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Focal three-dimensional magnetic resonance spectroscopic imaging (3D MRSI) methods based on conventional point resolved spectroscopy (PRESS) localization are compromised by the geometric restrictions in volume prescription and by chemical shift registration errors. Outer volume saturation (OVS) pulses have been applied to address the geometric limits, but conventional OVS pulses do little to overcome chemical shift registration error, are not particularly selective, and often leave substantial signals that can degrade the spectra of interest. In this paper, an optimized sequence of quadratic phase pulses is introduced to provide very selective spatial suppression with improved B1 and T1 insensitivity. This method was then validated in volunteer studies and in clinical 3D MRSI exams of brain tumors and prostate cancer.

Introduction Recent initiatives have resulted in guidelines for the assessment of cognitive function in specific clinical populations including the MATRICS consensus cognitive test battery for schizophrenia and the EMEA guideline on medicinal products for the treatment of Alzheimer s disease and other dementias. There are a number of common criteria that emerge, including assessment of cognition at the level of individual cognitive domains; validation; utility; utility as a repeated measure; and data allowing interpretation of results and understanding of the clinical relevance (i.e., normative/relationship to functional outcomes). It is apparent that such common criteria could usefully be applied to cognitive function assessment in all clinical populations. The publication of normative data is of use in the interpretation of clinical trials data. Methods Five-hundred and seventy (570) patients with newly diagnosed epilepsy, aged 12–75 years, from 21 countries within Europe, Latin America, and Australasia, not previously exposed to AEDs, were recruited to a clinical trial comparing the efficacy and safety of remacemide versus carbamazepine. Patients completed a 30 minute cognitive test battery comprised of the CDR System; Rey auditory verbal learning test; color-word Stroop test; symbol digit modalities test; Lafayette grooved pegboard; digit cancellation test; and the non-verbal matrices subtest of the Kaufman brief intelligence test. Normative data in treatment-naive patients across the studied age range were generated. Results Assessments showed a common relationship with age, with those patients in the younger adult age cohorts tending to perform better on all measures than older patients and also than the youngest age cohort patients. Conclusions These data may be useful in the analysis and interpretation of cognitive assessment data from clinical trials of AEDs and/or studies in similar patient populations. Financial disclosure This study was sponsored by AstraZeneca. None of the authors has a financial relationship with the sponsor.

1H NMR has detected both the deoxygenated proximal histidyl NδH signals of myoglobin (deoxyMb) and deoxygenated Hb (deoxyHb) from human gastrocnemius muscle. Exercising the muscle or pressure cuffing the leg to reduce blood flow elicits the appearance of the deoxyMb signal, which increases in intensity as cellular[Formula: see text] decreases. The deoxyMb signal is detected with a 45-s time resolution and reaches a steady-state level within 5 min of pressure cuffing. Its desaturation kinetics match those observed in the near-infrared spectroscopy (NIRS) experiments, implying that the NIRS signals are actually monitoring Mb desaturation. That interpretation is consistent with the signal intensity and desaturation of the deoxyHb proximal histidyl NδH signal from the β-subunit at 73 parts per million. The experimental results establish the feasibility and methodology to observe the deoxyMb and Hb signals in skeletal muscle, help clarify the origin of the NIRS signal, and set a stage for continuing study of O2regulation in skeletal muscle.

The proximal histidyl NδH signal of myoglobin is detectable in 1H NMR spectra of myocardial and skeletal muscle, and its intensity reflects the intracellular oxygenation. At 1.5 Tesla (T), the typical field strength of clinical magnetic resonance imaging (MRI) magnets, the paramagnetic relaxation contribution decreases sufficiently to permit the implementation of chemical shift imaging technique to map the spatial distribution of the deoxy Mb NδH signal from human gastrocnemius muscle. One and two-dimensional chemical shift imaging experiments reveal clearly the localized deoxy Mb signal in muscle and consequently the spatial distribution of the cellular oxygenation. The results indicate the feasibility to assess the pO2 in tissue regions and to directly study the regulation of oxidative metabolism in human tissue. Copyright © 1999 John Wiley & Sons, Ltd.

