bluuebunny/crossref_metadata_2025 huggingface dataset:
Abnormal Temporal Lobe Response in Alzheimer's Disease during Cognitive Processing as Measured by 11C-2-Deoxy-D-Glucose and PET
Authors: Miller J. D. , de Leon M. J. , Ferris S. H. , Kluger A. , George A. E. , Reisberg B. , Sachs H. J. , Wolf A. P.
Published: April 2011

Elderly controls and probable Alzheimer's disease patients underwent serial positron emission tomography (PET) studies during a baseline condition and while performing a verbal memory task. for the temporal lobes, all 7 Alzheimer patients demonstrated a relative shift in glucose metabolic rates to the right hemisphere during the memory condition relative to baseline, and 5 of 7 controls showed a shift to the left hemisphere. Baseline absolute regional metabolic rates replicate previous findings and were somewhat less useful than the memory challenge in differentiating patients from controls. These results indicate that a temporal lobe abnormality in Alzheimer's disease is related to memory performance.
Three-Dimensional Mapping of Local Cerebral Perfusion in Alcoholic Encephalopathy with and without Wernicke-Korsakoff Syndrome
Authors: Hata Takashi , Meyer John Stirling , Tanahashi Norio , Ishikawa Yoshiki , Imai Akira , Shinohara Tamotsu , Velez Maria , Fann William E. , Kandula Prasab , Sakai Fumihiko
Published: April 2011

Seventeen severe chronic alcoholic patients with and without Wernicke-Korsakoff syndrome (WKS) were examined prospectively after being treated by withdrawal from alcohol. The WKS patients also received thiamine supplements. Three-dimensional measurements of local cerebral blood flow (LCBF) and local partition coefficients (LΛ) were made utilizing xenon contrast computed tomography (Xe CT-CBF). Results were displayed as color-coded brain maps before and after treatment and these were correlated with neurological and cognitive examinations. Before treatment chronic alcoholics without WKS (n = 10) showed diffuse reductions of LCBF values throughout all gray matter including hypothalamus, vicinity of nucleus basalis of Meynert, thalamus, and basal ganglia. Similar, but more severe, reductions were seen in patients with WKS (n = 7), however, white matter perfusion was also reduced. In WKS, most prominent reductions of LCBF were also seen in hypothalamus and basal forebrain nuclei but thalamus, basal ganglia, and limbic systems were severely reduced. After treatment, both groups with alcoholic encephalopathy showed marked clinical improvement and cerebral perfusion was restored toward normal. Chronic alcohol abuse, in the absence of thiamine deficiency, reduces CBF by direct neurotoxic effects. If thiamine deficiency is also present, more severe and localized hemodynamic reductions are superimposed.
NADH Fluorescence in vivo: Changes in Cerebral Oxidative Metabolism and Perfusion Induced by Pentobarbital, Indomethacin, and Salicylate
Authors: Nowicki J.-P. , Jourdain D. , MacKenzie E. T.
Published: April 2011

The effects of two prostaglandin synthesis inhibitors on brain oxidative metabolism and cerebral blood volume were studied by the nicotinamide adenine dinucleotide (reduced) (NADH) fluorescence technique in rats, Indomethacin (5, 10, and 15 mg/kg) and sodium salicylate (50, 100, and 300 mg/kg) were administered intravenously to groups of rats anesthetized with either nitrous oxide or pentobarbital (40 mg/kg, i.p.). The effects of pentobarbital alone were also examined: pentobarbital induced a progressive reduction in blood volume 4 min following intraperitoneal administration. A reduced NADH fluorescence (oxidation) was noted approximately 9 min after pentobarbital treatment. In N2O-anesthetized rats, the effects of salicylate were dose-dependent. Low doses (50 and 100 mg/kg) decreased both blood volume and NADH fluorescence; in contrast, salicylate at 300 mg/kg increased blood volume and NADH fluorescence. Following pentobarbital, the effects of salicylate (50 and 100 mg/kg) were reversed: increases in both blood volume and NADH fluorescence were seen. In the absence of pentobarbital, it would appear that salicylate induces a cerebral vasoconstriction, an effect that may be obscured by a central stimulation provoked by this drug. Under N2O anesthesia, indomethacin, in a dose-related manner, induced a decrease in blood volume that was accompanied by a dose-related increase in NADH fluorescence (reduction). The changes induced by the highest dose of indomethacin (15 mg/kg) were essentially abolished by pentobarbital. These results support those studies in which indomethacin-induced cerebral vasoconstriction could be abolished by barbiturates. Furthermore, our experiments demonstrate, following indomethacin infusion, a decrease in brain oxidative metabolism. With indomethacin, the NADH fluorescence technique would suggest that the metabolic effects of this drug are essentially to reduce oxygen consumption without any noticeable effect on glucose utilization; the observed changes in cerebral perfusion are likely to be directly correlated with the decreases in cerebral oxygen consumption.
Correction for Intravascular Activity in the Oxygen-15 Steady-State Technique is Independent of the Regional Hematocrit
Authors: Lammertsma Adriaan A. , Baron Jean-Claude , Jones Terry
Published: April 2011

The oxygen-15 steady-state technique to measure the regional cerebral metabolic rate for oxygen requires a correction for the nonextracted intravascular molecular oxygen-15. To perform this correction, an additional procedure is carried out using RBCs labeled with 11CO or C15O. The previously reported correction method, however, required knowledge of the regional cerebral to large vessel hematocrit ratio. A closer examination of the underlying model eliminated this ratio. Both molecular oxygen and carbon monoxide are carried by RBCs and are therefore similarly affected by a change in hematocrit.
Hydrogen Ions Kill Brain at Concentrations Reached in Ischemia
Authors: Kraig Richard P. , Petito Carol K. , Plum Fred , Pulsinelli William A.
Published: April 2011

