Localized 1H Magnetic Resonance Spectroscopy Research Articles

Glucagon promotes increased hepatic mitochondrial oxidation and pyruvate carboxylase flux in humans with fatty liver disease

We assessed invivo rates of hepatic mitochondrial oxidation, gluconeogenesis, and β-hydroxybutyrate (β-OHB) turnover by positional isotopomer NMR tracer analysis (PINTA) in individuals with metabolic-dysfunction-associated steatotic liver (MASL) (fatty liver) and MASL disease (MASLD) (steatohepatitis) compared with BMI-matched control participants with no hepatic steatosis. Hepatic fat content was quantified by localized 1H magnetic resonance spectroscopy (MRS). We found that invivo rates of hepatic mitochondrial oxidation were unaltered in the MASL and MASLD groups compared with the control group. A physiological increase in plasma glucagon concentrations increased invivo rates of hepatic mitochondrial oxidation by 50%-75% in individuals with and without MASL and increased rates of glucose production by ∼50% in the MASL group, which could be attributed in part to an ∼30% increase in rates of mitochondrial pyruvate carboxylase flux. These results demonstrate that (1) rates of hepatic mitochondrial oxidation are not substantially altered in individuals with MASL and MASLD and (2) glucagon increases rates of hepatic mitochondrial oxidation.

A Novel Biomarker of Neuronal Glutamate Metabolism in Nonhuman Primates Using Localized 1H-Magnetic Resonance Spectroscopy: Development and Effects of BNC375, an α7 Nicotinic Acetylcholine Receptor Positive Allosteric Modulator

BackgroundThe development of treatments for cognitive deficits associated with central nervous system disorders is currently a significant medical need. Despite the great need for such therapeutics, a significant challenge in the drug development process is the paucity of robust biomarkers to assess target modulation and guide clinical decisions. We developed a novel, translatable biomarker of neuronal glutamate metabolism, the 13C-glutamate+glutamine (Glx) H3:H4 labeling ratio, in nonhuman primates using localized 1H-magnetic resonance spectroscopy combined with 13C-glucose infusions. MethodsWe began with numerical simulations in an established model of brain glutamate metabolism, showing that the 13C-Glx H3:H4 ratio should be a sensitive biomarker of neuronal tricarboxylic acid cycle activity, a key measure of overall neuronal metabolism. We showed that this biomarker can be measured reliably using a standard 1H-magnetic resonance spectroscopy method (point-resolved spectroscopy sequence/echo time = 20 ms), obviating the need for specialized hardware and pulse sequences typically used with 13C-magnetic resonance spectroscopy, thus improving overall clinical translatability. Finally, we used this biomarker in 8 male rhesus macaques before and after administration of the compound BNC375, a positive allosteric modulator of the α7 nicotinic acetylcholine receptor that enhances glutamate signaling ex vivo and elicits procognitive effects in preclinical species. ResultsThe 13C-Glx H3:H4 ratios in the monkeys showed that BNC375 increases neuronal metabolism in nonhuman primates in vivo, detectable on an individual basis. ConclusionsThis study demonstrates that the ratio of 13C-Glx H3:H4 labeling is a biomarker that may provide an objective readout of compounds affecting glutamatergic neurotransmission and could improve decision making for the development of therapeutic agents.

Hypertonic sodium lactate reverses brain oxygenation and metabolism dysfunction after traumatic brain injury

