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Det er en progredierende nethindesygdom som gradvist f\u00f8rer til \u00f8del\u00e6ggelse af de celler som er ansvarlige for vores centralsyn. De tidlige stadier er ofte asymptomatiske, imens senstadie AMD, som opdeles i to former, neovaskul\u00e6r AMD (nAMD) og geografisk atrofi (GA), begge udviser gradvist synstab, dog generelt med forskellig hastighed. Tidlig AMD er karakteriseret ved tilstedev\u00e6relsen af druser og pigmentforandringer i nethinden mens nAMD og GA udviser henholdsvis karnydannelse i og atrofi af nethinden. \u00c6tiologien er multifaktoriel og udover alder omfatter patogenesen milj\u00f8\u2010 og genetiske risikofaktorer. Forskning har specielt fokuseret p\u00e5 lokale forandringer i \u00f8jet hvor man har fundet at inflammation spiller en betydelig rolle for udviklingen af sygdommen, men flere studier tyder ogs\u00e5 p\u00e5 at systemiske forandringer og specielt systemisk inflammation spiller en v\u00e6sentlig rolle i patogenesen.<\/jats:p><jats:p>De Philadelphia\u2010negative myeloproliferative neoplasier (MPNs) er en gruppe af h\u00e6matologiske kr\u00e6ftsygdomme med en erhvervet genetisk defekt i den tidlige pluripotente stamcelle som medf\u00f8rer en overproduktion af en eller flere af blodets modne celler. Sygdommene er fundet at udvikle sig i et biologisk kontinuum fra tidligt cancerstadie, essentiel trombocytose (ET) over polycyt\u00e6mi vera (PV) og endelig til det sene myelofibrose stadie (PMF). Symptomer hos disse patienter skyldes is\u00e6r den \u00e6ndrede sammens\u00e6tning af blodet, hyperviskositet, kompromitteret mikrocirkulation og nedsat v\u00e6vsgennembl\u00f8dning. Den \u00f8gede morbiditet og mortalitet beror i h\u00f8j grad p\u00e5 tromboembolier, bl\u00f8dninger og leukemisk transformation. En r\u00e6kke mutationer som driver MPN sygdommene er identificeret, bl.a. <jats:italic>JAK2V617F<\/jats:italic>\u2010mutationen som medf\u00f8rer en deregulering JAK\/STAT signalvejen, der bl.a. har betydning for cellers v\u00e6kst og overlevelse. Et tidligere stort registerstudie har vist at patienter med MPNs har en \u00f8get risiko for neovaskul\u00e6r AMD og et pilotstudie har vist \u00f8get forekomst af intermedi\u00e6r AMD. Dette \u00f8nsker vi at unders\u00f8ge n\u00e6rmere i et st\u00f8rre studie i dette Ph.d.\u2010 projekt. Flere studier har ogs\u00e5 vist at kronisk inflammation spiller en vigtig rolle for b\u00e5de initiering og udvikling af den maligne celleklon hos MPNs og herfra er en \u201cHuman Inflammationsmodel\u201d blevet udviklet. Siden er MPN sygdommene blevet anvendt som \u201cmodel sygdomme\u201d for en tilsvarende inflammationsmodel for udvikling af Alzheimers sygdom. I dette Ph.d.\u2010projekt vil vi tilsvarende fors\u00f8ge at unders\u00f8ge systemisk inflammation i forhold til forekomst af druser. Det vil vi g\u00f8re ved at sammenligne systemiske immunologiske mark\u00f8rer som tidligere er unders\u00f8gt hos patienter med AMD og sammenligne med MPN. Specielt er vi interesseret i systemiske immunologiske forskelle p\u00e5 patienter med MPN og druser (MPNd) og MPN med normale nethinder (MPNn).<\/jats:p><jats:p>Denne afhandling best\u00e5r af to overordnede studier. I Studie I, unders\u00f8gte vi forekomsten af retinale forandringer associeret med AMD hos 200 patienter med MPN (artikel I). Studie II, omhandlede immunologiske ligheder ved AMD og MPN, og var opdelt i yderligere tre delstudier hvor vi unders\u00f8gte hhv. systemiske mark\u00f8rer for inflammation, aldring og angiogenese (artikel II, III og IV). Vi unders\u00f8gte mark\u00f8rerne i fire typer af patienter: nAMD, intermedi\u00e6r AMD (iAMD), MPNd og MPNn. Unders\u00f8gelsen af forskelle mellem MPNd og MPNn, vil g\u00f8re det muligt at identificere forandringer i immunsystemet som kunne v\u00e6re relevante for AMD\u2010patogenesen. Vi vil endvidere sammenholde resultaterne for patienter med MPN med patienter som har iAMD og nAMD.<\/jats:p><jats:p>I studie I (Artikel I) fandt vi at patienter med MPN har en signifikant h\u00f8jere pr\u00e6valens af store druser og AMD tidligere i livet sammenlignet med estimater fra tre store befolkningsunders\u00f8gelser. Vi fandt ogs\u00e5 at forekomst af druser var associeret med h\u00f8jere neutrofil\u2010lymfocyt ratio, hvilket indikerer et h\u00f8jere niveau af kronisk inflammation i patienterne med druser sammenlignet med dem uden druser.