So, in the interest of time, we'll get started, just because I want to make sure we give our esteemed speakers plenty of opportunity to chat. So, I'm Dan Danischvar, I'm a brain injury doctor at Spalding Rehab, but I'm joined here by two incredible co-speakers here. I'd like to remind everybody to silence your cell phones for all sessions except workshops. Video recording is taking place in this room. I'd also like to remind you all to complete individual session evaluations, as they'll help us with future planning. And the session evaluations are located on your mobile app and in the online agenda, so search for the desired session in your mobile app or online agenda, clicking CME and evaluations to open the evaluation. And then I'd also like to remind you to visit the pavilion, which offers interactive resources and educational opportunities, including the AAPNR Learning Center, with complimentary hands-on education throughout the assembly on multiple topics. So, with those announcements out of the way, as I said, I'm Dan Danischvar, I'm a brain injury medicine physician, but I'm joined here with Dr. Sifu, who is an incredible speaker. We're really lucky to have him here. And he's going to be talking about some of the military applications of what I'll be leading with, which is the neurodegenerative sequelae of traumatic brain injuries and repetitive head impacts. He's the leader of the Chronic Effects of Neurotrauma Consortium and a professor and chair of PMNR at VCU. And I'm joined by another chair and professor of PMNR at Spalding, my boss, so I can't say anything bad about him, Dr. Raz Zafant, who's a leader in brain injury and leads the Philip Blair Cell Study, in addition to a million other things. So with that, let's get started with my portion of the talk, which is looking at CT pathogenesis. So I don't really have anything relevant to disclose for this, but when we're talking about the long-term effects of single or repetitive head impacts, it's important to understand the scope of the issue. And there's been a number of studies, really starting in this 2012 study, looking at professional fallout players, finding that professional fallout players have, you know, on average about three to four X times higher rates. Can you see the... This is about the smallest laser pointer here, so you can't really see it, but I have a real one there. There we go. All right. So showing that your professional fallout players have significantly higher rates of dementia and Alzheimer's disease and Parkinson's disease and ALS than the general population. And in a follow-up study by our team at Harvard, looking at the same NFL players, 3,500 or so, compared to Major League Baseball players, again, finding that there's about a three times higher rate of neurodegenerative disease and about a three times higher rate of ALS. So there's something going on that's responsible for these higher rates of neurodegenerative disease in athletes with lots of exposure or repetitive head impacts. Now, these studies can't tell us what's causing that, but there's certainly something there. And similarly, this is a follow-up study looking at, instead of 3,500 NFL players, all 20,000 individuals who ever played a single game in the NFL and found, again, that there's a four times higher rate of ALS in these groups compared to the general population. And this study went a little bit further because it had 20,000 individuals, and we were able to show that, in fact, there might be a dose-response relationship between how long these guys played in the NFL and problems later in life. Similarly, this is a study that's not just an NFL problem. This is from across the pond looking at professional soccer players. And similarly, finding that there's this four times higher rate of dementia in professional soccer players compared to the general population. And this is looking at rugby players, again, sounding like a broken record. There's this higher rate of dementia, Parkinson's disease. And this ALS number, you know, you can see it's a 15 times higher rate of ALS, but you look at the error bars on that. It's pretty substantial. But there certainly is some there there. And this also extends to other cohorts that have head impact exposure. So this is a study of veterans out of UCSF and found that the individuals who had a TBI history, which is this red line here, they developed dementia earlier and more frequently than individuals without TBI exposure. So there's something going on here. And I think the purpose of this first part of the talk is to try to figure out what that is. And so one of the possible neurodegenerative processes that might be responsible is tauopathy. So I think before we talk about tauopathies, it makes sense to talk about what tau is. So if you think about that beautiful, complex site architecture of the neuron, the neuron has this really intricate shape. The neuron structure is supported by microtubules. And so what you have in the top left of your cartoon here is a neuron where the axon's been transected. And the axon is comprised of these microtubules, a single one of which has been blown up. You can think of the microtubules as kind of the scaffolding of the neuron. They're responsible for, in part, transport of vesicles from one end of the neuron to the other. And you think about neurons as being the largest, the longest cells in the human body. That's particularly important. They also stabilize and support the structure, help remove toxic metabolic breakdown products from one part of the cell and help them move to the other parts of the cell. But the scaffolding, then, is supported by these nails, which are the tau molecules, these filaments that help support the microtubule structure that are represented here in these purple filaments. Now, in multiple different neurodegenerative disease processes, the most prominent of which is Alzheimer's disease, but there's 16 other neurodegenerative processes, this tau can become phosphorylated. And what that means is this large negative group attaches to the tau, changes the shape of that tau, and causes it to no longer be able to stabilize that microtubule structure. It falls out of the structure. Now, the problem comes in that this abnormal phosphorylated tau can induce the normal neighboring tau to also change shape, fall out of the structure, and clump along with it. In this way, these tau aggregates create neurofibrillary tangles, the neurons that are full of this disease tau. Now, problematically, in vitro studies have shown that normal neurons adjacent to neurofibrillary tangles with full of this P tau can have their tau induced to have this conformational change. And that's the way that these neurodegenerative disease processes are progressive. Basically, you have one abnormal neuron, in effect, infecting these other neurons. And so there's been a lot of research looking at different tauopathies, the most prominent of which when we're talking about repetitive head impacts is CTE. And so let's talk about CTE specifically. So CTE is not a new disease process. It was first described in 1928 by Harris and Martland, but it really came to prominence in the mid-2000s when it was first discovered in an NFL player. And so between 1928 and 2008, there were only 48 cases of CTE in the world's literature. Now, when we're talking about the number of publications afterward, there's been literally thousands of publications in the 80 years between Harris and Martland when there were only about five or six articles. But Ben Ramalu first described CTE in NFL players, and that really was, I think, part of what kicked off this process, followed by Dr. McKee reporting on the world's literature and then some additional facts that we'll be talking about in a little bit. But what does CTE look like? So this is a brain in which all cells have been stained so that they're purple, but neurofibrillary tangles have been stained such that they turn up brown. And in this whole slab, you can see that there's no brown, and microscopically, again, there's none of that brown pigment. But so the brain on the left was a 65-year-old gentleman from the Framingham Heart Study. The brain on the right is a 65-year-old gentleman with a decade of professional football experience and a total 17-year football career. And you don't need to bust out the microscope to see that there's a lot of that brown pigment, and