BackgroundThe mechanisms by which hypertonic sodium lactate (HSL) solution act in injured brain are unclear. We investigated the effects of HSL on brain metabolism, oxygenation, and perfusion in a rodent model of diffuse traumatic brain injury (TBI). MethodsThirty minutes after trauma, anaesthetised adult rats were randomly assigned to receive a 3 h infusion of either a saline solution (TBI–saline group) or HSL (TBI–HSL group). The sham–saline and sham–HSL groups received no insult. Three series of experiments were conducted up to 4 h after TBI (or equivalent) to investigate: 1) brain oedema using diffusion-weighted magnetic resonance imaging and brain metabolism using localized 1H-magnetic resonance spectroscopy (n = 10 rats per group). The respiratory control ratio was then determined using oxygraphic analysis of extracted mitochondria, 2) brain oxygenation and perfusion using quantitative blood-oxygenation-level-dependent magnetic resonance approach (n = 10 rats per group), and 3) mitochondrial ultrastructural changes (n = 1 rat per group). ResultsCompared with the TBI–saline group, the TBI–HSL and the sham-operated groups had reduced brain oedema. Concomitantly, the TBI–HSL group had lower intracellular lactate/creatine ratio [0.049 (0.047–0.098) vs 0.097 (0.079–0.157); P < 0.05], higher mitochondrial respiratory control ratio, higher tissue oxygen saturation [77% (71–79) vs 66% (55–73); P < 0.05], and reduced mitochondrial cristae thickness in astrocytes [27.5 (22.5–38.4) nm vs 38.4 (31.0–47.5) nm; P < 0.01] compared with the TBI–saline group. Serum sodium and lactate concentrations and serum osmolality were higher in the TBI–HSL than in the TBI–saline group. ConclusionsThese findings indicate that the hypertonic sodium lactate solution can reverse brain oxygenation and metabolism dysfunction after traumatic brain injury through vasodilatory, mitochondrial, and anti-oedema effects.

The Relation between Non-adipose Muscle Fat and Hepatic Steatosis Studied with Localized 1H Magnetic Resonance Spectroscopy (1H MRS) and LC-MS Techniques

Aim/objective: In this study we investigated ectopic fat storage in the muscle and the liver using 1H Magnetic Resonance Spectroscopy (1H-MRS). The inability to store fat in adipose tissue leads to ectopic Triacylglycerol (TG) accumulation in muscle followed by the liver: the so called “overflow hypothesis”. It is assumed that when steatosis occurs in organs like the liver we can speak from “Metabolic Syndrome”. Methods: We compared the effects of two different diet interventions, 24 h-starvation and 40 days High-fat diet (+0.25% cholesterol and 45% energy from bovine lard) with control mice. Characterization of lipid molecular species in non-adipose muscle homogenate was performed by comparing the groups using liquid chromatography coupled to mass spectrometry (LC-MS) techniques following a Systems Biology lipidomics based approach. Reversed phase liquid chromatography coupled to mass spectrometry (LC-MS) were used to quantify and qualify the rearrangement and repartitioning of the triacylglycerol compound in the liver organ. Results: The major message of this manuscript is the interaction of remnant organ/tissue called “carcass” in the absorption capacity of lipids and the spill-over of these lipid compounds (mainly TG’s) to the liver. Our data suggest that if the remnant muscle compartment is saturated with lipids until ≈500 g/kg dry matter there is no TGs accumulation in the liver, but above this level there is a spill over in the plasma resulting in fat accumulation in the liver. Conclusion: We demonstrated in this study that fat can be stored in the muscle but when this compartment is saturated the liver takes over the function as a fat sink, the overflow hypothesis resulting finally in hepatic steatosis and ‘Metabolic Syndrome’.

Evaluating Childhood Obesity: Magnetic Resonance-Based Quantification of Abdominal Adipose Tissue and Liver Fat in Children

The purpose of this study is to establish and validate a magnetic resonance (MR)-based fat quantification package that provides an accurate assessment of abdominal adipose tissue and liver fat in children. Ex vivo trials with a torso model and water-oil mixtures are conducted. Abdominal adipose tissue (AAT) is covered by magnetic resonance imaging (MRI) using a fat-selective sequence and is analyzed by a plug-in based on the open source software ImageJ. Liver fat (LF) is measured with localized 1H Magnetic Resonance Spectroscopy (1H MRS) and the jMRUI (java-based Magnetic Resonance User Interface) software package. Evaluation of the clinical methodology involved a study of 10 children in this feasibility study (mean age and body mass index: 13.3 yr; 33.3 kg/m²). To evaluate the method's validity, reference measurements were performed. Ex vivo trials with the torso model showed that adipose tissue was measured appropriately with a systematic underestimation by 9.3 ± 0.2 % (0.32 ± 0.064 kg). Coefficients of variation for both intra- and inter-observer measurements ranged between 0 - 2.7 % and repeated analyses showed significant equivalent results (p < 0.01). The lipid content obtained by 1H MRS ex vivo revealed significant equivalence with the predefined fat content in water-oil mixtures (p < 0.01). In vivo, the homemade plug-in significantly overestimated the AAT, with the visceral adipose tissue being most affected (+ 15.7 ± 8.4 %). Although an overestimation of the AAT by the presented plug-in should be taken into consideration, this children-friendly package enables the quantification of both LF and AAT within 30 min on a freeware-based platform.

