bluuebunny/crossref_metadata_2025 huggingface dataset:
Measurement of Regional Cerebral pH in Human Subjects Using Continuous Inhalation of 11CO2 and Positron Emission Tomography
Authors: Brooks David J. , Lammertsma Adriaan A. , Beaney Ronald P. , Leenders Klaus L. , Buckingham Peter D. , Marshall John , Jones Terry
Published: April 2011

The cerebral pH of four normal human subjects has been measured using continuous inhalation of 11CO2 and positron emission tomography (PET). 11CO2 was administered to each subject at a constant rate for 15 min, during which time serial arterial plasma 11C levels were determined and serial 11C cerebral uptake PET scans were performed at a fixed axial tomographic level. 11C uptake kinetics were analysed using a three-compartment model. Rate constants have been estimated for the free exchange of 11CO2 between plasma and cerebral compartments for each subject, and their cerebral pH calculated. Whole brain pH values ranged from 6.96 to 7.05, and no significant pH difference between regions containing predominantly grey or white matter was noted. Best fits to 11C uptake data were achieved by effectively neglecting the metabolic fixation of 11C by cerebral tissue. The purpose of this study was to test the feasibility of pH measurement using the 11CO2 continuous inhalation technique. It is concluded from the results and the error analysis that continuous 11CO2 inhalation combined with PET is potentially a simple and useful method for determining regional cerebral pH.
Brain Lipid Peroxidation Induced by Postischemic Reoxygenation in vitro: Effect of Vitamin E
Authors: Yoshida Shinichi , Busto Raul , Santiso Mercedes , Ginsberg Myron D.
Published: April 2011

The aerobic incubation of brain afer a period of ischemia induced lipid peroxidation. The effect was greatest in vitamin E—deficient rats, intermediate in vitamin E—normal rats, and least in animals supplemented with vitamin E. In contrast, nitrogen incubation following ischemia produced a small effect only in the vitamin E—deficient animals. It appears that reoxygenation is required for lipid peroxides to accumulate in the brain. However, a trace of oxygen remaining during extreme ischemic hypoxia may be sufficient to cause slow propagation of free radical reactions when the vitamin E level is low.
Dysautoregulation of the Cerebral Circulation in Primary Systemic Amyloidosis
Authors: Kobayashi Shotai , Katsube Tomoko , Yamaguchi Shuhei , Kitani Mitsuhiro , Okada Kazunori , Tsunematsu Tokugoro
Published: April 2011

A case of primary systemic amyloidosis associated with marked dysautoregulation of the cerebral circulation in response to hypotension is reported. The major amyloid protein was immunoglobulin A lambda type. An autonomic nerve function test showed severe and extensive disturbances of the autonomic nervous system. The cerebrovascular reactivity to 5% CO2 inhalation was spared. To our knowledge, this is the first case to demonstrate that amyloid peripheral autonomic neuropathy can be accompanied by dysautoregulation of the cerebral circulation.
Error Analysis of the Double-Integral Method for Calculating Brain Blood Perfusion from Inert Gas Clearance Data
Authors: Smith Gary T. , Stokely Ernest M. , Lewis Margaret H. , Devous Michael D. , Bonte Frederick J.
Published: April 2011

A single-photon dynamic computer-assisted tomograph (DSPECT) has been built and is currently being used to evaluate regional cerebral blood perfusion in patients and volunteers. A computer simulation of the system was created to analyze the effects of data collection, Poisson noise, attenuation compensation, and the reconstruction technique now employed in the DSPECT. Several methods of attenuation compensation were used to generate perfusion images from both ideal and noisy data. The results indicate that the mean perfusion is calculated to within 10.4% accuracy for all perfusion rates in a region of interest if attenuation correction is used. Without attenuation correction, perfusions are underestimated by as much as 27%. The three correctors tested have different effects on the calculated perfusion value, depending on the location of the region of interest in the picture. The algorithm introduces random noise that is proportional to both the random error in the input data and the perfusion rate. Air-curve delay errors result in inaccuracies in the final perfusion picture that are proportional to perfusion rate. Physiological values (0.8–1.5) of the partition coefficient cause overestimation of both gray (0–34%) and white (7–67%) matter perfusion values. Compton scatter and collimator effects were not addressed in this study.
A Quantitative Model for the Measurement of Cerebral Vascular Extraction Fraction In vivo following Intravenous Injection: Simulation Studies
Authors: Takagi Shigeharu , Kenny Peter J. , Gilson Albert J.
Published: April 2011

A mathematical method has been developed by which the cerebral vascular extraction fraction of flow- and diffusion-limited tracers injected intravenously can be measured quantitatively. Successive injections of three tracers are required: a test tracer such as 15O-labeled water; a completely diffusible tracer as a reference tracer and also as a flow tracer; and a tracer for cerebral blood volume (CBV). The arterial tracer concentration curves and total integrated head counts of the test and reference tracers, as well as CBF and CBV values, are required to calculate the extraction fraction. No calibration is required between the head counts and arterial curves. No decay correction of the head and arterial activity is required, because isotopic decay is explicitly included in the equation. The effect of nonextracted test tracer can be corrected. Simulation studies have shown that the calculated extraction fraction values are not sensitive to measurement error in CBF, CBV, partition coefficient, change in measurement time, or time shift effect between the arterial and head data. If there is mixing of two different tissues in the brain, the calculated extraction fraction values are close to the weighted mean values of extraction fraction by relative weight of the tissues. It is concluded that it is possible to apply this method to human studies with a positron emission tomograph scanner and to animal studies with external coincidence detectors.
Metabolic and Kinetic Considerations in the Use of [125I]HIPDM for Quantitative Measurement of Regional Cerebral Blood Flow
Authors: Lucignani G. , Nehlig A. , Blasberg R. , Patlak S. , Anderson L. , Fieschi C. , Fazio F. , Sokoloff L.
Published: April 2011

