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A Gjedde

Publications and source records attributed to A Gjedde.

At least 181 records · Page 10Linked to original sources
PubMed1987

Positron tomographic quantitation of neuroreceptors in human brain in vivo--with special reference to the D2 dopamine receptors in caudate nucleus.

The radioligand 3-N-[11C]methylspiperone (11C-NMSP) binds to D2 dopamine receptors with high affinity. We determined the rate of binding in 12 male volunteers, using a 3-compartment model to relate the time integral of the tracer plasma concentration to the distribution of the tracer in the caudate nucleus measured by positron tomography. The rate of binding (k3) was defined as the product of the bimolecular association rate (kon) and the quantity of available receptors (B'max). We calculated the product as the ratio between the steady-state rate of accumulation and the volume of distribution in the caudate nucleus. The average value was 0.100 min-1 in the normal volunteers. We varied k3 by reducing the number of available receptors with the D2 dopamine receptor blocking agent haloperidol ingested 4 hours before the tracer injection. In the normal volunteers, we calculated a receptor density of 17 pmol g-1 in the caudate nucleus and an inhibitory constant of haloperidol of 3 nM by comparing tracer accumulation in the absence and presence of the blocking agent. Bmax was also calculated in older men, drug-naive schizophrenics, and drug-treated schizophrenics (all men). The lowest value of Bmax was calculated in the older men (6 pmol g-1); the highest in the two groups of schizophrenic patients (39 and 41 pmol g-1, respectively).

Adult↗
PubMed1987

Double-label autoradiographic deoxyglucose method for sequential measurement of regional cerebral glucose utilization.

A new double-label autoradiographic glucose analog method for the sequential measurement of altered regional cerebral metabolic rates for glucose in the same animal is presented. This method is based on the sequential injection of two boluses of glucose tracer labeled with two different isotopes (short-lived 18F and long-lived 3H, respectively). An operational equation is derived which allows the determination of glucose utilization for the time period before the injection of the second tracer; this equation corrects for accumulation and loss of the first tracer from the metabolic pool occurring after the injection of the second tracer. An error analysis of this operational equation is performed. The double-label deoxyglucose method is validated in the primary somatosensory ("barrel") cortex of the anesthetized rat. Two different rows of whiskers were stimulated sequentially in each rat; the two periods of stimulation were each preceded by an injection of glucose tracer. After decapitation, dried brain slices were first exposed, in direct contact, to standard X-ray film and then to uncoated, "tritium-sensitive" film. Results show that the double-label deoxyglucose method proposed in this paper allows the quantification and complete separation of glucose utilization patterns elicited by two different stimulations sequentially applied in the same animal. The double-label deoxyglucose is of potential usefulness in sensory physiology since it makes possible the separate mapping of regional cerebral glucose utilization patterns elicited by two sequentially applied sensory stimulations in the same animal. The method allows the quantification of a step-like change in regional cerebral glucose utilization in the same animal. It could be used to study the cerebral metabolic effects induced by neuropharmacological agents or surgical interventions applied during the experiment. Using each animal as its own control eliminates intersubject variability. Thus experimental cost and effort can be saved, and the reliability of the results obtained can be increased.

Animals↗
PubMed1987

Hyperglycaemia protects against neuronal injury around experimental brain infarcts.

Regional glucose utilization was measured in the rat brain after occlusion of the middle cerebral artery. Normoglycaemic rat had increased glucose use in the cerebral cortex adjacent to the infarct. A fraction of the nerve cells were irreversibly injured in this region. In hyperglycaemic rats, the glucose metabolism remained normal and no nerve cell loss was found around the infarct. The findings indicate that hyperglycaemia protects against nerve cell injury in the areas next to experimental brain infarcts.

Animals↗
PubMed1987

Saturable retention of vasopressin by hippocampus vessels in vivo, associated with inhibition of blood-brain transfer of large neutral amino acids.

Vasopressin receptors have been reported in the endothelium of brain capillaries. The function of these receptors is not known. To test the prediction that vasopressin receptors in brain capillary endothelium affect amino acid transport across the blood-brain barrier and to assess the role of vasopressin transport across the cerebral vascular endothelium, we measured (a) the endothelial permeability to the large neutral amino acid leucine in the absence and presence of arginine vasopressin (AVP) and (b) the permeability of the blood-brain barrier to AVP relative to manitol. In brain regions protected by the blood-brain barrier, after circulation for 20 s, coinjection of leucine and AVP intravenously led to a decrease of leucine transport unrelated to changes of blood flow. The decrease was most pronounced in hippocampus (42%) and least pronounced in olfactory bulb and colliculi (17 and 19%, respectively). In the latter regions, the endothelial permeability to AVP did not significantly exceed that of mannitol. In hippocampus and in regions with no blood-brain barrier (pituitary and pineal glands), AVP retention in excess of mannitol retention was blocked by unlabeled AVP. The findings do not contradict the hypothesis of a role for AVP in the regulation of large neutral amino acid transfer into brain tissue.

