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S R Meikle

Publications and source records attributed to S R Meikle.

At least 19 recordsLinked to original sources
PubMed2006

In vivo evidence for microglial activation in neurodegenerative dementia.

Evidence from numerous neuropathological observations and in vivo clinical imaging studies suggests a prominent role of activated microglia, the main effector cell of the brain's innate immune system, in Alzheimer's disease and other neurodegenerative diseases. Though the comprehensive molecular definition of the microglial activation process is still incomplete, the de novo expression of 'peripheral benzodiazepine-binding sites (PBBS)' by activated but not resting microglia has been established as a useful descriptor of functional state changes in microglia. As microglial transformation to an activated state is closely linked to progressive changes in brain disease, the detection of activated microglia can provide information about disease distribution and rate of disease progression. Positron emission tomography (PET) and [(11)C](R)-PK11195, a specific ligand of the PBBS, have been used to study systematically microglial activation in vivo. Significant microglial activation is present in the brains of patients with neurodegenerative dementia even at early and possibly preclinical stages of the disease with a spatial distribution reflecting different clinical phenotypes. We review some of the posited functions of activated microglia in the pathophysiology of dementia and speculate on the relationship between increased regional [(11)C](R)-PK11195 signals and the ensuing changes in brain volume. Finally, we provide a brief outlook on the development of new radioligands for the PBBS.

Benzodiazepines↗
PubMed2001

In vivo imaging of nicotinic receptor upregulation following chronic (-)-nicotine treatment in baboon using SPECT.

To quantify changes in neuronal nAChR binding in vivo, quantitative dynamic SPECT studies were performed with 5-[(123)I]-iodo-A-85380 in baboons pre and post chronic treatment with (-)-nicotine or saline control. Infusion of (-)-nicotine at a dose of 2.0 mg/kg/24h for 14 days resulted in plasma (-)-nicotine levels of 27.3 ng/mL. This is equivalent to that found in an average human smoker (20 cigarettes a day). In the baboon brain the regional distribution of 5-[(123)I]-iodo-A-85380 was consistent with the known densities of nAChRs (thalamus > frontal cortex > cerebellum). Changes in nAChR binding were estimated from the volume of distribution (V(d) ) and binding potential (BP) derived from 3-compartment model fits. In the (-)-nicotine treated animal V(d) was significantly increased in the thalamus (52%) and cerebellum (50%) seven days post cessation of (-)-nicotine treatment, suggesting upregulation of nAChRs. The observed 33% increase in the frontal cortex failed to reach significance. A significant increase in BP was seen in the thalamus. In the saline control animal no changes were observed in V(d) or BP under any experimental conditions. In this preliminary study, we have demonstrated for the first time in vivo upregulation of neuronal nAChR binding following chronic (-)-nicotine treatment.

Animals↗
PubMed2001

Simultaneous estimation of physiological parameters and the input function--in vivo PET data.

Dynamic imaging with positron emission tomography (PET) is widely used for the in vivo measurement of regional cerebral metabolic rate for glucose (rCMRGlc) with [18F]fluorodeoxy-D-glucose (FDG) and is used for the clinical evaluation of neurological disease. However, in addition to the acquisition of dynamic images, continuous arterial blood sampling is the conventional method to obtain the tracer time-activity curve in blood (or plasma) for the numeric estimation of rCMRGlc in mg glucose/100-g tissue/min. The insertion of arterial lines and the subsequent collection and processing of multiple blood samples are impractical for clinical PET studies because it is invasive, has the remote, but real potential for producing limb ischemia, and it exposes personnel to additional radiation and risks associated with handling blood. In this paper, based on our previously proposed method for extracting kinetic parameters from dynamic PET images, we developed a modified version (post-estimation method) to improve the numerical identifiability of the parameter estimates when we deal with data obtained from clinical studies. We applied both methods to dynamic neurologic FDG PET studies in three adults. We found that the input function and parameter estimates obtained with our noninvasive methods agreed well with those estimated from the gold standard method of arterial blood sampling and that rCMRGlc estimates were highly correlated (r = 0.973). More importantly, no significant difference was found between rCMRGlc estimated by our methods and the gold standard method (P > 0.16). We suggest that our proposed noninvasive methods may offer an advance over existing methods.

