C imaging. The sequence exploits sparse spectra, which can occur in such applications, and prior knowledge of resonance frequencies to reduce the measurement time by undersampling the data in the spectral domain. As a consequence, multiple reconstructions of a given data set have to be computed in which only components with frequencies within a certain bandwidth are reconstructed “in focus” while others are severely blurred (“spectral tomosynthesis”). The sequence was tested at 3 T on a phantom containing approximately 1.5‐M solutions of alanine (Ala), lactate (Lac), and pyruvate‐pyruvate hydrate C1‐C2 ester (with two resonances, PPE1 and PPE2) at thermal equilibrium polarization, all enriched to 99% 13C in the C1 carbonyl positions. Results from spCSI with a single spatial interleaf (single‐shot spCSI) and three interleaves (three‐shot spCSI) were compared with those obtained by phase‐encoded free induction decay CSI (FIDCSI). The metabolic maps of all four resonances for three‐shot spCSI, and of PPE1 and PPE2 for single‐shot spCSI demonstrate resolution and localization properties similar to those of the FIDCSI images. The metabolic maps of Ala and Lac for single‐shot spCSI contain minor artifacts due to signal overlap of aliased resonances. Magn Reson Med, 2006.

T2 relaxation times of 13C metabolites in a rat hepatocellular carcinoma model measured in vivo using 13C-MRS of hyperpolarized [1-13C]pyruvate

A single‐voxel Carr‐Purcell‐Meibloom‐Gill sequence was developed to measure localized T2 relaxation times of 13C‐labeled metabolites in vivo for the first time. Following hyperpolarized [1‐13C]pyruvate injections, pyruvate and its metabolic products, alanine and lactate, were observed in the liver of five rats with hepatocellular carcinoma and five healthy control rats. The T2 relaxation times of alanine and lactate were both significantly longer in HCC tumors than in normal livers (p < 0.002). The HCC tumors also showed significantly higher alanine signal relative to the total 13C signal than normal livers (p < 0.006). The intra‐ and inter‐subject variations of the alanine T2 relaxation time were 11% and 13%, respectively. The intra‐ and inter‐subject variations of the lactate T2 relaxation time were 6% and 7%, respectively. The intra‐subject variability of alanine to total carbon ratio was 16% and the inter‐subject variability 28%. The intra‐subject variability of lactate to total carbon ratio was 14% and the inter‐subject variability 20%. The study results show that the signal level and relaxivity of [1‐13C]alanine may be promising biomarkers for HCC tumors. Its diagnostic values in HCC staging and treatment monitoring are yet to be explored. Copyright

Low Striatal Glutamate Levels Underlie Cognitive Decline in the Elderly: Evidence from In Vivo Molecular Spectroscopy

Glutamate (Glu), the principal excitatory neurotransmitter of prefrontal cortical efferents, potentially mediates higher order cognitive processes, and its altered availability may underlie mechanisms of age-related decline in frontally based functions. Although animal studies support a role for Glu in age-related cognitive deterioration, human studies, which require magnetic resonance spectroscopy for in vivo measurement of this neurotransmitter, have been impeded because of the similarity of Glus spectroscopic signature to those of neighboring spectral brain metabolites. Here, we used a spectroscopic protocol, optimized for Glu detection, to examine the effect of age in 3 brain regions targeted by cortical efferents--the striatum, cerebellum, and pons--and to test whether performance on frontally based cognitive tests would be predicted by regional Glu levels. Healthy elderly men and women had lower Glu in the striatum but not pons or cerebellum than young adults. In the combined age groups, levels of striatal Glu (but no other proton metabolite also measured) correlated selectively with performance on cognitive tests showing age-related decline. The selective relations between performance and striatal Glu provide initial and novel, human in vivo support for age-related modification of Glu levels as contributing to cognitive decline in normal aging.

Visualizing Implanted Tumors in Mice with Magnetic Resonance Imaging Using Magnetotactic Bacteria

Purpose: To determine if magnetotactic bacteria can target tumors in mice and provide positive contrast for visualization using magnetic resonance imaging. Experimental Design: The ability of the magnetotactic bacterium, Magnetospirillum magneticum AMB-1 (referred to from here as AMB-1), to confer positive magnetic resonance imaging contrast was determined in vitro and in vivo. For the latter studies, AMB-1 were injected either i.t. or i.v. Bacterial growth conditions were manipulated to produce small (∼25-nm diameter) magnetite particles, which were observed using transmission electron microscopy. Tumor targeting was confirmed using 64Cu-labeled bacteria and positron emission tomography and by determination of viable cell counts recovered from different organs and the tumor. Results: We show that AMB-1 bacteria with small magnetite particles generate T1-weighted positive contrast, enhancing in vivo visualization by magnetic resonance imaging. Following i.v. injection of 64Cu-labeled AMB-1, positron emission tomography imaging revealed increasing colonization of tumors and decreasing infection of organs after 4 hours. Viable cell counts showed that, by day 6, the bacteria had colonized tumors but were cleared completely from other organs. Magnetic resonance imaging showed a 1.22-fold (P = 0.003) increased positive contrast in tumors on day 2 and a 1.39-fold increase (P = 0.0007) on day 6. Conclusion: Magnetotactic bacteria can produce positive magnetic resonance imaging contrast and colonize mouse tumor xenografts, providing a potential tool for improved magnetic resonance imaging visualization in preclinical and translational studies to track cancer. (Clin Cancer Res 2009;15(16):5170–7)

In Vivo Evidence for Alcohol-Induced Neurochemical Changes in Rat Brain Without Protracted Withdrawal, Pronounced Thiamine Deficiency, or Severe Liver Damage

Magnetic resonance spectroscopy (MRS) studies in human alcoholics report decreases in N-acetylaspartate (NAA) and choline-containing (Cho) compounds. Whether alterations in brain metabolite levels are attributable to alcohol per se or to physiological effects of protracted withdrawal or impaired nutritional or liver status remains unclear. Longitudinal effects of alcohol on brain metabolites measured in basal ganglia with single-voxel MRS were investigated in sibling pairs of wild-type Wistar rats, with one rat per pair exposed to escalating doses of vaporized alcohol, the other to vapor chamber air. MRS was conducted before alcohol exposure and twice during exposure. After 16 weeks of alcohol exposure, rats achieved average blood alcohol levels (BALs) of ∼293 mg per 100 ml and had higher Cho and a trend for higher glutamine+glutamate (Glx) than controls. After 24 weeks of alcohol exposure, BALs rose to ∼445 mg per 100 ml, and alcohol-exposed rats had higher Cho, Glx, and glutamate than controls. Thiamine and thiamine monophosphate levels were significantly lower in the alcohol than the control group but did not reach levels low enough to be considered clinically relevant. Histologically, livers of alcohol-exposed rats exhibited greater steatosis and lower glycogenosis than controls, but were not cirrhotic. This study demonstrates a specific pattern of neurobiochemical changes suggesting excessive membrane turnover or inflammation, indicated by high Cho, and alterations to glutamate homeostasis in the rat brain in response to extended vaporized alcohol exposure. Thus, we provide novel in vivo evidence for alcohol exposure as causing changes in brain chemistry in the absence of protracted withdrawal, pronounced thiamine deficiency, or severe liver damage.