A method is introduced for obtaining proton spectra in vivo with all the advantages of a full water signal. The method, based on F1 oversampled J-resolved spectroscopy, makes it possible to separate metabolite signals from unwanted baseline artifacts. The dominant water resonance is used as a 2D reference signal for the phase-sensitive reconstruction of the 2D J-resolved metabolite spectra. The powerful specificity of this method is demonstrated with model compound spectra, phantoms, and in vivo examples.

Objectives:Cognitive impairment remains frequent in HIV, despite combination antiretroviral therapy (cART). Leading theories implicate peripheral monocyte HIV DNA reservoirs as a mechanism for spread of the virus to the brain. These reservoirs remain present despite cART. The objective of this study was to determine if the level of HIV DNA in CD14+ enriched monocytes predicted cognitive impairment and brain injury.Methods:We enrolled 61 cART-naïve HIV-infected Thais in a prospective study and measured HIV DNA in CD14+ enriched monocyte samples in a blinded fashion. We determined HAND diagnoses by consensus panel and all participants underwent magnetic resonance spectroscopy (MRS) to measure markers of brain injury. Immune activation was measured via cytokines in cerebrospinal fluid (CSF).Results:The mean (SD) age was 35 (6.9) years, CD4 T-lymphocyte count was 236 (139) and log10 plasma HIV RNA was 4.8 (0.73). Twenty-eight of 61 met HAND criteria. The log10 CD14+ HIV DNA was associated with HAND in unadjusted and adjusted models (p = 0.001). There was a 14.5 increased odds ratio for HAND per 1 log-value of HIV DNA (10-fold increase in copy number). Plasma CD14+ HIV DNA was associated with plasma and CSF neopterin (p = 0.023) and with MRS markers of neuronal injury (lower N-acetyl aspartate) and glial dysfunction (higher myoinositol) in multiple brain regions.Interpretation:Reservoir burden of HIV DNA in monocyte-enriched (CD14+) peripheral blood cells increases risk for HAND in treatment-naïve HIV+ subjects and is directly associated with CSF immune activation and both brain injury and glial dysfunction by MRS. © 2013 Valcour et al.

ObjectiveWe evaluated regional brain volumes and cerebral metabolite levels as correlates of HIV DNA in peripheral blood mononuclear cells (PBMCs).MethodsIn this cross-sectional study, 35 HIV+ subjects aged ≥40 years (25 with detectable PBMC HIV DNA; 10 with HIV DNA

Data from a previously published, multi-site trial (P.G. Webb, N. Sailasuta, S.J. Kohler, T. Raidy, R.A. Moats, R.E. Hurd. Automated single-voxel proton MRS: technical development and multisite verification. Magn. Reson. Med. 31, 365-373 (1994)) of a fully automatic, single-voxel, proton spectroscopy package (PROBE/SV, GE Medical Systems) was re-analyzed in terms of absolute metabolite concentrations using the cerebral water signal as an internal reference. In 100 spectra from parietal white matter in normal volunteers ranging in age from 22 to 34 years at eight sites, overall concentrations of choline (Cho) creatine (Cr), and N-acetyl-aspartate (NAA) resonances were found to be 2.00 +/- 0.50, 8.43 +/- 1.28, and 12.55 +/- 1.76 mumol/g wet weight, respectively. These values are in good general agreement with previously published values from quantitative, single-voxel studies. Metabolite concentrations for NAA, Cr, and Cho across all sites had standard deviations of 14.1%, 14.9%, and 25.1%, respectively. Quantitation of PROBE data sets is routinely possible by using the cerebral water signal as an internal reference.

To use (13) C magnetic resonance spectroscopy (MRS) and (31) P MRS to develop a direct assay for regional [HCO3-] in the human brain and to define brain pH and physiological response of [HCO3-] to fasting.Seven healthy subjects underwent MRS examinations on a 1.5T MRI scanner. Subjects were well fed with repeated examinations performed after 4 and 12 hours of fasting. Proton noise decoupling (13) C MRS were acquired using pulse and acquired acquisition while (31) P MRS were acquired using a 2D chemical shift imaging method with relaxation time (TR) of 2 seconds.Fasting brain bicarbonate concentrations (6.7 ± 2.5 mM for 12-hour fasting, P = 0.002 and 8.3 ± 2.1 mM for 4-hour fasting, P = 0.015) are significantly reduced compared to fed state (11.6 ± 1.3 mM). However, no significant difference in brain pH was observed, confirming the critical role of pCO2 in intracerebral pH homeostasis.We demonstrated that the intracellular HCO3- in human brain is readily modified by diet but appears to have no measurable effect on cerebral pH. Natural abundance (13) C can provide useful information relevant to human brain pH homeostasis by providing information for HCO3-.

