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Advanced Glycation End Products (Ages) in Early Glaucoma Patients

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Advanced Glycation End Products (Ages) in Early Glaucoma Patients University of Plymouth PEARL https://pearl.plymouth.ac.uk 04 University of Plymouth Research Theses 01 Research Theses Main Collection 2020 Advanced glycation end products as a biomarker for accelerated ocular ageing and glaucoma Smewing, Leanne http://hdl.handle.net/10026.1/15838 University of Plymouth All content in PEARL is protected by copyright law. Author manuscripts are made available in accordance with publisher policies. Please cite only the published version using the details provided on the item record or document. In the absence of an open licence (e.g. Creative Commons), permissions for further reuse of content should be sought from the publisher or author. Copyright statement This copy of the thesis has been supplied on condition that anyone who consults it is understood to recognise that its copyright rests with its author and that no quotation from the thesis and no information derived from it may be published without the author's prior consent. ADVANCED GLYCATION END PRODUCTS AS A BIOMARKER FOR ACCELERATED OCULAR AGEING AND GLAUCOMA by LEANNE SMEWING A thesis submitted to the University of Plymouth in partial fulfilment for the degree of DOCTOR OF PHILOSOPHY School of Health Professions April 2019 1 Acknowledgements I am very grateful to the College of Optometrists for sponsoring this body of research. I would like to thank my incredible supervisor, Dr Stephanie Mroczkowska for her expertise, guidance and support throughout this process. I would also like to thank my supervisor Dr Desley White for her patience teaching me phlebotomy and lab skills and Professor Paul Artes for all of his guidance. I would like to say thank you to all of the staff at the Royal Eye Infirmary, Derriford, in particular Mr Booth and Mr Waqar who helped with patient recruitment. Furthermore I would like to thank all of the wonderful patients and participants who gave up their time to make this research possible. To all of my friends and colleagues in FF01, thank you for making work in the office so enjoyable and being there for both support and the occasional well needed distraction. I would also like to thank Dr Steve Shaw for his statistical support. I want to say thank you to my family for all of their encouragement, especially in these last few months. A big thank you also goes to my partner in crime, Ricky, for keeping me sane and being so supportive throughout this journey. 2 Author's Declaration At no time during the registration for the degree of Doctor of Philosophy has the author been registered for any other University award without prior agreement of the Doctoral College Quality Sub-Committee. Work submitted for this research degree at the University of Plymouth has not formed part of any other degree either at the University of Plymouth or at another establishment. This study was financed with the aid of a studentship grant from the College of Optometrists. Presentations at conferences: Smewing L, White D, Artes P, Booth A, Mroczkowska S. Advanced glycation end-products as a marker of accelerated ageing in primary open angle glaucoma. Association for Research in Vision and Ophthalmology (ARVO). May 2018 Mroczkowska S, White D, Artes P, Booth A, Smewing L. The influence of tissue bound advanced glycation end-products on retinal vessel calibre. Association for Research in Vision and Ophthalmology (ARVO). May 2018 Smewing L, White D, Artes P, Mroczkowska S. The influence of advanced glycation end-products (AGEs) on retinal vessel calibre. Optometry Tomorrow. March 2018 Smewing L, White D, Artes P, Mroczkowska S. Design of a UK-specific Food Frequency Questionnaire for advanced glycation end products (AGE) BCOVS. September 2017 Smewing L, White D, Artes P, Mroczkowska S. The relevance of elevated tissue-bound levels of advanced glycation end products (AGEs) in early glaucoma patients. BCOVS. September 2016 Word count of main body of thesis: Signed: Date: 10.05.19 3 Abstract Advanced glycation end products as a biomarker for accelerated ocular ageing and glaucoma Leanne Smewing Advanced glycation end products (AGEs) have a large impact on the healthy ageing population and those diagnosed with pathology. Studies have linked AGEs to glaucomatous optic neuropathy, however there is little consensus on the role AGEs play in glaucoma development. Furthermore, it is known that diet is an exogenous source of AGEs, however it is not clear how dietary AGE (dAGE) influences tissue-bound levels in the body. The overarching theme of this thesis was to assess the impact of AGE level, measured both through diet and tissue- bound levels in the skin (skin autofluoresence, SAF), on retinal vessels and the cornea in healthy participants and patients diagnosed with ocular hypertension (OHT), early stage normal-tension glaucoma (NTG) and early stage primary open angle glaucoma (POAG). A UK-specific food frequency questionnaire (FFQ) was developed and found to reliable and valid. This newly designed FFQ was subsequently used throughout the thesis to measure dAGE. In healthy controls, the contribution of dAGE to tissue-bound AGE levels appeared to be minimal. The level of AGE taken in via diet was similar between healthy, OHT, NTG and POAG participants. Interestingly, tissue-bound AGE level (SAF) was found to be 16% higher in NTG and 14% higher in POAG than healthy control participants. Adding to the 4 evidence that SAF, as an accessible measure, may be a suitable long-term biomarker of glaucoma. Higher SAF was associated with narrower retinal arteries (CRAE) in a healthy population, adding to the evidence that AGEs may be an accessible marker of vascular health. The NTG group had a significantly narrower CRAE than healthy controls as well as the highest SAF level. Increased SAF was also associated with a less viscoelastic, stiffer cornea in the NTG group only. These findings pose interesting questions about the possible association of SAF with ocular rigidity and subsequent increased susceptibility to IOP or arterial blood supply related injury, however larger scale studies are needed before any conclusions could be drawn. 5 Contents Acknowledgements ..................................................................................................... 2 Author’s Declaration .................................................................................................... 3 Abstract ....................................................................................................................... 4 List of figures ............................................................................................................. 12 List of tables .............................................................................................................. 14 Abbreviations ............................................................................................................ 16 1. Introduction ........................................................................................................ 18 1.1 Accelerated ageing ............................................................................................ 18 1.2 Advanced glycation end products (AGEs) ......................................................... 19 1.3 Formation of AGEs ............................................................................................ 20 1.4 Dietary AGE ....................................................................................................... 24 1.5 Effect of AGEs on cells and tissues ................................................................... 28 1.5.1 AGE – RAGE binding mechanism .................................................................. 28 1.5.2 RAGE independent mechanism ...................................................................... 30 1.5.3 Soluble RAGE ................................................................................................. 31 1.6 Oxidative stress ................................................................................................. 32 1.7 AGE and Oxidative stress relationship .............................................................. 35 1.8 Endothelial function ............................................................................................ 36 1.9 Relationship between AGEs and endothelial function ....................................... 37 1.10 Advancing age as a risk factor for ocular disease............................................ 39 1.11 The effect of advancing age and AGEs on ocular structures ........................... 40 1.11.1 Sclera ............................................................................................................ 40 1.11.2 Cornea .......................................................................................................... 41 1.11.3 Trabecular meshwork ................................................................................... 42 1.11.4 Ciliary body ................................................................................................... 42 1.11.5 Intraocular Lens ............................................................................................ 43 1.11.6 Vitreous ......................................................................................................... 43 1.11.7 Retina ............................................................................................................ 44 1.11.8 RPE & Bruch’s membrane ............................................................................ 45 1.11.9 Choroid ........................................................................................................
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