bluuebunny/crossref_metadata_2025 huggingface dataset:
Linearization Correction of 99mTc-Labeled Hexamethyl-Propylene Amine Oxime (HM-PAO) Image in Terms of Regional CBF Distribution: Comparison to C15O2 Inhalation Steady-State Method Measured by Positron Emission Tomography
Authors: Inugami Atsushi , Kanno Iwao , Uemura Kazuo , Shishido Fumio , Murakami Matsutaro , Tomura Noriaki , Fujita Hideaki , Higano Shuichi
Published: April 2011

The radioisotope distribution following intravenous injection of 99mTc-labeled hexamethylpropyleneamine oxime (HM-PAO) in the brain was measured by single photon emission computed tomography (SPECT) and corrected for the nonlinearity caused by differences in net extraction. The “linearization” correction was based on a three compartment model, and it required a region of reference to normalize the SPECT image in terms of regional cerebral blood flow distribution. Two different regions of reference, the cerebellum and the whole brain, were tested. The uncorrected and corrected HM-PAO images were compared with cerebral blood flow (CBF) image measured by the C15O2 inhalation steady state method and positron emission tomography (PET). The relationship between uncorrected HM-PAO and PET–CBF showed a correlation coefficient of 0.85 but tended to saturate at high CBF values, whereas it was improved to 0.93 after the “linearization” correction. The whole-brain normalization worked just as well as normalization using the cerebellum. This study constitutes a validation of the “linearization” correction and it suggests that after linearization the HM-PAO image may be scaled to absolute CBF by employing a global hemispheric CBF value as measured by the nontomographic 133Xe clearance method.
[99mTc]-HM-PAO SPECT in Parkinson's Disease
Authors: Pizzolato G. , Dam M. , Borsato N. , Saitta B. , Da Col C. , Perlotto N. , Zanco P. , Ferlin G. , Battistin L.
Published: April 2011

Thirty-six patients affected by Parkinson's disease were studied using single photon emission computed tomography (SPECT) and [99mTc]–HM-PAO as a tracer. The scanning procedure was performed 16–24 h after discontinuation of specific therapy. Tracer activity ratios were determined in 10 pairs of cerebellar, cortical, and subcortical regions. Data were compared with those of 10 age-matched controls. Most of the regions examined did not show any relevant change between parkinsonian and control subjects. Notably, mean activity in striatal regions were similar in the two groups. Increased activity in caudate–putamen was found in patients who were on chronic DOPA therapy. Side-to-side asymmetries in the basal ganglia increased with the severity of the disease. Significant reductions of tracer uptake, from control values, were observed bilaterally in the parietal cortex. These deficits were more pronounced in patients with mental deterioration and in subjects who had been chronically treated with anticholinergic drugs. Parietal perfusion deficits in parkinsonian patients resemble those described in Alzheimer's dementia. These findings suggest that the heterogeneous alterations of regional cerebral blood flow (rCBF) in parkinsonian patients reflect the multifactorial pathophysiology of the disease.
The Use of Technetium-99m-HM-PAO in the Assessment of Patients with Dementia and other Neuropsychiatric Conditions
Authors: Smith Francis W. , Besson John A. O. , Gemmell Howard G. , Sharp Peter F.
Published: April 2011

One hundred fourteen patients suffering from neuropsychiatric conditions have been studied using 99mTc-labeled hexamethylpropyleneamine oxime (HM-PAO) and single photon emission computed tomography (SPECT). Ninety-one patients had a firm clinical diagnosis while 23 were examined without knowledge of the clinical diagnosis. Of the 91 patients, 51 were suffering from dementia, 25 multi-infarct type and 26 Alzheimer's disease. In 19 of the Alzheimer's patients, a characteristic pattern of decreased perfusion in the parieto-occipital regions was demonstrated while those with multi-infarct type showed varying degrees of irregular uptake in the cerebral cortex. These appearances are similar to those shown with positron emission tomography (PET) and we believe that HM-PAO will provide a widely available method for identifying patients with Alzheimer's disease. Twenty-nine patients were suffering from diseases involving the basal ganglia. Fifteen patients with Parkinson's disease showed no significant abnormality in basal ganglia uptake, while 7 or 8 patients with Huntington's disease who had full examinations showed decreased uptake in the caudate nuclei. Similarly, four of six patients with other basal ganglia diseases showed impaired uptake by basal ganglia, and it is concluded that HM-PAO may be useful for the diagnosis and management of this type of patient. Twenty-three patients received HM-PAO imaging as part of their diagnostic work-up; in 19 of them, detailed follow-up was obtained, which indicated that in 7 cases the result of the HM-PAO scan altered the clinical diagnosis and in 9 cases resulted in a change in management. In the remaining 13 cases, the study was found to be helpful in confirming the diagnosis.
Regional Specific Binding of [11C]RO 15 1788 to Central Type Benzodiazepine Receptors in Human Brain: Quantitative Evaluation by PET
Authors: Pappata S. , Samson Y. , Chavoix C. , Prenant C. , Mazière M. , Baron J. C.
Published: April 2011

The central type benzodiazepine receptors were studied in 17 healthy human subjects with 11C–RO 15 1788 and positron emission tomography (PET). The brain regional distribution of the tracer in eight control studies performed after injection of trace doses of 11C-RO 15 1788 was consistent with that of benzodiazepine receptors. Saturation studies with co-injected cold RO 15 1788 in the remaining subjects showed a dose-dependent decrease of brain radiotracer until full inhibition of specific binding was achieved with doses above 0.1 mg/kg (four studies). Based on the results, a simple method to estimate the specifically bound 11C-RO 15 1788 regionally in a single PET study is proposed, using the data from the full-saturation studies as a stable estimate of the nondisplaceable radioligand concentration. Using this method, it was found that quasiequilibrium between the estimated specifically bound and nondisplaceable components was achieved at times equal to or longer than 20 min after tracer administration. The validity of this method was partly supported by further results, showing a good agreement between the regional specific binding so calculated and postmortem data of receptor density.
Hemolysate Inhibits Cerebral Artery Relaxation
Authors: Toda Noboru
Published: April 2011

