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Biomedical subjects

V J Cunningham

Publications and source records attributed to V J Cunningham.

At least 55 records · Page 3Linked to original sources
PubMed1994

Separating Parkinson's disease from normality. Discriminant function analysis of fluorodopa F 18 positron emission tomography data.

OBJECTIVE: To explore the relationship between normal and parkinsonian fluorodopa F 18 (18F-6-L-fluorodopa [18F-dopa]) uptake data to identify clinically normal subjects who may have preclinical Parkinson's disease. DESIGN: A statistical comparison of striatal fluorodopa F 18 positron emission tomography scan data from patients with Parkinson's disease and normal controls. SETTING: Positron emission tomography unit within a postgraduate teaching hospital. MAIN OUTCOME MEASURES: Discriminant function analysis used to compare the pattern of striatal (left and right caudate and putamen) fluorodopa F 18 uptake in normal subjects and patients with Parkinson's disease. RESULTS: The discriminant score that best separates patients with Parkinson's disease from normal controls is a function of the lowest putamen influx constant minus a function of the caudate influx constant values. Borderline low normal subjects have slightly low fluorodopa F 18 uptake throughout the striatum, whereas patients with early Parkinson's disease have low fluorodopa F 18 uptake in one putamen with preserved uptake in the caudate (for normal subjects, subtracting the caudate influx constants from a function of the lowest putamen value lowers the discriminant score, although it remains positive; for patients, subtracting a larger caudate value from a function of the putamen uptake value leads to a negative score). One control subject had a borderline low discriminant score, compatible with focal nigral pathological changes as expected in preclinical Parkinson's disease. A repeated scan taken 3 years later showed a marked reduction in fluorodopa F 18 uptake, suggesting progressive nigral dysfunction. CONCLUSION: Normal and parkinsonian fluorodopa F 18 uptake data differ both in the overall level of tracer uptake and in its spatial distribution. Subjects whose overall striatal fluorodopa F 18 uptake falls at the borderline of normal and parkinsonian values are likely to be normal if they have uniformly low uptake, but may have early or preclinical Parkinson's disease if uptake into putamen is very much lower than uptake into caudate.

Aged↗
PubMed1994

Quantitation of [11C]diprenorphine cerebral kinetics in man acquired by PET using presaturation, pulse-chase and tracer-only protocols.

The quantitation of regional cerebral in vivo opioid receptor rate constants using [11C]diprenorphine and positron emission tomography (PET) using 3 types of protocol (presaturation, pulse-chase naloxone displacement and tracer-only protocols) together with measurements of regional cerebral blood flow is described in normal volunteers. Arterial blood was sampled continuously for radioactivity and was corrected for metabolites and plasma/blood partition of radioactivity to provide a continuous plasma input function. A compartmental model involving 3 tissue compartments was used to describe the regional cerebral pharmacokinetics of the tracer. The compartments comprised: (1) free plus rapidly exchanging non-specifically bound ligand, (2) specifically bound, naloxone displaceable ligand, and (3) a kinetically distinguishable non-specifically bound pool. Regional estimates of fractional rate constants relating to specific binding were obtained using naloxone in a pulse-chase design of tracer displacement. Less precise estimates of these rate constraints were obtained from single-tracer-only studies, but when binding was expressed as the tissue total volume of distribution relative to plasma there was good correlation with regional values obtained from pulse-chase studies performed in the same individuals. The application of these protocols to the measurement of indices of regional-specific opioid receptor binding in the human brain is discussed.

Adult↗
PubMed1994

Opiate receptors in idiopathic generalised epilepsy measured with [11C]diprenorphine and positron emission tomography.

