AGE-RELATED MACULAR DEGENERATION MACULAR AGE-RELATED UITNODIGING Eveline Kersten was born on December 12th, 1989 in voor het bijwonen van de Nijmegen, the Netherlands. In 2007, she graduated from secondary school at “Lindenholt College” in openbare verdediging van Nijmegen, and started her medical studies at the mijn proefschrift Radboud University in Nijmegen. During the internships AGE-RELATED MACULAR she developed her interest in ophthalmology, which AGE-RELATED lead her to do a research internship at the department DEGENERATION MACULAR of Ophthalmology of the Radboud university medical DEGENERATION center under supervision of prof. dr. Carel B. Hoyng. After her graduation from medical school in 2014, she joined the scientific Clinical and Molecular Studies Clinical and molecular research group of prof. dr. C.B. Hoyng and started her PhD project on age- studies related macular degeneration. Her research results are presented in this thesis. In November 2017, she started a residency in Ophthalmology at the door same institute. Eveline Kersten Vrijdag 5 juli 2019 om 12:30 uur precies Radboud Universiteit Nijmegen Aula Major Comeniuslaan 2 6525 HP Nijmegen Na afloop bent u van harte welkom op de receptie in de aula Paranimfen: Eveline Kersten Eveline Madelon Kersten 06-31793885 Eveline Kersten [email protected] Maartje Geerlings 06-26204642 Age‐related macular degeneration Clinical and molecular studies Eveline Kersten The work presented in this thesis was carried out within the Radboud Institute for Health Sciences. Research described in this thesis financially supported by the European Union’s Horizon 2020 research and innovation programme under grant agreement No 634479, the European Research Council under the European Union’s Seventh Framework Programme (FP/2007–2013)/ERC grant agreement no. 310644 (MACULA), Foundation Fighting Blindness USA (Grant C-GE-0811-0548-RAD04), Salentein fellowship, MD Fonds, Oogfonds, Algemene Nederlandse Vereniging ter Voorkoming van Blindheid, Stichting Nederlands Oogheelkundig Onderzoek, and Gelderse Blindenstichting. Financial support for the publication of this thesis was kindly provided by Radboud University Nijmegen, Radboud Institute for Health Sciences, Bayer B.V., Théa Pharma B.V., and Synga Medical B.V.. All funding organizations had no role in the design or conduct of this research. They provided unrestricted grants. ISBN 978-94-6323-671-3 Design cover Jack Roskam Design inside Gildeprint Photograph of the author DUTZU photography Printed by Gildeprint © Eveline Kersten, 2019 No part of this thesis may be reproduced or transmitted in any form without written permission by the copyright holder. Age-related macular degeneration Clinical and molecular studies Proefschrift ter verkrijging van de graad van doctor aan de Radboud Universiteit Nijmegen op gezag van de rector magnificus prof. dr. J.H.J.M. van Krieken, volgens besluit van het college van decanen in het openbaar te verdedigen op vrijdag 5 juli 2019 om 12.30 uur precies door Eveline Kersten geboren op 12 december 1989 te Nijmegen Promotoren Prof. dr. C. B. Hoyng Prof. dr. A.I. den Hollander Copromotor Dr. E.K. de Jong Manuscriptcommissie Prof. dr. G.J. van der Wilt Prof. dr. R. Silva (University of Coimbra, Portugal) Dr. F.D. Verbraak (Amsterdam UMC) Table of contents Chapter 1. General introduction 9 Chapter 2. Clinical studies 35 2.1 Clinical characteristics of familial and sporadic age-related 37 macular degeneration: differences and similarities Invest Ophthalmol Vis Sci. 2014 Oct 9;55(11):7085-92. 2.2 Burden of common genetic and environmental risk factors in 55 families affected with age-related macular degeneration Manuscript submitted 2.3 Risk factors for progression to late age-related macular 71 degeneration: 5-year follow-up of patients with early and intermediate AMD in the EUGENDA cohort Manuscript submitted 2.4 Phenotype characteristics of patients with age-related macular 93 degeneration carrying a rare variant in thecomplement factor H gene JAMA Ophthalmol. 2017 Oct 1;135(10):1037-1044. Chapter 3. Molecular studies 113 3.1 Systemic and ocular fluid compounds as potential biomarkers in 115 age-related macular degeneration Surv Ophthalmol. 2018 Jan - Feb;63(1):9-39. 3.2 Metabolomics in serum of patients with non-advanced age-related 223 macular degeneration reveals aberrations in glutamine pathway Manuscript accepted for publication in PLOSONE 3.3 Geographic distribution of rare variants associated with age-related 243 macular degeneration Mol Vis. 2018 Jan 27;24:75-82. 3.4 Genetic screening for macular dystrophies in patients clinically 253 diagnosed with dry age-related macular degeneration Clin Genet. 