RBD, Past, Present, Future, sponsored by the American Academy of Sleep Medicine, and co-sponsored by the Inter-Society Collaboration Presidential Committee of the AASM and the International RBD Study Group. My name is Alex Fidenovich, and I will be moderating today's webinar. This is actually part two of a two-part series where we will focus on the associations between REM behavior disorder and neurodegeneration, and highlight the significance of the RBD population for upcoming clinical trials, aiming to slow the progression of neurodegenerative disorders associated with REM behavior disorder. The first webinar in this series actually happened on May 4th and was greatly attended, and we are delighted that we have a large pool of attendees worldwide that have registered for this series, and we certainly hope to do more of these in the future. As I said, I'll be moderating today's webinar, and I will be introducing speakers in a bit, but at this time, I just want to take a few minutes to discuss the format of today's webinar. Today's hour will consist of three 15-minutes pre-recorded talks. If you have any questions, please type them in the chat, and we will have a live Q&A session at the end of the webinar, which will last about 10 to 15 minutes, and we'll certainly have an opportunity to answer many of your questions. Both webinars will be recorded, and if you pre-registered, you will receive a link to the recording within a few days, and webinars will be released on demand free of charge at the end of this month. So, without further ado, I would like to introduce our first speaker for the day. Dr. Ronald Postuma is a professor of neurology at McGill University. He is a movement disorder specialist with a research interest mainly centered around non-motor aspects of Parkinson's disease, emphasis of his work is on early detection of Parkinson's disease diagnosis and treatment of sleep disorders, including REM behavior disorder, as well as diagnostic criteria for Parkinson's disease and clinical trials in early stages of Parkinson's disease. Dr. Postuma will Dr. Postuma will speak today about REM behavior disorder and associated synuclein-specific neurodegenerative disorders. Hi everyone, I'm Ron Postuma from McGill University. I'm going to talk to you now, you've heard a lot about diagnosis of RBD and maybe treatment of RBD, the practical aspects from the sleep, and now we're going to cycle into more the implications of RBD for the rest of neurology and neurodegenerative disease in particular. And I'm going to talk specifically about the role of synuclein. And so the central point is that RBD is a very important window into other neurodegenerative diseases. And I'm going to dial down on how it helps us in the diagnosis of neurodegenerative synucleinopathies, how it's actually a very important prognostic marker, and it also is a predictive marker, which Dr. Stefani will talk about later. So first of all, let's just go over just for those of you who aren't aware, what are the synucleinopathies? So the synucleinopathies, essentially there's three conditions and two of them are relatively common, Parkinson's disease and dementia with Lewy bodies. These are both considered Lewy body disorders because they have Lewy bodies that are deposited in the brain. These are highly overlapping conditions and is now the feeling of most that they should not be considered mutually exclusive. So just you can have Parkinson's disease and dementia with Lewy bodies at the same time, just as you could have RBD and Parkinson's at the same time or constipation and dementia with Lewy bodies at the same time. Slightly different, but also a synucleinopathy is multiple system atrophy in which the synuclein is deposited, but not in Lewy bodies. This is much less common than the other conditions. So that's what we're talking about here. Now, the first point I'm going to make is RBD is actually a very useful diagnostic marker. And before I make that point, I do want to emphasize that RBD can exist in non-synuclein diseases. Here are some examples. This is a perfectly located stroke, just hitting the areas that are involved in generation of REM paralysis. This is a case of limbic encephalitis that we're seeing here with general inflammation of the brainstem, presumably therefore affecting those same areas. There are antibody mediated diseases, very commonly Iglon 5, which is one that's associated with tauopathy on autopsy, but is also associated with RBD. So it can happen in non-synuclein diseases, but it almost never does, practically speaking, in terms of numbers. And so let me just illustrate that. This is in Parkinsonism. So this is a comparison done by the Mayo Clinic. And what we're looking at here is polysomnograph data on patients who have a clinical diagnosis of synucleinopathy, tauopathy, and controls. And we see the percent of muscle activity on the, in other words, a loss of rematonia. And what you can see is a very dramatic difference between synucleinopathies and tauopathies. And if you cut it off at the right level, you can essentially get 100% specificity. In other words, if it's above a certain threshold, you can diagnose synucleinopathy almost 100% of the time. The sensitivity is not 100%. So there are definitely patients with Parkinson's disease, for example, who do not have REM sleep behavior disorder. And we're going to come back to that in a minute. The predictive value is even better in dementia. This is, again, the Mayo Clinic study documenting a very similar phenomenon here. This is not quite the same sort of plot, but these are non-synucleinopathy dementias, and these are synucleinopathy, in other words, dementia with Lewy bodies. Sensitivity 75%, specificity 92%. Of course, this is clinical diagnosis. The clinical diagnosis can be incorrect. Bradley Bove published this very interesting study of a large number of patients in a pathological series, and these were essentially patients who had neurodegenerative disease and had, at the same time, REM sleep behavior disorder. And of those who were polysomnographic proven REM sleep behavior disorder, 98% of those patients had synuclein in their brain. Now, if you think about the entire universe of all