Metabolite T2 Research Articles

T2 relaxation time abnormalities in bipolar disorder and schizophrenia

There are substantial abnormalities in the number, density, and size of cortical neurons and glial cells in bipolar disorder and schizophrenia. Because molecule-microenvironment interactions modulate metabolite signals characteristics, these cellular abnormalities may impact transverse (T2) relaxation times. We measured T2 relaxation times for three intracellular metabolites (N-acetylaspartate+N-acetylaspartylglutamate, creatine+phosphocreatine, and choline-containing compounds) in the anterior cingulate cortex and parieto-occipital cortex from 20 healthy subjects, 15 patients with bipolar disorder, and 15 patients with schizophrenia at 4 T. Spectra used in T2 quantification were collected from 8-cc voxels with varying echo times (30 to 500 ms, in 10-ms steps). Both bipolar disorder and schizophrenia groups had numerically shorter T2 relaxation times than the healthy subjects group in both regions; these differences reached statistical significance for creatine+phosphocreatine and choline-containing compounds in bipolar disorder and for choline-containing compounds in schizophrenia. Metabolite T2 relaxation time shortening is consistent with reduced cell volumes and altered macromolecule structures, and with prolonged water T2 relaxation times reported in bipolar disorder and schizophrenia. These findings suggest that metabolite concentrations reported in magnetic resonance spectroscopy studies of psychiatric conditions may be confounded by T2 relaxation and highlight the importance of measuring and correcting for this variable.

Estimation of metabolite T 1 relaxation times using tissue specific analysis, signal averaging and bootstrapping from magnetic resonance spectroscopic imaging data

Object A novel method of estimating metabolite T1 relaxation times using MR spectroscopic imaging (MRSI) is proposed. As opposed to conventional single-voxel metabolite T1 estimation methods, this method investigates regional and gray matter (GM)/white matter (WM) differences in metabolite T1 by taking advantage of the spatial distribution information provided by MRSI.Material and methods The method, validated by Monte Carlo studies, involves a voxel averaging to preserve the GM/WM distribution, a non-linear least squares fit of the metabolite T1 and an estimation of its standard error by bootstrapping. It was applied in vivo to estimate the T1 of N-acetyl compounds (NAA), choline, creatine and myo-inositol in eight normal volunteers, at 1.5 T, using a short echo time 2D-MRSI slice located above the ventricles.Results WM-T1,NAA was significantly (P < 0.05) longer in anterior regions compared to posterior regions of the brain. The anterior region showed a trend of a longer WM T1 compared to GM for NAA, creatine and myo-Inositol. Lastly, accounting for the bootstrapped standard error estimate in a group mean T1 calculation yielded a more accurate T1 estimation.Conclusion The method successfully measured in vivo metabolite T1 using MRSI and can now be applied to diseased brain.

Fast mapping of the T2 relaxation time of cerebral metabolites using proton echo‐planar spectroscopic imaging (PEPSI)

Metabolite T2 is necessary for accurate quantification of the absolute concentration of metabolites using long-echo-time (TE) acquisition schemes. However, lengthy data acquisition times pose a major challenge to mapping metabolite T2. In this study we used proton echo-planar spectroscopic imaging (PEPSI) at 3T to obtain fast T2 maps of three major cerebral metabolites: N-acetyl-aspartate (NAA), creatine (Cre), and choline (Cho). We showed that PEPSI spectra matched T2 values obtained using single-voxel spectroscopy (SVS). Data acquisition for 2D metabolite maps with a voxel volume of 0.95 ml (32 x 32 image matrix) can be completed in 25 min using five TEs and eight averages. A sufficient spectral signal-to-noise ratio (SNR) for T2 estimation was validated by high Pearson's correlation coefficients between logarithmic MR signals and TEs (R2 = 0.98, 0.97, and 0.95 for NAA, Cre, and Cho, respectively). In agreement with previous studies, we found that the T2 values of NAA, but not Cre and Cho, were significantly different between gray matter (GM) and white matter (WM; P < 0.001). The difference between the T2 estimates of the PEPSI and SVS scans was less than 9%. Consistent spatial distributions of T2 were found in six healthy subjects, and disagreement among subjects was less than 10%. In summary, the PEPSI technique is a robust method to obtain fast mapping of metabolite T2.

