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This month Aaron is talking to Dr. Tom McAllister, the Albert Eugene Sterne Professor and Chairman, Indiana University School of Medicine Department of Psychiatry. He specializes in studying brain injuries and chronic traumatic encephalopathy, and he'll tell about brain injuries, their treatment, and some of the advances in detecting such injuries.

The Healthcare Triage podcast is sponsored by Indiana University School of Medicine whose mission is to advance health in the state of Indiana and beyond by promoting innovation and excellence in education, research and patient care.

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Aaron: Hi! Welcome back to the Healthcare Triage Podcast. I'm your host, Aaron Carroll, and today our guest is Thomas McAllister, the Albert Stern professor and chair of the department of psychiatry at Indiana University School of Medicine.

The Healthcare Triage Podcast is sponsored by Indiana University School of Medicine, whose mission it is to advance health in the state of Indiana and beyond by promoting innovation and excellence in education, research, and patient care. IU School of Medicine is leading Indiana University's first grand challenge: the precision health initiative with bold goals to cure multiple myeloma, triple negative breast cancer, and childhood sarcoma, and prevent type-2 diabetes, and alzheimer's disease. 

Today, we're going to be talking about traumatic brain injury. What is it?  What can we do about it? How can we prevent it?

Thanks for joining us Tom.

Tom: Thank you Aaron.

A: I like to start these conversations by asking people, you know, how you got here. Um, how did you decide you wanted to get into psychiatry? What was your training? How did you get into traumatic brain injury?

T: Great, yeah, well, uh, the one thing I knew when I went to medical school that I was not going to be was a psychiatrist. So, you should take everything I say with a grain of salt from here on in. Uh, but it turns out that, um, I became fascinated with brain behavior relationships. If you injure the brain or if you have a disease in a particular part of the brain, how does that, uh, then influence mood, emotions, and, uh, behavior in general. And it, uh, sucked me in, and I ended up going into psychiatry. And, in particular, field of psychiatry called neuropsychiatry.

A: So where'd you go to medical school?

T: I went to Dartmouth Medical School, and I was ambivalent about being in psychiatry, so I did a year of internal medicine and then, uh, trained at Dartmouth, uh, in psychiatry.

A: So, how did you get into traumatic brain injury?

T: Well, this may seem like a recurrent theme, but, uh, I knew I was never going to take care of people with brain injury. I had jobs, uh, calling, saying "we really need somebody to help us care for the, um, behavioral disturbances that often are associated with brain injury." And, I said no thanks. And then, uh, one time in Philadelphia, during my Phildelphia phase, somebody called up and said, "are you the organic psychiatrist?" And I said, well, as far as I know. And, it turned out at that point and time, um, there was a lot of effort to bring people with brain injury who were, um, young when they were injured and were living with a profound array of neuropsychiatric problems, and nobody knew how to take care them. They were in institutions, and so forth. So, somebody was trying to bring them out into the community and needed some help, and I said sure. And, have been working in the field of brain injury for the last 30 years.

A: So, when we talk about traumatic brain injury, uh, does that mean any injury to the brain? Or is it mostly blunt? Or can it be a gun shot? Or, does it just not matter?

T: Well, it does matter from a couple of perspectives, but, strictly speaking, uh, there are a couple of broad, uh, division points. One is it has to be an injury that results from some kind of biomechanical force on the brain. It could be a penetrating injury from a bullet, for example. Um, or it could be a blunt injury; for example, your head hitting the windshield or you stumble and fall and you hit your head on the floor. Um, but, there has to be some kind of force acting on the brain that results in disruption of neurological function.

This separates is, therefore, from, uh, other kinds of injuries, such as a stroke or, um, conditions that people might be born with, um, that result in intellectual disability, and so forth. So, it has to be an acquired injury, but it has to be acquired by dint of biomechanical force on the brain.

A: How common is it?

T: It's really common. Um, if you look at the burden on neurological disorders in the country, um, it's probably, um, ranks first or second in terms of numbers. Um, some estimates put it that about 1% of the population are living with, um, some form of, ah, brain injury or TBI (Traumatic brain injury) related disability.

A: What causes it most of the time? Has that changed over time?

T: It has changed over time. So, back when I was turning down jobs in brain injury, the most common cause were motor vehicle accidents. And, typically was in people in their second or third decade. So, folks that were beginning to drive, were not particularly good at it or using alcohol and operating at the same time, uh, feeling they were immortal. Um, and, um, this was before seat-belt laws and airbags. So, that was the most common cause back in the '60s, '70s, and '80s. Right now, the most common cause is falls. So, um, and not just in the elderly, although that's driving a lot of it.