The metabolic degradation and the kinetics of the cerebral uptake of N, N, N'-trimethyl- N'-(2-hydroxy-3-methyl- 5-[125I]iodobenzyl)-1, 3-propanediamine ([125I]HIPDM) have been studied in conscious, adult male Sprague-Dawley rats to determine its suitability as a tracer for the quantitative measurement of regional CBF (rCBF). rCBF was calculated by the indicator fractionation and the tissue equilibration methods in experiments of different durations up to 1 h. The values of rCBF obtained with [125I]HIPDM were compared with those obtained in concurrent measurements with [14C]iodoantipyrine in the same animals. Results of the experiments demonstrate that [125I]HIPDM is an inadequate tracer for use with the indicator fractionation method and that any method that employs [125I]HIPDM for the determination of rCBF must take into account its metabolic degradation, diffusion limitations, and bidirectional flux across the blood-brain barrier. With the tissue equilibration method, consistent determinations of rCBF may be possible with [125I]HIPDM by measurement of the time course of its concentration in arterial blood, corrected for the presence of 125I-labeled metabolic products, and its concentration in the brain at any time up to 1 h after its administration. The method may be adapted to measure rCBF in humans by means of single-photon emission tomography with [123I]HIPDM.
Regional Blood-Brain Barrier Permeability Changes after Restoration of Blood Flow in Postischemic Gerbil Brains: A Quantitative Study
Authors: Picozzi Piero , Todd Nicholas V. , Crockard H. Alan
Published: April 2011

A quantitative technique utilising [14C]α-aminoisobutyric acid as a tracer was used to study cerebrovascular permeability in 22 Mongolian gerbils. Seven other animals were used to measure cerebral blood volumes. Global cerebral ischaemia was produced by temporary bilateral carotid artery occlusion (60 min) in 16 gerbils that were sacrificed at 1, 2, and 3 h following reperfusion. The blood-to-brain transfer constant was significantly increased after 2 h of reperfusion in the ischaemic zones and also in structures, like the cerebellum, not supplied by the carotid artery and not ischaemic during the vessel occlusion. The blood-brain barrier (BBB) alterations were coincident with the onset of ischaemia—induced seizures that were accompanied by sudden “spikes” of systemic blood pressure. Epilepsy may play an important role in the development of BBB damage in this ischaemic model, and this factor must be considered in the interpretation of BBB damage data in gerbils.
Relations between Neuropsychological and Cerebral Metabolic Asymmetries in Early Alzheimer's Disease
Authors: Haxby James V. , Duara Ranjan , Grady Cheryl L. , Cutler Neal R. , Rapoport Stanley I.
Published: April 2011

Regional CMRglc (rCMRglc) values were determined with positron emission tomography (PET) in 10 patients with mild to moderate clinically diagnosed Alzheimer's disease (AD) and in 26 healthy controls. rCMRglc in frontal, parietal, and temporal association cortices were significantly more laterally asymmetrical in AD patients than in controls (p < 0.05). Furthermore, lateral asymmetry of rCMRglc in AD patients but not in the control subjects correlated significantly with asymmetry of language and visuospatial functions such that lower left than right rCMRglc was associated with relatively greater impairment of language and vice versa. The results demonstrate that discrepancies between language and visuospatial deficits in patients with early AD are related to asymmetrical reductions in cerebral cortical glucose metabolism.
Role of Prostaglandins in Modulating Sympathetic Vasoconstriction in the Cerebral Circulation in Anesthetized Rabbits
Authors: Busija David W.
Published: April 2011

The effects of the interaction between sympathetic nerves and prostaglandins in the cerebral circulation were examined. The hypothesis tested was that inhibition of prostaglandin synthesis by indomethacin would potentiate decreases in CBF caused by sympathetic nerve stimulation. In anesthetized rabbits, following administration of either indomethacin (10 mg/kg) or vehicle, CBF was measured with 15-μm microspheres prior to stimulation and following 3–5 min of electrical stimulation (4, 8, 16 Hz) of both superior cervical ganglia. In the vehicle group, CBF was 33–42 ml/min/100 g prior to stimulation. Bilateral sympathetic stimulation reduced blood flow to the cerebrum by 12 ± 6% (mean ± SEM) (p < 0.05) at 4 Hz (n = 8), by 20 ± 4% (p < 0.05) at 8 Hz (n = 12), and 21 ± 6% (p < 0.05) at 16 Hz (n = 11). In the indomethacin group, CBF was 37–48 ml/min/100 g prior to stimulation. Bilateral stimulation decreased blood flow to the cerebrum by 7 ± 5% (NS) at 4 Hz (n = 8), by 25 ± 3% (p < 0.05) at 8 Hz (n = 6), and by 20 ± 6% (NS) at 16 Hz (n = 6). Decreases in CBF during nerve stimulation were blocked by prazosin, an α-adrenergic antagonist. In additional experiments, cerebral vascular constrictor responses to hypocapnia were found to be similar in the vehicle and indomethacin groups. This study provides evidence that sympathetic nerves can decrease CBF substantially even at low stimulation frequencies. Further, results of this study indicate that prostaglandins do not attenuate the effects of sympathetic stimulation on the cerebral circulation.
In vivo Studies of Energy Metabolism in Experimental Cerebral Ischemia Using Topical Magnetic Resonance. Changes in 31P-Nuclear Magnetic Resonance Spectra Compared with Electroencephalograms and Regional Cerebral Blood Flow
Authors: Horikawa Y. , Naruse S. , Hirakawa K. , Tanaka C. , Nishikawa H. , Watari H.
Published: April 2011