MO‐F‐211‐09: Scalar Coupling Effects on Lipid Composition Determination Using Localized 1H Magnetic Resonance Spectroscopy at 9.4 T

Purpose: To improve lipid composition determination by localized proton magnetic resonance spectroscopy (MRS) at 9.4 T by minimizing J‐coupling modulations of the 2.1 ppm, 2.3 ppm, and 2.8 ppm lipid peaks. Methods: Experiments were conducted on corn oil and sesame oil phantoms at 9.4 T. A regular PRESS (Point RESolved Spectroscopy) sequence was used to obtain spectra from the oils with echo times (TEs) of 20, 30, 40, 50, 80, 120, 180, and 240 ms. A modified PRESS sequence designed to minimize signal losses due to J‐coupling was also utilized to acquire spectra of the 2.1 ppm, 2.3 ppm, and 2.8 ppm resonances of the oils with TEs of 40, 50, 80, 120, 180 and 240 ms. The areas of the three lipid resonances obtained by both sequences were plotted as a function of echo time and the resulting curves were fitted to the function Moexp(−TE/T2), where Mo is proportional to the proton concentration of the target resonance. Oil compositions (% linoleic acid, % oleic acid, and % saturated fatty acids) were determined from extrapolated Mo values for the three resonances and from equations established in the literature. Results: The responses of the three proton groups to a regular PRESS sequence were modulated due to J‐coupling interactions. However, the responses to the modified PRESS sequence fit well to monoexponentially decaying functions. Oil compositions determined with the PRESS sequence designed to minimize J‐coupling effects agreed with results reported in the literature unlike those calculated from spectra acquired with the regular PRESS sequence. Conclusions: Lipid compositions determined by localized proton MRS can contain significant errors (as high as 49 %), even if they are determined from short‐ TE PRESS spectra corrected for T2 relaxation, if the influence of J‐coupling is not considered.

Longitudinal Assessment Of Activity, Muscle Composition, And Functional Ability In Children With Duchenne Muscular Dystrophy

Recent work has demonstrated decreased activity levels in boys with Duchenne muscular dystrophy (DMD) compared to healthy children, but we could find no investigations examining the change in activity level over time due to the natural course of disease progression. PURPOSE: The purpose of this study was to determine the extent of reduction in activity level in boys with DMD and to explore the relationship of physical activity to muscle composition and functional ability. METHODS: Six ambulatory boys with DMD (8.7+/-1.2 yrs) participated. Testing was done on two occasions with 16+/-5 mo between sessions. Activity was assessed for 7 days with an ActiGraph monitor, and activity levels were subsequently divided by intensity into light (500-1999 counts/min), moderate (2000-3000 counts/min), and hard (>3000 counts/min). Muscle composition was determined by localized 1H magnetic resonance spectroscopy of the soleus muscle at 3T. Relative concentrations of water and lipid were determined, and lipid:water ratios were calculated. Subjects also completed timed functional tests of 30ft walk and ascending 4 steps. Relationships were examined by correlation coefficients at each testing session. RESULTS: Activity intensity decreased (light 7%, moderate 32%, hard 19%), and lipid:water ratios increased 81% between testing sessions. Relationships were found at baseline between: 1) moderate activity with 30ft walk (r=-.33) and 4steps (r=-.36); and 2) heavy activity with muscle composition (r=-.28), 30ft walk (r=-.33), and 4 steps (r=-.31). Relationships at the follow-up time session included: 1) moderate activity with muscle composition (r=-.59), 30ft walk (r=-.34), and 4 steps (r=-.59); and heavy activity with muscle composition (r=-.66), 30ft walk (r=-.35), and 4 steps (r=-.58). CONCLUSIONS: The data from this pilot study provide information regarding the extent of activity level decline and muscle fatty infiltration in boys with DMD. The findings also demonstrate a relationship between activity level with both muscle composition and functional ability. With disease progression, these relationships appear to become even more pronounced. Further research is warranted to better understand the correlations between these variables and how they are impacted with therapeutic interventions for patients with DMD.

