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1.  Autoradiographic Mapping of 5-HT1B/1D Binding Sites in the Rhesus Monkey Brain Using [carbonyl-11C]zolmitriptan 
Zolmitriptan is a serotonin 5-HT1B/1D receptor agonist that is an effective and well-tolerated drug for migraine treatment. In a human positron emission tomography study, [11C]zolmitriptan crossed the blood-brain barrier but no clear pattern of regional uptake was discernable. The objective of this study was to map the binding of [11C]zolmitriptan in Rhesus monkey brain using whole hemisphere in vitro autoradiography with [11C]zolmitriptan as a radioligand. In saturation studies, [11C]zolmitriptan showed specific (90%) binding to a population of high-affinity binding sites (Kd 0.95–5.06 nM). There was regional distribution of binding sites with the highest density in the ventral pallidum, followed by the external globus pallidus, substantia nigra, visual cortex, and nucleus accumbens. In competitive binding studies with 5-HT1 receptor antagonists, [11C]zolmitriptan binding was blocked by selective 5-HT1B and 5-HT1D ligands in all target areas. There was no appreciable change in binding with the addition of a 5-HT1A receptor antagonist.
PMCID: PMC3195497  PMID: 22013519
2.  Performance of Principal Component Analysis and Independent Component Analysis with Respect to Signal Extraction from Noisy Positron Emission Tomography Data - a Study on Computer Simulated Images 
Multivariate image analysis tools are used for analyzing dynamic or multidimensional Positron Emission Tomography, PET data with the aim of noise reduction, dimension reduction and signal separation. Principal Component Analysis is one of the most commonly used multivariate image analysis tools, applied on dynamic PET data. Independent Component Analysis is another multivariate image analysis tool used to extract and separate signals. Because of the presence of high and variable noise levels and correlation in the different PET images which may confound the multivariate analysis, it is essential to explore and investigate different types of pre-normalization (transformation) methods that need to be applied, prior to application of these tools. In this study, we explored the performance of Principal Component Analysis (PCA) and Independent Component Analysis (ICA) to extract signals and reduce noise, thereby increasing the Signal to Noise Ratio (SNR) in a dynamic sequence of PET images, where the features of the noise are different compared with some other medical imaging techniques. Applications on computer simulated PET images were explored and compared. Application of PCA generated relatively similar results, with some minor differences, on the images with different noise characteristics. However, clear differences were seen with respect to the type of pre-normalization. ICA on images normalized using two types of normalization methods also seemed to perform relatively well but did not reach the improvement in SNR as PCA. Furthermore ICA seems to have a tendency under some conditions to shift over information from IC1 to other independent components and to be more sensitive to the level of noise. PCA is a more stable technique than ICA and creates better results both qualitatively and quantitatively in the simulated PET images. PCA can extract the signals from the noise rather well and is not sensitive to type of noise, magnitude and correlation, when the input data are correctly handled by a proper pre-normalization. It is important to note that PCA as inherently a method to separate signal information into different components could still generate PC1 images with improved SNR as compared to mean images.
PMCID: PMC2703833  PMID: 19572032
3.  A computerized Infusion Pump for control of tissue tracer concentration during Positron Emission Tomography in vivo Pharmacokinetic/Pharmacodynamic measurements 
A computer controlled infusion pump (UIPump) for regulation of target tissue concentration of radioactive compounds was developed for use in biological research and tracer development for PET.
Based on observed tissue or plasma kinetics after a bolus injection of the tracer an algorithm calculates the infusion needed to obtain a specified target kinetic curve. A computer feeds this infusion scheme into an infusion pump connected to an animal via a venous catheter. The concept was validated using [11C]Flumazenil administrated to Sprague-Dawley rats where the whole brain distribution and kinetic of the tracer was measured over time using a microPET-scanner. The accuracy and precision of the system was assessed by producing steady-state levels of the tracer and by mimicking kinetics after oral administration.
