Early metabolic response to tumor necrosis factor in mouse sarcoma: a phosphorus-31 nuclear magnetic resonance study.

To investigate the effects of recombinant human tumor necrosis factor alpha (rHuTNF-alpha) on high-energy phosphate metabolism of cancer cells, 31P nuclear magnetic resonance (NMR) studies were performed on a murine methylcholanthrene-induced sarcoma. Injection of 15 micrograms of rHuTNF-alpha caused progressive depletion of ATP and phosphocreatine within 90 min, together with an increase in inorganic phosphate. Metabolic changes were correlated with the early histological appearance of thrombosis and hemorrhage. A spatially localized NMR technique demonstrated that these changes were specific for the tumor. Acute ischemia of the tumor produced similar metabolic changes; thus the metabolic effects of rHuTNF-alpha could be due to either a primary action on tumor biochemistry or a secondary action produced by ischemia. These findings indicate that rHuTNF-alpha has a very rapid onset of action, which can be detected by 31P NMR. Furthermore, the results suggest that 31P NMR spectroscopy will be extremely useful for detecting early biochemical changes produced by rHuTNF-alpha or other treatments in animal and human cancers.

Nuclear magnetic resonance imaging-guided phosphorus-31 spectroscopy of the human heart.

Phosphorus-31 nuclear magnetic resonance spectroscopy can determine the status of high energy phosphates in vivo. However, its application to human cardiac studies requires precise spatial localization without significant contamination from other tissues. Using image-selected in-vivo spectroscopy (ISIS), a technique that allows three-dimensional localization of the volume of interest, 12 subjects were studied to determine the feasibility and reproducibility of phosphorus-31 spectroscopy of the human heart. Nuclear magnetic resonance imaging was performed using a commercial 1.5 tesla system to define the volume of interest. Phosphorus-31 spectra were obtained from the septum and anteroapical region of the left ventricle in 10 studies. Relative peak heights and areas were determined for high energy phosphates. The mean phosphocreatine to adenosine triphosphate ratio was 1.33 +/- 0.19 by height analysis and 1.23 +/- 0.27 by area analysis. Duplicate measurements in four subjects showed a reproducibility of less than or equal to 10% in three of the subjects. All spectra showed significant signal contribution from the 2,3 diphosphoglycerate in chamber red cells without evidence of skeletal muscle contamination. These results demonstrate the feasibility of image-guided phosphorus-31 spectroscopy for human cardiac studies and indicate the potential of this technique to study metabolic disturbances in human myocardial disease.

Metabolic characteristics of cortical malformations causing epilepsy.

PURPOSE: Cortical malformations (CMs) are increasingly recognized as the epileptogenic substrate in patients with medically refractory neocortical epilepsy (NE). The aim of this study was to test the hypotheses that: 1. CMs are metabolically heterogeneous. 2. The structurally normal appearing perilesional zone is characterized by similar metabolic abnormalities as the CM. METHODS: Magnetic resonance spectroscopic imaging (MRSI) in combination with tissue segmentation was performed on eight patients with NE and CMs and 19 age matched controls. In controls, NAA, Cr, Cho,NAA/Cr and NAA/Cho of all voxels of a given lobe were expressed as a function of white matter content and thresholds for pathological values determined by calculating the 95% prediction intervals. These thresholds were used to identify metabolically abnormal voxels within the CM and in the perilesional zone. RESULTS: 30% of all voxels in the CMs were abnormal, most frequently because of decreases of NAA or increases of Cho. Abnormal voxels tended to form metabolically heterogeneous clusters interspersed in metabolically normal regions. Furthermore, 15% of all voxels in the perilesional zone were abnormal, the most frequent being decreases of NAA and Cr. CONCLUSION: In CMs metabolically normal regions are interspersed with metabolically heterogeneous abnormal regions. Metabolic abnormalities in the perilesional zone share several characteristics of CMs and might therefore represent areas with microscopic malformations and/or intrinsic epileptogenicity.

Elevated lactate and alkalosis in chronic human brain infarction observed by 1H and 31P MR spectroscopic imaging.