In helical strips of dog middle cerebral arteries partially contracted with prostaglandin (PG) F2α, relaxations induced by angiotensin-II, possibly mediated by PGI2, and those induced by PGH2 were reversed to a contraction or markedly reduced by treatment with hemolysate, which, however, attenuated the PGI2-induced relaxation only slightly. The relaxant response of human middle cerebral arterial strips to PGH2 was also suppressed by hemolysate. Dog and monkey middle cerebral arteries responded to transmural electrical stimulation and nicotine with transient relaxations, which were quite susceptible to tetrodotoxin and hexamethonium, respectively; the relaxations were abolished almost completely by hemolysate and methylene blue. On the other hand, the relaxant response of dog cerebral arteries to a low concentration of K+ was not influenced by hemolysate or by methylene blue, but was reversed to a contraction by treatment with ouabain. Relaxations induced by substance-P and nitroglycerin were markedly inhibited by hemolysate; removal of endothelium abolished the relaxation by substance-P, but did not influence the nitroglycerin-induced relaxation. Hemolysate may interfere with the biosynthesis of PGI2 in the vascular wall, thereby reversing the relaxation induced by angiotensin-II and PGH2 to a contraction. Relaxations induced by electrical and chemical stimulation of vasodilator nerves innervating cerebral arteries appear to be elicited by a mechanism dependent on cellular cyclic guanosine monophosphate (GMP), like that underlying the substance-P-induced and nitroglycerin-induced relaxation. These actions of hemolysate may be involved in the genesis of cerebral vasospasm after subarachnoid hemorrhage.
Temporal Evolution of Regional Energy Metabolism following Focal Cerebral Ischemia in the Rat
Authors: Nowicki J.-P. , Assumel-Lurdin C. , Duverger D. , MacKenzie E. T.
Published: April 2011

Focal cerebral ischemia in the rat was induced by occlusion of the left middle cerebral artery. The temporal evolution of regional energy metabolism was studied over the 14 days consequent to the induction of ischemia in the frontal, cingulate, parietal, and occipital cortices as well as in the striatum. Regional concentrations of adenosine triphosphate (ATP), phosphocreatine, and lactate and, in addition, glucose and the cerebral/plasma glucose ratio (C/P) were measured in the hemispheres both ipsilateral and contralateral to the occlusion. Two hours after middle cerebral artery occlusion, the biochemical changes were severe in the striatum and moderate in cortical regions. Later on (at 24 and 48 h), an overall aggravated metabolic status was noted while lactate declined and glucose markedly increased. These latter biochemical changes likely indicate a marked inhibition of the rate of glucose utilization. At 48 h, the energy reserves (ATP, phosphocreatine) of parietal cortex no longer equaled those of other cortical regions, but abruptly fell to the levels found in the striatum without any increase in lactate level. Finally, at 7 and 14 days, the levels of the various metabolites in most cortical regions returned toward control values, although signs of a depressed glucose metabolism remained. However, in both striatum and parietal cortex, ATP and phosphocreatine concentrations, although higher than those observed at 48 h, remained significantly decreased. Our present biochemical study permits the classification of these selected brain regions into three categories. First there are those that are outside the area of infarction: the frontal, cingulate, and occipital cortices. These regions show little temporal evolution of brain energy metabolism but, notwithstanding, they are regions in which glucose use would appear to be greatly depressed. Second is a region considered to be the focus of infarction: the striatum. The caudate-putamen is a region with early and profound metabolic disturbances with no final restitution. Last is the region of metabolic penumbra—the parietal cortex, in which there is a time-related exacerbation of the consequences of middle cerebral occlusion in the rat.
Focal Brain Ischemia in the Rat: Methods for Reproducible Neocortical Infarction Using Tandem Occlusion of the Distal Middle Cerebral and Ipsilateral Common Carotid Arteries
Authors: Brint Steve , Jacewicz Michael , Kiessling Marika , Tanabe Jody , Pulsinelli William
Published: April 2011

This article describes a 3-year experience with focal neocortical ischemia in three rat strains. Multiple groups of adult Wistar (n = 50), Fisher 344 (n = 31), and spontaneously hypertensive (n = 72) rats were subjected to permanent occlusion of the distal middle cerebral (MCA) and ipsilateral common carotid arteries (CCA). Twenty-four hours later the animals were killed, and frozen brain sections were stained with hematoxylin and eosin to demarcate infarcted tissue. The infarct volume for each section was quantified with an image analyzer, and the total infarct volume was calculated with an iterative program that summed all interval volumes. Neocortical infarct volume was the largest and most reproducible in the spontaneously hypertensive rats (SHR). Statistical power analysis to project the numbers of animals necessary to detect a 25 or 50% change in infarct volume with α = 0.05 and β = 0.2 revealed that only the SHR model was practical in terms of requisite animals: i.e., <10 animals per group. Tandem occlusion of the distal MCA and ipsilateral CCA in the SHR strain provides a surgically simple method for causing large neocortical infarcts with reproducible topography and volume. The interanimal variability in infarct volume that occurs even in the SHR strain dictates that randomized, concomitant controls are necessary in each study to ensure the accurate assessment of experimental manipulations or pharmacologic therapies.
Muscarinic Cholinergic Receptors on the Endothelium of Human Cerebral Arteries
Authors: Tsukahara Tetsuya , Kassell Neal F. , Hongo Kazuhiro , Vollmer Dennis G. , Ogawa Hisayuki
Published: April 2011