A: So have the demographics changed? Is it more that you see it much more in the elderly now than it use to be?

T: We still continue to see it across the, uh, the lifespan, but in terms of what is the most common cause of it is, it is falls. But, there's peaks. So, there is a peak in the very young people, um, and then a peak in the elderly. But, there's still this bump in the second and third decade related to motor vehicle accidents.

A: So, have there been any changes with respect to how we diagnose it? With respect to imaging or anything else that have changed over time?

T: There have, actually and these are some of the more exciting areas in the field at this point and time. And, it takes a couple of different forms. Um, to date, uh, a brain injury has been, uh, especially on the mild brain injury side or concussion, has been a clinical diagnosis. It remains a clinical diagnosis, though you have to have a plausible force that is acting on the brain, which is hitting your head in a football game or whatever. And then, you have to have an alteration in the level of consciousness, manifested by incomplete memory or being dazed and confused and so forth. 

One of the big areas of interest is in neuroimaging. So, at this point and time, the most common imaging study in people who have brain injury remains a CAT scan, or a computed axial tomography scan, because it's really good, uh, at showing if there's accumulation of blood of if somebody needs a neurosurgical procedure. It's not so good at revealing very subtle, very tiny areas of hemorrhage or neuronal injury. So, MRI, magnetic resonance imaging, is a better tool for that. It's more expensive, it takes longer to acquire the image, but there are now new signal acquisition techniques, meaning ways of taking the image, that can reveal these subtle changes that we talked about in the fibres that connect one nerve cell to another called white matter imaging or diffusion imaging.

And, in some work that is coming out of this care study that we've been able to show, that our imaging group has been able to show, that there are subtle changes in white matter that persist beyond the point and time when athletes report that they are asymptomatic, or that they are fully recovered. So, that's not necessarily in diagnosis, although it could be used that way, but it's also in treatment and recovery monitoring.

The other big area is in so-called fluid biomarkers, where trauma's associated with the release of certain proteins and other compounds into the bloodstream. And, we are in the process of talking a look at a large sample of our concussed athletes from this study, and it shows very, very promising separation in certain of these biomarkers between people who are concussed, people who are teammates who are hitting their heads on a regular basis but not concussed, and people who are, you know, playing golf or swimmers who aren't hitting their head on a regular basis.

So, I think if you look a year or two down the road, I think we will probably have a panel of blood tests that we can do that, with fairly good accuracy, will at least help confirm and strengthen the diagnostic impression, if not actually be a stand-alone kind of diagnostic marker for concussion.

The next challenge will then be developing a point of service kind of machine that could do that on the sideline, for example, or in the theatre or war so that people could know right away.

A: So, given that most of it is blunt, how-- can you talk a little bit about the mechanism, about what happens to the brain when such injuries occur?

T: We generally talk about two different broad types. One is an impact or a contact mechanism in which something impacts or contacts the brain resulting in damage from that. And the other is more of an inertial kind of injury in which damage is inflicted on the brain by dint of a very rapid change in the momentum or motion of the brain, either by acceleration of the brain. So, think about standing still and someone comes up behind you and wacks you with a baseball bat or something, your head is going from zero to, you know, whatever speed very rapidly. And/or, a deceleration kind of event in which you're driving down the interstate at 70, and you hit the person in front of you and your head hits the windshield, and you're sort of decelerating from 70 miles per hour to nothing over the course of milliseconds. And then, associated with the conflicts in Iraq and Afganistan over the last couple of decades, there's been a lot more attention focused on blast injury as a potential other kind of way of damaging the brain.

A: Is it that we're actually smacking the grey matter or the white matter of the brain, or that there's a disruption of the blood flow, or is it something else entirely?

T: Ah, yes. So, it's all of those. But, basically, if we talk about, if you think about or can imagine the brain floating essentially in spinal fluid and partially tethered by the spinal cord, and now set the body in motion, what's happening is that the brain is essentially sloshing around in this bath of spinal fluid, and is moving out of phase with the skull. And, it turns out that the inside of the skull is not completely smooth. It has bumps, ridges, points of contact with the brain. And, it's great for protecting, you know, things from the outside, but when you set the brain in motion, or the head in motion, it becomes a sort of hostile work environment for the brain to live in. And, there are particular parts of the brain which are then bumping up against the inside of the skull. And, what happens is that those particular brain regions are extremely vulnerable to contusions or bruising and bleeding in those areas. And then, in addition, the motion and the out of phase motion of the brain with the skull sets up twisting and stretching and forces on the fibres of the neurons, which rips them or can stretch them in a way that renders them dysfunctional.


