<p>Simultaneous dual-isotope SPECT imaging has a number of applications, for exam- ple, cardiac, brain and cancer imaging. The major concern in simultaneous dual- isotope SPECT is the significant crosstalk contamination between the different isotopes used. The current study focuses on a method of crosstalk compensation between two isotopes in simultaneous dual isotope SPECT acquisition applied to cancer imaging using ^99mTc/¹¹¹In and breast SPECT using ^99mTc/¹²³I. Monte Carlo (MC), which is thought to offer the most realistic crosstalk and scatter compensation modelling, in typical implementations, has inherent long calculation times (often several hours or days) associated with it. This makes MC unsuitable for clinical applications. We have previously incorporated convolution based forced detection into SIMIND Monte Carlo (MC) program which have made MC feasible to use in clinical time frames. In order to evaluate the accuracy of our accelerated MC program a number of point source simulation results were compared to experimentally acquired data in terms of spatial resolution and detector sensitivity. We have developed an iterative MC based image reconstruction technique that simulates the photon down-scatter from one isotope into the acquisition window of a second isotope. The MC based estimation of scatter contamination contained in projection views is then used to compensate for the photon contamination during iterative reconstruction. We use a modified ordered subset expectation maximization (OSEM) alogrithm, named as simultaneous ordered subset-expectation maximization (Sim-OSEM), to perform this step. We have undertaken a number of simulation tests and phantom studies to verify this approach in case of both of the dual-isotope combinations (i.e. ^99mTc/¹¹¹In and ^99mTc/¹²³I). In breast SPECT studies three different breast sizes were simulated. For each of the breast sizes ten combinations of lesions with 3 lesions per combination, were selected randomly for acquisition and reconstruction of simulation data. The images reconstructed using Sim-OSEM showed crosstalk compensation when compared with images reconstructed using simultaneously (with crosstalk) acquired projection data using analytical attenuation based reconstruction. In case of Sim-OSEM the lesion to background ratios were much closer to actual values compared to images reconstructed for both separately (without crosstalk) and simultaneously (with crosstalk) acquired projection data using analytical attenuation based reconstruction. Activity estimation is also possible with Sim-OSEM and yielded accurate estimates of lesion activities with relatively small error compared to deposited activities. The proposed reconstruction technique also evaluated by reconstruction of experimentally acquired projection phantom data in case of ^99mTc/¹¹¹In. Reconstruction using Sim-OSEM showed very promising results in terms of crosstalk and small angle scatter compensation and uniformity of background compared to analytical attenuation based reconstruction after triple energy window (TEW) based scatter correction of projection data. In our case images obtained using Sim-OSEM showed more uniform background even when compared to the images reconstructed for separately acquired projection data using analytical attenuation based reconstruction may be due to better correction of photons scattered at small angle and got detected under photopeak.</p> / Master of Science (MSc)

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L'objectif de cette thèse est d’étudier temporellement des phénomènes évolutifs à l'aide de la tomographie d'émission monophotonique (TEMP). La première partie de cette thèse traite le problème du mouvement respiratoire dans les images TEMP de souris. Nous présentons ici une méthode permettant de détecter ce mouvement respiratoire dans les images TEMP 4D, d'extraire un signal respiratoire intrinsèque, et de déterminer la phase du cycle respiratoire sans mouvement la plus large possible. Les données enregistrées durant ces phases sans mouvement sont alors utilisées pour reconstruire une seule image TEMP 3D sans artefact de mouvement par acquisition. Les images ainsi reconstruites présentent un bon compromis en terme de statistiques et de précision des mesures par rapport aux images TEMP 3D de base et TEMP 4D. Dans la deuxième partie, nous étudions la cinétique d'incorporation de l'iode dans l'estomac de souris à partir d'images TEMP 4D. Afin de comprendre le rôle biologique de cette accumulation dans l'estomac, nous avons modélisé le phénomène par une approche d'analyse compartimentale avec un modèle simplifiée à deux compartiments (paroi et cavité stomacale) et une entrée (sang). Les courbes temps-activité (TAC) de chaque compartiment sont déduites des observations et une première estimation des paramètres a été obtenue. / The aim of this thesis is to investigate temporally evolving phenomena with the use of single photon emission computed tomography (SPECT).The first part of this thesis addresses the problem of respiratory