Non-invasive assessment of hepatic fat accumulation in chronic hepatitis C by 1H magnetic resonance spectroscopy

Background Liver biopsy is the standard method for diagnosis of hepatic steatosis, but is invasive and carries some risk of morbidity. Aims and methods Quantification of hepatocellular lipid content (HCL) with non-invasive single voxel 1H magnetic resonance spectroscopy (MRS) at 3 T was compared with histological grading and biochemical analysis of liver biopsies in 29 patients with chronic hepatitis C. Body mass index, indices of insulin resistance (homeostasis model assessment index, HOMA-IR), serum lipids and serum liver transaminases were also quantified. Results HCL as assessed by 1H MRS linearly correlated ( r = 0.70, p < 0.001) with histological evaluation of liver biopsies and was in agreement with histological steatosis staging in 65% of the patients. Biochemically assessed hepatic triglyceride contents correlated with HCL measured with 1H MRS ( r = 0.63, p < 0.03) and allowed discriminating between none or mild steatosis versus moderate or severe steatosis. Patients infected with hepatitis C virus genotype 3 had a higher prevalence of steatosis (62%) which was not explained by differences in body mass or whole body insulin resistance. When these patients were excluded from correlation analysis, hepatic fat accumulation positively correlated with insulin resistance in the remaining hepatitis C patients (HCL vs. HOMA-IR, r = 0.559, p < 0.020, n = 17). Conclusion Localized 1H MRS is a valid and useful method for quantification of HCL content in patients with chronic hepatitis C and can be easily applied to non-invasively monitoring of steatosis during repeated follow-up measurements in a clinical setting.

Reproducibility of hepatic triglyceride content assessment in normals using localized magnetic resonance spectroscopy

To investigate the reproducibility of measurements of hepatic triglyceride content (HTGC) in subjects with normal HTGC using localized (1)H-magnetic resonance spectroscopy ((1)H-MRS) and a clinical 1.5T scanner. The (1)H-MRS acquisition was performed with a common protocol using the whole-body coil and no respiratory triggering. An upper limit of normal HTGC of 5.56% was used. Duplicate measurements, including subject repositioning, were acquired from 23 subjects, 19 of whom had a normal HTGC. The mean coefficient of variation (CV) from the duplicate measurements was 14.8% (20.5% before exclusion of a subject who was considered to be an outlier). Mean CVs of subgroups below and above the 1% HTGC limit were 19.8 and 7.0 respectively. The mean CV calculated in subjects with HTGC in the normal range was found to be higher than CVs of wide range HTGC groups reported in the literature. It is concluded that the reproducibility of HTGC measurements using (1)H-MRS depends on the HTGC range. These findings are of importance in reproducibility studies and in estimations of required study group sizes.

Evolution of the Neurochemical Profile after Transient Focal Cerebral Ischemia in the Mouse Brain

Evolution of the neurochemical profile consisting of 19 metabolites after 30 mins of middle cerebral artery occlusion was longitudinally assessed at 3, 8 and 24 h in 6 to 8 microL volumes in the striatum using localized 1H-magnetic resonance spectroscopy at 14.1 T. Profound changes were detected as early as 3 h after ischemia, which include elevated lactate levels in the presence of significant glucose concentrations, decreases in glutamate and a transient twofold glutamine increase, likely to be linked to the excitotoxic release of glutamate and conversion into glial glutamine. Interestingly, decreases in N-acetyl-aspartate (NAA), as well as in taurine, exceeded those in neuronal glutamate, suggesting that the putative neuronal marker NAA is rather a sensitive marker of neuronal viability. With further ischemia evolution, additional, more profound concentration decreases were detected, reflecting a disruption of cellular functions. We conclude that early changes in markers of energy metabolism, glutamate excitotoxicity and neuronal viability can be detected with high precision non-invasively in mice after stroke. Such investigations should lead to a better understanding and insight into the sequential early changes in the brain parenchyma after ischemia, which could be used for identifying new targets for neuroprotection.

