Surgical resection versus watchful waiting in low-grade gliomas.

BACKGROUND: Infiltrating low-grade gliomas (LGG; WHO grade 2) typically present with seizures in young adults. LGGs grow continuously and usually transform to higher grade of malignancy, eventually causing progressive disability and premature death. The effect of up-front surgery has been controversial and the impact of molecular biology on the effect of surgery is unknown. We now present long-term results of upfront surgical resection compared with watchful waiting in light of recently established molecular markers. MATERIALS AND METHODS: Population-based parallel cohorts were followed from two Norwegian university hospitals with different surgical treatment strategies and defined geographical catchment regions. In region A watchful waiting was favored while early resection was favored in region B. Thus, the treatment strategy in individual patients depended on their residential address. The inclusion criteria were histopathological diagnosis of supratentorial LGG from 1998 through 2009 in patients 18 years or older. Follow-up ended 1 January 2016. Making regional comparisons, the primary end-point was overall survival. RESULTS: A total of 153 patients (66 from region A, 87 from region B) were included. Early resection was carried out in 19 (29%) patients in region A compared with 75 (86%) patients in region B. Overall survival was 5.8 years (95% CI 4.5-7.2) in region A compared with 14.4 years (95% CI 10.4-18.5) in region B (P < 0.01). The effect of surgical strategy remained after adjustment for molecular markers (P = 0.001). CONCLUSION: In parallel population-based cohorts of LGGs, early surgical resection resulted in a clinical relevant survival benefit. The effect on survival persisted after adjustment for molecular markers.

Did survival improve after the implementation of intraoperative neuronavigation and 3D ultrasound in glioblastoma surgery? A retrospective analysis of 192 primary operations.

BACKGROUND: Numerous observational studies indicate that more aggressive resection may prolong survival in glioblastoma patients. In Trondheim, Norway, intraoperative 3D ultrasound has been in increasing use since November 1997. The aim of the present study was to examine if the introduction of 3D ultrasound and neuronavigation (i. e., the SonoWand® system) may have had an impact on overall survival. PATIENTS/MATERIAL AND METHODS: Patient data were obtained retrospectively for the 192 glio-blastoma patients who received surgery and postoperative radiotherapy between 1990 and 2005. Overall survival, before and after 1997, was compared using the log rank test. Possible confounders were adjusted for in a multivariate Cox regression analysis. RESULTS: We observed an increase in survival for patients in the last study period (9.6 vs. 11.9 months; HR = 0.7; p = 0.034). The significant improvement in the latest time period was sustained after adjusting for age, WHO performance status (≥2) and type of radiotherapy (normofractioned or hypofractioned), and chemotherapy (yes/no), p = 0.034. 10 out of 14 patients who survived more than 3 years received treatment after the implementation of 3D ultrasound. CONCLUSION: Our study demonstrates that survival has improved within the same period that intraoperative ultrasound and neuronavigation was introduced and established in our department. The demonstrated association is a necessity for causation, but given the nature of this study, one must be cautious to claim causality. The improvement was, however, significant after adjustment for known major prognostic factors.

A new system for 3D ultrasound-guided placement of cerebral ventricle catheters.

PURPOSE: We present a new system for 3D ultrasound-guided placement of cerebral ventricle catheters. The system has been developed with the aim to provide accurate ultrasound-based guidance with only minimal changes to the current surgical technique and workflow. METHODS: The system consists of a pre-calibrated navigation adapter for the catheter and a reference frame attached to a standard surgical retractor in addition to an ultrasound-based navigation system with a probe that fits on top of a standard burr hole. RESULTS: The accuracy of the pre-calibrated system has been evaluated, and our measurements indicate that the accuracy of the pre-calibrated system is better than 3 mm. We also present a clinical case. CONCLUSIONS: The navigation accuracy is considered sufficient for clinical use, and initial clinical tests are promising. Further testing will be necessary to fully evaluate the performance of the system in a clinical setting.

Glutamate decreases pyruvate carboxylase activity and spares glucose as energy substrate in cultured cerebellar astrocytes.