The goal of this study was to investigate lactate and pH distributions in subacutely and chronically infarcted human brains. Magnetic resonance spectroscopic imaging (MRSI) was used to map spatial distributions of 1H and 31P metabolites in 11 nonhemorrhagic subacute to chronic cerebral infarction patients and 11 controls. All six infarcts containing lactate were alkalotic (pHi = 7.20 +/- 0.04 vs. 7.05 +/- 0.01 contralateral, p less than 0.01). This finding of elevated lactate and alkalosis in chronic infarctions does not support the presence of chronic ischemia; however, it is consistent with the presence of phagocytic cells, gliosis, altered buffering mechanisms, and/or luxury perfusion. Total 1H and 31P metabolites were markedly reduced (about 50% on average) in subacute and chronic brain infarctions (p less than 0.01), and N-acetyl aspartate (NAA) was reduced more (approximately 75%) than other metabolites (p less than 0.01). Because NAA is localized in neurons, selective NAA reduction is consistent with pathological findings of a greater loss of neurons than glial cells in chronic infarctions.

Lateralization of human focal epilepsy by 31P magnetic resonance spectroscopic imaging.

We attempted to lateralize the epileptogenic focus (seven temporal lobe hippocampal foci, one frontal lobe focus) in medically refractory unilateral complex partial seizures, using noninvasive 31P magnetic resonance spectroscopic imaging (MRSI) blindly and interictally to compare hippocampal or frontal regions. The seizure foci were more alkaline (intracellular pH = 7.17 +/- 0.03) compared with the contralateral region (7.06 +/- 0.02, p < 0.01) in all eight cases; the inorganic phosphate was relatively increased (240 +/- 50% of contralateral, seven of eight cases, p < 0.01); and phosphomonoesters were relatively reduced (68 +/- 9% of contralateral, seven of eight cases, p < 0.01). Other phosphorus metabolites were symmetric (+/- 10%). 31P MRSI correctly lateralized the seizure focus in all eight cases. By comparison, imaging correctly lateralized four cases and SPECT, two cases. In conclusion, 31P MRSI is a useful tool for the noninvasive clinical assessment of focal epilepsy and can accurately lateralize the epileptogenic focus.

Temporal lobectomy for epilepsy: recovery of the contralateral hippocampus measured by (1)H MRS.

(1)H MRS imaging was obtained from 10 patients with mesial temporal lobe epilepsy before and after surgery. After surgery, metabolic recovery in the contralateral hippocampus was detected. Preoperatively, reduced N-acetylaspartate (p < 0.04) increased after surgery nonsignificantly to equal control values. Cholines increased after surgery (p < 0.02) and creatine-phosphocreatine showed a trend to higher values. The results suggest that the contralateral hippocampus is affected by repeated seizure activity in the ipsilateral hippocampus, rather than presence of bilateral mesial temporal sclerosis.

1H MRSI predicts surgical outcome in MRI-negative temporal lobe epilepsy.

1H MRS imaging (MRSI) was performed on 15 patients with MRI-negative temporal lobe epilepsy (TLE) who underwent seizure surgery. The non-seizure-free patients (NSF) ipsilateral hippocampal N-acetylaspartate (NAA)/(Cr+Cho) z scores were lower than the contralateral scores (p = 0.04), and the NSF ipsilateral z scores were lower than the seizure-free patients' (SF) ipsilateral z scores (p = 0.0049). Similarly, NSF contralateral scores were lower than contralateral SF (p = 0.02). These findings suggest NAA predicts the surgical outcome in patients with TLE without evidence of mesial temporal sclerosis on MRI.

Hepatic cancers and their response to chemoembolization therapy. Quantitative image-guided 31P magnetic resonance spectroscopy.

RATIONALE AND OBJECTIVES: Hepatic embolization combined with intra-arterial administration of cytostatic drugs (chemoembolization) is frequently used to treat primary and metastatic cancers to the liver. Quantitative phosphorus-31 magnetic resonance spectroscopy (31P MRS) was used to assess the metabolic state of hepatic cancers and their metabolic response to chemoembolization. METHODS: Fifteen localized 31P MRS studies were performed on five patients with liver tumors. Thirteen healthy volunteers served as controls. Metabolite ratios and molar metabolite concentrations were calculated. RESULTS: Untreated hepatic tumors, relative to normal controls, showed elevated phosphomonoester/adenosine triphosphate (PME/ATP) ratios, reduced concentrations of ATP and inorganic phosphate (Pi), and normal phosphodiester (PDE) concentrations. As an acute response to chemoembolization, ATP, PME, and/or PDE concentrations diminished, whereas Pi concentrations increased or stayed relatively constant. Long-term follow-up after chemoembolization showed decreased PME/ATP and increased ATP concentrations in the absence of changes on standard magnetic resonance and computed tomographic images. CONCLUSIONS: These preliminary spectroscopic data suggest that quantitative 31P MRS can be successfully used to monitor directly metabolic response to hepatic chemoembolization.