it tends to predominate around blood vessels, which you'll see here in this microscopic view. But also, macroscopically, it tends to predominate at the depths of the sulci and in later stages of CTE in the medial temporal areas, predominantly in the hippocampus. And it's not just limited to the neocortex, though. It can go throughout the brainstem and cord as well. And so when we think about some of the Parkinsonism that's seen in predominantly boxers with CTE, it's not surprising to find that the substantia nigra and other areas associated with Parkinson's disease are also full of the neurofibrillary tangles. It's important to note, though, that when we're talking about Parkinson's disease, that's a completely different protein. It's alpha-synuclein. So this is phosphorylated tau in those same regions, so disease in the same regions, but it makes sense that they're phenotypically looking similar. And then with CTE specifically, it's been, in 2013, it was posited that there are four stages of the disease process, where you go from one or two foci of disease, predominantly in frontal and temporal and parietal lobes, to about a dozen or so foci by stage two. And stage three is where you have that prominent medial temporal involvement that I showed you in the previous slide. And stage four, although stage three and stage four, in many cases, grossly don't look that different, by stage four, the reason why it doesn't look that different is there's been profound neuronal loss, widespread atrophy, and by stage four, about 90% of individuals with this disease have dementia, meaning that they're unable to care for their basic ADLs anymore. So in a first proposed in 2017 consensus conference, and subsequently in 2021 published, there were new pathologic diagnostic criteria, which clarified, I think, one important point, which is that before the pathognomonic lesion of CTE was that P-Tau around a blood vessel, predominantly at the depths of the folds of the brain. But that changed, or it was clarified, I should say, in 2021, when now it was made clear that it needs to be specifically neuronal, it needs to be a neurofibrillary tangle, it can't be something in a Tau in an astrocyte or in glial cells that is diagnostic of CTE. And that becomes relevant. So what you see here is the diagnostic lesion of CTE around blood vessels. These are blood vessels, and this is the neurofibrillary tangles. But this is a glial Tau, and so it's not something that is diagnostic of CTE. And so with that staging criteria, though, where we said there's four different stages, the issue is that each person that passes away with CTE, because CTE can only be diagnosed post-mortem by looking at their brain, each person that passes away represents a snapshot in time. We don't know for sure if a person with, say, stage 1 CTE would have gotten stage 2 or stage 3 CTE if they'd lived longer, because we aren't able to assess the Tau in someone's brain in real time at this point. But what we can say is, based on the level of Tau burden when someone passed away, there's a statistically significant difference in age at death in individuals based on the stage that they had a disease. So individuals with stage 1 CTE, on average, die about a decade younger than those with stage 2, or a decade younger than those with stage 3, a decade younger than those with stage 4, suggesting, much like in other disease processes, that there's this progressive process to CTE. Now when we're talking about where we find the Tau in CTE, and this gets us to what's going on pathologically or pathophysiologically, the Tau is, as I said, predominantly the depths of those folds of the brain. So this is a really interesting study that was published in Brain in 2017, where they looked at computational models of simulated impacts. So these are simulated brains that are subjected to impacts, and they found that the highest shear and strain rotational and translational forces were focused at the depths of the sulci. So basically, the force wave propagates from the skull through the cerebrospinal fluid into the brain, and that depth of the folds of the brain are where they get the most rotational and linear accelerations. And that also makes sense, because these are the exact same regions where we find that phosphorylated Tau pathology. Similarly, and Dr. Savant's going to laugh when I show this slide, because he knows I love it, but this is a slide that I first have been presenting on CTE for about 15 years, and I found this comic about 15 years ago, and I'm including it in my talks. But last year, a group out of Mount Sinai ended up actually looking at head-butting bovids, brains. So these muskox, they're just living their muskox life hitting heads, and when they studied their brains, they found Tau predominantly at the depths of the sulci in these animals' brains. So phosphorylated Tau is not something that you'd show up normally, it's not something that, you know, I'm involved in the centurion study, which is looking at individuals who live over the age of 100, and in normal, healthy individuals, there isn't Tau in their brain. Now these bovids, they weren't, this isn't an experimental model, these weren't animals where some of them were hitting their heads and some of them were not. These were all hitting their heads and all of them had Tau, but I've actually spoken with Dr. Ackermans, and they're now doing a study where they're isolating some bovids to see if that Tau is directly related to the hits to the head. But at this point, the preponderance of evidence shows that CTE is caused by repeated hits to the head. And so these are all of the studies with at least 10 subjects that have individuals with head-to-back exposure and those without head-to-back exposure. And what you can see prominently is that in the studies of individuals without head-to-back exposure, very few of them, so around 1%, have CTE pathology. And in individuals with head-to-back exposure, there's a wide variability in the CTE prevalence, but it's something much higher than 1%. And so this is remarkable because it shows that there is a direct relationship between head impacts and the likelihood of an individual having CTE pathology. Now, a couple things to make note of. First off, in these control groups, this is just documented head-to-back exposure, but in multiple studies, it's unclear whether or not someone played a sport after they passed away because that's not something that was readily available for everybody. So some subset of these individuals probably do have head-to-back exposure. And then this exposed, the reason there's variability here is that these individuals are getting lots of different types of exposure. So for example, in this ADAM study, those with head-to-back exposure were predominantly professional athletes. So it makes sense that they have higher rates of CTE than in other populations where we're looking mostly at high school athletes. Now, I wanted to also highlight this study by one of my colleagues, Grant Iverson, where it's, you know, you can see a substantial outlier compared to the other studies. Now, if you were to run a chi-square on this and look at the likelihood that that difference is associated with random chance, it's a little less than one divided by the number of grains of sand on earth. So they're not, it's not random chance, it's a different cohort. So there's a couple of different possibilities. It could be that the cohort study there is substantially different. It could be that the methods of describing the pathology are substantially different. And that's where that difference in R-tag that I referred to earlier is relevant. So this is that study. And what they found in this study is that they looked at individuals that, they passed away around age 80, and the individuals that had CTE were all stage one CTE. Now, remember I said that CTE tends to get worse as you get older, and to find an individual with stage one CTE is kind of weird. But then on top of that, in their slides, there was an argument at least made that there was a, the CTE was not neuronal, that it was astrocytic, which is another disease process called R-tag. And so R-tag stands for age-related tau-astrogliopathy, so not going to go much beyond just the name of that. But it says age-related, and it's an astroglial process. So you tend to see it in individuals that are older, and you