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Dynamic ¹³C MRS using ¹³C/¹H Multichannel Coil as an Alternative to Imaging for Hyperpolarized Pyruvate Brain Studies

Junjie Ma¹, Marco C. Pinho^1,2, Crystal E. Harrison¹, Jun Chen¹, Galen D. Reed³, Albert P. Chen³, A. Dean Sherry^1,4, Craig R. Malloy^1,2,5, Christopher J. Madden⁶, and Jae Mo Park^1,2,7
¹Advanced Imaging Research Center, UT Southwestern Medical Center, Dallas, TX, United States, ²Radiology, UT Southwestern Medical Center, Dallas, TX, United States, ³GE Healthcare, Dallas, TX, United States, ⁴Biochemistry and Chemical Biology, UT Dallas, Richardson, TX, United States, ⁵Internal Medicine, UT Southwestern Medical Center, Dallas, TX, United States, ⁶Neurological Surgery, UT Southwestern Medical Center, Dallas, TX, United States, ⁷Electrical and Computer Engineering, UT Dallas, Richardson, TX, United States

Synopsis

This study demonstrates that time-resolved ¹³C MR spectroscopy with the multichannel ¹³C/¹H RF coils can be performed as an alternative to imaging for assessing pyruvate metabolism using hyperpolarized [1-¹³C]pyruvate in the human brain.

Background

Recent advances in clinical translation of hyperpolarized [1-¹³C]pyruvate imaging¹ has enabled metabolic imaging of the human brain in healthy subjects^2,3 and patients with brain tumors^4–6 or traumatic brain injury.⁷ However, accurate and reliable imaging of pyruvate metabolism in the brain is still challenging, especially for the measurement of [¹³C]bicarbonate production, which is a salient surrogate biomarker of in vivo pyruvate dehydrogenase activity and, potentially, mitochondrial integrity. Previous studies reported inconsistent measurement of [¹³C]bicarbonate, ranging from less than 2%⁸ to 8%³ relative to the [1-¹³C]pyruvate signals. In this study, we propose to use small flip-angle time-resolved ¹³C MRS with a multichannel ¹³C/¹H coil as an alternative to imaging to achieve reliable measurements and analysis of hyperpolarized [1-¹³C]pyruvate and its products, [1-¹³C]lactate and [¹³C]bicarbonate, in the brain from healthy volunteers.

Methods

All MR studies were performed using a wide-bore 3T 750w MR scanner (GE Healthcare, Waukesha, Wisconsin, USA). A ¹³C/¹H dual-frequency RF head coil that consists of ¹H quadrature transmit (Tx) and receive (Rx), ¹³C quadrature Tx and 8-channel ¹³C Rx arrays (Clinical MR Solutions, USA) was developed for the study.⁹ The structure of the head coil is shown in Figure 1A. Rx performance was tested using a cylindrical phantom (diameter = 14 cm) that contains non-labeled pure ethylene glycol (natural abundance 1.1% of ¹³C), Figure 1B. At the center of the cylindrical phantom, the coil sensitivity was 78% of the phantom. The cross-sectional signal changes demonstrate the reliable and relatively homogeneous signal detection from the entire phantom when all the coil elements are combined, and region-focused detections from individual coils.

To demonstrate the SNR advantage of a small flip-angle MRS over MRI, a phantom test was performed using the spherical [¹³C]bicarbonate phantom. A slice-selective single-shot spiral ¹³C imaging (flip-angle = 90°, slice thickness = 15 mm, TR = 3 s, FOV = 24 cm × 24 cm, 128 averages) was applied to acquire 2D ¹³C images with three different nominal in-plane spatial resolutions (3.0 cm × 3.0 cm, 1.5 cm × 1.5 cm, 1.0 cm × 1.0 cm) by adjusting the spiral readouts. With similar settings, ¹³C free induction decay (FID) was also acquired using a 6.5° slice-selective excitation (spectral bandwidth = 10000 Hz, spectral points = 4096).

Four healthy adults were recruited for the study (age: 24 – 65 years, 1 male and 3 females, body mass index = 26.4 ± 2.9). Each participant was imaged with the brain MR protocol, which includes two injections of hyperpolarized [1-¹³C]pyruvate and a series of ¹H MRI. The imaging protocol was approved by the local institutional review board (IRB#: STU 072017-009, ClinicalTrials.gov ID: NCT03502967). A clinical SPINlab^TM polarizer (GE Healthcare) was used for the dynamic nuclear polarization (DNP), and pyruvate samples were polarized as previously described.¹⁰

All the in vivo ¹³C data were reconstructed in absorption mode via a custom-made reconstruction using MATLAB (MathWorks, MA), and metabolite peaks were quantified from time-averaged ¹³C spectra.¹¹ Brain extraction and segmentation for ¹H human brain image was conducted using FSL package (FMRIB, UK).^12,13 Data are presented as mean ± standard deviation. Statistical significance in metabolite ratios between brain regions was evaluated by a paired t-test (α = 0.05, two-tailed). Least square fitting was used for linear regression between brain volumes and hyperpolarized signals, and Pearson product-moment correlation coefficient (r) was calculated to measure the linear relationship.