The effects of glutamate on [U-(13)C]glucose metabolism were studied in cerebellar astrocytes using (13)C magnetic resonance spectroscopy. Labeled glutamate, glutamine, aspartate, lactate, and alanine were observed both in the cell extracts and in media, and, additionally, labeled glycogen was detected in the cell extracts. However, only labeled lactate and alanine were quantifiable in the medium in addition to [U-(13)C]glucose. In the presence of unlabeled glutamate, the amount of [U-(13)C]glucose removed from the medium was decreased, indicating that glutamate might spare glucose as an energy substrate and thus decrease the uptake of glucose. Labeled glycogen, [4,5-(13)C]glutamate, [3,4,5-(13)C]glutamate, [3,4-(13)C]aspartate, and [U-(13)C]alanine were increased in the presence of glutamate. However, the increase in the amount of [3,4,5-(13)C]glutamate from the second turn in the tricarboxylic acid (TCA) cycle was less pronounced than that of [4,5-(13)C]glutamate from the first turn in the TCA cycle. This indicates the dilution of label, probably resulting from the synthesis of unlabeled oxaloacetate from glutamate in the TCA cycle. Furthermore, exogenous glutamate had an inhibiting effect on pyruvate carboxylation, presumably by formation of oxaloacetate from 2-oxoglutarate derived from glutamate. It could be shown that glucose is a better substrate for energy production than glutamate; it is, however, less efficient in labeling amino acids than glutamate in cerebellar astrocytes.

Differences in neurotransmitter synthesis and intermediary metabolism between glutamatergic and GABAergic neurons during 4 hours of middle cerebral artery occlusion in the rat: the role of astrocytes in neuronal survival.

Astrocytes are intimately involved in both glutamate and gamma-aminobutyric acid (GABA) synthesis, and ischemia-induced disruption of normal neuroastrocytic interactions may have important implications for neuronal survival. The effects of middle cerebral artery occlusion (MCAO) on neuronal and astrocytic intermediary metabolism were studied in rats 30, 60, 120, and 240 minutes after MCAO using in vivo injection of [1-13C]glucose and [1,2- 13C]acetate combined with ex vivo 13C magnetic resonance spectroscopy and high-performance liquid chromatography analysis of the ischemic core (lateral caudoputamen and lower parietal cortex) and penumbra (upper frontoparietal cortex). In the ischemic core, both neuronal and astrocytic metabolism were impaired from 30 minutes MCAO. There was a continuous loss of glutamate from glutamatergic neurons that was not replaced as neuronal glucose metabolism and use of astrocytic precursors gradually declined. In GABAergic neurons astrocytic precursors were not used in GABA synthesis at any time after MCAO, and neuronal glucose metabolism and GABA-shunt activity declined with time. No flux through the tricarboxylic acid cycle was found in GABAergic neurons at 240 minutes MCAO, indicating neuronal death. In the penumbra, the neurotransmitter pool of glutamate coming from astrocytic glutamine was preserved while neuronal metabolism progressively declined, implying that glutamine contributed significantly to glutamate excitotoxicity. In GABAergic neurons, astrocytic precursors were used to a limited extent during the initial 120 minutes, and tricarboxylic acid cycle activity was continued for 240 minutes. The present study showed the paradoxical role that astrocytes play in neuronal survival in ischemia, and changes in the use of astrocytic precursors appeared to contribute significantly to neuronal death, albeit through different mechanisms in glutamatergic and GABAergic neurons.

(13)C MR spectroscopy study of lactate as substrate for rat brain.

