Personalized and muscle-specific OXPHOS measurement with integrated CrCEST MRI and proton MR spectroscopy.

Creatine chemical exchange saturation transfer (CrCEST) MRI is an emerging high resolution and noninvasive method for measuring muscle specific oxidative phosphorylation (OXPHOS). However, CrCEST measurements are sensitive to changes in muscle pH, which might confound the measurement and interpretation of creatine recovery time (τCr). Even with the same prescribed exercise stimulus, the extent of acidification and hence its impact on τCr is expected to vary between individuals. To address this issue, a method to measure pH pre- and post-exercise and its impact on CrCEST MRI with high temporal resolution is needed. In this work, we integrate carnosine 1H- magnetic resonance spectroscopy (MRS) and 3D CrCEST to establish "mild" and "moderate/intense" exercise stimuli. We then test the dependence of CrCEST recovery time on pH using different exercise stimuli. This comprehensive metabolic imaging protocol will enable personalized, muscle specific OXPHOS measurements in both healthy aging and myriad other disease states impacting muscle mitochondria.

Repeatability of Lac+ measurements in healthy human brain at 3 T.

PURPOSE: In vivo quantification of lactate has numerous applications in studying the pathology of both cerebral and musculoskeletal systems. Due to its low concentration (~0.5-1 mM), and overlap with lipid signals, traditional 1H MR spectra acquired in vivo using a small voxel and short echo time often result in an inadequate signal to detect and resolve the lactate peak, especially in healthy human volunteers. METHODS: In this study, using a semi-LASER acquisition with long echo time (TE = 288 ms) and large voxel size (80 × 70 × 20 mm3), we clearly visualize the combined signal of lactate and threonine. Therefore, we call the signal at 1.33 ppm Lac+ and quantify Lac+ concentration from water suppressed spectra in healthy human brains in vivo. Four participants (22-37 years old; mean age = 28 ± 5.4; three male, one female) were scanned on four separate days, and on each day four measurements were taken. Intra-day values are calculated for each participant by comparing the four measurements on a single day. Inter-day values were calculated using the mean intra-day measurements. RESULTS: The mean intra-participant Lac+ concentration, standard deviation (SD), and coefficient of variation (CV) ranged from 0.49 to 0.61 mM, 0.02 to 0.07 mM, and 4% to 13%, respectively, across four volunteers. The inter-participant Lac+ concentration, SD, and CV was 0.53 mM, ±0.06 mM, and 11%. CONCLUSION: Repeatability is shown in Lac+ measurement in healthy human brain using a long echo time semi-LASER sequence with a large voxel in about 3.5 min at 3 T.

Optimization of 1H MR spectroscopy methods for large volume acquisition of low concentration downfield resonances at 3T and 7T.

Purpose: This goal of this study was to optimize spectrally selective 1H MRS methods for large volume acquisition of low concentration metabolites with downfield resonances at 7T and 3T, with particular attention paid to detection of nicotinamide adenine dinucleotide (NAD+) and tryptophan. Methods: Spectrally selective excitation was used to avoid magnetization transfer effects with water, and various sinc pulses were compared to a pure-phase E-BURP pulse. Localization using a single slice selective pulse was compared to voxel-based localization that used three orthogonal refocusing pulses, and low bandwidth refocusing pulses were used to take advantage of the chemical shift displacement of water. A technique for water sideband removal was added, and a method of coil channel combination for large volumes was introduced. Results: Proposed methods were compared qualitatively to previously-reported techniques at 7T. Sinc pulses resulted in reduced water signal excitation and improved spectral quality, with a symmetric, low bandwidth-time product pulse performing best. Single slice localization allowed shorter TEs with large volumes, enhancing signal, while low bandwidth slice selective localization greatly reduced the observed water signal. Gradient cycling helped remove water sidebands, and frequency aligning and pruning individual channels narrowed spectral linewidths. High quality brain spectra of NAD+ and tryptophan are shown in four subjects at 3T. Conclusion: Improved spectral quality with higher downfield signal, shorter TE, lower nuisance signal, reduced artifacts, and narrower peaks was realized at 7T. These methodological improvements allowed for previously unachievable detection of NAD+ and tryptophan in human brain at 3T in under five minutes.

In vivo B 1 + enhancement of calf MRI at 7 T via optimized flexible metasurfaces.

