Introdução: A doença de Wilson (DW) é uma doença genética rara, sistêmica, causada por déficit no metabolismo do cobre, levando a acúmulo em diversos órgãos, incluindo o cérebro, especialmente os núcleos da base. Apesar de distonia e disartria serem as alterações neurológicas mais comuns, alterações cognitivas, incluindo demência, podem surgir em casos não tratados. Objetivos: Avaliar as funções cognitivas de um grupo de pacientes com DW e correlacionar com os achados de RM e SPECT. Métodos: Todos os pacientes com DW atendidos consecutivamente em uma clínica de distúrbios do movimento, entre outubro de 2006 e agosto de 2007, foram submetidos ao Miniexame do Estado Mental (MEEM), Bateria Cognitiva Breve (BCB), teste de fluência verbal (animais, FAS e verbos), Bateria de Avaliação Frontal (BAF), STROOP, Extensão de Dígitos (ED) ordem direta e ordem inversa, Escala de Demência de Mattis (DRS), Teste de Seleção de Cartas de Wisconsin (WCST), Hooper e Blocos do WAIS. Depois dos testes, todos os pacientes realizaram RM e SPECT. Alterações de RM (hipersinal, hiposinal e atrofia) foram quantificadas em uma escala (0-17). O SPECT foi analisado por meio de SPM. Pacientes com depressão ou com anartria foram excluídos. Os resultados foram comparados com o desempenho de um grupo de voluntários sadios. Resultados: 20 pacientes com DW (11 homens) e 20 controles (9 homens) foram avaliados. A média de idade no grupo de pacientes com DW e controles foi 30,05±7,25 anos e 32,15±5,37 anos, respectivamente. A escolaridade média foi 11,15±3,73 anos nos pacientes com DW e 10,08 ± 2,62 anos nos controles. Pacientes com DW tiveram comprometimento cognitivo nos seguintes testes: MEEM (26,70±2,45 x 28,75±1,29), DRS (132,45 ±10,77 x 140,55±3,72), Fluência verbal: FAS (22,40±12,40 x 38,75±9,11) e Verbos (8,50±6,63 x 15,40±6,22); ED ordem direta (4,95±0,82 x 6,15±1,42), STROOP (4,40±4,87 x 0,50±0,68), BAF (12,95±2,85 x 16,25±1,25) e BCB: M2 (9,20±0,69 x 9,75±0,44), M5 (8,45±1,35 x 9,50 ±0,76). O diagnóstico de demência foi realizado em dois pacientes. Houve correlação entre o comprometimento cognitivo e a escala de RM (r=0,5348). Essa correlação foi mais forte com as alterações de hipersinal e atrofia (r=0,718). A avaliação por SPM mostrou uma hipoperfusão no caudado de forma simétrica, no cerebelo à esquerda e insula à esquerda. Conclusões: Pacientes com DW apresentam um comprometimento cognitivo, especialmente nas funções executivas, com boa correlação entre cognição e RM / Background: Wilsons disease (WD) is a rare, genetic and systemic disease, caused by a deficit in the copper metabolism, leading to its accumulation in different organs, including the brain, especially the basal ganglia. Although dystonia and dysarthria are the most common neurological signals, cognitive changes, including dementia, may emerge in untreated cases. Objective: To assess cognitive functioning of a group of WD patients and correlate with MRI and SPECT findings. Methods: All WD patients consecutively attended in a Movement Disorders Clinic between October 2006 and August 2007 were submitted to the Mini-Mental State Examination (MMSE), Brief Cognitive Screening Battery (BCSB), verbal fluency tests (animals, FAS and verbs), the Frontal Assessment Battery (FAB), STROOP, Digit Span forward and backward (DS), Dementia Ranting Scale (DRS), Wisconsin Card Sorting Test (WCST), Hooper and WAIS block design. After the tests, a MRI and SPECT were done in all patients. MRI abnormalities (high intensity signal, low intensity signal and atrophy) were ratted in a scale (0-17). SPECT was analyzed with SPM. Patients with depression or with anarthria were excluded. Results were compared with the performance of a group of healthy controls. Results: 20 WD patients (11 men) and 20 controls (9 men) were evaluated. Mean age in the WD and control groups were 30.05±7.25 years and 32.15±5.37, respectively. Mean