The energy state of the brain during and after transient cerebral ischemia was examined in rats by in vivo measurement of 31P-nuclear magnetic resonance (NMR) spectra using a topical magnetic resonance spectrometer. EEGs and regional CBF (rCBF) were monitored on the same ischemic models. Immediately after the induction of ischemia, the height of the ATP and phosphocreatine peaks in the spectrum began to decrease with a concurrent increase of the inorganic phosphate (Pi) peak. The calculated pH from the chemical shift of Pi decreased during ischemia. The EEG pattern became flat immediately after ischemic induction. The rCBF decreased below the sensitivity level of the measuring instrument. With 30-min ischemia, the 31P-NMR spectrum returned to a normal pattern rapidly after recirculation. However, recovery of the EEG was delayed. The rCBF after recirculation showed postischemic hyperemia followed by hypoperfusion. In cases of 120-min ischemia, none of the spectra showed recovery. Thus, we could investigate the dynamic process of pathophysiological changes occurring in the ischemic brain in vivo.
Influence of Acidosis on Lipid Peroxidation in Brain Tissues in vitro
Authors: Siesjö Bo K. , Bendek George , Koide Tohru , Westerberg Eva , Wieloch Tadeusz
Published: April 2011

To study the influence of acidosis on free radical formation and lipid peroxidation in brain tissues, homogenates fortified with ferrous ions and, in some experiments, with ascorbic acid were equilibrated with 5–15% O2 at pH values of 7.0, 6.5, 6.0, and 5.0, with subsequent measurements of thiobarbituric acid-reactive (TBAR) material, as well as of water- and lipid-soluble antioxidants (glutathione, ascorbate, and α-tocopherol) and phospholipid-bound fatty acids (FAs). Moderate to marked acidosis (pH 6.5–6.0) was found to grossly exaggerate the formation of TBAR material and the decrease in α-tocopherol content and to enhance degradation of phospholipid-bound, polyenoic FAs. These effects were reversed at pH 5.0, suggesting a pH optimum at pH 6.0–6.5. It is concluded that acidosis of a degree encountered in ischemic brain tissues has the potential of triggering increased free radical formation. This effect may involve increased formation of the protonated form of superoxide radicals, which is strongly prooxidant and lipid soluble, and/or the decompartmentalization of iron bound to cellular macromolecules like ferritin.
Adenosine Deaminase Inhibitors Enhance Cerebral Anoxic Hyperemia in the Rat
Authors: Phillis J. W. , DeLong R. E. , Towner J. K.
Published: April 2011

Cerebral blood flow in the rat was monitored by a venous outflow technique with an extracorporeal circulation, which allows for the continuous recording of flow over periods of several hours. The adenosine deaminase inhibitors erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) (1.0–100 μg/kg) and deoxycoformycin (0.1–1 μg/kg) potentiated the reactive hyperemia elicited by a brief (24-s) anoxic challenge. Basal flow rate was unaltered by EHNA administration and slightly enhanced by deoxycoformycin. The results are consistent with the hypothesis that adenosine plays a significant role in cerebral vascular regulation and suggest that low doses of these deaminase inhibitors may be useful in the treatment of cerebral vascular insufficiency.
Effect of the Calcium Antagonist Nimodipine on Local Cerebral Blood Flow and Metabolic Coupling
Authors: Mohamed A. A. , Mendelow A. D. , Teasdale G. M. , Harper A. M. , McCulloch J.
Published: April 2011

The effects of a continuous infusion of the calcium antagonist nimodipine (1μg kg−1 min−1) on local CBF (LCBF) and local cerebral glucose utilisation (LCGU) were studied, using the quantitative autoradiographic [14C]iodoantipyrine and [14C]2-deoxyglucose techniques in 34 anatomically discrete regions of the brain in lightly restrained, conscious rats. The infusion of nimodipine at this concentration produced only a small (8%) reduction in the MABP. The administration of nimodipine did not alter the rate of glucose utilisation in any of the regions examined. By contrast, in 24 regions, CBF was increased significantly by 39–84% from control levels (for example, cerebral cortices, hippocampus, hypothalamus, and most thalamic nuclei). In vehicle-treated animals, there was an excellent correlation (p < 0.01) between the local levels of CBF and glucose utilisation, with the ratio of flow to glucose use being ∼1.5 ml μmol−1 in each brain region. During nimodipine treatment, there was a similarly excellent correlation (p < 0.01) between LCBF and LCGU, but the median ratio between local flow and glucose use increased to 2.5 ml μmol−1.
Evaluation of a Double-Tracer Autoradiographic Technique for the Measurement of Both Local Cerebral Glucose Metabolism and Local Cerebral Blood Flow
Authors: Jones Stephen C. , Greenberg Joel H.
Published: April 2011

A solvent washout technique is evaluated that could be used to remove one 14C tracer after a combined autoradiographic CMRglu and CBF study using [14C]2-deoxyglucose (2DG) and [14C]iodoantipyrine (IAP). The technique permits the simultaneous measurement of local CBF and local CMRglu in the same animal without the use of the short-lived tracers of iodine, 123I and 131I, for iodoantipyrine labeling. This report shows that brain tissue sections did not retain 14C from [14C]2DG when chloroform was used as the washout solvent. Chloroform washing removes nearly all the 14C from [14C]IAP. For this study, careful attention was given to the control, pre-wash measurement of 14C concentration.
Influence of Reduced Oxygen Availability on Cerebral Metabolic Changes during Bicuculline-Induced Seizures in Rats
Authors: Blennow G. , Nilsson B. , Siesjö B. K.
Published: April 2011

