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Title: PROGRESS – Progression of Diabetic Retinopathy. Identification of Signs and Surrogate outcomes
Authors: Marques, Inês Pereira Dias 
Orientador: Fonseca, Maria da Conceição Lopes Lobo da
Figueira, João Pereira
Keywords: Diabetic Retinopathy; Multimodal imaging; Morphology and Function; Optical Coherence Angiography; Risk Predictors
Issue Date: 17-Sep-2021
Place of publication or event: Coimbra
Abstract: Diabetic retinopathy (DR) is the most frequent complication of diabetes mellitus and the leading cause of legal blindness in active populations of industrialized countries. Progression of DR does not occur at the same rate in all patients. Some never develop vision loss, whereas others rapidly progress to macular edema or neovascularization leading to vision loss. The already known risk factors are unable to predict the patients that will progress and develop complications. The main goal in diabetes is to prevent the development of DR. When DR lesions develop, early intervention should be attempt in order to preserve vision. It is essential to understand the mechanisms by which diabetes affects retina, improve the methods for early disease detection and find new molecules for targeted treatment. The understanding of the mechanisms that balance in different direction is the main objective of this thesis. This thesis represents the results of an observational longitudinal clinical study, the PROGRESS study (NCT03010397), that followed up 212 type 2 Diabetes mellitus patients with no or mild DR, in a 5-year period, with annual visits. The overall purpose of this research was to characterize both functionally and morphologically initial DR stages. We found that different DR pathways of disease may be identified in different eyes, representing ischemia, neurodegeneration and edema. We wanted to further characterize the already identified DR phenotypes that may be used as biomarkers of progression. Furthermore, understanding the extent of neuroretinal abnormalities and characterize the neurodegeneration progression in patients with or without detectable microvascular damage was a main goal of the study. I have started, in CHAPTER 1, with a general introduction, where I go through the epidemiology and pathophysiology of DR, principal risk factors, different classification systems and the main pathways of disease progression. In CHAPTER 2, 3 and 4 I present the results of the 5 year follow up study, with a description of the demographic and systemic characteristics of the study population and the 5 year progression to vision threatening complications (VTC) and ETDRS level progression. The predictive value of systemic and ocular risk factors were explored, and imaging biomarkers identified. Phenotype C patients present higher HbA1c levels and higher values of triglycerides when compared to other phenotypes. Phenotype C was identified mainly in eyes with ETDRS grade 35 suggesting that ETDRS grade 35 may be the turning point in the progression of DR. Different retinopathy phenotypes in T2D show different five-year risk for development of VTC: CSME, CIME and PDR. Phenotype C identifies eyes at higher risk for development of vision-threatening complications (CSME or PDR). In contrast, phenotype A identifies eyes that are at a very low risk of development of vision–threatening complications. Microaneurysm turnover and phenotype C correlate well with changes in ETDRS severity levels, independent of CRT values, validating its use as a simple to use biomarker of DR progression. Phenotype A and B, representing 70% of the entire cohort, have a very low risk for 2-or-more-step ETDRS worsening (2%). In CHAPTER 5 we presented a cross-sectional analysis of a cohort of NPDR patients, grouped according to the ETDRS grading protocol, in levels 10-20, 35, and 43-47. Three different pathways of disease were identified: neurodegeneration, ischemia and edema, with different prevalence in different patients, indicating that the predominant mechanism of retinal disease may be different in different individuals. They appear to occur independently of each other. Only the metrics of vessel density, indicating ischemia, appear to be associated with the ETDRS level. In the next 2 chapters, CHAPTER 6 and 7, I present the results of a 2-year and a 3-year follow up studies, performed in a subset of patients, characterizing the evolution of the three identified retinal pathways occurring in DR. In each ETDRS group, values of capillary dropout (reduced vessel density), edema and neurodegeneration covered a wide range, identifying different levels of damage in different eyes. Vessel density remained the only metrics significantly different between ETDRS groups, even after adjusting for multiple baseline factors. During the 2-year follow-up period the vessel density decreased in all retinal plexuses, particularly in the superficial capillary plexus, and was more important in eyes with worsening in ETDRS level comparing to eyes that maintained DR severity, whereas edema and neurodegeneration remained stable. In the 3-year follow up study it was evident a GCL+IPL thickness decreased (representing neurodegeneration) during the follow up, however, this decrease do not discriminate between eyes that will present worsening comparing to eyes that maintain the ETDRS severity level. In the last paper presented, in CHAPTER 8, we evaluated 105 eyes with the innovative Swept-Source OCTA (SS-OCTA, PlexElite, Carl Zeiss Meditec), that allow to explore a bigger area of the retina, using 15x9 mm and 3x3 mm protocol. We observe that capillary closure in the midperiphery in a diabetic retina is indicative of an advanced stage of retinopathy, whereas capillary closure limited to the perifovea suggests a milder stage of the disease. In the last chapter I performed a brief discussion of the obtained results. This information has a crucial impact in DR management, contributing for an individualized monitoring and care and open new perspectives concerning new therapies to be used in the early phase, before clinically significant complications o
Description: Tese no âmbito do Programa de Doutoramento em Ciências da Saúde – ramo de Medicina, orientada pela Professora Doutora Maria da Conceição Lobo Fonseca e pelo Professor Doutor João Pereira Figueira e apresentada à Faculdade de Medicina da Universidade de Coimbra.
Rights: openAccess
Appears in Collections:FMUC Medicina - Teses de Doutoramento
UC - Teses de Doutoramento

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