In metabolic MRI with hyperpolarized contrast agents, the signal levels vary over time due to T1 decay, T2 decay following RF excitations, and metabolic conversion. Efficient usage of the nonrenewable hyperpolarized magnetization requires specialized RF pulse schemes. In this work, we introduce two novel variable flip angle schemes for dynamic hyperpolarized MRI in which the flip angle is varied between excitations and between metabolites. These were optimized to distribute the magnetization relatively evenly throughout the acquisition by accounting for T1 decay, prior RF excitations, and metabolic conversion. Simulation results are presented to confirm the flip angle designs and evaluate the variability of signal dynamics across typical ranges of T1 and metabolic conversion. They were implemented using multiband spectral-spatial RF pulses to independently modulate the flip angle at various chemical shift frequencies. With these schemes we observed increased SNR of [1-(13)C]lactate generated from [1-(13)C]pyruvate, particularly at later time points. This will allow for improved characterization of tissue perfusion and metabolic profiles in dynamic hyperpolarized MRI.

In this work, we present a new MR spectroscopy approach for directly observing nuclear spins that undergo exchange, metabolic conversion, or, generally, any frequency shift during a mixing time. Unlike conventional approaches to observe these processes, such as exchange spectroscopy (EXSY), this rapid approach requires only a single encoding step and thus is readily applicable to hyperpolarized MR in which the magnetization is not replenished after T(1) decay and RF excitations. This method is based on stimulated-echoes and uses phase-sensitive detection in conjunction with precisely chosen echo times in order to separate spins generated during the mixing time from those present prior to mixing. We are calling the method Metabolic Activity Decomposition Stimulated-echo Acquisition Mode or MAD-STEAM. We have validated this approach as well as applied it in vivo to normal mice and a transgenic prostate cancer mouse model for observing pyruvate-lactate conversion, which has been shown to be elevated in numerous tumor types. In this application, it provides an improved measure of cellular metabolism by separating [1-(13)C]-lactate produced in tissue by metabolic conversion from [1-(13)C]-lactate that has flowed into the tissue or is in the blood. Generally, MAD-STEAM can be applied to any system in which spins undergo a frequency shift.

Metabolic imaging with hyperpolarized [1-(13)C]-pyruvate can rapidly probe tissue metabolic profiles in vivo and has been shown to provide cancer imaging biomarkers for tumor detection, progression, and response to therapy. This technique uses a bolus injection followed by imaging within 1-2 minutes. The observed metabolites include vascular components and their generation is also influenced by cellular transport. These factors complicate image interpretation, especially since [1-(13)C]lactate, a metabolic product that is a biomarker of cancer, is also produced by red blood cells. It would be valuable to understand the distribution of metabolites between the vasculature, interstitial space, and intracellular compartments. The purpose of this study was to better understand this compartmentalization by using a perfusion and diffusion-sensitive stimulated-echo acquisition mode (STEAM) MRSI acquisition method tailored to hyperpolarized substrates. Our results in mouse models showed that among metabolites, the injected substrate (13)C-pyruvate had the largest vascular fraction overall while (13)C-alanine had the smallest vascular fraction. We observed a larger vascular fraction of pyruvate and lactate in the kidneys and liver when compared to back muscle and prostate tumor tissue. Our data suggests that (13)C-lactate in prostate tumor tissue voxels was the most abundant labeled metabolite intracellularly. This was shown in STEAM images that highlighted abnormal cancer cell metabolism and suppressed vascular (13)C metabolite signals.

Purpose

To develop a new sequence for non-contrast-enhanced peripheral angiography using a sliding interleaved cylinder (SLINCYL) acquisition.

Methods

A venous saturation pulse was incorporated into a three-dimensional magnetization-prepared balanced steady-state free precession sequence for non-contrast-enhanced peripheral angiography to improve artery-vein contrast. The SLINCYL acquisition, which consists of a series of overlapped thin slabs for volumetric coverage similar to the original sliding interleaved ky (SLINKY) acquisition, was used to evenly distribute the venous-suppression effects over the field of view. In addition, the thin-slab-scan nature of SLINCYL and the centric-ordered sampling geometry of its readout trajectory were exploited to implement efficient fluid-suppression and parallel imaging schemes. The sequence was tested in healthy subjects and a patient.

Results

Compared to a multiple overlapped thin slab acquisition, both SLINKY and SLINCYL suppressed the venetian blind artifacts and provided similar artery-vein contrast. However, SLINCYL achieved this with shorter scan times and less noticeable artifacts from k-space amplitude modulation than SLINKY. The fluid-suppression and parallel imaging schemes were also validated. A patient study using the SLINCYL-based sequence well identified stenoses at the superficial femoral arteries, which were also confirmed with digital subtraction angiography.