The objective of the present work was to study cerebral energy metabolism at threshold levels of hypoxia, i.e., degrees of hypoxia that abolish cerebral electrical activity, in the “normal” and in the epileptic brain. Seizures were induced by intravenous bicuculline and cerebral oxygen availability was reduced by a combination of lowered Po2 and reduced blood pressure to give a transformation of the burst suppression pattern to either one with single spikes or overt EEG flattening. Nonepileptic control animals were exposed to degrees of hypoxia that gave either a markedly depressed EEG pattern with sparse slow waves or EEG flattening. Epileptic and nonepileptic groups proved comparable in terms of calculated oxygen availability and cerebral oxygen consumption at the threshold of “transmission failure.” At levels of hypoxia that markedly attenuated or completely abolished seizure discharge, the cerebral metabolic changes were more marked than in comparable nonepileptic animals. These changes comprised an imminent severe perturbation of cerebral cortical phosphorylation potential, a pronounced lactic acidosis with a precipitous redox change, and a marked accumulation of ammonia. The more labile energy balance of the epileptic brain may indicate that the “seizure state” either increases cellular energy demands in spite of the electrical silence or reduces the efficiency of ATP production at the prevailing oxygen availability. It is conceivable that energy failure elicited by complicating hypoxia can aggravate or precipitate brain cell damage in epilepsy.
Regional Quantitative Determination of Brain Glucose in Tissue Sections: A Bioluminescent Approach
Authors: Paschen W. , Mies G. , Kloiber O. , Hossmann K.-A.
Published: April 2011

A bioluminescent technique is described for the regional quantitative determination of brain glucose. A close linear interrelationship was obtained between the optical density of the bioluminescent images and the glucose content in tissue samples. The regression coefficients of this correlation permit the quantification of glucose bioluminescent pictures using an image-processing system. Regional distribution of glucose was correlated to regional tissue pH under both physiological and pathophysiological conditions.
Extra- and Intracellular pH in the Brain during Seizures and in the Recovery Period following the Arrest of Seizure Activity
Authors: Siesjö Bo K. , von Hanwehr Roger , Nergelius Görel , Nevander Gunilla , Ingvar Martin
Published: April 2011

The objective of the study was to estimate changes in extracellular pH (pHe) and intracellular pH (pHi) during seizures and in the recovery period following the arrest of seizure activity. Seizures of 5- and 20-min duration were induced in rats by fluorothyl added to the insufflated gas mixture, and recovery for 5, 15, and 45 min was instituted by withdrawal of the fluorothyl supply following 20 min of continuous seizures. Changes in pHe were measured by double-barreled, liquid ion-exchange pH microelectrodes, and in pHi by the CO2 method, following estimation of tissue PCO2 and extracellular fluid (ECF) volume. The animals were either normoxic or rendered moderately hypoxic (arterial Po2 40–50 mm Hg). Upon induction of seizures in normoxic animals, pHe decreased by a mean of 0.36 unit, the values being identical at 5 and 20 min. In moderate hypoxia, seizures sustained for 20 min were accompanied by a further fall in pHe (mean decrease 0.51 unit). The changes in pHe seemed mainly to reflect the nonionic diffusion of lactic acid from cells to the ECF (tissue lactate levels ∼ 10 and 15 μmol g−1 during seizures in normoxic and hypoxic animals, respectively). However, the gradual fall in pHe attributable to lactic acid production was preceded by rapid acidification, sometimes exceeding the steady-state values subsequently attained. This acidification was interpreted to reflect spreading depression and fast transcellular Na+/H+ exchange. Following cessation of seizure discharge, pHe normalized at a surprisingly slow rate, with some acidosis persisting even after 45 min. The difference between cerebrovenous and arterial Pco2 was reduced during seizures and increased in the recovery period, probably reflecting alterations in the blood flow/metabolic rate coupling. Impedance changes were slight, indicating only minor changes in ECF volume. Changes in pHi after 5 min of seizures ranged from 0.20 (normoxic animals) to 0.32 (hypoxic animals) unit, the pHi values after 20 min being 0.07–0.08 unit higher. The results suggest the regulation of pHi during ongoing seizures. Upon arrest of seizure activity, pHi rapidly increased to normal and subsequently to supranormal values. Postepileptic intracellular alkalosis occurred at a time when pHe was still reduced and in spite of the fact that tissue lactate values had not normalized. It is concluded that the rapid normalization of pHi and overt alkalosis were caused by the simultaneously occurring oxidation of lactate, with the removal of a stoichiometrical amount of H+, and the extrusion of H+ from cells, possibly via a Na+/H+ exchanger, the latter probably delaying normalization of pHe.
Regional Brain Energy Metabolism after Complete versus Incomplete Ischemia in the Rat in the Absence of Severe Lactic Acidosis
Authors: Yoshida Shinichi , Busto Raul , Martinez Elena , Scheinberg Peritz , Ginsberg Myron D.
Published: April 2011

