Background: Single photon emission computed tomography (SPECT) with dopamine transporter (DAT) and dopamine D2 receptor (D2R) ligands can visualise the integrity of the nigrostriatal dopamine system. Parkinson’s disease (PD) and the atypical parkinsonian diseases (APD), progressive supranuclear palsy (PSP) and multiple system atrophy (MSA), have similar symptoms and dopamine depletion, but differ in pharmacological response and prognosis. Clinical differentiation between PD and APD is often difficult in the early stages. The aims of the thesis were to evaluate the differential diagnostic and prognostic value of SPECT in early PD, MSA and PSP, to map the pattern of progression with dopamine SPECT, and map the pattern of dopamine SPECT in non-affected elderly volunteers with a prospective approach. Also, we evaluated the methodological aspects of dopamine SPECT with respect to image evaluation tools, reconstruction parameters and gamma cameras. Methods: 172 patients, included in an on-going clinical prospective study on idiopathic parkinsonism, participated in the SPECT study. Also, 31 age-matched healthy controls (HC) were followed within this study. SPECT was done with 123I-FP-Cit (DAT SPECT) and 123I-IBZM (D2R SPECT). Regions of interest (ROI) were used as a standard method for semi-quantitative image analysis. Results: SPECT uptake ratios from different gamma cameras could be equalised through correction equations derived from images of a brain-like phantom, provided that attenuation correction was applied. The ROI method had high reproducibility. SPECT uptake  in HC, measured with the ROI method and a volume based (VOI) method rendered similar trends, but gender and age differences in SPECT uptake were more marked with the VOI method, and less pronounced in DAT SPECT compared to D2R SPECT with both methods. The DAT SPECT uptake was significantly reduced in very early disease stage of PD and APD compared to HC. DATSPECT uptake was more reduced in PD with postural and gait disturbance (PIGD) compared to tremor-dominant PD. Decline in DAT SPECT uptake during the first year was more pronounced in PD and PSP compared to HC. D2R SPECT uptake overlapped between untreated PD and APD. After initiated treatment, the D2R SPECT uptake was significantly higher in MSA patients compared to PD, PSP and HC. Decline in D2R SPECT uptake during the first year was not significantly different between patients or compared to HC. Conclusions: 123I-FP-Cit SPECT is a valuable and sensitive method to detect early stage idiopathic parkinsonism. A different level of uptake between PIGD-PD compared to TD-PD indicates a prognostic potential. It is not possible to differ between PD, MSA and PSP in early stage with 123I-FP-Cit SPECT and no differential diagnostic value was found using 123I-IBZM SPECT in the early, untreated stage of PD, MSA and PSP. A different pattern of uptake of this ligand in MSA compared to PD and PSP during the first years of L-dopa treatment may, however, indicate a diagnostic value during the follow-up period.

O desenvolvimento da Medicina Nuclear, aliado à evolução dos equipamentos de diagnóstico e terapia, necessita, cada vez mais, da disponibilidade comercial de radioisótopos. Nesse contexto, o IPEN tem buscado atender e abastecer o mercado nacional. Um dos investimentos nesta área foi a aquisição de um ciclotron de 30 MeV, modelo Cyclone-30, que permitiu a produção dos radioisótopos tais como, o 18F, 67Ga, 201Tl e o 123I, sendo este último o foco do presente trabalho. Através de dados de produções rotineiras de 123I via irradiação com prótons em alvo gasoso de Xenônio com enriquecimento superior a 99,8% em 124Xe, foi realizado um estudo para identificar os fatores relevantes que influenciam diretamente o rendimento de obtenção de 123I com altíssimo grau de pureza. Embora a metodologia seja bem conhecida, quando se trata de produção comercial há uma escassez de dados sobre os parâmetros operacionais utilizados. Os parâmetros avaliados foram: pressão do gás 124Xe, intensidade de corrente de feixe de prótons, tempo de irradiação, temperatura de operação do sistema durante a irradiação, tempo de espera para formação de 123I, tempo de aquecimento do porta-alvo para recuperação do 123I formado, temperatura de aquecimento da solução de lavagem e influência do revestimento interno da câmara de irradiação com Ni. Com os resultados obtidos, foi possível alterar as condições operacionais nas produções rotineiras, conduzindo a um aumento de eficiência do processo em torno de 30%. / The development of diagnosis equipment and therapy procedures in nuclear medicine depends on the availability of commercial radioisotopes. IPEN is the most important institution that provides radioisotopes for national market. In order to achieve this function, IPEN had invested in the acquisition of a 30 MeV Cyclone-30 cyclotron to produce mainly 18F, 67Ga, 201Tl and 123I. The 123I production is the aim of the present work. With the 123I routine production data obtained by proton irradiation of Xe targets with an enrichment greater than 99.8%, it was possible to identify the important parameters that have direct influence on the production yield of high purity degree 123I. Even though the methodology for the commercial production of 123I, there are an scarcity of operational parameters data for this task. In this work the evaluated parameters were: 124Xe pressure, proton beam quality, irradiation time, operational temperature of the irradiation system under irradiation, waiting time to obtain 123I, temperature of washing solution and the impact of the internal Ni coating in the target. With the obtained results it was possible to modify the operational conditions for routine production and increasing the efficiency in about 30%.

