Ce travail de thèse réalisé à l’Institut de Chimie Moléculaire de l’Université de Bourgogne porte dans un premier temps sur la synthèse d’agents chélatants bifonctionnels adaptés à la chélation de radiométaux trivalents, notamment l’indium-111. La plus grande partie de ce travail a ensuite consisté à réaliser le greffage d’un agent chélatant bifonctionnel dérivé du DOTA sur différents anticorps ou fragments d’anticorps monoclonaux : le trastuzumab (anti HER2, traitement de cancers du sein), le cétuximab (anti EGFR, traitement de nombreux cancers, dont le cancer colorectal) et l’abciximab (antiagrégant plaquettaire). Une attention particulière a été apportée à la caractérisation des différents immunoconjugués. La dernière étape de ce travail de thèse porte sur le radiomarquage à l’indium-111 de deux immunoconjugués préparés : le trastuzumab et le cétuximab. Ces étapes de radiomarquage nous ont permis de déterminer la fraction immunoréactive et l’affinité de chaque radiotraceur. Nous avons ainsi pu étudier la biodistribution in vivo de ces radiotraceurs chez la souris par imagerie SPECT-CT. Nous avons également développé une méthode de greffage originale pour le marquage d’un fragment d’anticorps de type Fab, l’abciximab, dans le but de suivre la biodistribution de cet antiagrégant plaquettaire. Enfin, nous avons également validé le concept d’imagerie multimodale à travers le greffage et le radiomarquage d’un agent bimodal pour l’imagerie optique et la SPECT sur des lipopolysaccharides bactériens. Les travaux réalisés nous ont permis d’acquérir un savoir faire en matière de greffage d’anticorps et de radiomarquage. Les résultats obtenus permettent d’envisager le greffage d’autres anticorps ou biomolécules, ainsi que l’utilisation d’autres radionucléides pour l’imagerie PET ou la radioimmunothérapie / This work conducted at the “Institut de Chimie Moléculaire de l’Université de Bourgogne” carries at first on the synthesis of bifunctional chelating agents suitable for the chelation of trivalent radiometals, including indium-111. The greater part of this work was then dedicated to the grafting of a DOTA derivative bifunctional chelating agent on different antibodies or fragments of monoclonal antibodies: trastuzumab (anti-HER2 treatment of breast cancer), cetuximab (anti EGFR, treatment of many cancers, including colorectal cancer) and abciximab (antiplatelet). Particular attention was paid to the characterization of various immunoconjugates. The critical step of this thesis consisted in the indium-111 radiolabeling of two previously prepared immunoconjugates: trastuzumab and cetuximab. These steps of radiolabelling allowed us to determine the immunoreactive fraction and affinity of each radiotracer. Thus, we were able to study the in vivo biodistribution of the radiotracers in tumour-bearing mice by SPECT-CT. We also developed an original method for the labeling of a Fab antibody fragment in order to monitor the biodistribution of the antiplatelet agent (abciximab). Finally, we also validated the concept of multimodal imaging through grafting and radiolabeling of a bimodal agent for optical and SPECT imaging on bacterial lipopolysaccharide. Thank’s to this work, we gained an expertise in antibodies radiolabeling. The results obtained allow to consider the labeling of antibodies or other biomolecules, and the use of other radionuclides for PET imaging and radioimmunotherapy

99mTecknetium-tetrofosmin är ett radiofarmaceutiskt medel som används vid myokardscintigrafi för att bedöma myokardperfusionen genom att avbilda vänsterkammarens blodflöde. Radiofarmakat uppvisar ett lågt myokardiellt upptag på endast 1,2%, där majoriteten av resterande radiofarmaka rensas ut genom levern och utsöndras via gallsystemet. Det extrakardiella upptaget i buken kan minska bildkvalitén, dölja defekter och försämra diagnostisk noggrannhet. GE StarGuide är en SPECT/CT-kamera utrustad med avancerad detektorteknologi som möjliggör fokuserad fotoninsamling, vilket bidrar till högre bildupplösning. Syftet med den här studien var att undersöka effekten av bukupptag vid bedömning av vänsterkammarens blodfördelning vid myokardscintigrafi med hjälp av SPECT/CT-kameran StarGuide. För att uppnå detta användes en thoraxmodell med ett fantomhjärta och en slang som simulerade bukupptag. Slangen fylldes med varierande aktivitetskoncentrationer och avståndet mellan slangen och fantomhjärtat varierades systematiskt. Vårdpersonal inom området bedömde sedan om bildomtagning var nödvändig, baserat på bildkvalitén