motion in SPECT images of mice. The presented method permits us to detect the respiratory motion in 4D SPECT images, to extract an intrinsic respiratory signal and to determine the widest possible phase of the respiratory cycle without movement. The data recorded during these motionless phases are then used to reconstruct a single 3D SPECT image without motion artefacts per acquisition. Reconstructed motionless SPECT images present a good compromise in terms of statistics and accuracy of the measurements with respect to basic 3D SPECT and 4D SPECT images. In the second part, we study the iodide uptake kinetics in the stomach 99mTc-pertechnetate biodistribution with the of mice through the study of use of 4D SPECT images. To understand the biological role of the iodide accumulation in the stomach, we modelled the phenomenon with a compartmental analysis approach using a simplified two-compartment (stomach wall and cavity) model with one input (blood). Time activity curves (TAC) of each compartment are deduced from observations and a first estimation of the parameters was obtained.

Nous proposons dans le cadre de cette thèse une nouvelle approche permettant de s'affranchir de l'atténuation mammaire en tomographie par émission monophotonique (TEMP) de perfusion myocardique. Elle est constituée de deux parties : - la première consiste à rendre les projections acquises consistantes. - la deuxième consiste à pondérer ces même les projections corrigées durant la reconstruction. Nous avons effectué l'étude de validité de nos méthodes sur quelques exemples de simulation TEMP de perfusion myocardique simulant l'atténuation mammaire et sur quelques exemples d'études patients réelles notamment : des cas d'atténuation mammaire, d'infarctus inférieure, d'infarctus apical, d'infarctus antérieur, d'ischémie antérieure et inférieure. Les résultats semblent encourageants. Il s'agit dans le proche avenir de mener une étude de validation chez les patients versus un gold standard (coronarographie, coroscanner) / We propose in this thesis a new approach to correct the breast attenuation in SPECT myocardial perfusion imaging. It consists of two parts: -The first is to make the acquired projections consistent with each other. - The second is to weight the corrected attenuated projection during the reconstruction. We conducted a validation of our methods on some examples of myocardial perfusion SPECT imaging simulating the breast attenuation and some examples of real patient studies including: breast attenuation, anterior myocardial infarction, inferior myocardial infarction, anterior myocardial ischemia and inferior myocardial ischemia. The obtained results are encouraging. At this step, it is interesting in the near future to conduct a validation study in patients versus a gold standard (angiography, coroscan).Key words: SPECT, tomographic reconstruction, breast attenuation, Iterative reconstruction, attenuation correction, myocardial perfusion imaging, nuclear medicine

L’imagerie préclinique se pratique majoritairement sur des modèles animaux murins principalement des souris (61%), elle représente une étape indispensable en recherche préclinique car elle suit les deux premières recommandations de la règle des 3R (réduction, raffinement et remplacement). Pour donner une signification biologique aux mesures extraites des images acquises in vivo chez la souris, il est nécessaire d’évaluer les performances des instruments utilisés mais également des procédures expérimentales en jeu. La qualification des appareils nécessite l’usage de fantômes spécifiques, et l’évaluation des méthodes impose de tester les procédures sur des individus non pathologiques, avant le passage aux expérimentations proprement dites. L’objectif de ce travail a été de développer des outils et des méthodes permettant de qualifier les instruments d’imagerie et certaines procédures in vivo. La nécessité de quantification, à partir d’images réalisées chez le petit animal, nous amène à considérer les instruments d’imagerie préclinique comme des outils métrologiques ; ce qui amène à intégrer le principe d’incertitude de mesure dans l’expression des résultats. / Preclinical imaging is mostly performed on mouse animal models (61%). It is a necessary step in preclinical research, in compliance the first two recommendations of the 3Rs rules (reduction, refinement and replacement). In order to give a biological significance to measurements extracted from in vivo-acquired mouse images, it is necessary to evaluate instruments performances but also experimental procedures involved. The qualification of apparatuses requires the use of specific phantoms while the evaluation of methods requires procedures tests on non-pathological animals before experimentations. The scope of this work was to develop tools and methods to qualify imaging instruments and in vivo procedures. The need for quantification in small animal imaging, leads us to consider preclinical imaging instruments as metrological tools; which means integrating measurement uncertainty into.

