Head trauma and dementia risk. An important risk factor for Alzheimer’s disease is head trauma and the chronic traumatic encephalopathy that can result. It is causing us to rethink everything from  how we view high school tackle football consideration to whether headers should be allowed in high school soccer play.

Michael Alosco PhD is  co-director of the Boston University Alzheimer’s Disease Research Center Clinical Core. He completed his undergraduate studies at Providence College and he earned his doctoral degree in clinical psychology from Kent State University. He is an Associate Professor of Neurology at the Boston University School of Medicine. Dr. Alosco has >150 peer-reviewed publications.

 

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Robert Lufkin 0:01
 Welcome back to the health longevity secrets show and I’m your host, Dr. Robert Lufkin. An important risk factor for Alzheimer’s disease is head trauma and the chronic traumatic encephalopathy that can result it is causing us to rethink everything from how we do high school tackle football considerations to whether head or should be allowed in high school soccer play. Michael Blasco, PhD is co director of the Boston University Alzheimer’s Disease Research Center clinical core. He completed his undergraduate studies at Providence College and earned his doctoral degree in clinical psychology from Kent State University. He is an Associate Professor of Neurology at the Boston University School of Medicine. Dr. Lasco has over 150 peer reviewed scientific publications. And now, Dr. Michael Lasco. 

Michael Alosco 0:58
 Hello, everyone. My name’s Michael Lascaux. I am Associate Professor at Boston University School of Medicine where I helped oversee a lot of our clinical research on Alzheimer’s disease, as well as chronic traumatic encephalopathy or CTE a topic that all I’ll be presenting and talking to you about today, I first want to just thank you to Dr. Lufkin and others for organizing this incredible online virtual platform to discuss the latest advances in Alzheimer’s disease, Alzheimer’s disease risk and treatments and updates on prevention strategies. This is wonderful forum and I’m very grateful to be to be a part of it. So I do not have any disclosures other than receiving support from the National Institutes of Health. So I just first want to talk about a quick outline on on what we’re going to be discussing today. So first, I’m going to do a rather brief overview on traumatic brain injury and Alzheimer’s disease. I’ll go over what these terms mean, and what their association is. This is a these are. This is a topic that’s been studied for a while now. But really, the goal and the focus of this talk is on current chronic traumatic encephalopathy or CTE and risk factors for chronic traumatic encephalopathy and what this disease is, and what it looks like both in the brain and clinically the symptoms, the signs and symptoms that it presents with. So when we think about traumatic brain injury, the CDC defines it as a disruption in the normal function of the brain that can be caused by a bump blow or jolt to the head or a penetrating head injury. And here’s a table commonly used to to classify the different types of TBI. So there’s you can have a mild, moderate, or severe TBI. Most often you see the severity of TBI determined by the length of loss of consciousness, so people who hit their head and get knocked out or lose consciousness, it’s considered mild if it’s if the loss of consciousness is less than 30 minutes. Moderate. If it’s greater than 30 minutes or less less than 24 hours, then severe is anything greater than 24 hours. However, there’s also these other deaths, different types of criterias here to define the different head injuries. So alterations in consciousness, duration of loss of memory following the injury known as post traumatic amnesia. The longer the longer the time you have memory gap. For things that happened after the injury, the more severe it tended to be. There’s also the common Glasgow Coma Scale, Coma Scale. And these are all just different ways to classify the severity of TBI. 

Now, what are the signs and symptoms of TBI? If we think about TBI, there’s there’s actually four types of signs and symptoms that usually happen after this injury. So you have these somatic or these physical symptoms. These things include things like loss of consciousness, being overly sensitive to light or sound, having headaches, nausea, trouble, balance, balance 

problems being steady on your feet. There’s also the sleep problems. People often have a hard time falling asleep, staying asleep, and not resulting in some insomnia for some time. There’s the thinking and memory problems or cognitive difficulties. These include things like attentional difficulties, visual problems, trouble remembering information or memory disturbances. And then there’s also mood symptoms. often accompany of TBI. These include things like depression, being irritable, agitated, or having just overall mood swings. So these are the four domains of signs and symptoms that you typically see following a TBI. And again, these signs and symptoms they can become, they can last longer and become more severe as the injuries severity of the TBI increases. So here’s a nice figure adapted from a from a previously published study that shows the recovery of the different CV severity of TBI eyes. So if you look on the y axis here, or on the on the vertical axis, you can see that a person’s baseline so their normal function is at the top here. And then and then here is illustrating when the traumatic brain injury occurs at the time of their normal function. Now, someone who has a mild traumatic brain injury, they experience those symptoms that I just discussed. And typically someone with a mild traumatic brain injury will recover and return to the normal function within seven days to two weeks, right. And usually most, if not all, will will will recover by fully by one month. Although there is a small subgroup of people who will go on to have symptoms that persist for for a year or so or longer. Then there’s also the moderate and severe TBI, you can see the moderate TBI takes much longer for them to recover. And in fact, some people might not ever return back to their baseline or to the normal function, then you have a severe TBI. And similarly, it takes longer to recover from this injury. And again, most people and a lot of people do not ever kind of get back to their normal function though, though certainly there are people who can, but most most do not. So you can see this is a great figure showing the relatively acute recovery process of the different TBI eyes. And importantly, I just want to note again, or emphasize that people with mild TBI, almost all will recover within within two weeks to a month with a small subset who have prolonged symptoms. But again, even those people will recover within a year or so. Now, switching gears here, let’s talk about Alzheimer’s disease. So traumatic brain injury. Mild through severe has historically been researched and viewed as a risk factor for Alzheimer’s disease. So before I talk about that relationship a little bit more, I want to just briefly touch on what the biology of Alzheimer’s is. So what is Alzheimer’s disease. So here is a picture of a neuron. And, and you can see this is this, over here, this cell body, this is an axon or the white matter where information travels across. And the cardinal or the classic pathology of Alzheimer’s disease is the accumulation of what of a protein called beta amyloid. And in in these plot, these are normal proteins in our brain that in Alzheimer’s disease do not get cleared and they come together and plaques outside of the cell. 