In order to address the question whether lactate in blood can serve as a precursor for cerebral metabolites, fully awake rats were injected intravenously with [U-(13)C]lactate or [U-(13)C]glucose followed 15 min later by decapitation. Incorporation of label from [U-(13)C]glucose was seen mainly in glutamate, GABA, glutamine, aspartate, alanine and lactate. More label was found in glutamate than glutamine, underscoring the predominantly neuronal metabolism of pyruvate from [U-(13)C]glucose. It was estimated that the neuronal metabolism of acetyl CoA from glucose accounts for at least 66% and the glial for no more than 34% of the total glucose consumption. When [U-(13)C]lactate was the precursor, label incorporation was similar to that observed from [U-(13)C]glucose, but much reduced. Plasma analysis revealed the presence of approximately equal amounts of [1,2,3-(13)C]- and [1,2-(13)C]glucose, showing gluconeogenesis from [U-(13)C]lactate. It was thus possible that the labeling seen in the cerebral amino acids originated from labeled glucose, not [U-(13)C]lactate. However, the presence of significantly more label in [U-(13)C]- than in [2,3-(13)C]alanine demonstrated that [U-(13)C]lactate did indeed cross the blood-brain barrier, and was metabolized further in the brain. Furthermore, contributions from pyruvate carboxylase (glial enzyme) were detectable in glutamine, glutamate and GABA, and were comparatively more pronounced in the glucose group. This indicated that relatively more pyruvate from lactate than glucose was metabolized in neurons. Surprisingly, the same amount of lactate was synthesized via the tricarboxylic acid cycle in both groups, indicating transfer of neurotransmitters from the neuronal to the astrocytic compartment, as previous studies have shown that this lactate is synthesized primarily in astrocytes. Taking into consideration that astrocytes take up glutamate more avidly than GABA, it is conceivable that neuronal lactate metabolism was more prominent in glutamatergic neurons.

SonoWand, an ultrasound-based neuronavigation system.

OBJECTIVE: We have integrated a neuronavigation system into an ultrasound scanner and developed a single-rack system that enables the surgeon to perform frameless and armless stereotactic neuronavigation using intraoperative three-dimensional ultrasound data as well as preoperative magnetic resonance or computed tomographic images. The purpose of this article is to describe our two-rack prototype and present the results of our work on image quality enhancement. DESCRIPTION OF INSTRUMENTATION: The system consists of a high-end ultrasound scanner, a modest-cost computer, and an optical positioning/digitizer system. Special technical and clinical efforts have been made to achieve high image quality. A special interface between the ultrasound instrument and the navigation computer ensures rapid transfer of digital three-dimensional data with no loss of image quality. OPERATIVE TECHNIQUE: The positioning system tracks the position and orientation of the patient, the ultrasound probe, the pointer, and various surgical instruments. This makes it possible to update the three-dimensional map during surgery and navigate by ultrasound data in a similar manner as with magnetic resonance data. METHODS: The two-rack prototype has been used for clinical testing since November 1997 at the University Hospital in Trondheim. EXPERIENCE AND RESULTS: The image quality improvements have enabled us, in most cases, to extract information from ultrasound with clinical value similar to that of preoperative magnetic resonance imaging. The overall clinical accuracy of the ultrasound-based navigation system is expected to be comparable to or better than that of a magnetic resonance imaging-based system. CONCLUSION: The SonoWand system enables neuronavigation through direct use of intraoperative three-dimensional ultrasound. Further research will be necessary to explore the potential clinical value and the limitations of this technology.

Effects of thiopental on transport and metabolism of glutamate in cultured cerebellar granule neurons.

This study was performed to analyze the effects of the barbiturate thiopental on neuronal glutamate uptake, release and metabolism. Since barbiturates are known to bind to the GABA(A) receptor, some experiments were carried out in the presence of GABA. Cerebellar granule neurons were incubated for 2 h in medium containing 0.25 mM [U-(13)C]glutamate, 3 mM glucose, 50 microM GABA and 0.1 or 1 mM thiopental when indicated. When analyzing cell extracts, it was surprisingly found that in addition to glutamate, aspartate and glutathione, GABA was also labeled. In the medium, label was observed in glutamate, aspartate and lactate. Glutamate exhibited different labeling patterns, indicating metabolism in the tricarboxylic acid cycle, and subsequent release. A net uptake of [U-(13)C]glutamate and unlabeled glucose was seen under all conditions. The amounts of most metabolites synthesized from [U-(13)C]glutamate were unchanged in the presence of GABA with or without 0.1 mM thiopental. In the presence of 1 mM thiopental, regardless of the presence of GABA, decreased amounts of [1,2, 3-(13)C]glutamate and [U-(13)C]aspartate were found in the medium. In the cell extracts increased [U-(13)C]glutamate, [1,2, 3-(13)C]glutamate, labeled glutathione and [U-(13)C]aspartate were observed in the 1 mM thiopental groups. Glutamate efflux and uptake were studied using [(3)H]D-aspartate. While efflux was substantially reduced in the presence of 1 mM thiopental, this barbiturate only marginally inhibited uptake even at 3 mM. These results may suggest that the previously demonstrated neuroprotective action of thiopental could be related to its ability to reduce excessive glutamate outflow. Additionally, thiopental decreased the oxidative metabolism of [U-(13)C]glutamate but at the same time increased the detectable metabolites derived from the TCA cycle. These latter effects were also exerted by GABA.