PURPOSE: Ultrahigh field (≥7 T) MRI is at the cutting edge of medical imaging, enabling enhanced spatial and spectral resolution as well as enhanced susceptibility contrast. However, transmit ( B 1 + $$ {\mathrm{B}}_1^{+} $$ ) field inhomogeneity due to standing wave effects caused by the shortened RF wavelengths at 7 T is still a challenge to overcome. Novel hardware methods such as dielectric pads have been shown to improve the B 1 + $$ {\mathrm{B}}_1^{+} $$ field inhomogeneity but are currently limited in their corrective effect by the range of high-permittivity materials available and have a fixed shelf life. In this work, an optimized metasurface design is presented that demonstrates in vivo enhancement of the B 1 + $$ {\mathrm{B}}_1^{+} $$ field. METHODS: A prototype metasurface was optimized by an empirical capacitor sweep and by varying the period size. Phantom temperature experiments were performed to evaluate potential metasurface heating effects during scanning. Lastly, in vivo gradient echo images and B 1 + $$ {\mathrm{B}}_1^{+} $$ maps were acquired on five healthy subjects on a 7 T system. Dielectric pads were also used as a comparison throughout the work as a standard comparison. RESULTS: The metasurfaces presented here enhanced the average relative SNR of the gradient echo images by a factor of 2.26 compared to the dielectric pads factor of 1.61. Average B 1 + $$ {\mathrm{B}}_1^{+} $$ values reflected a similar enhancement of 27.6% with the metasurfaces present versus 8.9% with the dielectric pads. CONCLUSION: The results demonstrate that metasurfaces provide superior performance to dielectric padding as shown by B 1 + $$ {\mathrm{B}}_1^{+} $$ maps reflecting their direct effects and resulting enhancements in image SNR at 7 T.

Ketone Supplementation Dampens Subjective and Objective Responses to Alcohol: Evidence From a Preclinical Rat Study and a Randomized, Cross-Over Trial in Healthy Volunteers.

BACKGROUND: Previous preclinical and human studies have shown that a high-fat ketogenic diet and ketone supplements (KS) are efficacious in reducing alcohol craving, alcohol consumption, and signs of alcohol withdrawal. However, the effects of KS on alcohol sensitivity are unknown. METHODS: In this single-blind, cross-over study, 10 healthy participants (3 females) were administered a single, oral dose of a KS (25 g of ketones from D-ß-hydroxybutyric acid and R-1,3-butanediol) or placebo 30 minutes before an oral alcohol dose (0.25 g/kg for women; 0.31 g/kg for men). Assessments of breath alcohol concentration and blood alcohol levels (BAL) and responses on the Drug Effect Questionnaire were repeatedly obtained over 180 minutes after alcohol consumption. In a parallel preclinical study, 8 Wistar rats (4 females) received an oral gavage of KS (0.42 g ketones/kg), water, or the sweetener allulose (0.58 g/kg) followed 15 minutes later by an oral alcohol dose (0.8 g/kg). BAL was monitored for 240 minutes after alcohol exposure. RESULTS: In humans, the intake of KS before alcohol significantly blunted breath alcohol concentration and BAL, reduced ratings of alcohol liking and wanting more, and increased disliking for alcohol. In rats, KS reduced BAL more than either allulose or water. CONCLUSION: KS altered physiological and subjective responses to alcohol in both humans and rats, and the effects were likely not mediated by the sweetener allulose present in the KS drink. Therefore, KS could potentially reduce the intoxicating effects of alcohol.

Application of glutamate weighted CEST in brain imaging of nicotine dependent participants in vivo at 7T.

INTRODUCTION: With nicotine dependence being a significant healthcare issue worldwide there is a growing interest in developing novel therapies and diagnostic aids to assist in treating nicotine addiction. Glutamate (Glu) plays an important role in cognitive function regulation in a wide range of conditions including traumatic brain injury, aging, and addiction. Chemical exchange saturation transfer (CEST) imaging via ultra-high field MRI can image the exchange of certain saturated labile protons with the surrounding bulk water pool, making the technique a novel tool to investigate glutamate in the context of addiction. The aim of this work was to apply glutamate weighted CEST (GluCEST) imaging to study the dorsal anterior cingulate cortex (dACC) in a small population of smokers and non-smokers to determine its effectiveness as a biomarker of nicotine use. METHODS: 2D GluCEST images were acquired on 20 healthy participants: 10 smokers (ages 29-50) and 10 non-smokers (ages 25-69), using a 7T MRI system. T1-weighted images were used to segment the GluCEST images into white and gray matter tissue and further into seven gray matter regions. Wilcoxon rank-sum tests were performed, comparing mean GluCEST contrast between smokers and non-smokers across brain regions. RESULTS: GluCEST levels were similar between smokers and non-smokers; however, there was a moderate negative age dependence (R2 = 0.531) in smokers within the cingulate gyrus. CONCLUSION: Feasibility of GluCEST imaging was demonstrated for in vivo investigation of smokers and non-smokers to assess glutamate contrast differences as a potential biomarker with a moderate negative age correlation in the cingulate gyrus suggesting reward network involvement.