O desenvolvimento da Medicina Nuclear, aliado à evolução dos equipamentos de diagnóstico e terapia, necessita, cada vez mais, da disponibilidade comercial de radioisótopos. Nesse contexto, o IPEN tem buscado atender e abastecer o mercado nacional. Um dos investimentos nesta área foi a aquisição de um ciclotron de 30 MeV, modelo Cyclone-30, que permitiu a produção dos radioisótopos tais como, o 18F, 67Ga, 201Tl e o 123I, sendo este último o foco do presente trabalho. Através de dados de produções rotineiras de 123I via irradiação com prótons em alvo gasoso de Xenônio com enriquecimento superior a 99,8% em 124Xe, foi realizado um estudo para identificar os fatores relevantes que influenciam diretamente o rendimento de obtenção de 123I com altíssimo grau de pureza. Embora a metodologia seja bem conhecida, quando se trata de produção comercial há uma escassez de dados sobre os parâmetros operacionais utilizados. Os parâmetros avaliados foram: pressão do gás 124Xe, intensidade de corrente de feixe de prótons, tempo de irradiação, temperatura de operação do sistema durante a irradiação, tempo de espera para formação de 123I, tempo de aquecimento do porta-alvo para recuperação do 123I formado, temperatura de aquecimento da solução de lavagem e influência do revestimento interno da câmara de irradiação com Ni. Com os resultados obtidos, foi possível alterar as condições operacionais nas produções rotineiras, conduzindo a um aumento de eficiência do processo em torno de 30%. / The development of diagnosis equipment and therapy procedures in nuclear medicine depends on the availability of commercial radioisotopes. IPEN is the most important institution that provides radioisotopes for national market. In order to achieve this function, IPEN had invested in the acquisition of a 30 MeV Cyclone-30 cyclotron to produce mainly 18F, 67Ga, 201Tl and 123I. The 123I production is the aim of the present work. With the 123I routine production data obtained by proton irradiation of Xe targets with an enrichment greater than 99.8%, it was possible to identify the important parameters that have direct influence on the production yield of high purity degree 123I. Even though the methodology for the commercial production of 123I, there are an scarcity of operational parameters data for this task. In this work the evaluated parameters were: 124Xe pressure, proton beam quality, irradiation time, operational temperature of the irradiation system under irradiation, waiting time to obtain 123I, temperature of washing solution and the impact of the internal Ni coating in the target. With the obtained results it was possible to modify the operational conditions for routine production and increasing the efficiency in about 30%.