The neurochemical basis of absence seizures is uncertain. A previous PET study has provided evidence for release of endogenous opioids from cerebral cortex at the time of absence seizures, but it is has not yet been established whether there is an abnormality of opiate receptor numbers interictally. In the present study, the non-specific opiate receptor ligand, [11C]diprenorphine, was used to measure cerebral opiate receptors interictally in patients with childhood and juvenile absence epilepsy. Eight patients and eight normal controls had a single scan after a high specific activity injection of [11C]diprenorphine. The cerebral volume of distribution (Vd) of [11C]diprenorphine relative to plasma was calculated on a pixel-by-pixel basis. There were no significant differences in [11C]diprenorphine Vd between patients and control subjects in either cortex or thalamus, structures thought to be involved in the pathogenesis of absence seizures. The results suggest that there is no overall abnormality of opioid receptors in patients with childhood and juvenile absence epilepsy. Studies with specific ligands may provide information about the different receptor subtypes.

Adult↗
PubMed1994

Characterisation of tumour blood flow using a 'tissue-isolated' preparation.

Tumour blood flow was characterised in a 'tissue-isolated' rat tumour model, in which the vascular supply is derived from a single artery and vein. Tumours were perfused in situ and blood flow was calculated from simultaneous measurement of (1) venous outflow from the tumour and (2) uptake into the tumour of radiolabelled iodo-antipyrine (IAP). Comparison of results from the two measurements enabled assessment of the amount of blood 'shunted' through the tumours with minimal exchange between blood and tissue. Kinetics of IAP uptake were also used to determine the apparent volume of distribution (VDapp) for the tracer and the equilibrium tissue-blood partition coefficient (lambda). lambda was also measured by in vitro techniques and checks were made for binding and metabolism of IAP using high-pressure liquid chromatography. VDapp and lambda were used to calculate the perfused fraction (alpha) of the tumours. Tumour blood flow, as measured by IAP (TBFIAP), was 94.8 +/- 4.4% of the blood flow as measured by venous outflow, indicating only a small amount of non-exchanging flow. This level of shunting is lower than some previous estimates in which the percentage tumour entrapment of microspheres was used. The unperfused fraction ranged from 0 to 20% of the tumour volume in the majority of tumours. This could be due to tumour necrosis and/or acutely ischaemic tumour regions. For practical purposes, measurement of the total venous outflow of tumours is a reasonable measure of exchangeable tumour blood flow in this system and allows for on-line measurements. Tracer methods can be used to obtain additional information on the distribution of blood flow within tumours.

Animals↗
PubMed1994

Changes in central opioid receptor binding in relation to inflammation and pain in patients with rheumatoid arthritis.

A group of four patients with RA were examined to test the hypothesis that there is a change in the endogenous opioid system in the brain during inflammatory pain. Regional cerebral opioid receptor binding was quantified using the opioid receptor antagonist [11C] diprenorphine and positron emission tomography (PET). In the four patients studied in and out of pain, significant increases in [11C]diprenorphine binding were seen in association with a reduction in pain. Increases were seen in most of the areas of the brain that were sampled apart from the occipital cortex. Significant region-specific increases over and above the more generalized changes were also seen in the frontal, cingulate and temporal cortices in addition to the straight gyrus. These findings are consistent with the hypothesis that there are substantial increases in occupancy by endogenous opioid peptides during inflammatory pain.

Arthritis, Rheumatoid↗
PubMed1993

Spectral analysis of dynamic PET studies.

We describe a new technique for the analysis of dynamic positron emission tomography (PET) studies in humans, where data consist of the time courses of label in tissue regions of interest and in arterial blood, following the administration of radiolabelled tracers. The technique produces a simple spectrum of the kinetic components which relate the tissue's response to the blood activity curve. From this summary of the kinetic components, the tissue's unit impulse response can be derived. The convolution of the arterial input function with the derived unit impulse response function gives the curve of best fit to the observed tissue data. The analysis makes no a priori assumptions regarding the number of compartments or components required to describe the time course of label in the tissue. Rather, it is based on a general linear model, presented here in a formulation compatible with its solution using standard computer algorithms. Its application is illustrated with reference to cerebral blood flow, glucose utilization, and ligand binding. The interpretation of the spectra, and of the tissue unit impulse response functions, are discussed in terms of vascular components, unidirectional clearance of tracer by the tissue, and reversible and irreversible phenomena. The significance of the number of components which can be identified within a given datum set is also discussed. The technique facilitates the interpretation of dynamic PET data and simplifies comparisons between regions and between subjects.

