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A Gjedde

Publications and source records attributed to A Gjedde.

At least 163 records · Page 9Linked to original sources
PubMed1990

Blood-brain transfer and metabolism of 6-[18F]fluoro-L-dopa in rat.

In a study designed to reveal the rates of blood-brain transfer and decarboxylation of fluoro-L-3,4-dihydroxyphenylalanine (FDOPA), we discovered a major discrepancy between the DOPA decarboxylase activity reported in the literature and the rate of FDOPA decarboxylation measured in the study. "Donor" rats received intravenous injections of 6 mCi fluorine-18-labeled FDOPA. The donor rats synthesized methyl-FDOPA. Arterial plasma, containing both FDOPA and methyl-FDOPA, was sampled from the donor rats at different times and reinjected into "recipient" rats in which it circulated for 20 s. The blood-brain clearance of the mixture of labeled tracers in the plasma was determined by an integral method. The individual permeabilities were determined by linear regression analysis, according to which the average methyl-FDOPA permeability in the blood-brain barrier was twice that of FDOPA, which averaged 0.037 ml g-1 min-1. The permeability ratio was used to determine the fractional clearance from the brain of FDOPA (and hence of methyl-FDOPA), which averaged 0.081 min-1. In the striatum, the measured average FDOPA decarboxylation rate constant (kD3) was 0.010 min-1, or no more than 1% of the rate of striatal decarboxylation of DOPA measured in vitro and in vivo. We interpreted this finding as further evidence in favor of the hypothesis that striatum has two dopamine (DA) pools, of which only DA in the large pool is protected from metabolism. Hence, no more than 1% of the quantity of fluoro-DA theoretically synthesized was actually retained in striatum.

Animals↗
PubMed1990

Michaelis-Menten constraints improved cerebral glucose metabolism and regional lumped constant measurements with [18F]fluorodeoxyglucose.

In the three-compartment model of transfer of native glucose and [18F]fluorodeoxyglucose (FDG) into brain, both transport across the blood-brain barrier and phosphorylation by hexokinase can be described by the Michaelis-Menten equation. This permits the use of fixed transport (tau = K*1/K1) and phosphorylation (psi = k*3/k3) ratios and a common partition volume (Ve = K1/k2) for tracer and glucose. By substituting transfer constants of FDG for those of glucose, using tau and psi, the lumped constant was determined directly by positron tomography. The same constraints also eliminated k*2 and k*3 from the model, thus limiting the parameters to K* [equivalent to K*1k*3/(k*2 + k*3)], K*1, and the cerebral vascular volume (Vo). In six healthy elderly men (aged 61 +/- 5 years), time-activity records of cerebral cortical regions were analyzed with tau = 1.1 and psi = 0.3. The results were compared with those of the conventional FDG method. At 20 min, the goodness of fit by the new equation was as good as that of the conventional method at 45 min. The estimates obtained by the constrained method had stable coefficients of variation. After 20 min, regional differences between the estimates were independent of time, although we observed steady decreases of K* and (k*3). The decrease strongly suggested dephosphorylation of FDG-6-phosphate, particularly after 20 min. All estimates of variables with the constrained method were more accurate than those of the conventional method, including the cerebral glucose metabolic rate itself, as well as physiologically more meaningful, particularly with respect to k*2 and k*3.

Aged↗
PubMed1990

Reduction of functional capillary density in human brain after stroke.

The blood flow of brain tissue often returns to normal after an ischemic episode. As "luxury" rather than "reactive" reperfusion, this hyperemia is associated with low metabolism. It is not known to what extent the high blood flow accompanies a high, normal, or low density of capillaries. The resolution of this question may indicate whether the functional capillary density is variable and, if so, whether it is coupled to blood flow or metabolism. To answer these questions, we defined functional capillaries as capillaries that transport glucose. We then calculated the density of functional capillaries (Dcap) and the mean time of transit of blood through the capillaries (tcap) from hemodynamic variables obtained in vivo by positron tomography of five patients afflicted by cerebral ischemic stroke. Each patient was studied twice, within 36 h of the insult and 1 week later. We identified nominally "ischemic" regions in the first study as cortical gray matter regions, contiguous with the ischemic focus, in which the magnitude of blood flow did not exceed 20 ml 100 g-1 min-1. In these regions, values of metabolism and functional capillary density were proportionately low compared with normal values obtained in the contralateral hemisphere. The studies revealed a reduction of the functional density of exchange vessels in postischemic brain tissue as soon as 36 h after the insult. In "ischemic" regions, within 36 h of the insult, the net extraction of oxygen was inversely related to the capillary transit time and appeared to be limited mainly by the low functional density of the capillaries. Contrary to expectations, the reduced density persisted, even when more than adequate perfusion of the tissue returned. For these reasons, we concluded that changes of the capillary density were associated with changes of the metabolism of the tissue rather than with blood flow.

