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K A Frey

Publications and source records attributed to K A Frey.

At least 91 records · Page 5Linked to original sources
PubMed1993

Positron emission tomography measures of benzodiazepine receptors in Huntington's disease.

We performed positron emission tomographic (PET) measurements of the regional distribution volume of benzodiazepine receptors and regional glucose metabolism in 6 drug-free patients with early Huntington's disease following injection of [11C]flumazenil, a nonsubtype selective central benzodiazepine receptor antagonist, and 18F-2-fluoro-2-deoxy-D-glucose, respectively. Flumazenil data were analyzed with a recently developed two-compartment, two-parameter tracer kinetic model. Benzodiazepine receptor density is related to distribution volume for flumazenil. In comparison with a group of healthy volunteers, benzodiazepine receptor density was significantly decreased in the caudate nucleus. Glucose metabolism was significantly reduced not only in the caudate nucleus but also in the putamen and thalamus. The changes in benzodiazepine receptor density observed in the caudate nucleus are commensurate with data obtained in postmortem autoradiographic studies of receptor density. Based on such postmortem studies we also anticipated changes in putamen and thalamic benzodiazepine receptor density. However, relatively little is known on receptor changes in early Huntington's disease, because the autoradiographic data available were obtained mostly in patients with advanced disease. The decreased glucose metabolism in the caudate and putamen agrees well with previously published results of PET studies, whereas metabolic impairment of the thalamus has not yet been described in Huntington's disease. The present study suggests that regional metabolism and gamma-aminobutyric acid (GABA)-benzodiazepine receptor changes in subcortical structures of patients with early Huntington's disease do not occur with the same time course: Caudate benzodiazepine receptor density is already severely impaired when other subcortical structures reveal only minor abnormalities.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Discordance between F-18 fluorodeoxyglucose uptake and contrast enhancement in a brain abscess.

A 29-year-old human immunodeficiency virus-negative intravenous drug abuser with a right hemispheric staphylococcal brain abscess underwent PET imaging of 18F-fluorodeoxyglucose (FDG) brain uptake. Diffuse right cortical hypometabolism was noted, as well as crossed cerebellar diaschisis. Unlike previous PET findings on FDG uptake in a brain abscess, however, the most intense uptake of FDG was found within the abscess and not in the contrast-enhancing walls.

Adult↗
PubMed1993

Neuroimaging of epilepsy, movement disorders, and degenerative diseases.

Neuroimaging has improved the understanding, diagnosis, and management of several neurologic diseases and syndromes. Recent advances in the neuroimaging of epilepsy, movement disorders, and degenerative diseases of the nervous system are reviewed. Current research confirms that structural and functional neuroimages each provide unique, clinically useful information in these disorders. Quantification of images improves their diagnostic sensitivity and specificity. Presymptomatic or early neurochemical changes have been identified and followed longitudinally in several neurodegenerative diseases, providing a method for monitoring response to therapeutic intervention and pathophysiologic hypothesis testing. Functional activation studies and receptor-specific radioligands continue to advance our understanding of these disorders. Future methods will take increasing advantage of both the ability to measure neuropharmacological and neurochemical changes in vivo, and the ability to combine images and information obtained with distinct structural and functional neuroimaging modalities.

Brain↗
PubMed1993

In vivo imaging of vesicular monoamine transporters in human brain using [11C]tetrabenazine and positron emission tomography.

The pharmacokinetics of [11C]tetrabenazine, a high-affinity radioligand for the monoamine vesicular transporter, were determined in living human brain using in vivo imaging by positron emission tomography (PET). The radiotracer showed high brain uptake and rapid washout from all brain regions with relatively slower clearance from regions of highest concentrations of monoamine vesicular transporters (striatum), resulting in clear differential visualization of these structures at short intervals after injection (10-20 min). As the first human PET imaging study of a vesicular neurotransmitter transporter, these experiments demonstrate that external imaging of vesicular transporters forms a new and valuable approach to the in vivo quantification of monoaminergic neurons, with potential application to the in vivo study of neurodegenerative disorders such as Parkinson's disease.