Amino Acids↗
PubMed1987

Brain microvascular function during cardiopulmonary bypass.

Emboli in the brain microvasculature may inhibit brain activity during cardiopulmonary bypass. Such hypothetical blockade, if confirmed, may be responsible for the reduction of cerebral metabolic rate for glucose observed in animals subjected to cardiopulmonary bypass. In previous studies of cerebral blood flow during bypass, brain microcirculation was not evaluated. In the present study in animals (pigs), reduction of the number of perfused capillaries was estimated by measurements of the capillary diffusion capacity for hydrophilic tracers of low permeability. Capillary diffusion capacity, cerebral blood flow, and cerebral metabolic rate for glucose were measured simultaneously by the integral method, different tracers being used with different circulation times. In eight animals subjected to normothermic cardiopulmonary bypass, and seven subjected to hypothermic bypass, cerebral blood flow, cerebral metabolic rate for glucose, and capillary diffusion capacity decreased significantly: cerebral blood flow from 63 to 43 ml/100 gm/min in normothermia and to 34 ml/100 gm/min in hypothermia and cerebral metabolic rate for glucose from 43.0 to 23.0 mumol/100 gm/min in normothermia and to 14.1 mumol/100 gm/min in hypothermia. The capillary diffusion capacity declined markedly from 0.15 to 0.03 ml/100 gm/min in normothermia but only to 0.08 ml/100 gm/min in hypothermia. We conclude that the decrease of cerebral metabolic rate for glucose during normothermic cardiopulmonary bypass is caused by interruption of blood flow through a part of the capillary bed, possibly by microemboli, and that cerebral blood flow is an inadequate indicator of capillary blood flow. Further studies must clarify why normal microvascular function appears to be preserved during hypothermic cardiopulmonary bypass.

Animals↗
PubMed1986

Positron emission tomography reveals elevated D2 dopamine receptors in drug-naive schizophrenics.

In postmortem studies of patients with schizophrenia, D2 dopamine receptors in the basal ganglia have been observed to be more numerous than in patients with no history of neurological or psychiatric disease. Because most patients with schizophrenia are treated with neuroleptic drugs that block D2 dopamine receptors in the caudate nucleus, it has been suggested that this increase in the number of receptors is a result of adaptation to these drugs rather than a biochemical abnormality intrinsic to schizophrenia. With positron emission tomography (PET), the D2 dopamine receptor density in the caudate nucleus of living human beings was measured in normal volunteers and in two groups of patients with schizophrenia--one group that had never been treated with neuroleptics and another group that had been treated with these drugs. D2 dopamine receptor densities in the caudate nucleus were higher in both groups of patients than in the normal volunteers. Thus, schizophrenia itself is associated with an increase in brain D2 dopamine receptor density.

Adult↗
PubMed1986

Vasopressin binds to microvessels from rat hippocampus.

Recent evidence suggests that vasopressin may influence the permeability of the endothelium of brain capillaries. We measured the binding of [125I]arginine-8-vasopressin ([125I]AVP) to microvessels isolated from different regions of the rat brain. The study revealed saturable and specific binding of [125I]AVP to microvessels isolated from hippocampus. Scatchard analysis confirmed a single class of high affinity sites with an equilibrium dissociation constant, Kd, of 3.2 nM and an apparent maximal binding capacity of 205 fmol/mg protein. No binding was observed to microvessels from neocortex and striatum.

Animals↗
PubMed1986

Quantification of neuroreceptors in the living human brain. I. Irreversible binding of ligands.

A first step in the quantification of receptor density in the living human brain is the measurement of the binding of a labeled ligand to the receptor in question. In the present study, we determined the rate of binding of 11C-labeled N-methylspiperone (NMSP) to the D2 dopamine receptor in 11 normal volunteers, using a three-compartment model to relate the time integral of the measured plasma concentration to the distribution of the tracer in the caudate nucleus. The plasma concentrations of NMSP were separated from the contaminating metabolites by the ratio of radioactivities in cerebellum and blood plasma. Plasma concentrations calculated in this way agreed with plasma concentrations determined by HPLC. The rate of binding of labeled NMSP to its receptors (k3) was defined as the product of the bimolecular association rate (kon) and the quantity of available receptors (B'max) and calculated as the ratio between the steady-state rate of accumulation and the volume of distribution of labeled NMSP in the caudate nucleus. The average value of k3 in the 11 normal volunteers was 0.065 min-1. The fractional clearance of labeled NMSP from the caudate nucleus (k2) was 0.070 min-1 and thus close to the value of k3. We also examined several indexes of binding based on ratios between different regions in brain. The indexes required that binding be negligible compared to the efflux of labeled NMSP (i.e., k2 much greater than k3) and therefore yielded incorrectly low values of k3. Thus, the only accurate approach used measured plasma concentrations to estimate transfer constants at steady state and yielded the absolute rate of binding k3. The approach is applicable to other irreversibly bound ligands.