Adult↗
PubMed1990

Regional glucose phosphorylation rate in rat brain during acute ethanol intoxication.

The effect of ethanol on regional cerebral metabolic rate for glucose (rCMRglc) was studied in rats using [6-14C]glucose. After intravenous injection, radioactivity was determined in 14 brain regions, corrected for loss of label, and divided by the integral of the arterial plasma glucose concentration measured during tracer circulation. When blood ethanol concentration was maintained at 6 g/l by intravenous infusion of ethanol for approximately 1 h, rCMRglc was found to be reduced significantly in 7 forebrain regions, compared to values of conscious control animals. In 7 further regions including brain stem regions, rCMRglc was not significantly reduced. We conclude that the effects of severe acute alcohol intoxication resemble those of global anesthesia.

Animals↗
PubMed1990

Glucose phosphorylation rate in rat parietal cortex during normoglycemia, hypoglycemia, acute hyperglycemia, and in diabetes-prone rats.

Cerebral metabolic rate for glucose (CMRglc) was studied in rats using [6-14C]glucose. After intravenous injection, the radioactivity of the parietal cortex was corrected for loss of labeled CO2 and divided by the integral of the arterial plasma glucose concentration, determined during tracer circulation. Treatment with insulin, resulting in plasma glucose concentrations less than 2.6 mmol/l, reduced CMRglc to 64% of the values found in control animals. CMRglc did not change in animals with acute hyperglycemia produced by intraperitoneal injection of a glucose solution or in diabetes-prone rats with or without insulin treatment.

Animals↗
PubMed1990

Metabolic brain imaging. Direct regional measurement of transfer coefficients and lumped constant.

In the deoxyglucose method of measuring brain glucose utilization, the Michaelis-Menten formalism implies 1) symmetrical transport across the blood brain barrier, 2) identical ratios between forward and backward transport across the blood brain barrier for substrates of the same carrier, and 3) constant transport (tau) and phosphorylation (phi) ratios between native substrate and tracer. Incorporation of these assumptions into the fluoro-deoxyglucose method in humans allowed us to replace the brain blood transfer (k2*) and phosphorylation (k3*) coefficients by the coefficients of net (K*) and undirectional (K1*) transfer in the operational equation of the method, and to calculate the lumped constant directly. The reduction of the number of essential parameters amounts to a constraint of the freedom of the transfer coefficients to assume any value. On this basis, we were able to improve the estimates of the transfer coefficients. Seven healthy, older subjects were studied by this method. The values of K1*, k2* and k3* changed in parallel to K*. The values of the regionally calculated lumped constant ranged from 0.48 to 0.73 with a mean of 0.58.

Aged↗
PubMed1990

PET studies of domoic acid poisoning in humans: excitotoxic destruction of brain glutamatergic pathways, revealed in measurements of glucose metabolism by positron emission tomography.

We used positron emission tomography to measure hippocampal and medial temporal lobe metabolism in brains of patients intoxicated by domoic acid from Prince Edward Island mussels. This analog of kainic acid specifically excites certain neurons in the hippocampus, and the study revealed a severe reduction of glucose metabolism in this part of the brain which paralleled the absence of long-, medium-, or short-term memory in these patients.

Animals↗
PubMed1990

Nimodipine binding in focal cerebral ischemia.

We investigated the binding properties of the voltage-sensitive calcium channel antagonist nimodipine in a rat model of focal cerebral ischemia. Male Sprague-Dawley rats weighing 250 g underwent occlusion of both the proximal middle cerebral artery and the ipsilateral common carotid artery. 3H-nimodipine (130 Ci/mmol) was infused intravenously and circulated for 30 minutes before the rats were killed at 5 minutes, 4, 24, and 48 hours after occlusion. The brains were removed and examined by autoradiography. We observed a focal increase of nimodipine binding in severely ischemic regions at 5 minutes after occlusion, which also appeared in regions with presumed penumbral blood flow levels at 4 hours after occlusion. We hypothesize that nimodipine binds to activated calcium channels in ischemic tissue. This increased binding depends on the duration and severity of cerebral ischemia. Sequential measurements of nimodipine binding may allow the identification of regions with potentially reversible effects of ischemia and the monitoring of their response to therapy.

Animals↗
PubMed1989

In vivo quantification of blood-brain transfer and binding of [125I]HEAT, an alpha 1-adrenoceptor antagonist.

