published_or_final_version / abstract / Physics / Doctoral / Doctor of Philosophy

published_or_final_version / abstract / Physics / Doctoral / Doctor of Philosophy

Positron Emission Tomography (PET) is an imaging technique that uses biologically relevant molecules labelled with positron emitting radioisotopes to measure regional tissue function in living organisms. To maximise the detection efficiency, data are acquired in 3D, that is, all possible detector combinations in a scanner without inter-ring shielding (septa). The gain in sensitivity afforded by 3D PET is offset by the increase in random coincidences, scattered coincidences and deadtime. These problems must be overcome for the gain in sensitivity to be fully realised. The aim of this research project was to investigate strategies to increase the signal to noise ratio of the 3D PET data. Additional side shielding, both in neuro and body scanning, has been implemented and assessed. Large gains were achieved using the neuro shields in experimental and clinical studies. The potential of the body shields was tested in experimental and in-vivo studies which showed that they were scan dependent. For example, no gain was found for a cardiac blood flow (H2 IS0) study. A model-based scatter correction was assessed by companng compartment ratios within the 'Utah' phantom with radioactivity outside the field of view, with and without neuroshielding. Recovered ratios were within 6% of their actual values. The integration time was reduced in an effort to decrease the system deadtime. A peak increase of 150/0 in noise equivalent count rate was measured for a uniform cylinder inside the field of view. A random coincidence variance reduction technique was implemented and assessed to reduce the noise contained in the delayed window random coincidence estimate. The algorithm was evaluated using phantoms and tested on clinical data. A mean 16% reduction in coefficient of variation was measured for a C15O torso study.

<p>Patients suffering from different forms of neurodegenerative diseases, such as: Creutzfeldt Jacob Disease (CJD), Alzheimer disease (AD), mild cognitive impairment (MCI), frontotemporal dementia and Parkinson’s disease (PD) were examined with Positron Emission Tomography (PET) and the combination of different radiotracers: ¹⁵O-water, N-[¹¹C-methyl]-L-deuterodeprenyl (DED), [¹⁸F] 2-fluorodeoxyglucose: (FDG), N-methyl-[¹¹C]2-(4-methylaminophenyl)-6-hydroxybenzothiazole (PIB) and L-[¹¹C]-3,4-dihydroxiphenyl-alanine (DOPA). The radiotracers and the combinations of different radiotracers were selected with the intention to detect, in the brain, patterns of neuronal dysfunction, astrocytosis, axon degeneration or protein aggregation (amyloid), in the brain which are pathognomonic for specific diseases and may contribute to improve clinical differential diagnoses. Examinations in healthy volunteers were performed to allow comparisons with patients. In addition, animal studies were conducted to complement the information. In some cases, the PET findings could be compared with the results of autopsies.</p><p>In contrast to the micropathology, in which only a limited part of a tissue (obtained post-mortem or by biopsy) is inspected, one PET acquisition provides an image of the whole system (e.g.: the brain and the cerebellum). This form of imaging pathology is “<i>in vivo</i>”, where the examination is innocuous for the patient. </p><p>This thesis is an attempt to stimulate the development of new tracers, new tracer combinations and methods that directly or indirectly describe the anatomo-physiopathological changes produced in the brain in neurodegenerative diseases. A better description of different diseases can be obtained, confirming or questioning the clinical diagnoses and widening our understanding of the mechanisms underlying neurodegeneration. Different pathologies can produce similar symptoms and thus causing confusion regarding clinical diagnosis. The used PET combinations improved the accuracy of the diagnoses. The incipient knowledge emerging from a new neuroimaging pathology in combination with other disciplines may open the way to new classifications of dementias and neurodegenerative diseases based on an “<i>in vivo</i>” pathology. </p>

Des positrons s'annihilent dans les régions centrales de notre Galaxie. Ce fait est établi depuis la détection d'une forte émission de la raie à 511 keV en direction du centre Galactique. Cette raie gamma est émise lors de l'annihilation de positrons avec des électrons. Grâce à SPI, le spectro-imageur de l'observatoire spatial INTEGRAL, nous pouvons maintenant caractériser précisément cette raie d'émission. <br />Cette thèse présente une étude de l'émission d'annihilation des positrons basée sur la modélisation des interactions entre les positrons et les différentes composantes du milieu interstellaire. Les modèles présentés s'appuient sur les récents développements de nos connaissances des caractéristiques du milieu interstellaire dans les régions centrales de la Galaxie, où la majorité des positrons semblent s'annihiler, et la physique des positrons (production, propagation, annihilation). Afin d'obtenir des contraintes sur les sources des positrons et les sites d'annihilation, les résultats des modèles sont comparés aux données fournies par SPI.

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Diagnosis of diabetes mellitus, presence of hyperglycemia, and/or insulin resistance confer cardiovascular risk, particularly for diastolic dysfunction. Diabetes is associated with elevated myocardial norepinephrine (NE) content, enhanced sympathetic nervous system (SNS) activity, altered resting heart rate, and depressed heart rate variability. Positron emission tomography (PET) using the NE analogue [11C]meta-hydroxyephedrine ([11C]HED) provides an index of myocardial sympathetic neuronal integrity at the NE reuptake transporter (NET). The hypothesis of this project is that (i) hyperglycemia imparts heightened sympathetic tone and NE release, leading to abnormal sympathetic neuronal function in the hearts of diabetic rats, and (ii) these abnormalities may be reversed or prevented by treatments to normalize glycemia. Sprague Dawley rats were rendered insulin resistant by high fat feeding and diabetic by a single dose of streptozotocin (STZ). Diabetic rats were treated for 8 weeks with insulin, metformin or rosiglitazone, starting from either 1 week (prevention) or 8 weeks (reversal) after STZ administration. Sympathetic neuronal integrity was evaluated longitudinally by [11C]HED PET. Echocardiography measures of systolic and diastolic function were completed at serial timepoints. Plasma NE levels were evaluated serially and expression of NET and β-adrenoceptors were tested at the terminal endpoints. Diabetic rats exhibited a 52-57% reduction of [11C]HED standardized uptake value (SUV) at 8 weeks after STZ, with a parallel 2.5-fold elevation of plasma NE and a 17-20% reduction in cardiac NET expression. These findings were confirmed by ex vivo biodistribution studies. Transmitral pulse wave Doppler echocardiography established an extension of mitral valve deceleration time and elevated early to atrial velocity ratio, suggesting diastolic dysfunction. Subsequent treatment with insulin but not metformin restored glycemia, reduced plasma NE by 50%, normalized NET expression, and recovered [11C]HED SUV towards non-diabetic age-matched control. Diastolic dysfunction in these rats persisted. By contrast, early treatment with insulin, metformin, or rosiglitazone delayed the progression of diastolic dysfunction, but had no effect on elevated NE and reduced [11C]HED SUV in diabetic rats, potentially owing to a latent decrease in blood glucose. In conclusion, diabetes is associated with heightened circulating and tissue NE levels which can be effectively reversed by lowering glycemia with insulin. Noninvasive interrogation of sympathetic neuronal integrity using [11C]HED PET may have added value in the stratification of cardiovascular risk among diabetic patients and in determining the myocardial effects of glycemic therapy.