Tese de Doutoramento Ciências da Saúde 2024 Faculdade de Ciências Médicas, Universidade NOVA de Lisboa

Age-related Macular Degeneration (AMD) is an important cause of irreversible visual impairment, secondary to degenerative macular disorder. AMD can compromise central vision, essential for reading and for recognizing small details. Currently we recognize three stages in AMD: early, intermediate and late stage. Early AMD is characterized by the presence of medium (≥63μm and ≤125μm) drusen with no associated pigmentary abnormalities and intermediate AMD (iAMD) is characterized by the presence of large (>125μm) drusen associated or not with pigmentary abnormalities. Advanced or late AMD can be atrophic or neovascular, with death of photoreceptors associated or not with macular neovascularization. Intermediate stage is a common pathway to more advanced forms of the disease and has, recently, been arousing special interest as a field of AMD investigation. Althought some progress is being made towards a treatment for atrophic AMD no subsequent visual improvement can yet be obtained. Early and intermediate AMD stages have no preventive effective treatment besides general recommendations as eating healthfully, taking vitamin supplements, and not smoking. On the other hand, anti-vascular endothelial growth factor (anti-VEGF) therapies with repeated intravitreal administrations are a proven therapeutic option to control exudative disease. AMD pathophysiology has some known factors (age, genetics, smoke and nutrition) and some others are still under debate. There is a documented genetic background with genes encoding complement system, high-density lipoprotein metabolism, extracellular matrix remodeling, angiogenesis and cell survival. High risk genetic variants linked to AMD are found in the genes related complement system proteins (complement factor I, complement C2, C3, C9, and CFH). Other possible implicating factors identified as predictors for AMD development are human high-temperature requirement A-1 (HTRA1) and Age-related Maculopathy Susceptibility 2 (ARMS2) as well as other rare genetic variants. It seems possible that still other unknown elements may be involved not only in AMD pathophysiology but also in its progression. In this study we focus the issue on possible factors involved in AMD pathophysiology or in its progression. We propose to study iAMD patients, with follow-up visits every six months for two consecutive years, in a non-interventional prospective way. These patients will undergo a complete ophthalmologic evaluation and retinal imaging including Color Fundus Photography (CFP), Fundus Autofluorescence (FAF), Spectral Domain Optical Coherence Tomography (SD-OCT), OCT-Angiography (OCT-A) using Spectralis OCT with OCT Angiography Module (Heidelberg Eng. GmbH, Germany) at the baseline and during the follow-up period. Multimodal retinal imaging is used to explore biomarkers of disease progression. We studied imaging aspects of the macula of iAMD patients and hypothesized their relationship with the disease pathophysiology and with progression to advanced disease. The study develops in three lines of clinical investigation: fundus autofluorescence findings, chorioretinal vascular findings and finally identification of other disease progression biomarkers. Fundus autofluorescence findings - Drusen autofluorescence was correlated with drusen type and morphology and with additional outer retinal structural changes on SD-OCT. We found a statistically significant correlation between drusen autofluorescence (AF) and homogeneity, hyperreflective foci (HRF), external limiting membrane (ELM) integrity, ellipsoid zone (EZ) integrity, and choroidal hypertransmission (CH). All correlations were weak or moderate and no strong correlations were found with any parameter. These findings support the concept that drusen and lipofuscin emerge from biologic processes directly unrelated, both meaning RPE metabolic overload, and raise the hypothesis that FAF can be useful in monitoring iAMD patients. Further we found a statistically significant difference in the rate of progression to advanced AMD between patients with hypo and/or hyperautofluorescent drusen and patients with only isoautofluorescent drusen. Moreover, progression to geographic atrophy (GA) alone was significantly superior in patients with at least one hypo or hyperfluorescent drusen, meaning a more benign prognosis for isoautofluorescent drusen. Chorioretinal vascular findings - A non-interventional prospective study was conducted to evaluate choroidal and retinal vascular parameters in iAMD patients. We found significant differences concerning total subfoveal choroidal area, luminal area and choriocapillaris flow density in iAMD compared with age matched control eyes. No apparent relationship was found between those quantitative vascular parameters and progression to late AMD. Identification of other disease progression biomarkers - Prospective non-interventional study to investigate and characterize drusen, HRF and other OCT features (presence of incomplete retinal pigment epithelial and outer retinal atrophy, and EZ status) as biomarkers of disease progression. A risk prediction model for progression to late AMD was calculated, with estimates of odds ratio of each significant variable. The combination of incomplete retinal pigment epithelial and outer retinal atrophy (iRORA) and EZ disruption constitute a high risk of progression to complete retinal epithelial and outer retinal atrophy (cRORA) within two years. We further perform a retrospective analysis of data from a longitudinal study concerning nonexudative macular neovascularization and progression to exudative AMD; its ocorrence was found in 23.5% in the follow-up period, most frequently in younger patients, in eyes with foveal NE membranes and presenting exudative AMD in the fellow eye. The findings reported in this Thesis have the potential to contribute to AMD pathophysiology knowledge, exploring and understanding imaging retinal or choroidal biomarkers. This information could inspire investigators and clinicians in the prevention of disease progression and in the identification of potential treatment pathways, effective in early stages of AMD