Initial experience with stereoscopic visualization of three-dimensional ultrasound data in surgery.

Initial in vivo and in vitro experiments were performed to evaluate the feasibility of stereoscopically displaying three-dimensional (3D) ultrasound data from neurosurgery, laparoscopic surgery, and vascular surgery. Stereoscopic visualization was illustrated by four video sequences, which can be downloaded from http://www.us.unimed. sintef.no/. These sequences show a brain tumor, hepatic arteries in relation to the gallbladder, a model that mimics a neuroendoscope in a cyst, and a "flight" into model of an artery with an intima flap. The experiments indicate that stereoscopic display of ultrasound data is feasible when there is sufficient contrast between the objects of interest and the surrounding tissue. True 3D vision improves perception, thus enhancing the ability to understand complex anatomic structures such as irregular lesions and tortuous vessels.

In vivo effects of adenosine A1 receptor agonist and antagonist on neuronal and astrocytic intermediary metabolism studied with ex vivo 13C NMR spectroscopy.

Adenosine is a neuromodulator, and it has been suggested that cerebral acetate metabolism induces adenosine formation. In the present study the effects that acetate has on cerebral intermediary metabolism, compared with those of glucose, were studied using the adenosine A1 receptor agonist 2-chloro-N6-cyclopentyladenosine (CCPA) and antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). Fasted rats received an intravenous injection of CCPA, DPCPX, or vehicle. Fifteen minutes later either [1,2-13C]acetate or [1-13C]glucose was given intraperitoneally; after another 30 min the rats were decapitated. Cortical extracts were analyzed with 13C NMR spectroscopy and HPLC analysis. DPCPX affected neuronal and astrocytic metabolism. De novo synthesis of GABA from neuronal and astrocytic precursors was significantly reduced. De novo syntheses of glutamate and aspartate were at control levels, but their degradation was significantly elevated. In glutamine the anaplerotic activity and the amount of label in the position representing the second turn in the tricarboxylic acid cycle were significantly increased, suggesting elevated metabolic activity in astrocytes. CCPA did not influence GABA, aspartate, or glutamine synthesis. In glutamate the contribution from the astrocytic anaplerotic pathway was significantly decreased. In the present study the findings in the [1,2-13C]acetate and [1-13C]glucose control, CCPA, and DPCPX groups were complementary, and no adenosine A1 agonist effects arising from cerebral acetate metabolism were detected.

Decreased glutamate metabolism in cultured astrocytes in the presence of thiopental.

The effect of thiopental on glutamate metabolism was studied by 13C magnetic resonance spectroscopy. Cerebral cortical astrocytes were incubated with 0.5 mM [U-13C]glutamate for 2 hr in the presence of 0.5 or 1 mM thiopental. Labeled glutamate, glutamine, aspartate, and glutathione were observed in cell extracts, and glutamine, aspartate, and lactate in the medium. Not only present in the medium was uniformly labeled glutamate, but also glutamate derived from the tricarboxylic acid (TCA) cycle, and thus glutamate release could be detected. The amounts of [U-13C]glutamate and unlabeled glucose taken up by astrocytes were unchanged in the presence of 0.5 mM thiopental and decreased to about 50% and 80%, respectively when the concentration was increased to 1 mM. The amounts of most metabolites synthesized from [U-13C]glutamate were unchanged in the presence of 0.5 mM thiopental, but decreased [U-13C]glutamine, [U-13C]aspartate, and [U-13C]lactate were observed in the 1 mM group. Surprisingly, the amounts of [1,2,3-13C]glutamate, [2,3-13C]aspartate, and [3,4-13C]aspartate (2nd turn via the TCA cycle) were unchanged. However, this was not the case for [1,2-13C]lactate and [2,3-13C]lactate. Such variations indicate cellular compartmentation, possibly caused by a heterogeneous glutamate concentration within the cells affecting TCA cycle turnover rates differently.