Levels of energy metabolites were measured in forebrain regions in fasted rats subjected to 4-h recirculation after 1 h of either incomplete or complete ischemia. Both models of ischemia were produced by a procedure combining bilateral common carotid artery occlusion, systemic hypotension, and CSF pressure elevation; the degree of intracranial hypertension was varied to produce incomplete and complete ischemia. Levels of brain lactate at the end of ischemia ranged from 16 to 19 mmol/ kg in incomplete ischemia and from 11 to 13 mmol/kg in complete ischemia. Energy metabolism recovered evenly in the neocortical and subcortical regions with recirculation after incomplete ischemia. The metabolic recovery in the cerebral cortex after complete ischemia was similar to that observed after incomplete ischemia; however, recovery in the subcortical regions after complete ischemia was less extensive, NADH fluorescence remained high, and there was a fall in total creatine. Intracellular pH in the dorsal thalamus was more alkalotic after complete than incomplete ischemia. Thus, in the absence of profound tissue lactic acidosis, residual CBF during prolonged ischemia helps postischemic restitution of brain energy metabolism in subcortical regions. The pattern of poor recovery in these regions after complete ischemia suggests inadequate reperfusion. The decreased total creatine and the severe tissue alkalosis may be biochemical markers of advanced tissue injury during reflow.
Effects of Hypoxic Hypoxia on Cerebral Phosphate Metabolites and pH in the Anesthetized Infant Rabbit
Authors: González-Méndez Ricardo , McNeill Ann , Gregory George A. , Wall Susan D. , Gooding Charles A. , Litt Lawrence , James Thomas L.
Published: April 2011

The effects of hypoxic hypoxia on high-energy phosphate metabolites and intracellular pH (pHi) in the brain of the anesthetized infant rabbit were studied in vivo using 31P nuclear magnetic resonance spectroscopy. Five 10- to 16-day-old rabbits were anesthetized with 1.5% halothane. Ventilation was controlled to maintain normocarbia. Inspired O2 fraction was adjusted to produce three states of arterial oxygenation: hyperoxia (Pao2 > 250 mm Hg), normoxia (Pao2 ∼ 100 mm Hg), and hypoxia (Pao2 25–30 mm Hg). During hypoxia, blood pressure was kept within 20% of control values with a venous infusion of epinephrine. During hyperoxia, the phosphocreatine-to-ATP ratio was 0.86, a value that is 2–2.5 times less than that reported for adults. During normoxia, ATP decreased by 20% and Pi increased by 90% from hyperoxia values. During 60 min of hypoxia, the concentrations of high-energy phosphate metabolites did not change, but intracellular and arterial blood pH (pHa) decreased significantly. When hyperoxia was reestablished, pHi returned to normal and pHa remained low. These results suggest that during periods of hypoxemia, the normotensive infant rabbit maintains intracellular concentrations of cerebral high-energy phosphates better than has been reported for adult animals.
Cerebral Blood Flow and Cerebral Metabolic Rate of Oxygen Requirements for Cerebral Function and Viability in Humans
Authors: Powers William J. , Grubb Robert L. , Darriet Danielle , Raichle Marcus E.
Published: April 2011

This study was undertaken to determine the minimum CBF and CMRO2 required by the human brain to maintain normal function and viability for more than a few hours. Positron emission tomography (PET) was used to perform regional measurements in 50 subjects with varying degrees of cerebral ischemia but no evidence of infarction. There were 24 normal subjects, 24 subjects with arteriographic evidence of vascular disease of the carotid system, and two subjects with reversible ischemic neurological deficits due to cerebral vasospasm. Minimum values found in the 48 subjects with normal neurological function were 19 ml/100 g-min for regional cerebral blood flow (rCBF) and 1.3 ml/100 g-min for regional cerebral metabolic rate of oxygen (rCMRO2). Minimum values for all 50 subjects with viable cerebral tissue were 15 ml/100 g-min for rCBF and 1.3 ml/100 g-min for rCMRO2. Comparison of these measurements with values from 20 areas of established cerebral infarction in 10 subjects demonstrated that 80% (16/20) of infarcted regions had rCMRO2 values below the lower normal limit of 1.3 ml/100g-min. Measurements of rCBF, regional cerebral blood volume, and oxygen extraction fraction were less useful for distinguishing viable from infarcted tissue. These data indicate that quantitative regional measurements of rCMRO2 with PET accurately distinguish viable from nonviable cerebral tissue and may be useful in the prospective identification of patients with reversible ischemia.
Effect of Thiamine Deficiency and its Reversal on Cerebral Blood Flow in the Rat. Observations on the Phenomena of Hyperperfusion, “No Reflow,” and Delayed Hypoperfusion
Authors: Hakim Antoine M.
Published: April 2011

Local CBF (LCBF) was determined in the same rat model and at the same intervals of thiamine deficiency and reversal as in previous studies of local cerebral glucose utilization (LCGU) and pH (LCpH). The results showed that prior to the appearance of the clinical sequelae of thiamine deficiency (opisthotonus, which usually occurs on day 18 of deficiency) cerebral structures such as the mammillary body, vestibular nucleus, inferior colliculus, and thalamus showed significant hyperperfusion, reaching >200% of control values. At opisthotonus, there was a general decline in LCBF, but, in addition, the larger of these structures developed inhomo-geneous perfusion with patches of hyperperfusion adjacent to others of low flow. Seven days of thiamine replenishment at opisthotonus resulted in delayed hypoperfusion notably in the mammillary body, inferior colliculus, and thalamic nuclei. Superimposition of the LCBF, LCGU, and LCpH data reveals that structures known to be vulnerable to the development of histological lesions in this model showed an early phase of hyperperfusion uncoupled from declining LCGU and normal LCpH. Then, following a significant but only focal rise in LCGU between days 11 and 14 of deficiency, hyperperfusion persisted while the pH was dropping and LCGU was rapidly declining. The phase of patchy perfusion occurred only in the histologically vulnerable structures when LCGU was very low and acidosis was at its peak, suggesting that it may have resulted from these opposing influences on LCBF. Following replenishment with thiamine, the vulnerable structures showed delayed hypoperfusion coupled to LCGU. An important conclusion from this work is that perfusion changes previously noted only in work with ischemia are now reported in a model where the primary derangement is metabolic. This suggests that these phenomena have metabolic explanations even in ischemia.
Cortical Deafferentation in Cat Focal Ischemia: Disturbance and Recovery of Sensory Functions in Cortical Areas with Different Degrees of Cerebral Blood Flow Reduction
Authors: Graf Rudolf , Kataoka Kazuo , Rosner Gerd , Heiss Wolf-Dieter
Published: April 2011

