Introduction. Fused Positron Emission Tomography and Computed Tomography (PET/CT) is an emerging investigative tool in cardiovascular disease that provides an imaging-based quantification of pathophysiological processes of interest. The purpose of this thesis was to study the application of PET to identify fundamental pathophysiological processes driving 3 forms of cardiovascular disease: aortic stenosis, myocardial infarction, and atherosclerosis. Methods. Aortic Stenosis. Patients with a spectrum of calcific aortic valve disease (n=121) who underwent PET-CT imaging for the identification of valvular calcification (18Ffluoride) and inflammation (18F-fluorodeoxyglucose, 18F-FDG) underwent serial imaging and clinical follow-up over 2 years. Baseline imaging findings were compared with echocardiographic and CT markers of disease progression and clinical outcome. Myocardial Infarction. Patients underwent PET-CT imaging with 18F-fluciclatide (a novel αvβ3-selective radiotracer highlighting active angiogenesis, inflammation and fibrosis) after ST-segment elevation MI (n=21), alongside stable patients with chronic total occlusion (CTO) of a major coronary vessel (n=7), and healthy volunteers (n=9). Myocardial radiotracer uptake was compared with clinical and cardiac magnetic resonance imaging (CMR) markers of infarction and remodeling. Atherosclerosis. Patients with a spectrum of atherosclerotic disease categorized as stable or unstable (recent MI) underwent PET/CT imaging with 18F-fluciclatide (n=46). Thoracic aortic 18F-fluciclatide uptake was compared with aortic atherosclerotic burden quantified by CT plaque thickness, plaque volume and calcium scoring. Histological validation. Tissue from the aortic valve, myocardium and carotid arteries of study subjects was acquired and examined ex vivo using histology and autoradiography. Results. Aortic Stenosis. Baseline valvular 18F-fluoride uptake correlated strongly with the rate of progression in AVC (r=0.80, p < 0.001) and with haemodynamic progression (mean aortic valve gradient r=0.32, p=0.001). It emerged as independently associated with clinical outcome after age and sex-adjustment (HR 1.55 [1.33-1.81], p < 0.001). 18F-FDG demonstrated moderate correlations with disease progression as assessed by CT (r=0.43, p=0.001) and echocardiography (18F-FDG r=0.30, p=0.001), and was associated with clinical outcomes independent of age and sex (HR 1.35 [1.16-1.58], p < 0.001). Valvular 18F-fluoride uptake correlated with immunohistochemical markers of calcification activity. There was no correlation between 18F-FDG uptake and inflammation. Myocardial Infarction. 18F-Fluciclatide binding was demonstrated in ex vivo peri-infarct myocardium and uptake was increased in vivo at sites of acute infarction compared to remote myocardium (tissue-to-background ratio (TBRmean) 1.34±0.22 vs 0.85±0.17 respectively, p < 0.001) and myocardium of healthy volunteers (TBRmean 1.34±0.22 vs 0.70±0.03; p < 0.001). There was no 18F-fluciclatide uptake at sites of established prior infarction in patients with CTO, with myocardial activity similar to healthy volunteers (TBRmean 0.71±0.06 vs. 0.70±0.03,p=0.83). 18F-Fluciclatide uptake occurred at sites of regional wall hypokinesia (wall motion index ≥1 vs 0; TBRmean 0.93±0.31 vs 0.80±0.26 respectively, p < 0.001), was increased in segments displaying functional recovery (TBRmean 0.95±0.33 vs 0.81±0.27, p=0.002) and associated with increase in probability of regional recovery. Atherosclerosis. 18F-Fluciclatide vascular binding ex vivo co-localised with regions of increased αvβ3 integrin expression, and markers of inflammation and angiogenesis. 18F-Fluciclatide uptake in vivo correlated with measures of aortic atherosclerotic burden: plaque thickness (r=0.57, p=0.001), total plaque volume (r=0.56, p=0.001) and the CT aortic calcium score (r=0.37, p=0.01). Patients with recent MI had greater aortic 18F-fluciclatide uptake than those with stable disease (TBRmax 1.33 vs 1.21, p=0.01). Conclusions. In a range of cardiovascular diseases, PET-CT can provide insights into key pathophysiological processes, guide patient risk stratification and prognosis, and identify important biomarkers of disease activity that can be used for the development of future therapeutic interventions.