To characterize the muscarinic cholinergic receptors on the endothelium of human cerebral arteries, isometric tension measurement and receptor autoradiographic studies were performed. Acetylcholine (ACh) induced dose-dependent relaxation of human cerebral arteries precontracted by 10−5 M serotonin, with an EC50 of 1.9 ± 0.6 × 10−6 M (n = 7). The relaxation was abolished by 10−5 M hemoglobin. Autoradiography, using the muscarinic antagonist [3H]propylbenzilylcholine mustard, demonstrated the high density of muscarinic cholinergic receptors on the endothelial cells of human cerebral arteries, especially on the luminal surface of the endothelium. These findings suggest that ACh-induced relaxation mediated by muscarinic cholinergic receptors on the endothelium has a physiological function in human cerebral arteries.
The Selective Potentiation of Noradrenaline-Induced Tone by Bay K 8644 in the Rabbit Basilar Artery
Authors: Laher I. , Germann P. , Dowd A. L. , Bevan J. A.
Published: April 2011

A number of studies indicate that relative to the maximal tone possible, for example, to histamine, noradrenaline produces only weak contractile responses in the rabbit basilar artery. Various factors, including a limited number of α-adrenoceptors, have been proposed to account for the reduced response to noradrenaline. We examined the effect of the Ca2+ -channel activator, Bay K 8644 (0.1 and 1.0 n M) on dose-response curves to noradrenaline, histamine, calcium (Ca2+) and potassium (K+) in ring preparations of rabbit basilar artery and central ear artery. These concentrations of Bay K 8644 (0.1 and 1.0 n M) increased the magnitude of tension developed by noradrenaline (contractility) in the basilar artery, but did not alter its sensitivity (ED50) to the adrenergic vasoconstrictor. Bay K 8644 (0.1 and 1.0 n M) did not alter the contractility or sensitivity to histamine or K+ of the rabbit basilar artery. When dose–response curves to Ca2+ were made in K+-depolarized rabbit basilar artery rings, Bay K 8644 (0.1 and 1.0 n M) dose-dependently augmented tone generated by readmission of Ca2+. Bay K 8644 (0.1 and 1.0 n M) did not alter responses to noradrenaline, histamine, or K+ in rabbit central ear artery preparations. These results are compatible with a voltage-dependent mechanism of action of Bay K 8644 in the rabbit basilar artery, which may be partially depolarized in the resting state. We propose that in addition to other factors, the contractile response of rabbit basilar arteries is limited by a weak or inefficient coupling of α-adrenoceptors to Ca2+ channels. The effect of Bay K 8644 on cerebral vascular tone generated by noradrenaline is to improve coupling thus allowing a greater influx of extracellular Ca2+.
A Determination of the Regional Brain/Blood Partition Coefficient of Water Using Dynamic Positron Emission Tomography
Authors: Iida Hidehiro , Kanno Iwao , Miura Shuichi , Murakami Matsutaro , Takahashi Kazuhiro , Uemura Kazuo
Published: April 2011

In order to investigate the validity of the single compartment model in measuring CBF with the use of 15O-labeled water (H215O), dynamic positron emission tomography (PET) was performed following bolus injection of H215O. Careful attention was paid to accuracy in the measurement system (especially for the input function). In the region of the putamen, which includes the smallest mixture of gray and white matters in addition to the smallest contamination of cerebrospinal fluid (CSF) spaces, the partition coefficient obtained was 0.88 ± 0.06 (ml/g). The discrepancy from the prediction estimated from the brain/blood water content ratio was only 7%. This finding suggests that there is no more complicated model than the usual single compartment one to describe the physiological behaviour of 15O water. On the other hand, in the other cortical regions, the discrepancy was larger (e.g., about 12% for the insular cortex and 26% for the frontal cortex) than in the region of the putamen, and a significant fit–interval dependence was observed in the calculated parameters. These observations suggest a significant effect of tissue heterogeneity and/or contamination with nonperfusable spaces in actual clinical PET data.
Use of 19F NMR Spectroscopy for Measurement of Cerebral Blood Flow: A Comparative Study Using Microspheres
Authors: Barranco David , Sutton Leslie N. , Florin Sandra , Greenberg Joel , Sinnwell Teresa , Ligeti Laszlo , McLaughlin Alan C.
Published: April 2011

19F NMR was used to determine washout curves of an inert, diffusible gas (CHF3) from the cat brain. The cerebral blood flow was estimated from a bi- or tri-phasic fit to the deconvoluted wash-out curve, using the Kety-Schmidt approach. Cerebral blood flow values determined by 19F NMR show the expected responsiveness to alterations in Paco2, but are approximately 28% lower than cerebral blood flow values determined simultaneously by radioactive microsphere techniques. High concentrations of CHF3 have little effect on intracranial pressure, mean arterial blood pressure or Paco2, but cause small changes in the blood flow to certain regions of the brain. We conclude that 19F NMR techniques utilizing low concentrations of CHF3 have potential for the noninvasive measurement of cerebral blood flow.
Long-Term Sampling of Cerebral Venous Blood in Conscious Rats
Authors: Frerichs Kai U. , Lindsberg Perttu J. , Hallenbeck John M. , Feuerstein Giora Z.
Published: April 2011