1H metabolite relaxation times at 3.0 tesla: Measurements of T1 and T2 values in normal brain and determination of regional differences in transverse relaxation.

To measure 1H relaxation times of cerebral metabolites at 3 T and to investigate regional variations within the brain. Investigations were performed on a 3.0-T clinical whole-body magnetic resonance (MR) system. T2 relaxation times of N-acetyl aspartate (NAA), total creatine (tCr), and choline compounds (Cho) were measured in six brain regions of 42 healthy subjects. T1 relaxation times of these metabolites and of myo-inositol (Ins) were determined in occipital white matter (WM), the frontal lobe, and the motor cortex of 10 subjects. T2 values of all metabolites were markedly reduced with respect to 1.5 T in all investigated regions. T2 of NAA was significantly (P < 0.001) shorter in the motor cortex (247 +/- 13 msec) than in occipital WM (301 +/- 18 msec). T2 of the tCr methyl resonance showed a corresponding yet less pronounced decrease (162 +/- 16 msec vs. 178 +/- 9 msec, P = 0.021). Even lower T2 values for all metabolites were measured in the basal ganglia. Metabolite T1 relaxation times at 3.0 T were not significantly different from the values at 1.5 T. Transverse relaxation times of the investigated cerebral metabolites exhibit an inverse proportionality to magnetic field strength, and especially T2 of NAA shows distinct regional variations at 3 T. These can be attributed to differences in relative WM/gray matter (GM) contents and to local paramagnetism.

Time course of NAA T2 and ADC w in ischaemic stroke patients: 1H MRS imaging and diffusion-weighted MRI

Background and purpose: Proton spectroscopy and quantitative diffusion-weighted imaging (DWI) were used to investigate the pertinence of N-acetyl aspartate (NAA) as a reliable marker of neuronal density in human stroke. Methods: The time courses of tissue water apparent diffusion coefficient (ADC w) and metabolite T2 were investigated on a plane corresponding to the largest area of cerebral infarction, within and outside the site of infarction in 71 patients with a large cortical middle cerebral artery territory infarction. Results: Significant reductions are seen in NAA T2 deep within the infarction during the period comprised between 5 and 20 days postinfarction; the relaxation times appearing to normalise several months after stroke. After an acute reduction in ADC w, the pseudonormalisation of ADC w occurs at 8–12 days after the ischaemic insult. The minimum in N-acetyl aspartate T2 relaxation times and the pseudonormalisation of ADC w appear to coincide. Conclusions: The data suggest that modifications in the behaviour of the observed proton metabolites occur during the period when the vasogenic oedema is formed and cell membrane integrity is lost. For this reason, NAA may not be a reliable marker of neuronal density during this period.

Thyroid hormones regulate DNA-synthesis and cell-cycle proteins by activation of PKCalpha and p42/44 MAPK in chick embryo hepatocytes.

The molecular mechanism by which thyroid hormones exert their effects on cell growth is still unknown. In this study, we used chick embryo hepatocytes at different stages of development as a model to investigate the effect of the two thyroid hormones, T3 and T4, and of their metabolite T2, on the control of cell proliferation. We observed that T2 provokes increase of DNA-synthesis as well as T3 and T4, independently of developmental stage. We found that this stimulatory effect on the S phase is reverted by specific inhibitors of protein kinase C (PKC) and p42/44 mitogen-activated protein kinase (p42/44 MAPK), Ro 31-8220 or PD 98059. Furthermore, the treatment with thyroid hormones induces the activation of PKCalpha and p42/44 MAPK, suggesting their role as possible downstream mediators of cell response mediated by thyroid hormones. The increase of DNA-synthesis is well correlated with the increased levels of cyclin D1 and cdk4 that control the G1 phase, and also with the activities of cell-cycle proteins involved in the G1 to S phase progression, such as cyclin E/A-cdk2 complexes. Interestingly, the activity of cyclin-cdk2 complexes is strongly repressed in the presence of PKC and p42/44 MAPK inhibitors. In conclusion, we demonstrated that the thyroid hormones could modulate different signaling pathways that are able to control cell-cycle progression, mainly during G1/S transition.

