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  • Noninvasive quantification of ascorbate and glutathione concentration in the elderly human brain.

    24 October 2018

    In this study, ascorbate (Asc) and glutathione (GSH) concentrations were quantified noninvasively using double-edited (1)H MRS at 4 T in the occipital cortex of healthy young [age (mean ± standard deviation) = 20.4 ± 1.4 years] and elderly (age = 76.6 ± 6.1 years) human subjects. Elderly subjects had a lower GSH concentration than younger subjects (p < 0.05). The Asc concentration was not significantly associated with age. Furthermore, the lactate (Lac) concentration was higher in elderly than young subjects. Lower GSH and higher Lac concentrations are indications of defective protection against oxidative damage and impaired mitochondrial respiration. The extent to which the observed concentration differences could be associated with physiological differences and methodological artifacts is discussed. In conclusion, GSH and Asc concentrations were compared noninvasively for the first time in young vs elderly subjects.

  • SIMULTANEOUS MEASUREMENT OF GLUCOSE TRANSPORT AND UTILIZATION IN THE HUMAN BRAIN.

    24 October 2018

    Glucose is the primary fuel for brain function and determining the kinetics of cerebral glucose transport and utilization is critical for quantifying cerebral energy metabolism. The kinetic parameters of cerebral glucose transport, K(M)(t) and V(max)(t), in humans have so far been obtained by measuring steady-state brain glucose levels by proton ((1)H) NMR as a function of plasma glucose levels and fitting steady-state models to these data. Extraction of the kinetic parameters for cerebral glucose transport necessitated assuming a constant cerebral metabolic rate of glucose (CMR(glc)) obtained from other tracer studies, such as (13)C NMR. Here we present new methodology to simultaneously obtain kinetic parameters for glucose transport and utilization in the human brain by fitting both dynamic and steady-state (1)H NMR data with a reversible, non-steady-state Michaelis-Menten model. Dynamic data were obtained by measuring brain and plasma glucose time courses during glucose infusions to raise and maintain plasma concentration at 17 mmol/l for 2 hours in 5 healthy volunteers. Steady-state brain vs. plasma glucose concentrations were taken from literature and the steady-state portions of data from the 5 volunteers. In addition to providing simultaneous measurements of glucose transport and utilization and obviating assumptions for constant CMR(glc), this methodology does not necessitate infusions of expensive or radioactive tracers. Using this new methodology, we found that the maximum transport capacity for glucose through the blood-brain barrier was nearly two-fold higher than maximum cerebral glucose utilization. The glucose transport and utilization parameters were consistent with previously published values for human brain.

  • Feasibility and reproducibility of neurochemical profile quantification in the human hippocampus at 3 T.

    24 October 2018

    Hippocampal dysfunction is known to be associated with several neurological and neuropsychiatric disorders such as Alzheimer's disease, epilepsy, schizophrenia and depression; therefore, there has been significant clinical interest in studying hippocampal neurochemistry. However, the hippocampus is a challenging region to study using (1) H MRS, hence the use of MRS for clinical research in this region has been limited. Our goal was therefore to investigate the feasibility of obtaining high-quality hippocampal spectra that allow reliable quantification of a neurochemical profile and to establish inter-session reproducibility of hippocampal MRS, including reproducibility of voxel placement, spectral quality and neurochemical concentrations. Ten healthy volunteers were scanned in two consecutive sessions using a standard clinical 3 T MR scanner. Neurochemical profiles were obtained with a short-echo (T(E) = 28 ms) semi-LASER localization sequence from a relatively small (~4 mL) voxel that covered about 62% of the hippocampal volume as calculated from segmentation of T1 -weighted images. Voxel composition was highly reproducible between sessions, with test-retest coefficients of variation (CVs) of 3.5% and 7.5% for gray and white matter volume fraction, respectively. Excellent signal-to-noise ratio (~54 based on the N-acetylaspartate (NAA) methyl peak in non-apodized spectra) and linewidths (~9 Hz for water) were achieved reproducibly in all subjects. The spectral quality allowed quantification of NAA, total choline, total creatine, myo-inositol and glutamate with high scan-rescan reproducibility (CV ≤ 6%) and quantification precision (Cramér-Rao lower bound, CRLB < 9%). Four other metabolites, including glutathione and glucose, were quantified with scan-rescan CV below 20%. Therefore, the highly optimized, short-echo semi-LASER sequence together with FASTMAP shimming substantially improved the reproducibility and number of quantifiable metabolites relative to prior reports. In addition, the between-session variation in metabolite concentrations, as well as CRLB, was lower than the between-subject variation of the concentrations for most metabolites, indicating that the method has the sensitivity to detect inter-individual differences in the healthy brain.