the neurological diseases, neurodegenerative diseases out there, tauopathies, Alzheimer's disease, Huntington's disease, et cetera, et cetera, et cetera, the fact that 98% of them had proven synuclein is quite notable diagnostically. And as a result, this has actually made it into the new diagnostic criteria. So under the new dementia with Lewy bodies criteria, if you have polysomnographic proven REM sleep behavior disorder, that is sufficient in and of itself to make the diagnosis of dementia with Lewy bodies. So what helps us in diagnosis, REM sleep behavior disorder is also very useful for predicting prognosis. And I'm going to show this initially with Parkinson's disease. This is the first clue that there was something different about Parkinson's patients with REM sleep behavior disorder. This was, I guess, about 12 years ago now, a cross-sectional study looking at the prevalence of mild cognitive impairment. So here we have the isolated idiopathic REM sleep behavior disorder patients, and here we have controls, and here are Parkinson's patients. Those with RBD had about 70%, or a little bit more, a prevalence of MCI compared to PD patients without RBD who looked indistinguishable from controls. These patients were then followed up, and four and a half years later, those who had REM sleep behavior disorder at baseline, 48% of those developed dementia, but none of the RBD patients at that time ever developed dementia in that four-year period. In fact, a couple of years later, another patient of this group did develop dementia. He developed REM sleep behavior disorder and then developed dementia about a year afterwards. And this is a little bit straight about the fact that neurodegenerative diseases in general, and Parkinson's in particular, they're never one thing. There's always a lot of heterogeneity. And people have looked at this. This is one example that Sam Ferris-Tennish had, a fellow of mine did, looking at Parkinson's patients in a very large cohort study. You do these cluster analyses, which are essentially machine learning types of algorithms to divide patients into groups. The result of a cluster analysis is kind of a cloud. So then what we did, which you can't really work with very easily, but then what we did is we looked at the manifestations of Parkinson's, and then we translated that into individual rules. So now you can take patient X and say, you are this subtype, patient Y is this subtype, et cetera. And then we looked at the prognosis. And what we found was most notably, there was a subset of about 15% of patients who have what's called a diffuse form of Parkinson's disease. And what defines this diffuse form of Parkinson's disease is orthostatic hypotension, MCI, a UPDRS above average, and most importantly, REM sleep behavior disorder. Then we look at what happens to these patients over time. What we can see is that these diffuse malignants, in other words, RBD patients, are worse on just about every measure that we can see and progress worse and remain worse over a four-year follow-up. And this has been confirmed in a very large pathological study by the Queensway Group, who found that people who have this diffuse malignant Parkinson's disease have an 11-fold increased risk of ending up in a wheelchair, being demented or institutionalized, and a three-and-a-half-fold increased risk of dying. And so this leads to a general rule in Parkinson's disease, is that if you want to predict how a patient is going to do, ignore their substantia nigra, ignore their dopamine system, and focus instead on the non-motor symptoms. And one of the best things to identify prognosis is REM sleep behavior disorder. So that's Parkinson's disease. We see the same thing in dementia with Lewy bodies. In DLV patients, the presence of RBD is associated with more Parkinsonism, more hallucinations. And so in other words, these patients look more classic DLV-like than those who do not. But they also then have a faster progression and an earlier mortality. So in all the neurodegenerative disease, the presence of RBD is a poor prognostic marker. The final point is that REM sleep behavior disorder is a strong predictor of Parkinson's disease. This is a 1,280 patient study, and these are idiopathic or isolated REM sleep behavior disorder patients who are being followed over time. And every time the line drops, another patient has developed a neurodegenerative disease. And what we've found is that about 50% of patients at 7 1⁄2 years and 75% of patients at 12 years have developed a neurodegenerative condition. They all get dementia with Lewy bodies or Parkinsonism, PD, or multiple system atrophy. This translates to about 6% to 7% per year. Those centers that follow more closely get a higher phenoconversion rate than those who follow less closely. So it might be 8, it might be 10. But the bottom line is that polysomnographic proven REM sleep behavior disorder is a sign of neurodegenerative synucleinopathy until proven otherwise. And Dr. Stefani is going to expand upon that last point in detail. So in summary, REM sleep behavior disorder helps us in diagnosis. It's a very strong sign of an underlying synuclein in the brain. It helps with prognosis. It's not a good prognostic sign in all of the neurodegenerative diseases. And it's a predictive window of disease. The strongest predictor, by the way, by far, there is nothing close to REM sleep behavior disorder in predictive value. And we'll hear more about that in the next section. Thank you very much. Our second speaker for the day is Dr. Ambra Stefani. Dr. Stefani is a neurologist at the Medical University of Innsbruck. She joined the Department of Neurology in Innsbruck in 2013, and has done a remarkable research in the sleep lab and sleep program directed by Professor Birgit Högl. Dr. Stefani's main research interests are centered on video polysomnographic characterization of motor phenomena during sleep, with an emphasis on REM sleep behavior disorder and restless-like syndrome. Dr. Stefani will present today about biomarkers of neurodegeneration within REM sleep behavior disorder. Hello, everyone. My name is Ambra Stefani from the Medical University of Innsbruck in Austria. And in the next 15 