Proton-decoupled 31P MRS in untreated pediatric brain tumors.

Proton-decoupled (31)P and (1)H MRS was used to quantify markers of membrane synthesis and breakdown in eight pediatric patients with untreated brain tumors and in six controls. Quantitation of these compounds in vivo in humans may provide important indicators for tumor growth and malignancy, tumor classification, and provide prognostic information. The ratios of phosphoethanolamine to glycerophosphoethanolamine (PE/GPE) and phosphocholine to glycerophosphocholine (PC/GPC) were significantly higher in primitive neuroectodermal tumors (PNET) (16.30 +/- 5.73 and 2.97 +/- 0.93) when compared with controls (3.42 +/- 1.62, P < 0.0001 and 0.45 +/- 0.13, P < 0.0001) and with other tumors (3.93 +/- 3.42, P < 0.001 and 0.65 +/- 0.30, P < 0.0001). Mean PC/PE was elevated in tumors relative to controls (0.48 +/- 0.11 versus 0.24 +/- 0.05, P < 0.001), but there was no difference between PNET and other tumors. Total choline concentration determined with quantitative (1)H MRS was significantly elevated (4.78 +/- 3.33 versus 1.73 +/- 0.56 mmol/kg, P < 0.05), whereas creatine was reduced in tumors (4.89 +/- 1.83 versus 8.28 +/- 1.50 mmol/kg, P < 0.05). A quantitative comparison of total phosphorylated cholines (PC+GPC)/ATP measured with (31)P MRS and total choline measured with (1)H MRS showed that in tumors a large fraction of the choline signal (>54 +/- 36%) was not accounted for by PC and GPC. The fraction of unaccounted choline was particularly large in PNET (>78 +/- 7%). The pH of tumor tissue was higher than the pH of normal brain tissue (7.06 +/- 0.03 versus. 6.98 +/- 0.03, P < 0.001).     

In vivo monitoring response to chemotherapy of human diffuse large B-cell lymphoma xenografts in SCID mice by 1H and 31P MRS

RATIONALE AND OBJECTIVES: A reliable noninvasive method for in vivo detection of early therapeutic response of non-Hodgkin's lymphoma (NHL) patients would be of great clinical value. This study evaluates the feasibility of (1)H and (31)P magnetic resonance spectroscopy (MRS) for in vivo detection of response to combination chemotherapy of human diffuse large B-cell lymphoma (DLCL2) xenografts in severe combined immunodeficient (SCID) mice. MATERIALS AND METHODS: Combination chemotherapy with cyclophosphamide, hydroxy doxorubicin, Oncovin, prednisone, and bryostatin 1 (CHOPB) was administered to tumor-bearing SCID mice weekly for up to four cycles. Spectroscopic studies were performed before the initiation of treatment and after each cycle of the CHOPB. Proton MRS for detection of lactate and total choline was performed using a selective multiple-quantum-coherence-transfer (Sel-MQC) and a spin-echo-enhanced Sel-MQC (SEE-Sel-MQC) pulse sequence, respectively. Phosphorus-31 MRS using a nonlocalized, single-pulse sequence without proton decoupling was also performed on these animals. RESULTS: Significant decreases in lactate and total choline were detected in the DLCL2 tumors after one cycle of CHOPB chemotherapy. The ratio of phosphomonoesters to beta-nucleoside triphosphate (PME/betaNTP, measured by (31)P MRS) significantly decreased in the CHOPB-treated tumors after two cycles of CHOPB. The control tumors did not exhibit any significant changes in either of these metabolites. CONCLUSIONS: This study demonstrates that (1)H and (31)P MRS can detect in vivo therapeutic response of NHL tumors and that lactate and choline offer a number of advantages over PMEs as markers of early therapeutic response.     

Accuracy of 1H and 31P MRS analyses of lactate in skeletal muscle.

