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

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.

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.