A methodology for the thermodynamic-kinetic evaluation of circulating systems as TSA carbon capture processes is developed and used in the assessment of a novel CFB configuration against a benchmark (co-current riser). The novel CFB features a counter-current adsorber, a counter-current regenerator and a riser, the latter element playing a double role of solids conveyer and co-current adsorber. The advantages sought by using a counter-current adsorber are not only the more efficient gas-solid contact mode with respect co-current, but also a low pressure drop derived from operation at lower gas velocities and hydrostatic head partially supported on the contactor internals. Knowledge of the adsorption equilibrium alone is sufficient to realise the much higher sorbent circulation rates required by co-current configurations –compared to counter-current– to meet the stringent carbon capture specifications of 90% recovery and 95% purity. Higher solids circulation rates imply higher energy requirements for regeneration, and therefore research and development of co-current gas-solid contactors cannot be justified in terms of searching for energy-efficient post-combustion carbon capture processes. Parallel experimental investigation in the operation and fluid dynamics of cold model CFB rigs is carried out with the purposes of: 1) providing information that may impact the process performance and can be fed into the mathematical model used in the theoretical assessment for more realistic evaluation, and 2) determine gas and solids residence time distributions (RTDs), which are used for the estimation of axial dispersion and comparison with published results in similar systems. Gas RTD data is generated using a tracer pulse injection-detection technique, whereas RTD for the solid phase is studied using positron emission particle tracking (PEPT). The PEPT technique proved to be adequate for the identification of flow regimes in the novel design of the counter-current adsorber, featuring inclined orifice trays. At low gas velocities the particles flow straight down through the tray holes, whereas at higher velocities the particles flow down in zig-zag, increasing the residence time of the particles and reducing the particle axial dispersion, both beneficial in terms of separation efficiency.

This project contributes to the research and development studies towards successful commissioning of the SuperKEKB electron-positron collider. This accelerator and storage rings complex aims at delivering the high-luminosity collisions of beams of electrons and positrons needed for the Belle II experiment. Such beams produce parasitic radiation—called “machine-induced backgrounds”, or simply “beam backgrounds” — that have detrimental effects on the experimental apparatus performance and durability. The Beast II effort is dedicated to measuring the beam backgrounds, and aims at testing the predictive power of the background models that were used in various phases of the Belle II design. A second objective is to ensure that the environment is safe for the detector prior to installing it around the beam lines. A major component of beam backgrounds consists of electromagnetic radiation. This study focusses on measuring this radiation at the location of the Belle II electromagnetic calorimeter. The measurements were achieved by placing scintillator crystals at positions representative of the Belle II calorimeter crystals that are the closest to the beam lines, and comparing the data with predictions for different operating parameters of the accelerator. Different phenomena related to machine backgrounds were observed: vacuum scrubbing, the electron-cloud effect, injection-related noise, beam-gas scattering and Touschek losses. Studies on the positron ring showed average background levels 13.5 +/- 3.5 times larger than simulation, whereas that ratio reached O(100-1000) for the electron ring. In the latter, the large uncertainty on the pressure measurements and the gas constituents limit the predictive power of the measurements. Radiation shields were also designed, fabricated, delivered and installed in the detector to protect the electromagnetic calorimeter from radiation coming from the beam lines. / Graduate

