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Biomedical subjects

A Gjedde

Publications and source records attributed to A Gjedde.

At least 73 records · Page 4Linked to original sources
PubMed1999

Visual field recovery in a patient with bilateral occipital lobe damage.

We report on a patient with an asymmetrical bilateral developmental anomaly of the occipital lobes which led to a loss of almost the entire visual field. MRI and 18FDG scans confirmed the presence of a larger lesion of the visual cortex of the right hemisphere. The patient recovered parts of her visual field with time as measured by computerized perimetry, progressing from near blindness of the right eye to a remarkable recovery of vision. Because the patient had neonatal damage to both occipital lobes, we hypothesized a cortical plasticity process similar to that described in subhuman species.

Adult↗
PubMed1999

Myocardial glucose uptake measured with fluorodeoxyglucose: a proposed method to account for variable lumped constants.

UNLABELLED: Quantitative assessment of myocardial glucose uptake by the glucose tracer analog 2-deoxy-2-[18F]fluoro-D-glucose (FDG) depends on a correction factor (lumped constant [LC]), which may vary. We propose that this variability is caused by different affinities of FDG and glucose for membrane transport and phosphorylation and can be predicted from the time course of FDG retention. We therefore measured the LC under steady-state metabolic conditions and compared the results with values predicted from the tracer retention alone. METHODS: We measured rates of myocardial glucose uptake by tracer ([2-3H]glucose) and tracer analog methods (FDG) in isolated working Sprague-Dawley rat hearts perfused with Krebs buffer and glucose, or glucose plus insulin or beta-hydroxybutyrate. In separate experiments, we established the theoretical upper and lower limits for the LC (Rt and Rp), which are determined by the relative rates of FDG and glucose membrane transport (Rt, 1.73 +/- 0.22) and the relative rates of FDG and glucose phosphorylation (Rp, 0.15 +/- 0.04). RESULTS: The LC was decreased in the presence of insulin or beta-hydroxybutyrate or both (from 1.14 +/- 0.3 to 0.58 +/- 0.16 [insulin], to 0.75 +/- 0.17 [beta-hydroxybutyrate] or to 0.53 +/- 0.17 [both], P < 0.05). The time-activity curves of FDG retention reflected these changes. Combining the upper and lower limits for the LC with the ratio between unidirectional and steady-state FDG uptake rates allowed the prediction of individual LCs, which agreed well with the actually measured values (r = 0.96, P < 0.001). CONCLUSION: The LC is not a constant but is a predictable quotient. As a result of the fixed relation between tracer and tracee for both membrane transport and phosphorylation, the quotient can be determined from the FDG time-activity curve and true rates of myocardial glucose uptake can be measured.

Animals↗
PubMed1999

Measurement of myocardial glucose uptake in patients with ischemic cardiomyopathy: application of a new quantitative method using regional tracer kinetic information.

UNLABELLED: Quantification of myocardial glucose uptake (MGU) by 18F-fluoro-2-deoxyglucose (FDG) using PET may be inaccurate, because the correction factor that relates myocardial FDG uptake to MGU, the lumped constant (LC), is not a true constant. Recent studies have shown that analysis of FDG time-activity curves allows determination of individual LCs and that variable LCs yield accurate determination of MGU. We compared the magnitude of the LC in different regions of the heart in patients with ischemic cardiomyopathy. METHODS: Twenty patients with ischemic cardiomyopathy and an average ejection fraction of 33% underwent dynamic 13N-ammonia and FDG PET. We determined myocardial perfusion and MGU in 177 regions classified as control (71 regions), mismatch (50 regions) and match (56 regions), according to findings on PET and echocardiography. Regional MGU was calculated with both regional LCs and a fixed LC of 0.67. RESULTS: All results were expressed as mean +/- SD. Myocardial perfusion was highest in control regions (0.52+/-0.18 mL/g/min), reduced in mismatch regions (0.43+/-0.19 mL/g/min; P < 0.05 versus control) and severely reduced in match regions (0.28+/-0.17 mL/g/min; P < 0.001 versus control and mismatch). Regional LCs ranged from 0.45 to 1.30 and differed between patients (P < 0.001). Regional LCs were similar in regions diagnosed as control (0.78+/-0.23), mismatch (0.80+/-0.24) and match (0.72+/-0.21). MGU (micromol/g/min) calculated by regional LCs was similar in control (0.52+/-0.16) and mismatch (0.49+/-0.19) regions and decreased in match regions (0.31+/-0.12, P < 0.001). The agreement between MGU calculated with variable and fixed LCs was poor. CONCLUSION: The LC used in the calculation of MGU was not affected by regional differences in the metabolic state of the myocardium. However, the LC varied substantially between patients in control, mismatch and match regions. These findings indicate that quantitative measurements of MGU using a fixed LC must be interpreted with caution.

