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

Purpose: To explore the presence of new resonances beyond 9.4 ppm from the human brain, down-field proton MRS was performed in vivo in the human brain on 6 healthy volunteers at 7 T. Methods:To maximize the SNR, a large voxel was placed within the brain to cover the maximal area in such a way that sinus cavities were avoided. A spectrally selective 90 • E-BURP pulse with an excitation bandwidth of 2 ppm was used to probe the spectral chemical shift range between 9.1 and 10.5 ppm. The E-BURP pulse was integrated with PRESS spatial localization to obtain non-water-suppressed proton MR spectra from the desired spectral region. Results:In the down-field proton MRS obtained from all of the volunteers scanned, we identified a new peak consistently resonating at 10.1 ppm. Protons associated with this resonance are in cross-relaxation with the bulk water, as demonstrated by the water saturation and deuterium exchange experiments. Conclusion:Based on the chemical shift, this new peak was identified as the indole (-NH) proton of l-tryptophan (l-TRP) and was further confirmed from phantom experiments on l-TRP. These promising preliminary results potentially pave the way to investigate the role of cerebral metabolism of l-TRP in healthy and disease conditions. K E Y W O R D S1 H MRS, brain, down-field spectroscopy, NAD + , spectral excitation INTRODUCTIONRecently published studies on the in vivo detection of nicotinamide adenosine dinucleotide (NAD + ) in the 1 H-NMR spectrum by de Graff et al 1,2 has re-ignited a lot of interest in determining the characteristics of the down-field proton MRS (DF 1 H MRS) found at chemical shifts > 4.7 ppm. 3-5 A challenge of DF 1 H MRS is that many of the metabolite peaks that resonate in this region are either in direct chemical exchange or have significant cross-relaxation with water. [6][7][8] Consequently,

Section: Introductionmentioning

confidence: 99%

Identification of l‐Tryptophan by down‐field ¹H MRS: A precursor for brain NAD⁺ and serotonin syntheses

Nanga

Elliott

Swain

et al. 2022

“…To address some of these challenges, de Graff et al 2 performed frequency selective excitation using a spectrally selective 1D LASER excitation scheme with a surface coil for the detection of the NAD + metabolites 2 . In the recent work published by Bagga, et al, 3 a spatially selective excitation using the E‐BURP pulse sequences 10,11 was utilized to obtain localized downfield water unsuppressed spectra for detection of NAD + 12,13 . The utilization of this pulse sequence along with a large voxel to maximize SNR and change in frequency of spectrally selective excitation led to the detection of low‐concentration metabolite L‐tryptophan resonance in the DF 1 H MRS of the human brain 14 …”

Section: Introductionmentioning

confidence: 99%

“…2 In the recent work published by Bagga, et al, 3 a spatially selective excitation using the E-BURP pulse sequences 10,11 was utilized to obtain localized downfield water unsuppressed spectra for detection of NAD + . 12,13 The utilization of this pulse sequence along with a large voxel to maximize SNR and change in frequency of spectrally selective excitation led to the detection of low-concentration metabolite L-tryptophan resonance in the DF 1 H MRS of the human brain. 14 At present, no metabolite peaks have been reported in the human calf muscle beyond the NAD + resonances at 9.33 ppm, the concentration of which in a resting skeletal muscle of humans is reported in the range of 330 to 408 μM/kg.…”

Section: Introductionmentioning

confidence: 99%

Identification of new resonances in downfield ¹H MRS of human calf muscle in vivo: Potentially metabolite precursors for skeletal muscle NAD⁺