And it’s often thought the most common hypothesis of Alzheimer’s disease is that this accumulation leads to aggregation and mis folding of a protein called phospho tau, resulting in phosphorylated tau that accumulates within the cell. And as this accumulates, it strangles the cell and leads to cell death, eventually leading to two problems with thinking memory and dementia. So the presence of beta amyloid and phosphorylated tau are the are the two Cardinals pathology of Alzheimer’s disease. Now, in 2005, there was a Institute of Medicine issued a report and what this report was was it was an exhaustive literature review by a panel of experts, and they rated the evidence on the long term consequences of traumatic brain 

injury. So in total, they rated 10 studies on the relationship between traumatic brain injury and Alzheimer’s disease. And they concluded that there was sufficient evidence that a moderate for severe TBI is associated with Alzheimer’s disease. There seemed to be some suggestive evidence that when you had a mild TBI with loss of consciousness, remember you can have a mild TBI and it can be without loss of consciousness, but only those with lost consciousness. It seemed to be suggested that evidence of the risk factor for Alzheimer’s disease, but there was inadequate evidence that a mild TBI with outlaws of conscious could confer risk for Alzheimer’s disease. So that was that was some time ago now. But since that time, there has been numerous reports, a large studies, large epidemiology, large cohort studies, continuing to show that TBI is a risk factor for for Alzheimer’s disease, Alzheimer’s disease dementia in particular are in in this relatively recent article. This was this was published in JAMA neurology. This was over 7000 autopsy participants. So these were all deceased participants from these large kind of community based studies. And what they found in this again, these this was an autopsy sample where they could actually neuro pathologically define Alzheimer’s disease and other neurodegenerative diseases. They found no association between TBI with dementia or Alzheimer’s disease neuro pathologic changes, but they did find it was associated with some other neurodegenerative diseases. So or in neurological disorders like Lewy Body disease, Parkinson isms and Parkinson’s disease. So what’s different about this study, compared to some of the other studies I was talking about before, is that this actually had neuro pathologic evidence of that beta amyloid and that tau protein, I was talking about an Alzheimer’s disease, many of the other studies showing association between TBI and Alzheimer’s disease, it was the clinical diagnosis of Alzheimer’s disease using kind of medical records or similar methods to identify who had clinical Alzheimer disease. And here’s a study that that we published, it’s actually been accepted and is published, that that used a really large sample from the National Alzheimer’s Coordinating Center. And and I’m not going to go into too much detail because the take home message here is that traumatic brain injury did not correlate with Alzheimer’s disease, neuro pathologic changes in this out in these 1000s of of brain donors who came to autopsy. So very similar to the last study I showed you again, what’s novel about this study was that it was a large sample that had neuro pathologic evidence of Alzheimer’s disease. So why so what how do we make sense of this? So there’s this historical account and research showing the relationship between TBI and Alzheimer’s disease than these more recent studies. These more recent neuro pathology autopsy samples, do not actually find a link between TBI and these and these proteins of Alzheimer’s disease in the brain. So I think what we can conclude is that yes, TBI is a risk factor for dementia. And when I say dementia, what I mean is memory or thinking impairments that become so severe they interfere with someone’s ability to function. Right. So that’s a regardless of it of Alzheimer’s disease or Parkinson’s disease or whatever’s causing it. Dementia is a clinical syndrome. And we do think TBI is associated with risk for dementia, particularly moderate to severe and including evidence for mild TBI. 

That being said, perhaps TBI is not specifically associated with Alzheimer’s disease or maybe different types of TBI is caused different types of neurodegenerative diseases and related decline. But importantly, one one, or there’s two important factors that the literature has historically neglected up until recently, and that’s consideration for both repetitive head impacts and sub concussive blows. Right so the literature so far has focused on mild moderate 