educational level was 11.15±3.73 years among WD cases and 10.08 ± 2.62 years among controls. The WD patients had a cognitive impairment in the: MMSE (26.70±2.45 x 28.75±1.29), DRS (132.45 ±10.77 x 140.55±3.72), verbal fluency: FAS (22.40±12.40 x 38.75±9.11), Verbs (8.50±6.63 x 15.40±6.22); DS forward (4.95±0.82 x 6.15±1.42), STROOP (4.40±4.87 x 0.50±0.68), FAB (12.95±2.85 x 16.25±1.25) and BCSB: M2 (9.20±0.69 x 9.75±0.44), M5 (8.45±1.35 x 9.50 ±0.76). Dementia diagnostic was made in tow patients. There was a correlation between cognitive impairment and MRI scale (r=0.5348), this correlation was better with high intensity signal plus atrophy (r=0.718). The SPM showed a symmetrical caudate, left cerebellar and left insular hypoperfusion. Conclusion: WD patients presented cognitive impairment, especially in executive functions, with good correlation between cognition and MRI

No description available.

A tomografia por emissão de pósitrons (\"Positron Emission Tomography\" - PET) é uma técnica para obtenção de imagens tomográficas em Medicina Nuclear que permite o estudo da função e do metabolismo do corpo humano em diversos problemas clínicos, através do uso de fármacos marcados por radionuclídeos emissores de pósitrons. As aplicações mais frequentes ocorrem em oncologia, neurologia e cardiologia, através da análise qualitativa e quantitativa dessas imagens. Atualmente, a PET é realizada de duas maneiras: através de sistemas constituídos por anéis formados por alguns milhares de detectores operando em coincidência, chamados de sistemas dedicados; ou com o uso de câmaras PET /SPECT, formadas por dois detectores de cintilação em coincidência, que também servem para estudos com radionuclídeos emissores de fóton único (\"Single Photon Emission Computed Tomography\" - SPECT). O desenvolvimento desses sistemas PET /SPECT tornou viáveis os estudos com a fluor-deoxiglicose, [18 ANTPOT. F]-FDG, um fármaco marcado com 18 ANTIPOT. F (emissor de pósitrons com 109 minutos de meia-vida física), para um número grande de clínicas e hospitais, principalmente por estes serem de uma tecnologia economicamente mais acessível que os realizados com a PET dedicada. Neste presente trabalho, desenvolveu-se uma metodologia para caracterizar e avaliar um sistema PET /SPECT com dois detectores de cintilação e dispositivo com duas fontes pontuais de Cs-137, destinado à obtenção das imagens de transmissão para a correção de atenuação dos fótons. Ela se baseia em adaptações dos testes convencionais de câmaras SPECT, descritos no IAEA TecDoc - 602 - 1991 (\"lnternational Atomic Energy Agency\" - IAEA), e de sistemas PET dedicados, publicados no NEMA NU 2- 1994 (\"National Electrical Manufacturers Association\"NEMA). O resultado foi organizado em forma de roteiros que foram testados em uma câmara da ADAC Laboratories/Philips, a VertexlM - Plus EPIClMJMCDlM - AC, instalada no Serviço de Radioisótopos do lnCor - HCFMUSP (Instituto do Coração - Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo). Esta câmara foi a primeira instalada no Brasil e está sendo utilizada, predominantemente, para estudos oncológicos e de viabilidade miocárdica. O radiofármaco utilizado na obtenção das imagens foi a [18F]-FDG, fornecida regularmente pelo IPEN/CNEN-SP (Instituto de Pesquisas Energéticas e Nucleares/Comissão Nacional de Energia Nuclear - São Paulo), e a reconstrução tomográfica foi realizada com o software próprio do sistema, utilizando-se os parâmetros padrão dos protocolos clínicos. Foram utilizadas fontes pontuais suspensas no ar para as medidas de resolução espacial transversal e lineares imersas na água para as de fração de espalhamento e sensibilidade. Na avaliação da sensibilidade, uniformidade, taxa de eventos verdadeiros, taxa de eventos aleatórios e tempo morto do sistema eletrônico, foram feitas imagens de um simulador físico construído especialmente para o presente