Adult↗
PubMed2001

Instrumentation and methodology for quantitative pre-clinical imaging studies.

Radiotracer imaging studies performed on animals have the potential to play a major role in pharmaceutical development, pharmacology studies and basic biochemistry research. Recent developments in instrumentation and imaging methodology make it possible to image and quantify the kinetics of radiolabelled pharmaceuticals in a wide range of animal models from rodents to non-human primates. This article reviews the developments which have led to the current state-of-the-art, including advances in detector technologies, image reconstruction and tracer kinetic modelling. The practical issues specific to animal imaging studies are also discussed. With appropriate instrumentation and rigorous methodology, quantitative pre-clinical imaging has an important role to play in drug development.

Animals↗
PubMed2000

The influence of tomograph sensitivity on kinetic parameter estimation in positron emission tomography imaging studies of the rat brain.

We investigated the influence of tomograph sensitivity on reliability of parameter estimation in positron emission tomography studies of the rat brain. The kinetics of two tracers in rat striatum and cerebellum were simulated. A typical injected dose of 10 MBq and a reduced dose of 1 MBq were assumed. Kinetic parameters were estimated using a region of interest (ROI) analysis and two pixel-by-pixel analyses. Striatal binding potential was estimated as a function of effective tomograph sensitivity (S(eff)) using a simplified reference tissue model. A S(eff) value of > or =1% was required to ensure reliable parameter estimation for ROI analysis and a S(eff) of 3-6% was required for pixel-by-pixel analysis. We conclude that effective tomograph sensitivity of 3% may be an appropriate design goal for rat brain imaging.

Animals↗
PubMed1998

Pharmacokinetic assessment of novel anti-cancer drugs using spectral analysis and positron emission tomography: a feasibility study.

PURPOSE: The aim of this study was to investigate the feasibility of evaluating the pharmacokinetics of radiolabeled anti-cancer drugs using spectral analysis, a non-compartmental tracer kinetic modeling technique, and positron emission tomography (PET). METHODS: Dynamic PET studies were performed on patients receiving tracer doses of 5-fluorouracil (5-[18F]-FU) and two developmental drugs [11C]-temozolomide and [11C]-acridine carboxamide. Spectral analysis was then used to (a) determine individual and group average pharmacokinetics, (b) predict tumour handling in response to different drug administration regimens, and (c) produce functional parametric images describing regional pharmacokinetics. RESULTS: Spectral analysis could distinguish tumour kinetics from normal tissue kinetics in an individual [11C]-temozolomide study and demonstrated a markedly greater volume of distribution (VD) in glioma than in normal brain, although there was no appreciable difference in mean residence time. Analysis of pooled acridine carboxamide data (n = 22) revealed a relatively large VD (and prolonged retention) in the liver and spleen and a markedly lower VD (and initial uptake) in the brain. Continuous infusion of 5-[18F]-FU was predicted to achieve a concentration in colorectal metastases in liver approximately 10 times that achieved in plasma at 10 h after commencement of the infusion. CONCLUSIONS: We conclude that spectral analysis provides important pharmacokinetic information about radiolabeled anti-cancer drugs with relatively few model assumptions.

Acridines↗
PubMed1998

Parametric image reconstruction using spectral analysis of PET projection data.

Spectral analysis is a general modelling approach that enables calculation of parametric images from reconstructed tracer kinetic data independent of an assumed compartmental structure. We investigated the validity of applying spectral analysis directly to projection data motivated by the advantages that: (i) the number of reconstructions is reduced by an order of magnitude and (ii) iterative reconstruction becomes practical which may improve signal-to-noise ratio (SNR). A dynamic software phantom with typical 2-[11C]thymidine kinetics was used to compare projection-based and image-based methods and to assess bias-variance trade-offs using iterative expectation maximization (EM) reconstruction. We found that the two approaches are not exactly equivalent due to properties of the non-negative least-squares algorithm. However, the differences are small (< 5%) and mainly affect parameters related to early and late time points on the impulse response function (K1 and, to a lesser extent, VD). The optimal number of EM iteration was 15-30 with up to a two-fold improvement in SNR over filtered back projection. We conclude that projection-based spectral analysis with EM reconstruction yields accurate parametric images with high SNR and has potential application to a wide range of positron emission tomography ligands.

