A Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine. / Objective: Formed visual hallucinations are a common phenomenon in neurodegenerative disorders such as Parkinson’s Disease (PD), Alzheimer’s disease (AD) and Dementia with Lewy bodies (DLB). While Lewy‐type alpha‐synucleinopathy (LTSis the hallmark neuropathological finding in PD and DLB, amyloid plaques and neurofibrillary tangles are the pathological finding in AD. Previous research has linked complex or formed visual hallucinations (VH) to LTS in neocortical and limbic areas in patients with PD and DLB. As VH also occur in Alzheimer’s disease, and AD pathology often co‐occurs with LTS, we questioned whether this pathology might also be linked to VH. Methods: We performed a semi‐quantitative neuropathological study across brainstem, limbic, and cortical structures in subjects with a documented clinical history of VH and a clinicopathological diagnosis of Parkinson’s disease (PD), Alzheimer’s disease (AD), or dementia with Lewy bodies (DLB). 173 subjects – including 50 with VH and 123 without VH – were selected from the Arizona Study of Aging and Neurodegenerative Disorders. Clinical variables examined included the Mini‐mental State Exam, Hoehn & Yahr stage, and total dopaminergic medication dose. Neuropathological variables examined included total and regional LTS and plaque and tangle densities. Results: A significant relationship was found between the density of LTS and the presence of VH in all diagnostic groups. Plaque and tangle densities also were associated with VH in PD (p=.003 for plaque and p=.004 for tangles), but not in AD, where densities were high regardless of the presence of hallucinations.. Conclusion: Plaques and tangles as well as LTS may contribute to the pathogenesis of VH. Incident VH may be a clinical indicator of underlying pathological events: the development of plaques and tangles in patients with PD, and LTS in patients with AD.

Background: Atherosclerosis is a systemic inflammatory disease characterized by the formation of atheromatous plaques within arteries. These plaques can be classified as unstable or stable based on their morphology and cellular infiltrate. Anatomical location of plaques and age of atheroma defines the symptoms of disease. However, there is little in the literature to support this. The study aimed to compare the cellular composition, morphology, lipid biochemistry and 18F- flurodeoxyglucose (18F-FDG) positive emission tomography (PET) uptake between plaques from patients with recently symptomatic carotid disease and patients with symptomatic peripheral arterial disease undergoing intervention. Patients and Method Patients with symptomatic carotid (≥60%) or femoral stenosis undergoing intervention were recruited. All patients underwent 18F-FDG PET scanning prior to operation. The numbers of plaque macrophage and T cells were determined by immunohistochemistry (IHC). Double IHC defined the proportion of classically (M1) activated macrophages (iNOS, MHC II and SOCS-3 positive) or alternatively (M2) activated (dectin-1, CD163; SOCS-1). Plaque composition was quantified by a new morphological definition based on percentage area of fibrooconnective tissue, lipid, calcification and cellular infiltrate. The proportion of fatty acids within plaque lipids was estimated by liquid chromatography. Results 34 patients with symptomatic carotid disease and 34 with symptomatic femoral disease were recruited. 18F-FDG PET imaging was carried out successfully in 29 carotid and 29 femoral artery disease patients. 32 carotid and 25 femoral plaques were obtained. Significant differences were noted between carotid and femoral plaques with respect to the number of macrophages (p<0.001), T cells (p<0.001) and proportion of classical (p<0.001) and alternatively (p<0.001) activated macrophages and morphological analysis with evidence of more inflammation in carotid plaques. Lipid analysis revealed higher triglyceride n-6 PUFAs in carotid compared to femoral plaques (p=0.01). FDG uptake between carotid and femoral plaques was not significantly different and did not correlate with immunohistochemical, plaque morphometry or lipid analysis parameters. FDG uptake correlated with degree of symptomatic carotid stenosis (Spearman‟s coefficient=0.482;p=0.008) and symptomatic ABPI (Spearman‟s coefficient=-0.414;p=0.025). FDG uptake was higher in the symptomatic carotid compared to the contralateral asymptomatic carotid (p=0.016). Conclusion This study has shown substantial difference between morphological and cellular compositions of carotid and femoral plaques. Carotid plaques from recently symptomatic patients exhibited significantly greater percentage areas of lipid deposition, lymphocytic and monocyte/macrophage infiltrate and reduced cap thickness, in line with their more vulnerable nature. Moreover, there were a greater proportion of classically activated macrophages that are associated with plaque vulnerability. In contrast, percentage areas of fibroconnective tissue were higher in the femoral plaques. 18F-FDG PET imaging, although capable of identifying plaque inflammation, may not be adequately sensitive to differentiate between vulnerable and stable complex plaques.

Reproduction de : Thèse d'exercice : Médecine : Nancy 1 : 2003. / Titre provenant de l'écran-titre.

