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A Gjedde

Publications and source records attributed to A Gjedde.

At least 91 records · Page 5Linked to original sources
PubMed1997

In vivo estimation of cerebral blood flow, oxygen consumption and glucose metabolism in the pig by [15O]water injection, [15O]oxygen inhalation and dual injections of [18F]fluorodeoxyglucose.

There is a need for suitable non-primate laboratory animals for studies of brain function by positron emission tomography (PET). To provide a comparative index of the circulatory physiology of the pig, we have applied novel PET tracer methodology to seven anaesthetized pigs, and measured cerebral regional oxygen consumption (CMR[O2]), cerebral blood flow (CBF), and cerebral glucose metabolism (CMR[glc]). Blood flow and flow-metabolism couple were estimated for selected cerebral regions of interest. We found an average hemispheric CMR(O2) of 171 +/- 18 micromol/100 cm3/min. Individual hemispheric CBF measurements varied between 33 and 41 ml/100 cm3/min, with an average of 37 +/- 3 ml/100 cm3/min at an average PaCO2 of 4.3 +/- 0.9 kPa. The blood flow dependency on arterial PCO2 was calculated from the results of the carbon dioxide response in two pigs in which the CBF measurements obeyed the equation CBF (ml/100 cm3/min) = 8.9 PaCO2 (kPa). In each pig, CMR(glc) was studied twice with a double-injection FDG method. In the first session, the values of CMR(glc) averaged 27 +/- 3 and 23 +/- 4 micromol/100 cm3/min, estimated by multilinear and linear regression analysis, respectively. In the second session, the corresponding averages were 27 +/- 3 and 24 +/- 3 micromol/100 cm3/min, respectively. The average oxygen extraction fraction was 0.46 +/- 0.09 and the oxygen-glucose ratio was 6.1 +/- 0.8. The findings indicate that the pig is suitable for PET studies of cerebral blood flow, cerebral oxygen consumption and glucose metabolism.

Administration, Inhalation↗
PubMed1997

On the accuracy of an [18F]FDOPA compartmental model: evidence for vesicular storage of [18F]fluorodopamine in vivo.

The biological accuracy of a nonlinear compartmental model describing the in vivo kinetics of L-3,4-dihydroxy-6-[18F]fluorophenylalanine ([18F]FDOPA) metabolism was investigated. Tissue activities for [18F]FDOPA and its labeled metabolites 3-O-methyl-[18F]FDOPA ([18F]OMFD), 6-[18F]fluorodopamine ([18F]FDA), L-3,4-dihydroxy-6-[18F]fluorophenylacetic acid ([18F]FDOPAC), and 6-[18F]fluorohomovanillic acid ([18F]FHVA) were calculated using a plasma [18F]FDOPA input function, and kinetic constants estimated previously by chromatographic fractionation of 18F-labeled compounds in plasma and brain extracts from rat. Present data accurately reflected the measured radiochemical composition in rat brain for tracer circulation times past 10 min. We formulated the hypothesis that the discrepancy between calculated and measured fractions of [18F]FDOPA and the deaminated metabolite [18F]FDOPAC at times earlier than 10 min reflected storage of [18F]FDA in vesicles without monoamine oxidase. This hypothesis explained the initially rapid appearance of [18F]FDOPAC in striatum by delayed transfer of [18F]FDA from cytosol into vesicles. We conclude that the simpler model of [18F]FDOPA compartmentation is accurate when the cytosolic and vesicular fractions of [18F]FDA are at steady-state; the approach to equilibrium has a time constant of 15-30 min. The present model is valid for positron emission tomography studies of [18F]FDOPA metabolism in living brain.

Animals↗
PubMed1997

[A clinic for the study of dementia--110 consecutive patients].

