 So the two speakers that we have today have joined the Moran recently, Monica joined last year and Stefan started working with us this year. First speaker will be Monica Fleckenstein, who was originally Professor at the Department of Ophthalmology at the University of Bonn, where she also had the clinical trial center. She's an MD PhD and she's through her work has been involved in many clinical trial. She's made several major contributions to AMD research and probably she's probably the most known for her contribution to understanding phenotypes associated with geographic atrophy. She's won, well, many awards. And she moved to Utah primarily to lead the dream study, which is a prospective study designed to understand the natural history of AMD better. So we'll look forward to hearing from you. Thank you, Musa. Good morning, everyone. So our main headline today for both of us is AMD Revisited. And I would like to show you some other phases of AMD. These are my financial disclosures. I would like to start with the familiar phases of AMD. So we all know the different manifestation early intermediate AMD that is characterized by drusen, by hyperpigmentation on all CT. We see dome-shaped elevations. We see hyperreflective foci associated or correlating with hyperpigmentation changes. We know the late stages, coronary vascularization and geographic atrophy. Coroidal neovascularization, as we know it, or how is the common opinion, is that we have exudative corroidal neovascularization. The exudation is visible in intraretinal or subretinal fluid. We see from time to time hemorrhages in the fundus. And this is an angiography where you see this corroidal neovascularization. Angiographic atrophy is characterized by loss of the outer retinal layers on OCT. And fundoscopically, we see a lesion where the corroidal vessels shine through. And this is mainly hyperpigmented. And with fundosortrescence imaging, these lesions can be really nice, delineated. So fundosortrescence imaging allows for visualization of fluorophores, and these are mainly located in the RPE. And if there's loss of RPE, we have a decreased fundosortrescence signal. This is why fundosortrescence imaging is used in the diagnostics of geographic atrophy. I'm still fascinated by the different phases of geographic atrophy, visualized by fundosortrescence imaging. And fascinating about this is this high degree of symmetry between the right and the left eye in patients, not only of the shape of the lesion, also of this pattern surrounding the atrophic lesions. But it's also fascinating that we have a large variety of different phenotypes in geographic atrophy. And if we take a closer look, we see that some patients share the same phenotypic manifestation, like these, for example, or these two patients. Usually we say geographic atrophy or the dry late stage of A and B is slowly progressive. But I would like to highlight here that these different phenotypes behave differently in regard of the disease causes. So we have phenotypes that progress quite slowly, but we also have phenotypes with an aggressive progression. And I would like to draw your attention in the next minutes to this really aggressively progressing form of geographic atrophy, which is called trickling geographic atrophy. So what are the characteristics of this trickling geographic atrophy? As mentioned before, we have an extremely fast disease progression. I think the mic is not working anymore. And characteristic is also that we have this lobular configuration of the atrophic lesion as compared to non-trickling geographic atrophy. On OCT imaging, there is a striking finding in these patients. We have a so-called splitting of the N4 in OCT, coming back to OCT and trickling. So the striking finding of this splitting. So there's obviously material in between Buc's membrane and the RPE, and maybe this is related to this extremely fast progression of this phenotype. And compared to other non-trickling geographic atrophy, you see here an irregular border, but you do not see the splitting of this band 4 that is obvious in this phenotype. Another interesting finding in this phenotype is that the coroid is significantly thinner as compared to other GA phenotypes. So these are two examples here. You see I lighted the coroid. And this is an analysis with several patients with trickling and non-trickling geographic atrophy. And you see there is a significant difference in coroidal thickness. And if you compare both groups to control eyes or eyes without AMD, you also see a significant difference in coroidal thickness. So obviously, this phenotype goes along with a rarefication or a thinning of the coroidal esculature. What we saw additionally in these patients was that they are younger when they present the first time. And so their age of onset appears to be younger than other geographic atrophy patients. And of course, we talked to our patients. We asked them about comorbidities. And we realized that there was a weird change in the proportion of male when we looked at different ages of these patients. And this is highlighted in this graph. So these are these trickling geographic atrophy patients with an age younger than 65. And we had more than 50% male in this age group. When we looked at the older trickling patients, we had a significant decrease in the male proportion. So when we compared it to other geographic atrophy patients, where the proportion of male was about 40%, there was this significant shift in the male proportion with age. And when we again thought about what the patients told us, we realized that there was an interesting finding. And this was that more than 50% of these patients told us that they had already been hospitalized due to cardiovascular diseases when they were younger than 65 years. And man actually told us that more than one-third of the male patients told us that they already had myocardial infarction in the ages younger than 65. So taking these findings all together, we speculate or we hypothesize that this significant decrease in the male proportion with age in this specific phenotype is due to an increased mortality in men. And that this is a degenerative retinal disease that is mainly