Adult↗
PubMed1993

In vivo cerebral metabolism and central benzodiazepine-receptor binding in temporal lobe epilepsy.

Positron emission tomography measured interictal cerebral glucose metabolism with [18F]fluorodeoxyglucose and central benzodiazepine-receptor binding with [11C]flumazenil in 10 mesial temporal lobe epilepsy (TLE) patients and in normal subjects. Eight TLE patients had mesial temporal, lateral temporal, and thalamic hypometabolism ipsilateral to EEG ictal onsets, with additional extratemporal hypometabolism in four. One had unilateral anterior mesial temporal hypometabolism only, and one had normal metabolism. Each patient had decreased benzodiazepine-receptor binding in the ipsilateral anterior mesial temporal region, without neocortical changes. Thus, interictal metabolic dysfunction is variable and usually extensive in TLE, whereas decreased central benzodiazepine-receptor density is more restricted to mesial temporal areas. Metabolic patterns in TLE may reflect diaschisis, while benzodiazepine-receptor changes may reflect localized neuronal and synaptic loss that is specific to the epileptogenic zone. [11C]Flumazenil imaging may be useful in presurgical evaluation of refractory complex partial seizures.

Adult↗
PubMed1993

Autoradiographic mapping of M3 muscarinic receptors in the rat brain.

The regional distribution of putative M3 receptors was studied by quantitative autoradiography of rat brain sections labeled with 4-diphenylacetoxy-N-methyl-piperidine methioxide. The radioligand appears to label multiple muscarinic receptor subtypes in direct binding assays, as evidenced by competition experiments with unlabeled pirenzepine and 11-([2-[(2-(diethylamino)methyl]-1- piperidinyl]acetyl-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodi azepine-6-on. Conditions favoring the selective labeling of M3 receptors were determined on the basis of the competition studies and were subsequently applied to regional mapping of M3 receptor binding. Under the conditions used, autoradiographic images may be obtained with both 9-fold M3-to-M1 selectivity and 12-fold M3-to-M2 selectivity. Although distributed widely at relatively low prevalence throughout the neuraxis, M3 receptors are apparently enriched relative to M1 and M2 receptors in several diencephalic and brain stem regions including thalamic and hypothalamic nuclei, the substantia nigra, superior colliculus, periaqueductal gray and the pons. The present results suggest that the binding of 4-diphenylacetoxy-N-methyl-piperidine methioxide, under appropriate conditions, may permit direct estimation of M3 receptors in mammalian brain.

Animals↗
PubMed1993

Automated detection of the intercommissural line for stereotactic localization of functional brain images.

A technique has been developed for automated detection of the intercommissural (AC-PC) line for positron emission tomography (PET). The AC-PC line is estimated from the location of four internal landmarks; the frontal and occipital poles, the inferior aspect of the anterior corpus callosum, and the subthalamic point. The landmarks are detected automatically in PET mid-sagittal slices by combining edge detection, interpolation and profile curve analysis techniques. The anatomical relationships between the true and estimated AC-PC lines from the landmarks was confirmed by analysis of magnetic resonance (MR) images. Accuracy of the automated estimation technique was assessed in co-registered PET and MR images, which showed minimal angular differences and displacements of the estimated from the true AC-PC lines. The automated detection of the AC-PC line in a PET study enables accurate stereotactic localization of functional signals without the need for additional anatomical imaging and provides a basis for objective and reproducible intersubject comparison.

Brain↗
PubMed1992

In vivo muscarinic cholinergic receptor imaging in human brain with [11C]scopolamine and positron emission tomography.