Algorithms↗
PubMed1997

Does fluorine-18 fluorodeoxyglucose metabolic imaging of tumours benefit oncology?

Fluoro-deoxyglucose (FDG) is a metabolic marker, which follows the same route into cells as that of glucose, and it can be radiolabelled with fluorine-18, 18F-FDG making it suitable for imaging with positron emission tomography (PET). The fact that rapidly proliferating cells such as tumour cells accumulate 18F-FDG more avidly than those with a normal turnover rate has given rise to its potential in oncology. The rationale and previous published uses of 18F-FDG in oncology are reviewed, together with the various analysis techniques and associated methodological difficulties.

Deoxyglucose↗
PubMed1997

ECAT ART - a continuously rotating PET camera: performance characteristics, initial clinical studies, and installation considerations in a nuclear medicine department.

Advances in fully three-dimensional (3D) image reconstruction techniques have permitted the development of a commercial, rotating, partial ring, fully 3D positron emission tomographic (PET) scanner, the ECAT ART. The system has less than one-half the number of bismuth germanate detectors compared with a full ring scanner with the equivalent field of view, resulting in reduced capital cost. The performance characteristics, implications for installation in a nuclear medicine department, and clinical utility of the scanner are presented in this report. The sensitivity (20 cm diameterx20 cm long cylindrical phantom, no scatter correction) is 11400 cps.kBq-1.ml-1. This compares with 5800 and 40500 cps.kBq-1.ml-1 in 2D and 3D respectively for the equivalent full ring scanner (ECAT EXACT). With an energy window of 350-650 keV the maximum noise equivalent count (NEC) rate was 27 kcps at a radioactivity concentration of approximately 15 kBq.ml-1 in the cylinder. Spatial resolution is approximately 6 mm full width at half maximum on axis degrading to just under 8 mm at a distance of 20 cm off axis. Installation and use within the nuclear medicine department does not appreciably increase background levels of radiation on gamma cameras in adjacent rooms and the dose rate to an operator in the same room is 2 microSv. h-1 for a typical fluorine-18 fluorodeoxyglucose (18F-FDG) study with an initial injected activity of 370 MBq. The scanner has been used for clinical imaging with18F-FDG for neurological and oncological applications. Its novel use for imaging iron-52 transferrin for localising erythropoietic activity demonstrates its sensitivity and resolution advantages over a conventional dual-headed gamma camera. The ECAT ART provides a viable alternative to conventional full ring PET scanners without compromising the performance required for clinical PET imaging.

Equipment Design↗
PubMed1997

Airway closure measured by a technegas bolus and SPECT.

Absence of a maximal dose-response plateau and mathematical modeling suggest that asthmatic airways close during bronchoconstriction. Finding segmental areas affected by closure would be important in understanding asthmatic airway function. The aim of this study was to evaluate single-photon emission computed tomography (SPECT) as a method of investigating airway closure. Simultaneous SPECT transmission and emission studies were performed on a thoracic phantom to develop analysis methodology, and on 13 normal subjects after they inhaled a Technegas bolus from residual volume (RV), to measure airway closure. Single-breath nitrogen test values and lung volumes were measured. Airway closure was defined as the percent of Technegas-free lung volume (LVclosed). The mean error +/- 95% CI of the error, as determined by transmission scan, was 1.1 ml +/- 165 ml (0.8% +/- 15% lung volume) in the phantom studies, and 112 ml +/- 419 ml (4% +/- 31% of supine functional residual capacity [FRC]) in the human studies. LVclosed correlated with closing capacity (r = 0.86, p < 0.01 ) and closing volume (r = 0.86, p < 0.01), but not with RV/total lung capacity (TLC). This study indicates that simultaneous SPECT emission and transmission scans, using a Technegas bolus, are a valid method of measuring airway closure in vivo, with the added advantage of providing three-dimensional data that allow the detection of small, discrete areas of airway closure and determination of their volumes and shapes.