tend to see it in astrocytes and glial cells. And so this letter to the editor in response to that Iverson paper argued that based on the images, there wasn't a pathognomonic lesion of CTE, that those cases didn't actually have CTE. And so I trust what they say, because I'm not a pathologist, but this is the NIH NINDS R-tag criteria, where it was defined in 2016. And four of the six authors in that letter to the editor are people that define the R-tag. And so I basically trust what they say. So the point is that CTE is incredibly rare in the absence of repetitive head impacts. So this is a study of 310 individuals called the VITA cohort. So these are all individuals who were born in the left bank of the Danube in, like, 1928 or 1924 or something, and followed throughout their entire lives. And then they were all studied for evidence of CTE pathology at death. And in this cohort of 310 individuals from the community, none of them had CTE. Similarly, this is a study out of the Mayo, where they looked at 198 individuals with no exposure to repetitive head impacts. This is a neurodegenerative disease cohort, meaning that everybody here had neurodegenerative disease. They had some sort of dementia at death. And out of these 198 individuals with no exposure to repetitive head impacts, none of them had CTE. And this is a study that initially defined the criteria of Alzheimer's disease, looking at 83 brains. And in this, again, community cohort of individuals with dementia, all of whom had Alzheimer's disease, none of them had CTE pathology. So the point is that CTE is something that is really only occurring in individuals with head and back exposure. So what can we make from this pathologic information and what can we learn from this? So there was a study we published in 2017 where we reported that out of the first 111 NFL players to donate their brains to research, 110 of them had CTE. So just based on that number of 110 out of 111 and based on the number of NFL players who died during that study window, the possible number of people, if you assume that the only people who had CTE that died during the study window were all studied, all donated, all evaluated, that would give you the number just over 10% of all NFL players during that time period had CTE. Now if you make more reasonable assumptions about the probability of brain donation amongst those with CTE, the prevalence of CTE gets higher amongst NFL players and that's where it becomes especially concerning. But even that one in 10 NFL players have CTE is remarkable as a minimum considering that this isn't something you're seeing in the general population. So what else can we learn from the studies on brain donors? So as I mentioned before, there's a wide variability in the odds of CTE amongst individuals with histories of repetitive head impact versus massed controls going from 150 to two and this in large part is based on how much exposure those with repetitive head exposure in these cohorts actually had. So what we wanna do is figure out what characteristics of that exposure actually predict CTE pathology. So one of the most rough ways to look at it is based on duration of play. So let's say we took football players. So this study is 631 football players whose brains were donated and this isn't worth any fancy statistics. This is just looking at on the x-axis here the years of football played and on the y-axis number of athletes, regular histogram. Blue is no CTE and darker red is higher stage CTE. These are the exact same data on the right. It's just that instead of on the y-axis the number of athletes, it's the percent of athletes within that year. But both of these figures show you that as you go further to the right, you get less blue and you get more dark red. But if you do the fancy statistics, you see that there is in fact a dose response relationship between the number of years of football played and CTE pathology. So this is a study looking at 266 football players and found that each additional year of play confirmed about a 30% increased risk of CTE and an increased likelihood of CTE severity. And this is true throughout the entire range of play. So it's not something that's driven by one of the extreme ends of the spectrum. But we don't think it's actually years of play of football that are causing CTE pathology. We think it's something about those years, about the hits to the head that players get based on years. And so from there, we can actually do something pretty interesting. And what we did here is we said like a quarterback gets very different kinds of hits to the head than a linebacker. And a high school athlete gets very different kinds of hits to the head than a college player, right? And if you think about it, we can model those hits to the head based on the levels that people played at and the years that they played and figure out which characteristics of head impact exposures are most closely related to pathology. So to do that, we created what's called a positional exposure matrix where we coined the term positional exposure matrix, where we looked at over 20 years of helmet sensor data, over 6 million head impacts in athletes across different levels of play. And we aggregated them to say, for example, that an average linebacker gets 460 hits to the head in high school, whereas an average college tight end gets 600 hits to the head. And we can also determine what the average G-force is. And so the average G-force for high school athletes is about 27. And to put it in context, that's somewhere between a fighter pilot during a roll and a car crash at 30 miles per hour. And so then we're able to model the relationship between say the total force to the head an athlete got and their risk of CTE, their odds of CTE. And this is a figure, I'm kicking myself because I didn't include it in the paper, but the New York Times ended up arguing, showing basically that they requested that I put this figure together after the paper was published. And I did it in the same format as the other paper. And as you go further to the right, you get more orange and darker orange. And similarly, then when you look at the statistics, they're also, they also show that the cumulative force to the head ends up being the best predictor of CT status and CT severity. So what I've talked about here then is that this idea that repeated brain injuries are caused that lead to CT pathology, and that CT pathology in some cases, based on that early data that I showed, it leads to clinical symptoms. Now, Dr. Safat and Sifu are going to talk about the clinical symptoms portion of this, but what I want to point out is that there's other neuropathologies that probably are related to repetitive head impacts, and those are probably related to CT pathology as well. There's also other demographic genetic lifestyle and other factors like age, race, genetics, cardiovascular disease, pain, obstructive sleep apnea, headaches, cognitive reserve, socioeconomic status, stress, substance use. All of these probably play a role on whether or not clinical symptoms manifest, and may be related to brain impacts, and also, unfortunately, are probably related to CT pathology, and also are likely based on clinical symptoms too. So what we know overall then is that CT is this distinct neuropathologic process characterized by perivascular tau deposition, that there's been a lot of different studies, over 1,500 cases of CT in the world's literature, and the majority of cases all have repetitive head impact exposure that's been documented, and that repetitive head exposure increases your risk of CT. And with that, I'll turn it over. Thanks. Man, that was awesome. He knows more than I've ever learned in my life, man. You're amazing. I love this guy. I love the dancer. That was awesome. So I'm Dave Sifu. It's a pleasure to see you. So I'm gonna give you the practical stuff, what we're seeing, your boots on the ground. Before I start, though, I do want us all to just take a moment, a moment of silence, to think about our service members who are fighting right now and getting hurt, as well as those that have come back in the last 20 years, 30 years, that are defending our freedom, and of course those that have given it all for our country. So if we could just take a moment to do that. Thanks. Most people say that it's impossible for Dave Sifu to be quiet for any period of time. So one thing I've