In vivo 1H NMR spectroscopy of the human brain at 7 T.

In vivo 1H NMR spectra from the human brain were measured at 7 T. Ultrashort echo-time STEAM was used to minimize J-modulation and signal attenuation caused by the shorter T2 of metabolites. Precise adjustment of higher-order shims, which was achieved with FASTMAP, was crucial to benefit from this high magnetic field. Sensitivity improvements were evident from single-shot spectra and from the direct detection of glucose at 5.23 ppm in 8-ml volumes. The linewidth of the creatine methyl resonance was at best 9 Hz. In spite of the increased linewidth of singlet resonances at 7 T, the ability to resolve overlapping multiplets of J-coupled spin systems, such as glutamine and glutamate, was substantially increased. Characteristic spectral patterns of metabolites, e.g., myo-inositol and taurine, were discernible in the in vivo spectra, which facilitated an unambiguous signal assignment.

Proton magnetic resonance spectroscopy of human basal ganglia: response to cocaine administration

Background: Proton magnetic resonance spectroscopy was used to determine the effects of intravenous cocaine or placebo administration on human basal ganglia water and metabolite resonances. Methods: Long echo time, proton magnetic resonance spectra of water and intracellular metabolites were continuously acquired from an 8-cm 3 voxel centered on the left caudate and putamen nuclei before, during, and after the intravenous administration of cocaine or a placebo in a double-blind manner. Results: Cocaine, at both 0.2 and 0.4 mg/kg, did not alter the peak area for water. Cocaine at 0.2 mg/kg induced small and reversible increases in choline-containing compounds and N-acetylaspartate peak areas. Cocaine at 0.4 mg/kg induced larger and more sustained increases in choline-containing compounds and N-acetylaspartate peak areas. No changes in either water or metabolite resonances were noted following placebo administration. Conclusions: These increases in choline-containing compounds and N-acetylaspartate peak areas may reflect increases in metabolite T2 relaxation times secondary to osmotic stress and/or increased phospholipid signaling within the basal ganglia following cocaine administration. This is the first report of acute, drug-induced changes in the intensity of human brain proton magnetic resonance spectroscopy resonance areas.

Cerebral metabolism in experimental hydrocephalus: an in vivo 1H and 31P magnetic resonance spectroscopy study.

Brain damage in patients with hydrocephalus is caused by mechanical forces and cerebral ischemia. The severity and localization of impaired cerebral blood flow and metabolism are still largely unknown. Magnetic resonance (MR) spectroscopy offers the opportunity to investigate cerebral energy metabolism and neuronal damage noninvasively and longitudinally. Previous 1H MR spectroscopy studies have shown an increased lactate resonance that is suggestive of anaerobic glycolysis. The aim of this study was to assess cerebral damage and energy metabolism in kaolin-induced hydrocephalus in adult rats by using in vivo 1H and 31P MR spectroscopy. The presence of lactate was correlated with high-energy phosphate metabolism and intracellular pH. The measurement of relative concentrations of N-acetyl aspartate (NAA), choline (Cho), and total creatine (tCr) served to assess neuronal damage. Hydrocephalus was induced in adult rats by surgical injection of kaolin into the cisterna magna. Magnetic resonance studies, using a 4.7-tesla magnet, were performed longitudinally in hydrocephalic animals at 1 (10 rats), 8 (six rats), and 16 weeks (six rats) thereafter, as well as in eight control animals. To evaluate ventricular size and white matter edema T2-weighted MR imaging was performed. The 1H MR spectra were acquired from a 240-microl voxel, positioned centrally in the brain, followed by localized 31P MR spectroscopy on a two-dimensional column that contained the entire brain but virtually no extracranial muscles. The 1H and 31P MR spectroscopy peak ratios were calculated after fitting the spectra in the time domain, intracellular pH was estimated from the inorganic phosphate (Pi) chemical shift, and T2 relaxation times of 1H metabolites were determined from the signal decay at increasing echo times. In hydrocephalic rats, ventricular expansion stabilized after 8 weeks. White matter edema was most pronounced during acute hydrocephalus. Lactate peaks were increased at all time points, without a decrease in phosphocreatine (PCr)/Pi and PCr/adenosine triphosphate (ATP) peak ratios, or pH. Possibly lactate production is restricted to periventricular brain tissue, followed by its accumulation in cerebrospinal fluid, which is supported by the long lactate T2 relaxation time. Alternatively, lactate production may precede impairment of ATP homeostasis. The NAA/Cho and tCr/Cho ratios significantly decreased during the acute and chronic stages of hydrocephalus. These changes were not caused by alterations in metabolite T2 relaxation time. The decreases in the NAA/Cho and tCr/Cho ratios implicate neuronal loss/dysfunction or changes in membrane phospholipid metabolism, as in myelin damage or gliosis. It is suggested that 1H MR spectroscopy can be of additional value in the assessment of energy metabolism and cerebral damage in clinical hydrocephalus.