Objective Single voxel proton magnetic resonance spectroscopy (MRS) can be used to monitor changes in brain inflammation and neuronal integrity associated with HIV infection and its treatments. We used MRS to measure brain changes during the first weeks following HIV infection and in response to antiretroviral therapy (ART). Methods Brain metabolite levels of N-acetyl aspartate (NAA), choline (tCHO), creatine (CR), myoinositol (MI), and glutamate and glutamine (GLX) were measured in acute HIV subjects (n = 31) and compared to chronic HIV+individuals (n = 26) and HIV negative control subjects (n = 10) from Bangkok, Thailand. Metabolites were measured in frontal gray matter (FGM), frontal white matter (FWM), occipital gray matter (OGM), and basal ganglia (BG). Repeat measures were obtained in 17 acute subjects 1, 3 and 6 months following initiation of ART. Results After adjustment for age we identified elevated BG tCHO/CR in acute HIV cases at baseline (median 14 days after HIV infection) compared to control (p = 0.0014), as well as chronic subjects (p = 0.0023). A similar tCHO/CR elevation was noted in OGM; no other metabolite abnormalities were seen between acute and control subjects. Mixed longitudinal models revealed resolution of BG tCHO/CR elevation after ART (p = 0.022) with tCHO/CR similar to control subjects at 6 months. Interpretation We detected cellular inflammation in the absence of measurable neuronal injury within the first month of HIV infection, and normalization of this inflammation following acutely administered ART. Our findings suggest that early ART may be neuroprotective in HIV infection by mitigating processes leading to CNS injury.

Background. Reduction of cortical thickness and Hippocampal volume (HV) in Methamphetamine abusers (MA) has been reported. However, change of white matter volume (WMV) in MA group is inconclusive. We aim to compare cortical thickness, Hippocampal volume (HV), and WMV per intra-cranial volume (ICV) among MA in Thai adolescents. Methods. 3D T1-wighted high resolution MR images from 11 MAs and 10 HCs with gender and age match with mean age 25.48 ±4.9 were acquired on a 1.5T Philips MR scanner. Automated Talairach transform and images group analysis with general linear model (GLM) were performed using FreeSurfer software. HV, FWMV/ICV, and WMV/ICV between MA and HC groups were compared. Results. Significant thinner regions (p < 0.05) of cortical thickness in MA group were found at the right temporal and parietal lobes. Trends of smaller Hippocampal volume on left and right by 5.1% and 4.3% and increasing of Left FWMV/ICV, right FWMV/ICV, and tWMV/ICV by 3.1%, 4.5% and 3.8% respectively in MA group compared to HC group. Conclusions. The results demonstrated significant thinner of cortical thickness at the right temporal and parietal lobes and the trend of WM hypertrophy and smaller Hippocampus in MA group.

We describe and demonstrate a system to generate hyperpolarized water in the 0.35 T fringe field of a clinical 1.5 T whole-body magnetic resonance imaging (MRI) magnet. Once generated, the hyperpolarized water is quickly and continuously transferred from the 0.35 T fringe to the 1.5 T center field of the same magnet for image acquisition using standard MRI equipment. The hyperpolarization is based on Overhauser dynamic nuclear polarization (DNP), which effectively and quickly transfers the higher spin polarization of free radicals to nuclear spins at ambient temperatures. We visualize the dispersion of hyperpolarized water as it flows through water-saturated systems by utilizing an observed −15 fold DNP signal enhancement with respect to the unenhanced 1H MRI signal of water at 1.5 T. The experimental DNP apparatus presented here is readily portable and can be brought to and used with any conventional unshielded MRI system. A new method of immobilizing radicals to gel beads via polyelectrolyte linker arms is described, which led to superior flow Overhauser DNP performance compared to previously presented gels. We discuss the general applicability of Overhauser DNP hyperpolarization of water and aqueous solutions in the fringe field of commercially available magnets with central fields up to 4.7 Tesla.

