Biomedical subjects

Dieter Leibfritz

Publications and source records attributed to Dieter Leibfritz.

At least 19 recordsLinked to original sources

PubMed2007

Fast 3D 1H spectroscopic imaging at 3 Tesla using spectroscopic missing-pulse SSFP with 3D spatial preselection.

Three-dimensional (3D) (1)H MR spectroscopic imaging (SI) allows metabolic changes in human tissue to be identified. In clinical practice, fast acquisition techniques are required to achieve an adequate spatial resolution within acceptable total measurement times. In this study a novel fast pulse sequence for 3D (1)H SI based on the condition of steady-state free precession (SSFP), termed "spectroscopic missing-pulse SSFP" (spMP-SSFP), is proposed. It combines 3D spatial preselection with the acquisition of full spin echoes (SEs), and thus makes subsequent phase correction of spectra redundant. The sequence was applied to a phantom and healthy human brains in vivo at 3 Tesla. Metabolic images are acquired with a spatial resolution of 1.8 cm(3) within a total measurement time of about 6 min. With a lower signal-to-noise ratio (SNR) per unit measurement time compared to previous spectroscopic SSFP implementations, 3D spatial preselection can now be realized with spMP-SSFP. Since the method does not require separate techniques for water and lipid suppression, and employs a simple data-processing approach, spMP-SSFP is a robust, fast SI method that requires only minimal user interaction.

Brain↗

PubMed2006

Fast 1H spectroscopic imaging using steady state free precession and spectral-spatial RF pulses.

Recently, new methods for fast (1)H spectroscopic imaging based on the condition of steady state free precession (SSFP) were introduced to achieve a high signal-to-noise ratio at short minimum measurement times. In this work, a major improvement is presented to overcome a crucial drawback in some of the former sequences: the lack of spatial selectivity. Good spectral selectivity at very high sampling efficiency can be achieved by using spectral-spatial RF pulses, and combined with localised shimming. Results are shown from both phantom experiments and in vivo studies on the rat brain acquired at 4.7 T.

Animals↗

PubMed2006

Free radicals and antioxidants in normal physiological functions and human disease.

Reactive oxygen species (ROS) and reactive nitrogen species (RNS, e.g. nitric oxide, NO(*)) are well recognised for playing a dual role as both deleterious and beneficial species. ROS and RNS are normally generated by tightly regulated enzymes, such as NO synthase (NOS) and NAD(P)H oxidase isoforms, respectively. Overproduction of ROS (arising either from mitochondrial electron-transport chain or excessive stimulation of NAD(P)H) results in oxidative stress, a deleterious process that can be an important mediator of damage to cell structures, including lipids and membranes, proteins, and DNA. In contrast, beneficial effects of ROS/RNS (e.g. superoxide radical and nitric oxide) occur at low/moderate concentrations and involve physiological roles in cellular responses to noxia, as for example in defence against infectious agents, in the function of a number of cellular signalling pathways, and the induction of a mitogenic response. Ironically, various ROS-mediated actions in fact protect cells against ROS-induced oxidative stress and re-establish or maintain "redox balance" termed also "redox homeostasis". The "two-faced" character of ROS is clearly substantiated. For example, a growing body of evidence shows that ROS within cells act as secondary messengers in intracellular signalling cascades which induce and maintain the oncogenic phenotype of cancer cells, however, ROS can also induce cellular senescence and apoptosis and can therefore function as anti-tumourigenic species. This review will describe the: (i) chemistry and biochemistry of ROS/RNS and sources of free radical generation; (ii) damage to DNA, to proteins, and to lipids by free radicals; (iii) role of antioxidants (e.g. glutathione) in the maintenance of cellular "redox homeostasis"; (iv) overview of ROS-induced signaling pathways; (v) role of ROS in redox regulation of normal physiological functions, as well as (vi) role of ROS in pathophysiological implications of altered redox regulation (human diseases and ageing). Attention is focussed on the ROS/RNS-linked pathogenesis of cancer, cardiovascular disease, atherosclerosis, hypertension, ischemia/reperfusion injury, diabetes mellitus, neurodegenerative diseases (Alzheimer's disease and Parkinson's disease), rheumatoid arthritis, and ageing. Topics of current debate are also reviewed such as the question whether excessive formation of free radicals is a primary cause or a downstream consequence of tissue injury.