minutes, I will provide you an overview of biomarkers of neurodegeneration in isolated REM sleep behavior disorder. I have no conflict to disclose. As we heard before, we know that most of the patients with isolated REM sleep behavior disorder develop an overt alpha-synucleinopathy over time. And we also know from studies on longstanding patients with isolated RBD, which means who did not convert 10 years or more after the diagnosis of RBD, that also this patient presents markers of alpha-synuclein-related neurodegeneration. And therefore, we can say that RBD presents an underlying neurodegenerative process, and therefore, it's already an alpha-synucleinopathy. For this reason, isolated REM sleep behavior disorder represents a window of opportunity because we can use this condition to identify alpha-synuclein pathology in the early stages, to characterize alpha-synuclein pathologies in these early stages and also its progression over time, and also to identify different subtypes of RBD, which may have a different risk of short-term phenoconversion, but also different risk of phenoconversion to PD versus TLB versus MSA. How can we stratify this patient, or how can we use this window of opportunity? We can do this using biomarkers, and we can distinguish between markers of disease, which are also diagnostic biomarkers, markers of progression of disease, markers of short-term phenoconversion, and the markers of type of phenoconversion. And all these markers are overlapping, and if we consider biomarkers of disease in a very general way, all biomarkers are also biomarkers of disease. And I show you here different biomarkers that have been investigated in RBD, and so you see there is a long list, and now I would like to start to show you some biomarkers of disease, and I selected some which I consider particularly relevant. So I will start with some video polysomnography biomarkers of disease, and in particular with Ramsey without atonia, this is a good marker because it is always available, because it's part of the diagnostic workout and is needed for the diagnosis of RBD. There are cut-offs. This can be quantified, of course, so we have cut-offs. There are recommendations to use also the EMG of the upper extremities. Of course, the quantification is time-consuming, but there are also automatic methods available. The other aspect of video polysomnography is the video, and we know that complex movements are the typical one, are only a small proportion of all Raman-related movements, and most commonly we have, like you can see here, simple, distant, minor movements of the upper extremities usually. And in Parkinson's disease, seemingly pulse-forceful movements called Ramsey behavioral events have been proposed as a marker of neurodegeneration, and this could be used also in a patient with isolated Ramsey behavioral disorder. Of course, manual video analysis is really time-consuming, but promising automatic methods are under development. Other biomarkers of disease rely on the demonstration of the presence of pathologic alpha-synuclein, and two independent studies conducted, one in Germany, one in Italy, investigated skin-punch biopsies to analyze them with immunofluorescence with antibodies against phosphorylated alpha-synuclein, and could show a moderate to high sensitivity and very good specificity. Of course, this is quite invasive examination, requiring also a local anesthesia. A similar analysis to detect pathologic alpha-synuclein has been conducted in the CSF, and a recently published study show a very high sensitivity and specificity using ArticWik for alpha-synuclein in the CSF. Another recent study by our group used again alpha-synuclein ArticWik, but this time we thought about going to try to reach the brain through the nose, because if we go into the olfactory mucosa, we have the possibility to detect neurons in an easy way, and I would like to show you a short video. So you see it's done under anoscopy, the sampling, but it's very easy to perform. There are no side effects, no anesthesia is required, it's not contraindicated in patients under anticoagulants, and now you see after a few seconds it's done, and we have collected a million of a thousand of neurons that can be analyzed. And we could show a moderate sensitivity, but a good specificity to distinguish patients with alpha-synuclein against the controls. For what concerns biomarkers of progression of disease, we don't have so much that we can use, but an example is again REMS-seq without atonia, because it has been shown that isolated REMS-seq without atonia, without RBD, can even precede the REMS-seq behavior disorder, and is called then protoromal RBD, and increases over time. In subjects with isolated RBD also, the REMS-seq without atonia increases over time, and the same is true for patients with PD. So this is a good marker of progression. Another very good marker of progression, deriving from the neural imaging, is the DAT-spect, and it has been shown that there is a continuum in the tracer uptake loss from healthy controls to isolated RBD, isolated REMS-seq without atonia, isolated RBD, and Parkinson's disease, and also a study by the Barcelona group using serial DAT-spect showed a decline over time in the striatal tracer uptake, which is related to progressive neurostriatal dopaminergic dysfunction. Other biomarkers of progression include motor measures, and there are many that can be used, and the selected here is a complex motor measure, which is speech, because a recent multilingual study investigated 150 subjects with isolated RBD, and through a fully automated acoustic quantitative assessment for this outcome could show, could distinguish a patient with RBD and PD from healthy controls, and also at 12 months of follow-up, there was a slight progression of the overall acoustic speech impairment in both the subjects with isolated RBD and Parkinson's disease. So this is also a promising marker of progression. For what concerns the biomarkers of short-term phenocombustion, we have more options, and we can choose some and also we could also combine biomarker because this would increase the possibility to select patient at very high risk of short-term