Lactate storm marks cerebral metabolism following brain trauma.

Brain metabolism is thought to be maintained by neuronal-glial metabolic coupling. Glia take up glutamate from the synaptic cleft for conversion into glutamine, triggering glial glycolysis and lactate production. This lactate is shuttled into neurons and further metabolized. The origin and role of lactate in severe traumatic brain injury (TBI) remains controversial. Using a modified weight drop model of severe TBI and magnetic resonance (MR) spectroscopy with infusion of (13)C-labeled glucose, lactate, and acetate, the present study investigated the possibility that neuronal-glial metabolism is uncoupled following severe TBI. Histopathology of the model showed severe brain injury with subarachnoid and hemorrhage together with glial cell activation and positive staining for Tau at 90 min post-trauma. High resolution MR spectroscopy of brain metabolites revealed significant labeling of lactate at C-3 and C-2 irrespective of the infused substrates. Increased (13)C-labeled lactate in all study groups in the absence of ischemia implied activated astrocytic glycolysis and production of lactate with failure of neuronal uptake (i.e. a loss of glial sensing for glutamate). The early increase in extracellular lactate in severe TBI with the injured neurons rendered unable to pick it up probably contributes to a rapid progression toward irreversible injury and pan-necrosis. Hence, a method to detect and scavenge the excess extracellular lactate on site or early following severe TBI may be a potential primary therapeutic measure.

Comparison of T2 and T2*-weighted MR molecular imaging of a mouse model of glioma.

BACKGROUND: Standard MRI has been used for high-grade gliomas detection, albeit with limited success as it does not provide sufficient specificity and sensitivity to detect complex tumor structure. Therefore targeted contrast agents based on iron oxide, that shorten mostly T2 relaxation time, have been recently applied. However pulse sequences for molecular imaging in animal models of gliomas have not been yet fully studied. The aim of this study was therefore to compare contrast-to-noise ratio (CNR) and explain its origin using spin-echo (SE), gradient echo (GE), GE with flow compensation (GEFC) as well as susceptibility weighted imaging (SWI) in T2 and T2* contrast-enhanced molecular MRI of glioma. METHODS: A mouse model was used. U87MGdEGFRvIII cells (U87MG), derived from a human tumor, were injected intracerebrally. A 9.4 T MRI system was used and MR imaging was performed on the 10 day after the inoculation of the tumor. The CNR was measured prior, 20 min, 2 hrs and 24 hrs post intravenous tail administration of glioma targeted paramagnetic nanoparticles (NPs) using SE, SWI, GE and GEFC pulse sequences. RESULTS: The results showed significant differences in CNR among all pulse sequences prior injection. GEFC provided higher CNR post contrast agent injection when compared to GE and SE. Post injection CNR was the highest with SWI and significantly different from any other pulse sequence. CONCLUSIONS: Molecular MR imaging using targeted contrast agents can enhance the detection of glioma cells at 9.4 T if the optimal pulse sequence is used. Hence, the use of flow compensated pulse sequences, beside SWI, should to be considered in the molecular imaging studies.

Truncation of the krebs cycle during hypoglycemic coma.

There is a misconception that hypoglycemic nerve cell death occurs easily, and can happen in the absence of coma. In fact, coma is the prerequisite for neuronal death, which occurs via metabolic excitatory amino acid release. The focus on nerve cell death does not explain how most brain neurons and all glia survive. Brain metabolism was interrogated in rats during and following recovery from 40 min of profound hypoglycemia using ex vivo (1)H MR spectroscopy to determine alterations accounting for survival of brain tissue. As previously shown, a time-dependent increase in aspartate was equaled by a reciprocal decrease in glutamate/glutamine. We here show that the kinetics of aspartate formation during the first 30 min (0.36 +/- 0.03 micromol g(-1) min(-1)) are altered such that glutamate, via aspartate aminotransferase, becomes the primary source of carbon when glucose-derived pyruvate is unavailable. Oxaloacetate is produced directly from alpha-ketoglutarate, so that reactions involving the six-carbon intermediates of the tricarboxylic acid cycle are bypassed. These fundamental observations in basic metabolic pathways in effect redraw the tricarboxylic acid cycle from a tricarboxylic to a dicarboxylic acid cycle during hypoglycemia. The basic neurochemical alterations according to the chemical equilibrium of mass action augments flux through a truncated Krebs cycle that continues to turn during hypoglycemic coma. This explains the partial preservation of energy charge and brain cell survival during periods of glucose deficiency.

13C-Labeled substrates and the cerebral metabolic compartmentalization of acetate and lactate.

[1-13C]Glucose, [2-13C]acetate and [3-13C]lactate were infused into male Sprague-Dawley rats (150-170 g) for periods of 3-100 min (n=4 per time) and neocortex extracts were analyzed using 13C-edited 1H magnetic resonance (MR) spectroscopy. The time dependence of the [4-13C]glutamine/[4-13C]glutamate labeling ratio was significantly different for all three substrates infused (p<0.001) and showed that acetate is primarily utilized by glia and lactate by neurons, whereas glucose is ubiquitous. The ratio of second- to first-turn TCA cycle labeling for glutamine was significantly lower for acetate (30-100 min infusion; p<0.02) and greater for lactate (10-30 min; p<0.02) than for glucose infusions, while the C-2/C-4 glutamate labeling ratio was similar for all the three substrates. This indicated that transfer of [2-13C]acetate-derived [4-13C]glutamine to neurons was preferred to reentry of label into the glial TCA cycle and that the neuronal TCA cycle turnover is significantly faster than that for glia. Fitting parameters of a function representing a pseudo-first-order process to the time dependence of labeling demonstrated that GABA labeling reaches steady state faster with glutamine labeled from [2-13C]acetate than with glutamate labeled from [3-13C]lactate. It is concluded that lactate represents a significant improvement over glucose in the study of neuronal metabolism and complements the use of acetate to study glial metabolism and glial/neuronal metabolic relationships.