trabalho, a partir das instruções da publicação NEMA NU 2 - 1994 para sistemas PET dedicados. A acurácia da correção de atenuação foi verificada através das imagens do simulador físico citado com a inserção de três cilindros de densidades diferentes: água, ar e Teflon. Os roteiros deste trabalho poderão servir de guia para Programas de Controle e Garantia de Qualidade e avaliação da performance de sistemas PET /SPECT com dois detectores de cintilação em coincidência. A implantação destes roteiros pelos centros clínicos que utilizam este tipo de equipamento aumentará a qualidade e a confiabilidade nas imagens resultantes, assim como na sua quantificação. / Positron emission tomography, PET, is a Nuclear Medicine technique that allows the study of human body\'s function and metabolism in many clinical problems, with the help of pharmaceuticals labeled with positron emitters. The most frequent applications occur in oncology, neurology and cardiology, through qualitative and quantitative analysis of these images. Currently, PET is performed in two manners: by using dedicated systems, consisted of rings of thousands of detectors operating in coincidence; or with the use of PET /SPECT cameras, formed by two scintillation detectors in coincidence, which are also used in SPECT studies (single photon emission tomography). The development of PET /SPECT systems made possible the studies with fluor-deoxiglucose, [18F]-FDG, a pharmaceutical labeled with 18F (positron emitter with 109 minutes physical half-life), for a large number of clinics and hospitals, mainly due to their economical accessibility when compared to the dedicated PET studies. In this present work, a method was developed for characterizing and evaluating a PET /SPECT system with two scintillation detectors and device with two point sources of 137Cs, designed to obtain the transmission images for the photon attenuation correction. lt is based on adaptations of the conventional tests of SPECT cameras, described in IAEA TecDoc - 602 - 1991 (\"international Atomic Energy Agency \" - IAEA), and those for dedicated PET systems, published in NEMA NU 2 - 1994 (\"National Electrical Manufacturers Association \" - NEMA). The results were organized in a set of testing protocols and tested in the ADAC Laboratories/Philips camera, the VertexlM - Plus EPIClM/MCDlM - AC, installed in the Radioisotopes Service of lnCor - HCFMUSP (Instituto do Coração - Hospital das clínicas da Faculdade de Medicina da Universidade de São Paulo). This camera was the first one installed in Brazil and is being used, predominantly, for oncological studies and miocardial viability. The radiopharmaceutical used was [18F]-FDG, supplied regularly by IPEN/CNEN-SP (Instituto de Pesquisas Energéticas e Nucleares I Comissão Nacional de Energia Nuclear - São Paulo), and the tomographic reconstruction was performed with the system software, using the standard parameters of the clinical protocols. Point sources suspended in air were used in the measurements of spatial resolution and linear sources immersed in water for scattering fraction and sensitivity measurements. In the evaluation of sensitivity, uniformity, true events, random events and dead time of the electronic system, a phantom was constructed specifically for the present work, from the instructions of NEMA NU 2 - 1994 for dedicated PET systems. The accuracy of the attenuation correction was verified from the images of the phantom with three inserts of different densities: water, air and Teflon. The resultant protocols can serve as a guideline for Programs of Quality Control and Assurance, as well as for the evaluation of the performance of PET /SPECT systems with two scintillation detectors in coincidence. lf implemented by clinical centers that use this type of equipment, it will enhance the quality and confidence of the resulting images, as well as their quantification.