Animals↗

PubMed2006

Effects of zero-filling and apodization on spectral integrals in discrete Fourier-transform spectroscopy of noisy data.

The influence of noise on the standard deviation of spectral integrals is examined. Calculations assuming discrete Fourier-transform data are compared with Monte-Carlo simulations. The effects of zero-filling and apodization are examined for free-induction-decay (FID) signals and for symmetric spin-echo signals in one and two dimensions, with particular attention to features not previously presented in the literature. Findings suggest that for mild apodization, the known sensitivity enhancement due to zero-filling in either the real or the imaginary part signal [E. Bartholdi, R.R. Ernst, Fourier spectroscopy and the causality principle, J. Magn. Reson., 11 (1973) 9-19] is maintained; however, for stronger apodization filters, this enhancement can be obliterated completely. It is shown that results obtained by analysis of one-dimensional signals can be readily applied to multi-dimensional data. Furthermore, zero-filling has a negligible effect for symmetric spin-echo signals with implications for signal averaging in magnetic resonance imaging and spectroscopic imaging.

Journal Article↗

PubMed2006

Fast 3D echo planar SSFP-based 1H spectroscopic imaging: demonstration on the rat brain in vivo.

A fast proton spectroscopic imaging pulse sequence based on the condition of steady-state free precession is presented. High 3D spatial and temporal resolution is achieved using simultaneous detection of both one spatial and one spectral dimension, with a time-dependent gradient cycle known from echo planar imaging. Additionally, in order to increase the spectral width of the measurement, an interleaved acquisition scheme is shown either for systems with limited gradient switching capabilities or applications with a wide chemical shift range. The pulse sequence is implemented on a standard 4.7-T nuclear magnetic resonance animal imaging system. Measurements with a total measurement time of less than 2.5 min and a nominal voxel size of 6.75 microl using a total of 64 x 32 x 16 voxels are performed on phantoms and healthy rat brain in vivo allowing the rapid detection of signals from both uncoupled and J-coupled spin systems with high signal-to-noise ratio.

Animals↗

PubMed2006

Toward quantitative short-echo-time in vivo proton MR spectroscopy without water suppression.

A methodological development for quantitative short-echo-time (TE) in vivo proton MR spectroscopy (MRS) without water suppression (WS) is described that integrates experimental and software approaches. Experimental approaches were used to eliminate frequency modulation sidebands and first-order phase errors. The dominant water signal was modeled and extracted by the matrix pencil method (MPM) and was used as an internal reference for absolute metabolite quantification. Spectral fitting was performed by combining the baseline characterization by a wavelet transform (WT)-based technique and time-domain (TD) parametric spectral analysis using full prior knowledge of the metabolite model spectra. The model spectra were obtained by spectral simulation instead of in vitro measurements. The performance of the methodology was evaluated by Monte Carlo (MC) studies, phantom measurements, and in vivo measurements on rat brains. More than 10 metabolites were quantified from spectra measured at TE = 20 ms on a 4.7 T system.

Algorithms↗

PubMed2005

New method for the simultaneous detection of metabolites and water in localized in vivo 1H nuclear magnetic resonance spectroscopy.

A new two-scan method for localized 1H in vivo NMR spectroscopy (MRS) without water suppression (WS) is described. In one of the scans, two chemical shift selective 180 degrees pulses are applied prior to a standard localization sequence to invert all metabolite signals upfield and downfield from water, which remains unaffected. The difference spectrum records the metabolites whereas water and accompanying gradient induced artifacts are widely suppressed. The method was implemented on a 4.7-T system using point resolved spectroscopy with a short echo time of 18 ms. Phantom measurements proved the feasibility of absolute quantification using water as an internal reference. Measurements on healthy rat brain yielded comparable spectrum quality as measurements with water presaturation. The method does not require additional adjustments or sophisticated data postprocessing and scales favorably with increasing B(0) field. Therefore, the method should be useful for 1H MRS without WS. Although the two-step method doubles the minimum total measurement time, it may also be of interest for spectroscopic imaging (SI) without WS, in particular if fast SI techniques are applied.