caused by vascular changes so that there's a primary vascular pathogenesis. With any application of OCT angiography, and these are preliminary findings, this examination actually underscored this hypothesis. When we take a closer look to OCT-A, so these are slabs at the level of the coroid, we see in this trickling a phenotype, a rarefication of the coroidal structure as compared to other geographic atrophy. So this is within the geographic atrophy lesion, but this is also a rarefication outside the atrophic lesion that you do not see that obvious in other GA phenotypes. Now I would like to come to another type of vascularization, not the original coroidal vascularization, but the coroidal new vascularization. And I would like to share with you the images of this patient. So on OCT, we see a separation between Buc's membrane and the RPE, and we see some sub-retinal fluid. On funnasal fluorescence imaging, we see some areas with geographic atrophy, and on funnasal fluorescence angiography, we see window defects in these areas of geographic atrophy, and after almost five minutes, there is not really an obvious exudation or leakage in this patient. We may see some staining, maybe a little bit of leakage, but it's not really obvious. So this patient appears to have a non- or minimally exudative form of coroidal new vascularization. By application of OCT angiography, we can actually detect this coroidal new vascularization that is obviously non-leaky or only minimally leaky. Actually two years ago, I treated this patient with anti-vegeta therapy, and we see a decrease in the sub-retinal fluid here. To be honest, today I may wait with treatment because we learned that first, sub-retinal fluid might be not that harmful in AMD, and secondly, we also see that this sub-retinal fluid may disappear without any treatment. But there was successful reaction after treatment, and actually this was the only treatment in this patient, and we followed up on this patient for many years without any recurrence of exudation. This is another patient. On OCT, again, we see a lesion at the level of Brooks Membrane and RPE. The color fundless image does not show any significant changes. On fluorescent angiography, we see a stippled change, and ICGA shows a lesion, but it's also not really clear what is going on in this area. And again, by application of OCT angiography, and this is colored, actually, this small lesion, we can detect a small coroidal neovascularization. Obviously, this is, again, not exudative. We didn't treat this patient, and this is the follow-up of this patient over seven months, and it becomes obvious baseline one month, four months, seven months. This lesion is not harmful, it's silent or quiet, how these CNB lesions are called today, actually. Another patient. We saw her for many, many years, and these are the images of 2019. And again, you see this lesion, or this is also called a double-layer sign, so you see Brooks membrane and the RPE on top of it. FAA, again, does not really show us leakage on ICGA. We get an impression that there is a lesion, but again, OCTA is really nicely demonstrating us that this actually is a coroidal neovascularization, but again, without exudative activity. And going back in the history of this patient, so we saw her for many, many years, this is 2015. We didn't have OCTA in this time. This is 2013. This is 2011. So obviously, these lesions are there. They do not really change. She's from a family with sisters and cousins with severe AMD and she was the one not progressing her vision, was in 2019, still 2020, and she was never treated in this eye. Now I would like to come back to geographic atrophy. And this is actually a cause of GA that we know or that is familiar. We see a progression of these atrophic lesions over time. Of six years, we see a marked progression of this atrophic lesion. This is a patient also with a tiny area of geographic atrophy and this is also a follow-up of six years. And interestingly, this lesion did not really progress over all of this time. And the question, of course, is what is the difference here? Why is this patient this area and this second patient not progressing? And here, again, you see this double-layer sign and by OCT and geography, you can detect beneath this area of geographic atrophy that there's, again, a non-executive coroidal neurovascularization. And taking these observations all together, we had the hypothesis that non-executive A and D may or is a strong prognostic marker for a decreased geographic atrophy progression. And we asked the question, is this type of C and V maybe protective and protects and saves the RPE and photoreceptors? And to analyze this more systematically, we performed an analysis in the context of the prospective NTSGA study and we included 98 eyes of 59 patients. 81 of these patients had pure geographic atrophy. Seven of these eyes had geographic atrophy and treatment naive non-executive C and V. And 10 eyes had RPE atrophy with a history of exudative C and V. So this means these were patients that had minimally active C and V and had been treated in the past. We had a follow-up time only of 1.17 years. We performed multimodal imaging in these patients including OCTA. And our primary outcome was the odds-racia for reduced geographic atrophy progression in presence of occult or type I C and V. So these are the C and V lesions located between the, between Brooks member and NDRP. And these are two patients I would like to show you. And so actually we also included historical data in these patients. So we went back in the history of these patients and looked at the images before the era of OCTA imaging. So this is the one patient I showed you before. So we have this smaller trophic lesion here. This is fluorescent angiography in 2011. We have a double layer sign here and we try to delineate what we would think there was already a C and V lesion. And this is actually seven years later. Again, the atrophic lesion did not progress and on OCTA we clearly saw there is a non-exudative C and V lesion and again here you have this double layer sign. So we suspect that this lesion was already there seven years before and that this maybe had protected