This work has tried to provide better insight in some pathophysiological factors involved in functional dyspepsia. We have identified several experimental evidences supporting the hypothesis that activation of transducers of wall tension at the level the proximal stomach might be the key to the genesis of at least some of the symptoms. One of the mechanisms by which this activation may be enhanced in patients is the presence of defective accommodation of the proximal stomach in response to a meal. This abnormality was present in a large subgroup of patients and was associated to the presence of early satiety. Pharmacological modulation of the gastric wall tension resulted in concomitant changes in symptom severity, both in health and in functional dyspepsia patients. Special attention has been given to provide the clinician with better tools to investigate his patient, in the perspective of the prescription of a treatment aimed at restoring a defective mechanism. / Ce travail a tenté d'améliorer la compréhension de certains mécanismes physiopathologiques de la dyspepsie fonctionnelle. Nous avons identifié plusieurs arguments expérimentaux soutenant l'hypothèse disant que c'est l'activation de mécanorécepteurs sensibles à la tension pariétale qui est reponsable d'au moins un des symptômes de l'affection. Un des mécanismes par lesquels cette activation peut accrue chez les patients est la présence d'un défaut de l'accommodation gastrique post-prandiale. Cette anomalie a été retrouvée dans une large proportion des patients et est associée à la présence de satiété précoce. Les modifications du tonus gastrique ont résulté dans de modifications concomitantes des symptômes aussi bien chez les volontaires que chez les patients atteints de dyspepsie fonctionnelle.Une attention particulière a été portée sur le développement de nouveaux outils permettant de caractériser les patients dans la perspective de la prescription d'un traitement visant à corriger un mécanisme défectueux.

This work has tried to provide better insight in some pathophysiological factors involved in functional dyspepsia. We have identified several experimental evidences supporting the hypothesis that activation of transducers of wall tension at the level the proximal stomach might be the key to the genesis of at least some of the symptoms. One of the mechanisms by which this activation may be enhanced in patients is the presence of defective accommodation of the proximal stomach in response to a meal. This abnormality was present in a large subgroup of patients and was associated to the presence of early satiety. Pharmacological modulation of the gastric wall tension resulted in concomitant changes in symptom severity, both in health and in functional dyspepsia patients. Special attention has been given to provide the clinician with better tools to investigate his patient, in the perspective of the prescription of a treatment aimed at restoring a defective mechanism. / Ce travail a tenté d'améliorer la compréhension de certains mécanismes physiopathologiques de la dyspepsie fonctionnelle. Nous avons identifié plusieurs arguments expérimentaux soutenant l'hypothèse disant que c'est l'activation de mécanorécepteurs sensibles à la tension pariétale qui est reponsable d'au moins un des symptômes de l'affection. Un des mécanismes par lesquels cette activation peut accrue chez les patients est la présence d'un défaut de l'accommodation gastrique post-prandiale. Cette anomalie a été retrouvée dans une large proportion des patients et est associée à la présence de satiété précoce. Les modifications du tonus gastrique ont résulté dans de modifications concomitantes des symptômes aussi bien chez les volontaires que chez les patients atteints de dyspepsie fonctionnelle.Une attention particulière a été portée sur le développement de nouveaux outils permettant de caractériser les patients dans la perspective de la prescription d'un traitement visant à corriger un mécanisme défectueux.