Conclusion

Non-contrast-enhanced angiography using SLINCYL can provide angiograms with improved artery-vein contrast in the lower extremities.

Purpose

Magnetic resonance spectroscopy of hyperpolarized substrates allows for the observation of label exchange catalyzed by enzymes providing a powerful tool to investigate tissue metabolism and potentially kinetics in vivo. However, the accuracy of current methods to calculate kinetic parameters has been limited by T1 relaxation effects, extracellular signal contributions, and reduced precision at lower signal-to-noise ratio.

Theory and methods

To address these challenges, we investigated a new modeling technique using metabolic activity decomposition-stimulated echo acquisition mode. The metabolic activity decomposition-stimulated echo acquisition mode technique separates exchanging from nonexchanging metabolites providing twice the information as conventional techniques.

Results

This allowed for accurate measurements of rates of conversion and of multiple T1 values simultaneously using a single acquisition.

Conclusion

The additional measurement of T1 values for the reaction metabolites provides further biological information about the cellular environment of the metabolites. The new technique was investigated through simulations and in vivo studies of transgenic mouse models of cancer demonstrating improved assessments of kinetic rate constants and new T1 relaxation value measurements for hyperpolarized (13) C-pyruvate, (13) C-lactate, and (13) C-alanine.

Selective RF pulses are commonly designed with the desired profile as a low pass filter frequency response. However, for many MRI and NMR applications, the spectrum is sparse with signals existing at a few discrete resonant frequencies. By specifying a multiband profile and releasing the constraint on "don't-care" regions, the RF pulse performance can be improved to enable a shorter duration, sharper transition, or lower peak B1 amplitude. In this project, a framework for designing multiband RF pulses with improved performance was developed based on the Shinnar-Le Roux (SLR) algorithm and convex optimization. It can create several types of RF pulses with multiband magnitude profiles, arbitrary phase profiles and generalized flip angles. The advantage of this framework with a convex optimization approach is the flexible trade-off of different pulse characteristics. Designs for specialized selective RF pulses for balanced SSFP hyperpolarized (HP) (13)C MRI, a dualband saturation RF pulse for (1)H MR spectroscopy, and a pre-saturation pulse for HP (13)C study were developed and tested.

Purpose

A chemical shift separation technique for hyperpolarized (13) C metabolic imaging with high spatial and temporal resolution was developed. Specifically, a fast three-dimensional pulse sequence and a reconstruction method were implemented to acquire signals from multiple (13) C species simultaneously with subsequent separation into individual images.

Theory and methods

A stack of flyback echo-planar imaging readouts and a set of multiband excitation radiofrequency pulses were designed to spatially modulate aliasing patterns of the acquired metabolite images, which translated the chemical shift separation problem into parallel imaging reconstruction problem. An eight-channel coil array was used for data acquisition and a parallel imaging method based on nonlinear inversion was developed to separate the aliased images.

Results

Simultaneous acquisitions of pyruvate and lactate in a phantom study and in vivo rat experiments were performed. The results demonstrated successful separation of the metabolite distributions into individual images having high spatial resolution.

Conclusion

This method demonstrated the ability to provide accelerated metabolite imaging in hyperpolarized (13) C MR using multichannel coils, tailored readout, and specialized RF pulses.

Purpose

Balanced steady-state free precession (bSSFP) sequences can provide superior signal-to-noise ratio efficiency for hyperpolarized (HP) carbon-13 (¹³ C) magnetic resonance imaging by efficiently utilizing the nonrecoverable magnetization, but managing their spectral response is challenging in the context of metabolic imaging. A new spectrally selective bSSFP sequence was developed for fast imaging of multiple HP ¹³ C metabolites with high spatiotemporal resolution.

Theory and methods

This novel approach for bSSFP spectral selectivity incorporates optimized short-duration spectrally selective radiofrequency pulses within a bSSFP pulse train and a carefully chosen repetition time to avoid banding artifacts.

Results

The sequence enabled subsecond 3D dynamic spectrally selective imaging of ¹³ C metabolites of copolarized [1-¹³ C]pyruvate and [¹³ C]urea at 2-mm isotropic resolution, with excellent spectral selectivity (∼100:1). The sequence was successfully tested in phantom studies and in vivo studies with normal mice.