  • Noninvasive quantification of human brain antioxidant concentrations after an intravenous bolus of vitamin C.

    24 October 2018

    Until now, the lack of a means to detect a deficiency or to measure the pharmacologic effect in the human brain in situ has been a hindrance to the development of antioxidant-based prevention and treatment of dementia. In this study, a recently developed (1) H MRS approach was applied to quantify key human brain antioxidant concentrations throughout the course of an aggressive antioxidant-based intervention. The concentrations of the two most abundant central nervous system chemical antioxidants, vitamin C and glutathione, were quantified noninvasively in the human occipital cortex prior to and throughout 24 h after bolus intravenous delivery of 3 g of vitamin C. Although the kinetics of the sodium-dependent vitamin C transporter and physiologic blood vitamin C concentrations predict theoretically that brain vitamin C concentration will not increase above its homeostatically maintained level, this theory has never been tested experimentally in the living human brain. Therefore, human brain vitamin C and glutathione concentrations were quantified noninvasively using MEGA-PRESS double-edited (1) H MRS and LCModel. Healthy subjects (age, 19-63 years) with typical dietary consumption, who did not take vitamin supplements, fasted overnight and then reported for the measurement of baseline antioxidant concentrations. They then began controlled feeding which they adhered to until after vitamin C and glutathione concentrations had been measured at 2, 6, 10 and 24 h after receiving intravenous vitamin C. Two of the twelve studies were sham controls in which no vitamin C was administered. The main finding was that human brain vitamin C and glutathione concentrations remained constant throughout the protocol, even though blood serum vitamin C concentrations spanned from the low end of the normal range to very high.

  • Two-site reproducibility of cerebellar and brainstem neurochemical profiles with short-echo, single-voxel MRS at 3T.

    24 October 2018

    PURPOSE: To determine whether neurochemical concentrations obtained at two MRI sites using clinical 3T scanners can be pooled when a highly optimized, nonvendor short-echo, single-voxel proton MRS pulse sequence is used in conjunction with identical calibration and quantification procedures. METHODS: A modified semi-LASER sequence (TE = 28 ms) was used to acquire spectra from two brain regions (cerebellar vermis and pons) on two Siemens 3T scanners using the same B0 and B1 calibration protocols from two different cohorts of healthy volunteers (N = 24-33 per site) matched for age and body mass index. Spectra were quantified with LCModel using water scaling. RESULTS: The spectral quality was very consistent between the two sites and allowed reliable quantification of at least 13 metabolites in the vermis and pons compared with 3-5 metabolites in prior multisite magnetic resonance spectroscopy trials using vendor-provided sequences. The neurochemical profiles were nearly identical at the two sites and showed the feasibility to detect interindividual differences in the healthy brain. CONCLUSION: Highly reproducible neurochemical profiles can be obtained on different clinical 3T scanners at different sites, provided that the same, optimized acquisition and analysis techniques are used. This will allow pooling of multisite data in clinical studies, which is particularly critical for rare neurological diseases.

  • Neurochemical and BOLD responses during neuronal activation measured in the human visual cortex at 7 Tesla.