Made available in DSpace on 2015-07-22T20:49:29Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-01-26 / Objetivo: O objetivo do presente estudo foi avaliar o perfil da densidade do transportador dopaminérgico utilizando SPECT em pacientes com Movimento Periódico das Pernas (MPP) e a influência do exercício físico agudo na concentração do DAT após um teste de esforço máximo (TEM). Métodos: Para isso 16 pacientes (8 grupo CTRL e 8 grupo Experimental) realizaram uma polissonografia (PSG) basal para a avaliação do padrão de sono e do índice do MPP. Após a PSG basal foi realizado o SPECT basal. Posteriormente os voluntários realizaram um TEM no período da manhã, após 2 horas, um novo exame de SPECT, e na mesma noite uma PSG para avaliar o efeito do exercício físico agudo no DAT e no padrão do sono. Resultados: Os resultados encontrados demonstraram que o grupo experimental apresentou valores menores no perfil da densidade do DAT no momento basal na região do estriado (p=0,03), foi demonstrado também uma redução do índice de MPP no grupo experimental (p=0,01) e um aumento da porcentagem do estagio 1 do sono NREM em ambos os grupos após o TEM (p=0,02). O estagio 2 do sono (p=0,02) e sono de ondas lentas (p=0,01) apresentaram diferenças entre os grupos no momento basal. Conclusão: Nossos resultados mostram que pacientes com MPP apresentaram uma menor densidade de DAT na região do putâmen esquerdo comparado ao grupo CTRL e uma sessão de exercício físico agudo (TEM) não alterou este perfil. Esses achados sugerem que alterações na densidade do DAT, talvez estejam relacionados a prática de exercício físico crônico. / Restless legs syndrome and periodic leg movement are sleep-related movement disorders and studies have shown changes in striatal dopaminergic activity in patients with these disorders. Physical exercise has been shown to improve the symptoms of restless legs syndrome and periodic leg movement, as has treatment with dopamine agonists. However, the mechanism by which physical exercise acts as a nonpharmacological treatment in improving symptoms of restless legs syndrome and periodic leg movement remains unknown. We evaluated dopamine transporter density profiles in 16 sedentary patients (control and experimental - with periodic leg movement, groups) and the influence of acute physical exercise on its concentration after a maximal exercise test. Each patient underwent baseline polysomnography to evaluate sleep patterns and periodic leg movement index values. After obtaining the polysomnography baseline, the single photon emission computer tomography baseline was determined. Subsequently, the volunteers performed a maximal exercise test in the morning, followed by a single photon emission computer tomography two hours later and polysomnography that night, to assess the effect of acute physical exercise on dopamine transporter and sleep patterns. The results showed significant lower dopamine transporter baseline densities in the striatum region for the experimental group. The results also showed a significant reduction in the periodic leg movement rate in the experimental group and a significant increased percentage of stage-1 non-REM sleep in both groups after maximal exercise test. Significant differences between the groups were only observed for Stage 2 sleep and slow wave sleep. Our results show that patients with periodic leg movement had a lower dopamine transporter density in the left putamen region compared to the control group and an acute physical exercise (maximal exercise test) did not alter this profile, providing evidence that this improvement is the result of chronic physical exercise. / TEDE / BV UNIFESP: Teses e dissertações

A tomografia por emissão de pósitrons (\"Positron Emission Tomography\" - PET) é uma técnica para obtenção de imagens tomográficas em Medicina Nuclear que permite o estudo da função e do metabolismo do corpo humano em diversos problemas clínicos, através do uso de fármacos marcados por radionuclídeos emissores de pósitrons. As aplicações mais frequentes ocorrem em oncologia, neurologia e cardiologia, através da análise qualitativa e quantitativa dessas imagens. Atualmente, a PET é realizada de duas maneiras: através de sistemas constituídos por anéis formados por alguns milhares de detectores operando em coincidência, chamados de sistemas dedicados; ou com o uso de câmaras PET /SPECT, formadas por dois detectores de cintilação em coincidência, que também servem para estudos com radionuclídeos emissores de fóton único (\"Single Photon Emission Computed Tomography\" - SPECT). O desenvolvimento desses sistemas PET /SPECT tornou viáveis os estudos com a fluor-deoxiglicose, [18 ANTPOT. F]-FDG, um fármaco marcado com 18 ANTIPOT. F (emissor de pósitrons com 109 minutos de meia-vida física), para um número grande de clínicas e hospitais, principalmente por estes serem de uma tecnologia economicamente mais acessível que os realizados com a PET dedicada. Neste presente trabalho, desenvolveu-se uma metodologia para caracterizar e avaliar um sistema PET /SPECT com dois detectores de cintilação e dispositivo com duas fontes pontuais de Cs-137, destinado à obtenção das imagens de transmissão para a correção de atenuação dos fótons. Ela se baseia em adaptações dos testes convencionais