Case reports of 110 patients referred to a neurological dementia clinic were reviewed to evaluate a standardized diagnostic program. The patients were evaluated by a neurologist, a gerontopsychiatrist, and a neuropsychologist. ICD-10 criteria were used. Fifty-two patients had dementia while 58 had not; of these, 27 suffered from other non-dementia diseases and 31 were without dementia or other psychiatric or neurological disease. Thirteen patients with Alzheimer's disease were treated with tacrine. Four patients underwent cobalamin substitution treatment and seven started antidepressant medication. Ten patients received acetylsalicylic acid (150 mg Q.D.) and two a levo-dopa-type drug. Twenty-six patients were followed by gerontopsychiatric district care. Because only 47% of the patients suspected of dementia actually fulfilled dementia criteria, the evaluation suggests that patients suspected of dementia benefit from a standardized diagnostic program in a specialist setting.

Aged↗
PubMed1997

Cortical sites of sustained and divided attention in normal elderly humans.

Human brain mechanisms subserving attention have been assigned to prefrontal, midfrontal, and posterior parietal cortices, as well as to the anterior cingulate and the thalamus. To map these mechanisms in the brain, most studies have used selective attention tasks; few studies have mapped the brain under sustained or divided attention. The present study was designed to create maps of regional activity associated with sustained and divided attention using two different sensory modalities: visual checkerboard stimulation and vibrotactile stimulation of the right hand. Five cerebral PE-tomograms of 15O-labeled water uptake were acquired from 16 elderly healthy subjects during sustained or divided attention to the frequency of stimulation. To locate active brain regions, the t-statistic map of relative changes in cerebral blood flow was coregistered to the subjects' averaged brain MR images and to the standard Talairach brain coordinate system. Attention was associated with activity in two sites, the right middle frontal gyrus (Brodmann area 46) and the right inferior parietal lobule (Brodmann area 40). The frontal site was more active when the subjects attended to the visual stimulus and when the attention was divided, while the parietal site was more active during attention to the vibrotactile stimulus and during simple sustained attention. Our observations are consistent with the hypotheses (1) that the right posterior parietal attention center subserves attention to several sensory modalities and (2) that a cortical network of specific neuronal sites subserves both sustained and divided attention. These hypotheses must be tested in further studies.

Aged↗
PubMed1997

PET neuroimaging with [11C]venlafaxine: serotonin uptake inhibition, biodistribution and binding in living pig brain.

The brain binding kinetics and distribution of the antidepressant venlafaxine, labelled with 11C in the O-methyl position, was studied by PET after intravenous injection in anesthetized pigs. In addition, venlafaxine's action on serotonin (5-HT) uptake was studied in vitro in blood platelets obtain from humans or pigs. Venlafaxine resembled imipramine, paroxetine and citalopram in causing a dose-dependent inhibition of 5-HT uptake in blood platelets from pigs and humans. Venlafaxine-derived radioactivity entered the living brain readily and showed higher binding potentials in diencephalic and telencephalic regions than in cerebellum. Acute administration of an antidepressant drug (i.e. imipramine, citalopram or paroxetine) enhanced the distribution and altered the binding of venlafaxine in certain brain regions. The findings show that [11C]venlafaxine is not an ideal PET radiotracer mainly because of its relatively low binding potentials and its lack of specificity for the 5-HT transporter in living brain.

Animals↗
PubMed1997

Cerebral [15O] water clearance in humans determined by positron emission tomography: II. Vascular responses to vibrotactile stimulation.

When used to measure blood flow, water leaves a residue in the vascular bed, which may contribute to the calculation of increased blood flow during functional activation of brain tissue. To assess the magnitude of this contribution with the two-compartment positron emission tomography (PET) method, we mapped the water clearance (K1) of the brain as an index of cerebral blood flow (CBF) and the apparent vascular distribution of nonextracted H2 15O (Vo). The latter map represented mainly the cerebral arterial and arteriolar volume. We also prepared subtraction maps (delta K1, delta Vo) of the response to vibrotactile stimulation of the fingertips of the right hand of six normal volunteers. Using magnetic resonance (MR) images of all subjects, the data were rendered into Talairach's stereotaxic coordinates and the averaged subtraction images (activation minus baseline) merged with the corresponding averaged MRI image. The delta K1 map revealed the expected response in the primary sensory hand area; the delta Vo response was located about 13 mm more anteriorly, close to the central fissure, most likely reflecting changes of the arteries feeding the primary sensory hand area. We conclude that cerebral perfusion and cerebrovascular responses to vibrotactile stimulation may occur in disparate locations that can be identified separately by using the two-compartment method.

