Voxel- and ROI-based statistical analyses of PET parameters for guidance in the surgical treatment of intractable mesial temporal lobe epilepsy.

OBJECTIVE: Positron emission tomography (PET) can be used to locate epileptic foci in patients with mesial temporal lobe epilepsy (MTLE) by measuring multiple parameters of the brain. We investigated a series of patients with MTLE using PET measurements of three parameters: the cerebral blood flow measured with [15 O] H2O, the uptake of [18F] fluorodeoxyglucose (FDG), an index of the cerebral metabolism rate of glucose, and the distribution volume (DV) of [11C] flumazenil (FMZ), an index of the binding potential of central benzodiazepine receptor. We compared predictive values obtained from two methods: a voxel-based statistical analysis using statistical parametric mapping (SPM) and an asymmetry index obtained by placing regions of interest (ROIs) on PET images. METHODS: Preoperative PET data of 11 patients with surgically confirmed MTLE were retrospectively examined. In the voxel-based analysis, the PET data were analyzed using SPM99 by statistically comparing the voxel values of PET parameters between individual patients and the mean values of 12 normal volunteers. Voxels with values significantly lower than the normal control values were mapped on a standard brain atlas. In the ROI-based analysis, the asymmetry index was calculated to depict ROIs with abnormally decreased values when compared with the contralateral side. RESULTS: (1) Statistical parametric mapping and ROI analyses of the FDG uptake correctly determined epileptic temporal lobe in 73% and 82%, respectively. (2) The decreased DV of FMZ depicted by SPM revealed the mesial temporal pathology in 91%. CONCLUSIONS: Positron emission tomography measurement of FDG uptake was most sensitive in detecting the side of the epileptic focus. On the other hand, SPM analysis of the DV of FMZ was the most sensitive method for delineating the actual epileptic focus.

Imaging of somatotopic representation of sensory cortex with intrinsic optical signals as guides for brain tumor surgery.

OBJECT: Intrinsic optical signals in response to somatosensory stimuli were intraoperatively recorded during brain tumor surgery. In the present study, the authors report on the use of this technique as an intraoperative guide for the safe resection of tumors adjacent to or within the sensorimotor cortex. METHODS: In 14 patients with tumors adjacent to or within the sensorimotor cortex, intrinsic optical signals in response to somatosensory stimuli were recorded by illuminating the brain surface with Xe white light and imaging the reflected light passing through a bandpass filter (605 nm). Results were compared with intraoperative recordings of sensory evoked potentials in all 14 patients and with noninvasive mapping modalities such as magnetoencephalography and positron emission tomography in selected patients. In all but two patients, the somatosensory optical signals were recorded on the primary sensory cortex. Optical signals elicited by stimulation of the first and fifth digits and the three branches of the trigeminal nerve were recorded at different locations on the sensory strip. This somatotopic information was useful in determining the resection border in patients with glioma located in the sensorimotor cortex. CONCLUSIONS: Optical imaging of intrinsic signals is a useful technique with superior spatial resolution for delineating the somatotopic representation of human primary sensory cortex. Furthermore, it can be used as an intraoperative monitoring tool to improve the safety and accuracy of resections of brain tumors adjacent to or within the sensorimotor cortex.

Usefulness of L-[methyl-11C] methionine-positron emission tomography as a biological monitoring tool in the treatment of glioma.

OBJECT: The authors retrospectively analyzed the data obtained in patients who had undergone L-[methyl-11C] methionine (MET)-positron emission tomography (PET) studies to clarify the relationship between MET uptake and tumor biological features and to discuss the clinical usefulness of MET-PET studies. METHODS: One hundred ninety-four patients with cerebral glioma or suspected glioma underwent PET scanning 20 minutes after injection of MET, whose uptake into the tumor was expressed as a ratio to contralateral healthy brain tissue (T/N ratio). Analyses were performed to determine how MET uptake correlated with tumor pathological features and prognosis. The T/N ratios before and after various treatments were also examined. There were significant differences in the T/N ratio among the nonneoplastic lesions, low-grade gliomas, and malignant gliomas. Furthermore, there were significant correlations between patient survival and pretreatment T/N ratios. Among patients with malignant gliomas, a significant difference in survival was observed between cases with and without postoperative tumor remnant based on elevated MET uptake. The MET uptake was heterogeneous even among the homogeneous tumor areas demonstrated on MR imaging. Malignant pathological features were detected in the areas with the highest MET uptake. The effectiveness of radiotherapy or chemotherapy was expressed as a significantly decreased T/N ratio in some of the tumor types. CONCLUSIONS: The ability of MET-PET to reflect the biological nature of gliomas makes it an excellent method for monitoring active tumor tissue, and treatments based on its findings should provide a powerful clinical protocol in the course of glioma therapy.