Computed tomography imaging has revolutionised modern medicine and we can now study the body in greater detail than ever before. Cardiac computed tomography has the potential to provide information not just on coronary anatomy, but also on myocardial function, perfusion and viability. This thesis addresses the optimisation and validation of computed tomography imaging of the heart using a wide volume 320-multidetector scanner. Computed tomography coronary angiography now has diagnostic accuracy comparable to invasive coronary angiography. However, radiation dose remains an important concern. It is therefore important to minimise computed tomography radiation dose while maintaining image quality. I was able to demonstrate that iterative reconstruction and patient tailored imaging techniques led to a 39% reduction in radiation dose in computed tomography coronary angiography, while maintaining subjective and objective assessments of image quality. In addition, I demonstrated that diagnostic images can be obtained in 99% of unselected patients presenting with suspected coronary artery disease when using single heart-beat 320- multidetector computed tomography coronary angiography. Computed tomography myocardial perfusion imaging can provide additional and complementary information as compared to computed tomography coronary angiography that can aid diagnosis and management. I established both quantitative and qualitative assessment of computed tomography myocardial perfusion imaging and validated it against both a clinical “gold-standard”, fractional flow reserve during invasive coronary angiography, and a physiological “gold-standard”, positron emission tomography with oxygen-15 labelled water. Finally, I was able to show that techniques to reduce radiation dose can also be applied to computed tomography myocardial perfusion imaging, leading to a 60% reduction in radiation dose, while maintaining image quality. In my thesis, I have established that comprehensive cardiac angiographic and perfusion imaging can be performed with wide volume computed tomography in a broad generalizable population of patients with relatively low radiation exposure. These techniques provide both structural and functional assessments from a single imaging modality that are valid and readily applicable to the clinic in the assessment and management of patients with suspected coronary artery disease.

Positron Emission Tomography (PET) has great value in research and clinical applications from oncology to neurodegenerative disorders. However, there is a barrier in translating biological knowledge into new PET applications due in part to the lack of efficient, widely applicable methods for labelling compounds with PET radioisotopes. Herein, a generic approach to radiolabelling is presented which is direct, broadly applicable and potentially adaptable to either of the two most commonly used PET radioisotopes, 11C and 18F. This approach employs the advantages of solid phase synthesis to achieve selective release of only the desired radiolabelled product from a solid support in a single step, simplifying purification and hence improving synthetic efficiency. Polystyrene resin was functionalised with a 1,2-diol group; this allowed the covalent attachment of compounds bearing boronic acid groups via formation of a boronate ester linkage. A Suzuki-Miyaura reaction with methyl iodide was used to cleave a model compound from the resin in 61% conversion after five minutes. This reaction was adapted to develop a fully automated radiosynthesis with [11C]- methyl iodide which generated a radiolabelled model compound in 2 – 7% non-decay-corrected radiochemical yield. This provided proof of concept for the simultaneous cleavage of compounds from the resin and radiolabelling with 11C. A boronic acid precursor of the known radiotracer [11C]-M-MTEB was attached to the resin and successfully radiolabelled with 11C in 2.4% non-decay-corrected radiochemical yield and 96 – 100% radiochemical purity under the same conditions. Furthermore, the potential adaptability of this solid phase approach to 18F radiolabelling was demonstrated by treatment of the resin-bound small molecules and peptides with potassium bifluoride, which released the compounds rapidly as trifluoroborate salts.