We demonstrate a robust procedure for the quantitative characterization of glial metabolism in human brain. In the past, the slope of the uptake and production of enriched label at steady state were used to determine metabolic rates, requiring the patient to be in the magnet for 120 – 160 minutes. In the present method, 13C cerebral metabolite profiles were acquired at steady state alone on a routine clinical MR scanner in 25.6 minutes. Results obtained from the new short method (SAGA) were comparable to those achieved in a conventional, long method and effective for determination of glial metabolic rate in posterior-parietal and frontal brain regions.

Persistent neurochemical abnormalities in frontal brain structures are believed to result from methamphetamine use. We developed a localized 13C magnetic resonance spectroscopy (MRS) assay on a conventional MR scanner, to quantify selectively glial metabolic flux rate in frontal brain of normal subjects and a cohort of recovering abstinent methamphetamine abusers. Steady-state bicarbonate concentrations were similar, between 11 and 15 mmol/L in mixed gray-white matter of frontal brain of normal volunteers and recovering methamphetamine-abusing subjects ( P>0.1). However, glial 13C-bicarbonate production rate from [1-13C]acetate, equating with glial tricarboxylic acid (TCA) cycle rate, was significantly reduced in frontal brain of abstinent methamphetamine-addicted women (methamphetamine 0.04 μmol/g per min ( N=5) versus controls 0.11 μmol/g per min ( N=5), P=0.001). This is equivalent to 36% of the normal glial TCA cycle rate. Severe reduction in glial TCA cycle rate that normally comprises 10% of total cerebral metabolic rate may impact operation of the neuronal glial glutamate cycle and result in accumulation of frontal brain glutamate, as observed in these recovering methamphetamine abusers. Although these are the first studies to define directly an abnormality in glial metabolism in human methamphetamine abuse, sequential studies using analogous 13C MRS methods may determine ‘cause and effect’ between glial failure and neuronal injury.

In this communication, a scheme is described whereby in vivo 13 C MRS can safely be performed in the frontal lobe, a human brain region hitherto precluded on grounds of SAR, but important in being the seat of impaired cognitive function in many neuropsychiatric and developmental disorders. By combining two well known features of 13 C NMR—the use of low power NOE and the focus on 13 C carbon atoms which are only minimally coupled to protons, we are able to overcome the obstacle of SAR and develop means of monitoring the 13 C fluxes of critically important metabolic pathways in frontal brain structures of normal volunteers and patients. Using a combination of low-power WALTZ decoupling, variants of random noise for nuclear overhauser effect enhancement it was possible to reduce power deposition to 20% of the advised maximum specific absorption rate (SAR). In model solutions 13 C signal enhancement achieved with this scheme were comparable to that obtained with WALTZ-4. In human brain, the low power procedure effectively determined glutamine, glutamate and bicarbonate in the posterior parietal brain after [1- 13 C] glucose infusion. The same 13 C enriched metabolites were defined in frontal brain of human volunteers after administration of [1- 13 C] acetate, a recognized probe of glial metabolism. Time courses of incorporation of 13 C into cerebral glutamate, glutamine and bicarbonate were constructed. The results suggest efficacy for measurement of in vivo cerebral metabolic rates of the glutamate–glutamine and tricarboxylic acid cycles in 20 min MR scans in previously inaccessible brain regions in humans at 1.5T. We predict these will be clinically useful biomarkers in many human neuropsychiatric and genetic conditions.