Reduced transduction efficiency of adenoviral vectors expressing human p53 gene by repeated transduction into glioma cells in vitro.

PURPOSE: Recombinant adenoviral vectors are widely used in clinical and experimental studies to treat malignant tumors. Recently, host immune responses have been proposed as a major limitation in using adenoviral vectors for repeated gene delivery. We demonstrate another limitation unrelated to host immunity. EXPERIMENTAL DESIGN: We repeatedly transduced an adenoviral vector expressing the human p53 gene (AxCIhp53) into U373MG, a p53-susceptible cell line, and established the AxCIhp53-resistant cell line U373R. Most U373R cells survived even after AxCIhp53 treatment due to reduced transduction efficiency. Expression levels of adenovirus receptors were estimated to investigate the cause of reduced transduction efficiency. The mutant vector was used to overcome the resistance. RESULTS: The transduction efficiency of an adenoviral vector possessing the reporter LacZ gene (AxCAZ2-F/wt) for U373R cells was 25.4-fold less than that for parent cells. The expression levels of integrins alpha(v)beta(3) and alpha(v)beta(5) were found to be decreased in U373R cells without affecting the expression levels of Coxsackievirus and adenovirus receptor. The mutant vector AxCAZ2-F/K20, with a linker and a stretch of 20 lysine residues at the COOH-terminal of the fiber protein, improved the transduction efficiency of U373R cells to 12.6-fold of that of AxCAZ2-F/wt. A mutant vector carrying the p53 gene, AxCAhp53-F/K20, dramatically induced apoptosis in U373R cells. CONCLUSIONS: Glioma cells expressing low levels of adenovirus receptors might survive and proliferate to recur after repeated adenoviral transduction, even if the adenoviral transduction is effective at first. Changing the tropism of vectors is a potent method to overcome resistance.

Impairment of both apoptotic and cytoprotective signalings in glioma cells resistant to the combined use of cisplatin and tumor necrosis factor alpha.

PURPOSE: Tumor necrosis factor (TNF)-alpha elicits two opposing effects, the induction of apoptosis and the transcription of antiapoptotic genes. We have recently shown that cisplatin sensitizes glioma cells to TNF-induced apoptosis, but only in some cell lines. To understand the mechanism involved in the different susceptibilities, we examined both the activation of caspases and cytoprotective signaling by TNF-alpha. EXPERIMENTAL DESIGN: Caspase activation was examined by estimating the cleavage of substrate peptides and by immunoblot to identify the cleavage of procaspases. Peptide inhibitors of caspases were used to reverse the cytotoxicity. The binding of TNF-alpha to the receptor was analyzed by flow cytometry. Nuclear factor (NF)-kappaB activation was assayed by the binding of NF-kappaB to oligonucleotides containing the consensus binding site. Interleukin (IL)-1beta, IL-6, IL-8, and manganous superoxide dismutase (MnSOD) were measured by enzyme-linked immunoassays. RESULTS: T98G and U87MG underwent apoptosis on treatment with cisplatin and TNF-alpha, but U373MG and A172 were resistant. Caspases 2, 3, and 6-10, but not caspases 1, 4, and 5, were activated in sensitive cells, and none were activated in resistant cells. The binding of TNF-alpha to the receptor was the same in all four of the cell lines. In the sensitive cells, NF-kappaB activation and the production of IL-1beta, IL-6, IL-8, and MnSOD were significantly elevated by TNF-alpha. However, in the resistant cells, the production of IL-1beta and IL-6 were specifically impaired in response to TNF-alpha. CONCLUSIONS: Our results indicate that both apoptotic and cytoprotective pathways are impaired in glioma cells that are resistant to treatment with cisplatin and TNF-alpha.

Increased levels of tissue endostatin in human malignant gliomas.