The uptake and binding constants of [125I]iodo-2-[beta-(4-hydroxyphenyl)-ethyl-amino-methyl]tetralone ( [125I]HEAT) in rat brain were determined in vivo. The initial clearance of the radioligand from blood to brain, K1, was calculated from the initial uptake of the radioligand; it averaged 0.21 +/- 0.01 (SD) ml g-1 min -1, consistent with an initial extraction of 25% (i.e., one-quarter of the blood flow). The most strongly binding regions included the olfactory bulb, thalamic nuclei, medial geniculate body, and cerebral cortical layers. We identified saturable, specific binding in frontal cortex layers 1, 5a, and 5c (motor region), frontal cortex layers 3+4, ventral thalamic nuclei, medial geniculate body, striatum, cerebellum, and olfactory bulb. Addition of unlabeled ligand depressed binding in all regions to the same low level (partition coefficient) of 0.8 ml g-1. Displacement of [125 I]HEAT binding by unlabeled HEAT yielded a global affinity constant (KDVd) of 34 +/- 8 pmol g-1 and receptor densities (Bmax) that varied from 50 pmol g-1 in cerebellar cortex and caudate nucleus to 200 pmol g-1 in the region of highest specific binding, the medial geniculate body.

Adrenergic alpha-Antagonists↗
PubMed1989

Regional cerebral blood flow and glucose utilization during hypocapnia and adenosine-induced hypotension in the rat.

Hypocapnia and induced hypotension have been claimed by some to cause cerebral hypoxia because of insufficient perfusion. Regional cerebral blood flow (rCBF) and regional cerebral glucose utilization (rCMRglc) were measured simultaneously in the same animal subjected to hypocapnia or hypocapnia combined with induced arterial hypotension. The rCMRglc was measured with (3H) deoxyglucose and the rCBF with (14C) iodoantipyrine with the use of tissue biopsy methods and scintillation counting. Nineteen male Wistar rats were anesthetized with halothane and artificially ventilated. Anesthesia was maintained with nitrous oxide/oxygen (70:30) and succinylcholine. Six rats were maintained at normocapnia, six rats were ventilated to a PaCO2 of 20 mmHg, and seven animals were ventilated to PaCO2 20 mmHg combined with arterial hypotension of 50 mmHg (mean blood pressure) induced by infusion of adenosine. Although hypocapnia alone did not cause a statistically significant decrease of rCBF except in hippocampus, hypocapnia combined with hypotension resulted in a significant reduction of rCBF in four of seven regions when compared with hypocapnia alone; rCMRglc values were unchanged during hypocapnia. However, the addition of hypotension induced by adenosine led to a significant decline of glucose utilization in five of seven brain regions. In the present study the authors observed no increase of regional glucose utilization and hence no signs of cerebral ischemia during hypocapnia alone or combined with hypotension induced by adenosine.

Adenosine↗
PubMed1989

Hypocapnia prevents the decrease in regional cerebral metabolism during isoflurane-induced hypotension.

In neurologic surgery, induced hypotension is often used while the patient is hypocapnic. We investigated, by tissue biopsy methods and scintillation counting, the regional cerebral glucose utilization (rCMRglc) and blood flow (rCBF) in rats subjected to hypocapnia alone and in combination with hypotension. Anesthesia was maintained with 1.0% isoflurane in nitrous oxide/oxygen. Seven rats were maintained at PaCO2 of 40 mm Hg, six rats were ventilated to PaCO2 of 20 mm Hg, and six animals to PaCO2 of 20 mm Hg in combination with arterial hypotension of 50 mm Hg induced by isoflurane 2.5-3.5%. During hypocapnia, rCMRglc tended to increase in all regions, but the increase was statistically insignificant; rCBF was reduced uniformly by 40%. During combined hypocapnia/hypotension, rCMRglc was unaltered when compared to hypocapnia; compared to normocapnia, increases were seen in hippocampus and cerebellum. During hypocapnia/hypotension, rCBF was unaltered in cortical areas, while increases were seen in all subcortical areas compared to hypocapnia. Regional values of the ratio of rCBF/rCMRglc indicated that during hypocapnia and hypotension induced by isoflurane in nitrous oxide/oxygen, the individual brain areas were perfused according to their metabolic needs. It is suggested that hypocapnia may prevent the decrease in rCMRglc, which is usually observed during deep isoflurane anesthesia.

Journal Article↗
PubMed1989

Generalized decrease in brain glucose metabolism during fasting in humans studied by PET.

