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The retinal pigment epithelium (RPE) is a monolayer of cells located directly behind the photoreceptor cells in the retina. These cells are involved in a variety of functions that support the visual process in the eye, namely 1) they form a blood-retina barrier which separates the neural retina from the choroid's blood supply, 2) the apical processes of RPE cells diurnally phagocytose the outer segments of photoreceptor cells, and 3) they participate in the renewal of the photopigment 11-cis retinal. Age-related macular degneration (AMD) is the leading cause of blindness in people over the age of 50 years in North America and other developed countries. AMD involves the death of retinal pigment epithelial (RPE) cells in the macula early in the progress of the disease. Like some other postmitotic cells, the RPE accumulates autofluorescent lysosomal storage bodies (lipofuscin) during senescence. Lipofuscin is reported to begin accumulating in the human RPE around age 20 and continues to accumulate throughout an individual's life. This progressive accumulation of lipofuscin can eventually occupy a substantial fraction of the RPE cytoplasmic volume and may lead to impairment of normal RPE functions, resulting in retinal degeneration and loss of visual function as in AMD. Another autofluorescent granule that accumulates in RPE cells and may contribute to the etiology of AMD is a complex granule exhibiting properties of both melanosomes and lipofuscin granules called melanolipofuscin (MLF). In contrast with the accumulation of LF in the RPE, MLF accumulation has been reported by Feeney-Burns to more closely reflect the onset of AMD. Although there have been significant advances in our understanding of AMD, knowledge of the mechanisms responsible for its progression remain unclear. This dissertation details experiments that were designed to better understand the factors that may play a causal role in AMD as well as the development of methods to assist in AMD research. Specifically, the protein composition of retinal LF was assessed to elucidate its origin. These findings are reported in chapter 2. The accumulation, composition and phototoxicity of MLF were analyzed to assess MLF's origin and possible contribution to AMD. These results are reported in chapter 3. Because protein oxidation is possibly a common posttranslational modification to proteins which accumulate in lipofuscin and melanolipofuscin granules, a method for the detection and analysis of oxidized proteins was developed and is reported in chapter 4. Chapter 5 details the proteomic differences between ARPE-19 cells - the only human RPE cell line available for research - in their differentiated and undifferentiated states and compares these to the proteome of human RPE cells. These results are also compared to the phenotypic difference of these cells as observed by transmission electron microscopy.

Age-related macular degeneration (AMD) is the leading cause of blindness in the United States of America. The pyridinium bis-retinoid A2-ethanolamine (A2E) has been implicated to play a role in AMD. We have observed novel pyridinium bis-retinoids through melanolipofuscin and human RPE extractions that may also play a role in the pathology of AMD. We have begun the construction of an amino-retinoid library in order to identify these ocular compounds. The compounds from the amino-retinoid library are also used in a targeted and triggered drug delivery system for treating cancer. Folic acid is coupled with the amino-retinoids to specifically target cancer cells. The first two amino-retinoids to be synthesized and characterized were A2-dopamine (A2D) and A2-cadaverine (A2C). Both pyridinium bis-retinoids were shown to generate cytotoxic oxidation products similar to A2E. Successful coupling of folic acid to A2C was achieved to form the folic acid-A2-cadaverine (FA-A2C) product. Preliminary irradiation results suggest that the FA-A2C product may be more photoreactive than initially anticipated. This could mean less drug and light exposure required to induce apoptosis and could eventually lead to a less invasive and toxic cancer treatment.