Proton magnetic resonance spectroscopy of the primary motor cortex in patients with motor neuron disease: subgroup analysis and follow-up measurements.

To determine the motor cortex degeneration in patients with amyotrophic lateral sclerosis (ALS) using proton magnetic resonance spectroscopy, and to prove that proton magnetic resonance spectroscopy is suited to monitor the course of disease with follow-up examinations. We studied 33 patients with ALS whose conditions were diagnosed according to the El Escorial World Federation of Neurology criteria. Nine patients with ALS were followed up for up to 2 years. The control group included 20 healthy volunteers and 4 patients with multifocal motor neuropathy. Proton magnetic resonance spectroscopy determined levels of the brain metabolites N-acetylaspartate (NAA), choline, inositol-containing compounds, glutamate/glutamine, and phosphocreatine. Patients with ALS showed a significant reduction in the NAA-choline (P <.001) and NAA-phosphocreatine (P <.005) metabolite ratios and significantly elevated choline-phosphocreatine (P <.005) ratios compared with controls. Inositol-phosphocreatine ratios were also elevated in case patients, but the increase was less pronounced (P <.05). No differences in glutamate/glutamine-phosphocreatine ratios were detected between case patients and controls. An analysis of subgroups demonstrated less significant differences in NAA-choline metabolite ratios (P<.05), even in patients with pure lower motor neuron syndrome (suspected ALS). No changes in metabolite T1 and T2 relaxation times were observed. Patients with multifocal motor neuropathy showed normal metabolic ratios. Progressive alterations in affected metabolite ratios could be documented in the follow-up examinations. Spectroscopic changes in the motor cortices of patients with ALS correspond with a reduction in levels of NAA and an elevation in levels of choline and inositol compounds. Since NAA is exclusively expressed in neurons, the observed decrease of NAA reflects neuronal loss or dysfunction. Inositol and choline are associated with plasma membrane metabolism, so the release of these compounds may be related to membrane disorders.

Molar quantitation of hepatic metabolites in vivo in proton-decoupled, nuclear Overhauser effect enhanced 31P NMR spectra localized by three-dimensional chemical shift imaging.

Proton decoupling and nuclear Overhauser effect (NOE) enhancement significantly improve the signal-to-noise ratio and enhance resolution of metabolites in in vivo 31P MRS. We obtained proton-decoupled, NOE-enhanced, phospholipid-saturated 31P spectra localized to defined regions within the normal liver using three-dimensional chemical shift imaging. Proton-decoupling resulted in the resolution of two major peaks in the phosphomonoester (PME) region, three peaks in the phosphodiester (PDE) region and a diphosphodiester peak. In order to obtain molar quantitation, we measured the NOE of all hepatic phosphorus resonances, and we corrected for saturation effects by measuring hepatic metabolite T1 using the variable nutation angle method with phase-cycled, B1-independent rotation, adiabatic pulses. After corrections for saturation effects, NOE enhancement, B1 variations and point spread effects, the following mean concentrations (mmol/l of liver) (+/-SD) were obtained: [PME1] = 1.2 +/- 0.4, [PME2 + 2,3-DPG] = 1.1 +/- 0.1, [Pi + 2,3-DPG] = 2.8 +/- 0.5, [GPEth] = 2.8 +/- 0.7, [GPChol] = 3.5 +/- 0.6 and [beta-NTP] = 3.8 +/- 0.3. T1 and NOE enhancement were strongly correlated (r = 90), and indicated that the fractional contribution of 1H-31P dipolar relaxation to total 31P relaxation is minimal for NTPs, moderate for PMEs and high for PDEs in liver. Proton-decoupling and NOE enhancement permit one to obtain more information about in vivo metabolism of liver than previously available and should enhance the utility of 31P MRS for the study of hepatic disorders.