During and after 15-min occlusion of the middle cerebral artery (MCA) in cats, local CBF and neuronal activity were measured in cortical areas varying in the degree of CBF reduction. In an area within the ischemic center (primary auditory cortex, middle ectosylvian gyrus), CBF was severely suppressed. Click-induced auditory evoked potentials and evoked as well as spontaneous single-unit activity ceased within 1 min after occlusion. Recirculation resulted in a recovery of the different neurophysiological parameters with a time delay ranging from several minutes to 2 h. In two areas surrounding the ischemic focus (a visual area in the marginal gyrus and the forelimb representation area in the primary somatosensory cortex), CBF was reduced but remained above 30 ml/100 g/min during MCA occlusion. Visual flash-induced evoked potentials and somatosensory evoked potentials induced by median nerve electrical stimulation ceased in the corresponding areas with a somewhat slower time course as compared to the auditory responses and they recovered faster after recirculation. In another somatosensory area (hindlimb projection area in the primary somatosensory cortex), CBF stayed nearly at control levels during occlusion. Evoked potentials and single-unit activity induced by tibial nerve electrical stimulation decreased ∼5 min after occlusion and were abolished ∼5 min later. At that time, single-unit activity had changed to a nonresponsive pattern but persisted. However, potentials evoked transcallosally by electrical stimulation of the contralateral hemisphere were still recorded. After reopening the MCA, the recovery of neuronal functions was usually complete and occurred within ∼5 min. We conclude that attention has to be focused on those areas surrounding an acute ischemic focus that show either no or only slight CBF alterations. The functional impairment found in such areas is caused by the injury of subcortical structures leading to a cortical deafferentation. Considering the apparent lack of a CBF disturbance, such a condition should be distinguished from the so-called cortical ischemic penumbra.
Local Cerebral Glucose Utilization during Intracerebral pH Changes
Authors: Van Nimmen D. , Weyne J. , Demeester G. , Leusen I.
Published: April 2011

The effect of ventriculocisternal perfusion with mock CSF with alkaline or acidic pH on the local CMRglu (LCMRglu) in the caudatoputamen was studied in artificially ventilated and relaxed rats. In control rats both lateral cerebral ventricles were perfused with mock CSF at pH 7.4. In the experimental series one cerebral ventricle was infused with normal mock CSF while the other was infused with mock CSF in which the pH was decreased or increased by changing [HCO−3]. LCMRglu was depressed in acidotic brain tissue while it was strongly increased in alkalotic brain tissue. The importance of these alterations in brain glucose metabolism for the homeostatic regulation of brain pH is discussed.
Transformation of Postischemic Perineuronal Glial Cells. I. Electron Microscopic Studies
Authors: Petito C. K.
Published: April 2011

The effects of cerebral ischemia on perineuronal glia were studied in the rat model of transient four-vessel occlusion. Striatum containing irreversibly injured neurons and paramedian cerebral cortex containing re-versibly injured neurons were prepared for electron microscopy at intervals of 3 min up to 24 h following ischemia. Perineuronal astrocytes showed cytoplasmic swelling and configurational changes in and pleomorphism of mitochondria similar to those described previously in parenchymal astrocytes in this model. Dark oligodendroglia showed only transient swelling of cisterns of Golgi apparatus and endoplasmic reticulum. However, medium-light oligodendrocytes significantly increased in size and accumulated microtubules and tubovesicular profiles in the cytoplasm. Reactive glia with features of both oligodendrocytes and astrocytes appeared at 15 min. A sharp drop in the number of perineuronal medium-light oligodendrocytes occurred at 3 h after ischemia and was accompanied by increased numbers of astrocytes and intermediate glia. Cortical glia showed similar changes that were milder and reversible. These studies suggest that certain perineuronal glia are transformed into reactive astrocytes in areas of ischemic neuronal necrosis, although current data are insufficient to determine if the transforming cells are astrocytes, light oligodendrocytes, or intermediate glia. Possible stimuli for these glial reactions include loss of or changes in neuronal trophic factors upon CNS glia or alterations in the interstitial fluid composition.
Response of Regional Cerebral Blood Flow and Oxygen Metabolism to Thalamic Stimulation in Humans as Revealed by Positron Emission Tomography
Authors: Katayama Yoichi , Tsubokawa Takashi , Hirayama Teruyasu , Kido Goro , Tsukiyama Takashi , Iio Masaaki
Published: April 2011

To clarify functional neural pathways originating from the thalamic nucleus ventralis posterolateralis (VPL) in humans, the responses of regional CBF (rCBF) and regional CMRO2 (rCMRO2) to VPL stimulation were investigated by positron emission tomography in five patients who had undergone chronic implantation of electrodes into the VPL for therapeutic purposes. Measurement of rCBF and rCMRO2 under continuous inhalation of C15O2 and 15O2 by steady-state methods revealed significant increases of rCBF and rCMRO2 in the frontal, postcentral, and thalamic regions. The increases in rCBF and rCMRO2 of the postcentral regions were clearly predominant in the stimulated hemisphere insofar as the stimulation produced moderate paresthesia in restricted areas of the body. These results indicate that the VPL relays peripheral somatosensory information, which has previously been demonstrated to be transmitted to the frontal as well as postcentral regions.
Protein Synthesis in Postischemic Rat Brain: A Two-Dimensional Electrophoretic Analysis
Authors: Kiessling Marika , Dienel Gerald A. , Jacewicz Michael , Pulsinelli William A.
Published: April 2011