So, if you think about a Slinky, for example, many people are familiar with a Slinky, you know that you can bend those things to a certain point and all of the sudden they're not going to work the way they're suppose to.

A: That's an interesting-- So, well, first of all, it strikes me that I never really thought about this way, but, I guess, from an evolutionary standpoint, we were never meant to go that fast.

T: We were not. 

A: Yeah, so we're just not prepared for the sudden acceleration or deceleration,

T: Correct.

A: In a larger sense, how-- so what can we do about that? I mean, if we, if this damage occurs, what do you do?

T: That's the 64, whatever, million dollar question at this point and time. And, I think there are a couple of things to recognize. One is that I mentioned that there's particular brain regions that are vulnerable to these biomechanical forces in a typical injury, such as we're talking about. And, it turns out that they're the under surfaces of the frontal lobes, the front part of the brain, and the temporal lobes, which are the part below the temporal bone, and, then the white matter fibres, which connect these different brain regions. And, if you were to draw a map of those brain regions and overlay it on the brain regions which modulate mood, emotions, impulse control, judgement, executive functions, memory, and a variety of other cognitive functions, you really couldn't make a more careful overlapping Venn diagram.

And so, this is an injury that is the perfect storm from the standpoint of inflicting damage to what we usually think of as the essence of being human. So, our ability to plan, to make judgements, to modulate our impulses, and so forth.

And, fundamentally, that's what happened when I began working with folks with brain injury. This is a form of an acquired psychiatric illness, essentially, so the relative risk of depression goes way up, the relative risk of developing an anxiety disorder goes up. So, it's essentially getting at all that we view as being part of a complex, you know, organism with all the capacities that humans have.

A: Can we do anything about it?

T: So, yes, with a qualification that you can probably hear in my voice. The, uh, we have spent millions and millions of dollars trying to mitigate the downstream effects of that initial injury with so-called neuroprotective trials, medicines, and agents or interventions, such as cooling of the brain and so forth, which are designed to stop the damage from evolving once you have the impact of the brain on the skull, or whatever it hits. So, that's one strategy. Let's stipulate that the brain is going to get injured, but let's try and prevent the evolution of the damage that occurs over hours or days subsequent  to them.

A: So, I imagine you have to get to someone reasonably quickly, though, as soon as injury occurs to try any of that.

T: Exactly. And, sadly, every single one of the neuroprotective agent trials over the last probably two, well, three decades have failed, despite elegant, elegant evidence that they should work in animal models. And, it's in part because there's this cascade of events that I'm talking about as this elaborately choreographed multi-system kind of evolution that you just can't fix a single part of it. It's like putting up an umbrella in a hurricane. 

A: Ok, given that that doesn't work, do we have other options?

T: Let's just back up a second and say, really the best option is to prevent the injury to begin with.

A: Oh, I was going to get to that. Yeah, we're getting there.

T: So, we can return to that, but let's stipulate again, for the moment, that somebody gets injured. So then, there's aggressive rehabilitation that can work with people to regain a lot of the function that they may have temporarily lost. So, learning to, uh, learning to speak again, learning to walk again.

What's more challenging, and what is often the most problematic concern for both people with brain injury and the folks that take care of them, their family caregivers or loved ones, is this assault on who they were, their essence, their personalities that we, very commonly, hear that this is not the person I married or this is not my son or daughter. This is somebody completely different. And, at its essence, these are dysexecutive syndrome that have been brought about by the, uh, where in the brain the damage is likely to occur.

A: Do the people, themselves, feel like they're not the same person? Or is it just other people around them feel that way?

T: That's a great question. So, a lot of this depends on the severity of the injury. So, at the milder end of brain injury, people often do have an awareness, and sometimes an acute awareness, that they're not quite functioning the way they use to, and it can be enormously frustrating and challenging. At the more severe ends of this spectrum, there is often damage to the part of the brain, as we've been talking about, that allows people to be aware of their behavior in a social context and aware of what the social norms are. And, they're, it's as if they have, um, they're blind to that. And so, they are often, it's very common to see people who are quite unaware of their behavior, and how it differs from how they use to be, and how it differs from social norms or what people expect in a given context.

A: So, given all this difficulty, it does seem like prevention is the best thing that we can do. So, what are the major things we do to help prevent this from happening?