Line scan imaging of brain metabolites with CPMG sequences at 1.5 tesla.

A line scan Carr-Purcell-Meiboom-Gill (CPMG) spectroscopic imaging sequence has been implemented on a standard 1.5 T clinical scanner to map metabolite signals at multiple echo times from voxels along selected tissue columns through the brain. The CPMG multiecho spectroscopic image data sets are used to estimate brain metabolite T2 decay parameters in a group of healthy volunteers and in one tumor patient. Inherent trade-offs between T2 decay, spectral resolution, and echo spacing prove to be important limiting factors. In particular, separate quantitation of choline and creatine resonances at 1.5 T was not achieved in the present implementation. However, the ability to collect data sets suitable for T2 decay analyses of combined choline and creatine resonances and N-acetyl aspartate resonances in under 10 minutes may prove of clinical utility in the study of brain pathology.

Numerically Optimized Experiment Design for Measurement of Grey/White Matter Metabolite T2 in High-Resolution Spectroscopic Images of Brain

T 2 relaxation measurements for choline (Cho), total creatine (Cr = creatine + phosphocreatine), and N-acetylaspartate (NAA) were made separately in eight healthy volunteers using an average of forty 0.5 cc volumes (20 from grey matter and 20 from white matter) in spectroscopic images with a 32 × 32 resolution and a 240 mm field of view. In grey matter, the means and standard deviations of the T 2 values were 186 ± 23, 149 ± 10, and 232 ± 15 ms for Cho, Cr, and NAA, respectively, and in white matter, the mean T 2 values were 178 ± 16, 143 ± 8, and 228 ± 16 ms, respectively, with no significant differences between grey and white matter. The high-resolution measurements of T 2 values were possible because of experimental planning based on the minimization of predicted fitting uncertainties. Explicit expressions were derived to estimate the uncertainties in T 2 values, and it was found that two spectroscopic images with echo times of 50 and 250 ms, respectively, would yield sufficient precision for T 2 measurements. The derivation of the expressions, a discussion of their behavior, and the experimental planning and verification are presented.

Abnormal cerebral metabolite concentrations in patients with probable Alzheimer disease.

To establish whether recently described abnormalities of peak ratios are the result of changes in metabolite concentrations, quantitative 1H magnetic resonance spectroscopy was performed in 10 patients with Alzheimer disease (AD) and seven normal elderly. CSF volumes, metabolite T1 and T2 relaxation rates, ratios and concentrations of N-acetyl residues, creatine, choline residues, myo-inositol, glutamine plus glutamate (Glx), and glucose were obtained. Difference spectroscopy and quantitative assays showed a 50% increase in myo-inositol (6.4-9.8 mM; P < 0.005) and a decrease in N-acetyl in occipital gray matter. A reduction in beta, gamma-Glx and a significant increase in intracerebral [glucose], greater than attributable to CSF, were defined. Choline concentration increased with age, but was not elevated above normal in AD patients. These findings indicate the need for quantitative 1H MRS to substantiate metabolite ratios. The increased myo-inositol concentration in AD is demonstrated by these studies.

Development of the human brain: in vivo quantification of metabolite and water content with proton magnetic resonance spectroscopy.