Cerebral muscarinic cholinergic receptors were imaged and regionally quantified in vivo in humans with the use of [11C]scopolamine and positron emission tomography. Previous studies in experimental animals have suggested the utility of radiolabeled scopolamine for in vivo measurements, on the bases of its maintained pharmacologic specificity following systemic administration and the exclusion of labeled metabolites from the brain. The present studies describe the cerebral distribution kinetics of [11C]scopolamine in normal subjects following intravenous injection. Scopolamine is initially delivered to brain in a perfusion-directed pattern. After 30 to 60 min, activity is lost preferentially from cerebral structures with low muscarinic receptor density including the cerebellum and thalamus. Activity continues to accumulate throughout a 2 h postinjection period in receptor-rich areas including cerebral cortex and the basal ganglia. The late regional concentration of [11C]scopolamine does not, however, accurately parallel known differences in muscarinic receptor numbers in these receptor-rich areas. Tracer kinetic analysis of the data, performed on the basis of a three-compartment model, provides receptor binding estimates in good agreement with prior in vitro measurements. Kinetic analysis confirms significant contributions of ligand delivery and extraction to the late distribution of [11C]scopolamine, reconciling the discrepancy between receptor levels and tracer concentration. Finally, a novel dual-isotope method for rapid chromatographic processing of arterial blood samples in radiotracer studies is presented. The combination of rapid chromatography and compartmental analysis of tracer distribution should have broad utility in future in vivo studies with short-lived radioligands.

Brain↗
PubMed1992

Technetium-99m-N1-(2-mercapto-2-methylpropyl)-N2-(2-propargylthio-2- methylpropyl)-1,2-benzenediamine (T691): preclinical studies of a potential new tracer of regional cerebral perfusion.

We report in vitro and in vivo preclinical studies of a new cerebral blood flow tracer, [99mTc]N1-(2-mercapto-2-methyl-propyl)-N2-(2- propargylthio-2-methylpropyl)-1,2-benzenediamine (T691). The tracer demonstrates excellent in vitro chemical stability and accumulates regionally in the brain in a pattern consistent with that of cerebral blood flow. First-pass cerebral extraction determined with the use of the brain uptake index method in the rat was 0.76. Bolus intracarotid injection in monkeys indicated a cerebral extraction of 68% and prolonged retention of 67% of the initially extracted activity. Autoradiographic studies in rats revealed a pattern characteristic of cerebral blood flow at both 1 and 60 min after systemic injection. Dynamic tomographic imaging following systemic injection in the monkey revealed peak brain activity 1 to 2 min postinjection, without significant decline over 60 min. Chromatographic studies of brain as long as 60 min following systemic injection of [99mTc]T691 showed no evidence of tracer metabolism to account for its retention. Overall, [99mTc]T691 demonstrates promise as a potential new clinical tracer of cerebral perfusion.

Animals↗
PubMed1992

Quantitative autoradiography of muscarinic cholinergic receptor binding in the rat brain: distinction of receptor subtypes in antagonist competition assays.

Prior studies have suggested the presence of muscarinic acetylcholine receptor (MAChR) subtypes within the mammalian central nervous system on the bases of functional ligand binding or molecular biologic evidence. Autoradiographic differentiation of MAChR subtypes in ligand binding assays has previously relied on the use of agonists, results of homogenate binding assays to determine relative subtype binding affinities or both. In the present study, the binding of [3H]scopolamine to intact slide-mounted tissue sections is characterized. The rapid binding kinetics of the ligand permit autoradiographic saturation experiments. Autoradiographic competition assays utilizing [3H]scopolamine and the unlabeled subtype-selective ligands pirenzepine, 11-((2-[(diethylamino)methyl]-1-piperidinyl)acetyl)-5,11,-dihydro-6H-pyr ido (2,3-b)(1,4)benzodiazepin-6-on (AF-DX 116) and 4-diphenylacetoxy-N-methylpiperidine methiodide reveal evidence for the presence of multiple MAChR subtypes distributed heterogeneously throughout the brain. High-affinity pirenzepine MAChR (putative M1 subtype) predominate in the telencephalon. High-affinity AF-DX 116 MAChR (putative M2 subtype) are widely distributed, but are quantitatively minor populations, with the exception of motor cranial nerve nuclei and the basal pons, where they represent the dominant MAChR fractions. Evidence for relative enrichment of M3 receptors was obtained in the thalamus, the superficial layer of the superior colliculus, the periqueductal region, the substantia nigra pars reticulata and the pons. The autoradiographic assays developed in this work may assist in defining altered receptor populations arising in pathologic conditions or resulting from drug therapy.