T: Well, I mentioned at the outset that back a couple of decades ago, the most common causes of brain injury were motor vehicle accidents and crashes, and so, once seat belt laws were put into effect, and airbags were developed and became wide, you know, used widespread, that resulted in a pretty dramatic improvement, both in terms of reduction of frequency and also reduction in severity. Driving under the influence is obviously a huge contributor to motor vehicle accidents. Another major-- you know, all these things, it's not going to be any surprise to people who are listening, assaults are a huge problem, particularly in certain areas. And falls; so, anything that we can do to mitigate and prevent or reduce the risk of falls. That's a huge issue.

A: So, I imagine, in some of those areas, we have made great strides, and there's probably not so much. So where's the focus mostly these days?

T: So, the focus these days actually is on preventable causes of injury, and one of the major focus really is on sport-related concussions. So, basically, if you think about it, some of the activities we engage in, football being an example, is associated with a context in which there's a lot of repetitive head impacts, some of which can result in a concussion, and so forth.

A: So, as a pediatrician, this is the one that's constantly, you know, shoved in front of my face, and that we're talking about all the time, especially with ideas of, you know, should we let kids participate in these sports because... Why is it all of the sudden this is, or feels like all of the sudden, I should say, that this has entered our national consciousness. I mean, a lot of these sports have been going on for quite some time.

T: Yes they have, and it's a great question. And, I would point to a couple of different issues which brought this into focus for the last, it's really been about 15 or 20 years. Back when I started in this area, reluctantly, as I mentioned before, I began a clinic for people with brain injury and ended up seeing a lot of folks with so-called mild brain injury, which is synonymous in my mind with concussion so I'm going to use the terms interchangeably, but it's a mild traumatic brain injury. And, I thought that this was a horrible, horrible condition because I was being referred only those people who don't get better, and so it was a sort of sampling bias. But, nevertheless, I had to convince people that sometimes people don't have a good outcome after a seemingly mild brain injury. 

And then, in, um, with the emergence of the War of Terrorism and the appreciation that our military personnel were being exposed to increasing number of blast forces, and, it's important to point out that while the blast wave can damage the brain in and of itself, it's usually associated with a Humvee accident, or being blown up and colliding with a wall or hitting the ground, or whatever. So, it's typically a combination of blast forces and impact and inertial forces. And, there was a group of people who were psychiatrist, neurologist, physical medicine folks and others, who became aware that many of the military personnel were being to report signs and symptoms consistent with mild brain injury. So, the Department of Defense ended up, as most people are aware, naming brain injury or referring to it as the signature wound of the war, uh, was in Iraq and Afghanistan. That called a huge amount of attention to it. It created a huge funding stream through the Department of Defense to study this. If you look at the growth curve of papers published on traumatic brain injury over the 20 years, there's an exponential rise. I used to be able to do a PubMed search and complete it in about 5 minutes, and now it's not so much.

So, that was one. Then, in 2003, Bennet Omalu and colleagues published a paper on something called chronic traumatic encephalopathy in a NFL football player who had killed himself. And, this brought attention in a fairly stark way and surprising way to the potential risks of repetitive head impacts and repetitive concussions. Now, it turns out we had known about this for a long time. So, the original sort of work on this was published by Martland back in the 1920s and it was in professional boxers who, not surprisingly, had multiple concussions and multiple head impacts.

They described a similar neuropathology in this football player, and subsequently went on to summarize similar findings in a variety of other retired professional athletes and other contexts, including interestingly some military personnel who had been exposed to multiple blast events during the war.

So, the confluence of a high profile War on Terror and the fact that brain injury was a huge component of what the burden of morbidity associated with the conflict, and high profile papers dealing with CTE (or chronic traumatic encephalopathy) in retired athletes brought it into focus.

The other point is that, you know, a lot of these solders in OEF and OIF were protected by body armour that we didn't use to have to that extent. So, they were living now, but they were living with the sequelae of brain injury, which the body armour doesn't really protect.

A: That's really interesting, but if we're focused on sports for a minute. So, now, I mean, we keep hearing about, you know, NFL athletes especially having this, and it's interesting because, I'll read something in the news and it will seem like it's a crisis. Then it feels like it goes away, and then it comes back and it's a crisis. And then, it goes away. Is there a sense of how real or how prevalent this is in NFL players or just pro-sports players in general?