de câmaras SPECT, descritos no IAEA TecDoc - 602 - 1991 (\"lnternational Atomic Energy Agency\" - IAEA), e de sistemas PET dedicados, publicados no NEMA NU 2- 1994 (\"National Electrical Manufacturers Association\"NEMA). O resultado foi organizado em forma de roteiros que foram testados em uma câmara da ADAC Laboratories/Philips, a VertexlM - Plus EPIClMJMCDlM - AC, instalada no Serviço de Radioisótopos do lnCor - HCFMUSP (Instituto do Coração - Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo). Esta câmara foi a primeira instalada no Brasil e está sendo utilizada, predominantemente, para estudos oncológicos e de viabilidade miocárdica. O radiofármaco utilizado na obtenção das imagens foi a [18F]-FDG, fornecida regularmente pelo IPEN/CNEN-SP (Instituto de Pesquisas Energéticas e Nucleares/Comissão Nacional de Energia Nuclear - São Paulo), e a reconstrução tomográfica foi realizada com o software próprio do sistema, utilizando-se os parâmetros padrão dos protocolos clínicos. Foram utilizadas fontes pontuais suspensas no ar para as medidas de resolução espacial transversal e lineares imersas na água para as de fração de espalhamento e sensibilidade. Na avaliação da sensibilidade, uniformidade, taxa de eventos verdadeiros, taxa de eventos aleatórios e tempo morto do sistema eletrônico, foram feitas imagens de um simulador físico construído especialmente para o presente trabalho, a partir das instruções da publicação NEMA NU 2 - 1994 para sistemas PET dedicados. A acurácia da correção de atenuação foi verificada através das imagens do simulador físico citado com a inserção de três cilindros de densidades diferentes: água, ar e Teflon. Os roteiros deste trabalho poderão servir de guia para Programas de Controle e Garantia de Qualidade e avaliação da performance de sistemas PET /SPECT com dois detectores de cintilação em coincidência. A implantação destes roteiros pelos centros clínicos que utilizam este tipo de equipamento aumentará a qualidade e a confiabilidade nas imagens resultantes, assim como na sua quantificação. / Positron emission tomography, PET, is a Nuclear Medicine technique that allows the study of human body\'s function and metabolism in many clinical problems, with the help of pharmaceuticals labeled with positron emitters. The most frequent applications occur in oncology, neurology and cardiology, through qualitative and quantitative analysis of these images. Currently, PET is performed in two manners: by using dedicated systems, consisted of rings of thousands of detectors operating in coincidence; or with the use of PET /SPECT cameras, formed by two scintillation detectors in coincidence, which are also used in SPECT studies (single photon emission tomography). The development of PET /SPECT systems made possible the studies with fluor-deoxiglucose, [18F]-FDG, a pharmaceutical labeled with 18F (positron emitter with 109 minutes physical half-life), for a large number of clinics and hospitals, mainly due to their economical accessibility when compared to the dedicated PET studies. In this present work, a method was developed for characterizing and evaluating a PET /SPECT system with two scintillation detectors and device with two point sources of 137Cs, designed to obtain the transmission images for the photon attenuation correction. lt is based on adaptations of the conventional tests of SPECT cameras, described in IAEA TecDoc - 602 - 1991 (\"international Atomic Energy Agency \" - IAEA), and those for dedicated PET systems, published in NEMA NU 2 - 1994 (\"National Electrical Manufacturers Association \" - NEMA). The results were organized in a set of testing protocols and tested in the ADAC Laboratories/Philips camera, the VertexlM - Plus EPIClM/MCDlM - AC, installed in the Radioisotopes Service of lnCor - HCFMUSP (Instituto do Coração - Hospital das clínicas da Faculdade de Medicina da Universidade de São Paulo). This camera was the first one installed in Brazil and is being used, predominantly, for oncological studies and miocardial viability. The radiopharmaceutical used was [18F]-FDG, supplied regularly by IPEN/CNEN-SP (Instituto de Pesquisas Energéticas e Nucleares I Comissão Nacional de Energia Nuclear - São Paulo), and the tomographic reconstruction was performed with the system software, using the standard parameters of the clinical protocols. Point sources suspended in air were used in the measurements of spatial resolution and linear sources immersed in water for scattering fraction and sensitivity measurements. In the evaluation of sensitivity, uniformity, true events, random events and dead time of the electronic system, a phantom was constructed specifically for the present work, from the instructions of NEMA NU 2 - 1994 for dedicated PET systems. The accuracy of the attenuation correction was verified from the images of the phantom with three inserts of different densities: water, air and Teflon. The resultant protocols can serve as a guideline for Programs of Quality Control and Assurance, as well as for the evaluation of the performance of PET /SPECT systems with two scintillation detectors in coincidence. lf implemented by clinical centers that use this type of equipment, it will enhance the quality and confidence of the resulting images, as well as their quantification.