Adult↗
PubMed1996

Simultaneous emission and transmission measurements as an adjunct to dynamic planar gamma camera studies.

Anatomical imaging provides useful information which complements functional imaging performed using a gamma camera. We have previously used transmission measurements in single-photon emission tomography acquired simultaneously with the emission scan using either a plane flood source or a moving line source for attenuation and scatter correction. This approach is equally applicable in planar imaging and provides useful information to assist in detecting patient motion and in defining regions of interest in dynamic studies. We have adapted a moving transmission line source to acquire dynamic geometric mean measurements in the study of the mucociliary clearance of inhaled technetium-99m labelled colloids with a single-headed rotating gamma camera. The line source makes a return pass for each emission acquisition frame (alternating anterior/posterior views), each pass being initiated by a signal from the gamma camera. The result is a dynamic sequence of emission and transmission measurements obtained from a single acquisition. In this application transmission measurements are used to define the lung outline for clearance determination and to check for subject movement throughout the duration of the study.

Gamma Cameras↗
PubMed1996

Transmission-based scatter correction of 180 degrees myocardial single-photon emission tomographic studies.

Meaningful comparison of single-photon emission tomographic (SPET) reconstructions for data acquired over 180 degrees or 360 degrees can only be performed if both attenuation and scatter correction are applied. Convolution subtraction has appeal as a practical method for scatter correction; however, it is limited to data acquired over 360 degrees. A new algorithm is proposed which can be applied equally well to data acquired over 180 degrees or 360 degrees. The method involves estimating scatter based on knowledge of reconstructed transmission data in combination with a reconstructed estimate of the activity distribution, obtained using attenuation correction with broad beam attenuation coefficients. Processing is implemented for planes of activity parallel to the projection images for which a simplified model for the scatter distribution may be applied, based on the measured attenuation. The appropriate broad beam (effective) attenuation coefficients were determined by considering the scatter buildup equation. It was demonstrated that narrow beam attenuation coefficients should be scaled by 0.75 and 0.65 to provide broad beam attenuation coefficients for technetium-99m and thallium-201 respectively. Using a thorax phantom, quantitative accuracy of the new algorithm was compared with conventional transmission-based convolution subtraction (TDCS) for 360 degrees data. Similar heart to lung contrasts were achieved and correction of 180 degrees data yielded a 10.4% error for cardiac activity compared to 5.2% for TDCS. Contrast for myocardium to ventricular cavity was similarly good for scatter-corrected 180 degrees and 360 degrees data, in contrast to attenuation-corrected data, where contrast was significantly reduced. The new algorithm provides a practical method for correction of scatter applicable to 180 degrees myocardial SPET.

Algorithms↗
PubMed1996

Validation of postinjection transmission measurements for attenuation correction in neurological FDG-PET studies.

UNLABELLED: Accurate estimation of local cerebral metabolic rate of glucose utilization (LCMRGlu) with PET requires a separate measurement of photon attenuation using a transmission source that extends study duration. The feasibility of postinjection transmission, (PIT) scanning has been demonstrated but not previously validated in humans. METHODS: Preinjection and postinjection transmission scans were performed in 26 patients undergoing routine [18F]fluorodeoxyglucose (FDG) neurological PET. The PIT data were processed with two methods: One estimated emission contamination using an independent emission scan (PITind); the other estimated the contamination directly from the PIT scan, using simultaneously acquired emission data for subtraction (PITsim). These methods were compared with measured attenuation correction (AC) using preinjection transmission data (ACpre) and calculated AC (ACcalc). After reconstruction, image data were reformatted to fit a standard brain atlas to facilitate analysis of the region of interest and to allow subtraction of datasets averaged over all subjects. RESULTS: The ratios of LCMRGlu values with respect to those obtained by the ACpre method ranged from 0.98 to 1.06 (mean +/- s.d., 1.01 +/- 0.02) for PITind, from 0.96 to 1.04 (mean 0.99 +/- 0.02) for PITsim and from 0.77 to 1.12 (mean 0.96 +/- 0.07) for ACcalc. Both PIT methods agreed well with the ACpre method, whereas ACcalc gave rise to appreciable bias in structures near thick bone or sinuses. CONCLUSION: Accurate quantitative estimates of LCMRGlu can be obtained using PIT measurements. The PIT methods shorten study duration and increase patient throughput. The PITsim method has the further advantage that it is not affected by tracer redistribution and can therefore be applied to tracers with relatively rapid kinetics in vivo.

