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Biomedical subjects

A Gjedde

Publications and source records attributed to A Gjedde.

At least 55 records · Page 3Linked to original sources
PubMed1999

Stimulation of dopa decarboxylase activity in striatum of healthy human brain secondary to NMDA receptor antagonism with a low dose of amantadine.

The efficacy of amantadine in alleviating motor symptoms of Parkinson's disease may be mediated in part by stimulation of cerebral dopa decarboxylase (DDC) activity, secondary to antagonism of N-methyl-D-aspartate (NMDA) type glutamate receptors. We tested the specific hypothesis that amantadine increases the decarboxylation rate of 6-[(18)F]fluoro-L-DOPA (FDOPA), an exogenous substrate for DDC, in healthy human brain. Radioactivity concentrations in brain tissue of neurologically normal volunteers (n = 5) injected intravenously with FDOPA ( approximately 4.5 mCi) were recorded by positron emission tomography (PET) for 120 min, first in a baseline condition, and again following three consecutive days of treatment with amantadine (100 mg/day, p.o.). Data from four telencephalic regions of interest containing appreciable DDC activity were analyzed with the tissue slope-intercept plot, using cerebellar cortex as the reference tissue, to estimate a coefficient of in situ FDOPA decarboxylation (k(3)(r), min(-1)). Mean estimates of k(3)(r) were increased following amantadine treatment in caudate nucleus (+12%), putamen (+28%), ventral striatum (+27%), and frontal cortex (+9%). For an initial confidence level of 95%, paired one-sided Student's t-tests with Bonferroni correction for multiple comparisons revealed a statistically significant drug effect in ventral striatum. Present results are consistent with stimulation of DDC activity in striatum of healthy human brain secondary to NMDA receptor antagonism with a low dose of amantadine, and suggest that this response is an important mechanism underlying the anti-parkinsonian properties of amantadine. Nonetheless, PET studies in parkinsonian patients using higher, clinically effective doses of amantadine may reveal more pronounced enhancements of cerebral DDC activity.

Adult↗
PubMed1999

Cerebral 6-[(18)F]fluoro-L-DOPA (FDOPA) metabolism in pig studied by positron emission tomography.

We measured 6-[(18)F]fluoro-L-DOPA (FDOPA) uptake and metabolism in the brain of 4-month-old female pigs (n = 8) using a high-resolution positron emission tomograph (PET) in 3D mode. The mean net blood-brain clearance of FDOPA (K(i)(D)) to striatum was 0.011 ml g(-1) min(-1). Correcting for the elimination of decarboxylated metabolites from striatum (k(loss) = 0.004 min(-1)) increased the apparent magnitude of the estimate of K(i)(D) by 50%, at the expense of doubling the variance of the mean estimate. The mean decarboxylation rate of FDOPA in striatum relative to the cerebellum input (k(3)(s)) was 0.008 min(-1). For multicompartmental analyses, the FDOPA partition volume (V(e)(D)) was constrained to the individual value observed in cerebellum (mean = 0.53 ml g(-1)), with correction for the presence in brain of the plasma metabolite 3-O-methyl-FDOPA (OMFD). Using the first 60 min of the dynamic PET scans, the rate constant of FDOPA decarboxylation (k(3)(D)) was estimated to be 0.037 min(-1 )in striatum, but was not significantly different than zero in frontal cortex. Fitting of a compartmental model correcting for elimination of decarboxylated metabolites to the complete PET frame-sequence (120 min) increased the variance of the estimate of k(3)(D) in striatum. The magnitude of k(3)(D) in striatum of young pig was less than values estimated previously in neonatal piglet, adult monkey, and human. MRI-based simulations predicted that recovery of radioactivity from pig striatum was highly sensitive to the volume of interest. We conclude that the spatial resolution of our tomograph reduces the apparent magnitude of k(3)(D) in striatum. However, anaesthetised pigs are an appropriate experimental model for PET studies of DOPA decarboxylation in striatum.

Aging↗
PubMed1999

Pharmacokinetics of radiotracers in human plasma during positron emission tomography.