Conclusion

This sequence is expected to benefit applications requiring dynamic volumetric imaging of metabolically active ¹³ C compounds at high spatiotemporal resolution, including preclinical studies at high field and, potentially, clinical studies. Magn Reson Med 78:963-975, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Purpose

The purpose of this study was to develop a new 3D dynamic carbon-13 compressed sensing echoplanar spectroscopic imaging (EPSI) MR sequence and test it in phantoms, animal models, and then in prostate cancer patients to image the metabolic conversion of hyperpolarized [1-¹³ C]pyruvate to [1-¹³ C]lactate with whole gland coverage at high spatial and temporal resolution.

Methods

A 3D dynamic compressed sensing (CS)-EPSI sequence with spectral-spatial excitation was designed to meet the required spatial coverage, time and spatial resolution, and RF limitations of the 3T MR scanner for its clinical translation for prostate cancer patient imaging. After phantom testing, animal studies were performed in rats and transgenic mice with prostate cancers. For patient studies, a GE SPINlab polarizer (GE Healthcare, Waukesha, WI) was used to produce hyperpolarized sterile GMP [1-¹³ C]pyruvate. 3D dynamic ¹³ C CS-EPSI data were acquired starting 5 s after injection throughout the gland with a spatial resolution of 0.5 cm³ , 18 time frames, 2-s temporal resolution, and 36 s total acquisition time.

Results

Through preclinical testing, the 3D CS-EPSI sequence developed in this project was shown to provide the desired spectral, temporal, and spatial 5D HP ¹³ C MR data. In human studies, the 3D dynamic HP CS-EPSI approach provided first-ever simultaneously volumetric and dynamic images of the LDH-catalyzed conversion of [1-¹³ C]pyruvate to [1-¹³ C]lactate in a biopsy-proven prostate cancer patient with full gland coverage.

Conclusion

The results demonstrate the feasibility to characterize prostate cancer metabolism in animals, and now patients using this new 3D dynamic HP MR technique to measure k_PL , the kinetic rate constant of [1-¹³ C]pyruvate to [1-¹³ C]lactate conversion.

Purpose

Heating of gradient coils and passive shim components is a common cause of instability in the B₀ field, especially when gradient intensive sequences are used. The aim of the study was to set a benchmark for typical drift encountered during MR spectroscopy (MRS) to assess the need for real-time field-frequency locking on MRI scanners by comparing field drift data from a large number of sites.

Method

A standardized protocol was developed for 80 participating sites using 99 3T MR scanners from 3 major vendors. Phantom water signals were acquired before and after an EPI sequence. The protocol consisted of: minimal preparatory imaging; a short pre-fMRI PRESS; a ten-minute fMRI acquisition; and a long post-fMRI PRESS acquisition. Both pre- and post-fMRI PRESS were non-water suppressed. Real-time frequency stabilization/adjustment was switched off when appropriate. Sixty scanners repeated the protocol for a second dataset. In addition, a three-hour post-fMRI MRS acquisition was performed at one site to observe change of gradient temperature and drift rate. Spectral analysis was performed using MATLAB. Frequency drift in pre-fMRI PRESS data were compared with the first 5:20 minutes and the full 30:00 minutes of data after fMRI. Median (interquartile range) drifts were measured and showed in violin plot. Paired t-tests were performed to compare frequency drift pre- and post-fMRI. A simulated in vivo spectrum was generated using FID-A to visualize the effect of the observed frequency drifts. The simulated spectrum was convolved with the frequency trace for the most extreme cases. Impacts of frequency drifts on NAA and GABA were also simulated as a function of linear drift. Data from the repeated protocol were compared with the corresponding first dataset using Pearson's and intraclass correlation coefficients (ICC).

Results

Of the data collected from 99 scanners, 4 were excluded due to various reasons. Thus, data from 95 scanners were ultimately analyzed. For the first 5:20 min (64 transients), median (interquartile range) drift was 0.44 (1.29) Hz before fMRI and 0.83 (1.29) Hz after. This increased to 3.15 (4.02) Hz for the full 30 min (360 transients) run. Average drift rates were 0.29 Hz/min before fMRI and 0.43 Hz/min after. Paired t-tests indicated that drift increased after fMRI, as expected (p < 0.05). Simulated spectra convolved with the frequency drift showed that the intensity of the NAA singlet was reduced by up to 26%, 44 % and 18% for GE, Philips and Siemens scanners after fMRI, respectively. ICCs indicated good agreement between datasets acquired on separate days. The single site long acquisition showed drift rate was reduced to 0.03 Hz/min approximately three hours after fMRI.

Discussion

This study analyzed frequency drift data from 95 3T MRI scanners. Median levels of drift were relatively low (5-min average under 1 Hz), but the most extreme cases suffered from higher levels of drift. The extent of drift varied across scanners which both linear and nonlinear drifts were observed.