Elevation of brain glucose before the onset of nearly complete ischemia leads to increased lactic acid within brain. When excessive, such acidosis may be a necessary factor for converting selective neuronal loss to brain infarction from nearly complete ischemia. To examine the potential neurotoxicity of excessive lactic acid concentrations, we microinjected (0.5 μl/min) 150 m M sodium lactate solutions (adjusted to 6.50–4.00 pH) for 20 min into parietal cortex of anesthetized rats. Interstitial pH (pH0) was monitored with hydrogen ion–selective microelectrodes. Animals were allowed to recover for 24 h before injection zones were examined with the light microscope. Injectants produced brain necrosis in a histological pattern resembling ischemic infarction only when pH0 was ≤ 5.30. Nonlethal injections showed only needle tract injuries. Abrupt deterioration of brain acid-base homeostatic mechanisms correlated with necrosis since pH0 returned to baseline more slowly after lethal tissue injections than after nonlethal ones. The slowed return of pH0 to baseline after the severely acidic injections may reflect altered function of plasma membrane antiport systems for pH regulation and loss of brain hydrogen ion buffers.
Tracer-Kinetic Models for Measuring Cerebral Blood Flow Using Externally Detected Radiotracers
Authors: Larson Kenneth B. , Markham Joanne , Raichle Marcus E.
Published: April 2011

All tracer-kinetic models currently employed with positron-emission tomography (PET) are based on compartmental assumptions. Our first indication that a compartmental model might suffer from severe limitations in certain circumstances when used with PET occurred when we implemented the Kety tissue-autoradiography technique for measuring CBF and observed that the resulting CBF estimates, rather than remaining constant (to within predictable statistical uncertainty) as expected, fell with increasing scan duration T when T > 1 min. After ruling out other explanations, we concluded that a one-compartment model does not possess sufficient realism for adequately describing the movement of labeled water in brain. This article recounts our search for more realistic substitute models. We give our derivations and results for the residue-detection impulse responses for unit capillary-tissue systems of our two candidate distributed-parameter models. In a sequence of trials beginning with the simplest, we tested four progressively more detailed candidate models against data from appropriate residue-detection experiments. In these, we generated high-temporal-resolution counting-rate data reflecting the history of radiolabeled-water uptake and washout in the brains of rhesus monkeys. We describe our treatment of the data to yield model-independent empirical values of CBF and of other parameters. By substituting these into our trial-model functions, we were able to make direct comparisons of the model predictions with the experimental dynamic counting-rate histories, confirming that our reservations concerning the one-compartment model were well founded and obliging us to reject two others. We conclude that a two-barrier distributed-parameter has the potential of serving as a substitute for the Kety model in PET measurements of CBF in patients, especially when scan durations for T > 1 min are desired.
Effects of Cerebroprotective Agents on Cerebral Blood Flow and on Postischemic Energy Metabolism in the Rat Brain
Authors: Bielenberg Gerhard Wilhelm , Beck Thomas , Sauer Dirk , Burniol Marta , Krieglstein Josef
Published: April 2011

Male Wistar rats were subjected to forebrain ischemia of 10 min duration by clamping both common carotid arteries and simultaneously lowering systemic blood pressure to 40 mm Hg by exsanguination. Recovery was achieved by removing the arterial clamps and reinfusing the blood. Cortical levels of high-energy phosphates and glycolytic substrates were determined enzymatically. Naftidrofuryl (10 or 20 mg/kg i.p.) or ketamine (5 mg/kg i.v.) were applied 30 min prior to the induction of ischemia. S(-)-Emopamil (4 mg/kg) or nimodipine (50 μg/kg) were administered by intravenous infusion over 30 min. Nimodipine and emopamil increased the blood glucose level and lowered preischemic blood pressure. Under control conditions, a tendency toward a higher cortical glucose level was observed in treated brains. Brain energy stores were exhausted after ischemia in control and treated animals to the same degree. Lactate levels, however, were higher in emopamil-treated animals. This effect was attributed to the elevated pre-ischemic glucose levels. During the early recovery period, the restoration of high-energy phosphates was accelerated by both calcium entry blockers. Nimodipine and emopamil increased the levels of glucose and glucoses-phosphate in the early postischemic period. Naftidrofuryl (10 mg/kg) increased the level of creatine-phosphate and ATP after 2 min of recovery. Naftidrofuryl (20 mg/kg) exerted no effect on cerebral energy metabolism, but considerably reduced postischemic blood pressure (possibly thereby masking its ameliorative action). Ketamine accelerated the postischemic restoration of high-energy phosphates. In the conscious rat, local cerebral blood flow (LCBF) was determined with the 14C-iodoantipyrine technique following emopamil (20 mg/kg s.c.) or naftidrofuryl (10 mg/kg i.v.) application. Both compounds increased LCBF values in the majority of grey matter structures. It was concluded that the cerebroprotective agents investigated share an accelerating effect on the postischemic restoration of high-energy phosphates in cerebral cortex.
Brain Blood Volume, Flow, and Oxygen Utilization Measured with 15O Radiotracers and Positron Emission Tomography: Revised Metabolic Computations
Authors: Videen Tom O. , Perlmutter Joel S. , Herscovitch Peter , Raichle Marcus E.
Published: April 2011

We have revised our methods for calculating regional blood volume, flow, oxygen extraction, and oxygen utilization from positron emission tomography data obtained using 15O-labeled radiotracers. These revisions include radioactive decay explicitly within the model equations instead of requiring all measured activity to be corrected for decay prior to incorporation in the equations. The revised equations yield small but significant differences in the computed values.
Immunohistochemical Demonstration of Vasopressin Nerve Fibers in the Cerebral Artery
Authors: Itakura Toru , Okuno Takashi , Veno Masami , Nakakita Kazuo , Nakai Kunio , Naka Yutaka , Imai Harumichi , Kamei Ichiro , Komai Norihiko
Published: April 2011