A characteristic feature of Chronic Obstructive Pulmonary Disease (COPD) is an abnormal inflammatory response in the lungs to inhaled particles or gases. The ability to assess and monitor this response in the lungs of COPD patients is important for understanding the pathogenic mechanisms, but also provides a measure of the activity of the disease. Disease activity is more likely to relate to lung inflammation rather than the degree of airflow limitation as measured by the FEV1. Preliminary studies have shown the 18F fluorodeoxyglucose positron emission tomography (18F FDG-PET) signal, as a measure of lung inflammation, is quantifiable in the lungs and is increased in COPD patients compared to controls. However, the methodology requires standardisation and any further enhancement of the methodology would improve its application to assess inflammation in the lungs. I investigated various methods of assessing FDG uptake in the lungs and assessed the reproducibility of these methods, and particularly evaluated whether the data was reproducible or not in the COPD patients (smokers and ex-smokers). This data was then compared with a group of healthy controls to assess the role of dynamic 18F FDG-PET scanning as a surrogate marker of lung inflammation. My data showed a good reproducibility of all methods of assessing FDG lung uptake. However, using conventional Patlak analysis, the uptake was not statistically different between COPD and the control group. Encouraging results in favour of COPD patients were nonetheless shown using compartmental methods of assessing the FDG lung uptake, suggesting the need to correct for the effect of air and blood (tissue fraction effect) when assessing this in a highly vascular organ like the lungs. A prospective study analysis involving a bigger cohort of COPD patients would be desirable to investigate this further.

Reconstructed tomographic image resolution of small animal PET imaging systems is improving with advances in radiation detector development. However the trend towards higher resolution systems has come with an increase in price and system complexity. Recent developments in the area of solid-state photomultiplication devices like silicon photomultiplier arrays (SPMA) are creating opportunities for new high performance tools for PET scanner design. Imaging of excised small animal organs and tissues has been used as part of post-mortem studies in order to gain detailed, high-resolution anatomical information on sacrificed animals. However, this kind of ex-vivo specimen imaging has largely been limited to ultra-high resolution μCT. The inherent limitations to PET resolution have, to date, excluded PET imaging from these ex-vivo imaging studies. In this work, we leverage the diminishing physical size of current generation SPMA designs to create a very small, simple, and high-resolution prototype detector system targeting ex-vivo tomographic imaging of small animal organs and tissues. We investigate sensitivity, spatial resolution, and the reconstructed image quality of a prototype small animal PET scanner designed specifically for imaging of excised murine tissue and organs. We aim to demonstrate that a cost-effective silicon photomultiplier (SiPM) array based design with thin crystals (2 mm) to minimize depth of interaction errors might be able to achieve sub-millimeter resolution. We hypothesize that the substantial decrease in sensitivity associated with the thin crystals can be compensated for with increased solid angle detection, longer acquisitions, higher activity and wider acceptance energy windows (due to minimal scatter from excised organs). The constructed system has a functional field of view (FoV) of 40 mm diameter, which is adequate for most small animal specimen studies. We perform both analytical (3D-FBP) and iterative (ML-EM) methods in order to reconstruct tomographic images. Results demonstrate good agreement between the simulation and the prototype. Our detector system with pixelated crystals is able to separate small objects as close as 1.25 mm apart, whereas spatial resolution converges to the theoretical limit of 1.6 mm (half the size of the smallest detecting element), which is to comparable to the spatial resolution of the existing commercial small animal PET systems. Better system spatial resolution is achievable with new generation SiPM detector boards with 1 mm x 1 mm cell dimensions. We demonstrate through Monte Carlo simulations that it is possible to achieve sub-millimeter spatial image resolution (0.7 mm for our scanner) in complex objects using monolithic crystals and exploiting the light-sharing mechanism among the neighboring detector cells. Results also suggest that scanner (or object) rotation minimizes artifacts arising from poor angular sampling, which is even more significant in smaller PET designs as the gaps between the sensitive regions of the detector have a more exaggerated effect on the overall reconstructed image quality when the design is more compact. Sensitivity of the system, on the other hand, can be doubled by adding two additional detector heads resulting in a, fully closed, 4π geometry.

Proton-neutron electron-positron pair production cross sections are calculated in the framework of the pseudoscalar one-pion exchange model in a fully relativistic manner. A computer program has been developed to evaluate invariants and Dirac traces for a given data point. The sections for symmetric coplanar events for laboratory kinetic energies of 10 to 250 MeV were calculated for pair angles of 20° to 120°. Frequency distributions were also calculated, at a laboratory energy of 200 MeV, using a random number generator to select data points. The frequency distributions are illustrated by curves. It was noted that the inclusion of heavier bosons will not significantly improve the results at laboratory energies less than 200 MeV.