Aged↗
PubMed1998

Quantitative PET analysis of regional cerebral blood flow and glucose and oxygen metabolism in response to fenfluramine in living porcine brain.

The serotonin agonist fenfluramine has been used widely in humans for studying neuronal activation. We carried out the present study in order to determine whether anesthetized pigs could be used for studying effects of fenfluramine on cerebral functions using positron emission tomography (PET). We obtained quantitative measures of regional cerebral blood flow (rCBF) and of glucose and oxygen utilization (rCMRglc and rCMR(O2)) during intravenous administration of fenfluramine, using [15O]water, [18F]FDG and [15O]oxygen, respectively. Fenfluramine (25 mg/h i.v.) caused a significant rise in rCBF and, to a lesser extent, in rCMR2(O2), but it failed to affect rCMRglc. The findings indicate that quantitative estimation of rCBF by repeated injection of [15O]water was more sensitive than either rCMRO2 or rCMRglc for detecting effects of fenfluramine on serotonin neurotransmission in living porcine brain.

Animals↗
PubMed1998

Compartmental analysis of dopa decarboxylation in living brain from dynamic positron emission tomograms.

The trapping of decarboxylation products of radiolabelled dopa analogs in living human brain occurs as a function of the activity of dopa decarboxylase. This enzyme is now understood to regulate, with tyrosine hydroxylase, cerebral dopamine synthesis. Influx into brain of dopa decarboxylase substrates such as 6-[18F]fluorodopa and beta-[11C]dopa measured by positron emission tomography can be analyzed by solution of linear differential equations, assuming irreversible trapping of the decarboxylated products in brain. The isolation of specific physiological steps in the pathway for catecholamine synthesis requires compartmental modelling of the observed dynamic time-activity curves in plasma and in brain. The several approaches to the compartmental modelling of the kinetics of labelled substrates of dopa decarboxylase are now systematically and critically reviewed. Labelled catechols are extensively metabolized by hepatic catechol-O-methyltransferase yielding brain-penetrating metabolites. The assumption of a fixed blood-brain permeability ratio for O-methyl-6-[18F]fluorodopa or O-methyl-beta-[11C]dopa to the parent compounds eliminates several parameters from compartmental models. However, catechol-O-methyltransferase activity within brain remains a possible factor in underestimation of cerebral dopa decarboxylase activity. The O-methylation of labelled catechols is blocked with specific enzyme inhibitors, but dopa decarboxylase substrates derived from m-tyrosine may supplant the catechol tracers. The elimination from brain of decarboxylated tracer metabolites can be neglected without great prejudice to the estimation of dopa decarboxylase activity when tracer circulation is less than 60 minutes. However, elimination of dopamine metabolites from brain occurs at a rate close to that observed previously for metabolites of glucose labelled in the 6-position. This phenomenon can cause systematic underestimation of the rate of dopa decarboxylation in brain. The spillover of radioactivity due to the limited spatial resolution of tomographs also results in underestimation of dopa decarboxylase activity, but correction for partial volume effects is now possible. Estimates of dopa decarboxylase activity in human brain are increased several-fold by this correction. Abnormally low influx of dopa decarboxylase tracers in the basal ganglia is characteristic of Parkinson's disease and other movement disorders. Consistent with postmortem results, the impaired retention of labelled dopa is more pronounced in the putamen than in the caudate nucleus of patients with Parkinson's disease; this heterogeneity persists after correction for spillover. Current in vivo assays of dopa decarboxylase activity fail to discriminate clinically distinct stages in the progression of Parkinson's disease and are, by themselves, insufficient for differential diagnosis of Parkinson's disease and other subcortical movement disorders. However, potential new avenues for therapeutics can be tested by quantifying the rate of metabolism of exogenous dopa in living human brain.