Cerebral metabolite concentrations and water content were measured by means of localized proton magnetic resonance spectroscopy in 50 children, while metabolite peak ratios in short echo time spectra were evaluated in 173 examinations. Normative curves for normal development were established for two cerebral locations. The current report presents the first study of absolute metabolite concentrations and T1- and T2- relaxation as a function of age. Myo-inositol was found dominating the spectra at birth (12 mmoles/kg), while choline is responsible for the strongest peak in older infants (2.5 mmoles/kg). Creatine and N-acetyl groups are at significantly lower concentrations in the neonate than in the adult (Cr: 6, NA: 5 mmoles/kg). NA and Cr are determined by gestational age, whereas the concentration of ml correlates best with postnatal age. Quantitative 1H MRS is expected to be of particular value in diagnosis and monitoring of pathology in infants, since metabolite ratios are often misleading.

Measurement of the T2 relaxation time of ethanol and cerebral metabolites, in vivo.

The SPACE volume selection technique was combined with a spin-echo sequence to measure the transverse relaxation time of the resonances of ethanol and cerebral metabolites in the dog brain, in vivo. The method was extended to measure brain metabolite T2 values in the rat using 1H NMR microspectroscopy. The T2 decays for the resonances of the metabolites N-acetylaspartate, creatine/phosphocreatine, and choline/phosphorylcholine were found to be biexponential with long T2 components of 490, 260, and 350 ms for the dog and 490, 220, and 355 ms for the rat brain, respectively. The existence of a second T2 component may originate from J-coupled nonresolved metabolite resonances. The relaxation decay for the ethanol triplet could be fitted to a single exponential giving a T2 relaxation time of 335 ms. However, given the large errors in the measurement of ethanol peak intensities at short echo times because of overlapping lipid signal and the effects of J-modulation, a biexponential decay with a long T2 component of 335 ms cannot be ruled out. Ambiguities regarding the reported partial detection of the 1H NMR signal of ethanol in the brain are discussed.

The effect of prolonged elevated glucose levels on the phosphate metabolism of the rabbit lens in perfused organ culture

13C and 31P nuclear magnetic resonance (NMR) techniques were used to monitor phosphate metabolite longitudinal (T1) relaxation times and metabolism, the sorbitol pathway, and related bioenergetic processes in cultured rabbit lenses through 9 days of incubation with constant perfusion. Lenses were incubated in a modified TC-199 medium containing either 5.5- or 35.5 mM [1-13C]-enriched glucose. The NMR studies were augmented by biochemical and cation analyses, and by the visual assessment of lens clarity. In the hyperglycemic rabbit lens, relative to normal values, longitudinal (T1) relaxation times for phosphorus metabolites increased from 33- to 50% [with the exception of inorganic phosphate (Pi)]. This provides the first documentation that a pathophysiological insult to the lens can alter phosphorus metabolite T1 values. The determination of steady state levels for the NMR visible phosphorus metabolites present in the lens was obtained after correction for T1 differential saturation effects, and normalization to reflect the content of phosphorus equivalents in each metabolite. Relative to control lenses (i.e. incubated in 5.5 mM glucose-containing medium) the NMR visible phosphate metabolite pool of rabbit lenses subjected to a hyperglycemic stress for an extended period of time (greater than 72 hr) is characterized by the following statistically significant differences: a 23% decrease in the mean level of ATP; a 51% increase in the mean level of alpha-glycerolphosphate (alpha GP); a 56% decrease in the mean level of Pi; the appearance of an unidentified resonance at 6.2 ppm after 115- to 120-hr incubation; and lenticular acidification of 0.10 to 0.17 pH units. No statistically significant differences in the mean levels of ADP, dinucleotides (predominantly NAD+-NADH), and phosphomonoesters (other than alpha GP) were evident. Parallel 13C NMR measurements provided a real-time confirmation of sorbitol production and accumulation in rabbit lenses incubated in 35.5 mM glucose-containing medium. In agreement with classical biochemical analysis (Chylack and Kinoshita, 1969) sorbitol production attained a plateau level after ca. 3 days of incubation. Cation determinations performed at the conclusion of the 9-day incubation indicated that the lenses incubated under the two conditions have similar Na+ and K+ levels. Rabbit lenses incubated in normal glucose medium remained clear for at least 8 days. By contrast, for the rabbit lenses incubated in elevated glucose medium, equatorial opacification became evident by day 5; by day 8 extensive bleb formation and opacification was evident.(ABSTRACT TRUNCATED AT 400 WORDS)