Molecular susceptibility weighted imaging of the glioma rim in a mouse model.

BACKGROUND: Glioma is the most common and most difficult to treat brain cancer. Despite many efforts treatment, efficacy remains low. As neurosurgical removal is the standard procedure for glioma, a method, allowing for both early detection and exact determination of the location, size and extent of the tumor, could improve a patient's positive response to therapy. NEW METHOD: We propose application of susceptibility weighted molecular magnetic resonance imaging using, targeted contrast agents, based on superparamagnetic iron oxide nanoparticles, for imaging of the, glioma rim, namely brain-tumor interface. Iron oxide attached to the targeted cells increases, susceptibility differences at the boundary between tumor and normal tissue, providing the opportunity, to utilize susceptibility weighted imaging for improved tumor delineation. We investigated potential, enhancement of the tumor-brain contrast, including tumor core and rim when using susceptibility, weighted MRI for molecular imaging of glioma. RESULTS: There were significant differences in contrast-to-noise ratio before, 12 and 120min after contrast, agent injection between standard gradient echo pulse sequence and susceptibility weighted molecular, magnetic resonance imaging for the core-brain, tumor rim-core and tumor rim-brain areas. COMPARISON WITH EXISTING METHODS: Currently, the most common MRI contrast agent used for glioma diagnosis is a non-specific, gadolinium-based agent providing T1-weighted enhancement. Susceptibility-weighted magnetic, resonance imaging is much less efficient when no targeted superparamagnetic contrast agents are, used. CONCLUSION: The improved determination of glioma extent provided by SWI offers an important new tool for, diagnosis and surgical planning.

In vivo open-bore MRI reveals region- and sub-arc-specific lengthening of the unloaded human posterior cruciate ligament.

Open-bore MRI scanners allow joint soft tissue to be imaged over a large, uninterrupted range of flexion. Using an open-bore scanner, 3D para-sagittal images of the posterior cruciate ligament (PCL) were collected from seven healthy subjects in unloaded, recumbent knee extension and flexion. PCL length was measured from one 2D MRI slice partition per flexion angle, per subject. The anterior surface of the PCL lengthened significantly between extension and flexion (p<0.001). Conversely, the posterior surface did not. Changes were not due to the PCL moving relative to the 2D slice partition; measurements made from 3D reconstructions, which compensated for PCL movement, did not differ significantly from measurements made from 2D slice partitions. In a second experiment, videos of knee flexion were made by imaging two subjects at several flexion angles. Videos allowed soft tissue tracking; examples are included. In a third experiment, unloaded knees of seven healthy, recumbent subjects were imaged at extension and at 40°, 70°, 90°, 100°, 110° and 120° flexion. The distance between PCL attachments increased between extension and 100°, and then decreased (p<0.001). The anterior surface of the PCL lengthened over the flexion angles measured (p<0.01). The posterior surface of the PCL lengthened between extension and 40° and then shortened (p<0.001). Both attachment separation and anterior surface length increased dramatically between extension and 40°, but varied less afterwards. Results indicate that PCL dynamics differ between terminal extension and active function sub-arcs. Also, attachment separation cannot predict the lengthening of all parts of the PCL, nor can lengthening of one part of the PCL predict the lengthening of another part. A potential connection between lengthening and loading is discussed. We conclude that low-field MRI can assess ligament lengthening during flexion, and that the dynamics of the PCL for any given region and sub-arc should be measured directly.

Differential neuronal and glial metabolic response during hypothermia in an experimental animal model.

OBJECTIVE: To study the effect of hypothermia on metabolic compartmentalization in an animal model. METHODS: [1-(13)C] glucose, [2-(13)C] glucose, [3-(13)C] lactate, and [2-(13)C] acetate were infused into male Sprague-Dawley rats. The (13)C label was detected using (13)C-edited H magnetic resonance spectroscopy or (13)C magnetic resonance spectroscopy to determine the isotopic enrichment of both glutamate and glutamine. The infusion was carried out at either normothermia (37 degrees C) or hypothermia (31 degrees C). RESULTS: The [1-(13)C] glucose infusion during hypothermia resulted in decreased labeling of glutamate and glutamine consistent with decreased metabolism or the shunting of glucose through the pentose phosphate pathway. Unexpectedly, [2-(13)C] glucose infusion during hypothermia resulted in decreased labeling of glutamate but not glutamine, implying decreased neuronal but unaltered glial metabolism. The lactate and acetate infusion showed no temperature effect on labeling, indicating that the dampened neuronal metabolism occurred during glycolysis. CONCLUSION: The results may explain the mechanism of action of hypothermia by differentially preserving the protective metabolism in glia while selectively dampening neuronal metabolism.

The integration of real and virtual magnetic resonance imaging experiments in a single instrument.

We present the design of an integrated system for performing both real and virtual (simulated) magnetic resonance imaging (MRI) experiments. We emphasize the approaches used to maximize the level of integration and also the benefits that tight real-virtual integration brings for a scientific instrument. The system has been implemented for both low field (0.2 T) and high field (9.4 T) imaging systems. The simulations can run for any MRI experiment and we demonstrate the operation of the system for T(1), T(2), T(2) ( *), and diffusion contrasts.