Orientador: Vania dos Santos Nunes Nogueira / Abstract: Although being controversial, some services use Whole Body Imaging (WBI) with 131I prior to the ablative dose with this radiopharmaceutical in the treatment of differentiated thyroid cancers (DTC). Proponents of this approach argue for a better optimization of the ablative dose, and opponents argue that this WBI could lead to the "stunning effect" characterized by reduced tissue uptake of 131I in ablative dose treatment, thereby compromising treatment and prognosis of these individuals. Objective: To evaluate whether WBI with 131I, ablative pre-dose, interferes with the efficacy of the therapeutic dose of iodine as remission of the disease after total or near total thyroidectomy in individuals with DTC. Methodology: A systematic review of the literature was conducted in which randomized, non-randomized and observational studies were included in which the patients were in the late postoperative period of total or subtotal thyroidectomy due to one of the DCT and were assigned the diagnostic WBI with I131 before the ablative dose (intervention) or they performed WBI with 123I before the ablative dose, or non-performance of the diagnostic WBI (directly ablative dose with 131I) (control). The primary outcome was disease remission assessed by the ablative success rate at least six months after follow-up. Results: After performing the searches in the following electronic databases Embase (1980-25/04/2017), Pubmed (1966-25/04/2017), CENTRAL (Cochrane Controlled Trials Register) (04/2... (Complete abstract click electronic access below) / Resumo: Apesar de existirem controvérsias, alguns serviços utilizam a pesquisa de corpo inteiro (PCI) com 131I previamente a dose terapêutica com esse radionuclídeo no tratamento dos cânceres diferenciados da tiroide (CDT). Os defensores dessa conduta argumentam uma melhor otimização da dose ablativa, e os contrários afirmam que essa PCI poderia ocasionar o “efeito stunning”, caracterizado pela redução da captação tecidual do 131I no tratamento com a dose ablativa, comprometendo com isso o tratamento e o prognóstico desses indivíduos. Objetivo: avaliar se a PCI com 131I, pré-dose ablativa, interfere na eficácia da dose terapêutica de iodo quanto a remissão da doença após a tireoidectomia total ou quase total em indivíduos com CDT. Metodologia: foi realizada uma revisão sistemática da literatura na qual foram incluídos estudos controlados randomizados, não randomizados e observacionais, nos quais os pacientes estavam em pós-operatório de tireoidectomia total ou subtotal devido um dos CDT, e foram alocados a um dos dois grupos: PCI diagnóstica com 131I realizada antes da dose terapêutica com I131(intervenção), ou a PCI realizada com 123I antes da dose ablativa, ou não realização da PCI diagnóstica antes da dose terapêutica (ambos controle). O desfecho principal foi a remissão da doença avaliada pela taxa de sucesso ablativo em pelo menos seis meses de seguimento. Resultados: depois de realizadas as pesquisas nas bases eletrônicas Embase (1980–25/04/2017), Pubmed (1966–25/04/2017), CENT... (Resumo completo, clicar acesso eletrônico abaixo) / Mestre

Le rôle que pourrait jouer l’interaction des systèmes cholinergiques (ACh) et dopaminergiques (DA) semble crucial dans la physiopathologie de certaines maladies neurodégénératives, en particulier dans la démence à corps de Lewy (DCL). Ce travail de thèse se propose de valider un protocole d’imagerie moléculaire en tomographie d’émission monophotonique, consistant en un marquage de l’ACh et de la DA chez un même individu, afin de pouvoir étudier in vivo les interactions ACh/DA.Après avoir mis au point chez des sujets âgés et des patients atteints de maladie d’Alzheimer une méthode d’imagerie cérébrale quantitative des neurones ACh utilisant un radioligand sélectif du transporteur vésiculaire de l’ACh, le [123I]-IBVM, et basée sur une modélisation pharmacocinétique, nous avons montré le potentiel de cette méthode à mettre en évidence une atteinte différentielle des circuits ACh dans la Paralysie Supranucléaire Progressive et l’Atrophie Multisystématisée. Dans la dernière partie de ce travail de thèse, nous avons pour la première fois réalisé un double marquage des systèmes ACh et DA dans la DCL, en utilisant, en plus du [123I]-IBVM, un radioligand sélectif du transporteur de la dopamine et validé en routine clinique, le [123I]-FP-CIT. En parallèle, une étude comportementale évaluant la présence d’hallucinations, de fluctuations cognitives, d’altérations des rythmes circadiens ainsi qu’un bilan des performances neuropsychologiques, ont été menés. Cette étude est actuellement en cours de réalisation. Les tous premiers résultats montrent l’existence de liens cohérents entre les données d’imagerie moléculaire et les données cliniques. / The question of how acetylcholine (ACh) and dopamine (DA) could be involved together in the pathophysiology of some neurodegenerative disorders is essential, particularly in dementia with Lewy bodies (DLB). The present study aims at assessing an in vivo molecular imaging method of both ACh and DA brain systems using single photon emission computed tomography. In the first part of the present study, a method based on pharmacokinetic analysis making it possible to quantify ACh neurons in vivo, using [123I]-IBVM, a specific radioligand of vesicular acetylcholine transporter, was developed and validated in healthy subjects and Alzheimer’s disease patients. Then, we showed the ability of our method to demonstrate a differential alteration of ACh pathways in Progressive Supranuclear Palsy and Multiple System Atrophy patients. In the last part of this study, we imaged for the first time both ACh and DA systems in DLB patients, using not only [123I]-IBVM, but also [123I]-FP-CIT, a specific radioligand of dopamine transporter. Concomitantly, a behavioral exploration of hallucinations, fluctuating cognition and disturbances of circadian rhythms was achieved in these patients, as well as a neuropsychological examination. This study is currently in progress. The first results show consistent links between imaging and clinical data.