The mechanisms of secondary brain damage following cerebral ischemia or CNS trauma are still unknown. A variety of mediators, released by the injured brain, are held to be responsible for delayed neuronal cell damage. No technique is available yet for repeated sampling of cerebral venous blood (CVB) on a long-term basis, which allows to assess the neurobiochemical responses to brain injury chronically in conscious laboratory animals. This is a report on the establishment of a method to sample CVB from the superior sagittal sinus (SSS) for at least 7 days in conscious freely moving rats. The torcular was exposed for implantation of a catheter into the caudal SSS. Patency was preserved by perfusion with a nonsystemic dose of heparin by an Alzet osmotic pump and verified daily by aspirating of 0.5 ml CVB for blood analysis. No neuropathology was seen in histological examination. The rats appeared comfortable and without distress, and the transient weight loss was rapidly regained. The present model provides the opportunity to evaluate acute or chronic neurobiochemical responses to stroke, CNS trauma, or any other type of brain injury in the conscious rat.
The Metabolic Effects of Mild Hypothermia on Global Cerebral Ischemia and Recirculation in the Cat: Comparison to Normothermia and Hyperthermia
Authors: Chopp Michael , Knight Robert , Tidwell Carl D. , Helpern J. A. , Brown Eileen , Welch K. M. A.
Published: April 2011

The metabolic effects of graded whole body hypothermia on complete global cerebral ischemia and recirculation was investigated in the cat. Hypothermia was induced to one of three levels prior to ischemia; T = 26.8° ± 0.5° (n = 4), T = 32.1° ± 0.2°C (n = 5), and T = 34.6° ± 0.3°C (n = 6), and maintained constant throughout 16 min of ischemia and 1.5–2 h of recirculation. Intracellular cerebral pH and relative concentrations of high-energy phosphate metabolites were continuously monitored, using in vivo 31P nuclear magnetic resonance (NMR) spectroscopy. Except for the first 4 min of ischemia, no significant differences were detected in the response of adenylate intensities and intracellular pH to ischemia and recirculation between the hypothermic groups. The three hypothermic groups were then pooled into one group, and the data compared to previously published data from a normothermic group, T = 38.4° ± 0.6°C (n = 14), and a hyperthermic group, T = 40.6° ± 0.2°C (n = 9), subjected to the identical ischemic and NMR measurement protocols. The hypothermic animals exhibited a statistically significant reduction of cerebral intracellular acidosis, both during ischemia and recirculation, as well as a more rapid return of adenylate intensities during recirculation, compared to the normothermic or hyperthermic groups. The data thus suggest that mild hypothermia has an ameliorative affect on brain energy metabolism and intracellular pH under conditions of complete global cerebral ischemia and recirculation.
Cerebral Energy Metabolism in Cyanide Encephalopathy
Authors: MacMillan V. H.
Published: April 2011

This study documents the effects of an intracarotid artery injection of a lethal threshold amount of KCN (2.5 mg · kg−1) on the energy metabolism and histology of the rat brain. This dose of KCN resulted in a rapid abolition of electroencephalographic activity, which remained essentially absent for up to 3 h. Cerebral metabolite measurements 0.25 h after KCN infusion indicated a 52% reduction in cytochrome oxidase activity, a 600% increase in lactate, a 32% reduction in ATP, a 73% increase in ADP, and an 85% decrease in glycogen. Measurements of the above energy metabolites over the ensuing 7 days showed a return to control of all metabolites by 6–24 h. Corresponding to the normalization of energy metabolism was a return of EEG and conscious activity. Histological examination of cyanide-exposed animals revealed a paucity of change with only one animal at 0.5 h showing several dark neurons, two animals at 1 h with minor pallor of corpus callosum and caudate-putamen, and one animal at 48 h with a small hippocampal infarction. It is concluded that it may be impossible to produce a serious enough disruption of cerebral metabolism with KCN injection, to produce neuronal damage by purely “histotoxic” mechanisms.
Fructose-1,6-Bisphosphate Protects Astrocytes from Hypoxic Damage
Authors: Gregory George A. , Yu Albert C. H. , Chan Pak H.
Published: April 2011

To determine the effects of glucose and fructose-1,6-bisphosphate (FDP) on hypoxic cell damage, primary cultures of astrocytes were incubated for 18 h in an air-tight chamber that had been flushed with 95% N2/5% CO2 for 15 min before it was sealed. Cultures containing 7.5 m M glucose without FDP or FDP without glucose showed evidence of significant cell injury after 18 h of hypoxia (increased lactate dehydrogenase content in the culture medium; cell edema and disruption by phase-contrast microscopy). Cultures exposed to glucose + FDP had normal lactate dehydrogenase concentrations and appeared normal microscopically. Maximal protection of hypoxic cells occurred at 6.0 m M FDP. Lactate concentrations of the culture medium of hypoxic cells increased 2.5 times above normoxic control values when glucose was present, but neither FDP alone nor glucose + FDP caused the lactate concentrations to increase further. This implies that anaerobic glycolysis was not increased by adding FDP to the medium. Cell volumes (water space) measured with [14C]-3-0-methyl-D-glucose were normal with glucose + FDP in the culture medium of hypoxic cells but were significantly larger than normal when glucose alone was present. Increases in cell volume paralleled changes in lactate dehydrogenase in the culture medium. Uptake of [14C]FDP occurred rapidly in normoxic cells and was maximal after 5 min of incubation. The data indicate that the presence of glucose + FDP in the culture medium protects primary cultures of hypoxic astrocytes from cell damage.
Effects of Electrical Stimulation of the Dorsal Raphe Nucleus on Local Cerebral Blood Flow in the Rat
Authors: Bonvento G. , Lacombe P. , Seylaz J.
Published: April 2011