Vasopressin-immunoreactive nerve fibers were demonstrated in the cerebral pial arteries by peroxidase immunohistochemistry. In the large pial artery (proximal part of the middle cerebral artery), they ran longitudinally to the long axis of the vessel. They ran in a spiral pattern in the distal part of the middle cerebral artery. Even in small arteries, vasopressin nerve fibers were found arranged in a longitudinal fashion. The present morphological data suggest that vasopressin nerve fibers in the cerebral artery may play a role in cerebral circulation.
Effect of Piracetam on Cerebral Glucose Metabolism in Alzheimer's Disease as Measured by Positron Emission Tomography
Authors: Heiss W.-D. , Hebold I. , Klinkhammer P. , Ziffling P. , Szelies B. , Pawlik G. , Herholz K.
Published: April 2011

The effect of piracetam (a putative enhancer of cerebral metabolism) on regional CMRGlu was studied by positron emission tomography of 2[18F]-fluoro-2-deoxy-D-glucose in nine patients with Alzheimer's disease, and in seven cases with multiinfarct dementia or unclassified dementia. In Alzheimer's disease, i.v. administration of piracetam, 6 g b.i.d. for 2 weeks, significantly improved rCMRGlu in most cortical areas, whereas no effect on CMRGlu of the drug was observed in the multiinfarct dementia/unclassified dementia groups. These results lend further support to the notion that adjuvant piracetam treatment is of benefit in Alzheimer's disease. They may also indicate that the typical metabolic depression in Alzheimer's disease is caused by complex interaction of disturbed transmitter and cellular function rather than by a specific deficit in the cholinergic system alone.
Enhanced Detection of Focal Brain Responses Using Intersubject Averaging and Change-Distribution Analysis of Subtracted PET Images
Authors: Fox Peter T. , Mintun Mark A. , Reiman Eric M. , Raichle Marcus E.
Published: April 2011

Intersubject averaging and change-distribution analysis of subtracted positron emission tomographic (PET) images were developed and tested. The purpose of these techniques is to increase the sensitivity and objectivity of functional mapping of the human brain with PET. To permit image averaging, all primary tomographic images were converted to anatomically standardized three-dimensional images using stereotactic anatomical localization and interslice interpolation. Image noise, measured in control-minus-control subtractions, was strongly suppressed by averaging. Signal-to-noise ratio, measured in stimulus-minus-control subtractions (hand vibration minus eyes-closed rest), rose steadily with averaging, confirming the accuracy of our method of anatomical standardization. Distribution analysis of CBF change images (outlier detection by gamma-2 statistic) was assessed as an omnibus test for state-dependent changes in regional neuronal activity. Sensitivity in detecting the somatosensory response rose steadily with averaging, increasing from 50% in individual images to 100% when three or more images were averaged. Specificity was 100% at all averaging levels. Although described here as a technique for functional brain mapping with H215O CBF images, image averaging, and change-distribution analysis are more generally applicable techniques, not limited to a single purpose or tracer.
The 15O Steady-State Method: Correction for Variation in Arterial Concentration
Authors: Senda Michio , Buxton Richard B. , Alpert Nathaniel M. , Correia John A. , Mackay Bruce C. , Weise Steven B. , Ackerman Robert H.
Published: April 2011

One of the factors limiting the accuracy of the 15O steady-state method for the measurement of regional cerebral blood flow and oxygen metabolism is the requirement that a constant arterial blood concentration be maintained over long periods. A new method has been developed to correct for the variation of the arterial concentration in the C15O2 and 15O2 steady-state inhalation technique. The time course of the arterial activity is obtained by multiple sampling over the study period. The same 15O model as is used in the steady-state method is employed but is solved without assuming equilibrium. Look-up tables are generated to relate flow and oxygen extraction fraction to tissue activity, and from them the regional parameters are estimated. Theory and simulation studies suggest that substantial improvement in accuracy can be obtained with no increase in statistical error. The validity of the method was checked experimentally by making repeated measurements in the same subject after perturbing the gas delivery. The conventional steady-state method showed significantly larger deviations in repeat measurement than did the new method. Thus, it is concluded that the proposed method is superior.
Autoradiographic Determination of Cerebral Glucose Content, Blood Flow, and Glucose Utilization in Focal Ischemia of the Rat Brain: Influence of the Plasma Glucose Concentration
Authors: Nedergaard Maiken , Jakobsen Johannes , Diemer Nils Henrik
Published: April 2011

Focal cerebral ischemia was produced by occlusion of the middle cerebral artery in rats. Cerebral blood flow measured with [14C]iodoantipyrine was severely reduced in the lateral portion of neostriatum. This area of dense ischemia was sharply demarcated against the surroundings. The adjacent cortex was perfused at one-third of normal, whereas blood flow in the medial neostriatum was only slightly reduced. This pattern of perfusion was independent of the plasma glucose concentration of the animal. In contrast, the glucose utilization calculated from the 2-[3H]deoxyglucose accumulation depended on the plasma glucose concentration. Enhanced glucose utilization was evident in the border areas surrounding the ischemic focus in normoglycemic animals. Neither acutely nor chronically diabetic animals had such an increase of metabolism in the borderzone. Moderately hyperglycemic rats had a narrow rim of enhanced glucose utilization immediately surrounding the ischemic core, whereas animals with plasma glucose values above 22 mmol/L had no such rim. In mild hypoglycemia (2–4 mmol/L), the glucose utilization was slightly enhanced in the border areas, but during severe hypoglycemia (<2.5 mmol/L), the glucose utilization declined gradually toward the ischemic core. Glucose content, and thereby the lumped constant (measured by 3-0-[14C]methylglucose) showed little regional variation, except in the ischemic core. These findings indicate that blood flow alterations after occlusion of the middle cerebral artery in rats are not influenced by the plasma glucose utilizations. In contrast, glucose utilization depends on a combination of plasma glucose concentration and blood flow instead of blood flow per se.
Time Course of Release in vivo of PGE2, PGF2α, 6-Keto-PGF1α, and TxB2 into the Brain Extracellular Space after 15 Min of Complete Global Ischemia in the Presence and Absence of Cyclooxygenase Inhibition
Authors: Stevens Mark K. , Yaksh Tony L.
Published: April 2011