Brain↗
PubMed1997

L-arginine infusion increases basal but not activated cerebral blood flow in humans.

Nitric oxide is a potent vasodilator. Infusion of its precursor, L-arginine, results in increased cerebral blood flow (CBF) in experimental animals. We examined the effects of L-arginine infusion on CBF in humans using positron emission tomography and the quantitative H2(15)O method. Six subjects received 500 ml of 0.9% NaCl solution, and six subjects received an infusion of L-arginine (16.7 mg/kg/min; 500 mg/kg). Before and after the i.v. infusion, paired CBF measurements were performed at baseline and with vibrotactile stimulation of the right hand. In scans performed without vibrotactile stimulation, mean whole-brain CBF increased from 34.9 +/- 3.7 ml 100 g-1 min-1 to 38.2 +/- 4.4 ml 100 g-1 min-1. (9.5%; p < 0.005) after L-arginine infusion. The temporal pattern of CBF changes differed from that of plasma growth hormone and insulin levels and of arterial pH. In contrast, in the saline group, mean whole-brain CBF did not change significantly (35.8 +/- 5.9 ml 100 g-1 min-1 to 35.9 +/- 6.4 ml 100 g-1 min-1; 0.3%). Vibrotactile stimulation produced significant focal increases in CBF, which were unaffected by L-arginine infusion. L-arginine infusion was associated with an increase in plasma L-citrulline, a byproduct of nitric oxide synthesis.

Adult↗
PubMed1997

Quantification of neuroreceptors in the living human brain: III. D2-like dopamine receptors: theory, validation, and changes during normal aging.

Dopamine receptor density is believed to decline in normal aging. To test this hypothesis, we measured the density of dopamine D2-like receptors in vivo in the neostriatum of normal living humans by using the graphical method. This method determines the D2-like dopamine receptor density in the human brain with an occupying ligand (unlabeled haloperidol) and a radioligand (labeled 3-N-methylspiperone). The method was examined critically, and the assumptions underlying the method were shown to be valid. The validation included comparison of the representation of tracer metabolism by high-pressure liquid chromatography and model assays, calculation of the lumped constant Dw from the value of its components, and comparable tracer partition coefficients in vitro and in vivo. In error analysis, the method consistently performed as well as the direct least-squares regression at statistical noise levels appropriate for the tomograph used in these studies. The method revealed that the density of the D2-like receptors that bind haloperidol in the caudate nucleus of normal humans declined 1% per year after the age of 18 years.

Aging↗
PubMed1997

Quantification of neuroreceptors in the living human brain: IV. Effect of aging and elevations of D2-like receptors in schizophrenia and bipolar illness.

In a previous study of 10 drug-naive schizophrenic patients, the density of D2 dopamine receptors was found to be elevated in the caudate nucleus. The study raised questions about the influence of the age of the patients, the relationship of receptor density to psychosis, and the accuracy of the method used to obtain this evidence. Using positron emission tomography and constrained analysis of the brain uptake of the radioligand N-[11C]methyl-spiperone ([11C]NMSP), we tested four questions: Were the assumptions underlying the quantitation valid? Is there an age decline of the density of D2-like dopamine receptors in drug-naive schizophrenia and bipolar illness? If so, is it different from that observed in normal aging? Are D2-like dopamine receptors elevated at any age in either drug-naive schizophrenic or psychotic bipolar illness patients? NMSP and haloperidol partition volumes and plasma protein fractions were not significantly different among patient groups and normal volunteers. The model-derived assay of radioligand metabolites in plasma was confirmed by high-performance liquid chromatography in the patient groups. D2-like dopamine receptors declined with age, and the slope did not differ significantly between the schizophrenic patients, bipolar affective illness patients, and normal controls. Taking the effect of age into account, increases in D2 dopamine receptor density were found in seven psychotic patients with bipolar affective illness compared with seven nonpsychotic patients and 24 control subjects as well as in 22 drug-naive schizophrenic patients compared with the 24 control subjects.