Liver cancer ranks the third most common cause of cancer related mortality worldwide. Radiomicrosphere therapy (RMT), a form of radiation therapy, involves administration of Yttrium-90 (90Y) microspheres to the liver via the hepatic artery. 90Y microspheres bremsstrahlung SPECT/CT or PET/CT imaging could potentially identify an extrahepatic uptake. An early detection of such an uptake, thus, could initiate preventative measures early on. However, the quantitative accuracy of bremsstrahlung SPECT/CT images is limited by the wide and continuous energy spectrum of 90Y bremsstrahlung photons. 90Y PET/CT imaging is also possible but limited by the extremely small internal pair production decay. These limitation lead to inaccurate quantitation of microsphere biodistribution especially in small tumors. SPECT/CT and PET/CT acquisition of a Jasczak phantom with eight spherical inserts filled with 90Y3Cl solution were performed to measure the quantitative accuracy of the two imaging modalities. 90Y microsphere SPECT/CT data of 17 patients who underwent RMT for primary or metastatic liver cancer were acquired. Technetium-99m macroaggregated albumin (99mTc-MAA) SPECT/CT scans were also collected, but available for only twelve of the patients. SPECT/CT images from phantoms were used to determine the optimal iteration number for the iterative spatial resolution recovery algorithm. Methods for image based calculation of calibration factors for activity estimation from the patient and phantom 90Y bremsstrahlung SPECT/CT images were developed. Tumor areas were segmented using an active contour method. The 99mTc-MAA and 90Y microsphere SPECT/CT images were co-registered a priori for correlation analysis. Comparison of uptake on 99mTc-MAA and 90Y microsphere SPECT/CT images was assessed using tumor to healthy liver ratios. Furthermore, a three dimensional absorbed dose estimation algorithm was developed using the voxel S-value method. Absorbed doses within the tumor and healthy part of the liver were investigated for correlation with administered activity. Improvement in contrast to noise ratio and contrast recovery coefficients (QH) on patient and phantom 90Y bremsstrahlung SPECT/CT images as well as PET/CT images were achieved. Total activity estimations in liver and phantom gave mean percent errors of -4 ± 12% and -23 ± 41% for patient and phantom SPECT/CT studies. The pre and post-treatment images showed significant correlation (r = 0.9, p < 0.05) with mean TLR of 9.2 ± 9.4 and 5.0 ± 2.2 on 99mTc-MAA and 90Y microspheres SPECT/CT respectively. The correlation between the administered activity and tumor absorbed dose was weak (r = 0.5, p > 0.05), however, healthy liver absorbed dose increased with administered activity (r = 0.8, p < 0.05).