the RPE and for the receptors in regard of degenerative changes. This is another patient. You see a smaller trophic lesion here in 2014 and we again try to delineate what we thought was the area where C and V was already presented this year. You can see a double layer sign here so splitting between the Brooks membrane and RPE. And in 2018 there was progression of this atrophic lesion but when you delineate in OCTA the area of C and V you see that it's more in this area here the direction of the spread of GA was more pronounced in the opposite direction and that the spread of atrophy in the direction of the C and V lesion was lower. Herein I would like to highlight how we did the analysis. So this is again a patient with a formal sparing actually and with a C and V lesion exactly beneath this formal sparing and what we did here and actually I would like to mention Maximium Faur who did the heavy lifting in this analysis at baseline we delineated the C and V lesion and then we analyzed the spread of geographic atrophy in the future. So this was the prospective part of this study and so in this patient and this is an autogonal representation of the spread of geographic atrophy we see in the area of the C and V lesion there was only minimal spread of the geographic atrophy lesion. So taking these observations together and maintaining together all the results of our analysis we showed or we could see that there is reduced probability of GA progression in presence of non-executive C and V alteration of 0.21 and also in the presence of executive occult C and V there was also a reduced probability of GA progression and so this raises again the question and this hypothesis is not new and this is the revisited part this head brought forward decades ago I mentioned Dink Green, the Saks, Haere, C and V evolution maybe or there is obviously a protective mechanism to save RPE and for the receptors maybe not in all types of C and V but I think this is a piece in AMD that needs to be further investigated and I would like to summarize the first part of the grand rounds differential clinical appearance and disease course may help to identify distinct AMD manifestations or let's see other AMD phases we saw the trickling AMD phenotype with an extremely rapid GA progression and there is rarefication of the caroid vasculature in this phenotype and the question is, is there maybe a generalized vascular deficiency in these patients given this high comorbidity of cardiovascular diseases and on the other side, another phase the non or minimally exodative scene with a decreased AMD progression and maybe there is a protective mechanism to save RPE and for the receptor and this is actually what we would like to focus on in the next years and we really hope to collaborate with all of you on this in general the role of vasculation in AMD progression I thank you for your attention I love it, it's fascinating two questions that come to mind and in regards to the non minimally exodated C and V so obviously many people would treat that and so do we have enough data to suggest if you do treat it and eliminate that then do you increase the risk of do we have evidence to show that you do increase the risk that this GA is going to increase more rapidly so you eliminate the protection is it going to get worse which would, the hypothesis would suggest that that had to be the case do we have evidence for that yet? so this is one of the main questions of course and Paul are you aware you really have evidence if we would increase GA progression so there's data out they show there's no increased GA progression when you treat it hard but there's also data out that shows there's an increased progression I don't know Paul, what do you think? it's controversial still I would just kind of wonder in thinking about this is there a difference in response are these kind of subclinical ones are they more resistant to anti-vegeta than the active lesions that we're seeing I don't know but it's a question that certainly has to be answered I mean obviously it's protective if you want to leave it alone and that's not been the general mindset the other one is so we're looking at phenotypes genotypes is fascinating is the trickling more commonly associated with homozygous risk of chromosome 10 or do we know that yet? so of course we started analyzing this we would have expected that it's more associated because it shares these phenotypic findings but in this patient group that we analyzed we didn't see a strong effect yet but the numbers were quite small they were small enough but it was not obvious this is almost a pathodermonic sign of homozygous chromosome 10 you definitely saw both 1 and 10 so we saw that arms 2 the organisms were more common in this phenotype but it was not a really strong finding that we would have expected so this trickling phenotype compared to other GAs showed differential AMD risk score so there is something different and actually maybe you saw it I put quotation marks on trickling AMD because you know what is AMD I'm not sure if you should call it AMD maybe it's more a syndrome yeah so there's many more to study that's fascinating though this is a great word thank you thank you yeah Paul very quick question as you know with geographic apathy there are now trials where we're doing anti complement inhibitors in there we're actually increasing the neovascularization do you have any thoughts? yeah see through that yeah so through that fascinating C5 so there's the discussion out that maybe by inducing so in this Philly trial phase 3 is right now running in the phase 2 trial there was a significant increase in GA progression in the treatment group but there was also a significant increase in V lesions and so there is one hypothesis that maybe by this compound CNV was increased or the evolution of CNV was increased in this treatment group and maybe this protected from faster GA progression but I think we still need to see what's coming out so I know that there was an analysis of retrospective analysis done and obviously some saw already at baseline CNV lesions in this treatment group so it's an interesting hypothesis but I think we still need to learn more about this