learned in working with the military for the last 21 years, that moment of silence thing, I've gotten really good at it. So thank you for sharing it with me. It's really important that we reflect on that. I hope all of you got to see the presidential lecture today, and then the amazing... Oh, go, dude. All right, got it. Yeah. You wanna give the talk to him? Come here. The amazing AI talk that went afterwards, because it's really cool. I don't think any of it is practical right now for what we're doing, but very shortly. Because this morning I was playing Solitaire on my phone, and one of those ads came up, and it said that if I wanna prevent dementia, all I have to do is figure out how to spell words. So I've got... I don't even need to give this talk. Just get that app and start spelling words. You know, it's ridiculous. All right, so I'm gonna be highlighting what we've found in the military and veterans over the last 20 plus years. No, no, it doesn't advance. All right, there you go. All right. All right. These are the old slides. That's okay, I don't mind. That's all right, they didn't... All right. So I'm gonna be describing a prospective cohort of over 3,000 service members and veterans that were all in Iraq and Afghanistan beginning as early as 2000, and that we've been following for the last about 10 years in our program, but many of the injuries are at least 20 years old. And we're gonna talk about what are we seeing? All right, that's what a concept, right? And we're gonna... And so our program has massive retro data as well. We've got two and a half million unique individuals. We can study that. But I'm just gonna be presenting six studies without any grasp, because I don't understand half of them. Just gonna give you the take-home message about what we have found, all right? And we're adding another cohort of 1,000 folks that have been followed for 13 years. So we're gonna have 4,000 individuals, 20% of whom have never had a TBI that we've been following for at least 10 years, up to 13, for injury, military injuries that occurred as early as 2000. But we also have all of their childhood injuries, all of their sports injuries, all right? The only caveat I will give you is that the way we find out if they had a history of things is we amazingly ask them. We don't use biomarkers. We do all that stuff, imaging. We ask them if they've had injuries. So that's the limitation to any study like this. Obviously, moving forward, we can get some of this stuff prospectively, but I have to always give that caveat. And our team has published a lot of this over the last years. And the reason I'm telling you this and showing this isn't because I wanna say how cool I am, how amazing it is. I mean, we all know that, right? What I'm actually saying is this is PM and R-led. This is our field, all right? Brain injury is our field. The research I'm talking about is PM and R. So A, be proud to be part of it, but this is what we can do as a field in research. So if I hear one more person say, oh, you can't study rehab. It's very qualitative. I'm like, that's not true, all right? We need to be doing this. So I'm gonna present what we found. And the updated slides, I had my true bottom line up front where I told you what all six studies said. So you don't have to listen to this. I'm gonna probably bang through these slides a little more quickly than I would have so that my mentor, Ross Safon, can really finish strong and give us information. But as part of this perspective team, we are looking at all of these things on the right-hand side. We're looking at long COVID. We've got pre-COVID and now post-COVID fluid and imaging and stuff. So there's nothing we're not looking at, all right? And then I have to say this part and then I'll tell you the truth. If you wanna access our data, you can get it for free for nothing off of Fitber. It's all there, all right? If you know Dave, i.e. me, and you just ask us and wanna be researchers with us, we're happy to give it to you directly if you partner with us. So this isn't Dave's data or even the limbic data set. It's the entire country's database. I've been working with Ross to share data from his set to ours, but we're really open to that. We have got tons of information and are excited to share it. Our system is across the country. We have 11 testing sites, 17 recruitment sites, yada, yada. I did this so I could take a lot of vacations and get paid for, but if you notice, we've got a nice site in Hawaii that I visit a lot. And if you wanna go online and look at all of their studies, all of the publications, summaries, it's all there in our Knowledge Translation Center. And importantly, we now have, I think, 10 brain health videos that are up there that are for service members and civilians who have brain injuries who actually wanna prevent what Dan has shown. All right, you wanna prevent dementia. We've got some cute little videos. They're really cool. I like those a lot. But we also have all the science that backs it up. All right, and it's not really a commercial because I don't get paid more for this. And so now we've got about 4,000 folks that we're seeing every year, following them up, see how their cognition is doing. Every five years, they're getting a deep dive, everything but a colonoscopy. All right, if someone wants to do it, they can do it. We're testing everything. Imaging, saliva, blood, evoke potentials, everything is in there, right? All right, and we have every possible important test that folks would ever want. It's all on the website as well, but I just wanna give you a snapshot. We're looking at lifetime TBI using a standardized published metrics. We also have all of their electronic data from the military and the VA so we can correlate it. We're looking at, Dan finished with the importance of looking at secondary factors in addition to the exposure, the brain exposure. So we've also got everything from their childhood exposures, ACEs to their, we've got their zip code. We've got how many TBIs they've had. They've all had TBIs. We have a cohort of about 20% who have no lifetime TBIs that are the comparators that served in Iraq and Afghanistan. I think they're telling the truth, but we also have everything that we could find related to blast exposure. I've been on two phone calls today with the military and the VA because our troops are having difficulties in Middle East right now related to the conflicts in Israel and et cetera, and they're having these difficulties again, all right? And PMNR is gonna help them and fix them, all right? Because we rock, all right? I'm trying to get them into my data set too, but I also wanna help them. And we have a standardized neurocognitive battery, four hours of testing, yada, yada. And it's all available online. So I'm not gonna, for the sake of time, I'm actually gonna jump ahead, but it's gonna be a summary of the next six slides. I will be more than happy to give you these slides if you wish. I promise you I'm not, there's no smoke and mirrors here, but I really wanna go to the findings, all right? Oh, Jesus, hold on. All right, it's here. All right, so in the first, and each of these studies uses this prospective cohort. So this is all prospective data. It's the same cohort, same group. Depending on when they were published, the ends vary. The smallest one is about 500. Again, about 20% comparators think the largest ones may be 18 or 1,900, all right? So now we've got 4,000. We're starting to do more longitudinal analyses. And what we're looking for, we're not actually doing it just because Dan asked us to do something on CTE. That's our end game is to see, is there cognitive decline in these human beings? Now, along the way, we're also looking at everything else, all the data we have, all right? And if you look at the last sentence, all right, and Dan's starting to cry, but to date, we don't have a single person in this cohort, none who have shown neurodegenerative cognitive decline, zero. 4,000 people followed between 10 and 13 years. Maybe it's not long enough. The average person's had three blast exposures. We've got the highest one is 17. Originally, he said 51, but we narrowed it down. 17 seemed to be actual TBIs, and most of those were blast. About 40% of the cohort has repetitive blast injury. So these are the real deal kind of folks, all right? The folks that we're terrified, the military's terrified of. Good news is certainly by 10 years after the, you know, they're averaging about 10 or 11 years post-TBI, they're not showing signs of cognitive decline. They are having other issues, and we're going to, those are going to be higher on the list. So again, so there's some, they're the, at least in the military cohort, we have hope that the rehab techniques and interventions can maybe forestall, prevent, delay, whatever it is, but more importantly, we can help their quality of life and their other issues right now. So the first, so the first study, I'm not going to go into the details. Again, the references can be in the slides if you like, but we found that in folks that have combat service members, all right, and veterans. So 20% of our cohort are still in the military. 