As the end product of anaerobic metabolism and a source of H(+), lactic acid is important in metabolism and pH regulation. Several methods have been introduced to calculate changes in the lactate anion (Lac(-)) concentration in exercising skeletal muscle from information derived from the (31)P spectrum. Alternatively, Lac-may be observed directly with (1)H MRS. Both (1)H and (31)P spectroscopy have potential problems, which could prevent accurate determination of [Lac(-)]. It is demonstrated that quantitatively accurate (1)H MRS measurements of changes in [Lac(-)] due to exercise are possible in isolated muscle. In general, calculation by (31)P MRS overestimates Lac-production. An analysis is presented of possible sources of errors in the (1)H and (31)P MRS methods.     

Developmental changes in choline- and ethanolamine-containing compounds measured with proton-decoupled (31)P MRS in in vivo human brain.

Cerebral phosphorylated metabolites, possibly involved in membrane and myelin sheath metabolism, were measured and quantified using proton-decoupled (31)P ({(1)H}-(31)P) MRS in 32 children and 28 adults. Age-dependent changes were determined for phosphorylethanolamine (PE), phosphorylcholine (PC), glycerophosphorylethanolamine (GPE), glycerophosphorylcholine (GPC), and phosphocreatine (PCr) concentrations. In the neonate, PE dominates the spectrum and decreases with age along with PC, whereas GPE, GPC, and PCr increase in concentration with postnatal age. PE (1.23 +/- 0.13 mM) and GPE (0.57 +/- 0.08 mM) co-resonate with choline in (1)H MRS. Together with PC (0.57 +/- 0.12 mM) and GPC (0. 94 +/- 0.13 mM) these four metabolites accounted for all of the visible (1)H MRS choline in normal adult brain. Children with diseases that affect myelination were found to have abnormal ?(1)H?-(31)P MRS. The new quantitative assay may provide novel insights in determining and monitoring normal and abnormal brain maturation noninvasively. Magn Reson Med 42:643-654, 1999.     

Biexponential transverse relaxation (T(2)) of the proton MRS creatine resonance in human brain.

Differences in proton MRS T(2) values for phosphocreatine (PCr) and creatine (Cr) methyl groups (3.0 ppm) were investigated in studies of phantoms and human brain. Results from phantom studies revealed that T(2) of PCr in solution is significantly shorter than T(2) of Cr. Curve-fitting results indicated that the amplitude-TE curves of the total Cr resonance at 3.0 ppm in human brain (N = 26) fit a biexponential decay model significantly better than a monoexponential decay model (P < 0.006), yielding mean T(2) values of 117 +/- 21 ms and 309 +/- 21 ms. Using a localized, long-TE (272 ms) point-resolved spectroscopy (PRESS) proton MRS during 2 min of photic stimulation (PS), an increase of 12.1% +/- 3.5% in the mean intensity of the total Cr resonance in primary visual cortex (VI) was observed at the end of stimulation (P < 0.021). This increase is consistent with the conversion of 26% of PCr in VI to Cr, which is concordant with (31)P MRS findings reported by other investigators. These results suggest a significantly shorter T(2) for PCr than for Cr in vivo. This difference possibly could be exploited to quantify regional activation in functional spectroscopy studies, and could also lead to inaccuracies in some circumstances when the Cr resonance is used as an internal standard for (1)H MRS studies in vivo.     

Lactate and T 2 measurements of synovial aspirates at 1.5 T: differentiation of septic from non-septic arthritis