Effect of Gd-DTPA-BMA on choline signals of HT29 tumors detected by in vivo1H MRS

To study the impact of Gd-DTPA-BMA on choline signals of HT29 colon carcinomas determined by localized 1H MRS in vivo at 4.7T. PRESS 1H MR spectra (2-second repetition time and echo times of 20-272 msec) were acquired from HT29 xenografts prior to and following intravenous administration of 0.1 or 0.2 mmol/kg Gd-DTPA-BMA. The magnetic resonance spectroscopy (MRS) data were analyzed by 1) normalizing choline and water peak areas to their precontrast values; and 2) estimating absolute choline concentration relative to tissue water. Changes in the T1 and T2 of choline and water were apparent following administration of Gd-DTPA-BMA. Administration of 0.1 mmol/kg Gd-DTPA-BMA induced significant increases in the choline peak area, concomitant with enhancements of the water peak area, whereas 0.2 mmol/kg Gd-DTPA-BMA induced no enhancement of choline peak area but significant increases in water peak area at short echo times. The effect of Gd-DTPA-BMA on estimation of tumor choline concentration varied with the dose of contrast agent, the echo time, and the time after contrast agent administration. These data highlight the potential pitfalls associated with the modulation of choline and water signals post-Gd-DTPA-BMA and may account for the apparently contradictory results previously reported.

New imaging approaches of metabolism in tumours

Purpose: These studies were performed to investigate the effects of radiation on levels of metabolites such as lactate and choline compounds detected by 1H magnetic resonance spectroscopy (MRS). The purpose was to determine the ability of spatially localized 1H MRS to detect tumor response to radiation therapy.Methods and Materials: Proton spectroscopic images were obtained from RIF-1 tumors with voxel spatial resolutions of 8–16 mm3 before and at 24 and 48 h following 2, 4, and 20 Gy of γ-radiation.Results: Lactate levels decreased significantly for all doses by 48 h. Tumors irradiated with 2 and 4 Gy showed a significant decrease by 48 h, but not at 24 h. A group of sham-irradiated control animals demonstrated no significant changes in lactate over the period of observation.Conclusions: Changes in lactate observed in this study are consistent with an increased blood flow observed in previous studies (15) in the same tumor model following 20 Gy X-irradiation. These studies point to the feasibility of detecting response to clinical doses of fractionated radiation therapy by 1H MRS.

Cardiac Steatosis in Diabetes Mellitus

The risk of heart failure in type 2 diabetes mellitus is greater than can be accounted for by hypertension and coronary artery disease. Rodent studies indicate that in obesity and type 2 diabetes mellitus, lipid overstorage in cardiac myocytes produces lipotoxic intermediates that cause apoptosis, which leads to heart failure. In humans with diabetes mellitus, cardiac steatosis previously has been demonstrated in explanted hearts of patients with end-stage nonischemic cardiomyopathy. Whether cardiac steatosis precedes the onset of cardiomyopathy in individuals with impaired glucose tolerance or in patients with type 2 diabetes mellitus is unknown. To represent the progressive stages in the natural history of type 2 diabetes mellitus, we stratified 134 individuals (age 45+/-12 years) into 1 of 4 groups: (1) lean normoglycemic (lean), (2) overweight and obese normoglycemic (obese), (3) impaired glucose tolerance, and (4) type 2 diabetes mellitus. Localized (1)H magnetic resonance spectroscopy and cardiac magnetic resonance imaging were used to quantify myocardial triglyceride content and left ventricular function, respectively. Compared with lean subjects, myocardial triglyceride content was 2.3-fold higher in those with impaired glucose tolerance and 2.1-fold higher in those with type 2 diabetes mellitus (P<0.05). Left ventricular ejection fraction was normal and comparable across all groups. In humans, impaired glucose tolerance is accompanied by cardiac steatosis, which precedes the onset of type 2 diabetes mellitus and left ventricular systolic dysfunction. Thus, lipid overstorage in human cardiac myocytes is an early manifestation in the pathogenesis of type 2 diabetes mellitus and is evident in the absence of heart failure.