Higher levels of antibodies against the psoriasis-associated antigen pso p27 in cerebrospinal fluid from patients with low back pain and sciatica.

STUDY DESIGN: A prospective study comparing the presence of antibodies against the psoriasis-associated antigen pso p27 in pain-free control subjects and patients with low back pain and/or sciatica. OBJECTIVES: To analyze the amount of local inflammation present in human lumbar disc disorders, using anti-pso p27 antibodies in the cerebrospinal fluid as a marker and to analyze whether pain intensity correlates with this marker of inflammation. SUMMARY OF BACKGROUND DATA: Pso p27 is a major antigen in psoriasis that is also present, mostly locally, in other inflammatory disorders, such as sarcoidosis, inflammatory bowel disease, and ankylosing spondylitis, inflammation is also thought to play a major role in the generation of lumbar and radicular pain in degenerative disc disorders. METHODS: Anti-pso p27 antibodies in cerebrospinal fluid were quantified using an indirect enzyme-linked immunosorbent assay with pso p27 obtained from patients with psoriasis for use as an antigen. Fifteen patients with spinal stenosis, 11 patients without myelographic disc herniation, 17 patients with disc herniation, and 24 pain-free patient control subjects were studied. RESULTS: Significantly higher levels of anti-pso p27 antibodies were found in patients with myelographic signs of disc herniation than in with patients with no signs of herniation, patients with spinal stenosis, and control subjects. Patients with no known signs of disc herniation and patients with myelographic signs of spinal stenosis (< 10 mm in diameter) caused by degenerative changes, had higher levels of anti-pso p27 antibodies than did control subjects. However, these differences reached only borderline statistical significance. CONCLUSIONS: The results support those in previous reports, that inflammation probably plays an important role in degenerative disk disorders, particularly in disk herniations. That there was no correlation between pain intensity and anti-pso p27 activity indicates that the antigen is probably not essential in pain generation per se. The results may indicate that pso p27 is expressed secondary to, not as an initiator of, inflammation.

In vivo injection of [1-13C]glucose and [1,2-13C]acetate combined with ex vivo 13C nuclear magnetic resonance spectroscopy: a novel approach to the study of middle cerebral artery occlusion in the rat.

Astrocytes play a pivotal role in cerebral glutamate homeostasis. After 90 minutes of middle cerebral artery occlusion in the rat, the changes induced in neuronal and astrocytic metabolism and in the neuronal-astrocytic interactions were studied by combining in vivo injection of [1-13C]glucose and [1,2-13C]acetate with ex vivo 13C nuclear magnetic resonance spectroscopy and HPLC analysis of amino acids of the lateral caudoputamen and lower parietal cortex, representing the putative ischemic core, and the upper frontoparietal cortex, corresponding to the putative penumbra. In the putative ischemic core, evidence of compromised de novo glutamate synthesis located specifically in the glutamatergic neurons was detected, and a larger proportion of glutamate was derived from astrocytic glutamine. In the same region, pyruvate carboxylase activity, representing the anaplerotic pathway in the brain and exclusively located in astrocytes, was abolished. However, astrocytic glutamate uptake and conversion to glutamine took place, and cycling of intermediates in the astrocytic tricarboxylic acid cycle was elevated. In the putative penumbra, glutamate synthesis was improved compared with the ischemic core, the difference appeared to be brought on by better neuronal de novo glutamate synthesis, combined with normal levels of glutamate formed from astrocytic glutamine. In both ischemic regions, gamma-aminobutyric acid synthesis directly from glucose was reduced to about half, indicating impaired pyruvate dehydrogenase activity; still, gamma-aminobutyric acid reuptake and cycling was increased. The results obtained in the current study demonstrate that by combining in vivo injection of [1-13C]glucose and [1,2-13C]acetate with ex vivo 13C nuclear magnetic resonance spectroscopy, specific metabolic alterations in small regions within the rat brain suffering a focal ischemic lesion can be studied.

In vitro and ex vivo 13C-NMR spectroscopy studies of pyruvate recycling in brain.