The time-dependent release of prostaglandin E2 (PGE2), prostaglandin F2α (PGF2α), thromboxane (Tx) B2, and 6-keto-PGF1α (6-keto) from brain was measured before, during, and after a 15-min interval of total ischemia (four-vessel occlusion) in halothane-anesthetized cats using the technique of cerebroventricular perfusion. Resting levels of PGE2, PGF2α, 6-keto, and Tx were: 253 ± 75, 953 ± 300, 650 ± 200, and 550 ± 170 pg/ml, respectively. During the 15-min ischemia, all prostanoids rose significantly, yet the highest levels were not observed until the first 15–60 min of the reflow at which time levels of PGE2, PGF2α, 6-keto, and Tx, as compared with the preischemic baseline, rose ∼8, 3.4, 3, and 55-fold, respectively. Significantly, although all prostanoids showed increases relative to baseline, the ratios of PGF2α/6-keto and PGE2/6-keto remained stable throughout the experiment in both groups of animals. In contrast, the Tx/6-keto ratio rose from ∼1 to ∼ 30 during the 60 min after reflow in untreated cats. Treatment with zomepirac sodium (5 mg/kg, i.v.), a cyclooxygenase inhibitor, resulted in highly significant reductions in the levels of all prostanoids during the preischemic period. In zomepirac sodium-treated animals, there were also highly significant reductions in the prostanoid response to ischemia. Of particular interest was that the degree of inhibition of Tx as compared with 6-keto, during the post-ischemic period of peak secretion was such that the Tx/6-keto ratio fell from 30 in the control ischemic animal to 0.3 in the zomepirac sodium-treated animal, suggesting a selective blockade of the formation of Tx as compared with prostacyclin.
Reoxygenation and Calcium-Induced Cerebroarterial Contractions as Affected by Vasodilator Agents
Authors: Bian Ka , Toda Noboru
Published: April 2011

In helical strips of dog cerebral arteries exposed to Ca2+-free medium under hypoxic conditions (95% N2 and 5% CO2), prostaglandin (PG) F2α produced a slight tonic contraction. The addition of Ca2+ evoked a phasic contraction followed by relaxation and a sustained contraction, and reoxygenation elicited an additional tonic contraction of moderate magnitude. When the PGF2α-induced contraction was stabilized in Ca2+-free medium, reoxygenation contracted the arteries only slightly. Treatment with the stable PGI2 analogues PGI2 methylester and TRK-100 attenuated the contractions caused by PGF2α and Ca2+ and abolished almost completely the reoxygenation-induced contraction. Treatment with nitroglycerin inhibited the contractions caused by PGF2α and Ca2+, but did not significantly alter the contraction induced by reoxygenation. The Ca2+ entry blockers diltiazem, flunarizine, and felodipine did not alter the PGF2α-induced contractions, but attenuated the contractions caused by Ca2+ and reoxygenation. The vasodilator agents used appear to interfere differently with the release of Ca2+ from intracellularly stored sites and the transmembrane Ca2+ influx through receptor-operated channels under hypoxia and normoxia. The cerebroarterial contraction caused by reoxygenation may be associated mainly with increased Ca2+ influx from receptor activation and tissue oxygenation, which is markedly suppressed by PGI2 analogues and moderately attenuated by Ca2+ entry blockers but not significantly influenced by nitroglycerin.
Brain Interstitial Adenosine and Sagittal Sinus Blood Flow during Systemic Hypotension in Piglet
Authors: Park T. S. , Van Wylen David G. L. , Rubio Rafael , Berne Robert M.
Published: April 2011

We sampled, using the brain dialysis technique, interstitial fluid adenosine from the frontal cortex of newborn piglets subjected to hemorrhagic hypotension while measuring sagittal sinus blood flow, cerebrovascular resistance (CVR), and cerebral O2 delivery. In group 1 (n = 8), MABP was reduced in successive steps from 76 to 30 mm Hg with decrements of ∼ 10 mm Hg. At 60 mm Hg, CVR decreased by 19% (p < 0.001), but sagittal sinus blood flow and interstitial fluid adenosine remained unchanged. At 50 mm Hg, both sagittal sinus blood flow and CVR decreased by 19% (p < 0.001) and interstitial fluid adenosine rose 4.7-fold (p < 0.05). At 40 and 30 mm Hg, sagittal sinus blood flow decreased further but CVR remained steady, whereas interstitial fluid adenosine rose 10- and 16-fold, respectively. In group 2 (n = 7), an abrupt reduction of MABP from 80 to 47 mm Hg produced no change in sagittal sinus blood flow and a 29% decrease in CVR (p < 0.01). Interstitial fluid adenosine increased twofold (p < 0.01). In group 3 (n = 7), an abrupt reduction of MABP from 79 to 40 mm Hg decreased sagittal sinus blood flow and CVR by 24 and 30%, respectively (p < 0.01). Interstitial fluid adenosine rose threefold (p < 0.01). In groups 1, 2, and 3, the increases in interstitial fluid adenosine accompanied decreases in cerebral O2 delivery. In group 4 (n = 7), artificial CSF with a Po2 of 152 mm Hg was perfused through the brain dialysis cannula during graded hypotension. In this group, interstitial fluid adenosine rose only at an MABP of 20 mm Hg. These data support the concept that adenosine participates in the regulation of CBF during hypotension in piglets.
In vivo Identification and Quantitative Evaluation of Carrier-Mediated Transport of Lactate at the Cellular Level in the Striatum of Conscious, Freely Moving Rats
Authors: Kuhr Werner G. , van den Berg Cees J. , Korf Jakob
Published: April 2011