    24 October 2018

    Several laboratories have consistently reported small concentration changes in lactate, glutamate, aspartate, and glucose in the human cortex during prolonged stimuli. However, whether such changes correlate with blood oxygenation level-dependent functional magnetic resonance imaging (BOLD-fMRI) signals have not been determined. The present study aimed at characterizing the relationship between metabolite concentrations and BOLD-fMRI signals during a block-designed paradigm of visual stimulation. Functional magnetic resonance spectroscopy (fMRS) and fMRI data were acquired from 12 volunteers. A short echo-time semi-LASER localization sequence optimized for 7 Tesla was used to achieve full signal-intensity MRS data. The group analysis confirmed that during stimulation lactate and glutamate increased by 0.26 ± 0.06 μmol/g (~30%) and 0.28 ± 0.03 μmol/g (~3%), respectively, while aspartate and glucose decreased by 0.20 ± 0.04 μmol/g (~5%) and 0.19 ± 0.03 μmol/g (~16%), respectively. The single-subject analysis revealed that BOLD-fMRI signals were positively correlated with glutamate and lactate concentration changes. The results show a linear relationship between metabolic and BOLD responses in the presence of strong excitatory sensory inputs, and support the notion that increased functional energy demands are sustained by oxidative metabolism. In addition, BOLD signals were inversely correlated with baseline γ-aminobutyric acid concentration. Finally, we discussed the critical importance of taking into account linewidth effects on metabolite quantification in fMRS paradigms.

  • Noninvasive quantification of T2 and concentrations of ascorbate and glutathione in the human brain from the same double-edited spectra.

    24 October 2018

    The transverse relaxation times (T(2)) and concentrations of Ascorbate (Asc) and glutathione (GSH) were measured from a single dataset of double-edited spectra that were acquired at several TEs at 4 T in the human brain. Six TEs between 102 and 152  ms were utilized to calculate T(2) for the group of 12 subjects scanned five times each. Spectra measured at all six TEs were summed to quantify the concentration in each individual scan. LCModel fitting was optimized for the quantification of the Asc and GSH double-edited spectra. When the fitted baseline was constrained to be flat, T(2) was found to be 67  ms (95% confidence interval, 50-83  ms) for GSH and ≤115  ms for Asc using the sum of spectra measured over 60 scans. The Asc and GSH concentrations quantified in each of the 60 scans were 0.62 ± 0.08 and 0.81 ± 0.11  µmol/g [mean ± standard deviation (SD), n = 60], respectively, using 10  µmol/g N-acetylaspartate as an internal reference and assuming a constant influence of N-acetylaspartate and antioxidant T(2) relaxation in the reference solution and in vivo. The T(2) value of GSH was measured for the first time in the human brain. The data are consistent with short T(2) for both antioxidants. These T(2) values are essential for the absolute quantification of Asc and GSH concentrations measured at long TE, and provide a critical step towards addressing assumptions about T(2), and therefore towards the quantification of concentrations without the possibility of systematic bias.

  • Multi-center reproducibility of neurochemical profiles in the human brain at 7 T.

    24 October 2018

    The purpose of this work was to harmonize data acquisition and post-processing of single voxel proton MRS ((1) H-MRS) at 7 T, and to determine metabolite concentrations and the accuracy and reproducibility of metabolite levels in the adult human brain. This study was performed in compliance with local institutional human ethics committees. The same seven subjects were each examined twice using four different 7 T MR systems from two different vendors using an identical semi-localization by adiabatic selective refocusing spectroscopy sequence. Neurochemical profiles were obtained from the posterior cingulate cortex (gray matter, GM) and the corona radiata (white matter, WM). Spectra were analyzed with LCModel, and sources of variation in concentrations ('subject', 'institute' and 'random') were identified with a variance component analysis. Concentrations of 10-11 metabolites, which were corrected for T1 , T2 , magnetization transfer effects and partial volume effects, were obtained with mean Cramér-Rao lower bounds below 20%. Data variances and mean concentrations in GM and WM were comparable for all institutions. The primary source of variance for glutamate, myo-inositol, scyllo-inositol, total creatine and total choline was between subjects. Variance sources for all other metabolites were associated with within-subject and system noise, except for total N-acetylaspartate, glutamine and glutathione, which were related to differences in signal-to-noise ratio and in shimming performance between vendors. After multi-center harmonization of acquisition and post-processing protocols, metabolite concentrations and the sizes and sources of their variations were established for neurochemical profiles in the healthy brain at 7 T, which can be used as guidance in future studies quantifying metabolite and neurotransmitter concentrations with (1) H-MRS at ultra-high magnetic field.