severe TBI, often focusing on does one or two or three result in in risk for later life outcomes. But literature has very rarely looked at repetitive head impacts or sub concussive blows. So what is a sub concussive blow? So that is just like a TBI. It’s an impact to the brain that has an effect on neuro neuronal functioning. But unlike a TBI, there’s no immediate symptoms. So the force applied to the brain is not adequate enough to cause symptoms, but it is adequate enough to cause injury to the neurons or the brain. So you often see these sub concussive blows and things like contact sports so American football, you can see on the background of this slide, it’s when when to two people are bumping heads every down every practice every play, and those heads you know, maybe they’re not getting symptoms every time but pretty Perhaps there is injury going on to the neurons. A lot of these particularly American football players can have, you know, 1000 plus of these had it had impacts per season. And so if you take someone’s career, 1015 20 year career over their, over their lifetime, that’s a lot of head impacts. So, so that’s sub concussive blows. Now, repetitive head impacts, it’s kind of just like, like it sounds. So repetitive head impacts. Again, it’s any type of force that’s applied to the head. And that head causes some type of injury to the brain. Right, and then and then that injury to the brain that can result in recurrent or repetitive concussions or to mild TBI and the symptoms, or recurrent or repetitive sub concussive injuries. And those are, again, those are injuries to the brain that don’t cause any symptoms. So you think of repetitive head impacts as an environmental exposure of force applied to the head. And that exposure or force causes injury to the brain to cause recurrent either concussions or mild TBI or sub concussive injuries. So you imagine, think about American football, a lot of these guys have repetitive concussions, but perhaps even more prominently or they have repetitive sub concussive injuries. So we recently set out to study the long term effects of repetitive head impacts, and TBI. So we also looked at not only sub concussive and repetitive, so I’ve come up because of injuries but also traumatic brain injury. And we looked at its long term effects on depression symptoms, and cognitive function. This was published in 2020. In neurology by our team. This study leveraged the Brain Health Registry. So this is an amazing resource out of the University of California, San Francisco, pis, Dr. Weiner. This is an online registry, that anybody across the country can sign up for. At the time of this study, there was about 60,000, that number has since grown significantly, but but it’s done all online, all internet base, and people register, they sign up, they complete a bunch of questions. You know about their medical history about who they are, they also complete computerized cognitive tests. They also complete self report measures of mood, and a whole host of every of questionnaires, sleep, medications, etc. They complete this. And then so they join, and they complete this, you know, at once as soon as they join, and then also there’s a regular follow up period that they continue to do to complete this. And the purpose of this registry is really to facilitate people fit fills to facilitate recruitment to clinical trials and other kinds of observational studies as well. So at the time of study, like I said, there’s about 60,000, we ended up with a final sample size of approximately 13,000. And again, this, this was after taking into account, 

people who had complete cognitive data on the computerized cognitive tests, complete data on on some of the mood tests. And we also restricted the people who were 40 or older. So this registry, you can be 18 or older to join, we’re interested in the long term effects. So we only want people who are 40 or older. We looked at TBI through the Ohio State University traumatic 

brain injury questionnaire. And that was only added to to the EHR in 2015. So the Ohio State University traumatic brain injury questionnaire, it asked whether or not people had their history of having a traumatic brain injury, with or without loss of consciousness. And then there’s also a single question that says, Have you ever been exposed to repetitive head impacts from things like contact sports, military service, domestic violence, and it’s a yes or no question, as well as military service as a yes or no question. So here through this questionnaire, we had history of traumatic brain injury, whether or not they lost consciousness from that traumatic brain injury, as well as that they had a history of repetitive head injury. The cognitive test we use was the Cox state brief battery, and the Lumos lab neurocognitive performance tests. And then depression symptoms were measured through the geriatric depression scale. And so of this of this final sample here of 13,000, you had we had about one to about six groups. So we had a group who had no history of repetitive head impacts or traumatic brain injury. We had a group who had repetitive Head Impact but no TBI and then so on. on different permutations of this. And what we found was quite interesting. So if you look at the top here, this is the geriatric depression scale. So this is the scale of reported symptoms. And then the left figure here, you see that those who had a history of repetitive Head Impact had more were more likely to report having more symptoms of depression later in life. And we found a similar finding for both TBI with and without loss of consciousness. And then interestingly, if you look at the right figure here at the different group groupings that I just reviewed, as you had repetitive Head Impact, and if you had more severe TBI, your symptoms of depression got more severe. So the group that had repetitive head impacts and TBI with loss of consciousness had the most severe symptoms depression. And we found a similar but not as strong as effect for the current state brief, better one back test of speed, which is your kind of reaction time working memory. And again, we see that those who had had a history of repetitive head impacts and TBI with him without loss of consciousness, were more likely to have a slower reaction time or slower speed performance in this test, and you found a similar kind of dose response trend on the right that you’re here as you did with this depression. 

So this was one is one of the largest studies to study both repetitive head impacts and traumatic brain injury on cognition and mood. And it’s similar to other studies in the literature that are finding smaller size studies that are finding finding similar effects and living and living individuals. Now the question that we were I devote a lot of my time to in my lab is do these repetitive head impacts lead to a nerve degenerative disease, so do these repetitive concussions and sub concussion injuries from things like contact sports, cause accumulation of neurodegenerative disease proteins in the brain, and in particularly, do these results in something called chronic traumatic encephalopathy or CTE? CTE it’s similar to Alzheimer’s disease and other neurodegenerative disease, but distinct, and I’ll go over the distinction soon. And it can currently only be diagnosed through neuro pathological examination. So I work very closely with and very fortunate to work closely with Dr. Al McKee, who has examined more brain to CT than any other neuro pathologist, we have the largest CT brain bank in the world. I think at the time of this recording, there’s something like over 900 brains examined in our brain, our brain bank. So I we’re just starting to learn a lot about CTE now, particularly in the past 510 years. Sadly, entirely new. And in fact, you can think about CTE dating back to 1928. In this in this seminal paper, punch drunk paper, where, where this is this clinical syndrome of 