Nanga

Elliott

Swain

et al. 2023

Purpose The purpose of this study was to identify and characterize newly discovered resonances appearing in the downfield proton MR spectrum (DF 1H MRS) of the human calf muscle in vivo at 7T. Methods Downfield 1H MRS was performed on the calf muscle of five healthy volunteers at 7T. A spectrally selective 90° E‐BURP RF pulse with an excitation center frequency at 10.3 ppm and an excitation bandwidth of 2 ppm was used for DF 1H MRS acquisition. Results In all participants, we observed new resonances at 9.7, 10.1, 10.3, and 10.9 ppm in the DF 1H MRS. Phantom experiments at 37°C strongly suggest the new resonance at 9.7 ppm could be from H2‐proton of the nicotinamide rings in nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) while the resonance at 10.1 ppm could be attributed to the indole –NH proton of L‐tryptophan. We observed that the resonances at 10.1 and 10.9 ppm are significantly suppressed when the water resonance is saturated, indicating that these peaks have either 1H chemical exchange or cross‐relaxation with water. Conversely, the resonances at 9.7 and 10.3 ppm exhibit moderate signal reduction in the presence of water saturation. Conclusion We have identified new proton resonances in vivo in human calf muscle occurring at chemical shifts of 9.7, 10.1, 10.3, and 10.9 ppm. These preliminary results are promising for investigating the role of NR/NMN and L‐tryptophan metabolism in understanding the de novo and salvage pathways of NAD+ synthesis in skeletal muscle.

“…Although there have been comparatively few prior research studies using DF MRS, 5–9 there are some indications of potential in either clinical or preclinical applications. For instance, DF MRS has shown metabolic changes compared to normal brain in a murine brain glioma model, 10 and changes in phenylalanine levels measured in patients with phenylketonuria 11 .…”

Section: Introductionmentioning

confidence: 99%

“…2 The amide protons of mobile proteins and NAA are usually the most prominent DF signals in brain, but signals from adenosine triphosphate, histidine, homocarnosine, phenylalanine, glucose, glutathione, and nicotinamide adenine dinucleotide (NAD) are also known to be present and resonate in the DF region of the proton spectrum. 3 Recently, small signals from I-tryptophan, a precursor of NAD(+) and serotonin syntheses, were also observed in DF MRS. 4 Although there have been comparatively few prior research studies using DF MRS, [5][6][7][8][9] there are some indications of potential in either clinical or preclinical applications. For instance, DF MRS has shown metabolic changes compared to normal brain in a murine brain glioma model, 10 and changes in phenylalanine levels measured in patients with phenylketonuria.…”

Section: Introductionmentioning

confidence: 99%

Downfield proton MRSI with whole‐brain coverage at 3T

Özdemir

Ganji

Gillen

et al. 2023

Purpose To develop a 3D downfield (DF) MRSI protocol with whole brain coverage and post‐processing pipeline for creation of metabolite maps. Methods A 3D, circularly phase‐encoded version of the previously developed 2D DF MRSI sequence with 1true3‾3true1‾$$ 1\overline{3}3\overline{1} $$ spectral‐spatial excitation and frequency selective refocusing was implemented and tested in five healthy volunteers at 3T. The DF metabolite maps with a nominal spatial resolution of 0.7 cm3 were recorded in eight slices at 3T in a scan time of 22 m 40 s. An MRSI post‐processing pipeline was developed to create DF metabolite maps. Metabolite concentrations and uncertainty estimates were compared between region differences for nine DF peaks. Results LCModel analysis showed Cramer Rao lower bounds average values of 3%–4% for protein amide resonances in the three selected regions (anterior cingulate, dorsolateral prefrontal cortex, and centrum semiovale); Cramer Rao lower bounds were somewhat higher for individual peaks but for the most part were less than 20%. While DF concentration maps were visually quite homogeneous throughout the brain, general linear regression analysis corrected for multiple comparisons found significant differences between centrum semiovale and dorsolateral prefrontal cortex for peaks at 7.09 ppm (p = 0.014), 7.90 ppm (p = 0.009), 8.18 ppm (p = 0.009), combined amides (p = 0.009), and between anterior cingulate and dorsolateral prefrontal cortex for the 7.30 ppm peak (p = 0.020). Cramer Rao lower bounds values were not significantly different between brain regions for any of the DF peaks. Conclusion The 3D DF MRSI of the human brain at 3T with wide spatial coverage for the mapping of exchangeable amide and other resonances is feasible at a nominal spatial resolution of 0.7 cm3.