Creatine uptake in brain and skeletal muscle of mice lacking guanidinoacetate methyltransferase assessed by magnetic resonance spectroscopy

Creatine (Cr) levels in skeletal muscle and brain of a mouse model of Cr deficiency caused by guanidinoacetate methyltransferase absence (GAMT-/-) were studied after Cr supplementation with 2 g.kg body wt-1.day-1 Cr for 35 days. Localized 1H magnetic resonance spectroscopy (MRS) was performed in brain (cerebellum and thalamus/hippocampus) and in hind leg muscle of GAMT-/- mice before and after Cr supplementation and in control (Con) mice. As expected, a signal for Cr was hardly detectable in MR spectra of GAMT-/- mice before Cr supplementation. In the thalamus/hippocampus region of these mice, an increase in N-acetylasparate (NAA) was observed. During Cr administration, Cr levels increased faster in skeletal muscle compared with brain, but this occurred only during the first day of supplementation. Thereafter, Cr levels increased by 0.8 mM/day in all studied locations. After 35 days of Cr supplementation, Cr levels in all locations were higher compared with Con mice on a Cr-free diet and NAA levels normalized. Only because of the repeated MRS measurements performed in this longitudinal Cr supplementation study on GAMT-/- mice were we able to discover the initial faster uptake of Cr in skeletal muscle compared with brain, which may represent muscular Cr uptake independent of Cr transporter expression. Our results can provide the basis for additional experiments to optimize Cr supplementation in GAMT deficiency, as increases in brain Cr are slow in patients after Cr supplementation.

Acute regulation of steady-state GABA levels following GABA-transaminase inhibition in rat cerebral cortex

Cellular GABA levels are determined by the dynamic balance between synthesis and catabolism and are regulated at the level of glutamate decarboxylase, precursor availability (e.g., glutamate and glutamine), and possibly GABA degradation. GABA levels rise and stabilize within hours in human cortex following orally administered vigabatrin, an irreversible inhibitor of GABA-T, suggesting potential product inhibition of GABA synthesis or enhanced GABA degradation through the non-inhibited GABA-T fraction. In this study time courses of the rise in cortical GABA were measured in anesthetized rats in vivo after vigabatrin treatment using localized 1H magnetic resonance spectroscopy and the times to reach steady-state for a given dose were determined. Rates of GABA synthesis were estimated for the period of constant GABA level from the accumulation of [2- 13C]GABA following a short intravenous infusion (20 min) of either [1,6- 13C 2]glucose or [2- 13C]acetate. No evidence of product inhibition of glutamate decarboxylase by the increased GABA concentration or reduced synthesis from [1,6- 13C 2]glucose (control, 0.031 ± 0.010; vigabatrin-treated, 0.037 ± 0.004 μmol/g/min, P = 0.30) or [2- 13C]acetate (control, 0.078 ± 0.010; vigabatrin-treated, 0.084 ± 0.006 μmol/g/min, P = 0.42) was found. Fractional changes in steady-state GABA levels and GABA-T activities 5–6 h after vigabatrin treatment were approximately equal. The lack of change in GABA synthesis (and GABA catabolic flux for constant GABA levels) suggests that GABA-T has a near-zero flux control coefficient in vivo-capable of greatly altering the steady-state GABA concentration but exerting little or no control on GABA synthesis or GABA/glutamine cycling flux. The findings are consistent with a Michaelis–Menten kinetic model whereby cellular GABA levels increase until flux through the remaining (uninhibited) transaminase equals the rate of GABA synthesis. The findings suggest that astroglia may be the site of continuing GABA catabolism after acute vigabatrin treatment.

Noninvasive QuantitativeIn VivoMapping and Metabolism of Boronophenylalanine (BPA) by Nuclear Magnetic Resonance (NMR) Spectroscopy and Imaging

10B-enriched L-p-boronophenylalanine (BPA) is one of the compounds used in boron neutron capture therapy (BNCT). In this study, several variations of nuclear magnetic resonance spectroscopy (MRS) and spectroscopic imaging (MRSI) were applied to investigate the uptake, clearance and metabolism of the BPA-fructose complex (BPA-F) in normal mouse kidneys, rat oligodendroglioma xenografts, and rat blood. Localized 1H MRS was capable of following the uptake and clearance of BPA-F in mouse kidneys with temporal resolution of a few minutes, while 1H MRSI was used to image the BPA distribution in the kidney with a spatial resolution of 9 mm3. The results also revealed significant dissociation of the BPA-F complex to free BPA. This finding was corroborated by 1H and 11B NMR spectroscopy of rat blood samples as well as of tumor samples excised from mice after i.v. injection of BPA-F. This investigation demonstrates the feasibility of using 1H MRS and MRSI to follow the distribution of BPA in vivo, using NMR techniques specifically designed to optimize BPA detection. The implementation of such procedures could significantly improve the clinical efficacy of BNCT.