och effekten av bukupptaget. Resultatet från studien indikerar en kvalitativ och kvantitativ påverkan av bukupptag vid bedömning av blodfördelningen i vänsterkammaren för de olika undersökta aktivitetskoncentrationerna och avstånden. Däremot observerades ingen statistisk signifikant skillnad mellan aktivitetskoncentrationerna vad gäller den kvantitativt påverkan. Vidare studier krävs för att validera dessa fynd och ge nya riktlinjer för att optimera användningen av StarGuide inom den nuklearmedicinska verksamheten. / 99mTechnetium-tetrofosmin is a radiopharmaceutical agent used for myocardial perfusion scintigraphy to assess myocardial perfusion by imaging the left ventricular bloodflow. The agent exhibits a low myocardial uptake of only 1,2%, with the majority of the agent being cleared through the liver and excreted via the biliary system. The extracardiac uptake in the abdomen can reduce image quality, conceal defects, and compromise diagnostic accuracy. The GE StarGuide is a SPECT/CT-camera equipped with advanced detector technology that allows for focused photon collection, thus contributing to improved image resolution. The objective of the present phantomstudy was to investigate the effect of abdominal uptake on the assessment of blood distribution in the left ventricle during myocardial perfusion scintigraphy using the SPECT/CT-camera StarGuide. To acieve this, a thorax model containing a phantomheart was used, with a tube simulating abdominal uptake. The tube was filled with varying activity concentrations, and the distance between the tube and the phantomheart was systematically varied. Healthcare professionals within the field then assessed whether image retakes were necessary based on the image quality and the impact of the abdominal uptake. The results of the study indicated that there is a qualitative and quantitative effect of extracardiac uptake on the assessment of left ventricular blood distribution for the different activity concentrations and distances examined, however, no statistically significant difference was observed between the activity concentrations quantitatively. Further investigations are needed to validate these findings and provide guidance for optimizing the use of the StarGuide camera in nuclear medicine practice.

ENGLISH ABSTRACT: Background: The detection of bone infection can be very difficult especially in bone with altered structure due to prior trauma or surgical procedures. Complicated osteomyelitis (COM) is becoming a public health problem especially with the difficult choice between, high cost surgery and prolonged courses of intravenous or oral antibiotic therapy, as well as the social and psychological effect of longterm disease and disability of the patient. The correct localisation of especially bone infection is still a challenge for the clinician. The single photon emission computed tomography/low dose computed tomography (SPECT/CT), by fusing the functional information with the anatomical parts, is a wellestablished tool used in many nuclear medicine studies. This improves the overall quality of the study with more clear answers. The aim of the study was to determine the added value of SPECT/CT in the management of complicated osteomyelitis (COM) in patients with endo-prosthesis, post traumatic osteomyelitis with and without metal implants and diabetic foot. Methods: This was a prospective study, between February 2010 and February 2012. Patients with suspected COM who fulfilled the selection and inclusion criteria were included. All had abnormal three phase bone scan followed by infection imaging with 99mTc labelled white blood cells and 99mTc -colloid if the99mTc labelled white blood cell study was abnormal. 67Ga citrate was used in vertebral involvement. Planar and SPECT/CT images were reviewed for presence of abnormal uptake and for its localization in bone and soft tissue. Scan results were defined as positive or negative. Both planar and SPECT/CT images were compared regarding diagnosis and precise localization of infection. The final diagnosis was obtained from surgical specimen or microbiological culture as well as clinical follow-up of all patients. Results: There were 72 patients, 29 male and 43 female with mean age of 57 yrs [range 27-88].There were 24 patients with prosthesis, 16 with hip prosthesis (PH=16), and 8 with knee prosthesis (PK=8). There were 44 patients with post traumatic osteomyelitis, 26 with metal implants (TOM=26) and 18 without metal implants (TOWM= 18). Four patients had diabetic foot (DF= 4). Infection was diagnosed in 19/72 patients on planar images and in 21/72 on SPECT/CT. Infection was diagnosed in 4 patients with prosthesis, 16 patients with post traumatic injury and one diabetic foot patient. The four patients with prosthesis, SPECT /CT added diagnostic value by excluding osteomyelitis in 3 patients and by defining the exact extent and localizing soft tissue and bone infection (STI/OM) in one patient. In 16 patients with post traumatic OM on planar images, SPECT /CT added diagnostic value, by excluding OM in 4 patients and confirming only STI, better localisation of the uptake in bone and soft tissue in 5 patients, of them 2 patient was negative on planar, and in 7 patients, confirmed and defined the exact extent of both OM and STI. One diabetic foot was positive for STI on the planar, the SPECT/CT added diagnostic value by defining the extent of the infection. In summary the added value of SPECT/CT was: a. Overall infection: 1. Exclusion of osteomyelitis by confirming only soft tissue involvement: 7 patients (10%) 2. Better localization in bone and soft tissue: 6 patients (8%) 3. Better delineation of extent of infection: 9 patients (12%) 4. None: 50 patients (70%) b. In positive cases only: 1. Exclusion of osteomyelitis by confirming only soft tissue involvement: 7 patients (33%) 2. Better localization in bone and soft tissue: 5 patients (24%) 3. Better delineation of extent of infection: 9 patients (43%) 4. None: 0 patients The overall sensitivity, specificity, positive predictive value, negative predictive value and accuracy for infection, on planar was 90%, 100%, 100%, 97%, 97%, respectively and for SPECT/CT 100%, 100%, 100%, 100%, 100%. For OM on planar, the sensitivity, specificity , positive predictive value, negative predictive value and accuracy was 100%, 89%, 53%, 100%, 90%, respectively and for SPECT/CT 100%, 100%, 100%, 100%, 100%. Conclusion: In complicated osteomyelitis, SPECT/CT is useful in localizing, defining the exact extent of infection where the planar images are abnormal, with no added value if the planar images are negative. We recommend in clinical practice the routine use of hybrid SPECT/CT imaging in complicated osteomyelitis when planar images are abnormal. / AFRIKAANSE OPSOMMING: Agtergrond: Die opspoor van beeninfeksie is veral moeilik in been wat as gevolg van vorige trauma of chirurgiese prosedures misvorm is. Gekompliseerde osteomiëlitis word ‘n gesondheidsprobleem veral as gevolg van die moeilike keuse tussen hoë koste chirurgie en langdurige kursusse binneaarse of orale antibiotika, asook die sosiale en sielkundige gevolge van langstaande siekte en die gestremdheid van die pasiënt. Die korrekte lokalisering van veral beeninfeksie is steeds ‘n uitdaging vir die geneesheer. Enkel foton emissie rekenaartomografie / lae dosis rekenaartomografie (SPECT/CT), die kombinasie van funksionele en anatomiese inligting, is ‘n goed gevestigde metode in baie kerngeneeskunde ondersoeke. Dit verbeter die algemene kwaliteit van die studie met ‘n meer spesifieke antwoord. Die doel van hierdie studie was om die bykomende waarde van SPECT/CT in die hantering van gekompliseerde osteomiëlitis in pasiënte met endo-protese, post traumatise osteomiëlitis met en sonder metaal prosteses asook diabetiese voet te bepaal. Metode: ‘n Prospektiewe studie is tussen Februarie 2010 en Februarie 2012 gedoen. Pasiënte met vermoedelik gekompliseerde osteomiëlitis wat aan die keuse en insluitingskriteria voldoen het, is ingesluit. Almal het abnormale drie-fase beenflikkergramme gehad, gevolg deur infeksiebeelding met 99mTc gemerkte witselle en 99mTc kolloïed indien die 99mTc gemerkte witselstudie abnormaal was. 67Ga sitraat is gebruik wanneer daar werwelaantasting teenwoordig was. Die planare en SPECT/CT beelde is vergelyk ten opsigte van diagnose en presiese lokalisering van die infeksie. Die finale diagnose is met behulp van chirurgiese monsters en mikrobiologiese kweking asook die kliniese opvolg van alle pasiënte bepaal. Resultate: Die studie het 72 pasiënte, 29 mans en 43 vroue, met gemiddelde ouderdom van 57 jaar [27 – 88 ingesluit]. Daar was 24 pasiënte met prosteses, waarvan 16 met heupprosteses (PH= 16) en 8 met knieprosteses (PK= 8). Van die 44 pasiënte met post traumatiese osteomiëlitis, het 26 metaal prosteses (TOM= 26) en 18 geen metaalprosteses gehad nie (TOWM= 18). Vier pasiënte het diabetiese voet gehad (DF= 4). By 19/72 van die pasiënte is infeksie op die planare beelde gediagnoseer en in 21/72 op die SPECT/CT beelde. Die bykomende