Adolescent↗
PubMed1986

Quantification of Neuroreceptors in the living human brain. II. Inhibition studies of receptor density and affinity.

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 nM 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.

Adolescent↗
PubMed1986

Focal ischemia of the rat brain: autoradiographic determination of cerebral glucose utilization, glucose content, and blood flow.

Focal cerebral ischemia was induced in rats by occlusion of the middle cerebral artery. By a triple-tracer technique, cerebral glucose utilization, glucose content, and blood flow were simultaneously determined. Computer-assisted autoradiography revealed a core of dense ischemia in the lateral two-thirds of the striatum. A border zone of increased 2-deoxy-D-glucose (DG) uptake surrounded the ischemic insult in the acute stage. The lumped constant was increased only moderately in the border zone. Therefore, the enhanced DG uptake reflected increased glucose consumption. CBF was reduced to 20-30% in the cortical border, while minor depression and in some animals hyperemia were evident in the striate border. Six hours after the insult, the border zones of increased glucose consumption had disappeared in half the animals. In no animals examined after 20 h was glucose consumption enhanced. The study indicated a stable metabolic response to a reproducible focal insult. We conclude that continued enhancement of glucose consumption in marginally perfused areas indicates neuronal damage.

Animals↗
PubMed1986

Blood-brain transfer of glucose and glucose analogs in newborn rats.

Little is known of the selectivity of the blood-brain barrier at birth. Hexoses are transported through the barrier by a facilitating mechanism. To study the capacity of this mechanism to distinguish between analogs of D-glucose, we compared the transport of fluorodeoxyglucose, deoxyglucose, glucose, methylglucose, mannose, galactose, mannitol, and iodoantipyrine across the cerebral capillary endothelium in newborn Wistar rats. Cerebral blood flow, glucose consumption, and the blood-brain permeabilities of the hexoses were 25-50% of the adult values but the ratios between the permeabilities of the individual hexoses were similar to the ratios observed in adult rats. The mannitol clearance into brain was considerably higher than in adult rats (about 10-fold), indicating a higher endothelial permeability to small polar nonelectrolytes. The brain water content was higher in newborn than in adult rats and was associated with a higher steady-state distribution of labeled methylglucose between brain and blood. Hexose concentrations were determined relative to whole blood because the apparent erythrocyte membrane permeability to glucose was as high as in humans and thus considerably higher than in adult rats. The half-saturation concentration of glucose transport across the blood-brain barrier was considerably higher than in adult rats, about three-fold, suggesting that net blood-brain glucose transfer is less sensitive to blood glucose fluctuation in newborn than in adult rats.

Animals↗
PubMed1985

Comparative regional analysis of 2-fluorodeoxyglucose and methylglucose uptake in brain of four stroke patients. With special reference to the regional estimation of the lumped constant.

The glucose metabolic rate of the human brain can be measured with labeled deoxyglucose, using positron emission tomography, provided certain conditions are fulfilled. The original method assumed irreversible trapping of deoxyglucose metabolites in brain during the experimental period, and it further requires that a conversion factor between deoxyglucose and glucose, the "lumped constant," be known for the brain regions of interest. We examined the assumption of irreversible trapping of fluorodeoxyglucose metabolites in brain of four patients in 365 normal and 4 recently infarcted regions. The average net, steady-state rate of fluorodeoxyglucose (KD) accumulation in normal regions of the four patients was 0.025 ml g-1 min-1. We also examined the variability of the lumped constant. We first confirmed that methylglucose is not phosphorylated in the human brain. We then estimated the lumped constant from the regional distribution of labeled methylglucose in brain. The average (virtual) volume of distribution of labeled methylglucose in the normal regions was 0.46 ml g-1 and was the same in both gray and white matter structures. The average brain glucose content corresponding to this value was 1.3 mumol g-1, assuming a Michaelis constant (Kt) of 3.7 mM for glucose transport across the blood-brain barrier. The lumped constant varied insignificantly between 0.4 and 0.5 in most regions, with an overall average of 0.44. It did not vary significantly between the patients and was the same in gray and white matter structures, but was inversely related to the calculated metabolic rate. This observation indicates that metabolic rates calculated with a fixed lumped constant (e.g., 0.40) would be slightly underestimated at high metabolic rates and slightly overestimated at low metabolic rates. The average glucose metabolic rates of the 365 normal regions, in which gray matter regions prevailed by 20:1, was 32 mumol 100 g-1 min-1. The average glucose phosphorylation rate in white matter was 20 mumol 100 g-1 min-1 with a lumped constant of 0.45. In the recently infarcted areas, the lumped constants varied from 0.37 to 2.83, corresponding to glucose metabolic rates varying from 2 to 18 mumol 100 g-1 min-1. Two infarct types were identified. In one type, the phosphorylation-limited type, glucose content and the lumped constant were close to normal (1 mumol g-1 and 0.40, respectively). In the other, the transport/flow-limited type, the glucose content was low (0.2 mumol g-1), and the lumped constant in excess of unity. The evidence from the present study upholds the model of Sokoloff et al. in every detail.