Animals↗
PubMed1998

Effect of catechol-O-methyltransferase inhibition on brain uptake of [18F]fluorodopa: implications for compartmental modelling and clinical usefulness.

The efficacy of levo-DOPA in the treatment of Parkinson's disease is potentiated by blockade of its peripheral metabolism with inhibitors of catechol-O-methyltransferase (COMT). Some COMT inhibitors may act entirely in the periphery (nitecapone, OR-462), while others may also have some activity in brain (entacapone, OR-611). We used positron emission tomography (PET) to test the effects of these two COMT inhibitors on the plasma kinetics and brain metabolism of the levo-DOPA analog 6-[18F]fluoro-L-dopa (FDOPA) in cynomolgus monkeys, employing a compartmental model for the assay of DOPA decarboxylase activity in living brain. Four monkeys each underwent two PET scans in the baseline condition, one PET scan after treatment with OR-462 (15 mg/kg, i.v.), and one PET scan after treatment with OR-611 (15 mg/kg, i.v.). Pharmacokinetic analysis of FDOPA metabolism in plasma indicated that these compounds blocked peripheral COMT activity by 80% for at least 60 minutes. Both COMT inhibitors increased the net availability of FDOPA in circulation, and increased the ratio of the radioactivity concentrations in striatum and occipital cortex, suggesting that [18F]fluorodopamine synthesis in striatum was potentiated. However, OR-611 treatment reduced the unidirectional (K1D) and net (Ki) blood-brain clearances of FDOPA, and also inhibited the rate of decarboxylation (k3D) of FDOPA in striatum. These observations suggest that high doses of OR-611 may partially antagonize the cerebral utilization of levo-DOPA. We used the present data to test the sensitivity of the compartmental model to the physiological constraint that the blood-brain permeabilities of the O-methylated plasma metabolite and FDOPA have a fixed ratio. In the groups with COMT inhibition, the estimates of k3D were insensitive to the magnitude of the permeability ratio. In the control group, the estimate of k3D increased by 40% as the magnitude of the constrained permeability ratio increased in the range of published estimates.

Animals↗
PubMed1998

Origin of human motor readiness field linked to left middle frontal gyrus by MEG and PET.

Combined magnetoencephalography and positron emission tomography identified a prior source of activity in the left middle frontal gyrus during uncued movements of the right index finger. Voluntary movements gave rise to a change in the cortical electrical potential known as the Bereitschaftspotential or Readiness Potential, recorded as early as 1500 ms before the onset of movement. The Readiness Field is the magnetic field counterpart to the Bereitschaftspotential. In the present study, magnetoencephalography identified four successively active sources of fluctuation in the Readiness Field in the period from 900 ms before, to 100 ms after, the onset of the movement. The first source to be active was registered between 900 and 200 ms prior to the onset of the movement. This source of initial activity was mapped by positron emission tomography to the middle frontal gyrus, Brodmann area 9. The three sources subsequently to be active were mapped to the supplementary motor area, premotor cortex, and motor cortex (M1), all in the left hemisphere.

Adult↗
PubMed1998

Cerebral blood-flow changes evoked by two levels of painful heat stimulation: a positron emission tomography study in humans.

