Biomedical subjects

R N Gunn

Publications and source records attributed to R N Gunn.

35 records · Page 2Linked to original sources

PubMed2000

Modeling dynamic PET-SPECT studies in the wavelet domain.

This work develops a theoretical framework and corresponding algorithms for the modeling of dynamic PET-SPECT studies both in time and space. The problem of estimating the spatial dimension is solved by applying the wavelet transform to each scan of the dynamic sequence and then performing the kinetic modeling and statistical analysis in the wavelet domain. On reconstruction through the inverse wavelet transform, one obtains parametric images that are consistent estimates of the spatial patterns of the kinetic parameter of interest. The theoretical setup allows the use of linear techniques currently used in PET-SPECT for kinetic analysis. The method is applied to artificial and real data sets. The application to dynamic PET-SPECT studies was performed both for validation purposes, when the spatial patterns are known, and for illustration of the advantages offered by the technique in case of tracers with an unknown pattern of distribution.

Benzamides↗

PubMed2000

On-line measurement of exhaled [11C]CO2 during PET.

UNLABELLED: The purpose of this study was to develop and evaluate a system for the continuous on-line measurement of expired 11CO2 during 11C PET studies. METHODS: A detector system was developed that allowed continuous sampling of expired air during PET. Healthy volunteers (n = 4) underwent PET with [11C]CO2 during which expired air, tomographic tissue activity, and blood data were collected. The measured expired-air 11CO2 radioactivity time courses were filtered, and an envelope was extracted and compared with the time course of 11CO2/H11CO3 in blood. RESULTS: Good agreement was found between the shapes of the expired-air envelope and the time course in blood, enabling quantitative calibration against discrete blood samples. CONCLUSION: A system for the continuous monitoring of expired radioactivity during PET has been developed and evaluated with [11C]CO2. This monitoring enables the quantitative continuous measurement of 11CO2/H11CO3- in blood.

Carbon Dioxide↗

PubMed2000

A general method to correct PET data for tissue metabolites using a dual-scan approach.

UNLABELLED: This article presents and analyses a general method of correcting for the presence of radiolabeled metabolites from a parent radiotracer in tissue during PET scanning. The method is based on a dual-scan approach, i.e., parent scan together with an independent supplementary scan in which the radiolabeled metabolite of interest itself is administered. The method corrects for the presence of systemically derived radiolabeled metabolite delivered to the tissues of interest through the blood. METHODS: Data from the supplementary scan are analyzed to obtain the tissue impulse response function for the metabolite. The time course of the radiolabeled metabolite in plasma in the parent scan is convolved with its tissue impulse response function to derive a correction term. This is not a simple subtraction technique but 1 that takes account of the different time-activity curves of the radiolabeled metabolite in the 2 scans. RESULTS: The method, its implications, and its limitations are discussed with respect to [11C]thymidine and its principal metabolite 11CO2. CONCLUSION: The general method, based on a dual-scan approach, can be used to correct for radiolabeled metabolites in tissues of interest during PET scanning. The correction accounts for radiolabeled metabolites that are derived systemically and delivered to the tissues of interest through the blood.

Carbon Dioxide↗

PubMed1999

[11C](R)-PK11195 positron emission tomography imaging of activated microglia in vivo in Rasmussen's encephalitis.

This study was designed to explore the feasibility of PET using [11C](R)-PK11195 as an in vivo marker of activated microglia/brain macrophages for the assessment of neuroinflammation in Rasmussen's encephalitis (RE). [11C](R)-PK11195 PET was carried out in four normal subjects, two patients with histologically confirmed RE, and three patients with clinically stable hippocampal sclerosis and low seizure frequency. Binding potential maps showing specific binding of [11C](R)-PK11195 were generated for each subject. Regional binding potential values were calculated for anatomically defined regions of interest after coregistration to and spatial transformation into the subjects' own MRI. In one patient with RE who underwent hemispherectomy, the resected, paraffin-embedded brain tissue was stained with an antibody (CR3/43) that labels activated human microglia. Whereas specific binding of [11C](R)-PK11195 in clinically stable hippocampal sclerosis was similar to that in normal brain, patients with RE showed a focal and diffuse increase in binding throughout the affected hemisphere. In RE, [11C](R)-PK11195 PET can reveal in vivo the characteristic, unilateral pattern known from postmortem neuropathologic study. PET imaging of activated microglia/brain macrophages offers a tool for investigation of a range of brain diseases where neuroinflammation is a component and in which conventional MRI does not unequivocally indicate an inflammatory tissue reaction. [11C](R)-PK11195 PET may help in the choice of appropriate biopsy sites and, further, may allow assessment of the efficacy of antiinflammatory disease-modifying treatment.

