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Paul K Marsden

Publications and source records attributed to Paul K Marsden.

10 recordsLinked to original sources
PubMed2006

Attenuation of insulin-evoked responses in brain networks controlling appetite and reward in insulin resistance: the cerebral basis for impaired control of food intake in metabolic syndrome?

The rising prevalence of obesity and type 2 diabetes is a global challenge. A possible mechanism linking insulin resistance and weight gain would be attenuation of insulin-evoked responses in brain areas relevant to eating in systemic insulin resistance. We measured brain glucose metabolism, using [(18)F]fluorodeoxyglucose positron emission tomography, in seven insulin-sensitive (homeostasis model assessment of insulin resistance [HOMA-IR] = 1.3) and seven insulin-resistant (HOMA-IR = 6.3) men, during suppression of endogenous insulin by somatostatin, with and without an insulin infusion that elevated insulin to 24.6 +/- 5.2 and 23.2 +/- 5.8 mU/l (P = 0.76), concentrations similar to fasting levels of the resistant subjects and approximately threefold above those of the insulin-sensitive subjects. Insulin-evoked change in global cerebral metabolic rate for glucose was reduced in insulin resistance (+7 vs. +17.4%, P = 0.033). Insulin was associated with increased metabolism in ventral striatum and prefrontal cortex and with decreased metabolism in right amygdala/hippocampus and cerebellar vermis (P < 0.001), relative to global brain. Insulin's effect was less in ventral striatum and prefrontal cortex in the insulin-resistant subjects (mean +/- SD for right ventral striatum 3.2 +/- 3.9 vs. 7.7 +/- 1.7, P = 0.017). We conclude that brain insulin resistance exists in peripheral insulin resistance, especially in regions subserving appetite and reward. Diminishing the link be-tween control of food intake and energy balance may contribute to development of obesity in insulin resistance.

Adult↗
PubMed2005

Validation of PET imaging by alignment to histology slices.

The aim of this project is to verify the accuracy of positron emission tomography (PET) in identifying the tumour boundary and eventually to enable PET-guided resection with removal of significantly smaller margins. We present a novel use of an image-guided surgery system to enable alignment of preoperative PET images to postoperative histology. The oral cancer patients must have a high resolution CT scan as well as undergoing PET imaging. Registration of these images to the patient during surgery is achieved using a device that attaches to the patient's upper or lower teeth. During the procedure markers are placed around the lesion within tissue that is to be resected. These are marked along with any convenient anatomical landmarks using the image guidance system, providing the location of the points in the preoperative images. After the sample has been resected, slices through at least 3 of these points are made and photographed. Registration should be possible using these landmarks, but the accuracy of alignment is much improved by marking the bone surface in the histology image and registering to preoperative CT.

Algorithms↗
PubMed2004

Dissociation between global markers of bone formation and direct measurement of spinal bone formation in osteoporosis.

UNLABELLED: Regional bone metabolism measured using 18F-fluoride PET was assessed in 72 postmenopausal women classified as normal, osteopenic, or osteoporotic. Lower values of regional bone formation activity at the lumbar spine were seen in osteoporotic women, whereas global markers of bone formation were significantly increased. INTRODUCTION: Evaluations of global bone remodeling have revealed that increased bone turnover is a feature of patients with osteoporosis. The noninvasive functional imaging technique of 18F-fluoride positron emission tomography (PET) allows the direct quantitative assessment of bone metabolism at specific sites in the skeleton, including the clinically important site of the lumbar spine. MATERIALS AND METHODS: The aim of this study was to compare regional skeletal kinetics in 72 postmenopausal women (mean age, 61 years) classified as normal, osteopenic, or osteoporotic according to their BMD T score at the lumbar spine. Each woman had a dynamic PET scan of the lumbar spine after injection of 90 MBq 18F-fluoride ion and measurements of biochemical markers of bone formation and resorption. The arterial plasma input function was derived using aorta arterial activity from the PET image. Time-activity curves were obtained by placing regions of interest over the lumbar vertebrae. A three-compartmental model was used to calculate bone blood flow (K1) and the net plasma clearance of tracer to bone mineral (Ki), reflecting regional osteoblastic activity (ml/minutes/ml). Rate constants k2, k3, and k4, which describe transport between plasma, the extracellular fluid (ECF) compartment, and the bone mineral compartment, were also measured. RESULTS: The net uptake of fluoride to the bone mineral compartment (Ki) was significantly lower in the osteoporotic group compared with both the osteopenic and normal groups, with a mean difference of 0.005 ml/minutes/ml (16.7%). The fraction of the tracer in the extravascular tissue space that underwent specific binding to bone mineral (k3/k2 + k3) was also significantly reduced in the women classified as osteoporotic. In contrast, levels of bone-specific alkaline phosphatase (BSALP) were significantly higher in the osteoporotic group compared with the normal and osteopenic groups by 35% and 27%, respectively. A significant negative correlation (r = -0.41) was observed between levels of BSALP and the fraction of the tracer that underwent specific binding to bone mineral. CONCLUSION: Lower values of Ki, a measurement of regional bone formation activity, were seen in women classified as osteoporotic, whereas levels of BSALP, a measure of global bone formation, were significantly increased. These findings are suggestive of increased global skeletal bone turnover in women with postmenopausal osteoporosis but with relatively reduced regional bone formation at the predominantly trabecular site of the lumbar spine.