Animals↗
PubMed1992

Involvement of pharmacy faculty in the development of policies for pharmaceutical sales representatives.

BACKGROUND: Few studies evaluating the impact of the pharmaceutical industry on postgraduate medical education have been done. Recently, position statements and professional guidelines have emerged to ensure the integrity of physician-industry relationships in the areas of clinical judgement, research, and medical education. METHODS: The present study surveyed directors of family practice residency programs in the United States to define the level of pharmacotherapy curriculum development and the existence of policies for pharmaceutical sales representatives. RESULTS: Of the 383 directors, 325 (85%) responded to a mailed survey. Nearly one third (32%) of the responding programs had pharmacist faculty, the majority of whom held a doctor of pharmacy degree. Approximately 30% of programs reported that they had printed guidelines for pharmaceutical sales representatives. CONCLUSIONS: Programs with pharmacist faculty are more likely to have a well-developed pharmacotherapy curriculum and printed guidelines for pharmaceutical sales representatives.

Curriculum↗
PubMed1991

Parametric in vivo imaging of benzodiazepine receptor distribution in human brain.

Emission computed tomographic methods for the in vivo quantification of radioligand-binding sites in human brain have previously been limited either by a lack of correction for possible effects of altered ligand transport or by highly complicated physiological models that preclude display of binding data in a detailed anatomical format. We investigated the application of a simplified compartmental model to the kinetic analysis of in vivo ligand binding to central benzodiazepine receptors. The human brain distribution of [11C]flumazenil, as determined by dynamic positron emission tomography, combined with metabolite-corrected arterial blood samples, permitted estimations of local cerebral ligand transport and of receptor binding. This approach allows calculation of transport and binding "maps" on a pixel-by-pixel basis, resulting in the display of binding data in a familiar tomographic format while maintaining much of the physiological accuracy inherent in more complex methods. The results obtained in a study of 6 normal volunteers revealed good interindividual precision, with coefficients of variation between 10 and 15% of mean regional values, suggesting the utility of this approach in future clinical studies of benzodiazepine receptor binding.

Adult↗
PubMed1991

Quantitative in vivo receptor binding. IV: Detection of muscarinic receptor down-regulation by equilibrium and by tracer kinetic methods.

Newly-developed methods for estimation of in vivo binding to neurotransmitter receptors should enable the detection and quantification of physiologic or pathologic changes in receptor numbers. In the present study, both equilibrium and kinetic experimental strategies for in vivo muscarinic receptor determination were applied to the detection of receptor changes induced by chronic inhibition of acetylcholinesterase in the rat. Following one week of treatment, in vitro receptor autoradiography utilizing [3H]scopolamine revealed significant losses of muscarinic binding in the cerebral cortex, hippocampus, striatum and in cranial nerve motor nuclei. The in vivo distribution of [3H]scopolamine, following infusion to approach equilibrium binding in the brain, revealed reductions in binding which paralleled the pattern and magnitude of changes detected in vitro. A simplified tracer kinetic estimation following bolus injection of the ligand also detected substantial reductions in forebrain muscarinic receptor binding. These results indicate the feasibility of detecting receptor changes underlying neuropathologic conditions in vivo, and suggest that either equilibrium or kinetic experimental approaches may be extended to clinical research applications with the use of positron or single-photon emission tomography.

Animals↗
PubMed1991

Compartmental analysis of [11C]flumazenil kinetics for the estimation of ligand transport rate and receptor distribution using positron emission tomography.