T: This is a subject of huge controversy, and basically, the way this story is evolving is that it seems clear that, in the same way that it was fairly clear in boxers, that there are a group of folks who are exposed to either repetitive concussions or repetitive head impacts or both, most commonly, for whom it is associated, that exposure is associated with the development of this neurodegenerative condition that we're labeling chronic traumatic encephalopathy or CTE.

The problem that we have, to date, is that we don't know what the denominator is. So, as you pointed out, people have been playing football for over a hundred years at an organized level. We, to our knowledge, don't have an epidemic of chronic traumatic encephalopathy, number one. Number two, the data that has been published, so far, is based on the brains of NFL players and other folks with other kinds of collision sport activities or military exposures, in which the families were motivated to donate the brain or the players and the people themselves were motivated to donate the brain, because they were convinced that they were not who they used to be, that they were undergoing these changes. So, it's a very selected sample. It's not a random sampling. We don't really know-- What we're not seeing are all the brains of the people who don't fall into that category.

Now, if you-- there was an interesting follow on some-- Let me back up, sorry. A couple of years ago, or maybe it was just last year, Ann McKee's group at Boston University published a study which they said 110, or out of 111, brains of NFL players had chronic traumatic encephalopathy. And, that made a big splash and appeared in The New York Times, as well. And, they made the point that, you know, this is a selected sample, we still don't know what the true prevalence is. So, another group of investigators said, we'll we could probably figure out, so the brains were collected over an 8 year period and they went to the NFL players association and figured out all the NFL players who had died over that same period of time. And, it turns out it was about 1,100. So, if you, if everybody who had CTE ended up in Ann McKee's group, then the rate would be about 10%. 

A: That still seems high. 

T: Well, so if only half of the people that have CTE ended up donating their brains, then we're getting up around 25, 30, 40 percent of folks. But, it's not everyone. And, the narrative in the lay press is that a single concussion may be sending you down the path to CTE, and we don't know that. And, in fact, there have been statements made that comparing letting your child play football to a form of child abuse because we're so certain that it's going to develop the, that it's going to be associated with CTE, we just don't know that.

A: That is partially what it is. I mean, I've read, and again, this is lay Aaron, compared to everything else, but it's a, you know, of course football players in the NFL are going to be striking each other with a lot more force in general than Pee Wee Football is going to have. And so, but of course, you know, we're all rolling dice with all kinds of things that we do, but we have no evidence at this time, I'm questioning this, that, that playing football at lower levels leads to this? The evidence we have at this point is from NFL players, is that correct?

T: Not entirely correct. So, there have been some reports of people who meet the criteria for CTE, and, and I should point out that this remains, uh, this condition remains a neuropathological diagnosis. Meaning that you can't make a definitive diagnosis until the person has passed away and the brain is autopsied. And, it wasn't until either 2016 or 2017, when the NIH convened consensus conference that the neuropathologist could agree on what the criteria were, and how many, how much slicing and dicing of the brain you needed to do in order to rule it in or rule it out.

So, that said, there have been reports of, for example, college football players who did not report any concussion by history, one of whom who committed suicide, went to- came to autopsy, and was found to have the hallmarks of CTE. Others, from different groups have undergone a, have done neuropathological diagnosis on a series of brains and found people who met the criteria for CTE who had no history of trauma. So, this is not an area that we have all the answers to. There also have been a few reports, quite a few reports, of folks exposed to the blast concussive force and other kinds of brain injury in the military. At last report, my understanding is that about, somewhere around 60% of the brains, again that were collected by a particular group, with this kind of exposure had findings suggestive of CTE.

So, it's, I think there's reason to be concerned. There's clearly reason to be concerned. What we don't know is are we asking the right question? Is hitting your head bad for everybody? Or is the question, a better question, is for whom is hitting your head bad? So, might there be individual factors which make one person more vulnerable that others?

A: So, what are we doing about all of that, or are we doing anything about all that?

T: Well, we are. So, one of the big advances, in the last decade or so, has been the development of sensors that we can put in, for example, football helmets or, conceivably, military helmets, that will measure, with some, obviously, measurement error built into that, the amount of force that people are exposed to. So, for example, in the case of football players, we've done studies in which the helmets are equipped with accelerometers, similar to what you might find in your iPhone or your watch, you Fitbit, that will measure the G-forces associated with a particular hit to the head. And, when we started this work, it seemed like it was going to be pretty straight forward and easy. We're going to equip the whole football team, we're going to measure them, and we're going to say, "you had a concussion and it was a 80 G hit, and you did not and it was a 79 G hit." And, we're going to say, there we go. There's the threshold. 