Adolescent↗

PubMed1999

Assessment of spatial normalization of PET ligand images using ligand-specific templates.

Recent advances allow robust computation of parametric maps of ligand-receptor binding from PET data sets. Parametric maps may be statistically analyzed at the voxel level, given suitable techniques for both the spatial normalization of image data into a standard space and the application of appropriate statistical tests. The purpose of this study was to spatially normalize parametric maps of [carbonyl-11C]WAY-100635 and [11C]raclopride binding using SPM 96 and ligand-specific templates. Ligand-specific templates were created from integral images taken from healthy subjects. For this, a MRI-based spatial normalization was used: T1-weighted MRI scans were coregistered to the PET integral images, and the spatial normalization of the MRI to the SPM 96 T1 MRI template was applied to the integral images. These integral images were meaned and smoothed to form [carbonyl-11C]WAY-100635 and [11C]raclopride templates. Reliability of spatial normalization using the ligand template method and the previous MRI-based spatial normalization was investigated by using a second set of integral images taken from a different cohort: Landmark coordinates were defined on all spatially normalized integral images. Mean coordinates were found in order to produce an overall (average) landmark for each location. For each image, at each location, the distance from the landmark coordinates to the overall landmark were found. A multivariate analysis of variance was used to examine the effects of observer variance, landmark location, and the method used. Visually acceptable templates were created. While observer variance was not significant, the landmark x method interaction was significant. The ligand template method had significantly smaller distances: Among the landmark locations with this method, the mean distances between individual image landmarks and overall image landmarks ranged from 1. 1 to 4.9 mm. The ligand template method provides a reliable approach for spatial normalization of PET ligand images.

Algorithms↗

PubMed1999

Dopamine release from nigral transplants visualized in vivo in a Parkinson's patient.

Synaptic dopamine release from embryonic nigral transplants has been monitored in the striatum of a patient with Parkinson's disease using [11C]-raclopride positron emission tomography to measure dopamine D2 receptor occupancy by the endogenous transmitter. In this patient, who had received a transplant in the right putamen 10 years earlier, grafts had restored both basal and drug-induced dopamine release to normal levels. This was associated with sustained, marked clinical benefit and normalized levels of dopamine storage in the grafted putamen. Despite an ongoing disease process, grafted neurons can thus continue for a decade to store and release dopamine and give rise to substantial symptomatic relief.

Aged↗

PubMed1999

Huntington's disease progression. PET and clinical observations.

Using serial [(11)C]SCH 23390- and [11C]raclopride-PET, we have measured the rate of loss of striatal dopamine D1 and D2 receptor binding over a mean of 40 months in nine asymptomatic adult Huntington's disease mutation carriers, four patients with symptomatic disease, seven mutation-negative controls and three subjects at risk for the disease. Eight of the nine asymptomatic Huntington's disease mutation carriers had serial [11C]raclopride-PET and showed a mean annual loss of striatal D2 binding of 4.0%. Only five of these eight, however, showed active progression, and they had a mean annual loss of D2 binding of 6.5%. All nine asymptomatic mutation carriers had serial [11C]SCH 23390-PET and showed a mean annual loss of striatal D1 binding of 2. 0%. Four of these subjects demonstrated active progression and they had a mean annual loss of 4.5%. Our four symptomatic Huntington's disease patients showed a mean annual loss of D2 binding of 3.0% and of D1 binding of 5.0%. Loss of striatal D1 and D2 binding was significantly greater in the known mutation carriers than in the combined at-risk and gene-negative groups (P < 0.05). At follow-up PET all subjects were clinically assessed using the Unified Huntington's Disease Rating Scale. Scores for motor function and total functional capacity correlated with PET measures of striatal dopamine receptor binding both in the asymptomatic mutation carriers (D1, P < 0.01) and across the combined asymptomatic and clinically affected Huntington's disease mutation carrier group (D1 and D2, P < 0.001). We conclude that PET measures of striatal D1 and D2 dopamine binding can be used to identify asymptomatic Huntington's disease mutation carriers who are actively progressing and who would thus be suitable for putative neuroprotective therapies. Measures of disease progression rates in Huntington's disease patients and asymptomatic mutation carriers will be of critical importance in future trials of experimental restorative treatments.