Pyruvate recycling is a well established pathway in the liver, but in the brain, the cellular localization of pyruvate recycling remains controversial and its physiological significance is unknown. In cultured cortical astrocytes, pyruvate formed from [U-13C]glutamate was shown to re-enter the TCA cycle after conversion to acetyl-CoA, as demonstrated by the labelling patterns in aspartate C-2 and C-3, lactate C-2, and glutamate C-4, which provides evidence for pyruvate recycling in astrocytes. This finding is in agreement with previous studies of astrocytic cultures, in which pyruvate recycling has been described from [U-13C]glutamine, in the presence of glutamate, and from [U-13C]aspartate. Pyruvate recycling in brain was studied in fasted rats receiving either an intraperitoneal or a subcutaneous injection of [1,2-13C]acetate followed by decapitation 30 min later. Extracts of cortical tissue were analysed with 13C-NMR spectroscopy and total amounts of amino acids quantified by HPLC. Plasma extracts were analysed with 1H- and 13C-NMR spectroscopy, and showed a significantly larger amount of [1, 2-13C]acetate in the intraperitoneal group compared to the subcutaneous group. Furthermore, a small amount of label was detected in glucose in both groups. In the subcutaneously injected rats, [4-13C]glutamate and [2-13C]GABA were less enriched than plasma glucose, which might have been the precursor. In the intraperitoneally injected rats, however, pyruvate formation from [1, 2-13C]acetate, and re-entry of this pyruvate into the TCA cycle was demonstrated by the presence of greater 13C enrichment in [4-13C]glutamate and [4-13C]glutamine compared to the subcutaneous group, probably resulting from the significantly higher [1, 2-13C]acetate concentration in brain and plasma.

[U-13C] aspartate metabolism in cultured cortical astrocytes and cerebellar granule neurons studied by NMR spectroscopy.

The metabolism of [U-13C]aspartate was studied in cultured cortical astrocytes and cerebellar granule neurons in the presence of glucose and during inhibition of glycolysis. Redissolved, lyophilized cell extracts and incubation media were analyzed by 13C nuclear magnetic resonance spectroscopy for the determination of metabolites labeled from aspartate. Uniformly labeled lactate was prominent in control media of astrocytes and cerebellar granule neurons. In both cell types, aspartate entered the tricarboxylic acid (TCA) cycle, as shown by labeling patterns in glutamate and, in astrocytes, in glutamine. From the complex labeling patterns in aspartate in astrocytic perchloric acid extracts it was clear that acetylcoenzyme A (acetyl-CoA) derived from aspartate via oxaloacetate and pyruvate could enter the TCA cycle. Such "recycling," however, could not be detected in cerebellar granule neurons. Inhibition of glycolysis reduced aspartate uptake and metabolism in both cell types. Most notably, lactate derived from aspartate showed a large reduction, and in astrocytes, incorporation of labeled acetyl-CoA into the TCA cycle was significantly reduced. Thus, astrocytes and cerebellar granule neurons differ in their handling of aspartate. Furthermore, inhibition of glycolysis clearly affected aspartate metabolism by such cells.

[U-13C]glutamate metabolism in astrocytes during hypoglycemia and hypoxia.

The ability of cultured astrocytes to metabolize [U-13C]glutamate in the absence of glucose was investigated by utilizing 13C nuclear magnetic resonance spectroscopy to identify 13C-labeled metabolites. Control cultures (3 mM glucose), hypoglycemic cultures (glucose-deprived), severe hypoglycemic cultures (glucose-deprived, 0.5 mM iodoacetate as an inhibitor of glycolysis), hypoglycemic/hypoxic cultures, and cultures deprived of all additional substrates were incubated for 2 hr in medium containing 0.5 mM glutamate (50% [U-13C]glutamate). Glucose deprivation alone had little effect on removal of glutamate from the culture medium, but the presence of iodoacetate or incubating cultures in a low-oxygen atmosphere decreased glutamate clearance. Only the withdrawal of all substrates other than glutamate decreased glutamine synthesis. Metabolism of glutamate through the tricarboxylic acid (TCA) cycle was evident by the appearance of [1,2,3-13C]glutamate and [U-13C]aspartate in cell extracts and [U-13C]lactate in cell media. Lactate derived from TCA cycle intermediates was significantly reduced after glucose deprivation and even more so after severe hypoglycemia. Release of glutamate from astrocytes was observed under all incubation conditions. [U-13C]Aspartate was not detected in control media but was released from glucose-deprived cells when oxygen was available. Increased release was observed in the presence of iodoacetate. After withdrawal of all substrates other than glutamate, [U-13C]aspartate was the only metabolite observed intracellularly, whereas aspartate, glutamine, and 5-oxoproline were detected in the incubation medium. The present results indicate that glutamate-to-aspartate conversion is preferentially utilized by astrocytes when oxygen is available but glycolysis is impaired.