Proton magnetic resonance spectroscopy was performed at 3 T using the echo time-averaged point-resolved spectroscopy method to determine the effects of age, gender and brain region on glutamate (Glu) concentrations in the healthy human brain. Thirty healthy men and 20 healthy women aged between 21 and 71 years were studied. Significant regional variations of Glu concentrations were observed. Glu concentration in the gray matter (GM) was approximately 25% higher than that in the white matter. Significant age-dependent decreases in Glu concentrations were observed in the basal ganglia (r=−0.75, P

We determined the reproducibility of GABA (gamma-aminobutyric acid) measurements using 2D J-resolved magnetic resonance spectroscopy (MRS) on a clinical 1.5-T MR imaging scanner. Two-dimensional J-resolved spectra were acquired in vitro across five GABA concentrations using a volume head coil and a 5-in. surface coil. Additional spectra using a sixth GABA phantom with a very low concentration and from a healthy volunteer were recorded in the 5-in. surface coil only. In each case, the 3.01-ppm GABA resonance was quantified; for comparison, the peak integrals of choline (3.2 ppm) and creatine (3.03 ppm) were recorded. At a physiological concentration (1.2 mM), in vitro GABA measurement was significantly more reproducible in the surface coil than in the volume coil (P=.005), with coefficients of variation (CVs) being less than 16% with the surface coil and up to 68% with the volume head coil. At the smallest concentration of in vivo GABA reported using other spectroscopy techniques (0.8 mM) and detected only using the surface coil, the CV for GABA was 23% and was less than 10% for choline and creatine, which compare favorably with results from published studies. In vivo, the CV for GABA measurement was 26%, suggesting that 2D J-resolved MRS would be suitable for detecting physiological changes in GABA, similar to those reported using other methods.

A sensitive proton magnetic resonance spectroscopy (1H MRS) acquisition scheme that is capable of discriminating between normal controls and a group of patients with early Alzheimer's disease (AD) is presented. The performance of this newly developed method, TE averaged PRESS (PRESS-J), in detecting neurodegeneration associated with early AD is compared with that of short echo time (TE) PRESS. A stepwise discriminant function analysis is used to construct discriminant functions for both pulse sequences. These functions are each composed of a single predictor: the N-acetyl aspartate (NAA)/creatine (Cr) ratio for PRESS-J, and the NAA/myoInositol (mI) ratio for PRESS. We observed lower P-values, higher areas under the receiver operating characteristic curves, and higher sensitivity at a given specificity for the PRESS-J discriminating function in comparison with the PRESS discriminating function. The higher sensitivity of PRESS-J is due to decreased variability when the singlets are fit in the spectra. This increased sensitivity enables new MR applications and, among other benefits, allows for smaller group sizes in drug trials, which can significantly reduce the cost of such trials. Magn Reson Med 53:777–782, 2005. © 2005 Wiley-Liss, Inc.

Histopathological reports of multiple sclerosis and its animal models have shown evidence of a link between axonal injury in active lesions and impaired glutamate metabolism. Mature oligodendrocytes play a role in glutamate uptake to maintain glutamate homeostasis but in multiple sclerosis white matter the loss of expression of glutamate transporters in the lesion vicinity results in ineffective glutamate removal. Using a magnetic resonance spectroscopy technique that isolates the glutamate resonance at 3 T, we compared glutamate levels between normal subjects and multiple sclerosis patients in different brain areas. Metabolite concentrations (glutamate, glutamine, N-acetyl-aspartate, myo-inositol, choline, creatine) were derived from LCmodel and corrected for T1 relaxation time. Glutamate concentrations were found to be elevated in acute lesions (P = 0.02) and normal-appearing white matter (P = 0.03), with no significant elevation in chronic lesions (P = 0.77). The N-acetyl-aspartate level in chronic lesions was significantly lower (P < 0.001) than in acute lesions and normal-appearing white matter. The choline level in acute lesions was significantly higher (P < 0.001) than in chronic lesions. Evidence was also found for increased glial activity in multiple sclerosis, with significantly higher (P < 0.001) myo-inositol levels in acute lesions compared with control white matter. These in vivo results support the hypothesis that altered glutamate metabolism is present in brains of multiple sclerosis patients.