Adult↗
PubMed1997

In vivo regulation of DOPA decarboxylase by dopamine receptors in rat brain.

To test the hypothesis that dopamine (DA) receptors influence cerebral DOPA-decarboxylase (DDC) activity in vivo, we used HPLC to measure the kinetics of the cerebral uptake and metabolism of [3H]DOPA in carbidopa-treated rats, and in rats also treated acutely with a DA receptor antagonist (flupenthixol, 2 mg/kg, intraperitoneally) or a DA receptor agonist (apomorphine, 200 microg/g, subcutaneously). The unidirectional blood-brain clearance of [3H]DOPA (K1DOPA, 0.030 mL g(-1) min(-1)) increased by 50% after flupenthixol. The magnitudes of the relative DDC activity (k3DOPA) in striatum (0.20 min(-1)), olfactory tubercle (0.11 min(-1)), and hypothalamus (0.15 min(-1)) of carbidopa-treated rats were doubled with flupenthixol, but cortical DDC activity was unaffected (0.02 min(-1)). Apomorphine reduced the magnitude of k3DOPA in striatum by 20%. The rate constant for catabolism of [3H]DA formed in brain (k7', monoamine oxidase [MAO] activity), which ranged from 0.025 min(-1) in striatum to 0.08 min(-1) in hypothalamus of carbidopa-treated rats, globally increased 2- to 4-fold after flupenthixol, and decreased to 0.003 min(-1) in striatum after apomorphine. These in vivo results confirm the claim that acute blockade of DA receptors with flupenthixol stimulates the synthesis of [3H]DA from [3H]DOPA, and that this [3H]DA is subject to accelerated catabolism. Conversely, activation of the DA receptors with apomorphine inhibits DDC activity and DA catabolism.

Animals↗
PubMed1997

Regional cerebral glucose utilization in immature fetal guinea pigs during maternal isocapnic hypoxemia.

Recent studies in immature fetal animals demonstrated only a slight or variable increase in the cerebral glycolytic rate during moderate isocapnic hypoxemia. However, the methods used in those studies did not allow for detection of small differences or of regional redistributions of the cerebral glycolytic rate. Hence, a global increase or a regional redistribution of the cerebral glycolytic rate during hypoxemia accompanied by a severe increase in tissue lactate concentration in a few brain areas may have been overlooked in these studies. Because these pathophysiologic mechanisms seem to considerably exacerbate neuronal cell damage due to hypoxic/ischemic insults, we were keen to clarify this point. We, therefore, applied the 2-deoxyglucose method to fetal guinea pigs in utero and measured total and regional cerebral glucose utilization in fetuses of this species at 0.75 of gestation during maternal isocapnic hypoxemia. At 0.75 of gestation guinea pig dams were chronically catheterized. Control groups were exposed to room air, whereas study groups were exposed to a hypoxic atmosphere (10% oxygen, 2% carbon dioxide, and 88% nitrogen). To measure total and regional cerebral glucose utilization during normoxemia and isocapnic hypoxemia, we injected i.v. 100 microCi of 2-[3H]deoxyglucose into the dams. Total and regional cerebral glucose utilization were determined from the steady-state clearance of 2-deoxyglucose between the maternal arterial plasma and the fetal brain, the glucose concentration in the maternal arterial plasma, and the "lumped constant." During isocapnic hypoxemia, total fetal cerebral glucose utilization was not significantly higher than that previously measured during normoxemia (8 +/- 0.8 versus 8 +/- 1.0 micromol/100 g/min). Furthermore, no redistribution of cerebral glucose utilization could be detected. We conclude that moderate isocapnic hypoxemia in the immature fetal brain does not lead to any significant increase or redistribution of glucose utilization or to any major lactate accumulation. This may be related to the low cerebral metabolic demands of brain tissue at this stage of development. Whether this is the main reason for the known resistance of the immature fetal brain toward ischemic neuronal cell damage remains to be established.