Algorithms↗
PubMed1993

Investigation of the opioid system in absence seizures with positron emission tomography.

The neuroanatomical and pathophysiological basis of primary generalised absences is uncertain. Administration of endogenous opioids has been shown to result in absence-like seizures in animal models. Positron emission tomography scans were performed in eight patients with primary generalised epilepsy and eight control subjects. Regional cerebral blood flow was measured interictally with C15O2, after which a 90 minute dynamic study with the opioid-receptor ligand 11C-diprenorphine was performed. Serial absences were precipitated by hyperventilation for 10 minutes, starting 30-40 minutes after injection of diprenorphine. Absences, with generalised spike-wave discharges on the EEG, occurred for between 10% and 51% of the provocation period. No individual (normal or patient) had any interictal focal abnormalities of cerebral blood flow. After provocation of serial absence seizures, there was increased diprenorphine elimination from the association cortex, but not from the thalamus, basal ganglia, or cerebellum, compared with control subjects and patients scanned without provocation of absences. It was possible to simulate the observed increased diprenorphine elimination following seizures in cerebral cortex using a two tissue compartment model, with an estimated 15-41% decrease in the specific tracer uptake rate constant (k3). These results suggest that endogenous opioids are released in the association cortex at the time of serial absences, lead to increased receptor occupancy, and may have an important role in the pathophysiology of generalised absences.

Adult↗
PubMed1991

In vivo distribution of opioid receptors in man in relation to the cortical projections of the medial and lateral pain systems measured with positron emission tomography.

In vivo opioid receptor binding in the cortical projections of the medial (cingulate and prefrontal cortex) and lateral pain system (primary somatosensory cortex) in male volunteers has been quantitated using [11C]diprenorphine and positron emission tomography. High levels of opioid receptor binding were seen in the cortical projections of the medial pain system in the cingulate and prefrontal cortex as has previously been observed in post-mortem studies. However, a focal reduction of opioid receptor binding was observed and quantitated in the primary motor/sensory strip when compared to surrounding parietal cortex. This new finding suggests that the medial pain system is likely to be more susceptible to exogenous and endogenous opioid neuromodulation than the so-called lateral pain system.

Adult↗
PubMed1991

Compartmental analysis of diprenorphine binding to opiate receptors in the rat in vivo and its comparison with equilibrium data in vitro.

The regional binding of the opiate receptor ligand diprenorphine has been examined in rat brain both in vivo and in vitro. The time course of total label in specific brain regions was followed up to 2 h after intravenous bolus injection of [3H]diprenorphine, with or without a pulse chase of unlabelled diprenorphine at 30 min. In addition, total label was measured 30 min after injection of labelled diprenorphine at nontracer concentrations over a range of specific activities. Total data sets for each region were fitted simultaneously to a compartmental model to give estimates of maximal binding capacity (Bmax), the second-order apparent association rate constant, and the first-order dissociation rate constant of the receptor-ligand complex. The model incorporated the use of a reference region with low specific binding (cerebellum). The binding of diprenorphine to rat brain homogenates was measured in vitro under equilibrium conditions at 37 degrees C, pH 7.4, in the presence and absence of naloxone, to give corresponding regional estimates of Bmax and the half-saturation constant Kd. The results showed a close correlation between in vitro and in vivo regional estimates of Bmax over a wide range. There were no significant interregional differences either in Kd in vitro or in the Kd derived from the in vivo analysis, although in vitro and in vivo estimates differed by an order of magnitude. This work was carried out as part of a validation study with a view to the application of the compartmental model to data obtained in vivo in humans using positron emission tomography, when successive studies over a range of specific activities are not feasible.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

A method of studying pharmacokinetics in man at picomolar drug concentrations.