80% are now veterans, but they were all in Iraq and Afghanistan as active duty. The majority of them had blast exposure and or TBI. But when we look at these service members and veterans who were in combat, had at least 12 months tour of duty, we don't see that compared to the controls. Same people, same combat, no TBI. We're not seeing any sign of cognitive decline on formal testing, but we are seeing a lot of cognitive symptoms, complaints. We're seeing plenty of that. But when we look at objective testing, same human beings, we dig into it, they look like controls. Probably look better than me, but they're at the same level, all right? And the controls are normal. So these folks look normal, all right? PTSD, post-traumatic stress disorder, big surprise here, right? And that's what's happening in our current conflict. All right, it's really stressful to be in war, all right? PTSD is the driver of people with TBI having cognitive symptomatology. All right, I just said they don't really get objective findings of cognitive decline, but they have a lot of challenges, of course, with behavioral dysfunction. That is lighting up the stage with cognitive issues. Yes, they're having PTSD issues, of course, and other somatic complaints. It isn't just PTSD. Chronic pain plays a role, all right? But PTSD is a huge driver of it, no surprise. We've actually found a signal. I like saying that. A signal, a electronic biomarker, just using a resting EEG, all right? There are certain wavelengths that we're seeing in our EEG that are associated with cognitive symptoms, not cognitive decline. Again, I'm gonna say it 12 more times. But we are, so EEG. Now, I myself, you know, maybe I'm naive. What I do is I actually just ask the person what their symptoms are. I don't know why I would need to use an EEG, maybe if they didn't speak English, but we are finding an objective biomarker in EEG, all right? And again, I will, you don't have to write this down. I'll send you the slides. Don't write. Don't write, stop. I'll send you the slides. They're awesome. And all these are, they're all online, all right? And if you can't get them, I'm happy to send you the PDF. You know, no worries on it. Importantly, let's get rehabby. Let's get physical. Regular aerobic exercise. So we've looked at four different levels of exercise. Regular is not the highest level, like I'm barely regular, I mean that in a bad way, but I'm in level three. Regular exercise is associated with improved executive functioning with TBI or without, but with TBI, people that report a decline in executive functioning, all right? We are seeing improvement with regular aerobic exercise, all right, which means 30 minutes three times a week, which is really not regular exercise. That's like what Ross does. Real people exercise do more than that. I'm kidding, Ross is doing it every day. Blast TBI, which is in every newspaper, it was in the New York Times, which is why I've been working overtime recently. The New York Times article like a week ago kind of said how bad blast TBI, particularly repetitive low-level blast, not the kind of blast that removes limbs or damages lungs. We're talking about multiple, like thousands of artillery rounds and low-level blast, right? People that are exposed to that, amazingly, have greater cognitive risk dysfunction. Again, more symptoms, all right? We are seeing that if they are ApoE4 positive or they have some elevated fluid biomarkers, that there's an association. Those things appear to follow that. So is there maybe something there we could follow over time? Perhaps. Again, right now, again, we can just ask them how they're doing, but people that are exposed to blast, again, these were all mild TBIs at worst, so these were low-level blasts, all right? These are not limb loss folks. These are not people that are getting organ damage. These are really blasts that are, and we have a specific criteria for what that means, but so these folks are doing worse than folks that aren't getting blast injury. Kind of makes sense. Again, if you pull the PTSD or other emotional behavioral things out of that, the association is still there, but it's a caress of an, you know, it's like I, and I can't fix blasts other than, you know, become a pacifist, but we certainly can fix and manage a lot of these other risk factors, including PTSD, all right? And there's one more slide that we are seeing people with blast injury are also getting specific areas of cerebral volume loss. So we are seeing, yes, and again, Dan talked a little bit about that. We are seeing that. We're not seeing a direct association with those changes in brain volume and cognitive outcomes. So they are having long-term, perhaps. Certainly Dan just, you know, highlighted that, but so blast injury is a bad thing. I guess I could have guessed that, right? Repetitive low-level blast is not a good thing. All right? Important, all right. Take-home message, all right? Let's do something about this. Let's build brain health. The VA is about to launch a brain health initiative that's gonna standardize brain care, mental health care, TBI care, stroke care across the VA, just like we've standardized cancer care in this country. For the good or the bad of it, it's standardized and it's prevention. They wanna do the same thing with brain health, and fortunately they've asked me to do that, which is cool, all right? I represent you guys when I'm doing this, and I'll be asking you all about standardized approaches. If you're not having your patients do a couple of these, this is from the Blue Zone, there's nothing magical about it. I do like the Blue Zone concept, but it's wellness, right? It's everything from plant-forward diet, exercise, sleep-wake cycle, sleep hygiene, social engagement, spirituality, you know, nothing is, this is rehab. I'm so annoyed that we've been doing interdisciplinary work, integrative work, holistic work for 30, 50, 70 years, and now it's cool and everybody wants to do it. We've been doing this forever, so we're gonna continue to push this forward, but this has been shown to not just prevent ongoing cognitive issues, improve symptoms, improve PTSD. There are great treatments for PTSD. I'm not saying this is a treatment alone. This is to build resilience. It's to go in partnership with appropriate other treatments, headache management, all right? So this isn't, I am kind of touchy-feely nowadays, but it isn't about that, and there's nothing wrong with being touchy-feely. This stuff absolutely works and builds what we need to in our clients. So I would just say that while eventually, if they keep funding me, I think they will, for the next 50 years to keep studying this cohort, I am gonna find what Dan has found, but until then, I'm gonna try to prove him wrong and prevent it in these 4,000 veterans, all right? There's actually 8.2 million veterans. I'm gonna try to prevent it in all of them, all right? But just right now, we are seeing folks with TBI having long-term problems. About a third of them are having these long-term issues, but there are things that rehabilitation in partnership with mental health and other folks can make a huge difference in, all right? So positive chi here, all right, as in chi-fu. Positive outcome is what we're seeing, so. And if you wanna learn more about us here, if you shoot me an email, I'd be happy to send you both the slides as well as any of these publications. So thank you. Ah! Probably even more entertaining if I did. Okay, so first I'd like to thank Dan for organizing this and his extraordinary introduction. Second, I'd like to simply say it's not easy to