Quantification of NAD⁺ in human brain with ¹H MR spectroscopy at 3 T: Comparison of three localization techniques with different handling of water magnetization

Purpose: The detection of nicotinamide-adenine-dinucleotide (NAD⁺) is challenging using standard ¹H MR spectroscopy, because it is of low concentration and affected by polarization-exchange with water. Therefore, this study compares three techniques to access NAD⁺ quantification at 3 T–one with and two without water presaturation. Methods: A large brain volume in 10 healthy subjects was investigated with three techniques: semi-LASER with water-saturation (WS) (TE = 35 ms), semi-LASER with metabolite-cycling (MC) (TE = 35 ms), and the non-water-excitation (nWE) technique 2D ISIS-localization with chemical-shift-selective excitation (2D I-CSE) (TE = 10.2 ms). Spectra were quantified with optimized modeling in FiTAID. Results: NAD⁺ could be well quantified in cohort-average spectra with all techniques. Obtained apparent NAD⁺ tissue contents are all lower than expected from literature confirming restricted visibility by ¹H MRS. The estimated value from WS-MRS (58 μM) was considerably lower than those obtained with non-WS techniques (146 μM for MC-semi-LASER and 125 μM for 2D I-CSE). The nWE technique with shortest TE gave largest NAD⁺ signals but suffered from overlap with large amide signals. MC-semi-LASER yielded best estimation precision as reflected in relative Cramer-Rao bounds (14%, 21 μM/146 μM) and also best robustness as judged by the coefficient-of-variance over the cohort (11%, 10 μM/146 μM). The MR-visibility turned out as 16% with WS and 41% with MC. Conclusion: Three methods to assess NAD⁺ in human brain at 3 T have been compared. NAD⁺ could be detected with a visibility of ∼41% for the MC method. This may open a new window for the observation of pathological changes in the clinical research setting.