Adult↗

PubMed1998

Evidence for striatal dopamine release during a video game.

Dopaminergic neurotransmission may be involved in learning, reinforcement of behaviour, attention, and sensorimotor integration. Binding of the radioligand 11C-labelled raclopride to dopamine D2 receptors is sensitive to levels of endogenous dopamine, which can be released by pharmacological challenge. Here we use 11C-labelled raclopride and positron emission tomography scans to provide evidence that endogenous dopamine is released in the human striatum during a goal-directed motor task, namely a video game. Binding of raclopride to dopamine receptors in the striatum was significantly reduced during the video game compared with baseline levels of binding, consistent with increased release and binding of dopamine to its receptors. The reduction in binding of raclopride in the striatum positively correlated with the performance level during the task and was greatest in the ventral striatum. These results show, to our knowledge for the first time, behavioural conditions under which dopamine is released in humans, and illustrate the ability of positron emission tomography to detect neurotransmitter fluxes in vivo during manipulations of behaviour.

Adult↗

PubMed1998

Tracer kinetic modeling of the 5-HT1A receptor ligand [carbonyl-11C]WAY-100635 for PET.

[Carbonyl-11C]WAY-100635 is a promising PET radioligand for the 5-HT1A receptor, having demonstrated more favorable characteristics for in vivo imaging than the previously available [O-methyl-11C]WAY-100635. The current study evaluates different tracer kinetic modelling strategies for the quantification of 5-HT1A receptor binding in human brain. Mathematical modelling of the carbonyl-labeled radiotracer is investigated using compartmental structures, including both plasma input and reference tissue approaches. Furthermore, the application of basis function methods allows for the investigation of parametric imaging, providing functional maps of both delivery and binding of the radioligand. Parameter estimates of binding from normal volunteers indicate a low intra- versus a high intersubject variability. It is concluded that a simplified reference tissue approach may be used to quantify 5-HT1A binding either in terms of ROI data or as parametric images.

Adult↗

PubMed1998

Pharmacological constraints associated with positron emission tomographic scanning of small laboratory animals.

With the stated aim of scanning small regions of interest in mice, several high-resolution positron emission tomographic (PET) systems are presently under development. Some, however, have low sensitivity and require high doses of radioactivity to achieve count statistics adequate to reconstruct small volumes. Using in vivo dissociation constants for three carbon-11 labelled ligands previously measured in rat brain, the present paper utilises simple saturation kinetics to estimate the limits on radioactivity and specific activity, to minimise the degree of receptor occupancy and achieve maximal specific binding of the radioligand. The extent of the problem is exemplified by considering a high-affinity ligand (dissociation constant in vitro approximately 0.1 nM; in vivo approximately 5 nmol/kg i.v. injected dose), where routinely produced levels of specific activity ( approximately 100 MBq/nmol) would limit the activity injected into mice to approximately 0.1 MBq for a 1% receptor occupancy. If, as is feasible, the new generation of high resolution PET systems requires an injected activity >10 MBq, then a >100-fold increase in specific activity would be needed for tracer kinetics to hold. The paper highlights the need to consider realistically achievable goals if high-resolution PET is to be accepted as a viable methodology to acquire pharmacologically and physiologically accurate ligand-receptor binding data in mice.

Animals↗

PubMed1998

A procedure for generating locally identifiable reparameterisations of unidentifiable non-linear systems by the similarity transformation approach.

A method is presented for the generation of locally identifiable reparameterisations of non-linear systems which have been shown to be unidentifiable via application of the similarity transformation approach. The existence of the reparameterised system in terms of the maximum permissible number of locally identifiable parameters is provided and is crucially dependent upon the ability to find the rank deficiency of an appropriate (and possibly infinite) jacobian matrix. The reparameterisation procedure is described in detail, and is illustrated with application to two known non-trivial examples of unidentifiable non-linear systems.

Mathematics↗

PubMed1998

Characterisation of the appearance of radioactive metabolites in monkey and human plasma from the 5-HT1A receptor radioligand, [carbonyl-11C]WAY-100635--explanation of high signal contrast in PET and an aid to biomathematical modelling.