OBJECTIVE: The aim of this study was to differentiate septic from non-septic arthritis by measuring lactate concentration with (1)H magnetic resonance spectroscopy (HMRS) and by estimating total protein content with the assessment of T (2) values. MATERIALS AND METHODS: In 30 patients with acute arthritis, synovial fluid was aspirated. Lactate concentrations were analyzed with single voxel HMRS at 1.5 T. T (2) relaxation times were mapped with a multi-spin echo sequence. All samples underwent microbiological testing and routine laboratory analysis to quantify lactate concentration and total protein content. Values obtained in septic and non-septic arthritis were compared with a Mann-Whitney U test. RESULTS: Synovial fluid from patients with septic arthritis (n = 10) had higher concentrations of lactate (11.4 +/- 4.0 mmol/L) and higher total protein content (51.8 +/- 10.7 g/L) than fluid obtained in non-septic arthritis (n = 20; 5.2 +/- 1.1 mmol/L and 40.4 +/- 6.9 g/L, respectively, p < 0.001 and <0.01, respectively). Measured lactate concentrations and T (2) relaxation times (as an indicator of total protein content) were moderately correlated to laboratory-confirmed lactate concentration (r (2) = 0.71) and total protein content (r (2) = 0.73). Markedly increased lactate concentrations (>6 mmol/L) in combination with low T (2) values (<550 ms) identify septic arthritis with a sensitivity of 70% and a specificity of 89%. CONCLUSION: Spectroscopic measurements of lactate concentration in combination with the estimation of protein content using T (2) may be of value in the differentiation of septic from non-septic arthritis.     

Direct validation of in vivo localized 13C MRS measurements of brain glycogen.

With the use of localized 13C MRS in conjunction with [1-(13)C]-D-glucose infusion, it is possible to study brain glycogen metabolism in vivo. The purpose of this study was to validate in vivo 13C MRS measurements by comparing them with results from a standard biochemical assay. To increase the [1-(13)C] glycogen concentration, 11 rats were subjected to an episode of acute hypoglycemia followed by a mild hyperglycemic recovery period during which [1-(13)C]-D-glucose was infused. The total brain [1-(13)C] glycogen of the same animal was determined from the enzymatically determined total brain glycogen content, which was fixed by focused microwave irradiation (4 kW in 1.4 s) immediately after the end of the in vivo NMR measurements. The corresponding isotopic enrichment (IE) of glycogen was measured by in vitro 1H MRS of protons bound to glucose C1-alpha. The in vivo [1-(13)C] glycogen concentration was strongly correlated to the in vitro [1-(13)C] glycogen content determined by biochemical measurement in a linear manner (R=0.79). The results are consistent with the notion that localized 13C MRS measurements closely reflect 13C glycogen content in the brain.     

Non-invasive determination of metabolite concentrations in human transplanted kidney in vivo by 31P MR spectroscopy

PURPOSE: To investigate concentrations of phosphorus-containing metabolites in human transplanted kidney in vivo by quantitative 31P MR spectroscopy (MRS) using surface coils and to compare the obtained values with previous data. MATERIAL AND METHODS: In 5 patients with well-functioning transplanted kidneys, 31P spectra were obtained with the three-dimensional localization image-selected in vivo spectroscopy technique applying a protocol for quantitative spectroscopy using surface coils. Relaxation corrected signal intensities determined by time domain fitting were used to derive absolute molar concentrations for phosphate-containing metabolites. RESULTS: Little or no phosphocreatine in all spectra verified the absence of muscle contamination, confirming proper volume localization. The mean concentrations in the transplanted kidneys were as follows: ATP 1.60 +/- 0.26 mmol/ 1, PDE 2.14 +/- 0.91 mmol/l, Pi 0.66 +/- 0.25 mmol/l, PME 2.32+ /- 0.50 mmol/l. These values are consistent with previously reported values determined by other techniques. CONCLUSION: The non-invasive determination of absolute metabolite concentrations in human kidney using MRS supplements the use of signal intensity ratios to detect pathologic changes in the energy metabolism of transplanted kidneys.     

Influence of training on NIRS muscle oxygen saturation during submaximal exercise