This study examined the pattern of protein synthesis in the neocortex, caudate–putamen, and the hippocampus following transient forebrain ischemia in rats. The animal model of temporary ischemia used in this study causes permanent damage to vulnerable neurons with a time course of injury that varies from hours (caudate nucleus) to days (hippocampus). To examine the spectrum of proteins synthesized in these regions at 3 and 18 h after recirculation, cerebral proteins were pulse-labeled in vivo by an intravenous injection of [35S]methionine. Newly synthesized (35S-labeled) and constitutive (unlabeled) proteins were analyzed by two-dimensional gel electrophoresis and fluorography. In all three brain regions, specific proteins underwent preferential synthesis (Mr ∼27,000, ∼65,000, ∼70,000, ∼110,000), while others showed decreased synthesis (neuron-specific enolase, α- and β-tubulin). There was an early (3 h post ischemia) induction of the Mr ∼70,000 mammalian “stress” protein; at 18 h post ischemia, its synthesis remained high in the hippocampus but was diminished in the neocortex and had largely subsided in the caudate–putamen. All regions at 18 h showed increased synthesis of an Mr ∼50,000 protein, tentatively identified as glial fibrillary acidic protein. The results show that temporary forebrain ischemia induces changes in protein synthesis that include features similar to those observed in other eukaryotic cells subjected to injurious stress. These postischemic changes in protein synthesis are qualitatively similar in all brain regions examined despite regional differences in the severity of subsequent neuronal damage. The persistent synthesis of the Mr ∼70,000 stress protein in the hippocampus, however, may reflect continued metabolic injury long after the ischemic episode has passed.
Model Dependency and Estimation Reliability in Measurement of Cerebral Oxygen Utilization Rate with Oxygen-15 and Dynamic Positron Emission Tomography
Authors: Huang Sung-Cheng , Feng DaGan , Phelps Michael E.
Published: April 2011

The use of oxygen-15 and dynamic positron emission tomography (PET) for the measurement of CMRO was investigated in terms of the achievable accuracy of CMRO and its sensitivity to model configuration assumed in the estimation. Three models of different descriptions for the vascular radioactivity in tissue were examined by computer simulation. By simulating the tracer kinetics with one model and curve fitting them with another, it was found that the CMRO measurement was very sensitive to the model configuration used and it needed kinetic data of low noise level to determine the correct model to use. The approach of sensitivity functions and covariance matrices was used to examine the estimation reliability and error propagation of the model parameters. It was found that for all three model configurations examined the reliability of the CMRO estimate was dependent on the blood flow and oxygen extraction fraction in tissue (∼2% in tissues of high blood flow and normal extraction and 10% in tissues of low blood flow and low extraction fraction, in a study of 1 × 106 counts/brain slice in 3 min). The estimation reliability is drastically decreased if the total data collection time is reduced to 1 min but is not critically sensitive to the scan sampling interval used. Estimating blood flow or vascular volume simultaneously with CMRO will reduce the reliability of the CMRO estimate by ∼50%. Propagation of parameter error from blood flow or vascular volume to CMRO is dependent on the model configuration as well as the scanning schedule and estimation procedure used. Results from the study provide useful information for improving the study procedure of CMRO measurements. The present study also illustrates a general representation of PET measurements and an approach that can be applied to other tracer techniques in PET for selecting appropriate model configurations and for designing proper experimental procedures.
Noninvasive Xenon-133 Measurements of Cerebral Blood Flow Using Stationary Detectors Compared with Dynamic Emission Tomography
Authors: Schroeder Torben , Vorstrup Sissel , Lassen Niels A. , Engell Hans C.
Published: April 2011

Repeated bedside measurements of CBF have been made possible by the recent development of a mobile unit with 10 stationary detectors using the intravenous xenon-133 method. To evaluate this technique, comparative CBF studies at rest and following the application of a cerebral vasodilatory stimulus (acetazolamide, 1 g i.v.) were performed with the mobile equipment and with xenon-133 single-photon emission inhalation tomography in patients with cerebrovascular disease. The CBF level and the flow response to acetazolamide as determined with the two methods were well correlated, although at low flow levels the stationary detectors yielded somewhat lower CBF values than did emission tomography. Considering the side-to-side asymmetry, an excellent correlation was obtained. Using the initial slope index, the stationary detectors revealed quantitatively 83% of the interhemispheric asymmetry and 63% of the asymmetry in the middle cerebral artery territory shown with the tomograph. As illustrated by a case history, the nontomographic CBF unit used in this study may provide reliable and useful information in patients with occlusive cerebrovascular disease by performing repeated CBF studies and challenging the cerebral circulation with acetazolamide.
Quantification of Neuroreceptors in the Living Human Brain. II. Inhibition Studies of Receptor Density and Affinity
Authors: Wong Dean F. , Gjedde Albert , Wagner Henry N. , Dannals Robert F. , Douglass Kenneth H. , Links Jonathan M. , Kuhar Michael J.
Published: April 2011