mood behavior, motor signs and symptoms in a group of boxers that were described by Harrison Marlon, a forensic pathologist, but then even in 1949, the term chronic traumatic encephalopathy was actually used, and again, in reference to a group of boxers or fighters who had this, these clinical signs and symptoms of behavior mood motor disturbances, then in the 1970s, paper by core Celis, describe this this neuro pathological features in 15, retired boxers and again, what was described was this abnormal accumulation of tau in the brain, something that it was a accumulation of tau that didn’t look like any other other neurodegenerative disease. And then even in the 1990s, we continue to we continue to get reports neuro pathological reports, of accumulation of this tau and people with this history, repetitive head impacts mostly boxers where they’re seeing this this tau patterns that very different and unlike other other neurodegenerative diseases. And then it was not until 2005 When When Mike Webster passed and donated his brain to Dr. Bennett omalo, who, who then at the time, examined the brain. And the reason that led to the examination was was because he was having a lot of symptoms during life at at a very young age at 52 years old. So they wanted to do an autopsy examination to see what might be going on. And and lo and behold, they found this again, accumulation of tau in a brain that that seemed to be very unique and different from anything else. And this is where were they Where chronic traumatic encephalopathy is reported in the first national football league player. And this is when when kind of the science and the attention around this disease really begin to explode and move forward at a rapid pace since then. So like I said, it’s really been Dr. McKee and the brain bank at the Boston VA Boston University and concussion Legacy Foundation brain bank that’s been leading the charge on on defining CTE and what it is neuro pathologically, this is a great picture of the group. 

And, and led by Dr. McKee, they proposed and developed the neuro pathological diagnostic criteria for for CTE. So this was published in 2016. This was a this was a consensus meeting of a group of neuro pathologists who, who looked at various various neurodegenerative diseases. And they all agree that in CTE, what I’m showing you here on the screen is the path of dynamic lesion, meaning that this is a lesion that’s unique to CTE and not found another nerve generative diseases. And what’s unique about it is, so this the Brown, the brown, you see everywhere is phosphorylated tau, what I described to you at the beginning of this presentation, and while thought this tau protein is found in other neurodegenerative diseases, it’s unique and CT because it tends to accumulate around small blood vessels, as you see here. And also it tends to accumulate at the depths of the soul side. So and it didn’t, it has to be a neuron. So the path anomalies of CT is the deposition of phosphorylated tau around small blood vessels, often at the depths of the source side. Dr. McKie also developed a staging scheme called the McKee staging scheme for CTE. And the purpose of this was to stage the progression of phosphorylated, tau and CTE. And so you can see the there’s four stages, stage one being the least severe stage four being the most severe. So stage ones, CT really get these isolated faux sigh of patchy lesions of phosphorylated tau the depths of so sigh around the small blood vessels, state and they often present most most initially in the frontal cortex. By stage two, these these lesions progressed to the adjacent cortices parietal lobe, there’s usually three or more of these lesions throughout the brain, they tend to be older and, and they also have problems with thinking in memory. Stage one, you also get problems with thinking and memory, although it’s really unclear if these isolate Italians are responsible for it is it or is this 

really a marker for more widespread dysfunction, you know, functional disk connectivity throughout the brain might be causing some of this dementia. And stage three, you starting to get into more severe disease. So this, this is the stage where it starts to spread into the medial temporal lobe, and it starts to kind of progress throughout the brain. Here, they tend to be a little bit older, and the number of people who have dementia, the stages is quite significant. And then stage four CT you really have widespread tau throughout the brain, you’re again older and more people are likely dent dementia. So as mentioned before, this is a disease that’s different from a Alzheimer’s disease particularly and how it presents. So as I was just discussing the last side CT, you often get the tau beginning in the frontal areas of the brain, whereas in Alzheimer’s disease, it’s often starting, you know, the look is really this or that Toronto cortex in the early stages, and then progressing and then progressing up through the cortex, frontal cortex, parietal temporal cortex, throughout the, in the later stages. In contrast to Alzheimer’s disease, CTE begins in the cortex frontal lobe and then you don’t hit the medial temporal lobe and Toronto cortex hippocampus until later in the disease and stage three. So it’s a very unique pattern from Alzheimer’s season. Not only is the pattern something I’m not presenting here, but the type of tau is also different. There’s now studies out there that shows the type of tau or tau species and CTE is different from Alzheimer’s disease is different from FTL, frontotemporal lobar, degeneration degenerations as well. So what are the risk factors for CT so why do some people get CT and others others do not? So I can tell you that in our brain bank and and and others to that, all neuro pathologically confirmed cases have had a history of repetitive head impacts. There have been reports now that there’s been findings of CTE and in people who Do not have repetitive head impacts or or or maybe in a single TBI. And I will say that that if you read those studies, some of those studies, I think there’s issues with both Miss classification of diagnosing CTE, but then there’s also issues with how repetitive head impacts were assessed, or more importantly, were not assessed in detail. 