We have studied the effects of electrical stimulation of the dorsal raphe nucleus on local cerebral blood flow (LCBF), as assessed by the quantitative [14C]-iodoantipyrine autoradiographic technique. Stimulation of the dorsal raphe nucleus in the α-chloralose anesthetized rat caused a significant decrease in LCBF, ranging from – 13 to – 26% in 24 brain structures out of 33 investigated. The most pronounced decreases (– 23 to – 26%) were observed in the accumbens, amygdaloid, interpeduncular nuclei and in the median raphe nucleus, limbic system relays. The decreases also concerned cortical regions and the extrapyramidal system. These results indicate that activation of ascending serotonergic system produces a vasoconstriction and that the dorsal raphe nucleus has a widespread modulatory influence on the cerebral circulation.
Deoxyglucose Kinetics in a Rat Brain Tumor
Authors: Graham Michael M. , Spence Alexander M. , Muzi Mark , Abbott Gregory L.
Published: April 2011

Accurate quantitation of local glucose metabolic rates (LMRglc) of abnormal tissues such as brain tumors with the 2-deoxyglucose (DG) method requires knowledge of the tissue rate constants and lumped constant. The deoxyglucose rate constants were measured in an experimental intracerebral glioma in 24 awake rats with a dual tracer [(3H)-DG and (14C)-DG] method. Tissue time points were obtained at 2, 5, 10, 18, 30, 60, 90, and 180 min after injection by decapitation and liquid scintillation counting. Blood samples were obtained at 1 min intervals initially and at longer intervals later. The rate constants were estimated with parameter estimation. LMRglc was calculated from the rate constants, assuming a lumped constant of 0.5. K1 for normal cerebrum was found to be 0.258 ml/g/min, and k2– k4 were 0.406, 0.075, and 0.0103 min−1; LMRglc = 65.1 μ;mol/100 g/min. The corresponding values for the glioma were 0.108, 0.126, 0.040, and 0.0019 with LMRglc = 41.7. The considerably lower k4 in the glioma was reflected in persistent higher activity in the glioma at longer times. Thus, tissue activity alone cannot be used to assess relative glucose metabolic rates in abnormal tissues such as gliomas, particularly at late times after injection.
The Metabolic Centroid Method for PET Brain Image Analysis
Authors: Levy A. V. , Brodie J. D. , Russell JJ. A. G. , Volkow N. D. , Laska E. , Wolf A. P.
Published: April 2011

The method of centroids is an approach to the analysis of three-dimensional whole-brain positron emission tomography (PET) metabolic images. It utilizes the brain's geometric centroid and metabolic centroid so as to objectively characterize the central tendency of the distribution of metabolic activity in the brain. The method characterizes the three-dimensional PET metabolic image in terms of four parameters: the coordinates of the metabolic centroid and the mean metabolic rate of the whole brain. These parameters are not sensitive to spatially uniform random noise or to the position of the subject's head within a uniform PET camera field of view. The method has been applied to 40 normal subjects, 22 schizophrenics who were treated with neuroleptics, and 20 schizophrenics who were neuroleptic-free. The mean metabolic centroid of the normal subjects was found to be superior to the mean geometric centroid of the brain. The mean metabolic centroid of chronic schizophrenics is lower and more posterior to the mean geometric centroid than is that of normals. This difference is greater in medicated than in unmedicated schizophrenics. The posterior and downward displacement of the mean metabolic centroid is consistent with the concepts of hypofrontality, hyperactivity of subcortical structures, and neuroleptic effect in schizophrenics.
Multicompartmental Analysis of [11C]-Carfentanil Binding to Opiate Receptors in Humans Measured by Positron Emission Tomography
Authors: Frost J. J. , Douglass K. H. , Mayberg H. S. , Dannals R. F. , Links J. M. , Wilson A. A. , Ravert H. T. , Crozier William C. , Wagner H. N.
Published: April 2011

[11C]-Carfentanil is a high affinity opiate agonist that can be used to localize mu opiate receptors in humans by positron emission tomography (PET). A four-compartment model was used to obtain quantitative estimates of rate constants for receptor association and dissociation. PET studies were performed in five normal subjects in the absence and presence of 1 mg/kg naloxone. Arterial plasma concentration of [11C]-carfentanil and its labeled metabolites were determined during each PET study. The value of k3/ k4 = Bmax/ kd was determined for each subject in the presence and absence of naloxone. There was a significant reduction in the value of k3/ k4 from 3.4 ± 0.92 to 0.26 ± 0.13 in the thalamus ( p < 0.01) and from 1.8 ± 0.33 to 0.16 ± 0.065 in the frontal cortex ( p < 0.001). Mean values of frontal cortex/occipital cortex and thalamus/occipital cortex ratios were determined for the interval 35–70 min after injection when receptor binding is high relative to nonspecific binding. The relationship between the measured region/occipital cortex values and the corresponding values of k3/ k4 in the presence and absence of naloxone was: regions/occipital cortex = 0.95 + 0.74 ( k3/ k4) with r = 0.98 ( n = 20). Simulation studies also demonstrated a linear relationship between the thalamus/occipital cortex or frontal cortex/occipital cortex ratio and k3/ k4 for less than twofold increases or decreases in k3/ k4. Simulation studies in which thalamic blood flow was varied demonstrated no significant effect on the region/occipital cortex ratio at 35–70 min for a twofold increase or fourfold decrease in blood flow. Therefore, the region/occipital cortex ratio can be used to quantitate changes in k3/ k4 when tracer kinetic modeling is not feasible.
Ischemic Damage in Hippocampal CA1 is Dependent on Glutamate Release and Intact Innervation from CA3
Authors: Benveniste H. , Jørgensen M. B. , Sandberg M. , Christensen T. , Hagberg H. , Diemer N. H.
Published: April 2011