The in vivo kinetic behavior of [11C]flumazenil ([11C]FMZ), a non-subtype-specific central benzodiazepine antagonist, is characterized using compartmental analysis with the aim of producing an optimized data acquisition protocol and tracer kinetic model configuration for the assessment of [11C]FMZ binding to benzodiazepine receptors (BZRs) in human brain. The approach presented is simple, requiring only a single radioligand injection. Dynamic positron emission tomography data were acquired on 18 normal volunteers using a 60- to 90-min sequence of scans and were analyzed with model configurations that included a three-compartment, four-parameter model, a three-compartment, three-parameter model, with a fixed value for free plus nonspecific binding; and a two-compartment, two-parameter model. Statistical analysis indicated that a four-parameter model did not yield significantly better fits than a three-parameter model. Goodness of fit was improved for three- versus two-parameter configurations in regions with low receptor density, but not in regions with moderate to high receptor density. Thus, a two-compartment, two-parameter configuration was found to adequately describe the kinetic behavior of [11C]FMZ in human brain, with stable estimates of the model parameters obtainable from as little as 20-30 min of data. Pixel-by-pixel analysis yields functional images of transport rate (K1) and ligand distribution volume (DV"), and thus provides independent estimates of ligand delivery and BZR binding.

Adult↗
PubMed1991

Differentiation of radioligand delivery and binding in the brain: validation of a two-compartment model for [11C]flumazenil.

We recently developed a two-compartment, two-parameter tracer kinetic model to estimate the in vivo ligand transport rate (K1) and distribution volume (DV) for the benzodiazepine antagonist [11C]flumazenil (FMZ) as measured by positron emission tomography (PET). The aim of the present study was to validate that this simplified model provides a stable measure of regional benzodiazepine receptor availability even when ligand delivery is altered. Six young normal volunteers underwent two PET studies subsequent to intravenous injections of [11C]FMZ. Each FMZ study was immediately preceded by measurements of CBF following injection of [15O]water. One set of scans (water/FMZ) was acquired under resting conditions and the other set during audiovisual stimulation. Six additional volunteers underwent two FMZ studies under identical resting conditions. Parametric images were analyzed and a comparison of test-retest studies in the stimulation group revealed a significant increase of CBF and K1 of FMZ in the occipital cortex evoked by visual activation, whereas no regional changes were noted for the DV of FMZ. No significant changes were noted for either K1 or DV of FMZ when comparing studies in the rest-rest setting. The results indicate that the use of a simple two-compartment model for the tracer kinetic analysis of [11C]FMZ makes it possible to separate high-affinity binding from altered radio-ligand delivery to the human brain.

Adult↗
PubMed1991

Scintigraphic portrayal of beta receptors in the heart.

Myocardial beta adrenergic receptors play important roles in physiology and disease, but the receptors have not before been portrayed. The beta antagonist, iodocyanopindolol (ICYP), was used to develop a scintigraphic method for depicting the receptors in the living heart. Labeled with 125I, ICYP bound firmly to beta receptors in the rat heart; the data conformed to a mathematical model. In vivo saturation kinetics indicated binding sites with two affinities. Inhibition of ICYP binding by beta antagonists of different potency and different selectivity for beta-1 and beta-2 receptors produced the expected pharmacologic effects. Inhibition by lipophilic and hydrophilic antagonists gave no evidence that ICYP was appreciably bound to internalized receptors. Fractional binding by tracer quantities of (-) ICYP and (+/-) ICYP demonstrated stereospecificity. Labeled with 123I, ICYP bound to the hearts of intact dogs so that scintigraphic tomographs depicted ventricular myocardium. Small doses of beta antagonists selectively reduced the binding of ICYP to lung enabling better visualization of the heart. Thus, 123I-ICYP appears to portray the beta receptors in the living heart, and the characteristics of binding permit the development of mathematical models and lay the basis for quantifying this receptor binding.

Animals↗
PubMed1991

Alcohol abuse and alcoholism in primary health care settings.

Alcohol problems are common in primary care patients, yet they are often not detected and treated. Methods for improving the detection and diagnosis of alcohol problems in the primary care setting are reviewed in terms of pertinent history, physical examination, and laboratory findings. Screening instruments such as the CAGE questionnaire and the Michigan Alcoholism Screening Test are recommended for routine use by primary care physicians. Such instruments have been shown to have higher sensitivity than laboratory tests alone. Although less is known about intervention and management, earlier intervention with innovative (less costly) management techniques may be both efficacious and acceptable to the patient.

Alcoholism↗