In prolonged fasting, the brain derives a large portion of its oxidative energy from the ketone bodies, beta-hydroxybutyrate and acetoacetate, thereby reducing whole body glucose consumption. Energy substrate utilization differs regionally in the brain of fasting rat, but comparable information has hitherto been unavailable in humans. We used positron emission tomography (PET) to study regional brain glucose and oxygen metabolism, blood flow, and blood volume in four obese subjects before and after a 3-wk total fast. Whole brain glucose utilization fell to 54% of control (postabsorptive) values (P less than 0.002). The whole brain rate constant for glucose tracer phosphorylation fell to 51% of control values (P less than 0.002). Both parameters decreased uniformly throughout the brain. The 2-fluoro-2-deoxy-D-glucose lumped constant decreased from a control value of 0.57 to 0.43 (P less than 0.01). Regional blood-brain barrier transfer coefficients for glucose tracer, regional oxygen utilization, blood flow, and blood volume were unchanged.

Adult↗
PubMed1989

Double-label and conventional deoxyglucose methods: a practical guide for the user.

The autoradiographic deoxyglucose method is widely used to map functional activity in mammalian brain. Whereas the method is simple to use, the underlying kinetic model is complex. This paper reviews the deoxyglucose kinetic model and the relevant implications for the user who does not have extensive knowledge of tracer kinetics. In generally understandable terms, single-label and double-label deoxyglucose approaches are discussed. Experimental procedures are described in detail. The calculations required for qualitative and quantitative experiments are explained. The deoxyglucose method is compared to other methods that map functional activity in mammalian brain.

Animals↗
PubMed1988

Influx of a choline analog to dog brain measured by positron emission tomography.

The influx of the 11C-labeled choline analog pyrrolidinocholine into tissue was measured in the brain of three dogs by positron emission tomography (PET). During the first 90 s after the intravenous bolus injection of the tracer, transfer of tracer from plasma to tissue was unidirectional. The influx constant for pyrrolidinocholine into intracranial tissue, Kin, was 0.017 ml/g/min (0.008 SD), and the initial volume of distribution, V0, was 0.08 ml/g (0.03 SD). The influx constant was at least five times larger than the value expected if simple diffusion were to account for tissue uptake. The method presented in this paper can be used to investigate the availability of plasma choline and its analogs to the living human brain and other tissue in degenerative diseases affecting the cholinergic system, and to provide in vivo information on a choline transport system.

Animals↗
PubMed1988

Workshop on schizophrenia, PET, and dopamine D2 receptors in the human neostriatum.

Recently, two research groups published numbers for D2 receptor sites in the neostriatum of drug-naive schizophrenic patients, obtained in vivo by positron emission tomography (PET). One study appeared to confirm the increase of D2 receptor numbers, while the other study did not. A workshop was convened in Montreal to examine the reasons for the discrepancy between the results obtained by the two groups. The workshop considered patient populations, PET instrumentation and scanning methods, pharmacology, and modeling. The workshop identified differences between the approaches of the two groups that could contribute to the divergent results, including age and chronicity of the patient samples, brain region selected for study, metabolism of the different radioligands in blood and brain, reversibility of binding, PET instrumentation, and complexity of data analysis. The workshop concluded that these initial efforts had made considerable progress in establishing the role of PET in the understanding of the biochemical processes underlying mental illness. In particular, the unique ability to quantify regional neuroreceptor density at different stages in the evolution of the disease has been implemented. At the same time, the work so far and this conference served to identify the main sources contributing to the different findings from the two centers. This information will be important in designing the next phase of the research which will build upon and reconcile these apparent discrepancies.

Adult↗
PubMed1988

Measuring brain glucose phosphorylation with labeled glucose.

This study tested whether glucose labeled at the C-6 position generates metabolites that leave brain so rapidly that C-6-labeled glucose cannot be used to measure brain glucose phosphorylation (CMRGlc). In pentobarbital-anesthetized rats, the parietal cortex uptake of [14C]glucose labeled in the C-6 position was followed for times ranging from 10 s to 60 min. We subtracted the observed radioactivity from the radioactivity expected with no loss of labeled metabolites from brain by extrapolation of glucose uptake in an initial period when loss was negligible. The observed radioactivity was a monoexponentially declining function of the total radioactivity expected in the absence of metabolite loss. The constant of decline was 0.0077.min-1 for parietal cortex. Metabolites were lost from the beginning of the experiment. However, with correction for the loss of labeled metabolites, it was possible to determine an average CMRGlc between 4 and 60 min of circulation of 64 +/- 4 (SE; n = 49) mumol.hg-1.min-1.

Animals↗