2018 Dec;94(6):569-574. doi: 10.1111/cge.13447. Chapter 4. General discussion 269 Chapter 5. Epilogue 291 5.1 Summary/Samenvatting 293 5.2 List of publications 297 5.3 Data management page 303 5.4 PhD portfolio 307 5.5 Acknowledgements/Dankwoord 311 Appendix. Acute metamorfopsie bij senioren vraagt om snel handelen 319 Accepted for publication in Nederlands Tijdschrift voor Geneeskunde Chapter 1 General Introduction Chapter 1 BACKGROUND Age-related macular degeneration (AMD) is a complex, multifactorial disease affecting the central retina. It is characterized by progressive changes to the macula eventually leading to central vision loss. In western countries, AMD is the leading cause of visual impairment among elderly people.1 AMD and its accompanying vision loss are associated with difficulties performing daily activities, increased emotional distress and depression. It negatively influences the quality of life, not only of the affected individual but often also that of close relatives.2 Since 2006, the number of people with visual impairment secondary to AMD has decreased in Europe. This is most probably due to the introduction of anti-vascular endothelial growth factor treatment for a subset of AMD patients along with healthier lifestyles.3 However, as a consequence of the ageing population, the number of patients worldwide is expected to increase substantially from 196 million in 2020 to 288 million in 2040. Therefore, AMD remains a significant public health problem.4 STAGES OF AMD Early and intermediate AMD The major hallmark of the early and intermediate AMD stages are yellowish deposits between the retinal pigment epithelium (RPE) and Bruch’s membrane, known as drusen.5 These drusen consist of various lipids and proteins, and are considered to be cellular residues and debris from RPE cell degeneration constituting chronic inflammation.6-8 The appearance of drusen varies greatly and several subtypes can be distinguished.9 Drusen can be classified based on their diameter: small (<63 µm), intermediate (63-124 µm), and large drusen (≥125 µm). Additionally, drusen can be categorized by their appearance: small hard drusen have sharp edges and uniform colour density, whereas soft drusen are less sharp demarcated, often larger in size, and can be distinct (uniform colour density) or indistinct (graded colour density).9-12 Larger soft drusen are associated with higher risk of developing advanced AMD,13- 16 whereas small hard drusen are considered to be normal changes related to aging as they are very common and confer minimal risk of development of advanced AMD.10 A specific subtype of small drusen, known as cuticular drusen, can be distinguished (Figure 1A). These are numerous (≥50) discrete, small, round drusen scattered throughout the macula, often extending to the peripheral retina. Cuticular drusen are best visible on fluorescein angiography and have a typical “stars in the sky” appearance.9,17 This subphenotype has been associated with an earlier age of onset and is frequently clustered in families, suggesting a stronger genetic component in the development of cuticular drusen.18,19 Additionally, all drusen can undergo calcification. Calcified drusen, also known as refractile drusen, have a 10 General Introduction characteristic glistening or crystalline appearance on color fundus imaging (Figure 1B), and have been associated with the development of geographic atrophy.20,21 1 Next to drusen, reticular pseudodrusen can be observed in AMD patients. These reticular pseudodrusen differ both phenotypically and anatomically from drusen. Reticular pseudodrusen are subretinal deposits, in contrast to genuine drusen that are located beneath the RPE. Phenotypically, reticular pseudodrusen can be recognized as grey-white spots arranged in a reticular network (Figure 1C). Also, they are more commonly located at the superotemporal quadrant of the macula.22 Reticular pseudodrusen are associated with development of advanced AMD, especially geographic atrophy.22-24 Figure 1. Examples of different types of drusen A. Cuticular drusen on color fundus photograph (left) and fluorescein angiography (right). B. Crystalline drusen on color fundus photograph (left) and infrared imaging (right). C. Reticular pseudodrusen on color fundus photograph (left) and infrared imaging (right). 11 Chapter 1 Other frequently observed features of early and intermediate AMD are hypo- and hyperpigmentations of the RPE.5 The presence of these pigmentary abnormalities together with intermediate drusen are associated with 4-fold increased risk of advanced AMD compared to intermediate drusen alone.14 Advanced AMD In time, early and intermediate AMD can progress to advanced AMD. Two subtypes of advanced AMD can be distinguished: geographic atrophy and neovascular AMD. Geographic atrophy (GA) is characterized by the presence of a sharp