phenoconversion. Short-term, it depends on the studies, but it's usually two to five years. And I would like to show you here again some example, REMSY with aptatonia. It has been shown that the mixed activity, which means a simultaneous tonic and phasic, which means that tonic activity with superimposed phasic activity is predicting phenoconversion in a short time. Also, several studies with similar results show that the presence of a pathological aspect at baseline is also predicting short-term phenoconversion. And the same is true for olfactory dysfunction. This has been associated with a more than sevenfold risk of developing a levy body disease within five years of follow-up. So as the testing of olfactory dysfunction is quite easy and not invasive, one could think that maybe this subject, even without a PD, can be a good candidate for studies investigating prodromal Parkinson's disease. But a recent study by the Barcelona group showed that among subjects with idiopathic hyposmia, prodromal Parkinson's disease is very rare, is infrequent. So this olfactory dysfunction is always to be considered in the context of a PD. Also, recently, the same groups that investigated initially alpha-synuclein in skin biopsy put together their patient and provided follow-up data showing that around 22 percent converted to PD or DLB at follow-up, and none of the skin biopsy negative patients converted. So this is also a potential marker of conversion. The same is true for the demonstration of alpha-synuclein in the CSF. As you can see, starting from two years of follow-up up to 10 years, the presence of alpha-synuclein at baseline can distinguish patients at high, short-term risk of conversion. And also in our study investigating olfactory mucosa, we found the correlation between the positivity for alpha-synuclein at the week and the presence of olfactory dysfunction. And as I said before, olfactory dysfunction is a marker of short-term conversion. Of course, we need follow-up data, but this could also be a possible marker of short-term phenoconversion, more specific than olfactory dysfunction. Also, there are some markers that can indicate which type of phenoconversion is going to occur in this patient. And again, we have here the REMSUV with atatonia, because in isolated REMSUV, we saw that the severity of rematonia loss on baseline PSG is predicting the development of Parkinson's disease. This has been shown already 10 years ago. And also, we know that tonic and phasic hemangiactivity may have different significance. And the studies showed that the severe tonic and phasic hemangiactivity were associated with early development of PD and DLP, respectively. For what concerns neuroimaging, there is a recent study showing that also in subjects with isolated REMSUV disorder, conventional MRI, which is usually conducted at the time of the diagnosis to exclude the secondary causes of APD, can also show specific abnormalities of manifest MSA, like the hot cross band sign that we can see in the image below in the first one. And so, if you detect these abnormalities in isolated APD patient, this can predict conversion to MSA. Cognition is another very important aspect. And parabolic response, which is the recognition of a visual stimulus as a pattern, like the recognition of faces in object, like you can imagine in this image to see a face, parabolic responses have been associated with cognitive decline. And in APD, parabolic errors have been associated to poor cognitive function. So, this can represent a marker of phenoconversion to DLP. Autonomic function is another possible marker of phenoconversion, as severe baseline cardioviral autonomic dysfunction has been associated to phenoconversion to dementia with levy bodies, but not to Parkinson's disease. Also, recently, the Montreal Group investigated a combination of biomarkers, putting together neuroimaging and clinical variables, including cognitive and motor variables, and could find out the brain clinical signature of APD predicting conversion into more severe or dementic forms of synucleinopathy. So, concluding, as you saw, there is a very high number of possible biomarkers that can be used. REMSY with autotonia is, in my opinion, a very high potential because it's a marker of disease itself, it's a marker of progression, and it's also a marker of conversion, and it's always available as we need it for the diagnosis. Biomarkers have a different significance, so they can be used to demonstrate the presence of pathology, to monitor disease progression, to understand the temporal dynamics of alpha-synuclein deposition, and also to identify patients which are at high risk of short-term phenoconversion. And this is key for future neuroprotective trials, and we will hear more about this in the next talk by Professor Videnovic. So, I'm ending my presentation. I would like to thank you for your attention, and I will be happy to answer any question at the end of the session. I will be the final, the third speaker for today's webinar. My name is Alex Videnovic. I work at Massachusetts General Hospital in Boston, where I direct a division of sleep medicine and program on circadian biology, sleep, and neurodegeneration. My clinical interests cover a wide range of movement disorders and sleep disorders, and the emphasis of our group is on the intersection of sleep and neurodegeneration, or all of circadian biology in neurodegenerative disorders, and I do a lot of clinical trials in the space of movement disorders, specifically Parkinson's disease. We also have a clinical and research program centered on idiopathic REM sleep behavior disorder here at MGH. Today, I will speak about preparing and executing successful clinical trials in the REM sleep behavior disorder space, and it's my great pleasure to be part of this webinar. Hello, everyone. My name is Alex Videnovic. I am a neurologist and work at Massachusetts General Hospital. In this last presentation for today's webinar, I will speak about clinical trials in REM sleep behavior disorder and outline some challenges and opportunities in this research space. These are my disclosures, and none of them are relevant to the topic that I will be speaking about today. I will discuss