Many radiopharmaceuticals for positron emission tomography (PET) are substantially metabolized in peripheral organs. Pharmacological treatments intended to alter cerebral metabolism might also alter radiotracer metabolism, consequently altering the cerebral uptake. First-order rate constants for the metabolism of PET tracers can be calculated by a linear graphical method from the precursor and metabolite concentrations measured in plasma extracts fractionated by HPLC. We tested the effects of specific pharmacological challenges on the plasma kinetics of six tracers used for PET studies of neurotransmission. The rate of O-methylation of circulating [(18)F]fluorodopa, a tracer of dopa decarboxylase activity in brain, was unaffected by pretreatment with amantadine, an antagonist of glutamate receptors. [(11)C]Deprenyl, a tracer of monoamine oxidase activity, was rapidly metabolized to [(11)C]methamphetamine and polar metabolites in healthy volunteers. The net rate constant of this metabolism was three times higher in a group of subjects under treatment for epilepsy, consistent with induction of hepatic microsomal enzymes by antiepileptic drugs. [(11)C]Sch 23390, a ligand for dopamine D1 receptors, was rapidly metabolized to polar metabolites. The net rate constant of metabolism was unaffected by pretreatment with lorazepam. [(11)C]-(S)-Nicotine, a ligand for nicotinic receptors, was rapidly metabolized to [(11)C]-(S)-cotenine, which is less polar than the parent compound. Pretreatment with mazindol, a dopamine uptake inhibitor, was without effect on peripheral metabolism of [(11)C]-(S)-nicotine. [(11)C]WIN 35,428, a tropane derivative which labels dopamine uptake sites, was metabolized to a nonpolar metabolite, but so slowly that the rate constant of this process could not be calculated. [(11)C]Raclopride, a ligand for dopamine D2 receptors, was first metabolized to a nonpolar metabolite, which then yielded two hydrophilic metabolites. The initial metabolic step was substantially blocked by pretreatment with amphetamine, possibly indicative of competitive inhibition of microsomal oxidation. Together, these results indicate that the linear graphic method is useful for estimating the kinetics of the plasma metabolism of many widely used PET tracers. Drug-drug interactions were revealed in subjects treated with specific pharmacological agents prior to tracer administration.

Benzazepines↗
PubMed1999

Activation of human extrageniculostriate pathways after damage to area V1.

We have used positron emission tomography (PET) to specify the cortical and subcortical structures activated following visual stimulation of the scotomatous field in a patient with an asymmetric bilateral developmental anomaly of the visual cortex. Computerized perimetry indicated a left visual field defect only although MRI and 18FDG-PET scans showed abnormalities in both occipital lobes. The visual stimuli were semicircular gratings moving in opposite directions on a dynamic random-dot background. They were specifically constructed to eliminate intra- and extraocular light scatter and to optimize the activation of extra-striate cortical areas and their projecting subcortical relays. For anatomical localization PET images were coregistered to the subject's MRI in Talairach coordinates. After subtraction of the baseline conditions from the stimulation conditions, a t-statistic map was created on a voxel-by-voxel basis. Stimulation of the scotomatous hemifield yielded significant activations of Brodmann cortical areas 18-19 and 47 as well as the pulvinar thalami of the left hemisphere, in addition to a less prominent activation in the right hemisphere. Stimulation of the intact hemifield produced significant activation of Brodmann cortical areas 30 and 47 of the left hemisphere. These results suggest that in the absence of area V1, residual vision observed in the blind hemifield could be mediated by a retinofugal pathway to extrastriate cortex via the pulvinar.

Adult↗
PubMed1999

Cortical responses to sustained and divided attention in Alzheimer's disease.

Neuropsychological data suggests that divided attention is more impaired than sustained attention during the early phases of Alzheimer's disease. The purpose of the present study was to compare cerebral activation patterns during sustained and divided attention between Alzheimer patients and healthy elderly. The O-15-water PET activation method was used to map sustained and divided attention in 16 patients with Alzheimer's disease (mean age +/- SD: 68 +/- 5 years; MMSE: 11-25, mean +/- SD = 19.5 +/- 4.9) and in 16 healthy age-matched control subjects. After stereotactical normalization, voxel-by-voxel t statistics was used to assess the significance of activated brain areas and to compare activations between patients and control subjects. In the healthy elderly, sustained and divided attention both elicited activation of the right inferior parietal lobule, and the right middle frontal gyrus, whereas the anterior cingulate gyrus was activated during sustained attention only. Only medial frontal structures (Brodmann Area (BA) 32/34) were activated in Alzheimer patients, and both frontal (BA-10), posterior cingulate (BA-23/31), and subcortical sites were deactivated. Compared to the healthy elderly, the activations in the patients of the right medial (BA-11) superior (BA-10) and inferior (BA-47) frontal gyri, the right middle temporal (BA-20), and the left lingual (BA-17) gyri were significantly reduced. More cortical sites differed statistically between Alzheimer patients and control subjects during divided than during sustained attention. The activation pattern elicited by attention supports the neuropsychological data that divided attention is more impaired than sustained attention in early Alzheimer's disease.

Aged↗
PubMed1999

On the oxygenation of hemoglobin in the human brain.