Brain↗
PubMed1995

Simultaneous emission and transmission measurements for attenuation correction in whole-body PET.

UNLABELLED: We describe a methodology for measuring and correcting for attenuation in whole-body PET using simultaneous emission and transmission (SET) measurements. METHODS: The main components of the methodology are: (a) sinogram windowing of low activity (< or = 50 MBq) rotating 68Ge/Ga rod sources, (b) segmented attenuation correction (SAC) and (c) maximum likelihood reconstruction using the ordered subsets EM (OS-EM) algorithm. The methods were implemented on a whole-body positron emission tomograph. Quantitative accuracy and the signal-to-noise ratio (SNR) were measured for a thorax-tumor phantom as functions of acquisition time (range: 2-20 min per position). RESULTS: When a typical rod source activity (200 MBq 68Ge/Ga) was used, emission SNR was 60% lower in simultaneous than in separate measurements. The difference was only 14% when the rods contained 45 MBq 68Ge/Ga. The SNR was further improved by SAC in conjunction with OS-EM reconstruction and the relative gain increased with increasing acquisition time. Quantitative estimates of tumor, liver and lung radioactivity agreed with values obtained from a separate high count measurement to within 8%, independent of acquisition time. CONCLUSION: Attenuation correction of whole-body PET images is feasible using SET measurements. There is good quantitative agreement with conventional methods and increased noise is offset by the use of SAC and OS-EM reconstruction.

Adult↗
PubMed1994

Accelerated EM reconstruction in total-body PET: potential for improving tumour detectability.

Total-body positron emission tomography (PET) is a useful diagnostic tool for evaluating malignant disease. However, tumour detection is limited by image artefacts due to the lack of attenuation correction and noise. Attenuation correction may be possible using transmission data acquired after or simultaneously with emission data. Despite the elimination of attenuation artefacts, however, tumour detection is still hampered by noise, which is amplified during image reconstruction by filtered backprojection (FBP). We have investigated, as an alternative to FBP, an accelerated expectation maximization (EM) algorithm for its potential to improve tumour detectability in total-body PET. Signal to noise ratio (SNR), calculated for a tumour with respect to the surrounding background, is used as a figure of merit. A software tumour phantom, with conditions typical of those encountered in a total-body PET study using simultaneous acquisition, is used to optimize and compare various reconstruction approaches. Accelerated EM reconstruction followed by two-dimensional filtering is shown to yield significantly higher SNR than FBP for a range of tumour sizes, concentrations and counting statistics (deltaSNR = 6.3 +/- 3.9, p < 0.001). The methods developed are illustrated by examples derived from physical phantom and patient data.

Algorithms↗
PubMed1994

A convolution-subtraction scatter correction method for 3D PET.

3D acquisition and reconstruction in positron emission tomography (PET) produce data with improved signal-to-noise ratios compared with conventional 2D slice-oriented methods. However, the sensitivity increase is accompanied by an increase in the number of scattered photons and random coincidences detected. This paper presents a scatter correction technique for 3D PET data where an estimate of the scattered photon distribution is subtracted from the data before reconstruction. The scatter distribution is estimated by iteratively convolving the photopeak projections with a mono-exponential kernel. The method accounts for the 3D acquisition geometry and nature of scatter by performing the scatter estimation on 2D projections. The assumptions of the method have been investigated by measuring the variation in the scatter fraction and the scatter function at different positions in a cylinder. Both parameters were found to vary by up to 50% from the centre to the edge of a large water-filled cylinder. Despite this, in a uniform cylinder containing water with different concentrations of radioactivity, scatter was reduced from 25% in a non-radioactive region to less than 5% using the convolution-subtraction method. In addition, the relative concentration of a cylinder containing an increased concentration, which was underestimated by almost 50% without scatter correction, was within 5% of the true concentration after correction.

Algorithms↗