The removal of glutamatergic afferents to CA1 by destruction of the CA3 region is known to protect CA1 pyramidal cells against 10 min of transient global ischemia. To investigate further the pathogenetic significance of glutamate, we measured the release of glutamate in intact and CA3-lesioned CA1 hippocampal tissue. In intact CA1 hippocampal tissue, glutamate increased sixfold during ischemia; in the CA3-lesioned CA1 region, however, glutamate only increased 1.4-fold during ischemia. To assess the neurotoxic potential of the ischemia-induced release of glutamate, we injected the same concentration of glutamate into the CA1 region as is released during ischemia in normal, CA3-lesioned, and ischemic CA1 tissue. We found that this particular concentration of glutamate was sufficient to destroy CA1 pyramids in the vicinity of the injection site in intact and CA3-lesioned CA1 tissue when administered during control (non-ischemic) conditions. In contrast, the same amount injected during ischemia in the CA3-lesioned CA1 region destroyed pyramidal cells in a widely distributed zone around the injection site in the CA1 region. It is concluded that the ischemia-induced damage of pyramidal cells in CA1 is dependent on glutamate release and intact innervation from CA3.
Brain Capillary 46,000 Dalton Protein is Cytoplasmic Actin and is Localized to Endothelial Plasma Membrane
Authors: Pardridge William M. , Nowlin Dawn M. , Choi Thomas B. , Yang Jing , Calaycay Jimmy , Shively John E.
Published: April 2011

The most abundant protein of the brain capillary, which makes up the blood-brain barrier (BBB) in vivo, is a protein that migrates at a molecular weight of approximately 46 kDa on sodium dodecylsulfate–polyacrylamide gel electrophoresis (SDS–PAGE). The bovine brain capillary 46kDa protein was purified by SDS–PAGE and Sephadex G–25 gel filtration. The purified protein migrated as a single band of molecular weight of approximately 42,000 Da on subsequent SDS–PAGE followed by silver staining. The protein was digested by trypsin and tryptic peptides were analyzed by reverse phase high-performance liquid chromatography (HPLC). Two of these peptides, 11 and 18 amino acids in length, were sequenced and found to be identical to amino acid sequences corresponding to portions of cytoplasmic actin. The SDS–PAGE gel-purified 46kDa protein was also subjected to limited proteolysis using S. aureus V8 protease, and this resulted in the formation of a prominent 31kDa doublet as well as smaller proteolytic fragments, and these fragments were of identical molecular weight to those generated from limited proteolysis of bovine actin. Electron microscopic immunoperoxidase studies with primary cultures of bovine brain capillary endothelium showed that immunoreactive actin is intimately associated with the plasma membranes. In conclusion, the brain capillary 46kDa protein is cytoplasmic actin and is localized to the endothelial plasma membrane. Modulations of brain capillary endothelial actin may play a role in the regulation of BBB permeability.
Kinetic Analysis of Central [11C]Raclopride Binding to D2-Dopamine Receptors Studied by PET—A Comparison to the Equilibrium Analysis
Authors: Farde L. , Eriksson L. , Blomquist G. , Halldin C.
Published: April 2011

[11C]Raclopride binding to central D2-dopamine receptors in humans has previously been examined by positron emission tomography (PET). Based on the rapid occurrence of binding equilibrium, a saturation analysis has been developed for the determination of receptor density ( Bmax) and affinity ( Kd). For analysis of PET measurements obtained with other ligands, a kinetic three-compartment model has been used. In the present study, the brain uptake of [11C]raclopride was analyzed further by applying both a kinetic and an equilibrium analysis to data obtained from four PET experiments in each of three healthy subjects. First regional CBV was determined. In the second and third experiment, [11C]-raclopride with high and low specific activity was used. In a fourth experiment, the [11C]raclopride enantiomer [11C]FLB472 was used to examine the concentration of free radioligand and nonspecific binding in brain. Radio-activity in arterial blood was measured using an automated blood sampling system. Bmax and Kd values for [11C]raclopride binding could be determined also with the kinetic analysis. As expected theoretically, those values were similar to those obtained with the equilibrium analysis. In addition, the kinetic analysis allowed separate determination of the association and dissociation rate constants, kon and koff, respectively. Examination of [11C]raclopride and [11C]FLB472 uptake in brain regions devoid of specific D2-dopamine receptor binding indicated a fourth compartment in which uptake was reversible, nonstereoselective, and nonsaturable in the dose range studied.
A New Method to Measure Brain Serotonin Synthesis in vivo. I. Theory and Basic Data for a Biological Model
Authors: Diksic M. , Nagahiro S. , Sourkes T. L. , Yamamoto Y. L.
Published: April 2011

We describe here an autoradiographic method to measure the in vivo rate of serotonin synthesis in rat brain. The method is based on the use of the l-tryptophan analogue a-methyl-l-tryptophan ( a-MTrp), which is converted in vivo into a-methylserotonin ( a-M5HT). Since a-M5HT is not a substrate for monoamine oxidase, it is accumulated in the brain tissue. Data are presented to confirm time-dependent conversion of a-MTrp into a-M5HT in the dorsal raphe nucleus and also in the pineal body, an organ outside the blood–brain barrier. It has also been shown that washing brain slices in 10% trichloroacetic acid results in <3% incorporation of a-MTrp into brain proteins. The rates of synthesis are calculated in several grossly dissected brain structures by using tracer kinetics and a three-compartment biological model. The half-life of the precursor pool is estimated to be ∼20 min. The rate of serotonin synthesis is highest in the pineal body.
Delayed Increases in Regional Brain Quinolinic Acid Follow Transient Ischemia in the Gerbil
Authors: Heyes Melvyn P. , Nowak Thaddeus S.
Published: April 2011