N-(2-(4-(2-Methoxy-phenyl)-1-piperazin-1-yl)ethyl)-N-(2-pyridyl)++ +cyclohexanecarboxamide (WAY-100635), labelled in its amido carbonyl group with 11C (t1/2 = 20.4 min), is a promising radioligand for the study of brain 5-HT1A receptors with positron emission tomography (PET). Thus, in PET experiments in six cynomolgus monkeys and seven healthy male volunteers, [carbonyl-11C]WAY-100635 was taken up avidly by brain. Radioactivity was retained in regions rich in 5-HT1A receptors, such as occipital cortex, temporal cortex and raphe nuclei, but cleared rapidly from cerebellum, a region almost devoid of 5-HT1A receptors. [Carbonyl-11C]WAY-100635 provides about 3- and 10-fold higher signal contrast (receptor-specific to nonspecific binding) than [O-methyl-11C]WAY-100635 in receptor-rich areas of monkey and human brain, respectively. To elucidate the effect of label position on radioligand behaviour and to aid in the future biomathematical interpretation of the kinetics of regional cerebral radioactivity uptake in terms of receptor-binding parameters, HPLC was used to measure [carbonyl-11C]WAY-100635 and its radioactive metabolites in plasma at various times after intravenous injection. Radioactivity cleared rapidly from monkey and human plasma. Parent radioligand represented 19% of the radioactivity in monkey plasma at 47 min and 8% of the radioactivity in human plasma at 40 min. [Carbonyl-11C]desmethyl-WAY-100635 was below detectable limits in monkey plasma and at most a very minor radioactive metabolite in human plasma. [11C]Cyclohexanecarboxylic acid was identified as a significant radioactive metabolite. In human plasma this maximally represented 21% of the radioactivity at 10 min after radioligand injection. All other major radioactive metabolites in monkey and human plasma were even more polar. No-carrier-added [carbonyl-11C]cyclohexanecarboxylic acid was prepared in the laboratory and after intravenous administration into cynomolgus monkey was shown with PET to give only a low uptake of radioactivity into brain tissue. The acid rapidly gave rise to several radioactive metabolites of higher polarity in plasma. The observed lack of any significant metabolism of [carbonyl-11C]WAY-100635 to highly lipophilic or pharmacologically potent radioactive compounds is consistent with its high signal contrast in primate brain.

Animals↗

PubMed1997

Parametric imaging of ligand-receptor binding in PET using a simplified reference region model.

A method is presented for the generation of parametric images of radioligand-receptor binding using PET. The method is based on a simplified reference region compartmental model, which requires no arterial blood sampling, and gives parametric images of both the binding potential of the radioligand and its local rate of delivery relative to the reference region. The technique presented for the estimation of parameters in the model employs a set of basis functions which enables the incorporation of parameter bounds. This basis function method (BFM) is compared with conventional nonlinear least squares estimation of parameters (NLM), using both simulated and real data. BFM is shown to be more stable than NLM at the voxel level and is computationally much faster. Application of the technique is illustrated for three radiotracers: [11C]raclopride (a marker of the D2 receptor), [11C]SCH 23390 (a marker of the D1 receptor) in human studies, and [11C]CFT (a marker of the dopamine transporter) in rats. The assumptions implicit in the model and its implementation using BFM are discussed.

Animals↗

PubMed1997

Demonstration of clomipramine and venlafaxine occupation at serotonin reuptake sites in man in vivo.

We describe the use of 11CRTI-55 and the Multiple Objects Coincidences Counter (MOCC) to detect in-vivo binding to peripheral serotonin reuptake sites (left chest comprising platelet and lung serotonin reuptake sites) in man. Displacement and preloading experiments with clomipramine and venlafaxine in two healthy volunteers demonstrated that 11CRTI-55 binding is decreased in a dose-dependent fashion by both these drugs which bind to the serotonin transporter. In addition parallel data from the total head curve (representing 11CRTI-55 binding to central serotonin and dopamine (DA) reuptake sites) suggest that prior blockade of the serotonin transporter may be a useful strategy to maximize radioactive counts in the head when measuring the DA transporter. The MOCC is likely to be useful to determine sequential indices of relative serotonin reuptake blockade in patients on treatment.

Adult↗

PubMed1996

Non-invasive measurement of left ventricular volumes and function by gated positron emission tomography.