twee gevalle was 1 met TOM en 1 met TOWM. Infeksie is by 4 pasiënte met prosteses, 16 pasiënte met post traumatiese besering en 1 met diabetiese voet gediagnoseer. In die vier pasiënte met prosteses, het SPECT/CT ‘n diagnostiese bydrae gelewer om osteomiëlitis by 3 van die pasiënte uit te skakel en die presiese omvang en lokalisering van sagte weefsel en beeninfeksie (STI/OM) in een pasiënt te bepaal. In 16 pasiënte met post traumatise osteomiëlitis op die planare beelde, was SPECT/CT van diagnostiese waarde, waar osteomiëlitis in 4 pasiënte uitgesluit is, en slegs STI bevestig is. Beter lokalisering van die opname in been en sagte weefsel was in 5 pasiënte moontlik, van wie 2 op die planare beelde negatief was, en in 7 pasiënte bevestig en die presiese omvang met beide OM en STI gedefinieer is. Een diabetiese voet was positief vir STI op die planare beelde, maar die SPECT/CT het diagnostiese waarde verbeter deur die omvang van die infeksie beter te toon. Ter opsomming, was die waarde van die SPECT/CT: 1. Uitsluiting van osteomiëlitis deur slegs van sagte weefsel aantasting te bevestig: 7 pasiënte 10% 2. Beter lokalisering in been en sagte weefsel: 5 pasiënte 7% 3. Beter definisie van omvang van infeksie: 9 pasiënte 12% 4. Geen bykomende waarde: 51 pasiënte 71% Die algehele sensitiwiteit, spesifisiteit, positiewe voorspellingswaarde, negatiewe voorspellingswaarde en akkuraatheid vir die opspoor van infeksie vir die planare beelde was 90%, 100%, 100%, 97%, 97%, onderskeidelik en vir die SPECT/CT 100%, 100%, 100%, 100% en 100%. Vir osteomiëlitis was sensitiwiteit, spesifisiteit, positiewe voorspellingswaarde, negatiewe voorspellingswaarde en akkuraatheid van planare beelde 100%, 89%, 53%, 100%, 90%, onderskeidelik en die van SPECT/CT 100%, 100%, 100%, 100% , 100%. Gevolgtrekking: SPECT/CT is nuttig in die lokalisering en definiëring van die presiese omvang van die infeksie in gekompliseerde osteomiëlitis in gevalle waar die planare beelde abnormaal is, met geen bykomende waarde wanneer planare beelde negatief is nie. Ons beveel SPECT/CT beelding as roetine in kliniese praktyk aan wanneer planare beelde in gekompliseerde osteomiëlitis abnormaal is.

Computational tools of use in the objective assessment of image quality for tomography systems were developed for computer processing units (CPU) and graphics processing units (GPU) in the image quality lab at the University of Arizona. Fast analytic x-ray projection code called IQCT was created to compute the mean projection image for cone beam multi-slice helical computed tomography (CT) scanners. IQCT was optimized to take advantage of the massively parallel architecture of GPUs. CPU code for computing single photon emission computed tomography (SPECT) projection images was written calling upon previous research in the image quality lab. IQCT and the SPECT modeling code were used to simulate data for multimodality SPECT/CT observer studies. The purpose of these observer studies was to assess the benefit in image quality of using attenuation information from a CT measurement in myocardial SPECT imaging. The observer chosen for these studies was the scanning linear observer. The tasks for the observer were localization of a signal and estimation of the signal radius. For the localization study, area under the localization receiver operating characteristic curve (A(LROC)) was computed as A(LROC)^Meas = 0.89332 ± 0.00474 and A(LROC)^No = 0.89408 ± 0.00475, where "Meas" implies the use of attenuation information from the CT measurement, and "No" indicates the absence of attenuation information. For the estimation study, area under the estimation receiver operating characteristic curve (A(EROC)) was quantified as A(EROC)^Meas = 0.55926 ± 0.00731 and A(EROC)^No = 0.56167 ± 0.00731. Based on these results, it was concluded that the use of CT information did not improve the scanning linear observer's ability to perform the stated myocardial SPECT tasks. The risk to the patient of the CT measurement was quantified in terms of excess effective dose as 2.37 mSv for males and 3.38 mSv for females.Another image quality tool generated within this body of work was a singular value decomposition (SVD) algorithm to reduce the dimension of the eigenvalue problem for tomography systems with rotational symmetry. Agreement in the results of this reduced dimension SVD algorithm and those of a standard SVD algorithm are shown for a toy problem. The use of SVD toward image quality metrics such as the measurement and null space are also presented.