Les nouvelles gamma-caméras à semi-conducteurs utilisant des détecteurs au CZT sont dédiées aux explorations cardiaques. Leurs sensibilité, résolution spatiale et en énergie nettement améliorées comparativement aux gamma-caméras conventionnelles sont une révolution en médecine nucléaire. Ces gamma-caméras utilisent de nouvelles géométries d’acquisition, de nouveaux algorithmes de reconstruction, et ouvrent de nouvelles perspectives dans les études simultanées en double-isotope de l’123I et du 99mTc, dont les pics énergétiques sont proches.Nous avons étudié l’impact de l’amélioration de la résolution en énergie en comparant deux modèles de gamma-caméras à détecteurs semi-conducteurs aux gamma-caméras conventionnelles. A l’aide d’études sur fantômes anthropomorphes et chez des patients porteurs d’insuffisance cardiaque, notre travail s’est concentré sur les acquisitions scintigraphiques (i) de la fonction ventriculaire gauche (99mTc) en présence d’123I, (ii) de la perfusion myocardique (99mTc) en présence d’123I (innervation), et (iii) du rapport cardiomédiastinal de la fixation d’123I- métaiodobenzylguanidine (123I-MIBG) lors d’acquisitions double-isotope (123I-MIBG/99mTc- tétrofosmine) chez les patients souffrant d’insuffisance cardiaque.Nos résultats montrent que la meilleure résolution en énergie des gamma-caméras CZT permet en étude double-isotope (i) une évaluation de la FEVG et du mouvement régional dans les différentes fenêtres d'énergie (123I ou 99mTc) et les types d'acquisition (simple- vs double-isotope), (ii) une évaluation simultanée et combinée de la perfusion (99mTc) et de l’innervation (123I) du myocarde, et (iii) l’évaluation du rapport cardiomédiastinal de la fixation d’123I-MIBG. Chacune de ces trois parties a fait l’objet d’une publication. / New dedicated-cardiac cameras using CZT detectors have dramatically transformed the routine of myocardial perfusion imaging. With a better count detection sensitivity, an improved spatial and energy resolution, they potentially enable combined assessment of myocardial innervation (123I) and perfusion (99mTc) within a single imaging session. These cameras images with different sharpness and contrast-to-noise ratios.Using two CZT cameras with anthropomorphic phantom, and clinical studies in heart failure patients, our work focused on (i) the left ventricular function assessment within the 99mTc window in presence of 123I, (ii) the evaluation of regional myocardial innervation (123I) and perfusion (99mTc) match and mismatch with single- (separate 123I and 99mTc acquisition) and simultaneous dual-isotope acquisitions, and (iii) the late heart-to-mediastinal ratio (HMR) of 123I-MIBG uptake determined using dual-isotope CZT acquisition with that determined using conventional planar imaging in patients with heart failure.Our results found no impact of the acquisition mode (single vs dual) or the type of CZT camera on 123I and 99mTc defect size and mismatch, LVEF, and HMR of 123I-MIBG uptake.This work provides a new step toward simultaneous dual-isotope acquisition for combined innervation, perfusion and ventricular function assessment.

京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第12945号 / 論医博第2097号 / 新制||医||1010(附属図書館) / 32204 / (主査)教授 髙橋 良輔, 教授 富樫 かおり, 教授 髙橋 淳 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24786号 / 医博第4978号 / 新制||医||1066(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 花川 隆, 教授 村井 俊哉, 教授 高橋 淳 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 新制・課程博士 / 博士(人間健康科学) / 甲第23825号 / 人健博第96号 / 新制||人健||7(附属図書館) / 京都大学大学院医学研究科人間健康科学系専攻 / (主査)教授 椎名 毅, 教授 精山 明敏, 教授 中本 裕士 / 学位規則第4条第1項該当 / Doctor of Human Health Sciences / Kyoto University / DFAM