Early-stage mapping of macromolecular content in APPNL-F mouse model of Alzheimer's disease using nuclear Overhauser effect MRI.

Non-invasive methods of detecting early-stage Alzheimer's disease (AD) can provide valuable insight into disease pathology, improving the diagnosis and treatment of AD. Nuclear Overhauser enhancement (NOE) MRI is a technique that provides image contrast sensitive to lipid and protein content in the brain. These macromolecules have been shown to be altered in Alzheimer's pathology, with early disruptions in cell membrane integrity and signaling pathways leading to the buildup of amyloid-beta plaques and neurofibrillary tangles. We used template-based analyzes of NOE MRI data and the characteristic Z-spectrum, with parameters optimized for increase specificity to NOE, to detect changes in lipids and proteins in an AD mouse model that recapitulates features of human AD. We find changes in NOE contrast in the hippocampus, hypothalamus, entorhinal cortex, and fimbria, with these changes likely attributed to disruptions in the phospholipid bilayer of cell membranes in both gray and white matter regions. This study suggests that NOE MRI may be a useful tool for monitoring early-stage changes in lipid-mediated metabolism in AD and other disorders with high spatial resolution.

B 1 + $$ {\mathrm{B}}_1

PURPOSE: Nuclear Overhauser effect magnetization transfer ratio (NOEMTR ) is a technique used to investigate brain lipids and macromolecules in greater detail than other techniques and benefits from increased contrast at 7 T. However, this contrast can become degraded because of B 1 + $$ {\mathrm{B}}_1^{+} $$ inhomogeneities present at ultra-high field strengths. High-permittivity dielectric pads (DP) have been used to correct for these inhomogeneities via displacement currents generating secondary magnetic fields. The purpose of this work is to demonstrate that dielectric pads can be used to mitigate B 1 + $$ {\mathrm{B}}_1^{+} $$ inhomogeneities and improve NOEMTR contrast in the temporal lobes at 7 T. METHODS: Partial 3D NOEMTR contrast images and whole brain B 1 + $$ {\mathrm{B}}_1^{+} $$ field maps were acquired on a 7 T MRI across six healthy subjects. Calcium titanate DP, having a relative permittivity of 110, was placed next to the subject's head near the temporal lobes. Pad corrected NOEMTR images had a separate postprocessing linear correction applied. RESULTS: DP provided supplemental B 1 + $$ {\mathrm{B}}_1^{+} $$ to the temporal lobes while also reducing the B 1 + $$ {\mathrm{B}}_1^{+} $$ magnitude across the posterior and superior regions of the brain. This resulted in a statistically significant increase in NOEMTR contrast in substructures of the temporal lobes both with and without linear correction. The padding also produced a convergence in NOEMTR contrast toward approximately equal mean values. CONCLUSION: NOEMTR images showed significant improvement in temporal lobe contrast when DP were used, which resulted from an increase in B 1 + $$ {\mathrm{B}}_1^{+} $$ homogeneity across the entire brain slab. DP-derived improvements in NOEMTR are expected to increase the robustness of the brain substructural measures both in healthy and pathological conditions.

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

PURPOSE: The purpose of this study was to identify and characterize newly discovered resonances appearing in the downfield proton MR spectrum (DF 1 H MRS) of the human calf muscle in vivo at 7T. METHODS: Downfield 1 H 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 1 H MRS acquisition. RESULTS: In all participants, we observed new resonances at 9.7, 10.1, 10.3, and 10.9 ppm in the DF 1 H 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 1 H 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.

In vivo assessment of ß-hydroxybutyrate metabolism in mouse brain using deuterium (2 H) MRS.