We test three hypotheses arising from a model of oxygen delivery to brain tissue. The hypotheses claim that mitochondrial oxygen is negligible in brain tissue such that oxygen consumption depends solely on the mean capillary oxygen tension for a given capillary density; that capillary density is adjusted to satisfy the average steady-state oxygen requirement; and that sudden changes of brain function are subserved by changes of blood flow which adjust the mean capillary oxygen tension in the required direction. The results of the tests did not reject the two former hypotheses and only partly rejected the latter: Sudden changes of blood flow are not always accompanied by increases of oxygen consumption. When they are, changes of apparent capillary density (physiological recruitment) can occur.

Brain↗
PubMed1999

Positron emission tomography of cortical centers of tinnitus.

Tinnitus is associated with a wide variety of disorders in the auditory system. Whether generated peripherally or centrally, tinnitus is believed to be associated with activity in specific cortical regions. The present study tested the hypothesis that these cortical centers subserve the generation, perception and processing of the tinnitus stimulus and that these processes are suppressed by lidocaine and masking. Positron emission tomography was used to map the tinnitus-specific central activity. By subtracting positron emission tomography images of regional cerebral blood flow distribution obtained during suppression of the tinnitus from positron emission tomography images obtained during the habitual tinnitus sensation, we were able to identify brain areas concerned with the cerebral representation of tinnitus. Increased neuronal activity caused by tinnitus occurred predominantly in the right hemisphere with significant foci in the middle frontal and middle temporal gyri, in addition to lateral and mesial posterior sites. The results are consistent with the hypothesis that the sensation of tinnitus is associated with activity in cortical regions functionally linked to subserve attention, emotion and memory. For the first time, the functional anatomy of conditions with and without the habitual tinnitus sensation was obtained and compared in the same subjects.

Adult↗
PubMed1999

Uptake and distribution of a new SSRI, NS2381, studied by PET in living porcine brain.

This study tests the utility of a new selective serotonin reuptake inhibitor (SSRI), [11C]NS2381 {(+/-)-(8-[11C]methyl-3-(4-trifluoromethyl-phenyl)-8-azabicyclo[3.2.1]oc t-2-ene)}, as positron-emitting radioligand for labelling serotonin (5-HT) reuptake sites in living brain. Studies of monoamine uptake were carried out initially in vitro using rat brain synaptosomes. They showed that NS2381 and its precursor NS2435 are selective inhibitors of serotonin (5-HT) uptake. Then, studies were carried out in vivo on the uptake and distribution of [11C]NS2381 in living porcine brain. They showed that the radiotracer accumulates readily in brain, and binds reversibly in regions rich in serotonin uptake sites (e.g. raphe, basal ganglia and thalamus). In addition, [11C]NS2381 was displaced from brain tissue by the potent SSRI citalopram. The enantiomers of [11C]NS2381 were, in general, found to be similar to the racemate in terms of their uptake and distribution in living pig brain. Thus, [11C]NS2381 fulfilled several criteria of a PET radioligand for studying 5-HT uptake sites in the living brain.

Animals↗
PubMed1999

Stimulus-dependent central processing of auditory stimuli: a PET study.

Positron emission tomography (PET) was used to investigate the neural systems involved in the central processing of different auditory stimuli. Noise, pure tone and pure-tone pulses, music and speech were presented monaurally. O-15-water PET scans were obtained in relation to these stimulations presented to five normal hearing and healthy subjects. All stimuli were related to a basic scan in silence. Processing of simple auditory stimuli, such as pure tones and noise, predominantly activate the left transverse temporal gyrus (Brodmann area [BA] 41), whereas sounds with discontinued acoustic patterns, such as pure-tone pulse trains, activated parts of the auditory association area in the superior temporal gyri (BA 42) in both hemispheres. Moreover, sounds with complex spectral, intensity, and temporal structures (words, speech, music) activated spatially even more extensive associative auditory areas in both hemispheres (BA 21, 22). PET has revealed a remarkable potential to investigate early central auditory processing, and has provided evidence of the coexistence of functionally linked, but individually active parallel and serial auditory networks.

Acoustic Impedance Tests↗
PubMed1999

Brief vibrotactile stimulation does not increase cortical oxygen consumption when measured by single inhalation of positron emitting oxygen.

Vibrotactile stimulation of the hand elicits no increase in oxygen consumption commensurate with the increase in blood flow measured in human sensory cortex. To test the hypothesis that previous failures to detect a proportionate increase in oxygen consumption could be an artefact of the sequential bolus, or three-step, method used to measure this parameter in the human brain in vivo, the authors compared the measurements with the results of a novel single bolus, or one-step, method of measuring oxygen consumption. The time of completion of the three-step method was 40 to 50 minutes, whereas the one-step method lasted only 3 minutes. The baseline whole-brain oxygen consumption averaged 185 +/- 32 micromol hg(-1) min(-1) by the three-step method and 153 +/- 15 micromol hg(-1) min(-1) by the one-step method. Vibrotactile stimulation did not elicit a significant increase in oxygen consumption measured by either method. This finding rejects the hypothesis that failure to detect an increase of oxygen consumption could be an artefact caused by limitations of the method used previously. Conversely, it also rejects the hypothesis that observations of an increase of oxygen consumption by the new method are artefacts caused by limitations of the one-step method.