Absorptiometry, Photon↗
PubMed2003

Lactate: a preferred fuel for human brain metabolism in vivo.

Recent in vitro studies suggest that lactate, rather than glucose, may be the preferred fuel for neuronal metabolism. The authors examined the effect of lactate on global brain glucose uptake in euglycemic human subjects using 18 fluoro-deoxyglucose (FDG) positron emission tomography (PET). Eight healthy men, aged 40 to 54 years, underwent a 60-minute FDG-PET scan on two occasions in random order. On one occasion, 6.72% sodium lactate was infused at a rate of 50 micro mol. kg-1. min-1 for 20 minutes and then reduced to 30 micro mol. kg-1. min-1; 1.4% sodium bicarbonate was infused as a control on the other occasion. Plasma glucose levels were not different between the two groups (5.3 +/- 0.23 and 5.3 +/- 0.24 mmol/L, P = 0.55). Plasma lactate was significantly elevated by lactate infusion (4.08 +/- 0.35 vs. 0.63 +/- 0.22 mmol/L, P < 0.0005. The whole-brain rate of glucose uptake was significantly reduced by approximately 17% during lactate infusion (0.195 +/- 0.022 vs. 0.234 +/- 0.020 micro mol. g-1. min-1, P = 0.001). The authors conclude that, in vivo in humans, circulating lactate is used by the brain at euglycemia, with sparing of glucose.

Adult↗
PubMed2003

A prospective study of risedronate on regional bone metabolism and blood flow at the lumbar spine measured by 18F-fluoride positron emission tomography.

UNLABELLED: The effect of risedronate on bone metabolism at the lumbar spine was assessed in 18 women who had a 18F-fluoride PET scan at baseline and after 6 months of therapy. The net plasma clearance of fluoride to bone mineral reflecting osteoblastic activity decreased significantly after therapy. INTRODUCTION: Quantitative radionuclide studies of bone reflect bone blood flow and regional osteoblastic activity, and the latter should change after treatment with a bisphosphonate, although this has not been previously demonstrated. The aim of this study was to examine regional 18F-fluoride kinetics in the lumbar spine measured by 18F-fluoride positron emission tomography (PET) before and after treatment with risedronate. MATERIALS AND METHODS: Eighteen women, with a mean age of 67.0 years and a T-score of less than -2 at the spine or hip, had a dynamic PET scan of the lumbar spine after the injection of 90 MBq 18F-fluoride ion at baseline and 6 months after commencing risedronate therapy. The arterial plasma input function was derived using aorta arterial activity from the PET image. Time-activity curves were measured by placing regions of interest over the lumbar vertebrae. A three-compartmental model was used to calculate bone blood flow (K(1)) and the net plasma clearance of tracer to bone mineral (K(i)). Rate constants k(2), k(3), and k(4), which describe transport between plasma, the extracellular fluid (ECF) compartment, and the bone mineral compartment, respectively, were also measured. RESULTS: Mean vertebral K(i) decreased significantly by 18.4% from baseline (3.32 x 10(-2) ml/min/ml) to 6 months post-treatment (2.71 x 10(-2) ml/min/ml; p = 0.04). This decrease was similar in magnitude to the decrease observed for bone-specific alkaline phosphatase, a marker of bone formation. There was no significant difference in K(1) from baseline (1.49 x 10(-1) ml/min/ml) to 6 months after treatment (1.38 x 10(-1) ml/min/ml; p > 0.05). There was a significant increase in k(2), reflecting the reverse transport of fluoride from the extravascular tissue compartment to plasma, after 6 months of treatment (2.90 x 10(-1)/min versus 4.43 x 10(-1)/min; p = 0.01). No significant changes were seen for k(3) or k(4). There was a significant decrease from baseline in the fraction of tracer in the extravascular tissue space that underwent specific binding to the bone matrix (k(3)/[k(2) + k(3)]), decreasing by 18.1% (p = 0.02). CONCLUSION: K(i), the net plasma clearance to bone mineral reflecting regional osteoblastic activity, displayed a significant decrease after 6 months of antiresorptive therapy. This is the first study to show a direct metabolic effect of antiresorptive therapy on skeletal kinetics at the clinically important site of the lumbar spine. The use of 18F-fluoride PET may provide a useful noninvasive tool to assess novel treatments currently being developed for osteoporosis.