So, it turns out, sadly, that it's way more complicated than that. In part, probably because these sensors may not be completely accurate at measuring what's really going on. But, it's very clear that people can be diagnosed with a concussion at relatively low impacts, not that I would want them, but at 50 or 60 G's, for example, and there are other people can sustain 110 G, 120 G hit, bounce right up, and have no, apparently, no symptoms associated with concussion.

And, so that has lead us, the group that we're working with and other, to speculate that perhaps context matters. So, might it be that it's not just a particularly smoking gun hit, but it's the fact that the person was hit five or six times earlier in the game, or in the practice, or earlier in the week, and there's a kind of priming or kindling of the brain that's going on which makes that next blow the one that sort of is associated with concussion.

A: So, is there anything we can do in the short term about all of this? Is there things, actions we can take to try to limit the damage?

T: So, I think there are. I mean, we're part of a large study that has been funded by the Department of Defense, the US Department of Defense, and the NCAA, called the Care Consortium, and that has basically allowed us to put together a concussion research network. We now have 30, um, 26 civilian universities and colleges who are participating in four of the military service acadmies. And basically, the way it works is that we do a set of baseline measures before any season starts in all sports, and both men and women, so it's going to be the largest study of, to date, of sport-related concussion. And then, if somebody's identified as having a concussion we repeat these measures at five time points, so that we have a really good idea of what the natural history of the, of the injury is. And, we've now been funded to do a follow-on study, so that we're getting an additional time point when these participants graduate from university or service academy to look at whether there are cumulative effects of hitting your head over and over and over again. And, we're working to, hopefully, be able to extend that study of this cohort for decades if we can. 

A: Right, I mean, of course, that's part of it, is following what happens over a lifetime, but in the short term, how long you expect that study to run?

T: So, we have, let's see, it's run for about, we're in our fifth year now. We have funding for two years to do the cumulative study, and we're apply for, you know, the more longitudinal component in five year increments. So, we'll see in a few months how that works.

A: You know, we always talk about long term cohort study, it's so fascinating. Because, of course, it takes so much work to get this going, but, you know, what we really are so often interested is the long term downstream fix. But, you need to start so many years ago to find those thing out. I mean, it's good that that's going on, but I imagine we'll be getting data for years to decades to come.

T: Yes, indeed. Absolutely.

A: Is there any other work that you're working on in this area that we should know about?

T: As part of this study that we're talking about, there's a subgroup of the athletes and participants who undergo a much more detailed characterization of brain structure and function. So, these folks undergo multimodal MRI imaging, which allows us to look at the structure and function of the brain's white matter. We're looking at regional blood flow in these folks. And, of great interest to me, is this idea that people probably differ in their vulnerability to both the injury itself, the sequelae of the injury, and the recovery trajectory. So, we've been looking at fluid biomarkers of good response and bad response. We've been looking at genetic predictors of outcome, as well as vulnerability. And, I think that what we want to do going forward is to actually begin to look at some of the, what we think are the hallmarks of this chronic traumatic encephalopathy. Meaning a pet study of the protein tau, which we think is one of the markers for the condition.

A: And is that something is a marker to tell us that it's happened or something you think you can act upon to limit or reverse some of the damage?

T: Yeah, that's the million dollar question. So, like Alzheimer's, it's a condition in which the, and, and many other neurodegenerative disorders, tau is a protein that is a normal part of the brain, but if it accumulates in certain areas it can provoke, we think, an inflammatory response, which can have destructive downstream effects. And, it turns out that many of these proteins can be folded improperly, and that can lead to accumulation and failure to remove it. So, your question is exactly the right one, which is, is that just a marker for something bad that's already happened or is that the precipitating cause? And, we don't know that at this point in time. If it's the precipitating cause, then one could think about vaccines that might do or medications that might facilitate its removal from the brain. But, similar to Alzheimer's disease, where a lot of work has focused on amyloid, another protein in the collection of, of that and whether we can vaccinate against it, or we can, it hasn't worked out the way everybody hoped, yet. And so, you know, it's the kind of work that we're going to just have to go through until we get the answer.

A: Well, until then, it sounds like prevention is still our best bet.

T: It is, indeed. It is, indeed. Yeah. 

A: Tom, thanks so much for being here. This has been fascinating. If we can, I'm sure we'd love to have you back again as new details and new information arises. 

T: My pleasure. As you can tell, I love to talk about this stuff. So, I'm glad you're shutting me off. 

A: We love even better. Thank you very much.

T: Alright, thanks Aaron.

[Outro]

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