Two inverse problems are investigated in this dissertation, taking into account both the spatial and temporal aspects. The first problem addresses the under determined image reconstruction problem for dynamic SPECT. The quality of the reconstructed image is often limited due to having fewer observations than the number of voxels. The proposed algorithms make use of the generalized α-divergence function to improve the estimation performance. The first algorithm is based on an alternating minimization framework to minimize a regularized α-divergence objective function. We demonstrate that selecting an adaptive α policy depending on the time evolution of the voxels gives better performance than a fixed α assignment. The second algorithm is based on Newton's method. A regularized approach has been taken to avoid stability issues. Newton's method is generally computationally demanding due to the complexity associated with inverting the Hessian matrix. A fast Newton-based method is proposed using majorization-minimization techniques that diagonalize the Hessian matrix. In dynamically evolving systems, the prediction matrix plays an important role in the estimation process. An estimation technique is proposed to estimate the prediction matrix using the α-divergence function. The simulation results show that our algorithms provide better performance than the techniques based on the Kullback-Leibler distance. The second problem is the recovery of data transmitted over free-space optical communication channels using orbital angular momentum (OAM). In the presence of atmospheric turbulence, crosstalk occurs among OAM optical modes resulting in an error floor at a relatively high bit error rate. The modulation format considered for the underlying problem is Q-ary pulse position modulation (PPM). We propose and evaluate three joint detection strategies to overcome the OAM crosstalk problem: i) maximum likelihood sequence estimation (MLSE). ii) Q-PPM factor graph detection. iii) branch-and-bound detection. We compare the complexity and the bit-error-rate performance of these strategies in realistic scenarios.

Molecular probes capable of detecting colorectal cancer (CRC) are needed for early CRC diagnosis. The objective of this study was to characterize c[CTPSPFSHC]OH (TCP-1), a small peptide derived from phage display selection, for targeting human CRC xenografts using technetium-99m ((99m)Tc)-labeled TCP-1 and fluorescent cyanine-7 (Cy7)-labeled form of the peptide (Cy7-TCP-1). (99m)Tc-TCP-1 was generated by modifying TCP-1 with succinimidyl-6-hydrazino-nicotinamide (S-HYNIC) followed by radiolabeling. In vitro saturation binding experiments were performed for (99m)Tc-TCP-1 in human HCT116 colon cancer cells. SCID mice with human HCT116 cancer xenografts were imaged with (99m)Tc-TCP-1 or control peptide using a small-animal SPECT imager: Group I (n=5) received no blockade; Group II (n=5) received a blocking dose of non-radiolabeled TCP-1. Group III (n=5) were imaged with (99m)Tc-labeled control peptide (inactive peptide). SCID mice with human PC3 prostate cancer xenografts (Group IV, n=5) were also imaged with (99m)Tc-TCP-1. Eight additional SCID mice bearing HCT116 xenografts in dorsal skinfold window chambers (DSWC) were imaged by direct positron imaging of (18)F-fluorodeoxyglucose ((18)F-FDG) and fluorescence microscopy of Cy7-TCP-1. In vitro(99m)Tc-HYNIC-TCP-1 binding assays on HCT 116 cells indicated a mean Kd of 3.04±0.52nM. In cancer xenografts, (99m)Tc-TCP-1 radioactivity (%ID/g) was 1.01±0.15 in the absence of blockade and was reduced to 0.26±0.04 (P<0.01) with blockade. No radioactive uptake was observed in the PC3 tumors with (99m)Tc-TCP-1 or HCT116 tumors with inactive peptide. Cy7-TCP-1 activity localized not only in metabolically active tumors, as defined by (18)F-FDG imaging, but also in peritumoral microvasculature. In conclusion, TCP-1 probes may have a distinct targeting mechanism with high selectivity for CRC and tumor-associated vasculature. Molecular imaging with TCP-1 probes appears promising to detect malignant colorectal lesions.

L'évaluation de l'asynchronisme mécanique ventriculaire sous stress a soulevé une attention importante en tant que facteur prédictif de la réponse au traitement de resynchronisation cardiaque (CRT). De plus, il semble exister une relation significative entre le devenir du patient et la présence d’asynchronisme au repos. Plusieurs méthodes échocardiographiques peuvent être utilisées pour évaluer l’asynchronisme. Cependant, parmi toutes les différentes méthodologies ou index existant dans ce domaine, aucun critère ne fait l’unanimité. Cette thèse étudie l'importance des techniques d'imagerie nucléaire dans le cadre de l’évaluation de l’asynchronisme cardiaque induit par le stress en utilisant trois différents modèles canins expérimentaux. Le premier chapitre vise à examiner les effets du stress sur le synchronisme de la contraction du ventricule gauche (VG) en utilisant l'imagerie synchronisée de perfusion myocardique dans une cohorte canine normale. Le stress a été induit par différents niveaux d’infusion de dobutamine sur six sujets sains. Les paramètres hémodynamiques et l’asynchronisme ont été évalués par des mesures de pressions ventriculaires. L'analyse de phase sur l’imagerie s’est effectuée en utilisant un logiciel commercialement disponible (QGS) et un logiciel interne (MHI4MPI), basée sur le déplacement et l’épaississement des parois ventriculaires. L’augmentation de la concentration de dobutamine a démontré une amélioration de la capacité fonctionnelle et une réduction de l’asynchronisme ventriculaire. L’analyse de l’asynchronisme calculée à