A quantitative evaluation of single photon emission computed tomography (SPECT) and planar scintigraphic imaging may be valuable for both diagnostic and therapeutic purposes. For an accurate quantification it is usually necessary to correct for attenuation and scatter and in some cases also for septal penetration. For planar imaging a background correction for the contribution from over- and underlying tissues is needed. In this work a few correction methods have been evaluated and further developed. Much of the work relies on the Monte Carlo method as a tool for evaluation and optimisation. A method for quantifying the activity of I-125 labelled antibodies in a tumour inoculated in the flank of a mouse, based on planar scintigraphic imaging with a pin-hole collimator, has been developed and two different methods for background subtraction have been compared. The activity estimates of the tumours were compared with measurements in vitro. The major part of this work is attributed to SPECT. A method for attenuation and scatter correction of brain SPECT based on computed tomography (CT) images of the same patient has been developed, using an attenuation map calculated from the CT image volume. The attenuation map is utilised not only for attenuation correction, but also for scatter correction with transmission dependent convolution subtraction (TDCS). A registration method based on fiducial markers, placed on three chosen points during the SPECT examination, was evaluated. The scatter correction method, TDCS, was then optimised for regional cerebral blood flow (rCBF) SPECT with Tc-99m, and was also compared with a related method, convolution scatter subtraction (CSS). TDCS has been claimed to be an iterative technique. This requires however some modifications of the method, which have been demonstrated and evaluated for a simulation with a point source. When the Monte Carlo method is used for evaluation of corrections for septal penetration, it is important that interactions in the collimator are taken into account. A new version of the Monte Carlo program SIMIND with this capability has been evaluated by comparing measured and simulated images and energy spectra. This code was later used for the evaluation of a few different methods for correction of scatter and septal penetration of I-123 brain SPECT. The methods were CSS, TDCS and a method where correction for scatter and septal penetration are included in the iterative reconstruction. This study shows that quantitative accuracy in I-123 brain SPECT benefits from separate modelling of scatter and septal penetration.

The aim of this doctoral thesis was to study the influence of memory, pain, age and education on the regional cerebral blood flow (rCBF), i.e. brain function, in early Alzheimer's disease (AD) and in chronic neck pain patients in comparison to healthy controls and in healthy elderly per se. This was done by optimizing single photon emission computed tomography (SPECT) as a method to study rCBF with the tracer Technetium-99m (99mTc) hexamethylpropyleneamine oxime (HMPAO) and by matching all image data to a brain atlas before evaluation. The rCBF-SPECT was evaluated and developed to obtain higher diagnostic accuracy in AD and in chronic neck pain patients it was used to study basic pain related cerebral processes in chronic pain of different origin. A new semimanual registration method, based on fiducial marker, suitable for investigations with low spatial resolution was developed. The method was used to reconstruct images with an improved attenuation and scatter correction by using an attenuation-map calculated from the patients' previously acquired CT images. The influence of age and education on rCBF was evaluated with statistical parametric mapping, SPM in healthy elderly. The main findings were age related changes in rCBF in regions close to interlobar and interhemispheric space but not in regions typically affected in early AD, except for the medial temporal lobe. The theory of a 'cognitive reserve' in individuals with a longer education was supported with findings in the lateral temporal lobe, a region related to semantic memory, and in the frontal lobe. A cross-sectional study of chronic neck pain patients showed extensive rCBF changes in coping related regions in a non-traumatic pain patients compared to both healthy and a pain group with a traumatic origin, i.e. whiplash syndrome. The whiplash group displayed no significant differences in rCBF in comparison with the healthy controls. This suggests different pain mechanisms in these groups. The AD-patients showed a significantly lower rCBF in temporoparietal regions including left hippocampus. These changes were associated to episodic memory performance, and especially to face recognition. The diagnostic sensitivity for AD was high. The face recognition test (episodic memory) was used in AD patients to improve the sensitivity of method, i.e. memory-provoked rCBF-SPECT (MP-SPECT). The results were compared to healthy controls and the reductions of rCBF in temporoparietal regions were more pronounced in mild AD during provocation. Memory provocation increased the sensitivity of AD-related rCBF changes at group level. If a higher sensitivity for AD at the individual level is verified in future studies, a single MP-SPECT study might then be of help to set diagnosis earlier. In conclusion rCBF in temporoparietal regions are associated to an impaired episodic memory in early AD. Changes in these regions do not have a strong connection to chronological age. The diagnostic sensitivity of rCBF-SPECT in AD is high and there is a potentially higher sensitivity if memory provoked investigations are used. The findings in this thesis have given an increased knowledge of underlying cerebral pain processing in non-traumatic and traumatic (whiplash) neck pain. Preliminary results supporting the theory of 'cognitive reserve' by showing a correlation between long education and preserved rCBF was found in healthy elderly.