3-O-Methylglucose↗
PubMed1985

Double-tracer study of the fine regional blood-brain glucose transfer in the rat by computer-assisted autoradiography.

Glucose is transported from blood to brain tissue by facilitated diffusion of limited capacity. The regional variation of the glucose transport capacity is not known in detail because methods used previously have been too gross to detect fine regional differences. Therefore, it is not known to what extent the glucose transport capacity varies in proportion to regional blood flow and metabolic rate. To resolve this question, we used double-tracer, dual-label autoradiography to measure blood-brain glucose clearance and blood flow simultaneously in hypo-, normal, and hyperglycemic rats. From the values of glucose clearance and blood flow at various plasma glucose levels, we calculated the affinity constant and maximal transport capacity of the glucose transport system. The transport capacity (Tmax) varied in approximate proportion to the blood flow and, by inference, the metabolic rate. In contrast, the affinity constant (Kt) did not vary systematically between the regions (mean value 7.1 mM). The variation of Tmax from 270 to 890 mumol hg-1 min-1 reflected a parallel variation of total regional capillary length and surface. We conclude from the study that the cerebral capillary is a fixed unit, i.e., that the number of glucose transporters per unit of capillary surface area is the same in all regions. Regional differences are the result of different capillary densities in the regions of the brain.

Animals↗
PubMed1985

Metabolic effect of topical application of metrizamide to rat brain cortex.

The x-ray contrast material metrizamide is structurally related to 2-deoxyglucose and inhibits brain glucose phosphorylation both in vitro and in vivo. in vivo. In vivo, however, the present autoradiographic study with labeled 2-deoxyglucose revealed a local increase of glucose metabolic rate in an area of direct metrizamide application to the cerebral cortex. The local increase was 137% above the metabolic rate calculated for the contralateral region. Regions outside the application site showed no difference between the glucose metabolic rates of the ipsi- and contralateral hemispheres. Evidence from the literature suggests that metrizamide may stimulate cortical activity by inhibiting acetylcholinesterase.

Administration, Topical↗
PubMed1985

Nonpulsatile cardiopulmonary bypass disrupts the flow-metabolism couple in the brain.

The effect of cardiopulmonary bypass on the relationship between brain glucose consumption and regional blood flow is unknown. We measured this relationship in pigs subjected to 3 hours of pulsatile or nonpulsatile cardiopulmonary bypass at normothermia and compared the results to the relationship established in a control group of pigs. A total of 10 regions were sampled in both hemispheres of the porcine brain. In control pigs, cerebral blood flow averaged 46 ml/100 gm and the glucose consumption, 21 mumol/100 gm/min. The ratio between blood flow and glucose consumption was close to 2 ml/mumol in all regions. In pulsatile cardiopulmonary bypass both the whole-brain average and the regional values declined, so that the ratio remained the same, about 2 ml/mumol. In nonpulsatile cardiopulmonary bypass regional blood flow remained normal; the average was 49 ml/100 gm/min, whereas the average glucose consumption declined to 16 mumol/100 gm. In regions with high blood flow rates, the ratio between blood flow and glucose consumption increased to about 3 ml/mumol, indicating perfusion in excess of metabolic demand. We conclude that nonpulsatile cardiopulmonary bypass at normothermia affects the metabolic flow regulation in the brain by interfering with the myogenic contractility of cerebral arterioles.

Blood Flow Velocity↗
PubMed1984

Effects of age on dopamine and serotonin receptors measured by positron tomography in the living human brain.

D2 dopamine and S2 serotonin receptors were imaged and measured in healthy human subjects by positron emission tomography after intravenous injection of 11C-labeled 3-N-methylspiperone. Levels of receptor in the caudate nucleus, putamen, and frontal cerebral cortex declined over the age span studied (19 to 73 years). The decline in D2 receptor in males was different from that in females.

Aging↗