Algorithms↗

PubMed2005

Contribution of extracellular glutamine as an anaplerotic substrate to neuronal metabolism: a re-evaluation by multinuclear NMR spectroscopy in primary cultured neurons.

Multinuclear NMR spectroscopy is used to investigate the effect of glutamine on neuronal glucose metabolism. Primary neurons were incubated with [1-(13C)]glucose in the absence or presence of glutamine (2 mM) and/or NH4Cl (5 mM). After ammonia-treatment, the concentrations of high-energy phosphates decreased up to 84% of control, which was aggravated in glutamine-containing medium (up to 42% of control). These effects could not be attributed to changes in mitochondrial glucose oxidation. Withdrawal of glutamine decreased amino acid concentrations, e.g. of glutamate to 53%, but also considerably lessened the 13C enrichment in [4-(13C)]glutamate to 8.3% of control, and decreased the 13C-enrichment in acetyl-CoA entering the Krebs cycle (P < 0.001). Thus, although glutamine is potent in replenishing neuronal glutamate stores, glutamate formation is mainly attributed to its de novo synthesis from glucose. Furthermore, mitochondrial glucose metabolism strongly depends on the supply of carbons from glutamine, indicating that exogenous glutamine is a well-suited substrate to replenish neuronal Krebs cycle intermediates.

Ammonium Chloride↗

PubMed2005

Ammonia toxicity under hyponatremic conditions in astrocytes: de novo synthesis of amino acids for the osmoregulatory response.

This study investigates how the metabolic activity and de novo synthesis of amino acids from glucose correlate with changes in intracellular organic osmolytes involved in astrocytic volume regulation during hyperammonemia and hyponatremia. Multinuclear (1H-, 31P-, 13C-) NMR spectra were recorded to quantify water-soluble metabolites, the cellular energy state, as well as the incorporation of [1-(13)C]glucose into amino acids of primary astrocyte cultures. Myo-inositol levels were strongly decreased already at 3h after treatment with NH4Cl; other intracellular osmolytes, such as hypotaurine and choline-containing compounds were also decreased, along with a concomitant increase of both the total concentration and the amount of newly synthesized glutamine, alanine, and glutathione. During ammonia stress, the decrease of organic osmolytes compensated in part for increased intracellular osmolarity caused by amino acid synthesis. Hypotonic conditions alone also lowered the content of organic osmolytes including cellular amino acids, but much less than in hyperammonemia. This was due to impaired mitochondrial metabolic activity via the Krebs cycle, which also enhanced ammonia-induced ATP decrease. However, the changes in the sum of organic osmolytes were not significantly different after ammonia-treatment in hypoosmotic compared to anisoosmotic media, suggesting that the decrease of cellular organic osmolytes may not adequately compensate for the increased intracellular osmolarity caused by amino acids under hyponatremia. Therefore, the ammonia-induced release of osmolytes is an early process in response to increased intracellular osmolarity evoked by increased glutamine and alanine as a consequence of stimulated metabolic activity. The imperfect correlation of changes in astrocytic glutamine, other organic osmolytes, and the cellular energy state under hyperammonemic stress in isoosmotic and hypoosmotic media, however, point to additional mechanisms contributing to astrocyte dysfunction in hyperammonemic states, which are independent from glutamine formation.

Alanine↗

PubMed2004

Alterations in glucose metabolism by cyclosporine in rat brain slices link to oxidative stress: interactions with mTOR inhibitors.