Evidence for glutamatergic neuronal dysfunction in the prefrontal cortex in chronic but not in first-episode patients with schizophrenia: a proton magnetic resonance spectroscopy study

Based upon pharmacological challenge and postmortem studies, schizophrenia has been hypothesized to be caused by decreased glutamatergic neurotransmission. We investigated the glutamatergic neuronal metabolism of the dorsolateral prefrontal cortex with localized 1H magnetic resonance spectroscopy in 18 first-episode patients, 21 chronic patients with schizophrenia, and 21 age-matched controls. Chronic patients had significantly lower levels of glutamate/glutamine (Glx) and N-acetylaspartate (NAA) compared to healthy controls and first-episode patients. Reduced metabolite levels were not correlated with duration of illness or medication. Our results indicate glutamatergic dysfunction in chronic schizophrenia that could be evidence of a progressive brain disorder.

Non-invasive observation of acetyl-group buffering by 1H-MR spectroscopy in exercising human muscle.

The observation of a previously unidentified peak in localized 1H magnetic resonance (MR) spectra of human muscle during and after a work load is reported. Basic NMR properties of this resonance, as well as physiologic circumstances of its observation, suggest that it is due to the acetyl group of acetylcarnitine. The relatively large pool of muscular carnitine acts as a buffering system stabilizing the ratio of acetylated to free coenzyme A. Free carnitine can be acetylated to a large extent whenever a mismatch occurs between the fluxes through pyruvate dehydrogenase and the TCA cycle. Results of initial applications of 1H MR spectroscopy in several muscles and under different exercise regimens are in agreement with earlier invasive measurements of acetylcarnitine. It is demonstrated that the detailed dynamics of acetyl group formation are now likely to be observable non-invasively in humans by localized 1H magnetic resonance spectroscopy on standard MR imaging systems, and that acetylcarnitine buffering as a function of exercise type, oxygenation states, diet and pathology could thus be studied repeatedly and in various muscle groups with much improved temporal resolution.

Magnetic resonance spectroscopy study of low grade extra and intracerebral human neoplasms.

In this study we report an in vitro 1H magnetic resonance spectroscopy (MRS) characterization of water soluble metabolites obtained from 17 low grade extra and intracerebral human tumors (8 meningiomas, 5 oligodendrogliomas, 2 subependimomas and 2 ependimomas). In addition, the in vivo localized 1H MRS results for 4 of the meningiomas are reported. The main metabolic features characterizing low grade tumors were investigated. Meningiomas are characterized by high Cho/Cr and Ala/Cr ratios; in many cases both in the in vitro and the in vivo spectra these ratios cannot be evaluated, due to the absence of the Cr metabolite. Low grade oligodendrogliomas are characterized by low Cho/Cr ratios. High amounts of myo-inositol are found in the spectra of ependimomas and subependimomas which are distinguished by different Cho/Cr ratio values and by a different Ala content.

Effect of temperature on the kinetics of lactate production and clearance in a rat model of forebrain ischemia

To investigate the effect of brain temperature on metabolic perturbations during and following forebrain ischemia, localized 1H magnetic resonance spectroscopy was used to measure the kinetics of lactate production and clearance in a rat model of 12- or 20-min forebrain ischemia (two-vessel occlusion with hypotension) at a brain temperature of either 34.5 ± 0.5°C or 37.5 ± 0.5°C. During ischemia, lactate production was modeled with apparent first order kinetics. Hypothermia did not affect the rate or the extent of lactate production during ischemia. Upon reperfusion, a delay in the decrease of the cerebral lactate level was found in the normothermia groups. Such a delay was absent in hypothermia groups, which may reflect faster resumption of cerebral oxidative metabolism upon reperfusion in the hypothermic animals. The rate constant for lactate clearance postischemia was larger for normothermic animals and for the 20-min ischemia groups, perhaps because of increased blood-brain barrier permeability following more severe ischemia.Key words: forebrain ischemia, temperature, hypothermia, lactate, magnetic resonance spectroscopy.