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京都大学 / 新制・課程博士 / 博士(工学) / 甲第25273号 / 工博第5232号 / 新制||工||1997(附属図書館) / 京都大学大学院工学研究科建築学専攻 / (主査)教授 小椋 大輔, 教授 原田 和典, 教授 石田 泰一郎 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DFAM

Deutschsprachige Zusammenfassung Dissertation zur Erlangung des akademischen Grades Dr. med. Titel: Mögliche Korrelation zwischen dem Stadium der altersabhängigen Makuladegeneration und der zentralen Hornhautdicke eingereicht von: Christian Koch angefertigt an der: Klinik und Poliklinik für Augenheilkunde Universität Leipzig betreut von: Professor Dr. med. Peter Wiedemann Klinik und Poliklinik für Augenheilkunde Universität Leipzig Monat und Jahr: Juni 2015 Annahme: Es soll ein statistischer Zusammenhang zwischen der zentralen Hornhautdicke in der Pupillenmitte mit dem nicht exsudativen frühen Stadium der AMD, dem exsudativen späten Stadium der AMD und einer Kontrollgruppe überprüft werden. Methodik: Die erste Studiengruppe stellten 48 Augen von 48 Patienten mit einer Form der frühen AMD dar (Durchschnittsalter 75,4 Jahre, 70,8% der Probanden waren Frauen). Die zweite Studiengruppe bildeten 49 Augen von 49 Patienten mit einer Form der späten AMD (Durchschnittsalter 79,8 Jahre, 59,2% der Probanden waren Frauen). Als Kontrollgruppe wurden 49 Augen von 49 Individuen ohne retinale oder korneale Erkrankungen genutzt (Durchschnittsalter 68,9 Jahre, 59,2% der Probanden waren Frauen). Die Vermessung der Hornhautdicke in Pupillenmitte im Sinne der Hornhautmittendicke erfolgte als Pachymetrie mit der Oculus Pentacam. Ergebnisse: Die durchschnittliche zentrale Hornhautdicke betrug bei der Kontrollgruppe 552,76 μm (SD 36,27 μm), bei der nicht exsudativen Gruppe 552,19 μm (SD 31,27 μm) und bei der exsudativen Gruppe 553,73 μm (SD 33,11 μm). Die Extrempunkte der Kontrollgruppe lagen bei 483 und 640 μm, der Gruppe der nicht exsudativen AMD bei 480 und 617 μm und Minimum und Maximum der exsudativen Gruppe bei 473 und 617 μm. Es gab keine statistisch signifikanten Unterschiede im arithmetischen Mittel der zentralen Hornhautdicke in Pupillenmitte bei der Studiengruppe mit früher AMD im Vergleich mit der Studiengruppe mit später AMD und jeweils im Vergleich zur Kontrollgruppe (P > 0,05). Schlussfolgerung: Die Messwerte der zentralen Hornhautdicke bei Patienten mit früher AMD, später AMD und Kontrollindividuen unterscheiden sich nicht. Die Erhebung der Hornhautmittendicke bietet somit keine Screeningmöglichkeit zur Erkennung einer AMD. / English Abstract Central corneal thickness in patients with AMD Koch, C.; Jochmann, C.; Wiedemann, P. University of Leipzig, Department of Ophthalmology and Eye Hospital, Leipzig, Germany Purpose: To evaluate central corneal thickness in patients with AMD in the early and late phase and a control group. Method: The first study group was made up of 48 eyes of 48 patients with early AMD (mean age 75.4 years, 70.8 % women), the second study group was made up of 49 eyes of 49 patients with late AMD (mean age 79.8 years, 59.2 % women). 49 eyes of 49 individuals without any retinal or corneal damage (mean age 68.9 years, 59.2 % women) were used as control group. The central corneal thickness was measured with the Oculus Pentacam pachymetry. Results: The mean central corneal thickness in early non-exudative AMD group was found to be 552.19 μm (SD 31.27 μm), while the mean central corneal thickness in the late exudative AMD group was measured as 553.73 μm (SD 33.11 μm). The control group had a mean central corneal thickness of 552.76 μm (SD 36.27 μm). There were no statistically significant differences in the mean central corneal thickness in the early non-exudative AMD group in comparison with the late exudative AMD group and each of them compared to the control group (P > 0,05). Conclusion: The central corneal thickness measurements do not differ in patients with early non-exudative AMD, late exudative AMD and control subjects.