partir de l’épaississement de la paroi semble plus robuste et plus sensible que l’utilisation du déplacement des parois. (Salimian et. al., J Nucl Cardiol., 2014) Le second chapitre étudie les différents paramètres d’asynchronisme au repos et à différents niveaux de stress dans un modèle de cardiomyopathie dilatée et à QRS étroit. Ce modèle a été créé sur dix chiens par tachycardie via stimulation de l'apex du ventricule droit pendant 3-4 semaines, permettant d’atteindre une fraction d'éjection cible de 35% ou moins. Le stress a ensuite été induit par une perfusion de dobutamine jusqu'à un maximum de 20 μg/kg/min. Les données hémodynamiques et l’asynchronisme ont été analysés par des mesures de pression ventriculaire et l’analyse de l’imagerie dynamique du compartiment sanguin. L’importante variabilité individuelle des sujets inclus dans notre cohorte empêche toute conclusion définitive sur la mesure de l’asynchronisme interventriculaire. Cependant, les différents niveaux de stress, même dans des intervalles rapprochés, ont démontré un effet significatif sur les paramètres hémodynamiques et l’asynchronisme. (Salimian et. al., J Nucl Cardiol., 2015) La troisième section vise à déterminer si l’estimation du mode de stimulation optimal effectuée au repos demeure le choix optimal lorsque le niveau d’activité cardiaque s’intensifie pour des sujets avec bloc auriculo-ventriculaire (AV) et fonction ventriculaire normale. Cinq chiens ont été soumis à une ablation du nœud AV et des sondes de stimulation ont été insérées dans l'oreillette droite pour la détection, l’apex du ventricule droit (VD) et une veine postérolatérale du VG pour la stimulation. Cinq modes de stimulation ont été utilisés : LV pur, biventriculaire (BiV) avec pré-activation de 20 ms du LV (LVRV20), BiV pur, BiV avec pré-activation de 20 ms du VD (RVLV20), VD pur. Des niveaux jusqu’à 20 μg/kg/min de dobutamine ont été atteints. Le stress a modifié l’étendue de l’asynchronisme de base et ce, pour tous les modes de stimulation. De plus, les effets physiologiques intrinsèques du stress permettent une évaluation plus précise de l’asynchronisme ventriculaire, diminuant la variabilité inter-sujet. Le mode de stimulation LVRV20 semble le mode optimal dans ce modèle, supportant l’utilisation de la stimulation bi-ventriculaire. / Assessment of ventricular mechanical dyssynchrony (MD) under stress has attracted a large amount of attention as a stronger predictor of response to cardiac resynchronization therapy (CRT) and as a parameter whose variation bears a greater relationship to clinical outcomes than resting-MD either in CRT candidates or another subset of patients. Several echocardiographic methods can be used to assess stress-MD. However, no standardized approach is currently used to explore stress-induced variations in inter- and intraventricular MD. This dissertation studies the importance of nuclear imaging techniques in assessing stress-induced MD variations by providing three different experimental canine models. The first chapter sought to examine the impacts of stress on the left ventricular (LV) synchrony with phase analysis of gated SPECT myocardial perfusion imaging (GMPS) within a normal canine cohort. Stress was induced by different levels of dobutamine infusion in six healthy subjects. Hemodynamic and LV MD parameters were assessed by LV pressure measurements and phase analysis of GMPS using commercially available QGS software and in-house MHI4MPI software with thickening- and displacement-based methodology. The increase of dobutamine level was shown to be in accordance with the improvement of LV functional capacity and reduction of MD parameters. MD analysis based on wall thickening was more robust and sensitive than the global wall displacement. (Salimian et. al., J Nucl Cardiol., 2014) The second chapter investigated the range of difference in inter- and intraventricular MD parameters from rest to various levels of stress in a dilated cardiomyopathy (DCM) and narrow QRS complex model. Ten large dogs were submitted to tachycardia-induced DCM by pacing the right ventricular apex for 3-4 weeks to reach a target ejection fraction of 35% or less. Stress was then induced by infusion of dobutamine up to a maximum of 20 μg/kg/min. Hemodynamic and MD data were analyzed by LV pressure measurements and gated-blood pool SPECT (GBPS) imaging. Individual differences in the magnitude and pattern of change in the various levels of stress precluded any definitive conclusion about interventricular MD. However, different levels of stress, even in close intervals, showed a significant positive impact on hemodynamic and intraventricular MD parameters. (Salimian et. al., J Nucl Cardiol., 2015) The third chapter sought to examine if the optimal pacing mode at rest could be the best one during the maximum stress level in terms of MD parameters in subjects with an atrioventricular (AV) block and normal function. Five dogs were submitted to AV node ablation and pacing leads were placed in the right atrium for sensing, in right ventricular (RV) apex, and in posterolateral LV vein for pacing in five modes of LV, biventricular (BiV) with 20 ms of LV pre-activation (LVRV20), BiV, BiV with 20 ms of RV pre-activation (RVLV20) and RV pacing. Stress was induced by dobutamine infusion up to a maximum of 20 μg/kg/min. Data analyses were the same as chapter one. Dobutamine stress changed the extent of resting-LV MD at all pacing modes. Intrinsic physiologic effects of stress resulted in more accurate MD assessment with lesser variability in subjects who underwent pacing. LVRV20 was the preferred site of stimulation in this model rather than single-site pacing.