PURPOSE: Endurance training improves the oxygen delivery and muscle metabolism. Muscle oxygen saturation measured by near infrared spectroscopy (IR-SO(2)), which is primarily influenced by the local delivery/demand balance, should thus be modified by training. We examined this effect by determining the influence of change in blood lactate and muscle capillary density with training on IR-SO(2) in seven healthy young subjects. METHODS: Two submaximal exercise tests at 50% (Ex1) and 80% pretraining VO(2max) (Ex2) were performed before and after a 4-wk endurance-training program. RESULTS: VO(2max) increased only slightly (+8%, NS) with training but the training effect was confirmed by the increased capillary density (+31%, P < 0.01) and citrate synthase activity (50%, P < 0.01), determined from muscle biopsy samples. Before training, blood lactate increased during the first 5 min of Ex1 and then remained constant (3.8 +/- 0.5 mmol x L(-1), P < 0.01), whereas it increased continuously during Ex2 (8.9 +/- 1.8 mmol x L(-1), P < 0.001). After training, lactate decreased significantly and remained constant during the two bouts of exercise (2.0 +/- 0.4 and 3.7 +/- 1.2 at the end of Ex1 and Ex2, respectively, both P < 0.001). During Ex1, IR-SO(2) dropped initially at the onset of exercise and recovered progressively without reaching the resting level. Training did not change this pattern of IR-SO(2). During Ex2, IR-SO(2) decreased progressively during the 15 min of exercise (P < 0.05); IR-SO2 kept constant after the initial drop after training. We found a significant relationship (r = 0.42, P = 0.03) between blood lactate and IR-SO(2) at the end of both bouts of exercise; this relationship was closer before training. By contrast, IR-SO(2) or IR-BV was not related to the capillary density. CONCLUSION: The training-induced adaptation in blood lactate influences IR-SO(2) during mild- to hard-intensity exercise. Thus, NIRS could be used as a noninvasive monitoring of training-induced adaptations.     

Changes in axonal morphology in experimental autoimmune neuritis as studied by high b-value q-space (1)H and (2)H DQF diffusion magnetic resonance spectroscopy.

Experimental autoimmune neuritis (EAN) has been studied in rat sciatic nerves by a combination of high b-value (1)H and (2)H double quantum filtered (DQF) diffusion MRS. The signal decays of water in the (1)H and (2)H DQF diffusion MRS were found to be not monoexponential and were analyzed using the q-space approach. The q-space analysis of the (1)H diffusion data detected two diffusing components, one having broad and the other having narrow displacement profiles. These components were shown to be very sensitive to the progression of EAN disease. The q-space parameters were found to be abnormal at day 9 postimmunization before the appearance of clinical signs. The assignment of the component with the narrow displacement profile to axonal water has been corroborated by the (2)H DQF diffusion MRS results. The displacement and the relative population of this slow and restricted diffusing component followed the processes of demyelination, axonal loss, and remyelination that occur in EAN. The displacements extracted from the slow-diffusing component with the narrow displacement correlated well with the average size of the axons as deduced from electron microscopy (EM). The component with the broad displacement showed significant changes which were attributed to the formation of endoneurial edema. This observation was also corroborated by the (2)H DQF diffusion MRS experiments. It seems, therefore, that q-space analysis of high b-values diffusion MRS is a promising new approach for early detection and better characterization of the different pathologies associated with EAN. This study demonstrates the utility of high-b-value q-space diffusion MRS for studying white matter-associated disorders in general.     

In vivo 31P magnetic resonance spectroscopy of human brain at 7 T: an initial experience.

In vivo (31)P spectra were acquired from the human primary visual cortex at 7 T. The relaxation times of the cerebral metabolites, intracellular pH, rate constant (k(f)) of the creatine kinase (CK) reaction, and nuclear Overhauser enhancement (NOE) on the detected phosphorus moieties from irradiation of the water spins were measured from normal subjects. With a 5-cm-diameter surface coil, 3D (31)P chemical shift imaging was performed with a spatial resolution of 7.5 ml and an acquisition resolution of 8 min, resulting in a signal-to-noise ratio (SNR) for phosphocreatine (PCr) resonance of 32. The apparent T(1) and T(2) of PCr measured at 7 T were 3.37 +/- 0.29 s and 132.0 +/- 12.8 ms, respectively, which were considerably longer than those of adenosine triphosphate (ATP) (T(1): 1.02-1.27 s; T(2): 25-26 ms). The NOE measured in this study was 24.3% +/- 1.6% for PCr, and 10% for ATP. The k(f) measured in the human primary visual cortex was 0.24 +/- 0.03 s(-1). The results from this study suggest that ultra-high-field strength is advantageous for performing in vivo (31)P magnetic resonance spectroscopy (MRS) in the human brain.     