Bien que différents facteurs endogènes et exogènes soient impliqués dans la pathogenèse de la sclérose en plaques (SP), qui est une maladie auto-immune, des résultats contradictoires ont été rapportés concernant les niveaux de synthèse et la fonction de la mélatonine dans la SP. La mélatonine circadienne est une hormone qui est libérée en réponse à la baisse de la luminosité parla glande pinéale. Dans la présente thèse de recherche, nous avons étudié le rôle de la mélatonine dans la SP à l'aide de différents modèles. Tout d'abord dans le chapitre 1, on découvre que la mélatonine a tendance à augmenter dans le modèle de Cuprizone de la SP. Nous avons constaté que le fait de maintenir les souris dans l'obscurité constante entraîne une augmentation supplémentaire de l'effet de renforcement immunitaire de la mélatonine et l'exacerbation de la démyélinisation et l'infiltration. En revanche, la luminothérapie a considérablement atténué la démyélinisation en inhibant la synthèse de la mélatonine et en augmentant l'effet immunosuppresseur du cortisol. Deuxièmement dans le chapitre 2, nous avons utilisé le modèle EAE de la SP pour traiter les souris avec de la mélatonine exogène. Bien que la mélatonine ait déjà montré une réduction chez le modèle de l'EAE, cette étude a montré que la mélatonine améliore la remyélinisation mais que celle-ci est associée à une inhibition de l'enzyme PDC via PDK4, ce qui inhibe donc la synthèse des acides gras nécessaires à une remyélinisation efficace. Cet effet secondaire est éliminé par la co-administration de mélatonine et de la DADA, un inhibiteur de PDK4. Troisièmement dans le chapitre 3, nous avons proposé une voie mécanistique par laquelle la réduction de la mélatonine par le vieillissement et le changement de mode de vie jouent un rôle critique dans la prolifération incontrôlée des cellules souches neurales dans la SVZ. Il s'agit de l'étape initiale de l'initiation du glioblastome. Cet effet de la mélatonine sur la SVZ a mis en évidence l'importance de la mélatonine dans le processus d'oligodendrogenèse, étant donné que les précurseurs d'oligodendrocytes peuvent provenir de la SVZ dans la SP. En résumé, nos études suggèrent que la synthèse de la mélatonine pinéale devrait être suivie pour chaque cas afin de déterminer le profil de l'oscillation de la mélatonine du patient en fonction de son régime alimentaire, de son mode de vie, etc. L'administration de mélatonine peut favoriser la SP, en cas de carence en mélatonine, ou l'exacerber, en cas de surdosage en mélatonine. En outre, la luminothérapie peut être une approche efficace pour contrôler la mélatonine du SNC et augmenter le cortisol immunosuppresseur dans la SP. / Different endogenous and exogenous factors are involved in multiple sclerosis (MS) pathogenesis, an autoimmune disease. However, conflicting results are reported concerning melatonin synthesis levels, and function in MS. Circadian melatonin is a hormone released in response to the darkness from the pineal gland. In the current research thesis, we investigated the role of melatonin by different models in MS. First, in chapter 1, it is uncovered that melatonin tends to increase in the cuprizone model of MS. We figured out that keeping mice in constant darkness caused further increase in immunoenhancing function of melatonin and exacerbated the demyelination and infiltration. In contrast, light therapy significantly improved demyelination by inhibiting melatonin synthesis and boosting the cortisol immunosuppressant. Second, in chapter 2, we used the EAE model of MS to treat the mice with exogenous melatonin. The current study showed that melatonin improves remyelination; however, is associated with the inhibition of the PDC enzyme via PDK4, which inhibits the fatty acid synthesis required for efficient remyelination. This side effect is eliminated by the co-administration of melatonin and DADA, a PDK4 inhibitor. Third, in chapter 3, we proposed a mechanistic pathway by which melatonin reduction by aging and different lifestyle play a critical role in the uncontrolled proliferation of neural stem cells in the subventricular zone (SVZ). This is the initial step in glioblastoma initiation. This effect of melatonin on SVZ, highlighted the importance of melatonin in the oligodendrogenesis process as oligodendrocyte precursor can originate from SVZ in MS. To sum up, it suggested that pineal melatonin synthesis should be monitored in each induvial to figure out what is the patient's pattern in melatonin oscillation based on his/her diet, lifestyle, etc. Melatonin administration can improve MS, in case of melatonin deficiency or can exacerbate it, in case of melatonin overdose. Furthermore, light therapy may be an efficient approach for controlling the CNS melatonin and increasing the cortisol immunosuppressant in MS.

No description available.

Thèse : Médecine : Paris : 1885. / Numéro d'ordre : 147.

Reproduction de : Thèse d'exercice : Médecine. Médecine du travail : Nantes : 2009. / Bibliogr.

Thèse doct.-ing.--Paris-Sud, 1973. / Bibliogr. p. 80-82.

Th. univ.--Geologie--Paris V, 1986. / En appendice, choix d'articles en anglais du même auteur. Bibliogr. p. 213-214.

Th.--Sci.-nat.--Nancy, 1982. / Bibliogr. p. 233-250. Résumé en français et en anglais.