Blood Flow Velocity↗
PubMed1999

Oxygen consumption of cerebral cortex fails to increase during continued vibrotactile stimulation.

The coupling of oxidative metabolism to the blood flow of the sensory motor hand area is uncertain. The authors tested the hypothesis that continued vibrotactile stimulation ultimately must lead to increased oxygen consumption consumption. Twenty-two healthy right-handed young volunteers underwent positron emission tomography (PET) with the [(15)O]water bolus injection method to measure water clearance (K1H2O an index of blood flow (CBF), and with the [(15)O]oxygen bolus inhalation method to measure CMR(O2). The CMR(O2) was measured 30 seconds and 20 minutes after onset of intermittent (1 second on, 1 second off) vibrotactile stimulation (110 Hz) and compared with baseline measurements without stimulation. The K1H2O and CMR(O2) changes (delta K1H2O and delta CMR(O2)) were determined using intersubject averaging, together with magnetic resonance imaging based stereotaxic registration technique. The K1H2O increase was 21 +/- 4% and 12 +/- 4% at 30 seconds and 20 minutes after onset of stimulation, respectively. No significant increase of CMR(O2) was found until 30 minutes after the onset of stimulation. The authors conclude that blood flow and oxidative metabolism undergo uncoupling during sustained phasic stimulation of the sensory hand area. Therefore, neuronal activity stimulated in this manner does not rely on significantly increased oxidative phosphorylation.

Blood Flow Velocity↗
PubMed1999

Frequency-dependent changes in cerebral metabolic rate of oxygen during activation of human visual cortex.

To test the hypothesis that brain oxidative metabolism is significantly increased upon adequate stimulation, we varied the presentation of a visual stimulus to determine the frequency at which the metabolic response would be at maximum. The authors measured regional CMR(O2) in 12 healthy normal volunteers with the ECAT EXACT HR+ (CTI/Siemens, Knoxville, TN, U.S.A.) three-dimensional whole-body positron emission tomograph (PET). In seven successive activating conditions, subjects viewed a yellow-blue annular checkerboard reversing its contrast at frequencies of 0, 1, 4, 8, 16, 32, and 50 Hz. Stimulation began 4 minutes before and continued throughout the 3-minute dynamic scan. In the baseline condition, the subjects began fixating a cross hair 30 seconds before the scan and continued to do so for the duration of the 3-minute scan. At the start of each scan, the subjects inhaled 20 mCi of (15)O-O2 in a single breath. The CMR(O2) value was calculated using a two-compartment, weighted integration method. Normalized PET images were averaged across subjects and coregistered with the subjects' magnetic resonance imaging in stereotaxic space. Mean subtracted image volumes (activation minus baseline) of CMR(O2) then were obtained and converted to z statistic volumes. The authors found a statistically significant focal change of CMR(O2) in the striate cortex (x = 9; y = -89; z = -1) that reached a maximum at 4 Hz and dropped off sharply at higher stimulus frequencies.

Administration, Inhalation↗
PubMed1999

NMSP binding to dopamine and serotonin receptors in MPTP-induced parkinsonism: relation to dopa therapy.

We tested the hypothesis that N-methylspiperone binding to dopamine D2 receptors must be reduced when L-dopa therapy of parkinsonism augments the binding of dopamine to the receptors and improves the clinical state expressed by the Hoehn & Yahr stage. A patient with MPTP-induced parkinsonism underwent two positron emission tomographic studies of the D2-like dopamine receptors with N-[11C]methylspiperone (NMSP). The first study took place 3 days after cessation of the L-dopa medication, the second 5 days after its resumption. Noticeable clinical deterioration occurred during both studies, consistent with significant dopamine receptor blockade by NMSP and elevated NMSP binding in both scans. The dopa treatment did not reduce the NMSP binding. On the contrary, the rate of binding of NMSP (k3) was increased on-dopa, compared to off-dopa. The increase was consistent with the slightly greater dopamine receptor density estimated after resumption of the dopa therapy. The NMSP binding to serotonin receptors suggested lower synaptic serotonin on-dopa than off-dopa. The results are consistent with negative correlation between the Hoehn & Yahr stage and the amount of dopamine bound to dopamine D2 receptors. Low synaptic serotonin may explain the depression seen in some patients on dopa for Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