A method is introduced that provides improved in vivo spectroscopic measurements of glutamate (Glu), glutamine (Gln), choline (Cho), creatine (Cre), N-acetyl compounds (NAtot, NAA + NAAG), and the inositols (mI and sI). It was found that at 3T, TE averaging, the f1 = 0 slice of a 2D J-resolved spectrum, yielded unobstructed signals for Glu, Glu + Gln (Glx), mI, NA(tot), Cre, and Cho. The C4 protons of Glu at 2.35 ppm, and the C2 protons of Glx at 3.75 ppm were well resolved and yielded reliable measures of Glu/Gln stasis. Apparent T1/T2 values were obtained from the raw data, and metabolite tissue levels were determined relative to a readily available standard. A repeatibility error of5%, and a coefficient of variation (CV) of10% were observed for brain Glu levels in a study of six normal volunteers.

A clinical 3-T scanner equipped with a custom-made transmit/receive birdcage coil was used to collect 2D J-resolved single-voxel spectroscopy in vivo of rat brain. Four adult Wistar rats were scanned twice each, with a 2-week interval. Voxel size was approximately 5 x 10 x 5 mm(3). Total spectroscopic acquisition time was 14 min for collection of two 4:20 min water-suppressed acquisitions and one 4:20 min acquisition acquired in the absence of water suppression. The unsuppressed water data were used in post-processing to reduce residual water side bands, as well as for metabolite signal normalization to account for variations in coil loading and voxel size. Peak areas were estimated for resonances from N-acetyl aspartate (NAA), creatine, choline, taurine, glutamate, and combined glutamate and glutamine. T(2)-relaxation times were estimated for NAA and creatine. The average deviation from the mean of repeated measures for glutamate, combined glutamate and glutamine, and taurine ranged from 7.6% to 18.3%, while for NAA, creatine, and choline, the deviation was less than 3%. The estimated T(2) values for NAA (mean +/- SD = 330 +/- 57 ms) and creatine (174 +/- 27 ms) were similar to those reported previously for rat brain and for human gray and white matter. These results indicate that reliable, small animal brain MR spectroscopy can be performed on a human clinical 3-T scanner.

Background. Cerebral injury from MA use and HIV infection are well established. Frontal or the executive brain functions are most affected in MA abusers with development neurological conditions of inability to attend and concentrate slowness in thinking and moving. HIV infection, on the other hand, is thought to be indirect process due as neurons are not infected by the virus. Cells including brain microphages, microglia is infected and a reactive astrocytosis is often present. Methods. Fifteen healthy volunteers, 15 HIV seropositive patients with no history of MA use, 15 MA users with no HIV infection and 15 MA users who are HIV infected during the next 15 months. This is cross-sectional study, each participant will undergo MRI/MRS scans and neuropsychological evaluation. We present results of single voxel proton MRS in MA users's brain. Results. Significant reduction (p = 0.041) for neuronal marker, N-acetylaspartate in the frontal white matter was observed with mean NAA/Cr for healthy control and MA users of 0.855 and 0.746, respectively. Similar reduction (p = 0.028) was also observed in the basal ganglia with mean NAA/Cr for healthy control and MA users of 0.687 and 0.548 respectively. Conclusions. The results demonstrated significant neuronal loss in methamphetamine users.

1H NMR solution-state study of elephant seal ( Mirounga angustirostris) myoglobin (Mb) and hemoglobin (Hb) establishes the temperature-dependent chemical shifts of the proximal histidyl NδH signal, which reflects the respective intracellular and vascular Po2in vivo. Both proteins exist predominantly in one major isoform and do not exhibit any conformational heterogeneity. The Mb and Hb signals are detectable in M. angustirostris tissue in vivo. During eupnea M. angustirostris muscle maintains a well-saturated MbO2. However, during apnea, the deoxymyoglobin proximal histidyl NδH signal becomes visible, reflecting a declining tissue Po2. The study establishes a firm methodological basis for using NMR to investigate the metabolic responses during sleep apnea of the elephant seal and to secure insights into oxygen regulation in diving mammals.

The regulation of oxygen transport to the mitochondria in exercising muscle is a key issue in biology, since oxygen demand can increase dramatically from the resting state. As the oxygen consumption (VO2) increases, a coordinate set of controls must enhance the oxygen delivery from the lung to the cell. As VO2 approaches its maximum rate (VO2max), convection, diffusion or enzymatic activity must also become limiting. Identifying the rate- determining step is then a central issue (Sutton, 1992).