So what we think is that repetitive head impacts exposure is necessary, but not sufficient, meaning that you need to have repetitive head impacts to get CTE. However, there’s millions of people and tongue many people who, who have a history of repetitive head impacts, but do not go on to develop CTE or other long term problems and are doing quite are doing just fine. So there’s other risk factors at play. So one study that, I think is an incredibly important study to the field, it was back in 2015, but it was led by Dr. Bini at the Mayo Clinic. And they went into their to their nerd gender disease brain bank, and they wanted to determine the presence of CTE in their, in their, for neurodegenerative disorders among individual individuals with and without a history contact sport play. So what’s really important about this, this paper is that their brain bank isn’t devoted to the study of repetitive head impacts or to the study of CTE. So it’s not it’s not biased in that way. So what they did was that they had available medical records for about 1700 men. And they reviewed evidence that they reviewed for evidence of a history of TBI or participation in context sports. They process the brain tissue in people with a documented history of sports and group of Asian disease match with men and women without exposure. They looked at the brain tissue for CT. And they found that 21 of 66 former contact sport athletes had the tau pathology that’s consistent with a CT diagnosis, meaning that they had that lesion of tau around small blood vessels, often at the depths of the soul side. They did not find CT in any of the 198 individuals without exposure to context for it in Sport play. 

Importantly, 33 who had a single TBI from falls or motor vehicle accidents, domestic violence, they also did not have a CTE. So that again, this kind of reaffirms that CTE pathology is only in people’s context boards, and that it reaffirms that exposure to repetitive head impacts from things like contact sports is a great is a risk factor for CTE. Now, more recently, a really close colleague of mine, Dr. mez, he published a paper in 2009. I think 20 actually apologized on it in Annals of Neurology that I was fortunate to be a part of, that sought to directly test the relationship between years of exposure, repetitive head impacts and chronic traumatic encephalopathy. Now, the years of exposure, repetitive head impacts was defined by the duration American football play. So that was that was used as a proxy. And so who, who This sample was was a group of brain Dover’s from the Boston University at UCLA left brain Bay. And I’m going to talk about that brain bank a little bit, but that the purpose of that brain bank is to study the long term consequences of repetitive head impacts, including CTE. And to be eligible to get into the brain bank, you have to have a history of repetitive head impacts, most of the brain base is made up of American football players. So here this was a group of brain donors who played American football and we had a total of 266 145 had severe CTE. So stages three and 478 had mild CTE. So stage one, two and then 43 had had no CTE. You can see here that a lot of these played a lot of these individuals played a elite football, so, college or above professional football, you know, on average, than the the mean duration of a football player is about 16 years for severe about 12 years from mild CTE. Now, the no CD group played you know, could have also played football, but they obviously did not have CTE, you know, the they’re considered quote the control group, and the control here is defined by the outcome so not having CTE and again, these are all men. 

What they found was quite striking. So if you look here, the first sociation tested was does what is Relationships relationship between years of play and risk of having CTE. And they found that the odds of CTE increased by 30% for each additional year of American football played. And in similarly, they looked at among those with CTE does duration of play affect the severity of CTE developed, and it does, and that among those with CTE odds of developing severe CTE increased by 14% for each additional year plate. So, we now have seen in the literature both an association between repetitive head impacts defined by things like yours American American football play, and this study quantified the actual strength of that relationship. So we’ve now consistently see this relationship as repetitive head impacts being as a primary risk factor for CTE. But again, there are likely other factors at play things like genetics, and so on that I’ll go into. So now what about the clinical presentation of CTE? So, so far, I told you what it looks like in the brain, I told you what we think is the primary risk factor for this disease. But what how does this affect people. And this is something that we’ve been studying, through what we call the United study, and I describing this process a little bit before. But the United study is, is this really large operation, and it’s the brain bank that has the over 900 brains have CT tissue, and there’s two arms to this study. So a brain is donated, and it goes through two parallel processes. So first, the brain goes through the neuro pathology side, and it gets, it gets, you know, it gets comprehensive examination for all types of neurodegenerative diseases, including CTE. And then as that’s happening, the family members or the informants of the brain donor are also going through this rigorous clinical interview as well. And so they they complete online questionnaires, they complete telephone phone calls with clinicians and research assistants. 