1. We describe a new method that enables the tissue kinetics of picomolar concentrations of drugs to be measured in man. The method is based on the administration of a drug, labelled with a short-lived positron-emitting radioisotope, such as carbon-11 (t1/2 = 20.4 min, beta + = 99.8%) or fluorine-18 (t1/2 = 109.8 min, beta + = 96.9%), which is then detected in vivo by an array of 10 large uncollimated sodium iodide scintillation detectors, arranged as five opposing pairs, with each pair collecting data over one major organ or region of the body. 2. To illustrate the scope of the new method we report the results of administering [O-methyl-11C]-diprenorphine, an established radioligand for central opiate (mu, kappa, and delta) receptors and L-6-[18F]-fluoro-DOPA, a marker for dopaminergic neurons. 3. Only 2-10 muCi (74-370 kBq) of radioactivity are used and, as a consequence of the high specific activities with which carbon-11 and fluorine-18 labelled compounds can be prepared, the method requires less than a nanomole of drug to be administered. In many cases, this amount of drug might be considered low enough to avoid any adverse biological effect. Furthermore repeat studies are possible in many without delivering unacceptable radiation burdens. 4. The high sensitivity realised for both radioactivity and mass suggests a mean for determining the human biodistribution of a new drug at a very early stage in its development. This has potential benefit to drug discovery programmes and to ensuing drug therapies.

Blood-Brain Barrier↗
PubMed1990

Combination of dynamic and integral methods for generating reproducible functional CBF images.

A new method to measure regional CBF is presented, applying both dynamic and integral analyses to a dynamic sequence of positron emission tomographic scans collected during and following the administration of H2(15)O (inhalation of C15O2). The dynamic analysis is used to correct continuously monitored arterial whole-blood activity for delay and dispersion relative to tissue scans. An integral analysis including corrections for this delay and dispersion is then used to calculate CBF on a pixel-by-pixel basis. Normal values and reproducibility over a 2-h period are presented, together with the results of validation and simulation studies. The results indicate that the single-tissue compartment model adequately describes the distribution of H2(15)O in the brain, without recourse to postulating a nonexchanging water pool.

Carbon Radioisotopes↗
PubMed1989

Anatomical mapping of glucose transporter protein and pyruvate dehydrogenase in rat brain: an immunogold study.

The regional and cellular distributions of glucose transporter protein (GT) and pyruvate dehydrogenase (PDH) have been studied with an enhanced immunogold method. The results showed significant amounts of GT in neuropil within regions known to exhibit high demands for glucose whilst neuronal perikarya showed little immunostaining. In contrast PDH immunostaining was most intense in neuronal perikarya. The distributions of these proteins were compared and discussed in relation to existing data on local cerebral glucose utilization and the distribution of other important metabolic enzymes. The results suggest that glucose is transported and metabolised in neuropil and that metabolic products such as pyruvate are transported into the neuronal cell body to undergo further metabolism.

Animals↗
PubMed1989

The colour centre in the cerebral cortex of man.

Anatomical and physiological studies have shown that there is an area specialized for the processing of colour (area V4) in the prestriate cortex of macaque monkey brain. Earlier this century, suggestive clinical evidence for a colour centre in the brain of man was dismissed because of the association of other visual defects with the defects in colour vision. However, since the demonstration of functional specialization in the macaque cortex, the question of a colour centre in man has been reinvestigated, based on patients with similar lesions in the visual cortex. In order to study the colour centre in normal human subjects, we used the technique of positron emission tomography (PET), which measures increases in blood flow resulting from increased activity in the cerebral cortex. A comparison of the results of PET scans of subjects viewing multi-coloured and black-and-white displays has identified a region of normal human cerebral cortex specialized for colour vision.

Cerebral Cortex↗
PubMed1989

Effect of 6-phosphogluconate on phosphoglucose isomerase in rat brain in vitro and in vivo.