<\/jats:p><jats:p>I studie II (Artikel II, III og IV) fandt vi flere immunologiske forskelle mellem patienter med MPNd og MPNn. Da vi unders\u00f8gte mark\u00f8rer for inflammation, fandt vi en h\u00f8jere grad af systemisk inflammation i MPNd end MPNn. Dette blev vist ved en h\u00f8jere inflammationsscore (udregnet p\u00e5 baggrund af niveauer af pro\u2010inflammatoriske mark\u00f8rer), en h\u00f8jere neutrofil\u2010lymfocyt ratio, samt indikationer p\u00e5 et dereguleret komplementsystem. Ved unders\u00f8gelse af aldringsmark\u00f8rer fandt vi tegn p\u00e5 accelereret immunaldring hos MPNd i forhold til MPNn, hvilket kommer til udtryk ved en st\u00f8rre procentdel af \u201ceffector memory T celler\u201d. Endelig fandt vi en v\u00e6sentlig lavere ekspression af CXCR3 p\u00e5 T celler og monocytter hos patienter med nAMD sammenlignet med iAMD, MPNd og MPNn. Dette er i overensstemmelse med tidligere studier hvor CXCR3 ekspression er fundet lavere end hos raske kontroller. Derudover fandt vi en faldende CXCR3 ekspression p\u00e5 monocytter over det biologiske MPN\u2010kontinuum. Disse studier indikerer en involvering af CXCR3 i b\u00e5de nAMD og PMF, begge sygdomsstadier som er karakteriseret ved angiogenese og fibrose.<\/jats:p><jats:p>Ud fra resultaterne af denne afhandling kan vi konkludere at forekomsten af druser og AMD hos MPN er \u00f8get i forhold til baggrundsbefolkningen. Endvidere viser vores resultater at systemisk inflammation muligvis spiller en v\u00e6sentlig st\u00f8rre rolle i udviklingen af AMD end tidligere antaget. Vi foresl\u00e5r derfor en AMD\u2010model (Figur 18) hvor inflammation kan initiere og accelerere den normale aldersafh\u00e6ngige akkumulation af affaldsstoffer i nethinden, som senere udvikler sig til druser, medf\u00f8rende \u00f8get lokal inflammation og med tiden tidlig og intermedi\u00e6r AMD. Dette resulterer i den \u00f8gede risiko for udvikling til de invaliderende senstadier af AMD.<\/jats:p><\/jats:sec><jats:sec><jats:title>English summary<\/jats:title><jats:p>Age\u2010related macular degeneration (AMD) is the most common cause of irreversible vision loss and blindness in high\u2010income countries. It is a progressive retinal disease leading to damage of the cells responsible for central vision. The early stages of the disease are often asymptomatic, while late\u2010stage AMD, which is divided into two entities, neovascular AMD and geographic atrophy (GA), both show vision loss, though generally with different progression rates. Drusen and pigmentary abnormalities in the retina characterise early AMD, while nAMD and GA show angiogenesis in and atrophy of the retina, respectively. The aetiology is multifactorial and, in addition to ageing, which is the most significant risk factor for developing AMD, environmental\u2010 and genetic risk factors are implicated in the pathogenesis. Research has focused on local changes in the eye where inflammation has been found to play an essential role, but studies also point to systemic alterations and especially systemic inflammation to be involved in the pathogenesis.<\/jats:p><jats:p>The Philadelphia\u2010negative myeloproliferative neoplasms (MPN) are a group of haematological cancers with an acquired genetic defect of the pluripotent haematopoietic stem cell, characterised by excess haematopoiesis of the myeloid cell lineage. The diseases have been found to evolve in a biological continuum from early cancer state, essential thrombocythemia, over polycythaemia vera (PV), to the advanced myelofibrosis stage (PMF). The symptoms in these patients are often a result of the changes in the blood composition, hyperviscosity, microvascular disturbances, and reduced tissue perfusion. The major causes of morbidity and mortality are thromboembolic\u2010 and haemorrhagic events, and leukemic transformation. A group of mutations that drive the MPNs has been identified, e.g., the <jats:italic>JAK2V617F<\/jats:italic> mutation, which results in deregulation of the JAK\/STAT signal transduction pathway important, for instance, in cell differentiation and survival. A previous large register study has shown that patients with MPNs have an increased risk of neovascular AMD, and a pilot study has shown an increased