PURPOSE: Malignant gliomas are typically angiogenic and express greater amounts of angiogenic factors. We examined glioma tissues for their expression of an endogenous inhibitor of angiogenesis, endostatin, a COOH-terminal fragment of collagen XVIII. EXPERIMENTAL DESIGN: We examined frozen tissues from 51 patients with astrocytic tumors (grade 2, 13; grade 3, 9; and grade 4, 29). Frozen tissues were subjected to immunoblot analysis and immunohistochemistry for endostatin. Tumor vascular density was determined by calculating the percentage of tumor capillary vessel areas/tissue section area. Tissue concentrations of vascular endothelial growth factor and basic fibroblast growth factor were examined by enzyme immunoassay. RESULTS: The levels of endostatin protein estimated by immunoblotting were significantly higher in grade 4 than lower-grade glioma tissues. The immunoreactive bands for endostatin were identified as the fragment derived from noncollagenous domain 1 of collagen XVIII, a peptide 15 residues longer than endostatin toward the NH(2)-terminal end, by NH(2)-terminal amino acid sequencing. In addition to an intense immunoreactivity for endostatin in tumor blood vessels, sections from malignant gliomas showed widely distributed immunoreactivity around tumor cells near the hyperplastic microvessels. The tumor vascular density and the levels of vascular endothelial growth factor in grade 4 glioma tissues were significantly higher than grade 2 and grade 3 gliomas, whereas the levels of basic fibroblast growth factor were the same. CONCLUSIONS: The results indicate a positive correlation between the levels of tissue endostatin and malignancy grades in gliomas. The endostatin may be released near the tumor blood vessels with hyperplasia to counteract angiogenic stimuli in malignant gliomas.

PET imaging of adenosine A(1) receptors with (11)C-MPDX as an indicator of severe cerebral ischemic insult.

UNLABELLED: We examined whether measurement of the adenosine A(1) receptor (A1-R) with PET can predict the severity of ischemic brain damage using an occlusion and reperfusion model of the cat middle cerebral artery (MCA) and [1-methyl-(11)C]8-dicyclopropylmethyl-1-methyl-3-propylxanthine (MPDX), a positron-emitting radioligand developed at our institution. METHODS: Eighteen adult cats underwent PET measurement of cerebral blood flow (CBF), A1-R, central benzodiazepine receptor (BDZ-R), and glucose metabolism with (15)O-labeled water, MPDX, (11)C-flumazenil (FMZ), and (18)F-FDG, respectively. The right MCAs of 13 cats were transiently occluded via a transorbital approach with microvascular clips. CBF was measured before occlusion of MCA, during occlusion, and immediately after reperfusion. After CBF measurement, A1-R, BDZ-R, and (18)F-FDG uptake were serially measured in the order listed. Two months later, the degree of ischemic damage was evaluated by T2-weighted MR images obtained with an animal MRI system and by analysis of histologic specimens. Five cats that received no operations were used as controls. RESULTS: The cats that underwent occlusion were divided into 3 groups: cats that did not survive the first day because of severe neurologic and systemic conditions (n = 4), cats that survived and had infarcted lesions in both the cortex and the striatum (n = 3), and cats that survived and had infarcted lesions only in the striatum (n = 6). CBF during occlusion of the MCA was significantly lower in all 3 ischemic groups than in the control group, but there was no significant difference among the ischemic groups. Right-to-left ratios of CBF and (18)F-FDG uptake did not significantly differ among the groups. MPDX binding and FMZ binding were significantly lower in the groups with severe ischemic insult than in the groups with little to no insult. CONCLUSION: The degree of decreased MPDX binding to A1-Rs after reperfusion was a sensitive predictor of severe ischemic insult. MPDX PET has good potential to become a suitable in vivo imaging technique for evaluating the function of adenosine and A1-Rs in relation to cerebral ischemia.

Increased binding of inhibitory neuronal receptors in the hippocampus in kainate-treated rats with spontaneous limbic seizures.

To gain a better understanding of the relationship between epileptogenicity and inhibitory neuronal mechanisms, we examined variations in A1 adenosine (A1A) receptor binding in the hippocampi of rats with spontaneous limbic seizures in the chronic phase after systemic kainic acid treatment. Six weeks after kainate treatment, rats with spontaneous limbic seizures were killed for histological and in vitro autoradiographic analyses of the brain. The analyses were performed using [(3)H] 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), an A1A receptor antagonist. Relative to controls, DPCPX binding was increased in the CA3 region and in the molecular layer of the dentate gyrus in the kainate-treated rats. This is the first evidence of upregulation of the A1A receptor in a model of chronic temporal lobe epilepsy. Increased binding of the A1A receptor may contribute to epileptogenesis in the epileptic focus.

Inhibitory effect of activated protein C on cerebral vasospasm after subarachnoid hemorrhage in the rabbit.