Intracerebral dialysis has allowed the continuous, on-line measurement of lactate in the extracellular fluid (ECF) of conscious, freely moving rats. The rapid time response of the technique allows the direct determination of the time course of changes in lactate in ECF following externally imposed stimuli. The time course of lactate appearance in ECF was found to be considerably slower than that observed in tissue following electroconvulsive shock or during ischemia following cardiac arrest. The ECF data could be fit to an integrated Michaelis-Menten model that assumed reversible transport of lactate across the cell membrane. This transport was found to act only when energy supplies could maintain membrane integrity and function, since ECF levels of lactate failed to follow tissue levels after cardiac arrest when energy resources are depleted. The calculated rate of cellular lactate transport was two orders of magnitude faster than transport of lactate across the blood-brain barrier in the adult rat, and passive diffusion of lactate was not found to contribute significantly across either cell or blood-brain barriers. Probenecid, an inhibitor of acid transport, was able to block both the efflux of lactate from cell to ECF and the consequent reuptake of lactate by cells in the striatum of the rat following electroconvulsive shock or ischemia.
Inhibition of Glycolysis Alters Potassium Ion Transport and Mitochondrial Redox Activity in Rat Brain
Authors: Raffin Cesar N. , Sick Thomas J. , Rosenthal Myron
Published: April 2011

To examine the relationships between brain glycolysis, ion transport, and mitochondrial reduction/oxidation (redox) activity, extracellular potassium ion activity (K+0) and redox shifts of cytochrome oxidase (cytochrome a,a3) were recorded previous to and during superfusion of rat cerebral cortex with the glycolytic inhibitor iodoacetic acid (IAA). IAA produced oxidation of cytochrome a,a3, increased local oxygenation, increased K+0, and, in response to neuronal activation, slowed rates of K+0 reaccumulation. Rates of rereduction of cytochrome a,a3, after the oxidation of this cytochrome by stimulation, were also slowed by IAA. These effects of IAA demonstrate the dependence of K+0 reaccumulation on the integrity of glycolysis, support the concept that active processes are involved in brain ion transport, and suggest a link between ATP supplied by glycolysis and ion transport activity. These data are also compatible with the suggestion that residual dysfunctions after brain ischemia result from derangements in glycolytic functioning rather than from limitations in oxygen availability or oxidative metabolic activity.
Extracellular Lactic Acid as an Indicator of Brain Metabolism: Continuous On-Line Measurement in Conscious, Freely Moving Rats with Intrastriatal Dialysis
Authors: Kuhr Werner G. , Korf Jakob
Published: April 2011

Lactic acid was measured continuously in the dialysis perfusate emerging from the striatum of conscious, freely moving rats. The continuous measurement utilized a specific enzymatic/fluorometric detector that provided temporal information about the changes in the concentration of lactate in extracellular fluid (ECF). The level of lactate in extracellular fluid was found to be directly linked to local cellular metabolism. Inhibition of glycolysis with 2-deoxyglucose decreased the ECF level of lactate, whereas increased lactate production was observed after uncoupling mitochondrial electron transport with 2,4-dinitrophenol. A transient increase in the extracellular level of lactate was found after neuronal stimulation (e.g., electroconvulsive shock or local administration of kainic acid). The response to electroconvulsive shock could be attenuated by inhibiting the electrical activity of neurons with tetrodotoxin. Thus, this system is of providing novel information about transient changes in the extracellular concentration of lactic acid in real time, and these changes can be related to changes in metabolism and neuronal activity.
Hyperosmolar Opening of the Blood-Brain Barrier in the Energy-Depleted Rat Brain. Part 1. Permeability Studies
Authors: Greenwood J. , Luthert P. J. , Pratt O. E. , Lantos P. L.
Published: April 2011

A simple saline perfusion system was used to investigate the effects of hyperosmolar solutions of arabinose and mannitol upon the permeability of the blood-brain barrier. The small, polar molecule [14C]mannitol and the larger, visual marker Evans blue were used as indicators of barrier integrity in the perfused energydepleted brain. One-minute perfusion of hyperosmolar solutions consistently opened the barrier suggesting that the mechanism of osmotic barrier opening is independent of energy-producing metabolism. The accumulation of radiolabel in the brain was expressed as the ratio of tissue to perfusate radioactivity ( Rt/ Rp) and, for cerebrum, this increased from a control value of 0.0022 ± 0.0007 (mean ± SEM; n = 4) to a value of 0.0124 ± 0.0008 (n = 4) following 0.9 M arabinose and to 0.0495 ± 0.0072 (n = 4) following 1.8 M arabinose. There was a significant reduction of water content of hyperosmolar perfused brains. These findings support the hypothesis that osmotic barrier opening is the result of the passive shrinkage of endothelial cells and the surrounding tissue.
The Retention of [99mTc]-d,l-HM-PAO in the Human Brain after Intracarotid Bolus Injection: A Kinetic Analysis
Authors: Lassen Niels A. , Andersen Allan R. , Friberg Lars , Paulson Olaf B.
Published: April 2011