Nuclear magnetic resonance spectroscopy of cerebrospinal fluid from patients with low back pain and sciatica.

STUDY DESIGN: This study was carried out to assess the metabolic differences between pain-free control subjects and patients with low back pain, either with or without disc protrusion or herniation. OBJECTIVES: To analyze various metabolites in human cerebrospinal fluid using proton nuclear magnetic resonance spectroscopy. The potential use of this technique as an additional tool for diagnostic assessment was also evaluated. SUMMARY OF BACKGROUND DATA: Inflammation is thought to play a major role in the generation of lumbar spine pain, a theory supported both by animal and in vitro studies. The effect of the inflammation in terms of increased metabolism has not yet been studied. METHODS: Cerebrospinal fluid was obtained from patients by lumbar puncture, frozen, redissolved, and analyzed for metabolites by proton nuclear magnetic resonance spectroscopy. RESULTS: Significantly lower values for several key metabolites were found in patients with low back pain or sciatica, with the lowest values in the subgroup of patients with myelographic signs of disc protrusion or herniation. CONCLUSIONS: The results indicate a higher level of metabolic activity in patients with low back pain or sciatica compared with pain-free control subjects, with this difference being most pronounced in the subgroup of patients with myelographic evidence of disc protrusion or herniation.

NMR spectroscopy study of the effect of 3-nitropropionic acid on glutamate metabolism in cultured astrocytes.

3-Nitropropionic acid (3-NPA) is a selective and irreversible inhibitor of succinate dehydrogenase. The effect of this compound on the metabolism of [U-13C]glutamate was studied in astrocytes using 13C nuclear magnetic resonance spectroscopy. The appearance of [1,2,3-13C]glutamate in cell extracts and [1,2,3-13C]glutamine and [U-13C]lactate in cell media demonstrated the metabolism of labeled glutamate via the tricarboxylic acid cycle. Such labeling was observed in the control situation and also in cells treated with 3 mM 3-NPA. In the cells treated with 3 mM 3-NPA, however, the labeling was significantly reduced, and with 10 mM 3-NPA no such labeling was observed. Labeled aspartate was observed in untreated cells only. Labeled succinate was not detectable under control conditions, but increased dose dependently in the presence of 3-NPA. Glutamate uptake and conversion of [U-13C]glutamate to [U-13C]glutamine was largely unaffected by 3-NPA, and ATP content was unchanged. In a previous study using cerebellar neurons, tricarboxylic acid cycle metabolism was blocked with 3 mM 3-NPA. The present results show that astrocyte metabolism is more adaptable to blockade of the tricarboxylic acid cycle by 3-NPA than neuronal metabolism.

Cerebrospinal fluid lactate and glutamine are reduced in multiple sclerosis.

OBJECTIVES: To analyse various metabolites in human cerebrospinal fluid from healthy controls and patients with multiple sclerosis. PATIENTS AND METHODS: Cerebrospinal fluid was obtained from patients by lumbar puncture, frozen, redissolved, and analysed for metabolites by proton nuclear magnetic resonance spectroscopy. RESULTS: Significantly lower values for lactate and glutamine were found in patients with multiple sclerosis in comparison with controls. No significant differences were found between patients with the relapsing-remitting and chronic progressive forms of the disease for any of the metabolites measured. CONCLUSION: There is a concomitant reduction in both lactate and glutamine in the cerebrospinal fluid of patients with multiple sclerosis compared to controls. This may be related to altered astrocytic metabolism during the disease. The results clearly show the diagnostic potential of magnetic resonance spectroscopy in diseases such as multiple sclerosis.