Repeatability of deuterium metabolic imaging of healthy volunteers at 3 T

Abstract

Background: Magnetic resonance (MR) imaging of deuterated glucose, termed deuterium metabolic imaging (DMI), is emerging as a biomarker of pathway-specific glucose metabolism in tumors. DMI is being studied as a useful marker of treatment response in a scan-rescan scenario. This study aims to evaluate the repeatability of brain DMI.

Methods: A repeatability study was performed in healthy volunteers from December 2022 to March 2023. The participants consumed 75 g of [6,6'-²H₂]glucose. The delivery of ²H-glucose to the brain and its conversion to ²H-glutamine + glutamate, ²H-lactate, and ²H-water DMI was imaged at baseline and at 30, 70, and 120 min. DMI was performed using MR spectroscopic imaging on a 3-T system equipped with a ¹H/²H-tuned head coil. Coefficients of variation (CoV) were computed for estimation of repeatability and between-subject variability. In a set of exploratory analyses, the variability effects of region, processing, and normalization were estimated.

Results: Six male participants were recruited, aged 34 ± 6.5 years (mean ± standard deviation). There was 42 ± 2.7 days between sessions. Whole-brain levels of glutamine + glutamate, lactate, and glucose increased to 3.22 ± 0.4 mM, 1.55 ± 0.3 mM, and 3 ± 0.7 mM, respectively. The best signal-to-noise ratio and repeatability was obtained at the 120-min timepoint. Here, the within-subject whole-brain CoVs were -10% for all metabolites, while the between-subject CoVs were -20%.

Conclusions: DMI of glucose and its downstream metabolites is feasible and repeatable on a clinical 3 T system.

Trial registration: ClinicalTrials.gov, NCT05402566 , registered the 25th of May 2022.

Relevance statement: Brain deuterium metabolic imaging of healthy volunteers is repeatable and feasible at clinical field strengths, enabling the study of shifts in tumor metabolism associated with treatment response.

Key points: • Deuterium metabolic imaging is an emerging tumor biomarker with unknown repeatability. • The repeatability of deuterium metabolic imaging is on par with FDG-PET. • The study of deuterium metabolic imaging in clinical populations is feasible.

Keywords: Biomarkers (tumor); Brain; Deuterium; Glucose; Magnetic resonance imaging.

Fig. 1

Repeatability of deuterium metabolic imaging (DMI) was investigated in six healthy volunteers. Uptake of glucose and its conversion into lactate, water, and glutamine + glutamate (Glx) was examined after oral intake of 75 g of [6,6-²H₂]-glucose. The imaging was repeated four times for two sessions 6 weeks apart (a). Each examination consisted of T1-weighted imaging and ²H chemical shift imaging resulting in a 10 × 10 × 10 grid of spectra (b). Each spectrum was fitted to water, glucose, lactate, and Glx peaks. Here, a single spectrum from the cortex is shown (c). All peaks increased in amplitude over time (d); the solid line is a second-degree polynomial fit on the individual data points from the two sessions pooled. The glucose and lactate peaks reached plateau between 75 and 120 min, while the water and Glx peaks continued to increase close to linearly

Fig. 2

In deuterium metabolic imaging, the water signal is evenly distributed, while metabolite signals display some variation across the brain. The signal outside the brain is from the external phantoms (a, a single individual at 120 min is shown, see supplement for grayscale images). Quantification revealed significant differences between regions of the brain that were different between metabolites (b). The p-values represent a linear-mixed effects model for the effect of region

Fig. 3

Repeatability effects of post-processing. The deuterium metabolic imaging data were processed using commonly employed techniques (a). Coefficients of variation (CoV) within the same individual and between individuals seems to improve with post-processing (b). AMARES, Advanced method for accurate, robust, and efficient spectral fitting; Glx, Glutamate + glutamine; tMPPCA, Tensor Marchenko-Pastur principal component analysis

Fig. 4

Repeatability effects of normalization. Deuterium metabolic imaging was normalized to either a baseline examination acquired before ²H-glucose administration, to the cerebellum in the same examination, or to external phantoms (a). Normalization to the baseline allows absolute quantification of apparent metabolite concentrations but requires two examinations. In principle, normalization to external phantoms does the same in a single examination. Internal normalization to the cerebellum is does not give metabolite concentrations. The whole-brain within- and between-subject coefficients of variation (CoV) were lowest with internal normalization to the cerebellum, while normalization to a baseline scan or external phantoms yielded higher variation (b, c). Glx Glutamate + glutamine