Objectif : Nous avons voulu évaluer le risque d’élévation chronique de la pression intraoculaire suite à des injections de ranibizumab dans le traitement de la dégénérescence maculaire liée à l’âge de type néovasculaire. Méthode : Nous avons réalisé une étude rétrospective sur 161 patients ayant reçu des injections de ranibizumab dans un œil seulement. Les critères excluent les patients ayant du glaucome non contrôlé au départ (PIO>21mmHg) et ceux qui ont eu moins de 9 semaines de suivi après l’injection. L’élévation de la PIO est définie comme une augmentation de >5mmHg sur deux visites consécutives. Résultats : Nous n’avons pas déterminé de différence de pourcentage entre les yeux ayant reçus des injections pour lesquels il y a une élévation de la PIO (n=8.5%), comparé au pourcentage de yeux n’ayant pas reçus d’injections pour lesquels il y a une élévation de la PIO (n=9.6%). Cependant, un plus grand nombre d’injections d’anti-VEGF est associé avec une élévation chronique de la PIO (P=0.032). D’autres facteurs de risque de l’élévation chronique de la PIO sont le diabète, une PIO faible au départ, et une PIO maximale plus élevée (P<0.05). Conclusion : Un plus grand nombre d’injections semble augmenter le risque d’élévation de la PIO. Les patients atteints de diabète semblent être plus à risque et nécessiter une étroite surveillance. / Purpose: Conflicting evidence exists about the risk of chronic elevation of intraocular pressure (IOP) after ranibizumab injections for neovascular age-related macular degeneration. The goal of this study is to evaluate this risk. Methods: A retrospective cohort study of 161 people. Inclusion criteria included receiving at least three ranibizumab injections in one eye only and having at least 9 weeks of follow-up. Exclusion criteria included the presence of uncontrolled glaucoma or ocular hypertension at baseline (IOP>=21mmHg). Chronic IOP elevation was defined as an increase >5mmHg of IOP on at least 2 consecutive visits. Results: There was no difference in the percentage of injected eyes that experienced a chronic IOP increase (n=8, 5%) compared to the percentage of uninjected eyes that experienced an IOP increase (n=9, 6%). However, a greater number of anti-VEGF injections was associated with chronic IOP elevation (P=0.032). Other risk factors for chronic IOP elevation included diabetes, a lower baseline IOP, and a higher maximum IOP (P<0.05). Conclusions: A greater number of injections appears to increase the risk of chronic IOP elevation. Also, diabetics appear to be more at risk and may need more careful follow-up or preventive pharmacological treatment.

White matter changes (WMC) seen on CT and MRI brain scans of healthy subjects and of vascular or dementia patients are strongly associated with age. Their pathogenesis is still under debate, and associations with vascular risk factors have varied according to studies. Their prognostic meaning, both in the general population and in stroke patients, is also not completely established. I systematically reviewed the literature on prevalence and associations of WMC and then evaluated CT and MRI scans of the first 8 years of a population-based study of all strokes and TIA in Oxfordshire (OXVASC). In this population I researched sex and age-specific associations between WMC and different types of strokes (TOAST), different components of blood pressure, and possible vascular risk factors. I also looked into their prognostic meaning for stroke recurrence and outcome, cognitive performance and mortality. 1840 patients were assessed by MRI (520) and/or CT (1717). White matter changes were independently associated with the lacunar type of stroke. The association with hypertension was confirmed (using 10 years of pre-morbid blood pressure readings), and it was particularly strong in the younger patients, mainly for diastolic hypertension. There was no association with blood pressure variability and peripheral pulse pressure. Hypercholesterolaemia, diabetes, smoking, ischaemic heart disease, carotid stenosis and atrial fibrillation were not associated with white matter changes. There was also no association with gender. Severe WMC posed a higher risk of disability and cognitive impairment at one year from the stroke, and of death in the following 10 years. This is the first study on white matter changes associations and on their prognostic meaning, to be set in a large population-based cohort of stroke and TIA. I confirmed the association between white matter changes and higher blood pressure, in particular diastolic hypertension. I also showed the association with lacunar type of stroke to be independent from vascular risk factors, and WMC to reduce life expectancy and functional and cognitive outcome of patients with stroke.