Dopamine appears to play a critical role in regulating spatial working memory (SWM) in non-human primates, and SWM deficits are observed in patients with Parkinson�s disease and schizophrenia. Unfortunately, the current experimental literature in humans is marred by inconsistent behavioural findings, and there is a void in neuroimaging studies examining dopaminergic manipulation of SWM-related brain activity. The present thesis used a combination of behavioural neurocognitive testing and brain imaging to further examine dopaminergic manipulation of SWM in healthy humans, using two pharmacological challenges: 1) acute tyrosine depletion (TPD) (to acutely deplete tonic dopamine), and 2) D1/D2 receptor activation using the dopamine receptor agonist pergolide (to stimulate dopamine neurotransmission) under conditions of TPD. The effects of TPD on behavioural performance were examined using three SWM tasks: 1) a delayed-recognition task previously impaired by TPD (Experiment 1) and 2) two delayed-response tasks designed to vary only in response requirements (Experiment 2). The findings demonstrated an apparent failure of TPD to impair performance on any of the tasks. Further, the effects of TPD on SWM-related brain activity during a SWM n-back task were examined using regional Cerebral Blood Flow (rCBF) measured by H2 150 Positron Emission Tomography (Experiment 2), and Steady State Visually Evoked Potentials (SSVEP) measured by Steady State Probe Topography (Experiment 4). TPD failed to produce discernable effects on either neural networks (task-related rCBF) or temporal electrophysiological activity (SSVEP) associated with the SWM n-back task. In contrast, D1/D2 receptor stimulation under dopamine depleted conditions impaired performance on both a SWM delayed-response task (Experiment 1) and SWM n-back task (Experiment 2), and resulted in task-related increases in fronto-temporal SSVEP latency (suggestive of increased inhibition) and decreases in parieto-occipital SSVEP amplitude (suggestive of increased activation) during the early delay period of the SWM n-back task (Experiment 4). These changes are consistent with the undisputed role of frontal and parietal regions in n-back task performance, and with previous evidence of dopaminergic modulation of these regions in animals and humans. In summary, TPD did not modulate SWM behavioural performance on four different SWM tasks with differing task demands, and failed to produce measurable changes to either SWM-related neural networks (task-related rCBF) or cortical electrophysiological activity (SSVEP) associated with the SWM n-back task. The implication of these findings, when taken together with previous studies, is that the degree of dopaminergic depletion achieved with TPD may be insufficient to consistently and robustly modulate SWM networks in healthy humans, questioning the utility of TPD as a probe of dopaminergic function. In addition, these findings demonstrate the complexity of stimulating D1/D2 receptors under dopamine depleted conditions, and highlight the critical importance of baseline dopamine levels in influencing the effects of acute dopamine challenge on SWM performance.

L'origine des positrons galactiques reste un des sujets les plus controversés de l'Astrophysique des hautes énergies depuis la découverte de la raie d'annihilation électron-positron en provenance du centre galactique à la fin des années 1970. L'étude de la raie d'annihilation à 511 keV est actuellement un des objectifs majeurs de SPI : le spectromètre d'INTEGRAL.<br />Cette thèse s'ouvre sur l'étude de la partie centrale de SPI: son plan de détection. La procédure de calibration en énergie ainsi que l'étude de la dégradation des détecteurs sont reportées. Par la suite, une étude approfondie du bruit de fond instrumental permet d'utiliser SPI dans les meilleures conditions. Le traitement des données aboutit alors à des cartes du ciel et des spectres avec une précision inégalée. Pour finir, les contributions des diverses sources potentielles de positrons galactiques sont confrontées aux résultats obtenus.