Absorptiometry, Photon↗
PubMed2002

PET-MR image fusion in soft tissue sarcoma: accuracy, reliability and practicality of interactive point-based and automated mutual information techniques.

The fusion of functional positron emission tomography (PET) data with anatomical magnetic resonance (MR) or computed tomography images, using a variety of interactive and automated techniques, is becoming commonplace, with the technique of choice dependent on the specific application. The case of PET-MR image fusion in soft tissue is complicated by a lack of conspicuous anatomical features and deviation from the rigid-body model. Here we compare a point-based external marker technique with an automated mutual information algorithm and discuss the practicality, reliability and accuracy of each when applied to the study of soft tissue sarcoma. Ten subjects with suspected sarcoma in the knee, thigh, groin, flank or back underwent MR and PET scanning after the attachment of nine external fiducial markers. In the assessment of the point-based technique, three error measures were considered: fiducial localisation error (FLE), fiducial registration error (FRE) and target registration error (TRE). FLE, which represents the accuracy with which the fiducial points can be located, is related to the FRE minimised by the registration algorithm. The registration accuracy is best characterised by the TRE, which is the distance between corresponding points in each image space after registration. In the absence of salient features within the target volume, the TRE can be measured at fiducials excluded from the registration process. To assess the mutual information technique, PET data, acquired after physically removing the markers, were reconstructed in a variety of ways and registered with MR. Having applied the transform suggested by the algorithm to the PET scan acquired before the markers were removed, the residual distance between PET and MR marker-pairs could be measured. The manual point-based technique yielded the best results (RMS TRE =8.3 mm, max =22.4 mm, min =1.7 mm), performing better than the automated algorithm (RMS TRE =20.0 mm, max =30.5 mm, min =7.7 mm) when registering filtered back-projection PET images to MR. Image reconstruction with an iterative algorithm or registration of a composite emission-transmission image did not improve the overall accuracy of the registration process. We have demonstrated that, in this application, point-based PET-MR registration using external markers is practical, reliable and accurate to within approximately 5 mm towards the fiducial centroid. The automated algorithm did not perform as reliably or as accurately.

Fluorodeoxyglucose F18↗
PubMed2002

Rapid solid phase synthesis and biodistribution of 18F-labelled linear peptides.