Positron emission tomography (PET) and accumulation of H(2)(15)O as a marker of neuronal activity were used to create maps of cerebral blood-flow changes evoked by painful heat stimulation in 10 subjects. Two levels of painful tonic and phasic heat stimuli were applied with use of a newly developed contact heat thermode on the volar surface of the dominant (right) arm. The subjects participated in two separate PET sessions. Maps reflecting low and high levels of painful tonic heat were obtained in the first session, and low and high levels of painful phasic heat in the second session. The subjects scored their peak pain intensity and unpleasantness on 10-cm visual analogue scales. For each subject, PET images were aligned to nuclear magnetic resonance (NMR) images and remapped into the standardized co-ordinate system of Talairach. After normalization of the PET volumes, subtraction images were formed voxel-by-voxel and converted to a t-statistic volume. The perceived pain intensity and unpleasantness were identical with painful tonic and phasic heat stimulation. Directed searches revealed significant blood-flow increases in the contralateral primary sensorimotor cortex (MI/SI), SII, insular cortex and cingulate cortex when the low tonic heat map was subtracted from the high. A similar, but not identical, pain-processing network was observed for the maps representing the subtraction of low and high phasic heat. In this subtraction, the blood-flow increases in MSI/SI did not reach statistical significance, and significant blood flow decreases were found in the contralateral middle temporal gyrus. Finally, the location of the activation site in the cingulate cortex was different from that observed during tonic heat pain. This study has provided more evidence for the existence of a common pain-processing network engaged during the perception of different levels of toxic and phasic heat pain. Copyright 1998 European Federation of Chapters of the International Association for the Study of Pain.

Journal Article↗
PubMed1998

Enhanced [3H]DOPA and [3H]dopamine turnover in striatum and frontal cortex in vivo linked to glutamate receptor antagonism.

We tested the hypothesis that blockade of NMDA glutamate receptors in brain enhances dopamine turnover. We blocked this class of glutamate receptors in the rat brain in vivo with dizocilpine (MK-801) and measured the accumulation of radiolabeled DOPA and its metabolites as functions of time after intravenous bolus injection. Using the time courses of the accumulated metabolites, we calculated the turnover constants of enzymes mediating dopamine synthesis and catabolism. Dizocilpine treatment for 8 days enhanced the rates of DOPA decarboxylation and dopamine oxidation (monoamine oxidation) 4- and 16-fold, respectively, in neostriatum and 10- and 3-fold, respectively, in frontal cortex. The findings are not inconsistent with the hypothesis that the psychotomimetic properties of dizocilpine may be the manifestation of denervation hypersensitivity linked to activation of key enzymes of dopamine turnover in striatum.

Animals↗
PubMed1998

Absolute cerebral blood flow and blood volume measured by magnetic resonance imaging bolus tracking: comparison with positron emission tomography values.

The authors determined cerebral blood flow (CBF) with magnetic resonance imaging (MRI) of contrast agent bolus passage and compared the results with those obtained by O-15 labeled water (H215O) and positron emission tomography (PET). Six pigs were examined by MRI and PET under normo- and hypercapnic conditions. After dose normalization and introduction of an empirical constant phi Gd, absolute regional CBF was calculated from MRI. The spatial resolution and the signal-to-noise ratio of CBF measurements by MRI were better than by the H215O-PET protocol. Magnetic resonance imaging cerebral blood volume (CBV) estimates obtained using this normalization constant correlated well with values obtained by O-15 labeled carbonmonooxide (C15O) PET. However, PET CBV values were approximately 2.5 times larger than absolute MRI CBV values, supporting the hypothesized sensitivity of MRI to small vessels.

Animals↗
PubMed1998

[3H]DOPA formed from [3H]tyrosine in living rat brain is not committed to dopamine synthesis.