follow Dr. Sifu. I want you all to know that this is a special occasion because he no longer does two shows a night. But what we'll try to do is talk about some of our work at the Football Players Health Study and how we've taken a cohort that's relatively similar but somewhat different to that of David's and looked at why is the 1% having a challenge. So these are my disclosures. One has to do with that I'm the PI for the Football Players Health Study at Harvard and a few others. Okay, so we're going to use mostly data from the FPHS but a little bit of others. We're going to say what life lessons can we learn for the rest of us. As David I think brilliantly pointed out, what matters is what happens to our quality and I'll show that at the end. And so some years ago we decided to take a little bit of a different look. We were interested in the footballers not only because of the media surrounding neurodegenerative disease and in the United States anyway. If you look at the 15 top-ranked television programs, 14 are the National Football League. It is that amazing. We're interested in a different reason. Here are the 1% of the 1% bigger, stronger, faster and frankly selected in many ways. They also often test out visually, spatially far superior to most people. They had to. You've got to integrate information rapidly and be able to execute it in a visual motor way. So how could we look at all of this? Is it all repetitive head injury or does repetitive head injury, at least in my humble estimation, need a little bit of an igniter? Is it the gasoline that needs the ignition for further badness to flower? So this is a cartoon taken from David Arsenaga's chapter in our book in which we really look at the whole person or in this case the whole player. Pre-injury factors, injury factors, post-injury factors integrate to produce cognitive, emotional, physical disturbance and player concerns. Those could be sleep. They could be pain, which is underappreciated. It could also be cognitive and mood disorders. The other thing, if we look at the data, everybody does poorly. Do we know that in head injury? In fact, it's not the case. This is a slide from Raquel Gardner's work with our old COBRAT study in which we took the complicated, mild cohort of people and we said the group of people who should behave like one group with latent class modeling behave like eight, eight. So people have their own path, some of which have been determined by their genetics, some by other things that we'll talk about. Now Dan did an elegant and lovely job talking about the links to chronic disease and I'm just going to touch on a few of them. This is again Raquel's work with two separate California administrative data sets showing that as you get older and you have a head injury, there's an enhanced dementia risk and indeed also a Parkinson's disease risk. The more significant the injury, the more likely for the Parkinson's disease to flower. That's not new to that paper. Rita Formasano in Italy talked about this nearly 20 years ago. And then I'm going to make a profound statement that Dan loves, but I think it's true. Repeated brain injury is not good. After 30 years of studying this, I've come to that conclusion. But a lot of things matter, one of which is resilience. The greatest single determinant of how you do in life, in almost any insult, aging in some ways as we'll talk about, is what? It's our resilience to a stimulus, our ability to respond. Aging matters in almost everything. Now I would argue to you that the vast majority of people who are less than 55, which goes to the end of our talk, should be mostly healthy, right? And everyone will eventually age, except for Dr. Sifu. The other thing that Dan, we're not even going to. So I think among the things to consider here is dosage. Dan did a brilliant job showing you among a select group of people who are mostly professionals that dosage matters. We also have to consider that pathology and phenotype are not the same thing. I sometime get into it about this, but look, I might have right coronary artery pathology or calcium deposition and inflammation, but I don't have the phenotype. One may be a risk factor that needs covariates to fulfill a syndromic. So this is a very cool old study from Deshpande et al. Actually, John White was on it, as well as Amanda Rabinowitz, and it's a bunch of people who were followed, who were high school football players in 1957 in Wisconsin. And they followed them all the way through for years and years and years. And these people have no difference with everybody else, none, zero. One reason may be they have no difference. The other reason may be they have no difference because they didn't get enough dosage. So my friends and our advisors that I showed you in the very beginning, their dose is insane, corresponding exactly to what Dan showed. When they're high schoolers, they never come off the field. No rational coach would let them off the field because they want to win. This is the 1% of the 1% versus the rest of us here. So we might make an argument that there is a Gordian knot to all of this, the great knot from mid-Asia that was once cut in half by Alexander the Great. And we're going to try to take people, pieces of this apart. So Dan showed you this work from Danny McKay that suggests that it's not exclusive to American football, but that here, as you get older, the hazards ratio among professional soccer players in the north of Scotland goes up for neurodegenerative disease. And it certainly held, as he showed you, in American-style football players. But this is a paper we did some time ago, and Dan showed the first part of it, but I'll show the second part of it. The first part of it is, we chose not to compare the American football players to Bobby the accountant. They're not Bobby the accountant, and worse yet, they're not like the people who could never get on the field like Bobby the accountant did, right? There is a healthy worker bias to this group. So let's compare them to major league baseball players. And what you find is, Dan's spot on. Later in life, there is a difference to neurodegenerative disease. That is unquestioned. But it happens in the 70s and 80s. And if you look at the very top of the slide, early in life, in their middle 30s, they separate on cardiovascular mortality. And I would make the claim, as I will in a second, that the heart and the brain are connected. Brain injury is bad. The heart and the brain are connected. So we're going to go through these big conceptuals. Dan talked about ALS and other neurodegenerative disease, and I'm going to go quickly through a few of these. This is the old Lehman paper, where they looked at those who had played in seasons from 1959 to 1988. This was a death mortality study, just like ours. They found higher rates of dementia and ALS and Parkinson's. And they separated that out by those who were in so-called linemen or force positions or speed positions. This wonderful young doctor led a study looking at the incidence of mortality of ALS in NFL athletes, and noted a pretty significant odds ratio. From 1960 to 2019. And it's been shown in other contact sports, in the military, and other things. However, while the odds ratio may be high, the absolute numbers are low. Okay, so what is this maladaptive phenotype, which is sort of this idea that some people aren't doing as well? And what does that mean? Some of it might be related to how we think about things. If we used prior concepts, and Dan did not talk about the syndromic, of this idea that the pathology has a distinct set of reported symptoms, well, you can find this pretty loosely in people who had no contact sport or limited contact sport. But recently, Doug Katz led a group of people to talk about a research criteria for traumatic encephalopathy syndrome. Progressive course, cognitive impairment, substantial exposure to repeated head impacts, memory or executive functional, measurable decline. So it's not just explainable by one thing, but it could be comorbid. So is everything one thing? Is everything related to their head injury? So if you look at this old paper by Askin, who was in Steve Dukosky's group, what you see here is that there are many factors that could be involved. Yes, there's the repeated brain trauma, but there's genetics, there's normal aging, anesthesia exposure. Some of our friends have been in under