Les accidents vasculaires cérébraux (AVC) représentent l’une des premières causes de morbi-mortalité dans les pays industrialisés et sont en constante augmentation. Pour l’heure, aucune autre thérapie que la thrombolyse intraveineuse n’est validée, or moins de 10% des patients y sont éligibles.Les premiers essais de thérapie régénérative par greffe de progéniteurs endothéliaux ont montré leur efficacité au niveau préclinique sur la récupération fonctionnelle, mais très peu de cellules parviennent jusqu’au site de la lésion pour y exercer leurs effets. De précédents travaux ont montré que l’érythropoïétine (EPO) augmentait la mobilisation et la prolifération de progéniteurs endothéliaux depuis la moelle osseuse, ainsi que leur adressage vers les sites ischémiés in vivo.Nous avons formulé l’hypothèse que l’EPO pouvait permettre aux progéniteurs endothéliaux vrais (ECFCs) d’atteindre le site ischémié en plus grand nombre pour y exercer un effet plus important, plus rapidement. Nous avons donc décidé d’évaluer trois stratégies d’optimisation : coadministration d’ECFCs et d’EPO, administration d’ECFCs prétraités à l’EPO, et enfin coadministration d’ECFCs et d’un dérivé de l’EPO dénué d’effet hématopoïétique. Pour nos derniers travaux, nous nous sommes aidés de l’imagerie isotopique µSPECT/CT pour quantifier l’adressage au niveau de la lésion des ECFCs avec ou sans optimisation pharmacologique à l’EPO, et évaluer longitudinalement leurs effets bénéfiques sur la rupture de la barrière hémato-encéphalique, l’apoptose cérébrale et le débit sanguin cérébral résiduel, en complément des techniques référentes et de l’évaluation clinique neurofonctionnelle. / Stroke represents a leading cause of morbidity and mortality in industrialized countries and prevalence steadily increases. For now, no other therapy that intravenous thrombolysis is validated, still, less than 10% of patients are eligible.The first preclinical regenerative therapy trials using endothelial progenitor cells engraftment gave evidence of their efficacy on functional recovery, although very few cells reached the site of injury to exert their effects are. Previous works showed that erythropoietin (EPO) increased mobilization and proliferation of endothelial progenitor cells from bone marrow, as well as their homing to the ischemic sites in vivo.We hypothesized that EPO could enable true endothelial progenitor cells (ECFCs) to reach the ischemic site in larger quantity, faster, to exercise a greater effect. We decided to evaluate three optimization strategies: coadministration of ECFCs and EPO, administration of EPO-pretreated ECFCs, and finally coadministration of ECFCs and an EPO derivative devoid of hematopoietic effect.In this work, we used μSPECT/CT imaging to quantify the ECFCs homing to the ischemic site with or without EPO optimization after cerebral ischemia, and longitudinally assessed their beneficial effects on blood-brain barrier disruption, cerebral apoptosis and residual cerebral blood flow, complementary to the referent techniques and neurofunctional clinical evaluation.

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.