Correlations between in vivo 1H MRS and ex vivo 1H HRMAS metabolite measurements in adult human gliomas

Purpose:

To assess how accurately ex vivo high‐resolution magic angle spinning (HRMAS) proton magnetic resonance spectroscopy (¹H MRS) from small biopsy tissues relate to in vivo ¹H MRS (from larger tumor volumes) in human astrocytomas.

Materials and Methods:

In vivo (PRESS, TE = 30 msec) and ex vivo (presaturation) ¹H spectra of 17 human astrocytomas (4 grade II, 1 grade III and 12 glioblastomas) were quantified using LCModel. Concentrations of 11 metabolites and 2 lipid/macromolecules were retrospectively compared, with histogram analysis of the in vivo MRI data used to evaluate tumor heterogeneity.

Results:

For homogeneous‐appearing tumors, significant correlations were found between in vivo and ex vivo ¹H MRS concentrations of those metabolites known to be metabolically stable in postmortem tissues (eg, creatine, myo‐inositol, total cholines, and the ≈1.3 and 0.9 ppm lipids). Anaerobic glycolysis during biopsy surgical removal depletes the tissue of glucose, increasing alanine and lactate, and resulted in no correlation between these in vivo and ex vivo metabolite concentrations.

Conclusion:

Within defined limitations, ex vivo astrocytoma biopsy HRMAS ¹H spectra have similar metabolic profiles to that obtained in vivo and therefore detailed ex vivo characterization of glioma biopsies can directly relate to the original tumor. J. Magn. Reson. Imaging 2010; 31: 289–297. © 2010 Wiley‐Liss, Inc.     

1H NMR detection of vitamin C in human brain in vivo.

Vitamin C (ascorbate) is well established as an essential nutrient that functions as an antioxidant. Since it is present in the human brain at detectable concentrations, this study was designed to detect and quantify ascorbate in the human brain in vivo using 1H NMR spectroscopy (MRS). Ascorbate was consistently detected in all five study subjects, and was measured using MEGA-PRESS difference editing. The in vivo resonance pattern was consistent with that of ascorbate based on position, line width, peak pattern, and relative intensity. Metabolites with a potential for coediting were assessed using phantom solutions. The putative resonances of myo-inositol, lactate, glycerophosphocholine, phosphocholine, and phosphoethanolamine were detected at positions distinct from those of ascorbate. This study represents the first in vivo detection of vitamin C in the human brain using 1H MRS. A concentration of 1.3 +/- 0.3 micromol/g (mean +/- SD, N = 4) was estimated.     

Muscle glycogenolysis is not activated by changes in cytosolic P-metabolites: a 31P and 1H MRS demonstration.

Skeletal muscle contraction and glycogenolysis are closely coupled. The standard explanation for this coupling, as taught in modern biochemistry textbooks, is that the metabolic products of contraction (ADP, AMP, P(i)) feed back to activate glycogenolytic enzymes, thus providing for resynthesis of ATP. However, both in vivo (31)P MRS analyses and chemical analyses of muscle extracts have provided results that are contrary to this theory, at least in its simplest form. The MRS studies suffer from ambiguous assumptions. More importantly, in (31)P MRS studies the dependent and independent variables are often confounded because the glycogenolytic rate is calculated from the same data which are used to calculate the other metabolic variables. The analysis of biopsies has been necessarily quite limited, and suffers from a different set of experimental artifacts. Thus, the problem of contraction-glycogenolysis-coupling was reassessed using a quantitatively accurate (1)H MRS method. It is confirmed that glycogenolysis and contractions are closely coupled during repetitive exercise, while glycogenolysis and P-metabolite concentrations are not. A simple metabolic feedback system cannot explain contraction-glycogenolysis-coupling.     