Excessive activity or release of excitatory amino acids has been implicated in the neuronal injury that follows transient cerebral ischemia. To investigate the metabolism of the endogenous excitotoxin, quinolinic acid, and its potential for mediating cell loss following ischemia, the concentrations of quinolinic acid, L-tryptophan, 5-hydroxytryptamine, and 5-hydroxyindoleacetic acid were quantified in gerbil brain regions at different times after 5 or 15 min of ischemia induced by bilateral carotid artery occlusion. Significant elevation of brain tryptophan levels, accompanied by increased 5-hydroxyindoleacetic acid concentrations, occurred during the first several hours of recirculation, but regional brain quinolinic acid concentrations were found either to decrease or remain unchanged during the first 24 h after the ischemic insult. However, significant increases in quinolinic acid concentrations occurred in striatum and hippocampus at 2 days of recirculation after 5 min of ischemia. After a further 4 and 7 days, strikingly large increases in quinolinic acid concentrations were observed in all regions examined, with the highest levels observed in the hippocampus and striatum, regions that also show the most severe ischemic injury. These delayed increases in brain quinolinic acid concentrations are suggested to reflect the presence of activated macrophages, reactive astrocytes, and/or microglia in vulnerable regions during and subsequent to ischemic injury. While the results do not support a role for increased quinolinic acid concentrations in early excitotoxic neuronal damage, the role of the delayed increases in brain quinolinic acid in the progression of postischemic injury and its relevance to postischemic brain function remain to be established.
The Quantitative Analysis of D2-Dopamine Receptors in Baboon Striatum in vivo with 3-N-[2'-18F]Fluoroethylspiperone Using Positron Emission Tomography
Authors: Jovkar S. , Wienhard K. , Pawlik G. , Coenen H. H.
Published: April 2011

We used the ligand 3- N-[2'-18F]fluoroethylspiperone (FESP), which binds to D2-dopamine receptors in the striatum, and positron emission tomography (PET) to quantify striatal D2-dopamine densities ( Bmax) and binding kinetics in baboon brain in vivo. Sequential PET scans were obtained for 4 h post injection. Various similar models based on a nonlinear kinetic four-compartment model that takes into account the effect of ligand specific activity were used. We investigated the effect of exact model configuration on the reliability of Bmax and other kinetic transfer coefficients. We found that with the ligand FESP and dynamic PET studies, the estimated values of Bmax and other model parameters are sensitive to the choice of model configuration, ligand specific activity, and data analysis technique. The limitations of the reliability of parameter estimates in a complex kinetic model for receptor ligands were studied in simulation calculations. Results showed that the accuracy of estimated values of Bmax is affected by both the ligand binding properties and the injected dose of ligand. The estimated average value of kinetic model parameters was as follows: ligand-receptor dissociation constant k4 = 0.0080 min−1; the product of ligand-receptor association constant and fraction of ligand available to bind to specific receptors f2 ka = 0.0052 (min n M)−1; and D2-dopamine receptor density Bmax = 37.5 pmol g−1.
PAF Antagonist Ginkgolide B Reduces Postischemic Neuronal Damage in Rat Brain Hippocampus
Authors: Oberpichler Heike , Sauer Dirk , Roßberg Christine , Mennel Hans-Dieter , Krieglstein Josef
Published: April 2011

We investigated the effect of the known antagonist of platelet-activating factor (PAF), ginkgolide B, on postischemic neuronal damage in the rat. Neuronal necroses were evaluated in the hippocampus 7 days after a 10-min forebrain ischemia. Preischemic application of ginkgolide B (50 mg/kg p.o.) significantly reduced neuronal damage. It is suggested that the antagonism of PAF is responsible for this beneficial effect of ginkgolide B.
Influence of MK-801 on Brain Extracellular Calcium and Potassium Activities in Severe Hypoglycemia
Authors: Zhang Entan , Hansen Anker Jon , Wieloch Tadeusz , Lauritzen Martin
Published: April 2011

The purpose of the present study was to examine the effect of blockade of N-methyl-d-aspartate (NMDA) receptors on the depolarization associated with severe hypoglycemia, which is commonly preceded by one or a few transient depolarizations reminiscent of cortical spreading depression (CSD). In the cerebral cortices of rats [K+]e and [Ca2 +]e were measured with ionselective microelectrodes. NMDA blockade was achieved by injection of MK801 in doses that block CSD. In control rats, the latency from the time point when blood glucose reached minimal levels to onset of ionic shifts was 33.2 ± 3.5 min, and [K+]e rose from 3.2 ± 0.2 to 55 ± 5 m M. All variables remained unchanged in rats treated with MK801. In another four rats treated with MK801, [Ca2+]e declined from 1.06 ± 0.22 to 0.12 ± 0.02 m M. Plasma glucose measurements indicated that the cortex depolarized at a plasma glucose concentration between 0.7 and 0.8 m M, i.e., within a narrow range, suggesting a threshold phenomenon. In conclusion, activation of NMDA receptors seems of minor importance for hypoglycemic depolarization. The ionic transients that precede the persistent hypoglycemic depolarization are probably mediated by mechanisms distinct from those of electrically induced CSD.
In vitro Pharmacological Profile of 3-N-(2-Fluoroethyl)Spiperone
Authors: Goffinet André M. , Leysen Josée , Labar Daniel
Published: April 2011