Spectral simulations incorporating gradient coherence selection.

Computer-aided methods can considerably simplify the use of the product operator formalism for theoretical analysis of NMR phenomena, which otherwise becomes unwieldy for anything but simple spin systems and pulse sequences. In this report, two previously available programming approaches using symbolic algebra (J. Shriver, Concepts Magn. Reson. 4, 1-33, 1992) and numerical simulation using object-oriented programming (S. A. Smith, T. O. Levante, B. H. Meier, and R. R. Ernst, J. Magn. Reson. A 106, 75-105, 1994) have been extended to include the use of gradient operators for simulation of spatially localized NMR spectroscopy and gradient coherence selection. These methods are demonstrated using an analysis of the response of an AX(3) spin system to the STEAM pulse sequence and verified with experimental measurements on lactate.

An integrated program for amplitude-modulated RF pulse generation and re-mapping with shaped gradients.

Efficient generation of amplitude modulated, frequency selective RF pulses has been demonstrated by the Shinnar-Le Roux (SLR) algorithm. In the present article, we provide an overview of a relatively comprehensive computer program that includes a version of the SLR algorithm and also incorporates an algorithm for re-mapping a selective RF pulse onto a new dwell time with modulated gradients. The re-mapping may be used to reduce SAR, or to shorten the RF pulse time by increasing the gradient and RF strength in regions where the original RF pulse amplitude was low. The program includes additional useful features including a Bloch equations algorithm, and pulse scaling, to enable examination of pulse profiles under a variety of conditions such as RF inhomogeneity and even nuclear relaxation. The program, MATPULSE, was developed with the MATLAB for Windows programming language and makes extensive use of the MATLAB graphical user interface (GUI) features to generate a user-friendly interface. A number of examples are provided to illustrate the capabilities of the MATPULSE program.

Molar quantitation of in vivo proton metabolites in human brain with 3D magnetic resonance spectroscopic imaging.

A method for molar quantitation of in vivo proton metabolites in human brain with three-dimensional (3D) proton magnetic resonance spectroscopic imaging (MRSI) is described. The method relies on comparison of brain and calibration phantom measurements, with corrections for coil loading, and spin-lattice and spin-spin relaxation times. A 3D proton MRSI pulse sequence was developed which acquires two echoes and enables acquisition of both the TMS coil loading reference phantom and proton metabolite signals from a single experiment. With the aqueous fraction (tissue water) taken into account, the calculated molar concentrations from 24 centrum semiovale white matter voxels from 4 control subjects were (mmol/l +/- SD): N-acetyl aspartate = 14.6 +/- 2.8, total creatine+phosphocreatine = 6.0 +/- 1.2, total choline = 1.9 +/- 0.4. These values are equivalent to previously reported results obtained from single volume localized proton magnetic resonance spectroscopy.

3D phase encoding 1H spectroscopic imaging of human brain.

A three-dimensional (3D) phase-encoding proton spectroscopic imaging method is presented for a whole body MRI/MRS system. Metabolite images at 2 T of choline, creatine, and N-acetyl aspartate (NAA) of normal brain were obtained with a spatial resolution of 1.5 cc. With PRESS volume preselection and outer volume suppression pulses, brain regions close to the skull could be studied without significant contamination by lipid and water signals.

Quantitation of in vivo phosphorus metabolites in human brain with magnetic resonance spectroscopic imaging (MRSI).

A method for quantitation of in vivo 31P metabolite concentrations in human brain with 31P magnetic resonance spectroscopic imaging (MRSI) is described. The method relies on comparison of brain and calibration phantom measurements, with corrections for coil loading and metabolite magnetic relaxation. Estimated metabolite concentrations for the centrum semiovale in 11 normal adults (mean +/- SD) were: phosphomonoesters = 3.0 +/- 0.7 mM, inorganic phosphate = 0.7 +/- 0.2 mM, phosphodiesters = 10.9 +/- 1.8 mM, phosphocreatine = 2.7 +/- 0.5 mM, and adenosine triphosphate = 2.9 +/- 0.3 mM. These values are similar to previous results obtained from single-volume localized spectroscopy.