prevalence of intermediate AMD. We wish to study this further in a larger scale study. Several studies have also shown that systemic inflammation plays an essential role in both the initiation and progression of the malignant cell clone in MPNs. From this knowledge, a \u201cHuman inflammation model\u201d has been developed. Since then, the MPNs has been used as model diseases for a similar inflammation model for the development of Alzheimer's disease. In this PhD project, we would like to investigate systemic inflammation in relation to drusen presence. We will do this by comparing systemic immunological markers previously investigated in patients with AMD and compare with MPN. We are primarily interested in systemic immunological differences between patients with MPN and drusen (MPNd) and MPN with normal retinas (MPNn).<\/jats:p><jats:p>This thesis consists of two main studies. Study I investigated the prevalence of retinal changes associated with AMD and the prevalence of different AMD stages in 200 patients with MPN (paper I). Study II examined immunological similarities between AMD and MPNs. This study was divided into three substudies exploring systemic markers of inflammation, ageing and angiogenesis, respectively. This was done in four types of patients: nAMD, intermediate AMD (iAMD), MPNd and MPNn. Investigating, differences between MPNd and MPNn, will make it possible to identify changes in the immune system, relevant for AMD pathogenesis. Additionally, we will compare patients with MPNs with patients with iAMD and nAMD.<\/jats:p><jats:p>In study I (Paper I), we found that patients with MPNs have a significantly higher prevalence of large drusen and consequently AMD from an earlier age compared to the estimates from three large population\u2010based studies. We also found that drusen prevalence was associated with a higher neutrophil\u2010to\u2010lymphocyte ratio indicating a higher level of chronic low\u2010grade inflammation in patients with drusen compared to those without drusen.<\/jats:p><jats:p>In study II (papers II, III and IV), we found immunological differences between patients with MPNd and MPNn. When we investigated markers of inflammation, we found a higher level of systemic inflammation in MPNd than MPNn. This was indicated by a higher inflammation score (based on levels of pro\u2010inflammatory markers), a higher neutrophil\u2010to\u2010lymphocyte ratio, and indications of a deregulated complement system. When examining markers of ageing, we found signs of accelerated immune ageing in MPNd compared to MPNn, shown by more senescent effector memory T cells.<\/jats:p><jats:p>Finally, when exploring a marker of angiogenesis, we found a lower CXCR3 expression on monocytes and T cells in nAMD compared to iAMD, MPNd and MPNn, in line with previous studies of nAMD compared to healthy controls. Further, we found decreasing CXCR3 expression over the MPN biological continuum. These studies indicate CXCR3 involvement in both nAMD and PMF, two disease stages characterised by angiogenesis and fibrosis.<\/jats:p><jats:p>From the results of this PhD project, we can conclude that the prevalence of drusen and AMD is increased in patients with MPN compared to the general population. Further, our results show that systemic inflammation may play a far more essential role in AMD pathogenesis than previously anticipated. We, therefore, propose an AMD model (Figure\u00a018) where inflammation can initiate and accelerate the normal age\u2010dependent accumulation of debris in the retina, which later evolve into drusen, resulting in increased local inflammation, and over time early\u2010 and intermediate AMD. This results in the increased risk of developing the late debilitating stages of AMD.<\/jats:p><\/jats:sec>","DOI":"10.1111\/aos.15247","type":"journal-article","created":{"date-parts":[[2022,10,6]],"date-time":"2022-10-06T07:07:09Z","timestamp":1665040029000},"page":"3-35","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Age\u2010related macular degeneration and myeloproliferative neoplasms \u2013 A common pathway"],"prefix":"10.1111","volume":"100","author":[{"given":"Charlotte","family":"Liisborg","sequence":"first","affiliation":[{"name":"Department of Ophthalmology Zealand University Hospital  Roskilde 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