[99mTc]– d,l-HM-PAO (HM-PAO) was injected rapidly into the internal carotid artery and its retention in the brain was recorded by external scintillation cameras in eight human subjects. A model is described based on three compartments: the lipophilic tracer in the blood pool of the brain, the lipophilic tracer inside the brain, and the hydrophilic form retained in the brain. The retention curve initially drops abruptly, corresponding to the nonextracted fraction of the injectate leaving the brain; it then falls exponentially towards the asymptotic level of the fractional steady-state retention R. Cerebral blood flow ( F) was measured using the xenon-133 intracarotid injection method. The first-pass extraction E of HM-PAO was calculated from F using an empiric regression equation. The residue curves for the whole brain after intracarotid HM-PAO injection were analyzed to yield a retention fraction ( R') and the brain clearance backflux constant of lipophilic HM-PAO ( k). From the kinetic model and the measured values of R', k, and F, the following parameter values could be calculated: the average retained fraction of all tracer supplied to the brain, R = 0.38 ± 0.05 (mean ± SD), the conversion rate constant (lipophilic to hydrophilic tracer) in the brain k3 = 0.80 ± 0.12 min− 1, the efflux rate constant (brain to blood) k2 = 0.69 ± 0.11 min− 1, the conversion/clearance ratio α = k3/ k2 = 1.18 ± 0.25, the influx (blood clearance) constant K1 = 0.45 ± 0.11 ml/g/min, and the brain/blood partition ratio Λ = K1/ k2 = 0.67 ± 0.23 ml/g. Using the kinetic model and assuming constancy of α, an algorithm was developed that corrects for the blood flow dependent backflux of HM-PAO and results in a more linear relation between regional cerebral blood flow (rCBF) and HM-PAO distribution.
Flow Thresholds for Cerebral Energy Disturbance and Na+ Pump Failure as Studied by in vivo 31P and 23Na Nuclear Magnetic Resonance Spectroscopy
Authors: Naritomi Hiroaki , Sasaki Masahiro , Kanashiro Masaru , Kitani Mitsuhiro , Sawada Tohru
Published: April 2011

The relationships among CBF, cerebral energy metabolism, Na+ pump activity, and electrocorticograms (ECoG) following graded hypotension were studied in 48 gerbils. Energy metabolism and Na+ pump activity were estimated by in vivo 31p and 23Na nuclear magnetic resonance (NMR) spectroscopy, and CBF was determined by [14C]iodoantipyrine methods at the end of the experiments. The CBF measured in normotensive animals was 0.51 ± 0.07 ml/g brain/min. Following graded hypotension, no 31P spectral change was observed until CBF fell to 0.21–0.27 ml/g brain/min, at which level the intracellular pH began to decrease in association with ECoG voltage reduction. At a CBF level of 0.18–0.23 ml/g brain/min, phosphocreatine (PCr) began to decrease in association with inorganic phosphate (Pi) elevation. At this level, ECoG became isoelectric, although no adenosine triphosphate (ATP) change yet resulted. At a flow level of 0.12–0.14 ml/g brain/min, ATP began to decrease gradually. At 0.04–0.05 ml/g brain/min, PCr and ATP virtually disappeared, and the 23Na signal intensity suddenly changed. The present study demonstrated flow thresholds for the development of tissue acidosis, PCr–Pi changes, and ATP reduction. It appears that functional suppression occurs prior to ATP changes, whereas Na+ pump failure results after ATP depletion.
SPECT with [99mTc]-d,l-Hexamethyl-Propylene Amine Oxime (HM-PAO) Compared with Regional Cerebral Blood Flow Measured by PET: Effects of Linearization
Authors: Yonekura Yoshiharu , Nishizawa Sadahiko , Mukai Takao , Fujita Toru , Fukuyama Hidenao , Ishikawa Masatsune , Kikuchi Haruhiko , Konishi Junji , Andersen Allan R. , Lassen Niels A.
Published: April 2011

In order to validate the use of technetium-99m– d,l-hexamethylpropyleneamine oxime (HM-PAO) as a flow tracer, a total of 21 cases were studied with single photon emission computerized tomography (SPECT), and compared to regional cerebral blood flow (rCBF) measured by position emission tomography (PET) using the oxygen-15 CO2 inhalation technique. Although HM-PAO SPECT and rCBF PET images showed a similar distribution pattern the HM-PAO SPECT image showed less contrast between high and low activity flow regions than the rCBF image and a nonlinear relationship between HM-PAO activity and rCBF was shown. Based on the assumption of flow-dependent backdiffusion of HM-PAO from the brain, we applied a “linearization algorithm” to correct the HM-PAO SPECT images. The corrected HM-PAO SPECT images revealed a good linear correlation with rCBF ( r = 0.901, p < 0.001). The results indicated HM-PAO can be used as a flow tracer with SPECT after proper correction.
Tomographic Studies of rCBF with [99mTc]-HM-PAO SPECT in Patients with Brain Tumors: Comparison with C15O2 Continuous Inhalation Technique and PET
Authors: Langen K.-J. , Herzog H. , Kuwert T. , Roosen N. , Rota E. , Kiwit J. C. W. , Bock W. J. , Feinendegen L. E.
Published: April 2011

In 10 patients with malignant gliomas, the intracerebral distribution of [99mTc]–hexamethylpropyleneamine oxime ([99mTc]–HM-PAO) was studied with single photon emission computed tomography (SPECT) in comparison with C15O2 steady-state inhalation technique to measure cerebral blood flow using positron emission tomography (PET). In all instances, the cerebral [99mTc]–HM-PAO distribution was comparable with the regional pattern of cerebral blood flow (rCBF) observed with PET. This was confirmed by a significant correlation of tumor to cortex and tumor to white matter ratios between these two experimental methods. However, the contrast between high and low activity regions in the SPECT scans was significantly less than that in the PET scans. Contrast enhancement of the SPECT scans was accomplished using a correction formula proposed by Lassen.
Adenosine Receptors and the Nucleoside Transporter in Human Brain Vasculature
Authors: Kalaria Rajesh N. , Harik Sami I.
Published: April 2011