And the purpose of these questionnaires and interviews over the phone is to gather what are the clinical symptoms, signs and symptoms of the brain donor before they died throughout their life. So we determine the type of symptoms they had the course of the symptoms, the severity of the symptoms, and we use the symptoms all to come up to see kind of what kind of syndrome they have. Importantly, both the clinicians or the clinicians are blind to the pathology during this process. And then neuropathologists are blinded to any clinical information, as well. So through these methods, we’ve been able to get an idea of what of what the signs and symptoms of CTE are starting to look like this was published way back in 2013. But back then we there was a this was among a small group of, of brain donors who had CTE and no other neurodegenerative disease. And there was two presentations that were described, that are that are being shown here. So you had one presentation of individuals who develop these memory and thinking problems at around a mean age 60. And then they continued to have a progressive decline after that. Then you had another group of individuals who actually begin to start with symptoms of mood and behavior. So things like depression, things like irritability, aggressive behaviors, impulsivity, and they started develop that at a relatively younger age around mean age of between 30 and 40. And then subsequent decline. You know, the issue here and it really an issue that’s been been that we’re continuing to try to figure out is these cognitive symptoms. How are they different from Alzheimer’s disease? How are they different from from temporal lobar? degeneration? There’s a lot of overlap in symptoms. More importantly, and is the behavior mood symptoms, this is something that’s been that’s seems to be somewhat unique and CTE and then in terms of the type of symptoms and the age they start. So what are these behavior mood symptoms? Are they related to that tau protein that I’ve been describing and CTE or are they from other pathologies of repetitive head effects, maybe white matter injury? Or are they individuals who are just predisposed to psychiatric illness? So are they just these idiopathic psychiatric illness, perhaps unrelated to CTE are unrelated repetitive I think that those those are questions we’re still trying to figure out. 

In subsequent study, and fast forwarding about four years later, in 2017, this was published in JAMA. This was a case series of, of American football players who had seats From the from the brain bank, here is showing you clinical features reported 111 American football players who had CTE. And here you can see this is just describing the type of cognitive symptoms in the course, you can see that there’s this is broken down by mild CTE severe CD and then everybody, almost everybody had a progressive course, particularly the severe CTE difficulties with executive function, memory attention, those are the some of the more common symptoms associated with CTE. And then, a lot of people, a lot of individuals with severe CTE tend to have dementia. Also, in that same sample, there’s a description of the behavioral mood symptoms. And again, what you see here is impulsivity being being relatively very common in this sample of American football players with CTE as well as depression symptoms, and some other you know, explosivity was also a common app, the anxiety, there was some social inappropriateness a port. Importantly, we’re not unlike FTD are the behavioral variant FTD. We don’t see that kind of silly social disinhibition or inappropriateness. But it’s more kind of just trouble, impulse control difficulties kind of. And as opposed to those silly behaviors that you might see in some of other neurodegenerative diseases. So this was just so traumatic. So this was just published in 2021. So this is a revised Traumatic Encephalopathy syndrome research 

diagnostic criteria. So in 2014, there was an initial set of Te s criteria, proposed and published. And the purpose of that criteria was to define the clinical syndrome of CTE. So T s is the clinical disorder of CTE. And it was proposed originally in 2014. And then just, you know, the last couple of months, a revised version of this was was published these criteria are meant for research only, they’re not meant to be used in the clinic, because they’re not yet ready to be in the clinic. And there’s really again, just, that’s kind of a big, yellow font, at least in my mind is this is for research purposes only. But what it describes is some of these symptoms, so really these new criteria, what they emphasize, in addition to having sufficient exposure to repetitive head impacts, the core clinical features are problems with episodic memory executive function, and then this new term, neuro behavioral dysregulation. So these, this refers to emotional dysregulation, impulsivity, explosiveness, as well as trouble with activities of daily living. And then there’s also supportive teachers, again, they have to have two or more of these motor signs, anxiety, apathy, depression, paranoia. So this, this was a huge advancement in the field. And hopefully it will will facilitate the research to get us closer to the point where we can can start to get criteria in the clinic. But again, a lot that the one of the reasons why I can’t be in the clinic yet is because these criteria so far been proven to be sensitive, but not specific. So what is this what I want to give you a good idea of what this looks like both in person, as well as what our research process looks like when some when a brain is donated? So I’m going to give you some case examples next. So this is this is Tom McHale, he died at age 45. And again, these are individuals who have given our permission to present on them because of or their families have given permission to present on them to educate. But this time, McHale is one of the first brain donors actually, of the brain bank, and he was a nine year NFL veteran lineman he played for the Tampa Bay. And what’s fascinating about him was that this is really when we start to get into sub concussive because he came in and there was no reported or known concussions. And so at the time, we thought 

we weren’t sure if he was going to have CTE because we didn’t really we weren’t focusing on the sub concussive blows. So he was a sec sec. Cornell University graduate, successful entrepreneur, after the NFL, he had a heart. He’s a husband, he’s a father of three boys. He was just a wonderful person he had he had a life. He had a really long struggle, though with drug use, and addiction. And so he can’t you donate his brain to the brain bank and His brain was examined and lo and behold, he had the classic lesion of CTE. And again, this is when we this, this is when we first start to kind of put the pieces together of sub concussive blows. And again when I say we there’s a little bit before my time, but this is really when this was someone who had no history concussion but had CTE. So here’s another great example. This is this was an 82 year old former NFL wide receiver, so he played 16 years of football started playing at age 14, nine years in the NFL, he was a wide receiver cornerback and a kick returner. So he estimated having 500 concussions 10 with brief lost consciousness, no hospitalization. So in his mid 60s, he was retired as a construction sales manager and he began to have trouble with memory, trouble with executive dysfunction, navigational difficulty, but he continued to function at a relatively high level publishing novels, his symptoms progress in his 77 he started to have trouble functioning, struggled activities, daily living 70 to 74. He had a workup in the behavioral neurologist, neurosciences psychologist and psychiatrist. And the clinical evaluation show global impairment on neuropsychological testing impairment in all domains. He had a head CT 