clinical trials, two types, symptomatic trials, and disease modification trials. When we say clinical trials in DRVD, obviously, we think about clinical trials that aim to improve symptom control of a REM behavior disorder. The notion is completely different when we speak about disease modification trials. As you've heard extensively throughout these webinar talks, REM behavior disorder is associated with subsequent development of synuclein-specific neurodegenerative disorders in a large number of cases. These diseases are Parkinson's disease, dementia with Lewy body, and multiple systems atrophy. None of them have cure at the moment. Since RBD starts years prior to the onset of cardinal features needed for the diagnosis of these neurodegenerative diseases, when the neurodegenerative process related to them is in its earlier stages, it is very reasonable to position RBD patients as a population for clinical trials that aim to arrest or modify the disease progression for these chronic neurodegenerative diseases. In that sense, I will speak today also about disease modification trials in addition to RBD symptomatic trials. Let's start with the symptomatic trials and symptomatic care for REM behavior disorder. We are well familiar with the usefulness of benzodiazepines, specifically clonazepam and melatonin in symptomatic treatment paradigm for REM behavior disorder. It is important to point out, however, that evidence for use of these two agents is based on case series reports and that high-level clinical trial evidence for use of these two agents is just not present. For example, colleagues from Australia and Korea have recently conducted two randomized clinical trials, one with melatonin, the second with clonazepam, and compared its effectiveness to placebo. Both clinical trials, as outlined here on the graphs for this melatonin trial and the table for clonazepam trial, failed to reach and achieve and demonstrate the benefit of active compound, either clonazepam or melatonin, over placebo. We are here facing a situation where we have two agents that have been for a long time successfully used to manage symptoms of REM sleep behavior disorder, yet in these two clinical trials that has not been demonstrated. It has not been demonstrated likely due to outcome measures that have chosen to capture a severity of RBV and effectiveness of the intervention. The field of symptomatic clinical trials for REM sleep behavior disorder suffer from this lack of adequate primary outcome measures that will accurately capture those changes in the symptom severity and frequency when it comes to these RBV symptoms. Let's now touch base and speak a little bit about disease modification trials. As I say, when we say disease modification, we think about a process that will stop or arrest progression of these synuclein-specific neurodegenerative disorders. Here on the slide, I have listed, I actually took one published table that lists just a few of agents, although many are listed here, there's just a few of how many have been tested so far, disease modification properties for Parkinson's disease. All of these compounds tested negative in their capacity to slow the progression of Parkinson's disease. For many of these studies, when we talked after the studies were completed, why did this happen and how come these agents were not effective? One of the regular arguments is that perhaps we are targeting this synuclein-specific neurodegenerative process too late when neurodegeneration has already took a substantial toll on these dopaminergic neurons. Therefore, with REM sleep behavior disorder, we are at the opportune situation to have a clearly identified disease that represents a prodromal synucleinopathy, likely representing patients who are at an earlier stages of neurodegeneration, where some of these disease-modifying therapies may be effective if applied so early within the isolated RBD phenotype. This is a really whole premise of disease modification within the RBD population. When we speak about clinical trials for any disorder, including RBD, these are segments or concepts of clinical trials that need to be considered. Everything really starts with selecting appropriate patients to each trial. Here, obviously, the characteristics of RBD patients that will end up in disease-modifying versus symptomatic clinical trial are somewhat different. Obviously, for both type of trials, we would like to select well-defined patients with REM sleep behavior disorder based on the ASM diagnostic criteria. For clinical trials where we aim to do this test, where we aim to test the disease modification, we like to have patients with isolated RBD, or someone uses the word pure RBD. The challenge may be how long it will take for these patients to convert to one of those neurodegenerative disorders. Therefore, we want to enroll patients who we can call enriched isolated RBD, enriched for some additional markers that suggest that neurodegenerative process have already started. Here in this table, I have illustrated, this is from one of our papers, possibility, how we can enrich that purely isolated RBD with additional features that will allow us to achieve that conversion to one of these neurodegenerative disorders within a reasonable timeframe, what can be a duration of such a clinical trial. For symptomatic clinical trials, this stringency is somewhat less important. We want to have patients with REM sleep behavior disorder of sufficient frequency intensity so that we can capture, develop potential symptomatic benefits of the intervention we are studying in such clinical trial. Diagnosis of REM behavior disorder is very important as it is critical for selecting an appropriate study cohort. Therefore, one needs to point to many questionnaires that are excellent screening tools for REM sleep behavior disorder, but also to emphasize that all of these screening tools and questionnaires that have been developed have not been validated in a community dwelling individuals unselected for sleep complaints. Therefore, while they may be useful to pre-screen population for presence of REM sleep behavior disorder, likely multi-tiered approach, which will encompass interviews with the