anesthesia 20, 22 times. Sleep disorder, as I will show you, pain, social withdrawal. The great Dr. Sifu said, stay engaged with others. He could not possibly be more right. What is the percentage, though, of people who have been told they have CTE and they have maybe some other things as well? So this is a paper from our group and Rachel Gaschow, in which people who were given the clinical diagnosis of CTE, remember, this is only a pathologic diagnosis, so they shouldn't have been told this, have high rates of depression, obesity, pain meds, hypertension, sleep apnea, high cholesterol, and low testosterone. Does brain injury lead to other comorbidities? So now we're going out of the world of sport for just a second. This is a paper we did using the data sets at Mass General Brigham, in which we compared those individuals who had never had any form of diagnosis in the past. They had nothing. They were completely naive. And they were concussed or they were control patients. We did it in orthopedic trauma controls. And what you see is that over a decade, regardless of age, there's a linkage to some form of cardiovascular comorbidity, mostly hypertension, but other things as well. And as Dave hinted, there's a heck of a link to anxiety, depression, and other behavioral entities. So could this Gordian Knot go one direction and then the other as well. So let's go back to sports. So when we took this on, we wanted to look at the whole player, the whole life, not just their heads. And if you were going to really deal with this in animals, what you do is you go, well, I'd knock out the mice. I'd knock out a gene. Well, we get in trouble in Boston for doing that in humans. So what you can do is use principles from HIV medicine and cancer and compare the extremes. I have gentlemen who are my age who played a long time in pro football and they're perfectly well and they're selling property in Arizona. And I have people who are around my age who are profoundly dependent, dependent in multiple different areas. So we took these extremes to compare and we brought them to Boston. And our cohort is over almost 5,000. So we brought hundreds of guys to Boston. And we looked at everything from x-rays to olfactory testing, to their heart, to liver and brain MRIs, to sleep studies, to physical function and pain measures. So they got the works for several days. And so we looked at some things related to risk. For years, people have talked about the age of first exposure. If you start early, you're going to do poorly. And we did not find that to be true. It may simply be that these guys all have a toxic dosage. Or it may be that this isn't a good idea for other reasons besides purely neurodegenerative disease. I don't think it's a good idea, but for many other reasons. Among the things we also looked at was adverse childhood experiences. So if you had, as McEwen talks about, a lot of allostatic load and you had many adverse childhood life experiences, that is associated without a doubt with poor cognition-related quality of life, depression, pain, anxiety, and dementia. Remember, we are many things, not just one thing. Another thing that is disconcerting but very real is this issue of health equity. So among the issues we examined was a simple hypothesis with our colleagues at Morehouse. You get to play professional football, you get a free college education, you get a pretty good salary for X number of years, you get benefits, you get some elements of recognition. This should equitize a lot of societal badness. This group of people should be slightly different, and indeed they are not. Indeed they are not. That does not get rid of what are societal and structural issues that we all need to be aware of. Health characteristics. David talked about staying connected. This is a work we published with Amer to hand, which is a little bit more of a mechanistic link to that, and that is personal network studies. I'm friends with Dan, and Dan's friends with David, and how are we connected? Those network connectivities have an impact on our overall health. Think about it. If you want to lose weight, you don't hang out with the people who eat a lot of French fries, you hang around with the people who exercise. They bend health habits profoundly. Social isolation or hanging around with a bad cohort structure results in poor health outcome. This is my bias. I can show this slide, having played baseball there at one time a long, long time ago. This is 1980. I wasn't quite there then, but also 2019. Please look at the size of the guys on the offensive line. That is another human being. They added a human on top of the human. That has some profound impact. This is a paper by Tim Churchill from our group. Early life weight gain at this extent is toxic. They take these gentlemen who are blessed to be six foot five, six foot six, and make them consume 12,000 calories a day. It is an inflammatory toxin with long-term health impact, even if people lose weight. This is another paper that was unsuspected. Bill Meehan led this one. People tear their ACL. We know in a best of repairs, some folks wind up with arthritis at a 70, 75% rate. That's not surprising. People needing a joint replacement, that's not surprising. A 52% increased risk of a heart attack, that is surprising. Who would have ever guessed that? Immobility may be NSAIDs to some degree, but it's a real. David talked about really doing what we can do now, the Arthur Ashe thing. I can't believe in that more. One of this is really a theme I'll show you in the next slide. This is some work from colleagues at the UK Brain Bank where they show that early life hypertension is associated with brain structure and incident dementia. Early life hypertension, now watch what I will show you. That is, we see it in our guys very, very young. Very young. This is some work by John Kim and my collaborator, Aaron Baggish, who's a well-known exercise cardiologist. When you lift this much, you don't get a nice floppy heart like a runner. You get strong. You can squat 700, but you get a very stiff heart and a noncompliant system. Remember, not many plays in football last more than six seconds. We took Harvard athletes, or rather Aaron did, trained them that way and followed them, and they developed hypertrophic cardiomyopathy, which is associated at least on the Harvard side and we'll see on ours with white matter and memory problems. People are people. They're interactive. Let me go quickly here for just a second. We have a pretty strong association with hypertension in our group of guys, and that hypertension is, again, this vicious Gordian knot linked to concussions. Maybe it's many things, weight gain. I'm lifting a lot, and I've been hitting the head a lot. Indeed, one of my former mentors who recently passed away, who helped coin Takasabu syndrome, linking the brain to the heart, Marty Samuels, talked about the fact that this is not only possible, it's probable as an interaction term. Our group took a look at this and said, hey, how could this mechanistically be? This was recently in the Lancet Neurology, in which we looked at single versus repetitive brain injury and how it's linked to cardiovascular and cardiometabolic dysfunction over time. Now, that's not the only badness these guys might see. So if you've had loss of consciousness episodes, your odds of reporting low testosterone and erectile dysfunction are elevated significantly. It could be hypothalamic pituitary accident, could also be associated with depression. We think it's neuroendocrine. We know that sleep is critical for clearing neurotoxins. That's unquestioned as well. The oscillations in the sleep paradigm are important for normal brain function, but we see sleep apnea rates as high as 70% in some of these guys. That's incredible and can't do good for your heart or your brain. We don't count on this enough, but remember, the vast majority of footballers come from where I come from, which is somewhere in the U.S. South. A high-salt diet, vascularly comorbid, that may impact tau formation, and if you look where people come from, it's my good old home state of Florida, but Texas, California, and other places that probably have a little bit more bias in the diet. I'm going to just show this one from Adam, and that is the number of folks in our study versus NHANES, the study of the American male population, or the way we pulled it out was