that showed a caveum septum lucidum. And that’s what that is, is it’s kind of hard to see on this on here and B, but it’s a separation of the tissue that separates the the ventricles that we think that that’s associated repetitive head impacts. You know, a lot of the people normal population can have them, but we’re seeing them more and people with these repetitive head injury. He also had atrophy shrinkage of the brain with clear hippocampal atrophy and he was diagnosed with with Alzheimer disease during life. His symptoms progressed, he began to develop Parkinsonism at age 84. He was severely demented. So he donated his brain. We did the full clinical workup with the family. And we all like like he presented thought he had Alzheimer’s disease. His clinical course was very consistent with what you might see in Alzheimer’s these now we thought CT might be possible given his years of repetitive head injury but really his presentation painted a picture of Alzheimer’s disease. Neuro pathologically, though he had absolutely no Alzheimer’s disease in the brain and he had the most severe CT you could have there was not the neurotic or there sparse neurotic amyloid plaques again, that’s the pathology you need to have for Alzheimer disease. And that was sparse. So it wasn’t it was not it was not there. So again, this the the the lesson from this case is how hard it can be diagnosed at in life because of the overlap symptoms with Alzheimer’s disease. But importantly, a lot of these individuals with Alzheimer’s disease diagnosis in life could very well have have CTE. 

This is another case published in JAMA neurology. This is a 25 year old, he played 16 years of football starting at age six, three years of division one, here’s a linebacker he had more than 10 concussions without hospitalizations. So in his freshman year of college, he had a concussion and then he had this classic post concussive, persistent post concussive syndrome presentation headaches, neck pain, blurry vision, anxiety, trouble memory concentration, he continued to play despite some of the symptoms staying there and then his junior year he stopped playing altogether due to the symptoms. He left college 12 credits short graduating with a 1.9 GPA. His symptoms continually begin to develop some suicidal ideation, he had trouble maintaining a job began to use marijuana daily. There’s some physical and verbal aggression, neuropsychological testing showed deficits in memory and an executive function. He ended up having incidental cardiac death. He came to the brain bank and again very classic for this post persisted post concussive syndrome. And that’s what we all thought, and, and that we thought given, you know, he’s young as well. So depression might be contributing, but also, maybe CTE, although that wasn’t high on the differential because of his age and because it painted a picture, postcards of syndrome. He ended up having CTE again, stage two or three at a four and no other pathology, just CTE. Now, he could have very well had post concussive syndrome, but how much of that was coming from post concussive syndrome or CTE? really unclear. But the important part of this case is that we’re finding this disease and young individuals. So related to that point, and actively investigating what are the causes have these symptoms we published I published this in 2020, specifically looking at the Tao of CTE. And in fact, we did see, using the key staging scheme, we saw that the tau CTE was strongly associated with a history of dementia. For every one level increase in the stage of CTE, there’s a 1.64 increase odds for dementia. And if you look at this pie chart here, so these are among people with CTE, so the each color, you know, going clockwise, each color is stage 123, and four, and you can see that by by each stage, that the amount of people who have dementia increases. And then here on this on the right here is the illustration of the pathology and people with them without 

dementia. So here on the left is someone who had mild CTE and, and you can see that both the frontal cortex and hippocampus is not, it’s not that full of towers come in this person does not have deep dementia compared to someone who has severe CTE and dementia. Now, a really important point is that we’re also seeing that not all symptoms are related to the Tao of pathology. And this is incredibly consistent with it without steimer disease, we now have this really growing appreciation that there’s that dementia and other clinical signs and symptoms are caused a mix pathologies, and Dr. mez just published this paper and 336 brain donors 244 was CT. And the strongest predictor of CT pathology was cognitive symptoms, but we didn’t find an association for the behavior, mood, or motor symptoms. So perhaps there’s other types of pathologies causing these motor behavior symptoms or, you know, there also could be issues with measurement here. Again, these are based on informant retrospective reports. But again, it’s a it’s really important take home message that there’s likely other pathologies that play causing symptoms. And I really like to use this as a framework to how we’re thinking about CTE. So we see that repetitive head impacts is causing CTE neuro pathology, which is linked to symptoms. But there’s also this other pathway below here where that a lot of our work from our group has shown that other neuro pathologies cause clinical symptoms as well. And importantly, repetitive head impacts is not sufficient to cause CTE. And we also need to think about demographics, genetics, lifestyle, medical, psychosocial factors as well. 