Various kinetic profiles could be generated, including rapid achievement of constant levels, or step-wise increased levels. The resulting tissue curves had low deviation from the target curves according to the specified criteria: AUC (%): 4.2 ± 2.8, Maximal deviation (%): 13.6 ± 5.0 and R2: 0.95 ± 0.02.
The UIPump-system is suitable for use in PET-research for assessment of PK/PD properties by simulation of different tracer tissue kinetics in vivo.
PMCID: PMC2430701  PMID: 18513382
4.  Application of the multicellular tumour spheroid model to screen PET tracers for analysis of early response of chemotherapy in breast cancer 
Positron emission tomography (PET) is suggested for early monitoring of treatment response, assuming that effective anticancer treatment induces metabolic changes that precede morphology alterations and changes in growth. The aim of this study was to introduce multicellular tumour spheroids (MTS) to study the effect of anticancer drugs and suggest an appropriate PET tracer for further studies.
MTS of the breast cancer cell line MCF7 were exposed to doxorubicin, paclitaxel, docetaxel, tamoxifen or imatinib for 7 days for growth pattern studies and for 3 or 5 days for PET tracer studies. The effect on growth was computed using the semi-automated size determination method (SASDM). The effect on the uptake of PET tracers [18F]3'-deoxy-3'-fluorothymidine (FLT), [1-11C]acetate (ACE), [11C]choline (CHO), [11C]methionine (MET), and 2-[18F]fluoro-2-deoxyglucose (FDG) was calculated in form of uptake/viable volume of the MTS at the end of the drug exposures, and finally the uptake was related to effects on growth rate.
The drugs paclitaxel, docetaxel and doxorubicin gave severe growth inhibition, which correlated well with inhibition of the FLT uptake. FLT had, compared with ACE, CHO, MET and FDG, higher sensitivity in monitoring the therapy effects.
SASDM provides an effective, user-friendly, time-saving and accurate method to record the growth pattern of the MTS, and also to calculate the effect of the drug on PET tracer uptake. This study demonstrate the use of MTS and SASDM in combination with PET tracers as a promising approach to probe and select PET tracer for treatment monitoring of anticancer drugs and that can hopefully be applied for optimisation in breast cancer treatment.
PMCID: PMC2206720  PMID: 17659092
5.  Multicellular Tumour Spheroid as a model for evaluation of [18F]FDG as biomarker for breast cancer treatment monitoring 
In order to explore a pre-clinical method to evaluate if [18F]FDG is valid for monitoring early response, we investigated the uptake of FDG in Multicellular tumour spheroids (MTS) without and with treatment with five routinely used chemotherapy agents in breast cancer.
The response to each anticancer treatment was evaluated by measurement of the [18F]FDG uptake and viable volume of the MTSs after 2 and 3 days of treatment.
The effect of Paclitaxel and Docetaxel on [18F]FDG uptake per viable volume was more evident in BT474 (up to 55% decrease) than in MCF-7 (up to 25% decrease).
Doxorubicin reduced the [18F]FDG uptake per viable volume more noticeable in MCF-7 (25%) than in BT474 MTSs.
Tamoxifen reduced the [18F]FDG uptake per viable volume only in MCF-7 at the highest dose of 1 μM.
No effect of Imatinib was observed.
MTS was shown to be appropriate to investigate the potential of FDG-PET for early breast cancer treatment monitoring; the treatment effect can be observed before any tumour size changes occur.
The combination of PET radiotracers and image analysis in MTS provides a good model to evaluate the relationship between tumour volume and the uptake of metabolic tracer before and after chemotherapy. This feature could be used for screening and selecting PET-tracers for early assessment of treatment response.
In addition, this new method gives a possibility to assess quickly, and in vitro, a good preclinical profile of existing and newly developed anti-cancer drugs.