clinical sleep experts and polysomnography, will be needed to finally assemble this cohort of patients with isolated RBD for disease modifying therapies or for other symptomatic trials in this disease space. Other aspects that are very relevant when we talk about clinical trials are clinical trial design and the duration of such clinical trial. Golden standard of a clinical trial is a randomized double-blind placebo-controlled trial, which can either have a parallel arm or crossover design. There are particularly specific designs that have been created to measure disease modification. Some of these are washout design, delayed start design, or a futility design. For the sake of time, I will not go into a lot of details here about each of these designs. This is something for you to become familiar with, with this terminology, if you are not doing a lot of clinical trials in your daily activities. Other aspect that is very relevant is a clinical trial duration. Here, the duration of the trial will also depend whether in RBD we focus on symptom control or on a disease modification. For disease modifications, we really want to have a trial that will have a good chance of capturing phenoconversion. Therefore, the length of the trial will need to be in years, as opposed to symptomatic therapy, where one can judge the effectiveness to control symptoms within three to six to nine months. These trials centered on symptomatic therapy are much shorter than the trials that will focus on disease modification. Clinical trial endpoint, clinical trial outcome is another critical aspect for any clinical trial. For disease modification trials in REM behavior disorder, it is normally to propose that phenoconversion be the primary outcome measure. Phenoconversion being the time point in a trial when one individual converts from having isolated REM sleep behavior disorder as the key entry diagnosis to one of those neurodegenerative disorders, Parkinson's disease, dementia with Lewy body, multiple system atrophy. The challenge here is that we want to have such a population of isolated RBD patients that will have substantial chance to achieving phenoconversion within the reasonable practical duration of the clinical trial. To achieve this, we really should focus and study markers that will allow us to select the subpopulation of patients with REM behavior disorder who are at the highest risk of phenoconversion. Here are some of the surrogate markers that can fulfill this role. It is also important to define a dynamic biomarker which will be able to track progression of cyanuclein pathology throughout this prodromal phase, throughout this phenotype of patients which will be enrolled in these disease modification trials. Unfortunately, well-defined dynamic biomarker of such type is not present at this time, although many are being explored and considered for becoming a dynamic biomarker. For symptomatic trials, obviously, clinical trial endpoints should center on appropriately capturing the severity and frequency of RBD events. Video polysomnography may be very useful in adequately capturing these events, although this technology has a lot of barriers with it, accessibility, cost, etc. A lot of innovation will be needed for design of appropriate symptomatic treatment trials in the RBD space as well. This table outlines increasing number of registries and resources that are available for clinical trials and clinical investigations in RBD. I invite you to visit these groups and learn about them. I would particularly like to highlight this North American Prodromal Sinucleinopathy Consortium for M.Slee Behavior Disorder that was formed through collaboration of 10 large academic centers that are scattered through the US. Here you see where these sites are located. Investigators from these sites are depicted here in our photo, which is one of our last meeting that this NAPCS consortium held in St. Louis. The goal of this consortium is to bring the RBD medical and scientific community, as well as patient and general public together, to enroll patients with M.Slee Behavior Disorder in RBD registry, to follow them longitudinally through series of yearly assessments, which are multimodal assessments, and therefore advance understanding of biomarkers of progression of neurodegeneration within the RBD phenotype, but also to curate and prepare registry of patients that will become available for rapid enrollment in the clinical trials, aim at disease modification, then promising disease-modifying interventions become available. I would also like to highlight the International RBD Study Group, which is comprised from a worldwide group of physicians and scientists who dedicate most of their professional time to clinical care and research of M.Slee Behavior Disorder. We held annual meetings where we discuss progress and share collaborative ideas and research together. These are two photos from two of our recent annual meetings of the RBD Study Group. At the end of the talk, I would like to present to you these two references for your knowledge. They are both centered on clinical trials in M.Slee Behavior Disorder and derived by this very same International RBD Study Group experts. It's a nice reading source if you would like to delve into details into some concepts that I have just introduced due to brevity of time during my talk today. At the end, I would like to put a call for really collaborative efforts, many of which are currently underway, that will bring all of these key stakeholders together as we continue the dialogue behind disease modification and other trials in the RBD space to benefit not only RBD patients, but also to address broader community and help one day slow the progression of these ominous neurodegenerative disorders such as Parkinson's disease, dementia with Lewy body, and multiple system atrophy. Really, we are at an opportune time to come together as a community and take advantage of our collective knowledge, enthusiasm, and wisdom to help address this large unmet needs in neurological care. With this, I would like to thank my colleagues who joined the webinar today. I would like to thank the AASM and the RBD Study Group for sponsoring this event and having