Radionuclide molecular imaging is an emerging multidisciplinary technique that is used in modern medicine to visualise diseases at cellular and molecular levels. This thesis is based on five papers (I-V) and focuses on the development of site-specific radiolabelled recombinant anti-HER2 Affibody molecules and preclinical evaluations in vitro and in vivo of the labelled conjugates. This work is part of a preclinical development of an Affibody molecule-based tracer for molecular imaging of HER2 expressing tumours. Papers I and II report the evaluation of the Affibody molecule ZHER2:2395-C, site-specifically labelled with the radiometals 111In (for SPECT) and 57Co (as a surrogate for 55Co, suitable for PET applications) using a thiol reactive DOTA derivative as a chelator. Both conjugates demonstrated very suitable biodistribution properties, enabling high contrast imaging just a few hours after injection. Papers III and IV report the development and optimization of a technique for site-specific labelling of ZHER2:2395-C with 99mTc using an N3S chelating peptide sequence. 99mTc-ZHER2:2395-C demonstrated high and specific tumour uptake and rapid clearance of non-bound tracer from the blood, resulting in high tumour-to-non-tumour ratios shortly after injection, enabling high contrast imaging. In addition, in the study described in paper IV, freeze-dried kits previously developed for 99mTc-labelling were optimised, resulting in the development of a kit in which all the reagents and protein needed for labelling of ZHER2:2395-C with 99mTc were contained in a single vial. Paper V reports the evaluation of an anti-HER2 Affibody molecule, ABY-025, with a fundamentally re-engineered scaffold. Despite the profound re-engineering, the biodistribution pattern of 111In-ABY-025 was very similar to that of two variants of the parental molecule. It seems reasonable to believe that these results will also be applicable to Affibody molecules towards other targets. Hopefully, this work will also be helpful in the development of other small proteinaceous tracers.

Certes malalties neurològiques estan associades amb problemes en els sistemes de neurotransmissió. Una aproximació a l'estudi d'aquests sistemes és la tomografia d'emissió SPECT (Single Photon Emission Computed Tomography) com a tècnicano-invasiva que proporciona imatges funcionals representatives de l'activitat neuronal. Aquesta tècnica permet la visualització i l'anàlisi de diferents òrgans i teixits dins l'àmbit de la Medicina Nuclear.Malgrat que la inspecció visual de la imatge a vegades és suficient per establir el diagnòstic, la quantificació dels paràmetres de la imatge reconstruida poden millorar la fiabilitat i exactitud del diagnòstic precoç de la malaltia. En particular, la quantificació d'estudis de neurotransmissors de dopamina pot ajudar a detectar els estadis inicials de malalties com el Parkinson. Així mateix, la quantificació permet un seguiment més acurat de l'evolució de la malaltia i una evaluació dels efectes de la terapèutica aplicada.La quantificació es veu afectada pels efectes degradants de la imatge com són el soroll estadístic, la resposta del sistema col.limador/detector i l'efecte de dispersió i/o atenuació dels fotons en la seva interacció amb la matèria. Alguns d'aquests efectes poden ser corregits mitjançant l'ús d'algoritmes de reconstrucció iteratius.L'objectiu d'aquesta tesi és aconseguir una quantificació tant absoluta com relativa dels valors numèrics de la imatge reconstruida de manera que reprodueixin la distribució d'activitat real del pacient en el moment de l'adquisició de l'estudi de SPECT. Per aconseguir-ho s'han desenvolupat diferents codis i algoritmes per millorar els mètodes de reconstrucció existents i validar-ne els seus resultats.La validació i millora dels algoritmes s'ha basat en l'ús de tècniques de simulació Monte Carlo. S'han analitzat els diferents codis Monte Carlo disponibles en l'àmbit de la Medicina Nuclear i s'ha escollit SimSET. La interpretació dels resultats obtinguts i la comparació amb els resultats experimentals ens van dur a incorporar modificacions en el codi original. D'aquesta manera vam obtenir i validar SimSET com a generador d'estudis de SPECT a partir de pacients i objectes virtuals.La millora