PMCID: PMC1459213  PMID: 16556298
6.  A new, fast and semi-automated size determination method (SASDM) for studying multicellular tumor spheroids 
Considering the width and importance of using Multicellular Tumor Spheroids (MTS) in oncology research, size determination of MTSs by an accurate and fast method is essential. In the present study an effective, fast and semi-automated method, SASDM, was developed to determinate the size of MTSs. The method was applied and tested in MTSs of three different cell-lines. Frozen section autoradiography and Hemotoxylin Eosin (H&E) staining was used for further confirmation.
SASDM was shown to be effective, user-friendly, and time efficient, and to be more precise than the traditional methods and it was applicable for MTSs of different cell-lines. Furthermore, the results of image analysis showed high correspondence to the results of autoradiography and staining.
The combination of assessment of metabolic condition and image analysis in MTSs provides a good model to evaluate the effect of various anti-cancer treatments.
PMCID: PMC1315357  PMID: 16283948
7.  Noise correlation in PET, CT, SPECT and PET/CT data evaluated using autocorrelation function: a phantom study on data, reconstructed using FBP and OSEM 
Positron Emission Tomography (PET), Computed Tomography (CT), PET/CT and Single Photon Emission Tomography (SPECT) are non-invasive imaging tools used for creating two dimensional (2D) cross section images of three dimensional (3D) objects. PET and SPECT have the potential of providing functional or biochemical information by measuring distribution and kinetics of radiolabelled molecules, whereas CT visualizes X-ray density in tissues in the body. PET/CT provides fused images representing both functional and anatomical information with better precision in localization than PET alone.
Images generated by these types of techniques are generally noisy, thereby impairing the imaging potential and affecting the precision in quantitative values derived from the images. It is crucial to explore and understand the properties of noise in these imaging techniques. Here we used autocorrelation function (ACF) specifically to describe noise correlation and its non-isotropic behaviour in experimentally generated images of PET, CT, PET/CT and SPECT.
Experiments were performed using phantoms with different shapes. In PET and PET/CT studies, data were acquired in 2D acquisition mode and reconstructed by both analytical filter back projection (FBP) and iterative, ordered subsets expectation maximisation (OSEM) methods. In the PET/CT studies, different magnitudes of X-ray dose in the transmission were employed by using different mA settings for the X-ray tube. In the CT studies, data were acquired using different slice thickness with and without applied dose reduction function and the images were reconstructed by FBP. SPECT studies were performed in 2D, reconstructed using FBP and OSEM, using post 3D filtering. ACF images were generated from the primary images, and profiles across the ACF images were used to describe the noise correlation in different directions. The variance of noise across the images was visualised as images and with profiles across these images.
The most important finding was that the pattern of noise correlation is rotation symmetric or isotropic, independent of object shape in PET and PET/CT images reconstructed using the iterative method. This is, however, not the case in FBP images when the shape of phantom is not circular. Also CT images reconstructed using FBP show the same non-isotropic pattern independent of slice thickness and utilization of care dose function. SPECT images show an isotropic correlation of the noise independent of object shape or applied reconstruction algorithm. Noise in PET/CT images was identical independent of the applied X-ray dose in the transmission part (CT), indicating that the noise from transmission with the applied doses does not propagate into the PET images showing that the noise from the emission part is dominant. The results indicate that in human studies it is possible to utilize a low dose in transmission part while maintaining the noise behaviour and the quality of the images.
The combined effect of noise correlation for asymmetric objects and a varying noise variance across the image field significantly complicates the interpretation of the images when statistical methods are used, such as with statistical estimates of precision in average values, use of statistical parametric mapping methods and principal component analysis. Hence it is recommended that iterative reconstruction methods are used for such applications. However, it is possible to calculate the noise analytically in images reconstructed by FBP, while it is not possible to do the same calculation in images reconstructed by iterative methods. Therefore for performing statistical methods of analysis which depend on knowing the noise, FBP would be preferred.