To improve clinical utility, an integrated method has been developed to automatically acquire and process single-voxel in vivo proton spectra on a 1.5 T clinical scanner. This method includes automated adjustment of linear shims using a very rapid modified simplex method, automated water suppression, and applies a water referencing scheme to correct for phase and residual eddy current effects. No operator intervention is required for the acquisition and processing of these pure-absorption spectra. This method was tested in a preliminary multisite trial to determine intersite and intrasite variability of metabolite ratio measurements. In a sample of over 100 examinations, the standard deviation of the ratios NAA:Cr, Cho:Cr, and ml:Cr were found to be under 15% when using this method, a substantially narrower range than has been found in studies relying on manual adjustment of the instrument and/or manual processing. This result indicates that automated setting of acquisition and processing parameters is of critical importance in the clinical application of in vivo spectroscopy.

Objective 13C MRS to determine cerebral glutamate turnover rate in partial ornithine transcarbamylase deficiency (OTCD). Background Patients with OTCD manifest neuropsychological disorders. Proton magnetic resonance spectroscopy (1H MRS) demonstrates neurochemical abnormalities in OTCD similar to chronic and subclinical hepatic encephalopathy (SCHE) in whom impaired cerebral glucose metabolism and reduced glutamine-glutamate cycling or glutamate neurotransmission rate (GNT) have been observed. We hypothesize impaired GNT may underlie cognitive deficits in OTCD. Design/Methods MRI, 1H MRS and 13C MRS were performed on a clinical GE 1.5 T MR scanner in 6 patients with OTCD and 4 normal controls, imaged in stable condition. Each received i.v. 13C glucose (0.2 g/kg) C1 or C2, as a 15-min bolus. Cerebral metabolites were determined with proton decoupling, in posterior cingulate gyrus (PCG, N = 9) and without proton decoupling, in anterior (N = 1) cingulate gyrus (ACG) over 60–100 minutes. Results 1. Uptake and removal of cerebral glucose (13C-C1 or C2) were comparable in normal controls and subjects with OTCD ( p > 0.1). 2. Glucose C1 was metabolized to glutamate C4 and glucose C2 to glutamate C5 at comparable rates which were significantly reduced in OTCD (combined p p > 0.1). 4. 13C - 2 glucose and its metabolic products were observed in ACG without proton decoupling in a single subject with OTCD. Conclusions/Relevance Reduced GNT secondary to impaired cerebral glucose metabolism was documented in OTCD using 13C MRS of occipital lobe. Feasibility of this measurement in more relevant frontal brain structures was demonstrated. Treatment(s) which improve cerebral glucose metabolism and GNT may improve neurological outcome in OTCD where prevention and treatment of hyperammonemic episodes appears insufficient.

The present study evaluated whether intracellular partial pressure of O2([Formula: see text]) modulates the muscle O2uptake (V˙o2) as exercise intensity increased. Indirect calorimetry followedV˙o2, whereas nuclear magnetic resonance (NMR) monitored the high-energy phosphate levels, intracellular pH, and intracellular[Formula: see text] in the gastrocnemius muscle of four untrained subjects at rest, during plantar flexion exercise with a constant load at a repetition rate of 0.75, 0.92, and 1.17 Hz, and during postexercise recovery.V˙o2increased linearly with exercise intensity and peaked at 1.17 Hz (15.1 ± 0.37 watts), when the subjects could maintain the exercise for only 3 min.V˙o2reached a peak value of 13.0 ± 1.59 ml O2⋅ min−1⋅ 100 ml leg volume−1. The31P spectra indicated that phosphocreatine decreased to 32% of its resting value, whereas intracellular pH decreased linearly with power output, reaching 6.86. Muscle ATP concentration, however, remained constant throughout the exercise protocol. The1H NMR deoxymyoglobin signal, reflecting the cellular[Formula: see text], decreased in proportion to increments in power output andV˙o2. At the highest exercise intensity and peakV˙o2, myoglobin was ∼50% desaturated. These findings, taken together, suggest that the O2gradient from hemoglobin to the mitochondria can modulate the O2flux to meet the increasedV˙o2in exercising muscle, but declining cellular [Formula: see text]during enhanced mitochondrial respiration suggests that O2availability is not limitingV˙o2during exercise.