To date cardiac positron emission tomography (PET) studies have focussed on the measurement of myocardial blood flow, metabolism and receptors while left ventricular (LV) function and dimensions have been derived from other modalities. The main drawback of this approach is the difficulty of data co-registration, which limits clinical interpretation. The aim of this study was to evaluate whether it is possible to measure absolute cardiac volumes, and consequently LV function parameters such as ejection fraction, and wall motion with gated PET. Nineteen patients underwent a PET scan and planar radionuclide ventriculography (MUGA) within 9+/-9 days. A 9-min scan (16 gates/cardiac cycle) was acquired after inhalation of 3 MBq/ml of oxygen-15 labelled carbon monoxide at the rate of 500 ml/min over 4 min using a multislice PET camera. Noise reduction was performed on the gated image to enhance the definition of the ventricles before reslicing to the short-axis view. A threshold value was used to detect the edge of the LV at each gate. LV volumes at each gate were estimated by summing the volume of voxels within the LV boundary. PET measurements of LV volumes were as follows: LV end-diastolic volume ranged from 72 to 233 ml and LV end-systolic volume ranged from 24 to 203 ml. Phantom experiments supported the validity of this approach for estimating volumes. LV ejection fraction measured with MUGA was 38.4%+/-16.3% (range 15%-71%) and that measured with PET was 39.6%+/-17.7% (range 9%-72%) (P=NS). The LV ejection fraction measurements were highly correlated (r2=0.824). These results indicate that: (1) absolute end-diastolic and end-systolic volumes can be quantified using gated PET and (2) LV ejection fraction can be accurately measured by gated PET simultaneously with the other physiological PET parameters.

Coronary Disease↗

PubMed1996

Benzodiazepine site pharmacokinetic/pharmacodynamic quantification in man: direct measurement of drug occupancy and effects on the human brain in vivo.

To date, the study of the relationship between drug occupancy and action in the brain has had to rely on the use of either animal models or of indirect kinetic measures in man, e.g. serum concentrations of unbound drug (as a measure of "free" drug in brain). We describe the first set of experiments which directly measure agonist-induced changes in both pharmacodynamic effects and pharmacokinetic parameters simultaneously and which demonstrate the feasibility of these studies in man. Five healthy volunteers each had two PET scans using [11C]flumazenil (a radiolabelled benzodiazepine site antagonist) as part of a study investigating kinetic models and the relationship between occupancy and effect of benzodiazepine site ligands. In both studies the [11C]flumazenil was displaced from the brain by infusion of midazolam administered i.v. 30 min into the scan. In one study a higher dose of midazolam was administered than in the other (range 12.5-50 micrograms/kg). Time-activity curves of the concentration of radioligand were derived in 17 different brain regions using a stereotactic automatic method of region selection. We demonstrated that there are significant differences in an index of occupancy, induced by the two different doses of midazolam, both across brain regions and within subjects. There was a significant correlation between measured occupancy index change and pharmacodynamic effects as measured by the peak change in beta 1 spectral power on EEG. There was no significant correlation between dose administered and EEG changes; plasma concentrations of midazolam were correlated with the occupancy index and with the EEG measures. In addition, we have demonstrated that a non-regional total index of brain occupancy can be obtained by analysing the non-tomographic data obtained with the PET scanner (total radioactivity counts head curve) and that this index shows significant correlations both with the dose administered and with the pharmacodynamic measure. This last finding validates the use of other non-tomographic counting techniques (Malizia et al., 1995a) where an index of displacement can be obtained after the administration of less than 1% of the dose of radiation needed for a PET study. These studies are likely to be useful in human psychopharmacology, in particular in the assessment of tolerance and of putative changes in benzodiazepine sensitivity in anxiety disorders. The same principles can be applied to other ligand studies and will be useful to validate current PK/PD models.

Adult↗

PubMed1996

Uptake of [N-methyl-11C]propionyl-L-carnitine (PLC) in human myocardium.

We studied the uptake of propionyl-L-carnitine from plasma by the myocardium in 10 human subjects using positron emission tomography. Propionyl-L-carnitine was labeled in the N-methyl position with carbon-11 (T1/2 = 20.4 min) and administered i.v. in trace amounts. The uptake of the radiolabel by the myocardium was then scanned over a period of 1 1/2 h. The activity-time course of the tracer in blood and plasma and the exchange of the label in plasma between propionyl carnitine, acetyl carnitine and free carnitine was followed during the scans. Myocardial blood flow was also measured in the same subjects. The results show an exchange of the tracer between the myocardium and plasma, and they show an apparently irreversible component of uptake, a result consistent with the incorporation of the label into relatively large intracellular carnitine pools.

Adult↗