way out males, and the general population, the number of folks with arthritis, and it's pretty distinct. And then lastly, I want to remember that there are nocebo-based effects, right? If we tell everybody they're going to do bad, they're going to do bad, and so we have to be careful how we talk to our patients and the kinds of things that impact them. So all of these things are aging in many ways. Are we seeing what we believe is an aging maladaptive phenotype? David, Dan rather, elegantly put up a slide where there were a lot of interactions, and what we think is there's a silent period of some of these interaction diseases that we can affect, that we can do exactly what David talked about, which is push people out, push people towards longer-term health by doing all of those right things. So our hypothesis is that obesity, pain, racism, head injury, depression pushes people left, earlier manifestation of a maladaptive agent, and maybe even nocebo. This data is shown by the fact that when we look at our football guys, no matter how young you get them, in a paper we put in BJSM, they lose about a decade of health span. Health span is this idea, and you heard a little bit about it, a trace in the plenary session today, that you have agency, you can do what you want to do, and that disease is not causing a burden. So in closure, brain injury may increase the risk of health problems via primary neurodegenerative processes or others, biopsychosocial health covariates count. We may be seeing a maladaptive aging phenotype. The directionality of these things may go multiple different ways, and I believe there's implications not only for our footballers, but for all of us. So thank you guys. Thank you. That was an incredible talk. I think we were blessed to just get a chance to fly through, I think, probably three hours of information in an hour. So we have time for some questions, though. I think that there's one virtual. No, there's nothing virtual yet, so yeah, come on up. This is great information. I think the question is, football's not going away, the need for military's not going away. How are we helping these people in terms of diagnosis early on, and then what other treatment options besides what you presented, which is maybe more pharmacologic, what have you? Because again, we can't do anything about the situation, what can we do about early diagnosis treatment? What does that look like? So it's a great question. I feel like I'm in front of the US Senate, David's used to that. I'm more demure. From a football perspective, it's trying to understand what is the role of early exposures. There are things that have been rule changers, there are other things that have decreased the exposure early in life, or even in mid-season, that probably decrease risk. Do we really need to have a 16-year-old be eating 12,000 calories a day? What can we do from a athletic surface perspective to really impact the whole player, the whole life? What kinds of things can we instruct people as they leave the league? One of the things that people don't appreciate that I think is very similar to your cohort, David, is when people leave that, they go from like this to that. Their lives become disorganized, and they can never get that kind of lift again. And many of our military colleagues say the same thing. How do we provide transition services, whether that's the military or our group of guys, to probably make that path a little bit more congealed? I would just add that making the diagnosis of the TBI, and there's probably been about a billion dollars spent on that, and I don't understand why it's not that hard. I actually don't even care if they've had a TBI, and I mean that in a bigger sense, because I want to build their resilience before they have a risk. So as soon as they're joining the military or in high school, if they know they're going to play football in the military, let's start building brain health right there. Let's put it in the back, right? And yeah, it's nice to know if they had a TBI, and nice to treat acute symptoms, and the military is doing a lot of things forward now to actually have concussion programs in battle or obviously in the green zone of battle to actually treat the symptomatology. But if we're not doing stuff after that, it's not enough. So I was just telling Dan, we need to have a course here on how to assess and manage mental health problems as brain injury specialists, because managing a concussion, if you don't know how to do that, see me after, all right? But really, managing mental health problems and realizing we have better evidence-based research for that than we do for concussion, and yet we're like, well, send them to somebody. No, own it. So that's one way, and that's true in the NFL as well and other things. So that's, I would just say, build resilience and stop with the diagnosis, manage the symptoms. They really do well, which is what the VA has pushed forward. Yeah, and the symptom-like management actually holds in other populations of people. We see former professional American-style football players, people who have left the league clinically, and it's 100% that people are often responsive to symptomatic management. Dan has been preaching that for some time. But I would say two other things. We need to a priori avoid social isolation, and we can do that by building people's network of connectivity. And the only thing that I'd add, then, is that we can, if the evidence now shows that this cumulative exposure is what puts you at most risk later in life, well, two-thirds of hits are happening in practice, right? Do we need all those hits? So many years of exposure are happening at age like six to 10. Do those make you a better NFL player? Probably not, right? So there are ways that we can limit the exposure as well. I think we have time. I guess the one question I was asking specifically, objective diagnostic criteria, blood samples of Tau, whatever the case, right, like, it'd be nice to have an objective measure as opposed to a more subjective. I think they're going to put a blue tent on the battlefield and just put them in there like they do in the NFL. It would be okay. But I would lean towards, is what I tell my colleagues in the military and the VA, I said, then, if it's that difficult for you to figure it out, that's fine. Let's assume they have it and let's manage their acute difficulties as if they had a mild TBI, treat their sleep like day one, treat their headache. So I don't, I think we're spending way too much money, way too much time on objective tests. I got fluid and saliva on everybody. I got images. I got- Doesn't that worry all of you? It's in my trunk, but we have it all and we're really, I mean, yeah, we're finding signals, but nothing is better than a somewhat trained clinician talking to them and going through a simple history. Nothing is more accurate than that. So I think the value of a marker, I think David's- Point, counterpoint. No, I think he's dead spot on. I think the value of a marker would be not so much in diagnosis, okay, fine, but monitoring, diagnosis, telling us about the time and maybe it could help us to think about inclusion, exclusion for targeting certain therapies in the future. I agree a hundred percent. Monitoring recovery is vital, but again, these people have ears and can tell you how they're doing. All right? You may need to ask the questions more open-ended. You may need to have more knowledge about how to do motivational interviewing and time But that's on us. All right? You know, I would love to have a marker, but until we do, we're going to have to, you know, deal with it as well. So let me make a quick comment to doctor. This is- Dan, break us up. No, let me make a good comment to what David said, because I think it's certainly important. You know, in the middle of the pandemic, my good collaborator Maurizio Fava said that between kids 18 and 25, 63% had depression. This country's 16, 17,000 psychiatrists short. It's got to be about 50, 60,000 behavioral therapists short. There aren't enough people to treat headache. A lot of this we can learn to do. We're getting the signal. Yeah. Thank you guys very much.

neurodegenerative sequelae

traumatic brain injuries

repetitive head impacts

dementia

Alzheimer's disease

Parkinson's disease

ALS

chronic traumatic encephalopathy

CTE

long-term effects of TBI

military personnel