Short echo time multislice proton magnetic resonance spectroscopic imaging in human brain: metabolite distributions and reliability.

Multislice proton magnetic resonance spectroscopic imaging (1H MRSI) at 25 ms echo time was used to measure concentrations of myo-inositol (mI), N-acetylaspartate (NAA), and creatine (Cr) and choline (Cho) in ten normal subjects between 22 and 84 years of age (mean age 44 +/- 18 years). By co-analysis with MRI based tissue segmentation results, metabolite distributions were analyzed for each tissue type and for different brain regions. Measurement reliability was evaluated using intraclass correlation coefficients (ICC). Significant differences in metabolite distributions were found for all metabolites. mI of frontal gray matter was 84% of parietal gray matter and 87% of white matter. NAA of frontal gray matter was 86% of parietal gray matter and 85% of white matter. Cho of frontal gray matter was 125% of parietal gray matter and 59% of white matter and Cho of parietal gray matter was 47% of white matter. Cr of parietal gray matter was 113% of white matter. Reliability was relatively high (ICC from.70 to.93) for all metabolites in white matter and for NAA and Cr in gray matter, though limited (ICC less than.63) for mI and Cho in gray matter. These findings indicate that voxel gray/white matter contributions, regional variations in metabolite concentrations, and reliability limitations must be considered when interpreting 1H MR spectra of the brain.

Correlation of seizure frequency with N-acetyl-aspartate levels determined by 1H magnetic resonance spectroscopic imaging.

Using 1H MRSI, we measured N-acetyl-aspartate (NAA), a neuronal marker, in the seizure focus of 16 patients with partial epilepsy. Decreasing NAA correlated with increasing seizure frequency in frontal lobe epilepsy (r = -0.72, p < 0.02) and a similar trend was present in temporal lobe epilepsy (r = -.60, p < 0.06). NAA was not related to the duration of epilepsy. We conclude that patients with higher seizure frequency have evidence of greater neuron loss or dysfunction.

Phosphorus-31 MR spectroscopic imaging (MRSI) of normal and pathological human brains.

The goals of this study were to evaluate 31P MR spectroscopic imaging (MRSI) for clinical studies and to survey potentially significant spatial variations of 31P metabolite signals in normal and pathological human brains. In normal brains, chemical shifts and metabolite ratios corrected for saturation were similar to previous studies using single-volume localization techniques (n = 10; pH = 7.01 +/- 0.02; PCr/Pi = 2.0 +/- 0.4; PCr/ATP = 1.4 +/- 0.2; ATP/Pi = 1.6 +/- 0.2; PCr/PDE = 0.52 +/- 0.06; PCr/PME = 1.3 +/- 0.2; [Mg2+]free = 0.26 +/- 0.02 mM.) In 17 pathological case studies, ratios of 31P metabolite signals between the pathological regions and normal-appearing (usually homologous contralateral) regions were obtained. First, in subacute and chronic infarctions (n = 9) decreased Pi (65 +/- 12%), PCr (38 +/- 6%), ATP (55 +/- 6%), PDE (47 +/- 9%), and total 31P metabolite signals (50 +/- 8%) were observed. Second, regions of decreased total 31P metabolite signals were observed in normal pressure hydrocephalus (NPH, n = 2), glioblastoma (n = 2), temporal lobe epilepsy (n = 2), and transient ischemic attacks (TIAs, n = 2). Third, alkalosis was detected in the NPH periventricular tissue, glioblastoma, epilepsy ipsilateral ictal foci, and chronic infarction regions; acidosis was detected in subacute infarction regions. Fourth, in TIAs with no MRI-detected infarction, regions consistent with transient neurological deficits were detected with decreased Pi, ATP, and total 31P metabolite signals. These results demonstrate an advantage of 31P MRSI over single-volume 31P MRS techniques in that metabolite information is derived simultaneously from multiple regions of brain, including those outside the primary pathological region of interest. These preliminary findings also suggest that abnormal metabolite distributions may be detected in regions that appear normal on MR images.