Co-administration of the calcineurin inhibitor cyclosporine and the mTOR inhibitors sirolimus or everolimus increases the efficacy of immunosuppression after organ transplantation. However, clinical studies showed enhancement of cyclosporine toxicity. To characterize the biochemical mechanisms involved, we assessed the time-dependent effects of cyclosporine in combination with mTOR inhibitors on energy production (ex vivo (31)P-MRS), glucose metabolism (ex vivo (13)C-MRS), and reactive oxygen species (ROS) formation (using the fluorescent agent 2',7'-dichlorofluorescein diacetate) in perfused rat brain slices. Cyclosporine alone inhibited energy production (ATP: 75+/-9%), the Krebs cycle (4-(13)C-glutamate from 1-(13)C-glucose: 61+/-27%), and oxidative phosphorylation (NAD(+): 62+/-25%) after 4 h of perfusion. After 10 h, activation of anaerobic glycolysis (3-(13)C-lactate: 140+/-17%) compensated for inhibition of mitochondrial energy production and lowered the intracellular pH. ROS formation was increased after 4 h (285+/-55% of untreated control), but not after 10 h. mTOR inhibitors alone inhibited lactate production. When combined with cyclosporine, sirolimus enhanced cyclosporine-induced inhibition of energy metabolism (ATP: 64+/-9%) and ROS formation (367+/-46%). Most importantly, sirolimus inhibited cytosolic glycolysis and therefore compensation for cyclosporine-induced ATP reduction after 10 h. In contrast to sirolimus, everolimus antagonized cyclosporine-induced inhibition of mitochondrial energy metabolism (ATP: 91+/-7%) and ROS formation (170+/-49%). The antioxidant tocopherol antagonized all cyclosporine effects on cell metabolism. Cyclosporine time-dependently inhibited mitochondrial metabolism and increased ROS, followed by compensation involving anaerobic glycolysis. Everolimus antagonized cyclosporine-induced mitochondrial dysfunction, whereas sirolimus inhibited compensatory anaerobic glycolysis, thus enhancing cyclosporine's negative effects. ROS play the key role in mediating the negative effects of cyclosporine on cell energy metabolism.

Adenosine Triphosphate↗

PubMed2004

Selective alterations of brain osmolytes in acute liver failure: protective effect of mild hypothermia.

The principal cause of mortality in patients with acute liver failure (ALF) is brain herniation resulting from intracranial hypertension caused by a progressive increase of brain water. In the present study, ex vivo high-resolution 1H-NMR spectroscopy was used to investigate the effects of ALF, with or without superimposed hypothermia, on brain organic osmolyte concentrations in relation to the severity of encephalopathy and brain edema in rats with ALF due to hepatic devascularization. In normothermic ALF rats, glutamine concentrations in frontal cortex increased more than fourfold at precoma stages, i.e. prior to the onset of severe encephalopathy, but showed no further increase at coma stages. In parallel with glutamine accumulation, the brain organic osmolytes myo-inositol and taurine were significantly decreased in frontal cortex to 63% and 67% of control values, respectively, at precoma stages (p<0.01), and to 58% and 67%, respectively, at coma stages of encephalopathy (p<0.01). Hypothermia, which prevented brain edema and encephalopathy in ALF rats, significantly attenuated the depletion of myo-inositol and taurine. Brain glutamine concentrations, on the other hand, did not respond to hypothermia. These findings demonstrate that experimental ALF results in selective changes in brain organic osmolytes as a function of the degree of encephalopathy which are associated with brain edema, and provides a further rationale for the continued use of hypothermia in the management of this condition.

Animals↗

PubMed2004

Experimental method to eliminate frequency modulation sidebands in localized in vivo 1H MR spectra acquired without water suppression.

An experimental method is described to eliminate frequency modulation sidebands in localized in vivo proton MR spectra acquired without water suppression. Based on the fact that the phases of the sideband artifact signals are coherent with the phases of the gradient pulses, the proposed method measures and combines signals with sequences using opposite gradients to cancel the sidebands. Factors effecting the results of the cancellation are investigated. Optimized cancellation is achieved by trimming the refocusing gradients, optimizing the spoiler gradients, or replacing the spoiler gradients with a 16-step RF phase cycling. The performance of the method is demonstrated by phantom and in vivo experiments on the healthy rat brain.