PURPOSE: To monitor the metabolic turnover of ß-hydroxybutyrate (BHB) oxidation using 2 H-MRS in conjunction with intravenous administration of 2 H labeled BHB. METHODS: Nine-month-old mice were infused with [3,4,4,4]-2 H4 -BHB (d4 -BHB; 3.11 g/kg) through the tail vein using a bolus variable infusion rate for a period of 90 min. The labeling of downstream cerebral metabolites from the oxidative metabolism of d4 -BHB was monitored using 2 H-MRS spectra acquired with a home-built 2 H surface coil on a 9.4T preclinical MR scanner with a temporal resolution of 6.25 min. An exponential model was fit to the BHB and glutamate/glutamine (Glx) turnover curves to determine rate constants of metabolite turnover and to aid in the visualization of metabolite time courses. RESULTS: Deuterium label was incorporated into Glx from BHB metabolism through the tricarboxylic acid (TCA) cycle, with an increase in the level of [4,4]-2 H2 -Glx (d2 -Glx) over time and reaching a quasi-steady state concentration of ∼0.6 ± 0.1 mM following 30 min of infusion. Complete oxidative metabolic breakdown of d4 -BHB also resulted in the formation of semi-heavy water (HDO), with a four-fold (10.1 to ∼42.1 ± 7.3 mM) linear (R2  = 0.998) increase in its concentration by the end of infusion. The rate constant of Glx turnover from d4 -BHB metabolism was determined to be 0.034 ± 0.004 min-1 . CONCLUSION: 2 H-MRS can be used to monitor the cerebral metabolism of BHB with its deuterated form by measuring the downstream labeling of Glx. The integration of 2 H-MRS with deuterated BHB substrate provides an alternative and clinically promising MRS tool to detect neurometabolic fluxes in healthy and disease conditions.

In vivo reproducibility of 3D relayed NOE in the healthy human brain at 7 T.

PURPOSE: Nuclear Overhauser effect (NOE) is based on dipolar cross-relaxation mechanism that enables the indirect detection of aliphatic protons via the water proton signal. This work focuses on determining the reproducibility of NOE magnetization transfer ratio (NOEMTR ) and isolated or relayed NOE (rNOE) contributions to the NOE MRI of the healthy human brain at 7 Tesla (T). METHODS: We optimized the B 1 + $$ {\mathrm{B}}_1^{+} $$ amplitude and length of the saturation pulse by acquiring NOE images with different B 1 + $$ {\mathrm{B}}_1^{+} $$ values with multiple saturation lengths. Repeated NOE MRI measurements were made on five healthy volunteers by using optimized saturation pulse parameters including correction of B0 and B 1 + $$ {\mathrm{B}}_1^{+} $$ inhomogeneities. To isolate the individual contributions from z-spectra, we have fit the NOE z-spectra using multiple Lorentzians and calculated the total contribution from each pool contributing to the overall NOEMTR contrast. RESULTS: We found that a saturation amplitude of 0.72 µT and a length of 3 s provided the highest contrast. We found that the mean NOEMTR value in gray matter (GM) was 26%, and in white matter (WM) was 33.3% across the 3D slab of the brain. The mean rNOE contributions from GM and WM values were 8.9% and 9.6%, which were ∼10% of the corresponding total NOEMTR signal. The intersubject coefficient of variations (CoVs) of NOEMTR from GM and WM were 4.5% and 6.5%, respectively, whereas the CoVs of rNOE were 4.8% and 5.6%, respectively. The intrasubject CoVs of the NOEMTR range was 2.1%-4.2%, and rNOE range was 2.9%-10.5%. CONCLUSION: This work has demonstrated an excellent reproducibility of both inter- and intrasubject NOEMTR and rNOE metrics in healthy human brains at 7 T.

Quantification of cross-relaxation in downfield 1 H MRS at 7 T in human calf muscle.