And that’s something I’ve been focusing on is what is the role of these other pathologies in particular I’m interested in in vascular disease or cerebrovascular disease and, and we published this paper in JAMA neurology back in 2019, to look at what is the contribution of white matter rarefaction or axonal loss to myelination and cerebrovascular disease things like our to sclerosis small vessel disease, with dementia in deceased former American football players. And we tested this we tested, we tested this large model. And first we sawed off the test, what is the relationship between years of American football play tau pathology in the frontal cortex and dementia. And this is something that’s been looked at before, but we really put the pieces together here. And what we found is that the effect of years of American football was completely mediated by by on dementia was completely mediated by tau. Andrew Stingley. Though we also show that years of American football play was associated with more severe white matter loss, which also predicted dementia. And we also found that small vessel disease or arteriosclerosis, which is commonly a result of things like hypertension, diabetes, also contributed to dementia, but not associated with years of American football play and instead associated with hypertension. And what’s even more important about the study is that the effect sizes for their for the effects of these other pathologies on dementia was equivalent to or equal to the tau pathology. So again, this paper really underscores the point that dementia CT is likely a result of pathology from both repetitive head impacts and other types of pathologies not associated with petabyte index. So what is the next step in this field, we’re continuing to try to define the clinical presentation continue to identify risk factors to continuing to identify the pathologies that cause the symptoms. But we need to really be able to diagnose this disease during life in order to start to think about how to treat and prevent this disease. And right now we can only diagnose it after death. And that’s a really big problem because There’s millions of people who play these contact sports that year and are exposed repetitive head impacts. So one thing we’re really focusing on is biomarkers. So similar to 

Alzheimer’s disease, biomarkers plus a clinical evaluation will help us get an accurate diagnosis during life. When I say biomarkers, I mean tools that we can administer and living people to detect the Tao of CTE like these are the biological underpinnings of CTE. And that’s something really that an effort that I’m that I’m leading and trying to focus on. In particular, I’m looking at tau, PET imaging, PET imaging or Positron Emission Tomography. closely collaborating with a colleague from University of California, San Francisco, Dr. Gill Rabinovich, CO. We’re a leading expert in PET imaging. And we’re testing out this you know, second generation tau tracer called Merker mk 6240. To see if that can, can bind to the tau that we see in CTE in living people. Dr. Stern, a close collaborator of mine at BU, recently looked at Flourtown disappear and published his findings and New England Journal of Medicine that was fortunate to be a part of and found some really interesting findings and for fatalis appear although in that paper and other papers on this tracer, it looks like it might be able to taxi T late in the disease stages, perhaps not early and and and also the correlations that are being found for foretells appear and CT and to be detected that tau is not overly overwhelmingly strong. So we’re looking at other types of tau tracers. We’re also looking at routine structural magnetic resonance imaging. So as part of every any and every dementia evaluation, you should get an MRI and you look for patterns of shrinkage in the brain. And, and this is a this is something we’ve been I’ve been looking at closely with a colleague Dr. Bez where we’re working on a paper that looking at the brain bank looking at MRIs from from individuals who’ve donated their brain and had an MRI during life. Then they died and had a neuro pathological evaluation. And we’re trying to see what are the patterns of shrinkage in the brain among people with autopsy confirmed CTE 

fluid biomarkers looking at, you can now through a lot of advances in immune assay technology, we can now quantify these proteins in the blood. We’ve always we’ve been able to do this for a while for lumbar puncture and CSF analysis, but we can now perhaps do it in the blood. We’ve looked at this in in former NFL players and this is a group of 96 former National Football League players 25 People same age man without a history of repetitive Head Impact or TBI. We looked at their blood for total tau levels, we calculate an index to estimate their cumulative exposure to repetitive head impacts. This is just a quick table kind of go over that who the sample was found a really interesting relationship, the more repetitive head impacts the greater levels of plasma total tau and the former NFL players. Now there were no group differences. But you see here and this year, there was a set or a group of former NFL players who are quite high plasma total towel levels. And so CTE is this huge public health priority. Given the amount of people that are exposed to repetitive head impacts a large proportion of society, we need to be able to attach a diagnosis to these in life in normal order to open door to treatment and prevention trials. We need to better understand risk factors we need to better understand clinical presentations. And those are things we’re doing we need to address also the limitations and in our in our current study. So a lot of our studies on the clinical presentation are based on retrospective report from family members of brain donors. A lot of the current studies are based on male former elite football players. What about the other context? Sports, soccer, ice hockey, what about what about women? What we need larger, more diverse samples. We need longer follow up prospective studies. That’s something we’re doing at the Boston University Alzheimer Disease Research Center, Dr. Meza myself oversee the clinical core. We’re recruiting all types of contact sport athletes, men, women, they they 

undergo very comprehensive assessments. They do this every year. We’re going to have great group of people to compare them to other Alzheimer’s disease, other types of disease groups. We have this also new you 54 initiative. This is an initiative where Dr. McKee is the PIO, myself, Dr. mez and Dr. Steen our project leads. This is combining science Brain banks. In order to better pathologically study, CTE and other diseases associated repetitive head impacts better characterize the clinical presentation and conduct clinical pathological correlation studies. So on that note, I want to thank everyone at the Boston University Alzheimer disease and CTE center, we have a fantastic team. I couldn’t imagine working with another team. I want to thank the Kushan Legacy Foundation, Lisa McHale, Krishna winsky, the CLF team, they play an instrumental role in our outreach and recruitment efforts. I want to thank the funders, national heads of health National Institute on Aging and IMDs. And really most important, I want to thank all the participants who participate in our research, this is something that we could not do without them. I hope you learned a little bit more about CTE and the risk of repetitive head impacts today, and if you have any questions and my email was on one of these slides, please feel free to reach out to me. Thank you for tuning in, and have a great rest of great rest of your summer. 

Unknown Speaker 1:01:10
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