A rapid method for radiolabelling short peptides with 18F ( t(1/2)=109.7 min) for use in positron emission tomography (PET) was developed. Linear peptides (13mers) were synthesised using solid phase peptide synthesis and 9-fluorenylmethoxycarbonyl (Fmoc) chemistry. The peptides were assembled on a solid-phase polyethylene glycol-polystyrene support using the "hyper acid labile" linker xanthen-2-oxyvaleric acid and were labelled in situ with 4-[19F]- or 4-[18F]fluorobenzoic acid. Optimum coupling of 4-[19F]fluorobenzoic acid to the peptidyl resin was achieved within 2 min using N-[(dimethylamino)-1 H-1,2,3-triazolo[4,5-b]pyridin-1-ylmethylene]- Nmethylmethanaminium hexafluorophosphate N-oxide (HATU/DIPEA), and optimum cleavage was achieved within 7 min using trifluoroacetic acid/phenol/water/Triisopropylsilane at 37 degrees C. The linear peptides were rapidly labelled with 4-[18F]fluorobenzoic acid with an overall radiochemical yield of 80%-90% (decay corrected), a radiochemical purity of >95% without HPLC purification and an overall synthesis time of 20 min. This novel method was used to label peptides containing the arginine-glycine-aspartic acid (RGD) motif, the binding site of many integrins. In vitro studies showed that the fluorobenzoyl prosthetic group had no deleterious effect on the ability of these peptides to inhibit the binding of human cells via integrins. Biodistribution studies in tumour-bearing mice showed that although the linear peptides were rapidly removed from the circulation by the liver and kidneys, there was a transient and non-RGD-dependent accumulation in the tumour of both the test and the control peptides. The use of more selective peptides with a longer half-life in the circulation combined with this rapid labelling technique will significantly enhance the application of peptides in PET.

Amino Acid Sequence↗
PubMed2002

Simultaneous PET and NMR.

There is currently great interest in combining data from different imaging modalities, either by image registration methods that are performed after the data has been acquired or using new devices that can acquire data from two modalities simultaneously, or near simultaneously. In this paper a small prototype NMR-compatible PET scanner capable of acquiring PET images simultaneously with either NMR images or NMR spectra is described. In an associated paper [1], Pamela Garlick describes some investigations of cardiac metabolism that have been made using this system. One of the main challenges in constructing an NMR-compatible PET scanner is that photomultiplier tubes, which are an essential element of nearly all current PET systems, will not function in a high magnetic field. In collaboration with Simon Cherry and the Crump Institute of Biomedical Imaging at UCLA Medical School, a small (5.4 cm diameter) NMR-compatible PET scanner that will operate within the bore of an NMR magnet has been developed. Long optical fibres are used to transport light from the scintillation crystals that form the detector head to photomultiplier tubes situated in a low magnetic field region several metres from the magnet. This system has been used to perform simultaneous PET and NMR spectroscopy measurements with a 9.4T spectroscopy system, and has also been used to obtain simultaneous PET and MR images in several MRI scanners including a 4.7T small bore animal imaging system. Current efforts in the development of this technology are directed at experimental studies on small animals, both because this is less demanding technically and because it is in this area that applications are likely to appear first. However, there is no reason in principle why human PET-MR would not be feasible. Below, work with the prototype system and the next stage in its development are described, and some of the future possibilities and challenges are discussed.

Animals↗
PubMed2002

The role of insulin in human brain glucose metabolism: an 18fluoro-deoxyglucose positron emission tomography study.

The effect of basal insulin on global and regional brain glucose uptake and metabolism in humans was studied using 18-fluorodeoxyglucose and positron emission tomography (FDG-PET). Eight healthy male volunteers aged 49.3 +/- 5.1 years were studied twice in random order. On each occasion, they received an infusion of 0.1 mg. kg(-1). min(-1) somatostatin to suppress endogenous insulin production. In one study 0.3 mU. kg(-1). min(-1) insulin was infused to replace basal circulating insulin levels, and in the other study a saline infusion was used as control. We sought stimulatory effects of basal insulin on brain glucose metabolism particularly in regions with deficiencies in the blood-brain barrier and high density of insulin receptors. Insulin levels were 27.07 +/- 1.3 mU/l with insulin replacement and 3.51 +/- 0.4 mU/l without (P = 0.001). Mean global rate of brain glucose utilization was 0.215 +/- 0.030 mmol. kg(-1). min(-1) without insulin and 0.245 +/- 0.021 mmol. kg(-1). min(-1) with insulin (P = 0.008, an average difference of 15.3 +/- 12.5%). Regional analysis using statistical parametric mapping showed that the effect of basal insulin was significantly less in the cerebellum (Z = 5.53, corrected P = 0.031). We conclude that basal insulin has a role in regulating global brain glucose uptake in humans, mostly marked in cortical areas.

Adult↗