A detailed analysis of localized J-difference GABA editing: theoretical and experimental study at 4 T.

The problem of low signal-to-noise ratio for gamma-aminobutyric acid (GABA) in vivo is exacerbated by inefficient detection schemes and non-optimal experimental parameters. To analyze the mechanisms for GABA signal loss of a MEGA-PRESS J-difference sequence at 4 T, numerical simulations were performed ranging from ideal to realistic experimental implementation, including volume selection and experimental radio frequency (RF) pulse shapes with a macromolecular minimization scheme. The simulations were found to be in good agreement with phantom and in vivo data from human brain. The overall GABA signal intensity for the simulations with realistic conditions for the MEGA-PRESS difference spectrum was calculated to be almost half of the signal simulated under ideal conditions (~43% signal loss). In contrast, creatine was reduced significantly less then GABA (~19% signal loss). The 'four-compartment' distribution due to J-coupling in the PRESS-based localization was one of the most significant sources of GABA signal loss, in addition to imperfect RF profiles for volume selection and editing. An alternative strategy that reduces signal loss due to the four-compartment distribution is suggested. In summary, a detailed analysis of J-difference editing is provided with estimates of the relative amounts of GABA signal losses due to various mechanisms. The numerical simulations presented in this study should facilitate both implementation of the more efficient acquisition and quantification process of J-coupled systems.

Ultraviolet-Stimulated KHCO(3) Efflux from Rose Cells: Regulation of Cytoplasmic pH.

Suspension-cultured cells of Rosa damascena that have been irradiated with ultraviolet light (254 nanometers, 2.1 x 10(4) joules per square meter) rapidly lose K(+) and HCO(3) (-) ions to the medium. If the HCO(3) (-) is derived from respiratory CO(2) inside the cell, then loss of HCO(3) (-) should be accompanied by an acidification of the cytoplasm. Estimates of the pH of control and ultraviolet-irradiated cells by (31)P-nuclear magnetic resonance spectroscopy indicated that, following irradiation, the pH of both cytoplasm and vacuole dropped by 0.2 to 0.3 units. This change was not as great as was predicted from the observed HCO(3) (-) loss. Analysis of nitrogenous compounds in the cell suggested that reduction of nitrate and synthesis of gamma-aminobutyric acid absorbed some of the protons formed by the synthesis and dissociation of bicarbonate.

Longitudinal (T1) relaxation times of phosphorus metabolites in the bovine and rabbit lens.

Longitudinal (T1) magnetic relaxation times for the major phosphorus-containing metabolites present in the bovine and rabbit lens under organ culture conditions and in the bovine and rabbit globe have been determined. Significant differences in T1 for the major phosphorus metabolites in each case are observed, as well as for the same metabolite in the two species examined. Species-dependent lens hydration may account, in part, for these differences. Because of the requirement for rapid repetitive pulsing for the attainment of optimum signal collection efficiency by the Fourier transform nuclear magnetic resonance method, significant differential saturation of metabolite resonance intensities occurs in circumstances where appreciable differences in T1 relaxation times are present, which, unless corrected, leads to erroneous determinations of relative metabolite levels. The net effect of assessing relative metabolite levels in terms of the percentage of total phosphate signal, without a correction for T1 discrimination, is to underestimate metabolites with a long T1 (sugar phosphates) and overestimate those metabolites with a short T1 (ATP). Individual metabolite T1 discrimination factors are calculated from integrated areas of spectra acquired using short and long repetition times as well as from metabolite T1 values. They are then employed, for the first time, for the correction of 31P-NMR spectra of bovine and rabbit lenses. Corrected spectra provide relative metabolite levels for lenticular ATP which are in excellent agreement with values determined by chemical and enzymatic assays.

Computer modeling of surface coil sensitivity.

A simple model is presented for the calculation of relative signal-to-noise (S/N) ratios of coils of different sizes and configurations when applied to in vivo MRS. Axial symmetry is assumed, which enables rather simple expressions to be used for the calculation of coil loading by the tissue. The model is calibrated to experiments through measurement of the loaded and unloaded coil Q's. Applications of the model demonstrate that for small, superficial regions of interest (ROI), small surface coils can provide a S/N much improved over that of a larger coil. However, for very deep ROIs, larger coils or coils producing uniform B1 provide improved S/N.