<p>X-ray mammography has been the gold standard for breast imaging for decades, despite the significant limitations posed by the two dimensional (2D) image acquisitions. Difficulty in diagnosing lesions close to the chest wall and axilla, high amount of structural overlap and patient discomfort due to compression are only some of these limitations. To overcome these drawbacks, three dimensional (3D) breast imaging modalities have been developed including dual modality single photon emission computed tomography (SPECT) and computed tomography (CT) systems. This thesis focuses on the development and integration of the next generation of such a device for dedicated breast imaging. The goals of this dissertation work are to: [1] understand and characterize any effects of fully 3-D trajectories on reconstructed image scatter correction, absorbed dose and Hounsifeld Unit accuracy, and [2] design, develop and implement the fully flexible, third generation hybrid SPECT-CT system capable of traversing complex 3D orbits about a pendant breast volume, without interference from the other. Such a system would overcome artifacts resulting from incompletely sampled divergent cone beam imaging schemes and allow imaging closer to the chest wall, which other systems currently under research and development elsewhere cannot achieve. </p><p>The dependence of x-ray scatter radiation on object shape, size, material composition and the CT acquisition trajectory, was investigated with a well-established beam stop array (BSA) scatter correction method. While the 2D scatter to primary ratio (SPR) was the main metric used to characterize total system scatter, a new metric called ‘normalized scatter contribution’ was developed to compare the results of scatter correction on 3D reconstructed volumes. Scatter estimation studies were undertaken with a sinusoidal saddle (±15° polar tilt) orbit and a traditional circular (AZOR) orbit. Clinical studies to acquire data for scatter correction were used to evaluate the 2D SPR on a small set of patients scanned with the AZOR orbit. Clinical SPR results showed clear dependence of scatter on breast composition and glandular tissue distribution, otherwise consistent with the overall phantom-based size and density measurements. Additionally, SPR dependence was also observed on the acquisition trajectory where 2D scatter increased with an increase in the polar tilt angle of the system. </p><p>The dose delivered by any imaging system is of primary importance from the patient’s point of view, and therefore trajectory related differences in the dose distribution in a target volume were evaluated. Monte Carlo simulations as well as physical measurements using radiochromic film were undertaken using saddle and AZOR orbits. Results illustrated that both orbits deliver comparable dose to the target volume, and only slightly differ in distribution within the volume. Simulations and measurements showed similar results, and all measured dose values were within the standard screening mammography-specific, 6 mGy dose limit, which is used as a benchmark for dose comparisons.</p><p>Hounsfield Units (HU) are used clinically in differentiating tissue types in a reconstructed CT image, and therefore the HU accuracy of a system is very important, especially when using non-traditional trajectories. Uniform phantoms filled with various uniform density fluids were used to investigate differences in HU accuracy between saddle and AZOR orbits. Results illustrate the considerably better performance of the saddle orbit, especially close to the chest and nipple region of what would clinically be a pedant breast volume. The AZOR orbit causes shading artifacts near the nipple, due to insufficient sampling, rendering a major portion of the scanned phantom unusable, whereas the saddle orbit performs exceptionally well and provides a tighter distribution of HU values in reconstructed volumes. </p><p>Finally, the third generation, fully-suspended SPECT-CT system was designed in and developed in our lab. A novel mechanical method using a linear motor was developed for tilting the CT system. A new x-ray source and a custom made 40 x 30 cm2 detector were integrated on to this system. The SPECT system was nested, in the center of the gantry, orthogonal to the CT source-detector pair. The SPECT system tilts on a goniometer, and the newly developed CT tilting mechanism allows ±15° maximum polar tilting of the CT system. The entire gantry is mounted on a rotation stage, allowing complex arbitrary trajectories for each system, without interference from the other, while having a common field of view. This hybrid system shows potential to be used clinically as a diagnostic tool for dedicated breast imaging.</p> / Dissertation