The binding affinities of spiperone and 3-N-(2-fluoroethyl)spiperone (FESP) have been compared for several rodent brain receptor sites and for inhibition of monoamine release and uptake sites. FESP and spiperone have almost identical profiles, namely a high affinity for dopamine-D2 and serotonin-S2 receptors, a low affinity for α1-adrenergic receptors, and negligible binding to other sites. These results suggest that available data on spiperone binding may be applied to the interpretation of PET data obtained with FESP.
A New Method to Measure Brain Serotonin Synthesis in vivo. II. A Practical Autoradiographic Method Tested in Normal and Lithium-Treated Rats
Authors: Nagahiro S. , Takada A. , Diksic M. , Sourkes T. L. , Missala K. , Yamamoto Y. L.
Published: April 2011

We describe here a practical autoradiographic method to estimate the rate of serotonin synthesis in brain. A two-time point method (60 and 150 min after injection of a-[14C]methyl-l-tryptophan) was first evaluated in 14 normal rats (7 at each time point). After this the method was tested in lithium-treated rats. In normal rats the rate of serotonin synthesis measured by the two-time point method generally correlated with known concentrations of tryptophan hydroxylase. The rate of synthesis in lithium-treated rats was compared with that in shamtreated rats (NaCl treatment). The results showed a significant increase in the synthesis rate in some cerebral structures. The greatest increases in the serotonin synthesis rate, attributable to the lithium treatment, were observed in the parietal cortex (52%) and caudate nucleus (47%). This is the first investigation to demonstrate, with autoradiographic resolution (∼100 μm), the differential changes in the rate of serotonin synthesis in the brain. Lithium had no significant effect on the rate of synthesis in the pineal gland.
Deoxyglucose Lumped Constant Estimated in a Transplanted Rat Astrocytic Glioma by the Hexose Utilization Index
Authors: Spence Alexander M. , Graham Michael M. , Muzi Mark , Abbott Gregory L. , Krohn Kenneth A. , Kapoor Rajesh , Woods Steven D.
Published: April 2011

The lumped constant (LC) for calculating the regional glucose (glc) metabolic rate by the deoxyglucose (DG) method was estimated in a transplanted rat glioma and normal rat brain. First, the hexose utilization index (HUI) was measured at 1.5, 3.0, and 4.5 min in right hemisphere glioma implants and uninvolved contralateral hemisphere following bolus intravenous injections of [3H]DG and [14C]glucose. At these times, the glioma HUI values were 0.639, 0.732, and 0.712, respectively, and the coordinate left hemisphere values were 0.432, 0.449, and 0.418. Second, the volumes of distribution of DG and glucose were determined to be 0.436 and 0.235 in glioma implants and 0.402 and 0.237 in left hemisphere, respectively. Third, following simultaneous intracarotid injections of [3H]DG and [14C]glucose, the ratio K*1/ K1 was 1.1 in glioma grafts and 1.3 in left hemisphere. With these values for HUI, volume of distribution, and K1 ratio, the LC in this rat glioma was estimated to be 2.1 times higher than the left hemisphere LC ( p < 0.02). These results suggest that measurement of brain tumor CMRglc using a normal brain LC may significantly overestimate the true tumor CMRglc.
Changes in Sensory-Cognitive Input: Effects on Cerebral Blood Flow
Authors: Cameron Oliver G. , Modell Jack G. , Hichwa Richard D. , Agranoff Bernard W. , Koeppe Robert A.
Published: April 2011

Eight healthy right-handed young men were subjected to local CBF measurement by [15O]water and positron emission tomography during partial sensory deprivation and during sensory-cognitive activation; physiological, hormonal, and subjective stress measurements were also performed. Results indicated that (a) “whole-brain” CBF increased during activation; (b) the greatest increase in CBF was in the primary visual cortex; (c) differences between hemispheres were not observed, but CBF was greater anteriorly than posteriorly in the deprivation condition only; (d) within-subject variability of CBF was not influenced by the sensory-cognitive condition; and (e) the procedure was not stressful.
Protection by NMDA Antagonists against Selective Cell Loss following Transient Ischaemia
Authors: Swan Jeanette H. , Meldrum Brian S.
Published: April 2011

We have administered antagonists acting competitively or noncompetitively at the N-methyl-D-aspartate receptor after a short period of incomplete ischaemia and evaluated selective neuronal loss in the CA1 region of the rat hippocampus. The competitive antagonists D-(–)-2-amino-7-phosphonoheptanoate (2APH); 100 or 330 mg/kg; 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonate (CPP); 3.3 or 10 mg/kg; and CGS 19755 ( cis-4-phosphonomethyl-2-piperidine carboxylate) 3.3 or 10 mg/kg; and the noncompetitive antagonists MK801 {(+)5-methyl-10, 11-dihydro-5H-dibenzo[ a,d]cyclohepten-5,10-imine maleate}, 0.3, 1, or 3 mg/kg, and dextrorphan, 2, 6, 18, or 54 mg/kg, were administered intraperitoneally 15 min and 5 h after a 10-min incomplete ischaemia period; additionally MK801 (1 or 3 mg/kg) and CGS 19755 (10 or 30 mg/kg) were administered 5 and 10 h postischaemia. Seven days after ischaemia, the brains were fixed by perfusion. CA1 pyramidal cell counts were performed on Nissl-stained sections using an ocular grid piece. Ventilated (no ischaemia) control animals had a mean of 406 ± 13 CA1 neurones/3 grid lengths. Ischaemia reduced this mean to 157 ± 23. A significant protective effect against this cell loss was seen after two injections (at 15 min and 5 h postischaemia) of 2APH, CPP (10 mg/kg), CGS 19755 (10 mg/kg), MK801 (1 mg/kg), and dextrorphan (54 mg/kg). Delayed injection (5 and 10 h postischaemia) of CGS 19755 (10 and 30 mg/kg) and MK801 (1 and 3 mg/kg) did not provide any protection against pyramidal cell loss.