Results and Discussion

In the phantom study, shown in Figure 2, SNR_peak from the MRS spectrum was 4.6×, 5.8× and 7.0× higher than SNR_peak of ¹³C images with 3 cm, 1.5 cm, and 1 cm of nominal spatial resolution, respectively. Time-averaged spectra of slice #1 – 4 from a representative participant are shown in Figure 3A. [1-¹³C]Lactate relative to the total hyperpolarized ¹³C signal (tC) was consistent throughout the slices, ranging from 0.212 to 0.244. [¹³C]bicarbonate production was 30 – 37 % of lactate (Fig. 3B-C). Areas under the curves (AUCs) for [1-¹³C]pyruvate, [1-¹³C]lactate, and [¹³C]bicarbonate signals were positively correlated to the volume of grey matter (GM, r > 0.5, p ≤ 0.03) and white matter (WM, r > 0.4, p = 0.06 – 0.10), and negatively correlated to cerebrospinal fluid (CSF, r < -0.4) volumes, respectively, Figure 4A. The pyruvate signal normalized by tC maintained the positive correlation with fractional GM (r = 0.57, p = 0.02) volumes and negative correlation with fractional CSF volume (r = -0.64, p = 0.008), Figure 4B. However, lactate/tC showed a strong negative correlation with fractional GM volume (r = -0.54, p = 0.03) and a positive correlation with fractional CSF volume (r = 0.54, p = 0.03). Region-weighted assessment, as shown in Figure 5, demonstrated that region-weighted [1-¹³C]lactate/tC and [¹³C]bicarbonate/tC could be generated from coil-wise assessment of the metabolites in the time-averaged spectra.

Conclusion

Dynamic MRS in combination with the ¹³C/¹H multichannel RF coil is an affordable and reliable alternative to imaging methods in investigating cerebral metabolism using hyperpolarized [1-¹³C]pyruvate.

Acknowledgements

Personnel Support: We appreciate the clinical research team and the supporting staffs of the Advanced Imaging Research Center at UT Southwestern for recruiting and imaging the volunteers – Jeannie Baxter, Lucy Christie, Kelley Derner, Maida Tai and Salvador Pena. We thank Ralph S. Hashoian for building the RF head coil.

Funding: The Mobility Foundation; The Texas Institute for Brain Injury and Repair; National Institutes of Health of the United States (R01 NS107409, P41 EB015908, S10 OD018468, S10 RR029119); The Welch Foundation (I-2009-20190330); UT Dallas Collaborative Biomedical Research Award (UTD 1907789).

References

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Figures

Figure 1. ¹³C/¹H dual-frequency RF head coil and its performance. (A) The ¹³C/¹H dual-frequency RF head coil that consists of ¹H quadrature Tx and Rx, ¹³C quadrature Tx and 8-channel ¹³C receive Rx arrays was developed for this study. (B) Rx performance was tested using a cylindrical phantom (non-labeled pure ethylene glycol, thus 1.1% natural abundance ¹³C). Enhanced ¹³C signals were detected from the margin of the phantom near the coil elements, as shown in the channel-combined ¹³C image (square of sum of square).

Figure 2. SNR comparison between ¹³C MRS with small flip-angle excitation and ¹³C MRI with 90° excitation. (A) ¹H T₂-weighted fast spin echo image of the gadolinium-doped spherical [¹³C]bicarbonate phantom was acquired with the ¹³C/¹H dual-frequency RF head coil. (B) ¹³C images of the phantom with three nominal in-plane spatial resolutions (3.0 cm × 3.0 cm, 1.5 cm × 1.5 cm and 1.0 cm × 1.0 cm) were acquired using a 2D slice-selective spiral imaging sequence with 90° excitation. (C) ¹³C spectrum acquired using MRS with 6.5° flip-angle from the same phantom.

Figure 3. Time-averaged ¹³C spectra of four axial brain slices. (A) Time-averaged, coil-combined, and phase-corrected spectra, normalized by the maximum pyruvate peak, from a representative participant. Prescription of four axial slices is shown in the sagittal ¹H MRI. (B) Hyperpolarized [1-¹³C]lactate, [¹³C]bicarbonate, [1-¹³C]alanine, and [1-¹³C]pyruvate-hydrate, normalized by total hyperpolarized ¹³C (tC). (C) Metabolite ratios of lactate-to-pyruvate, bicarbonate-to-pyruvate, pyruvate-hydrate-to-pyruvate, and bicarbonate-to-lactate.

Figure 4. Correlation of hyperpolarized signals to brain volumes. (A) Area under the curves (AUCs) for hyperpolarized [1-¹³C]pyruvate (black dots), [1-¹³C]lactate (red dots), and [¹³C]bicarbonate (blue dots) from each brain slice in relation to the brain volumes of WM, GM, and CSF within the slice. (B) Hyperpolarized ¹³C signal intensities of each metabolite relative to the total hyperpolarized ¹³C signal (tC) within the slice in relation to fractional brain volumes of WM, GM, and CSF of the slice. Lines indicate linear regressions (solid: p-value ≤ 0.05, dotted: p > 0.5).

Figure 5. Coil-wise reconstruction of hyperpolarized ¹³C spectra. Time-averaged ¹³C spectra and metabolite ratios for individual ¹³C coil elements. [1-¹³C]Lactate and [¹³C]bicarbonate, normalized by total hyperpolarized ¹³C signals (tC), from each ¹³C channel are color-coded in red and blue, respectively, and overlaid on the corresponding brain slice (slice #1) to indicate the region-weighted measurements.

Proc. Intl. Soc. Mag. Reson. Med. 30 (2022)

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DOI: https://doi.org/10.58530/2022/0310