The activity of phosphoglucose isomerase, its kinetic properties, and the effect of 6-phosphogluconate on its activity in the forward (glucose 6-phosphate----fructose 6-phosphate) and the reverse (fructose 6-phosphate----glucose 6-phosphate) reactions were determined in adult rat brain in vitro. The activity of phosphoglucose isomerase (in nmol/min/mg of whole brain protein) was 1,865 +/- 20 in the forward reaction and 1,756 +/- 32 in the reverse reaction at pH 7.5. It was 1,992 +/- 28 and 2,620 +/- 46, respectively, at pH 8.5. The apparent Km and Vmax of phosphoglucose isomerase were 0.593 +/- 0.031 mM and 2,291 +/- 61 nmol/min/mg of protein, respectively, for glucose 6-phosphate and 0.095 +/- 0.013 mM and 2,035 +/- 98 nmol/min/mg of protein, respectively, for fructose 6-phosphate. The activity of phosphoglucose isomerase was inhibited intensely and competitively by 6-phosphogluconate, with an apparent Ki of 0.048 +/- 0.005 mM for glucose 6-phosphate and 0.042 +/- 0.004 mM for fructose 6-phosphate as the substrate. With glucose 6-phosphate as the substrate, at concentrations from 0.05 to 0.5 mM, the activity of the enzyme was inhibited completely in the presence of 0.5-2.0 mM 6-phosphogluconate. With 0.05-0.2 mM fructose 6-phosphate as the substrate, it was inhibited greater than or equal to 85% at the same concentrations of the inhibitor. No significant changes were observed in the values of Km, Vmax, and Ki for phosphoglucose isomerase in the brain of 6-aminonicotinamide-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Aminonicotinamide↗
PubMed1988

Autoradiography of [3H]cytochalasin B binding in rat brain.

A technique is described for the autoradiographic localization of D-glucose inhibitable cytochalasin B binding in fresh frozen sections of rat brain. The technique has been used to study the regional distribution of glucose transporter proteins. Binding sites within the cerebellum and hippocampus were more concentrated in the synaptic zones, which would be expected to display relatively high metabolic rates for glucose. However, a general inter-regional correlation of cytochalasin B binding with metabolic rates was not apparent.

Animals↗
PubMed1988

Tracer 2-deoxyglucose kinetics in brain regions of rats given kainic acid.

The initial distribution of tracer amounts of 2-deoxyglucose between plasma and brain tissue, relative to native glucose, and the rate of accumulation of 2-deoxyglucose-6-phosphate were determined in brain regions of rats given kainic acid intravenously. Regional plasma flow was measured in a comparable group of animals. A previously described compartmental model was used to obtain estimates of rates of glucose transport and of glucose phosphorylation. Both rates were significantly increased in entorhinal cortex, hippocampus, amygdala, and septal nucleus. From measured brain tissue and plasma glucose concentrations, glucose fluxes were also calculated in terms of either irreversible or reversible Michaelis-Menten kinetics. In all brain regions of control rats and in six of the ten regions studied in rats given kainic acid, rates of glucose transport calculated in terms of the Michaelis-Menten models were consistent with those estimated by the tracer 2-deoxyglucose procedure. However, in the four regions in which glucose metabolism was stimulated, rates of glucose transport calculated from the behaviour of tracer 2-deoxyglucose were considerably higher than rates calculated from measured concentrations of glucose in plasma and brain tissue using Michaelis-Menten models. The possibility is considered that in those regions that are metabolically stimulated by kainate, there is an increasing asymmetry between the luminal and abluminal membranes of the capillary endothelium in the permeability to glucose and its analogs. An alternative proposal is that in the model used to analyse the tracer 2-deoxyglucose data, the assumption of a rapid mixing of tracer throughout the endogenous pool of tissue glucose prior to phosphorylation becomes invalid. The discrepancies between tracer and native glucose in these particular regions of rats given kainate are consistent with an apparent metabolic compartmentation. The influence of kainate on plasma flow was found to differ regionally, with flow in entorhinal cortex, hippocampus, and amygdala being unchanged. There is some evidence for increased rates of glycolysis relative to oxidative metabolism in these regions.

Animals↗