dels algoritmes es va basar en la incorporació de models analítics de la resposta del sistema col.limador/detector. La modelització del sistema es va implementar per diferents configuracions i energies de la font amb la utilització del codi Monte Carlo PENELOPE. Així mateix es va dissenyar un nou algoritme iteratiu que incorporés l'efecte 3D del sistema i es va tenir en compte la valoració de la imatge en tot el seu volum.Finalment, es va proposar una correcció de l'scattering utilitzant el simulador SimSET modificat per tal d'accelerar el procés de reconstrucció. Els valors reconstruits de la imatge ens han permès recuperar més d'un 95\% dels valors originals, permetent per tant la quantificació absoluta de les imatges de SPECT. / Many forms of brain diseases are associated with problems in the neurotransmission systems. One approach to the assessment of such systems is the use of Single Photon Emission Computed Tomography (SPECT) brain imaging. Neurotransmission SPECT has become an important tool in neuroimaging and is today regarded as a useful method in both clinical and basic research. SPECT is able to non-invasively visualize and analyze different organs and tissues functions or properties in Nuclear Medicine.Although visual inspection is often sufficient to assess neurotransmission imaging, quantification might improve the diagnostic accuracy of SPECT studies of the dopaminergic system. In particular, quantification of neurotransmission SPECT studies in Parkinson Disease could help us to diagnose this illness in the early pre-clinical stages. One of the main research topics in SPECT is to achieve early diagnosis, indeed preclinical diagnosis in neurodegenerative illnesses. In this field detailed analysis of shapes and values of the region of interest (ROIs) of the image is important, thus quantification is needed. Moreover, quantification allows a follow-up of the progression of disease and to assess the effects of potential neuroprotective treatment strategies. Therefore, the aim of this thesis is to achieve quantification of both the absolute activity values and the relative values of the reconstructed SPECT images.Quantification is affected by the degradation of the image introduced by statistical noise, attenuation, collimator/detector response and scattering effects. Some of these degradations may be corrected by using iterative reconstruction algorithms, which thus enable a more reliable quantification. The importance of correcting degradations in reconstruction algorithms to improve quantification accuracy of brain SPECT studies has been proved.Monte Carlo simulations are the --gold standard' for testing reconstruction algorithms in Nuclear Medicine. We analyzed the available Monte Carlo codes and we chose SimSET as a virtual phantom simulator. A new stopping criteria in SimSET was established in order to reduce the simulation time. The modified SimSET version was validated as a virtual phantom simulator which reproduces realistic projection data sets in SPECT studies.Iterative algorithms permit modelling of the projection process, allowing for correction of spatially variant collimator response and the photon crosstalk effect between transaxial slices. Thus, our work was focused on the modelling of the collimator/detector response for the parallel and fan beam configurations using the Monte Carlo code PENELOPE. Moreover, a full 3D reconstruction with OS-EM algorithms was developed.Finally, scattering has recognized to be one of the most significant degradation effects in SPECT quantification. Nowadays this subject is an intensive field of research in SPECT techniques. Monte Carlo techniques appear to be the most reliable way to include this correction. The use of the modified SimSET simulator accelerates the forward projection process although the computational burden is already a challenge for this technique.Full 3D reconstruction simultaneously applied with Monte Carlo-based scattering correction and the 3D evaluation procedure is a major upgrade technique in order to obtain valuable, absolute quantitative estimates of the reconstructed images. Once all the degrading effects were corrected, the obtained values were 95\% of the theoretical values. Thus, the absolute quantification was achieved.