Animals↗

PubMed2004

Metabolism of [U-(13)C]leucine in cultured astroglial cells.

Leucine is rapidly metabolized in astroglial primary cultures. Therefore, it is considered as valuable fuel in brain energy metabolism. Only few of the leucine metabolites generated and released by astroglial cells have been identified. Therefore, a more detailed study was performed analyzing by NMR techniques the 13C-labeled metabolites, which were released by astroglial primary cultures during the degradation of [U-(13)C]leucine. Confirming a former radioactive study this analysis revealed 13C-labeled 2-oxoisocaproate and ketone bodies. Additionally, 13C-labeled alanine, citrate, glutamine, lactate and succinate were identified. Their detailed isotopomer analysis proves that 13C-labeled acetyl-CoA enters the tricarboxylic acid cycle, that intermediates with a characteristic 13C-labeling pattern can be withdrawn at several positions of the cycle, and that in the case of lactate and alanine there appears to be a participation of an active phosphoenolpyruvate carboxykinase and/or malic enzyme pathway. Thus, astroglial cells generate and release into the extracellular fluid not only the leucine catabolites 2-oxoisocaproate and ketone bodies, but also several tricarboxylic acid cycle dependent metabolites.

Animals↗

PubMed2004

Brain energy metabolism in a sub-acute rat model of manganese neurotoxicity: an ex vivo nuclear magnetic resonance study using [1-13C]glucose.

Ex vivo high-resolution NMR spectroscopy combined with in vivo injection of [1-13C]glucose was applied to gain insight into the mechanism(s) leading to energy failure in manganese neurotoxicity. In rats treated for 4 days with 50mg/kg MnCl(2) (intraperitoneally, i.p.), the concentration of 13C-labeled lactate increased to 154% compared to control rats. Changes in the absolute amounts of lactate were much less, resulting in increased fractional 13C-enrichments in lactate (indicating relative changes of de novo synthesis from glucose via the glycolytic pathway) to 143% of control values (P < 0.001). Analysis of samples obtained from blood plasma and peripheral organs demonstrate a selective increase of lactate synthesis from [1-13C]glucose in the brain, which is released into the circulation. In parallel, manganese treatment resulted in stimulation of flux through pyruvate dehydrogenase (PDH), leading to accumulation of [4-13C]glutamate, [4-13C]glutamine and [2-13C]GABA to 168, 247 and 144% of control, respectively. The relative flux of glucose through astrocytic pyruvate carboxylase (PC), on the other hand, was impaired by manganese, as evident from a decreased ratio of [2-13C]/[4-13C]glutamate or [2-13C]/[4-13C] glutamine. Consistent with stimulated glucose oxidative metabolism, the fractional 13C-enrichment in [2-13C]acetyl-CoA entering the tricarboxylic acid (TCA) cycle and contributing to glutamate and glutamine synthesis increased to 138 and 156% of control, respectively (P < 0.001). In parallel, the TCA cycling ratio increased to 134% compared to control rats, prior to the label ending up in glutamate. In contrast, glutamine is synthesized mainly during the first TCA cycle turn. The present data provide new evidence in support of changes in brain energy metabolism playing an important role in manganese neurotoxicity. In particular, increased glycolytic flux and lactate synthesis may contribute to the deleterious effects of manganese in the brain. Furthermore, stimulated astrocytic glucose oxidation and glutamine synthesis may be associated with astrocytic pathology and altered astrocytic-neuronal metabolic trafficking in manganese neurotoxicity.

Animals↗

PubMed2003

PRESS-based proton single-voxel spectroscopy and spectroscopic imaging with very short echo times using asymmetric RF pulses.