A method for estimating receptor density ( Bmax) in the living human brain by positron emission tomography was exemplified by a ligand, 3- N-[11C]methylspiperone ([11C]NMSP), that binds to D2 dopamine receptors with high affinity. The ligand binds essentially irreversibly (i.e., with very little dissociation) to the receptors during the 2-h scanning period. Transfer constants were estimated at steady state. In a previous article, we presented a method for the determination of k3, the rate of binding of the labeled ligand. In the present work, we varied k3 by reducing the number of available receptors with a previously administered receptor blocking agent, haloperidol. We calculated a receptor density of 9.2 pmol g−1 in the caudate nucleus of four normal volunteers, and an inhibitory constant of haloperidol of 1.4 n M by comparing tracer accumulation in the absence and the presence of the blocking agent. The values agreed with measurements of NMSP receptor density and haloperidol inhibitory potency in vitro in brain homogenates from human autopsy material.
Weighted Integration Method for Local Cerebral Blood Flow Measurements with Positron Emission Tomography
Authors: Carson Richard E. , Huang Sung-Cheng , Green Michael V.
Published: April 2011

A new technique called the weighted integration method for the measurement of local CBF (LCBF) in humans with positron emission tomography (PET) is presented. LCBF is calculated from weighted time integrals of the blood and tissue radioactivity curves. This method is computationally efficient and achieves nearly optimal statistical estimation of LCBF. The predicted root mean squared error of the weighted integration method is verified by simulation studies and is only 1–2% larger than the minimum possible error that can be achieved by an ideal estimation algorithm. For LCBF of >30 ml/min/100 g, the weighted integration method provides reduced noise compared with the integrated projection technique, the PET autoradiographic method, and the steady-state technique. In addition, an error analysis is performed to study the sensitivity of the weighted integration method to tissue mixtures, blood sample timing errors, and changes in LCBF during the data collection period.
Glycogen Synthesis and Immunocytochemical Study of Fructose-1,6-Biphosphatase in Methionine Sulfoximine Epileptogenic Rodent Brain
Authors: Hevor T. K. , Delorme P. , Beauvillain J. C.
Published: April 2011

The effects of the convulsant methionine sulfoximine (MSO) on the glucose pathway have been investigated in mouse and rat brain. The key gluconeogenic enzyme fructose-1,6-biphosphatase (FBPase) (EC 3.1.3.11) was immunostained by rat anti-FBPase antibody. The rat cortex slices were very lightly stained, almost unstained in controls. After MSO injection, there was a marked staining only in astrocytes (perikarya, processes, and end feet). The activity of this enzyme also increased. MSO induced an increase of 63% in the stability at heating (47°C) and of 36% in the stability at proteolysis (trypsin, 10 μg/ml) of FBPase. The convulsant had no effect on the concentrations of the metabolites related to the FBPase–phosphofructokinase step, i.e., fructose-1,6-biphosphate, glyceraldehyde-3-phosphate, and dihydroxyacetone phosphate, before, during, or after the convulsions. These results show that the cellular site of glucose pathway impairment induced by MSO in rodent brain is presumably the astroglial cells and that one mechanism of glycogenesis could be the reinforcement of the molecules of FBPase, which enhances gluconeogenesis. A hypothetical diagram of glucose metabolism under the effect of MSO has been proposed.
Regional Blood—Brain Glucose Transfer in the Rat: A Novel Double-Membrane Kinetic Analysis
Authors: Cunningham Vincent J. , Hargreaves Richard J. , Pelling David , Moorhouse Stephen R.
Published: April 2011

Regional blood–brain glucose transfer was studied in pentobarbitone-anaesthetized rats using a programmed intravenous infusion technique that maintained steady levels of unlabeled (up to 55 m M) and tracer d-glucose in the circulating plasma. Regional cerebral blood flow, glucose phosphorylation rate, and tissue glucose content were also measured under comparable conditions. Data were analysed in terms of irreversible Michaelis–Menten kinetics assuming independent influx and efflux (Type I) and reversible Michaelis–Menten kinetics (Type II) across both the luminal and the abluminal membranes of the endothelial cell. The latter analysis corresponds to simple stereospecific membrane pores. The mathematical model allowed for changes in tissue glucose content and back-diffusion of tracer during the experiments. Type I analyses gave Kt values of ∼6.6 m M, whereas those by Type II were consistently lower. Interregional differences were not significant using either scheme. Comparison of Type II with Type I analyses revealed a possible explanation for discrepancies in the estimates of nonsaturable glucose transfer by different methods and highlighted the importance of tissue glucose measurements in studies of unidirectional glucose influx. Since the experimental data may be described equally well by either scheme and some interaction between influx and efflux across the endothelial cell might be expected, consideration of this alternative approach is suggested.
Sequential Assessment of Regional Cerebral Blood Flow, Regional Cerebral Blood Volume, and Blood—Brain Barrier in Focal Cerebral Ischemia: A Case Report
Authors: Di Piero V. , Perani D. , Savi A. , Gerundini P. , Lenzi G. L. , Fazio F.
Published: April 2011

Regional CBF (rCBF) and regional cerebral blood volume (rCBV) were evaluated by N,N,N'-trimethyl- N'-(2)-hydroxy-3-methyl-5-[123I]iodobenzyl-1,3-propanediamine-2 HCl- and 99mTC-labeled red blood cells, respectively, and single-photon emission computerized tomography (SPECT) in a patient with focal cerebral ischemia. Sequential transmission computerized tomography (TCT) and SPECT functional data were compared with clinical findings to monitor the pathophysiological events occurring in stroke. A lack of correlation between rCBF–rCBV distributions and blood–brain barrier (BBB) breakdown was found in the acute phase. In the face of more prolonged alteration of BBB, as seen by TCT enhancement, a rapid evolution of transient phenomena such as luxury perfusion was shown by SPECT studies. Follow-up of the patient demonstrated a correlation between the neurological recovery and a parallel relative improvement of the cerebral perfusion.