Cerebral metabolite dynamics during temporary complete ischemia in rats monitored by time-shared 1H and 31P NMR spectroscopy

The changes in cerebral phosphorus metabolites, intracellular pH, and lactate during 30 min of complete global ischemia and 2 h of reperfusion were monitored by time-shared 1H and 31P in vivo NMR spectroscopy in rats. After the induction of ischemia, intracellular pH decreased from 7.14 +/- 0.01 to 6.32 +/- 0.10, and lactate concentration increased from 1.6 +/- 0.4 to 15.8 +/- 2.5 mumol/g; ATP and phosphocreatine were totally depleted, while inorganic phosphate increased 715 +/- 47%. Within 1 h after blood flow was restored, high-energy phosphates and lactate levels had recovered close to baseline levels. The changes in intracellular pH and lactate levels during ischemia and reperfusion correlated well.     

Correlation of lactate and pH in human skeletal muscle after exercise by 1H NMR

We have made in vivo 1H NMR measurements of the time course of pH and lactate in human skeletal muscle after exercise. Spectra were obtained in a 4.7-T 30-cm bore Bruker Biospec spectrometer with a 2.5-cm diameter single surface coil. pH was determined from the shift of the endogenous carnosine H-C2 peak while lactate concentrations were determined by comparison with endogenous total creatine, taken to be 28.5 mM/kg wet wt. Fitting the data shows that the exponential decay of lactate (-0.094 +/- 0.014 min-1. t1/2 = 10.6 min) is slower than that of pH (-0.147 +/- 0.015 min-1, t1/2 = 4.7 min), n = 7 with two different volunteers. These values are significantly different with P less than 0.0005. Relaxation times of lactate and creatine were also measured for lactate quantitation; creatine T1, 1.23 +/- 12 s, T2, 136.2 +/- 26.4 ms (both in resting human muscle); lactate T1 (in postmortem rabbit muscle), 1.0 +/- 11 s and T2, 80 ms (in postexercise human muscle). At the end of intense exercise, the lactate level reached was 25.3 +/- 4.0 mM and the average pH drop was 1.0 pH unit. We discuss the implications of these measurements in conjunction with existing data on other sources of H+ flux, phosphocreatine resynthesis, H+ transport, and contribution of inorganic phosphate to buffering.     

Blood lactate concentration following maximum exercise in trained subjects.

The time when blood lactate reaches peak concentration following maximum exercise is unclear. The post exercise venous blood lactate concentration was determined serially for 30 minutes in 13 trained men following maximum exercise on a motor driven treadmill. Lactates were determined enzymatically in duplicate. The VO2 max and percent body fat was 65.1 +/- 4.8 ml.kg-1.min-1 and 11.4 +/- 1.4, respectively. The venous lactate reached a peak concentration at the 6th minute (14.2 mmol.L-1) of an inactive recovery, and declined linearly thereafter to reach a concentration of 7.43 +/- 0.60 mmol.L-1 at the 30th minute. The net rate of lactate removal was .30 mmol.L-1.min-1. Statistical analysis found no significant difference in lactate concentration during the 4th, 5th and 6th minute post exercise, indicating that these post exercise times may be appropriate to sample venous blood for peak lactate concentration.     

Comparison of the Lactate Pro and Analox GM7 blood lactate analysers

The purpose of this study was firstly, to determine the level of agreement between the Lactate Pro and Analox GM7 for the measurement of blood lactate, and secondly, to examine whether these analysers may be used interchangeably to identify lactate parameters routinely used in the physiological assessment of athletes. Twenty well-trained male cyclists performed an incremental cycle ergometry test; duplicate blood samples were taken simultaneously throughout the test for lactate determination using the two analysers. Power output and heart rate at LT, LT1, 2 mmol.L-1, and 4 mmol.L-1 were calculated from the lactate values obtained from the two analysers. There was a strong linear relationship between the two analysers (Lactate Pro=1.4541xAnalox GM7-0.1287; R2=0.969, p<0.001; SEE=0.704) though the Lactate Pro overestimated blood lactate when compared to the Analox GM7; 95% ratio limits of agreement (Lactate Pro/Analox GM7) were 1.40x//1.35. Differences were found between analysers for power output and heart rate at LT1 (p<0.01), 2 mmol.L-1 (p<0.001), and 4 mmol.L-1 (p<0.001); no differences were found between analysers for power output or heart rate at LT. In conclusion, the average difference in blood lactate concentration measured by the Lactate Pro and the Analox GM7 was 40%, with 95% of measures differing by between 4% and 89%. This poor level of agreement and the significant differences between the two analysers in power output and heart rate associated with a number of lactate parameters indicate that these analysers should not be used interchangeably.     