Modified point-resolved spectroscopy (PRESS) sequences for single voxel spectroscopy (MRS) and spectroscopic imaging (SI) with very short echo time ( T(E)) are described using asymmetric radio-frequency (RF) pulses as well as an optimized design and timing of the PRESS sequence. The proposed sequences were implemented on a standard 4.7 T imaging system yielding a T(E) of 6.0 ms only. Simulations and experimental data measured on phantoms and the rat brain in vivo are presented for MRS and SI showing a high signal-to-noise ratio and hardly any phase distortions caused by J-coupling.

Algorithms↗

PubMed2003

Fast U-FLARE-based correlation-peak imaging with complete effective homonuclear decoupling.

A new fast correlation-peak imaging technique is presented that combines 2D correlation spectroscopy with an ultrafast low-angle rapid acquisition with relaxation enhancement (U-FLARE) imaging module. Constant time chemical shift (CS) encoding is used in both time dimensions to achieve effective homonuclear decoupling in both frequency dimensions. The intervals between excitation and mixing (t(c1)) and between mixing and start of the MRI module (t(c2)) can be optimized to maximize the coherence transfer for a particular metabolite. Experiments were performed with evolution times t(c1) and t(c2) of 100 ms and 50 ms, respectively, which were determined by simulation of the spectroscopic part of the sequence for the spin systems of myo-inositol (Ins) and taurine (Tau). The use of a circularly reduced CS-encoding scheme shortened the minimum total measurement time to 35 min. The sequence was implemented on a 4.7 T imaging system and tested on a spherical phantom filled with a solution of Ins. The in vivo application of this method on healthy rat brain demonstrates its improved spectral resolution, as cross-peak signals from both Ins and Tau can be separated clearly.

Animals↗

PubMed2003

Fast proton spectroscopic imaging using steady-state free precession methods.

Various pulse sequences for fast proton spectroscopic imaging (SI) using the steady-state free precession (SSFP) condition are proposed. The sequences use either only the FID-like signal S(1), only the echo-like signal S(2), or both signals in separate but adjacent acquisition windows. As in SSFP imaging, S(1) and S(2) are separated by spoiler gradients. RF excitation is performed by slice-selective or chemical shift-selective pulses. The signals are detected in absence of a B(0) gradient. Spatial localization is achieved by phase-encoding gradients which are applied prior to and rewound after each signal acquisition. Measurements with 2D or 3D spatial resolution were performed at 4.7 T on phantoms and healthy rat brain in vivo allowing the detection of uncoupled and J-coupled spins. The main advantages of SSFP based SI are the short minimum total measurement time (T(min)) and the high signal-to-noise ratio per unit measurement time (SNR(t)). The methods are of particular interest at higher magnetic field strength B(0), as TR can be reduced with increasing B(0) leading to a reduced T(min) and an increased SNR(t). Drawbacks consist of the limited spectral resolution, particularly at lower B(0), and the dependence of the signal intensities on T(1) and T(2). Further improvements are discussed including optimized data processing and signal detection under oscillating B(0) gradients leading to a further reduction in T(min).

Animals↗

PubMed2003

Diffusion in compartmental systems. I. A comparison of an analytical model with simulations.

This article examines the way in which microscopic tissue parameters affect the signal attenuation of diffusion-weighted MR experiments. The influence of transmembrane water flux on the signal decay is emphasized using the Kärger equations, which are modified with respect to the cellular boundary restrictions for intra- and extracellular diffusion. This analytical approach is extensively compared to Monte-Carlo simulations for a tissue model consisting of two compartments. It is shown that diffusion-weighted MR methods provide a unique tool for estimation of the intracellular exchange time. Restrictions of applicability to in vivo data are examined. It is shown that the intracellular exchange time strongly depends on the size of a cell, leading to an apparent diffusion time dependence for in vivo data. Hence, an analytical model of a two-compartment system with an averaged exchange time is inadequate for the interpretation of signal curves measured in vivo over large ranges of b-values. Furthermore, differences of multiexponential signal curves, as obtained by different methods of diffusion weighting, can be explained by the influence of transmembrane water flux.

Algorithms↗