Evidence suggests that adenosine modulates neuronal and cerebral vascular functions by interacting with specific receptors on brain cells and blood vessels. Adenosine and other nucleosides are also transported across the blood-brain barrier via a saturable, carrier-mediated mechanism. Using direct ligand binding methods, we studied the two adenosine receptor subtypes, A1 and A2, and the nucleoside transporter moiety in human brain microvessels, pial vessels, choroid plexus, and cerebral cortex membranes. The following specific tritiated ligands were used: cyclohexyladenosine (CHA) for A1 receptors; 5'- N-ethylcarboxamide adenosine (NECA) for A2 receptors; nitrobenzylthioinosine (NBMPR) and dipyridamole (DPY) for nucleoside transporters. We find that cerebral microvessels, pial vessels, and choroid plexus have few, if any, A1 receptors, in contradistinction to cerebral membranes, which have a 10–20-fold higher density of A1 receptor sites. Specific high-affinity NECA binding to A2 receptors in cerebral microvessels, pial vessels, and choroid plexus was saturable and was equivalent to that of cerebral cortical membranes. The Bmax and Kd of the high-affinity NECA binding to vessel preparations were ∼1.3 pmol/mg protein and ∼250 n M, respectively, which is similar to our previous findings in the rat and pig. NBMPR and binding were also saturable and were consistent with a single class of high-affinity binding sites. The density of nucleoside transporters was ∼four-fold higher in cerebral microvessels than in cerebral cortex, pial vessels, and choroid plexus. These results suggest that human cerebral microvessels have A2, but not A1, receptors and are particularly enriched with the adenosine transporter moiety.
Effects of Adenosine and its Analogues on Porcine Basilar Arteries: Are Only A2 Receptors Involved?
Authors: McBean Douglas E. , Harper A. Murray , Rudolphi Karl A.
Published: April 2011

The aim of this study was to test the effect of adenosine and four of its analogues, 5'-( N-ethyl)carboxamidoadenosine (NECA), 2-chloroadenosine (2-CADO), L-phenylisopropyladenosine (L-PIA), and N6-cyclohexyladenosine (CHA), on prostaglandin (PG) F2α-constricted pig basilar arteries, and from their rank order of potency determine the receptor type involved, The order of potency for the relaxation of the PGF2α constriction was NECA > adenosine, 2-CADO > L-PIA > CHA, which is in keeping with the A2 receptor subtype, The study also investigated the effects of a known adenosine antagonist, namely, the xanthine derivative 8-phenyltheophylline, which at concentrations having no intrinsic effect (10−8 and 10−7 M) produced a significant shift to the right only for the NECA dose-response curve.
Influence of Ethanol on the Energy Metabolism of Ischemic and Postischemic Brain
Authors: MacMillan V.
Published: April 2011

This study documents the effects of an intoxicating dose of ethanol on the energy metabolism and electrophysiological function of rat brain exposed for 0.5 h to ischemia produced by electrocautery of the vertebral arteries and reversible occlusion of the carotid arteries. One-hour exposure to 5 g kg−1 ethanol led to no significant alterations of the preischemic cerebral contents of glucose, lactate, or energy phosphates. Animals receiving ethanol or isovolumetric amounts of 0.9% saline showed statistically equivalent decreases in glucose, ATP, and phosphocreatine and increases in lactate, ADP, and AMP during 0.5 h of ischemia. Upon recirculation for 0.5-24 h, animals receiving ethanol again showed no significant differences from saline-treated animals in the rate of return of glucose, lactate, and energy metabolites to control levels. Animals receiving ethanol showed a trend for a faster and more complete normalization of the EEG during recirculation. It is concluded that under controlled experimental conditions, intoxicating doses of ethanol have no detrimental effect on the energy metabolism of ischemic and postischemic brain.
Assessment of [11C]-L-Methionine Transport into the Human Brain
Authors: O'Tuama Lorcan A. , Guilarte Tomas R. , Douglass Kenneth H. , Wagner Henry N. , Wong Dean F. , Dannals Robert F. , Ravert H. T. , Wilson A. A. , LaFrance Norman D. , Bice Alden N. , Links Jonathan M.
Published: April 2011

Neutral amino acid transport into human brain was measured using a dual-probe positron detection system or positron emission tomography (PET). Rate constants (ml/min/cc) for brain accumulation of [11C]L-methionine measured with the dual detector ranged from 0.012 to 0.078 (average 0.031) under baseline conditions and from 0.010 to 0.017 (average 0.014) after administration of nonradioactive L-phenylalanine (100 mg/kg). The net rate of brain accumulation of L-methionine ranged from 0.42 to 2.89 (average 1.28) nmol/min/cc, and decreased by 27.5–91.2% (average 53.9%) after L-phenylalanine. PET-estimated accumulation rates (ml/min/cc) of [11C]L-methionine ranged from 0.004 to 0.028 (average 0.016) baseline and from 0.010 to 0.021 (average 0.017) after L-phenylalanine. Initial volumes of distribution (ml/cc) of [11C]L-methionine (dual detector) were 0.044–0.070 (average 0.058) baseline and 0.032–0.074 (average 0.051) after phenylalanine and (PET) 0.026–0.098 (average 0.051) baseline and 0.021–0.061 (average 0.042) after phenylalanine. PET permits more accurate measurement of tracer accumulation by brain, excluding noncerebral regions included in dual-detector measurements. The dual-detector system permits better temporal resolution, facilitating kinetic analysis, and requires only one-fortieth the dose of tracer needed for PET. Multiple studies in the same patient are thus possible at low cost.
Photothrombotic Occlusion of Rat Middle Cerebral Artery: Histopathological and Hemodynamic Sequelae of Acute Recanalization
Authors: Nakayama Hitoshi , Dietrich W. Dalton , Watson Brant D. , Busto Raul , Ginsberg Myron D.
Published: April 2011