A research report submitted to the Faculty of Health Sciences in fulfilment of the requirements for the degree of Master of Medicine, in Internal Medicine at the University of Witwatersrand, Johannesburg. September 2017 / Differentiating ischaemic left ventricular dysfunction (ILVD) from non-ischaemic left ventricular dysfunction (NILVD) is crucial since appropriately selected patients may benefit from coronary revascularisation. The aim of this study was to evaluate the diagnostic utility of myocardial perfusion imaging (MPI) in patients presenting with left ventricular dysfunction using coronary angiography (CA) as the gold standard. Methods This single centre retrospective study was conducted in 52 patients with heart failure with a reduced ejection fraction (EF< 40%) who had both MPI as well as CA at CHBAH between January 2005 and December 2012. ILVD was diagnosed when the distribution and severity of coronary disease on CA was sufficient to account for the degree of left ventricular dysfunction. Results From a total of 52 patients, 33 (63%) had ILVD and 19 (37%) had NILVD. As compared to patients with NILVD, those with ILVD were more likely to be Indian and White (p=0.0014), have more coronary risk factors (5(2) vs 3(2), p < 0.0001) and more commonly have q waves on the ECG (0% vs 55%, p < 0.0001). MPI had a sensitivity of 100% (95% CI 66-100%) and specificity of 52.63% (95% CI 30.18 - 75.08) for the diagnosis of ILVD. The presence of fixed perfusion defects on MPI was the best predictor of ILVD. Conclusion MPI has high sensitivity but low specificity for the diagnosis of ILVD. This makes it a useful screening test for the exclusion of coronary artery disease in patients presenting with heart failure. / MT2018

La tomoscintigraphie myocardique est considérée comme un examen de référence pour le diagnostic et l'évaluation de la maladie coronarienne. Mise au point dans les années 1980, cette technique est en pleine mutation depuis l'arrivée de nouvelles caméras à semi-conducteurs. Deux caméras à semi-conducteurs, dédiées à la cardiologie nucléaire et utilisant des détecteurs de Cadmium Zinc Telluride sont actuellement commercialisées : la Discovery NM-530c (General Electric) et la DSPECT (Spectrum Dynamics). Les performances de ces caméras CZT ont été évaluées : 1) à la fois sur fantôme et sur des examens d'effort provenant de patients à faible probabilité de maladie coronaire, et 2) avec les paramètres d'acquisition et de reconstruction utilisés en clinique. Les résultats ont démontré la nette supériorité des caméras CZT en termes de sensibilité de détection, de résolution spatiale et de rapport contraste sur bruit par rapport à la génération de caméras d'Anger. Ces propriétés vont permettre de diminuer très fortement les temps d'acquisition et les activités injectées, tout en améliorant la qualité des images. Néanmoins, on connaît encore mal les limites et possibles artéfacts liés à la géométrie particulière d'acquisition. C'est pourquoi nous avons développé, avec la plateforme de simulations Monte Carlo GATE, un simulateur numérique spécifique de la caméra DSPECT. Nous avons pu ensuite le valider en comparant des données effectivement enregistrées aux données simulées. Ce simulateur pourrait aider à optimiser les protocoles de reconstruction et d'acquisition, en particulier les protocoles les plus complexes (acquisitions double traceur, études cinétiques) / Myocardial single-photon emission computed tomography (SPECT) is considered as the gold standard for the diagnosis of coronary artery disease. Developed in the 1980s with rotating Anger gamma-cameras, this technique could be dramatically enhanced by new imaging systems working with semi-conductor detectors. Two semiconductor cameras, dedicated to nuclear cardiology and equipped with Cadmium Zinc Telluride detectors, have been recently commercialized: the Discovery NM- 530c (General Electric) and the DSPECT (Spectrum Dynamics). The performances of these CZT cameras were compared: 1) by a comprehensive analysis of phantom and human SPECT images considered as normal and 2) with the parameters commonly recommended for SPECT recording and reconstruction. The results show the superiority of the CZT cameras in terms of detection sensitivity, spatial resolution and contrast-to-noise ratio, compared to conventional Anger cameras. These properties might lead to dramatically reduce acquisition times and/or the injected activities. However, the limits of these new CZT cameras, as well as the mechanism of certain artefacts, remain poorly known. That?s why we developed, with the GATE Monte Carlo simulation plateform, a specific simulator of the DSPECT camera. We validated this simulator by comparing actually recorded data with simulated data. This simulator may yet be used to optimize the recorded and reconstruction processes, especially for complex protocols such as simultaneous dual-radionuclide acquisition and kinetics first-pass studies