Rapid in vivo apparent diffusion coefficient mapping of hyperpolarized (13) C metabolites

Abstract

Purpose: Hyperpolarized (13) C magnetic resonance allows for the study of real-time metabolism in vivo, including significant hyperpolarized (13) C lactate production in many tumors. Other studies have shown that aggressive and highly metastatic tumors rapidly transport lactate out of cells. Thus, the ability to not only measure the production of hyperpolarized (13) C lactate but also understand its compartmentalization using diffusion-weighted MR will provide unique information for improved tumor characterization.

Methods: We used a bipolar, pulsed-gradient, double spin echo imaging sequence to rapidly generate diffusion-weighted images of hyperpolarized (13) C metabolites. Our methodology included a simultaneously acquired B1 map to improve apparent diffusion coefficient (ADC) accuracy and a diffusion-compensated variable flip angle scheme to improve ADC precision.

Results: We validated this sequence and methodology in hyperpolarized (13) C phantoms. Next, we generated ADC maps of several hyperpolarized (13) C metabolites in a normal rat, rat brain tumor, and prostate cancer mouse model using both preclinical and clinical trial-ready hardware.

Conclusion: ADC maps of hyperpolarized (13) C metabolites provide information about the localization of these molecules in the tissue microenvironment. The methodology presented here allows for further studies to investigate ADC changes due to disease state that may provide unique information about cancer aggressiveness and metastatic potential.

Keywords: ADC mapping; diffusion-weighted imaging; dissolution DNP; hyperpolarized 13C; metabolic imaging.

FIG 1

(a) The bipolar pulsed-gradient double spin echo sequence used for diffusion weighting imaging of hyperpolarized ¹³C metabolites on a clinical 3T MR scanner. The flip angle (θ) of the spectral-spatial excitation pulse is changed according to the variable flip angle (VFA) scheme. A single-shot echo-planar imaging (EPI) readout is followed by a crusher gradient. For these experiments, the slice-select and diffusion gradients were applied on G_z, while the EPI readout gradients were applied on the orthogonal axes. (b) The bipolar pulsed-gradients can apply diffusion weightings (b-values) upwards of 1,000 s mm⁻² for ¹³C, as represented by the shaded area under |k ²_z(t)|.

FIG 2

A schematic of the methodology presented here for acquiring hyperpolarized ¹³C metabolite diffusion weighted (DW) images and generating apparent diffusion coefficient (ADC) maps. The example data shown is a hyperpolarized ¹³C pyruvate phantom at 22°C. (a) Each metabolite is scanned 4 times within 1 s with varying flip angles and b-values. (b) The SNR of the last 2 images are compared with a modified double angle method to produce a B₁ map. (c) The B₁ map is used for a voxel-wise flip angle correction of each image. ADC maps are calculated using the first 3 images.

FIG 3

Flip angle correction of the images based on the simultaneously acquired B₁ map improves ADC measurement accuracy. (a) This simulation demonstrates the effect that flip angle errors have on measured ADC, using the parameters presented in Figure 2. The black dotted line represents the diffusion coefficient of pyruvate at 22°C. (b) The voxel-wise distribution of ADCs for the hyperpolarized ¹³C pyruvate phantom presented in Figure 2, before (dark gray) and after (light gray) a flip angle correction based on the B₁ map. The mean ADC of the corrected data aligns with the diffusion coefficient for pyruvate (dotted line).

FIG 4

Using a VFA scheme that compensates for SNR loss due to diffusion weighting leads to greater ADC measurement precision. (a) Simulated DW data demonstrates smaller standard deviations and improved ADC measurement precision achieved with the diffusion compensated VFA scheme (blue) rather than the standard VFA scheme (red), both with low (left) and high (right) SNR. (b) A TRAMP mouse with a small tumor. (c) The DW images acquired with the standard VFA for both hyperpolarized ¹³C pyruvate and lactate show significantly decreased SNR at high b-values. (d) With the diffusion compensated VFA, the DW images of hyperpolarized ¹³C pyruvate and lactate have significantly improved SNR at higher b-values, which improves the precision of ADC measurements. The DW images in (c) and (d) were windowed to the same SNR for each metabolite to illustrate the SNR differences between the two schemes.

FIG 5

The ADC maps for water and hyperpolarized ¹³C pyruvate and lactate in a rat brain tumor model. (a) The proton FSE image with the brain (solid line) and the tumor (dotted line) outlined. (b) The water ADC map shows the tumor has an increased ADC relative to the surrounding normal brain tissue. Hyperpolarized ¹³C images were acquired with the standard VFA scheme. (c) The hyperpolarized ¹³C pyruvate ADC map showing relatively uniform ADCs across the normal brain and the tumor. (d) The ADC map of hyperpolarized ¹³C lactate shows a decreased tumor ADC relative to the surrounding tissue. The corresponding low and high b-value DW images are shown below.

FIG 6

The ADC map of hyperpolarized ¹³C lactate prostate tumor bearing TRAMP mouse, acquired with the standard VFA scheme. (a) The proton FSE image with the tumor outlined. (b) The low and high b-value DW images of hyperpolarized ¹³C lactate. Improved tumor contrast can be seen with a high b-value. (c) The ADC map clearly shows a decreased ADC in the tumor region in comparison to the surrounding tissue in the abdomen.

FIG 7

ADC mapping of hyperpolarized ¹³C HMCP in a normal rat using clinical trial-ready hardware. (a) The proton localizer image of the rat. (b) Having used a diffusion compensated VFA scheme and expecting constant SNR for all DW images, decreasing image SNR with decreasing b-values indicates that the transmitter power was too high. (c) The B₁ map reveals an average 22% ± 2 error in the flip angles and is use to correct the SNR in the DW images (d). (e) The resulting ADC map shows a homogeneous ADC in the abdomen with increased ADCs seen at the descending aorta and portion of the intestine.