Au travers des données cognitives de la cohorte stéphanoise PROOF, l’objectif de ce travail de thèse a été de déterminer quelle pouvait être la valeur pronostique de plusieurs facteurs, entre autres psychosociaux et physiologiques, d’un maintien optimal du fonctionnement cognitif avec l’âge.Le premier axe de recherche de ce travail, a mis en évidence que 70% des 632 participants âgés de 67 ans à la première évaluation cognitive de l’étude PROOF, présentaient une stabilité de leur fonctionnement cognitif après 8 ans de suivi. Le principal facteur mis en cause dans le vieillissement cognitif de cette population, que nous avons qualifié de « réussi », était, pour ces participants, d’avoir un haut niveau d’implication dans des activités sociales.Le second axe de recherche de ce travail, a mis en évidence que la dégradation de la régulation autonomique, et non la présence de facteurs de risque cardiovasculaires classiques, avait un impact négatif sur le fonctionnement mnésique des participants. Confortant ces résultats, nous avons montré que les pathologies respiratoires liées au sommeil avaient un impact négatif sur le vieillissement cognitif normal, avec un impact délétère de la fragmentation autonomique nocturne sur l’évolution des capacités mnésiques. Une préservation de l’activité du Système Nerveux Autonome (SNA) pourrait donc être une clé d’un maintien optimal des capacités mnésiques au cours du vieillissement normal.Le troisième axe de recherche de ce travail, a mis en évidence que les plaintes, qu’elles soient cognitives ou liées à la qualité de sommeil, étaient stables au décours du vieillissement normal. Nous avons pu démontrer que ce n’est pas l’âge qui génère la plainte, mais la qualité de vie et l’état anxiodépressif des personnes qui les expriment. Ceci n’est pas sans nous rappeler que le sujet, son symptôme et son histoire sont autant de déterminants du vieillissement cognitif « réussi ». Le quatrième axe de recherche de ce travail, a enfin mis en exergue que la prise en compte de la richesse des interactions sociales menées tout au long de la vie était un élément déterminant du niveau de performances dans des tâches de cognition sociale de personnes agées de 78 ans, et ce, indépendamment de la nature du fonctionnement exécutif et du niveau socioculturel. En conclusion, le vieillissement cognitif « réussi » n’est pas uniquement une vision optimiste du bien vieillir, allant contre des stéréotypes négatifs sur une perte systématique des fonctions cognitives liée à l’âge. Il s’agit d’un concept multidimensionnel qu’il convient de bien cerner si l’on veut mettre en place des stratégies efficaces susceptibles d’intervenir sur le maintien des capacités cognitives avec l’âge. Ce travail de thèse a permis de mettre en évidence l’identification de quatre facteurs déterminant du vieillissement cognitif « réussi » (et pour lesquels une intervention est possible !) qui sont : 1) le maintien des activités sociales tout au long de sa vie ; 2) la préservation d’un bon équilibre du système sympathique-parasympathique ; 3) l’absence de pathologies respiratoires liés au sommeil ; 4) la stabilité des plaintes (sommeil, cognition) exprimées avec l’âge. / The aim of this thesis was to examine cognitive performances of a large French cohort study of elderlies, i.e. the Saint Etienne PROOF-Siempre cohort, in order to assess among several factors which of them could play a prognostic role on a successful cognitive aging including physiological and psychosocial factors. In order to assess these key factors we developped several research axes frequently examining the long-term changes.The first axis of the research consider the overtime evolution of cognitive function in this population. We found that 70% of the 632 participants 67 yrs old at their inclusion in the study with or without sleep related breathing disorders had stable cognitive data 8-yr later. In this sample that we defined as having a successful cognitive aging, the predictive factor was the "high level of social activities" without any contribution of the demographic data, the hypoxemic load or classical vascular and metabolic factors.The second axis of the research we examined the influence of the autonomic nervous system activity of cognitive performances. In a sample of 916 older people, we found that a parameter reflecting the parasympathetic arm of the ANS, the baroreceptor sensitivity, affect when it was found altered the memory function without interference of other cardiovascular risk factor. These results were confirmed in a 8-yr assessment on 425 subjects of the previous sample in whom again a alteration of baroreceptor sensitity affect the long-term changes on memory function with contribution of the other examined factors. This would suggest that autonomic nervous system may also influence the memory changes with aging and assuring a more successful cognitive aging.The third axis of the research was to define how subjective cognitive and sleep complaints remain stable across time and whether subjective estimation of sleep quality may affect the changes on the subjective cognitive complaints. We found again a stability of the subjective cognitive complaint without any interference of sleep quality and aging itself, the quality of life and the presence of anxiety and depression being the most important factors. The four axis of the research examined the possible effect of the degree of social interaction developed along lifetime on the social cognition. We found in group of 100 elderly aged 78 yrs that quality of social interactions in the life-span was the key factor implicated in late social cognitive skills in the elderly without any effect of the executive function status nor the educational and intellectual level.In conclusion, we have demonstrated that in contrast to the most common recognized of a systematic loss of cognitive functions related to age healthy elderlies may have a successful cognitive aging. The "successful" cognitive aging is a multidimensional concept that should clearly identify if one wants to adopt effective strategies to maintain cognitive abilities with age. The different aspects examined in this thesis have highlighted the identification of four determinants of a "successful" cognitive aging: 1) the maintenance of social activities throughout the life; 2) the preservation of a sympathetic-parasympathetic balance of the autonomic nervous system; 3) the lack of sleep-disordered breathing; and 4) the stability of sleep and cognitive complaints generally reported in older population. The application of those strategies may help to prevent the cognitive decline in older populations.