Animals↗
PubMed1997

D2-like dopamine receptor density in Tourette syndrome measured by PET.

UNLABELLED: Tourette syndrome (TS) is a chronic neurologic disorder characterized by the presence of involuntary motor and phonic tics. There is evidence that TS is associated with an abnormality of the dopaminergic system, involving postsynaptic D2 receptors. We tested the hypothesis that D2-like dopamine receptors are elevated in TS. METHODS: Twenty-nine adult patients with TS were studied by PET imaging with [11C]3-N-methylspiperone ([11C]NMSP). Two methods of data analysis were used. The first was a caudate-to-cerebellar ratio, measured at 45 min. The second method, applied in 20 subjects, was a two-PET scan procedure. Both used high specific activity [11C]NMSP, but the second scan was preceded by a dose of unlabeled haloperidol, which partially occupied the D2-like dopamine receptors. This was done to provide an absolute measure of receptor density (Bmax). All patients were compared to age- and sex-matched controls. RESULTS: Neither group showed significant differences from their control group in caudate-to-cerebellar ratio. However, the two-PET scan Bmax measurement demonstrated that 4 of the 20 patients had significantly elevated D2-like receptors. In this group of 20 patients, multiple linear regression analysis revealed a trend between the severity of vocal tics and Bmax values. This Bmax measure also revealed a significant (p < 0.05) association with performance on the Wisconsin Card Sorting Test. CONCLUSION: These findings suggest that not all patients with TS have an abnormality of D2-like receptors, but a subgroup of TS subjects has a significant D2-like dopamine receptor elevation. These findings also support the importance of applying a more quantitative method for Bmax determination to PET imaging analysis. The Bmax findings in the subgroup do not exclude an effect of intrasynaptic dopamine competition, but this effect may be less likely due to the high affinity of [11C]NMSP.

Adult↗
PubMed1996

Dopamine transporters are markedly reduced in Lesch-Nyhan disease in vivo.

Dopamine (DA) deficiency has been implicated in Lesch-Nyhan disease (LND), a genetic disorder that is characterized by hyperuricemia, choreoathetosis, dystonia, and compulsive self-injury. To establish that DA deficiency is present in LND, the ligand WIN-35,428, which binds to DA transporters, was used to estimate the density of DA-containing neurons in the caudate and putamen of six patients with classic LND. Comparisons were made with 10 control subjects and 3 patients with Rett syndrome. Three methods were used to quantify the binding of the DA transporter so that its density could be estimated by a single dynamic positron emission tomography study. These approaches included the caudate- or putamen-to-cerebellum ratio of ligand at 80-90 min postinjection, kinetic analysis of the binding potential [Bmax/(Kd x Vd)] using the assumption of equal partition coefficients in the striatum and the cerebellum, and graphical analysis of the binding potential. Depending on the method of analysis, a 50-63% reduction of the binding to DA transporters in the caudate, and a 64-75% reduction in the putamen of the LND patients was observed compared to the normal control group. When LND patients were compared to Rett syndrome patients, similar reductions were found in the caudate (53-61%) and putamen (67-72%) in LND patients. Transporter binding in Rett syndrome patients was not significantly different from the normal controls. Finally, volumetric magnetic resonance imaging studies detected a 30% reduction in the caudate volume of LND patients. To ensure that a reduction in the caudate volume would not confound the results, a rigorous partial volume correction of the caudate time activity curve was performed. This correction resulted in an even greater decrease in the caudate-cerebellar ratio in LND patients when contrasted to controls. To our knowledge, these findings provide the first in vivo documentation of a dopaminergic reduction in LND and illustrate the role of positron emission tomography imaging in investigating neurodevelopmental disorders.

Adolescent↗