PURPOSE: The purpose of this study was to characterize the 1 H downfield MR spectrum from 8.0 to 10.0 ppm of human skeletal muscle at 7 T and determine the T1 and cross-relaxation rates of observed resonances. METHODS: We performed downfield MRS in the calf muscle of 7 healthy volunteers. Single-voxel downfield MRS was collected using alternately selective or broadband inversion-recovery sequences and spectrally selective 90° E-BURP RF pulse excitation centered at 9.0 ppm with bandwidth = 600 Hz (2.0 ppm). MRS was collected using TIs of 50-2500 ms. We modeled recovery of the longitudinal magnetization of three observable resonances using two models: (1) a three-parameter model accounting for the apparent T1 recovery and (2) a Solomon model explicitly including cross-relaxation effects. RESULTS: Three resonances were observed in human calf muscle at 7 T at 8.0, 8.2, and 8.5 ppm. We found broadband (broad) and selective (sel) inversion recovery T1 = mean ± SD (ms): T1-broad,8.0ppm = 2108.2 ± 664.5, T1-sel,8.0ppm = 753.6 ± 141.0 (p = 0.003); T1-broad,8.2ppm = 2033.5 ± 338.4, T1-sel,8.2ppm = 135.3 ± 35.3 (p < 0.0001); and T1-broad,8.5ppm = 1395.4 ± 75.4, T1-sel,8.5ppm = 107.1 ± 40.0 (p < 0.0001). Using the Solomon model, we found T1 = mean ± SD (ms): T1-8.0ppm = 1595.6 ± 491.1, T1-8.2ppm = 1737.2 ± 963.7, and T1-8.5ppm = 849.8 ± 282.0 (p = 0.04). Post hoc tests corrected for multiple comparisons showed no significant difference in T1 between peaks. The cross-relaxation rate σAB = mean ± SD (Hz) of each peak was σAB,8.0ppm = 0.76 ± 0.20, σAB,8.2ppm = 5.31 ± 2.27, and σAB,8.5ppm = 7.90 ± 2.74 (p < 0.0001); post hoc t-tests revealed the cross-relaxation rate of the 8.0 ppm peak was significantly slower than the peaks at 8.2 ppm (p = 0.0018) and 8.5 ppm (p = 0.0005). CONCLUSION: We found significant differences in effective T1 and cross-relaxation rates of 1 H resonances between 8.0 and 8.5 ppm in the healthy human calf muscle at 7 T.

Glutamate-weighted CEST (gluCEST) imaging for mapping neurometabolism: An update on the state of the art and emerging findings from in vivo applications.

Glutamate is the primary excitatory neurotransmitter in the mammalian central nervous system. As such, its proper regulation is essential to the healthy function of the human brain, and dysregulation of glutamate metabolism and compartmentalization underlies numerous neurological and neuropsychiatric pathologies. Glutamate-weighted chemical exchange saturation transfer (gluCEST) MRI is one of the only ways to non-invasively observe the relative concentration and spatial distribution of glutamate in the human brain. In the past 10 years, gluCEST has developed from a proof-of-concept experiment carried out in imaging phantoms and model systems to an increasingly sophisticated technique applied to reveal deviations from baseline neural metabolism in human beings, most notably in patients experiencing seizures of various origins or those on the psychosis spectrum. This article traces that progress, including in-depth discussion of the technical specifics of gluCEST and potential challenges to performing these experiments rigorously. We discuss the neurobiological context of glutamate, including the widely accepted hypotheses and models in the literature regarding its involvement in neurodegenerative diseases and other pathology. We then review the state of the art of in vivo glutamate detection by magnetic resonance imaging and the limitations on this front of in vivo MR spectroscopy. The gluCEST experiment is introduced and its advantages, challenges and limitations are thoroughly explored, beginning with the phantom experiment results demonstrated in the initial publication, through the latest approaches to correcting human brain images for B1 inhomogeneity. We then give a comprehensive overview of preclinical applications demonstrated to date, including Alzheimer's disease, Parkinson's disease, Huntington's disease, Traumatic brain injury and cancer, followed by a similar discussion of human studies. Finally, we highlight emerging applications, and discuss technical improvements on the horizon that hold promise for improving the robustness and versatility of gluCEST and its increasing presence in the arena of translational and precision medicine.

Mapping hippocampal glutamate in mesial temporal lobe epilepsy with glutamate weighted CEST (GluCEST) imaging.

Temporal lobe epilepsy (TLE) is one of the most common subtypes of focal epilepsy, with mesial temporal sclerosis (MTS) being a common radiological and histopathological finding. Accurate identification of MTS during presurgical evaluation confers an increased chance of good surgical outcome. Here we propose the use of glutamate-weighted chemical exchange saturation transfer (GluCEST) magnetic resonance imaging (MRI) at 7 Tesla for mapping hippocampal glutamate distribution in epilepsy, allowing to differentiate lesional from non-lesional mesial TLE. We demonstrate that a directional asymmetry index, which quantifies the relative difference between GluCEST contrast in hippocampi ipsilateral and contralateral to the seizure onset zone, can differentiate between sclerotic and non-sclerotic hippocampi, even in instances where traditional presurgical MRI assessments did not provide evidence of sclerosis. Overall, our results suggest that hippocampal glutamate mapping through GluCEST imaging is a valuable addition to the presurgical epilepsy evaluation toolbox.