The histopathological and hemodynamic consequences of photochemically induced middle cerebral artery (MCA) thrombosis and recanalization were studied in the rat. Recanalization of the thrombosed MCA segment was achieved by the topical application of nimodipine at 1 h following photochemically induced occlusion. Pathological consequences of permanent and temporary occlusion were compared by morphometric procedures 7 days following thrombus formation. Rats with permanent thrombosis exhibited consistent infarction of both striatum and cortex. MCA recanalization at 1 h was associated with a significant reduction in total infarct volume. In recanalized rats, small cortical infarcts, confined to the peripheral MCA territory, were observed in only three of six rats. In contrast, a mixed pattern of infarction and ischemic cell damage was documented throughout the striatum in all rats. Local CBF (ICBF), measured autoradiographically, was significantly reduced in the MCA territory following 1 h of MCA occlusion, especially within the striatum. At 1 h after recanalization, lCBF recovered within the previously ischemic brain regions to >50% of control. Perfusion deficits were detected by carbon black infusion within focal areas of the striatum following reperfusion. Thus, cortical neurons appear to tolerate 1 h of MCA occlusion in this model. In contrast, reperfusion following 1 h of photochemically induced MCA occlusion gives rise to selective injury to the striatum.
Effect of Centrally Administered Encephalinamides on Regional Cerebral Blood Flow in the Dog
Authors: Kirsch Jeffrey R. , Hanley Daniel F. , Wilson David A. , Traystman Richard J.
Published: April 2011

(D-ala2)-met5-encephalinamide (AM encephalinamide) and (D-ala2)-leu5-encephalinamide (AL encephalinamide) were administered into the cisterna magna in anesthetized dogs to determine whether these opiates effected the neurohypophyseal circulation differently than the circulation of other brain areas. At the beginning of the experimental protocol, animals were given either mock cerebral spinal fluid (CSF) or 5 or 25 mg of AM encephalinamide or 5 mg of AL encephalinamide in equal volumes of mock CSF into the cisterna magna. By 60 min after intracisternal injection, radiolabeled AM encephalinamide distributed throughout the brain with the highest concentration being in the area of the brainstem. Sixty minutes after intracisternal injection, heart rate was decreased 29.0 ± 5.1%, 41.3 ± 4.4%, and 36.0 ± 3.6%, and MABP was decreased 25.2 ± 8.0%, 26.4 ± 2.4%, and 32.3 ± 2.6% in animals treated with AL encephalinamide (5 mg), AM encephalinamide (5 mg), and AM encephalinamide (25 mg), respectively. Neither AL encephalinamide or AM encephalinamide altered CBF or CMRO2 when compared with animals treated with mock CSF, whereas both AL encephalinamide and AM encephalinamide reduced neurohypophyseal blood flow by 30 min (43 ± 11%, AL encephalinamide; 35 ± 7%, AM encephalinamide, 5 mg; 46 ± 8%, AM encephalinamide, 25 mg); the reduction was sustained throughout the 60-min protocol (34 ± 10%, AL encephalinamide; 37 ± 3%, AM encephalinamide, 5 mg; 38 ± 4% AM encephalinamide, 25 mg). Plasma arginine vasopressin was transiently elevated 15 (326 ± 75%, AL encephalinamide; 323 ± 109%, AM encephalinamide, 25 mg) and 30 min (271 ± 68%, AL encephalinamide; 368 ± 136%, AM encephalinamide, 25 mg) in animals treated with AL encephalinamide or AM encephalinamide (25 mg). Intravenous naloxone administered at the end of the 60-min encephalinamide protocol was associated with a rise toward control values in heart rate and MABP in the AL encephalinamide group and in heart rate, MABP, and neurohypophyseal blood flow in both the AM encephalinamide 5 mg and 25 mg groups. These data suggest that encephalinamides may play a role in the regulation of neurohypophyseal blood flow through their actions on opiate receptors.
Dexamethasone and Indomethacin Do Not Affect Brain Edema following Head Injury in Rats
Authors: Shapira Y. , Davidson E. , Weidenfeld Y. , Cotev S. , Shohami E.
Published: April 2011

Head trauma was induced in rats by a weight-drop device, falling over the exposed skull over the left hemisphere. The neurological state of the rats was evaluated by a neurological severity score at 1 h and 18 h post head trauma. At 18 h post head trauma, rats were decapitated and tissue from the vicinity of the injury and from a corresponding area in the contralateral hemisphere was taken for specific gravity (SG) determination using linear gradient columns. Slices were taken from the same sites for incubation in Krebs-Ringer solution, and the concentrations of prostaglandin (PG)E2, 6-keto-PGF1α, and thromboxane B2 accumulated in the medium during 1 h were measured by radioimmunoassay. In one experimental group, rats were pretreated with intraperitoneal dexamethasone sodium phosphate (4 mg/kg) 18 and 2 h before head trauma, and a third dose was given 8 h post head trauma. Another group was treated with intraperitoneal indomethacin (10 mg/kg) 1 h before and 7 h after head trauma. Other groups were treated immediately and 8 h after head trauma with 4, 8, 15, or 30 mg/kg of dexamethasone sodium phosphate. Another group of rats was treated with free dexamethasone (10 mg/kg) right after head trauma and 8 h later. Head trauma induced edema, as expressed by decreased SG, in the left hemisphere of all traumatized rats. Neither treatment protocol affected the neurological severity score of the injured rats or the SG of the contused hemisphere. PG synthesis, on the other hand, was significantly reduced following indomethacin or free dexamethasone, both in sham and traumatized rats, but not in dexamethasone sodium phosphate–treated rats. We conclude that pretreatment with indomethacin, dexamethasone sodium phosphate, or dexamathasone, used in the present protocols, does not affect posttraumatic cerebral edema. Thus, the role of PGs as mediators of edema formation remains unclear.