Evaluating a test protocol for predicting maximum lactate steady state

BACKGROUND: Maximum lactate steady state (MLSS) is defined as the highest steady state exercise level one can maintain while also maintaining an equilibrium between the elimination of blood lactate and the diffusion of lactate into the blood. MLSS is an excellent tool for assessing fitness level, predicting endurance performance, and designing training programs. METHODS: This investigation assesses the validity of the Lactate Minimum Test (LMT), which consists of inducing lactic acidosis through a VO2peak test, followed by an eight-minute walking recovery and an incremental exercise test, to determine if the running velocity associated with the minimum lactate value predicts the MLSS velocity. Following this LMT, two constant velocity 28-minute runs were performed, one at the predicted MLSS velocity (trial 1) and the other 0.13 m sec-1 (4-8%) above the predicted MLSS velocity (trial 2). Ten active female subjects participated (32 +/- 7 yrs (mean +/- SD); 65.7 +/- 16.4 kg; VO2peak 40.0 +/- 7.5 ml.kg-1.min-1). RESULTS: During trial 1, there was a -0.6 +/- 0.3 mmol l-1 (mean +/- SE) change in lactate. Based on a definition of lactate steady state (LSS) as less than a 0.5 mmol.l-1 increase, this value signified LSS. A similar comparison during trial 2 revealed a 1.8 +/- 0.3 mmol.l-1 increase in lactate, signifying a workload above LSS and therefore confirming trial 1 as the maximum LSS (MLSS). CONCLUSIONS: These results suggest that the test protocol accurately predicted the MLSS velocity.     

1-13C]glucose MRS in chronic hepatic encephalopathy in man.

[1-13C]-labeled glucose was infused intravenously in a single dose of 0.2 g/kg body weight over 15 min in six patients with chronic hepatic encephalopathy, and three controls. Serial 13C MR spectra of the brain were acquired. Patients exhibited the following characteristics relative to normal controls: 1) Cerebral glutamine concentration was increased (12.6 +/- 3.8 vs. 6.5 +/- 1.9 mmol/kg, P < 0.006) and glutamate was reduced (8.2 +/- 1.0 vs. 9.9 +/- 0.6 mmol/kg, P < 0.02). 2) 13C incorporation into glutamate C4 and C2 positions was reduced in patients (80 min after start of infusion C4: 0.43 +/- 0.09 vs. 0.84 +/- 0.15 mmol/kg, P < 0.001; C2: 0.20 +/- 0.03 vs. 0.45 +/- 0.07 mmol/kg, P < 0.0001). 3) 13C incorporation into bicarbonate was delayed (90 +/- 21 vs. 40 +/- 10 min, P < 0.003), and the time interval between detection of glutamate C4 and C2 labeling was longer in patients (22 +/- 8 vs. 12 +/- 3 min, P < 0.03). 4) Glutamate C2 turnover time was reduced in chronic hepatic encephalopathy (17.1 +/- 6.8 vs. 49.6 +/- 8.7 min, P < 0.0002). 5) 13C accumulation into glutamine C2 relative to its substrate glutamate C2 increased progressively with the severity of clinical symptoms (r = 0.96, P < 0.01). These data indicate disturbed neurotransmitter glutamate/glutamine cycling and reduced glucose oxidation in chronic hepatic encephalopathy. [1-13C] glucose MRS provides novel insights into disease progression and the pathophysiology of chronic hepatic encephalopathy.