This study investigated whether activated protein C (APC) improves the cerebral vasospasm in an experimental subarachnoid hemorrhage that was produced by the intracisternal injection of autologous blood. Male rabbits were divided into the following four groups: APC 0.1-and 0.5-mg groups, in which 0.1 and 0.5 mg APC were injected into the cisterna magna, respectively; a placebo group, in which saline was injected instead of APC; and a sham operation group that did not get injections of autologous blood, APC, and saline. On day 2, amount of clot in the basal cistern was significantly (p < 0.01) decreased in the APC 0.5-mg group. Percent diameter of the basilar artery on day 2 to that before injecting the blood was angiographically determined as 97.1 +/- 3.8% in the APC 0.5-mg group, which was significantly (p < 0.001) greater than the corresponding value in the placebo group (74.8 +/- 3.4%). The impaired endothelium-dependent relaxation following subarachnoid hemorrhage was normalized in the APC 0.5-mg group (p < 0.0001). These results suggest that APC would improve cerebral vasospasm following subarachnoid hemorrhage, possibly by decreasing the amount of subarachnoid clot and normalizing the impaired nitric oxide production/release.

Calcific deposits on degraded shunt catheters: long-term follow-up of V-P shunts and late complications in three cases.

OBJECT: Three cases with late complications and nine cases without late complications are presented to demonstrate the long-term results of ventriculoperitoneal (V-P) shunting, particularly those concerning degradation and mineral deposits of shunt catheters. METHODS: Plain X-rays were taken in every case to detect any calcification. The catheters removed following late complications were examined in a scanning electron microscope (SEM). Spectroscopy and conventional histology were also performed. CONCLUSION: Routine histology, spectroscopy, and SEM revealed that the mineral deposits consisted of hydroxyapatite. Plain X-ray and operative findings showed that the most extensive calcification was present in the neck, where the catheters were subject to heavy mechanical stress. No calcification was detected on catheters that did not contain barium particles. Our findings indicate that mechanical stress contributes to the process of degradation, and that barium sulfate admixed with silicone during the manufacturing process might accelerate late complications owing to the formation of cracks in the catheters and by enhancing the nucleation rate.

Neural damage due to temporal lobe epilepsy: dual-nuclei (proton and phosphorus) magnetic resonance spectroscopy study.

The aim of this study was to evaluate the usefulness of proton and phosphorus (1H and 31P) magnetic resonance spectroscopy (MRS) for temporal lobe epilepsy (TLE) patients, and to evaluate neural damage and metabolite dysfunction in the TLE patient brain. We performed 1H and 31P MRS of medial temporal lobes (MTL) in the same TLE patients (n = 14) with a relatively wide range of severity from almost seizure-free to intractable, and calculated the ratio of N-acetylasparate to choline-containing compounds and creatine + phosphocreatine (NAA/Cho + Cr) in 1H MRS and inorganic phosphate to all main peaks (%Pi) in 31P MRS. There was no significant correlation between NAA/(Cho + Cr) and %Pi in each side (ipsilateral, r = -0.20; contralateral, r =-0.19). The values of NAA/(Cho + Cr) showed a significant difference between ipsilateral and contralateral MTLs to the focus of TLE patients (P < 0.01, paired t-test). Although %Pi also had a tendency to show the laterality of TLE, there was no significance. Ipsilateral (r = -0.90, P < 0.0001) and contralateral (r = -0.70, P < 0.005) NAA/(Cho + Cr) decreases and contralateral %Pi increase (r = 0.81, P < 0.001) had significant correlation with seizure frequency. 1H MRS provides more important information concerning neuronal dysfunction in MTL of TLE patients than 31P MRS.

Intraoperative intrinsic optical imaging of neuronal activity from subdivisions of the human primary somatosensory cortex.

We performed intrinsic optical imaging of neuronal activity induced by peripheral stimulation from the human primary somatosensory cortex during brain tumor surgery for 11 patients. After craniotomy and dura reflection, the cortical surface was illuminated with a xenon light through an operating microscope. The reflected light passed through a bandpass filter, and we acquired functional images using an intrinsic optical imaging system. Electrical stimulation of the median nerve, or the first and fifth digits, induced biphasic intrinsic optical signals which consisted of a decrease in light reflectance followed by an increase. The decrease in light reflectance was imaged, and we identified a neural response area within the crown of the postcentral gyrus. In experiments on first and fifth digit stimulation, we identified optical responses in separated areas within the crown of the postcentral gyrus, i.e. near the central sulcus and near the postcentral sulcus. In the former response area, separate representations of the two fingers were observed, whereas in the latter response area, the two fingers were represented in the same region. A similar somatotopic representation was observed with electrical stimulation of the first and third branches of the trigeminal nerve. These results seem to support the hypothesis of hierarchical organization in the human primary somatosensory cortex.