Repeatability of B1 + inhomogeneity correction of volumetric (3D) glutamate CEST via High-permittivity dielectric padding at 7T.

PURPOSE: Ultra-high field MR imaging lacks B1 + inhomogeneity due to shorter RF wavelengths used at higher field strengths compared to human anatomy. CEST techniques tend to be highly susceptible to B1 + inhomogeneities due to a high and uniform B1 + field being necessary to create the endogenous contrast. High-permittivity dielectric pads have seen increasing usage in MR imaging due to their ability to tailor the spatial distribution of the B1 + field produced. The purpose of this work is to demonstrate that dielectric materials can be used to improve glutamate weighted CEST (gluCEST) at 7T. THEORY AND METHODS: GluCEST images were acquired on a 7T system on six healthy volunteers. Aqueous calcium titanate pads, with a permittivity of approximately 110, were placed on either side in the subject's head near the temporal lobes. A post-processing correction algorithm was implemented in combination with dielectric padding to compare contrast improvement. Tissue segmentation was performed to assess the effect of dielectric pads on gray and white matter separately. RESULTS: GluCEST images demonstrated contrast enhancement in the lateral temporal lobe regions with dielectric pad placement. Tissue segmentation analysis showed an increase in correction effectiveness within the gray matter tissue compared to white matter tissue. Statistical testing suggested a significant difference in gluCEST contrast when pads were used and showed a difference in the gray matter tissue segment. CONCLUSION: The use of dielectric pads improved the B1 + field homogeneity and enhanced gluCEST contrast for all subjects when compared to data that did not incorporate padding.

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

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.

Characterizing the neurological phenotype of the hyperinsulinism hyperammonemia syndrome.

BACKGROUND: Hyperinsulinism hyperammonemia (HI/HA) syndrome is caused by activating mutations in GLUD1, encoding glutamate dehydrogenase (GDH). Atypical absence seizures and neuropsychological disorders occur at high rates in this form of hyperinsulinism. Dysregulated central nervous system (CNS) glutamate balance, due to GDH overactivity in the brain, has been hypothesized to play a role. This study aimed to describe the neurologic phenotype in HI/HA syndrome and investigate CNS glutamate levels using glutamate weighted chemical exchange saturation transfer magnetic resonance imaging (GluCEST MRI). In this cross-sectional study, 12 subjects with HI/HA syndrome had plasma ammonia measurement, self- or parent-completed neurocognitive assessments, electroencephalogram (EEG), and GluCEST MRI at 7 T performed. GluCEST MRI measures were compared to a historic reference population of 10 healthy adults. RESULTS: Subjects were five males and seven females with median age of 25.5 years. Seventy-five percent of subjects reported a history of neurodevelopmental problems and 42% had neurocognitive assessment scores outside the normal range. Fifty percent had interictal EEG findings of generalized, irregular spike and wave discharges. Higher variability in hippocampal GluCEST asymmetry (p = 0.002), and in peak hippocampal GluCEST values (p = 0.008), was observed in HI/HA subjects (n = 9 with interpretable MRI) compared to the healthy reference population (n = 10). CONCLUSIONS: The high prevalence of abnormal neurocognitive assessment scores and interictal EEG findings observed highlights the importance of longitudinal neuropsychological assessment for individuals with HI/HA syndrome. Our findings demonstrate the potential application of GluCEST to investigate persistent knowledge gaps in the mechanisms underlying the unique neurophenotype of this disorder.

Emerging MR Imaging and Spectroscopic Methods to Study Brain Tumor Metabolism.

Proton magnetic resonance spectroscopy (1H-MRS) provides a non-invasive biochemical profile of brain tumors. The conventional 1H-MRS methods present a few challenges mainly related to limited spatial coverage and low spatial and spectral resolutions. In the recent past, the advent and development of more sophisticated metabolic imaging and spectroscopic sequences have revolutionized the field of neuro-oncologic metabolomics. In this review article, we will briefly describe the scientific premises of three-dimensional echoplanar spectroscopic imaging (3D-EPSI), two-dimensional correlation spectroscopy (2D-COSY), and chemical exchange saturation technique (CEST) MRI techniques. Several published studies have shown how these emerging techniques can significantly impact the management of patients with glioma by determining histologic grades, molecular profiles, planning treatment strategies, and assessing the therapeutic responses. The purpose of this review article is to summarize the potential clinical applications of these techniques in studying brain tumor metabolism.