me be part of the program. Finally, thank you all very much for joining this webinar, which is hopefully one of many that will be put together in the near future. Thank you very much. Be well. Hello, everyone again. Alex Fedenovich here. I am joined by Dr. Stefani this morning. I will see if Dr. Postema can join. Once again, I would like to thank you very much for joining this webinar today. We are now in a live session. I'd like to start by sharing with you that both webinars, one that was done on May 4th, and this one will be available on-demand live. The AASM staff told us sometime next week. You will also receive a link that will provide opportunity for you to access easy both of these webinars. I'd like to remind you all that you have an opportunity here to type your questions in the Q&A or our chat boxes here within this video platform. We will now start with the questions. I will read some questions here, and Ambra and I will try to share our thoughts about this. One of the first question, which is really interesting, came about isolated RAM without titanium. What does isolated RAM without titanium alone predict? There is no dream enactment clinically. Ambra, would you like to take this one? Yes. Hello, everyone. I think this is a very interesting and important question at this moment because I have to say we have few data on isolated RAMC without titanium, but these are increasing. This is part of the spectrum of prodromal RAMC behavior disorder. We have a couple of studies showing that biomarker of alpha-synuclein-related neurodegeneration are present also in these patients. One study showed decreased dopamine transport imaging with the aspect. One study showed the presence of autonomic dysfunction and one study from our group showed also the presence of analyzed five different biomarker and showed that these were positive in around 14 percent of patients. We also know that RAMC without titanium is also, when it's isolated, is increasing over time. Two recent studies, also a follow-up and also a less recent study from our group, and show a low conversion rate to RAMC behavior disorder, which was in the highest study with the highest percentage around 25-30 percent, and also some conversion to overt neurodegeneration, around 5-9 percent. I think we don't know enough, but I think we should identify the subject and we should follow them over time because probably this is just a prodromal stage of RAMC behavior disorder and is even an earlier stage of alpha-synucleinopathy. This is my opinion at least. Thank you, Ambra. Questions are really pouring in. We really appreciate that. We will try our best to collect all of these questions together and perhaps maybe have a platform where we can post our answers or address them in some of the upcoming programming and we develop them. The second question that came and it's relevant for clinical care is it's fair to say that it's paradoxical to use clonopin for symptomatic therapy for this problem, especially when this benzodiazepine use is reported to contribute to cognitive decline. This is obviously a very important and relevant issue that you are bringing. Chronic benzodiazepine use has been associated with some risk of cognitive disfunction down the road. Here in disease where symptoms can be very damaging to the patient, meaning REM sleep behavior disorder with just a few limited treatment choices that are effective, you are sometimes stuck between a rock and a hard place. I certainly will prefer to treat my patients and my patients are usually very athletic patients in the space of movement disorders. But even younger patients with REM behavior disorder, I would prefer to start with melatonin or melatonin agonist. But sometimes, I'm just going to really be forced to move to that benzodiazepine therapy, which indeed is quite effective in my opinion. Try to treat these patients with a minimal amount of benzodiazepine possible to try to at least mitigate that dose-dependent phenomenon of cognitive decline that may be dependent on a chronic benzodiazepine use. This is the best that I can answer. It's just a very challenging situation. The next question that we received is, is antidepressant-induced apparent RBD also a marker or separate? This issue, Ambra, about SSRIs and other antidepressants and RBD symptoms. What do you think about that? Yes. This is, again, something that has not been extensively investigated. We know that there is an association between use of antidepressants and REM sleep without atonia. We also know that depression itself is also an early symptom of Parkinson's disease, for example. It's difficult to disentangle this issue. We know, we have only a couple of studies on this subject with REM sleep without atonia and antidepressant, and we know that a biomarker of alpha-synuclein-related neurodegeneration are present, also in these subjects, and they also convert to overt neurodegeneration also. Usually, it is a younger patient and the rate of conversion is lower than in studies with RBD not related to antidepressant. But it seems that the most accepted opinion is that the use of antidepressant is not the cause of the development of REM sleep behavior disorder, but triggers REM sleep behavior disorder in subject who would develop this anyway at some point. Thank you. I'll take this question. If we have patients with RBD who are interested in participating in a clinical trial, how should we direct them? Well, certainly one idea that if this question came from North America, we do have this NAPCS consortium or RBD consortium with the 10 sites that are really geographically located throughout the country. I welcome you to learn about this NAPCS consortium, and there is a contact information. These individuals can be enrolled in a longitudinal annual natural history follow-study research project with the goal that these patients will then be well-characterized when these clinical trials begin, that we will have an opportunity to enroll patients. If this question came from outside North America, the rest of the world, we really encourage you to visit the International RBD Study Group website and reach out to an expert who may be a member in your local environment, in