Tyrosine hydroxylase of catecholamine neurons catalyzes the synthesis of 3,4-dihydroxphenylalanine (DOPA), which is subsequently metabolized to dopamine by DOPA decarboxylase (DDC). However, DOPA is not committed to decarboxylation in vivo because export of DOPA from brain and metabolism of DOPA other than decarboxylation are possible. To estimate the relative magnitudes of the several fates of DOPA, the kinetics of the uptake and metabolism of L-[3H]tyrosine ([3H]Tyr, intravenous infusion) was measured in brain of rats pretreated with NSD 1015, an inhibitor of DDC. Some rats were pretreated with haloperidol before the blockade of DDC. The [3H]Tyr was incorporated into brain protein at a rate constant of 0.03 min(-1). The relative tyrosine hydroxylase activity in striatum was 0.005 min(-1) at 30 minutes after NSD 1015, 0.011 min(-1) 3 hours later, and 0.020 min(-1) after haloperidol treatment. The rate constant for the clearance of DOPA from brain (0.06 min(-1)) and earlier estimates of the rate constant of DDC activity in striatum (0.26 min(-1)) together predict that 80% of DOPA formed in normal rat striatum normally is available for dopamine synthesis. It follows that modulation of DDC activity can influence the rate of DA synthesis by affecting the relative magnitude of the several fates of DOPA in living brain.

Animals↗
PubMed1998

Cerebral blood flow measurements by magnetic resonance imaging bolus tracking: comparison with [(15)O]H2O positron emission tomography in humans.

In six young, healthy volunteers, a novel method to determine cerebral blood flow (CBF) using magnetic resonance (MR) bolus tracking was compared with [(15)O]H2O positron emission tomography (PET). The method yielded parametric CBF images with tissue contrast in good agreement with parametric PET CBF images. Introducing a common conversion factor, MR CBF values could be converted into absolute flow rates, allowing comparison of CBF values among normal subjects.

Adult↗
PubMed1998

Increased oxygen consumption in human visual cortex: response to visual stimulation.

To test whether a sufficiently complex visual stimulus causes the consumption of oxygen to rise in the human visual cortex, we used positron emission tomography (PET) to measure the cerebral metabolic rate of oxygen (CMRO2) during visual stimulation in 6 healthy normal volunteers. A yellow-blue checkerboard, reversing its contrast at a frequency of 8 Hz, was presented for a period of 7 min, beginning 4 min before the onset of a 3-min scan. In the baseline condition, subjects fixated a cross-hair from 30 s before until the end of the 3-min scan. The CMRO2 was calculated with the two-compartment weighted integration method (1). The checkerboard minus baseline subtraction yielded statistically significant increases in CMRO2 in the primary (V1) and higher order visual cortices (V4 and V5). The significant CMRO2 increases were detected in these regions in both the group average and in each individual subject.

Adult↗
PubMed1998

[Positron emission tomography of the heart. From research to clinical practice].

Positron emission tomography (PET) is used as diagnostic and in identifying patients with reversible ischaemic dysfunction, and for non-invasive investigation of myocardial perfusion. The development of new positron-emitting tracers and user-friendly techniques suggests that the method is suitable for much wider usage, and usage over a large range of applications.

Coronary Circulation↗
PubMed1997

The kinetic behaviour of [3H]DOPA in living rat brain investigated by compartmental modelling of static autoradiograms.

The kinetic behaviour of [3H]DOPA in living rat brain was investigated by compartmental modelling of measured activities from combined metabolite pools in a time-series (180 min) of static autoradiograms from right cerebral hemispheres. Two models of [3H]DOPA uptake and metabolism that incorporated the removal of the decarboxylation product, [3H]dopamine, from brain were significantly more accurate than a model in which [3H]dopamine accumulated irreversibly in situ. Present estimates of [3H]DOPA kinetic constants were compared to previously published results based on the analysis of measured activities from individual metabolite pools separated by chromatographic fractionation of [3H]DOPA metabolites in the left cerebral hemispheres of the same rats. Autoradiographic estimates of DOPA decarboxylase activity with respect to [3H]DOPA in brain (k3DOPA) were under-estimated several-fold relative to chromatographic estimates; this discrepancy is explained by post-mortem enzyme activity and omission of biological compartments from the models. However, autoradiographic estimates of the unidirectional blood-brain clearance of [3H]DOPA (K1DOPA) and monoamine oxidase activity with respect to [3H]dopamine in brain (k7DA') agreed with chromatographic estimates. This concordance represents the first empirical validation of compartmental modelling of autoradiographic data as a method for quantitatively investigating the kinetic behaviour of radiolabelled L-DOPA in living mammalian brain.

Animals↗