PMCID: PMC1208889  PMID: 16122383
8.  Non-isotropic noise correlation in PET data reconstructed by FBP but not by OSEM demonstrated using auto-correlation function 
Positron emission tomography (PET) is a powerful imaging technique with the potential of obtaining functional or biochemical information by measuring distribution and kinetics of radiolabelled molecules in a biological system, both in vitro and in vivo. PET images can be used directly or after kinetic modelling to extract quantitative values of a desired physiological, biochemical or pharmacological entity. Because such images are generally noisy, it is essential to understand how noise affects the derived quantitative values. A pre-requisite for this understanding is that the properties of noise such as variance (magnitude) and texture (correlation) are known.
In this paper we explored the pattern of noise correlation in experimentally generated PET images, with emphasis on the angular dependence of correlation, using the autocorrelation function (ACF). Experimental PET data were acquired in 2D and 3D acquisition mode and reconstructed by analytical filtered back projection (FBP) and iterative ordered subsets expectation maximisation (OSEM) methods. The 3D data was rebinned to a 2D dataset using FOurier REbinning (FORE) followed by 2D reconstruction using either FBP or OSEM. In synthetic images we compared the ACF results with those from covariance matrix. The results were illustrated as 1D profiles and also visualized as 2D ACF images.
We found that the autocorrelation images from PET data obtained after FBP were not fully rotationally symmetric or isotropic if the object deviated from a uniform cylindrical radioactivity distribution. In contrast, similar autocorrelation images obtained after OSEM reconstruction were isotropic even when the phantom was not circular. Simulations indicated that the noise autocorrelation is non-isotropic in images created by FBP when the level of noise in projections is angularly variable. Comparison between 1D cross profiles on autocorrelation images obtained by FBP reconstruction and covariance matrices produced almost identical results in a simulation study.
With asymmetric radioactivity distribution in PET, reconstruction using FBP, in contrast to OSEM, generates images in which the noise correlation is non-isotropic when the noise magnitude is angular dependent, such as in objects with asymmetric radioactivity distribution. In this respect, iterative reconstruction is superior since it creates isotropic noise correlations in the images.
PMCID: PMC1142517  PMID: 15892891
9.  Detection of Helicobacter pylori Antibodies in a Pediatric Population: Comparison of Three Commercially Available Serological Tests and One In-House Enzyme Immunoassay 
Journal of Clinical Microbiology  1999;37(10):3328-3331.
A serum immunoglobulin G enzyme immunoassay (EIA) for Helicobacter pylori antibodies already in use in adults was evaluated with 99 pediatric serum samples to determine its usefulness for the study of H. pylori disease in children. The reference method used was either the 13C-urea breath test or a biopsy culture of gastric mucosa. In children, an EIA cutoff of 0.35 absorbancy unit yielded sensitivity, specificity, and positive and negative predictive values of 93, 97, 93, and 97%, respectively. The cutoff recommended when this EIA was published for use in adults was 0.70 absorbancy unit (H. Gnarpe, P. Unge, C. Blomqvist, and S. Mäkitalo, APMIS 96:128–132, 1988). Another subset of 169 serum samples taken from children was analyzed by four serological tests in order to compare the performance of the in-house EIA with the Pyloriset, HM-CAP, and Helico-G kits. For the 169 samples, 10 (5.9%) false-positives and no false-negatives occurred with the Helico-G, 3 (1.8%) false-positives and no false-negatives occurred with the Pyloriset, and 3 (1.8%) false-positives and 1 (0.6%) false-negative occurred with the HM-CAP. For the 169 samples, 1 (0.6%) false-positive and no false-negatives occurred with the in-house EIA. Serological detection of H. pylori antibodies with our EIA seems to be valuable in diagnosing H. pylori infection in children, but only if a lowered, specific pediatric cutoff is established. The commercial kits, particularly the Helico-G, seem to overdiagnose pediatric H. pylori infection. A positive serological test for H. pylori infection, particularly for children, needs to be confirmed by a reference method because of the possibility of spontaneous eradication of infection, with a lingering serological response.
PMCID: PMC85558  PMID: 10488200

Results 1-9 (9)