your country, and try to connect with that group. I'll just use this opportunity. We frequently get this question, are we ready for RBD trial? With the disease modification goals, readiness for clinical trial is really very broad concept. In order to be ready, there are many aspects that need to be prepared in advance to having just an agent that will be the key. But certainly, I'm not sure that we have an agent, that we are just ready to jump in. There are many good candidates, but we need to prepare all the infrastructure ahead of just initiating trial and selecting the agents. From that perspective, I would say that we are very much ready for disease-modifying trials in the RBD space. I would hope that our community, including all of you for this call, can work together with these groups and organizations and try to think strategically how we can work together towards the goal of really helping both patients with neurodegenerative diseases, but also these patients with RBD who are very much worried that they may be on the road of developing this disorder. This last segment that I said is a nice segue into the following question that we received. What do we tell? How do we counsel patients who are diagnosed with REM sleep behavior disorder in the clinical sleep lab or clinical program? Ambra, what are your thoughts about this piece? Yes, this is again, of course, I think it's something very subjective, how what we want to communicate to the patient, but what I think, and there is also an open discussion in the community field about this. So my opinion is we need to communicate the diagnosis when we have a certain diagnosis, which is video polysomnography based of REM sleep behavior disorder, because on the one side, I think patients deserve to notice because this can make some change in the patient's life. And also once they get the diagnosis, they can Google REM sleep behavior disorder. And it's very easy to find out the association with neurodegeneration. What I do in my clinical practice is just to start talking to the patient, saying there is a certain risk of developing over time, which can be short or longer, some kind of neurodegeneration. And then I try to see from the reaction of the patient how much they want to know. Some patients, they say, I don't care, I'm old enough. And if I get Parkinson's, it doesn't matter. I'm 80 years old already. And they enter my life and other patients say, I really want to know the numbers and the real risk. So I try to individualize the answer. Thank you, Ambra. One question was any developments on anti-synuclein vaccine? Well, this question relates to immunotherapy, which is a really very hot field for a broad space of neurodegenerative disorders. And immunotherapy with certain antibodies that target these pathological alpha-synuclein. Some of these trials are really underway. Some of these trials have been, unfortunately, just decently negative for individuals with early Parkinson's disease. But then there is always the question, right, whether that early Parkinson's disease population may be too late to initiate this type of intervention or any type of disease-modifying therapy that has been tried so far. And that's why this space of disease modification and REM behavior disorder is a very hot one and very relevant for neurology, neuroscience, and sleep medicine. The next question, which is also quite relevant for this talk and in general for our patients, is how do we differentiate possible, probable, prodromal, provisional RBD? There is really a lot of terminology, and maybe we can close this webinar. Andraine, you're telling us about what's this isolated, probable, idiopathic, prodromal. Let's talk about that. Yes, there is also some confusion because we need to make some clarity with terminology. So possible or probable RBD is RBD diagnosed through clinical history, questionnaire, or without a confirmation through video polysomnography, which is the only possibility to have a certain diagnosis. Then prodromal RBD is a quite recent concept that was proposed a few years ago and means a prodromal phase in which the criteria for REM sleep behavior disorder are not fulfilled, but there are some signs or symptoms that there is something going on, like REM sleep without atonia, which might be above the cutoffs, but no dream enactment in the video and no clinical history, or a lot of small movements during the video, in the video polysomnography, small jacks, but no real dream enactment behavior. And isolated REM sleep behavior disorder was previously called idiopathic. REM sleep behavior disorder is just REM sleep behavior disorder, which is polysomnography confirmed in the absence of an associated pathology, which can be alpha-synucleinopathy, narcolepsy, autoimmune disorders, anti-agglomerative disease, and so on. So I hope that this helps to put some clarity in these definitions. Yes, this really can be quite confusing, this terminology, and we should really do more of these webinars even to clarify this further. But for this one, we are now two minutes after the hour. Unfortunately, we can go probably another hour just to answer the questions that we received, but we don't have that luxury of time. Again, I thank you all for joining us today. Our gratitude goes to all AASM staff who helped us for this webinar, and to the AASM and the International RBD Study Group for creating this webinar program in collaboration with the AASM InterSociety Collaboration Committee. Ambra, thank you very much for joining today, and we wish you all to be well and stay safe and healthy, and hope we will continue to work with you in the upcoming months and years in order to capitalize on this association between what's something to be pure sleep disorder, which is clearly not purely sleep disorder, REM sleep behavior disorder. Please reach out to us with any suggestions, ideas, how you would like to collaborate. We are happy to receive your emails and really stay engaged during this exciting time. Thank you very much. Be well. Bye.

REM behavior disorder

neurodegeneration

RBD population

clinical trials

synuclein

Parkinson's disease

dementia with Lewy bodies

biomarkers

diagnostic marker

prognostic value