Hello everyone and welcome to our talk on repetitive head impacts and CTE. We're very excited that you're here we have a lot of really important updates to spread along, including a star studded panel group of panels lists that I'm going to be introducing before each of the talks. We'll have, we're also really happy to be able to provide some time at the end for questions as well so we're hoping to get a very good conversation going. We have quite a bit to discuss and a lot of new updates, I'll just get started. So my, I'll be speaking first, and my section is on the updates on the pathologic diagnosis of CTE. So my name is Dan Danischvar, I am an assistant professor at Harvard Medical School and I have been studying CTE for about 12 years now. I have no relevant conflicts of interest, and let's talk generally about neurodegenerative disease and TBI. So neurodegenerative disease has often been linked to TBI through multiple different mechanisms. Head trauma has been linked to Alzheimer's disease largely through epidemiologic studies, without neuropathologic follow up. Also to Parkinson's disease, and that's largely on the basis of animal models that suggests that there's a role between TBI and alpha-synuclein deposition. Similarly, it's been linked to head trauma and ALS largely in epidemiologic studies largely mostly from the UK and from Italy, in addition to some other work that's been done more locally by some of our colleagues that are speaking today. And, and what we're going to talk about today then is the linkage between repetitive head impacts, and the neurodegenerative disease chronic traumatic encephalopathy. So what is CTE? Well, CTE is a neurodegenerative process that's caused by the breakdown of one of the proteins in the neuron. So here we have a cartoon of a healthy neuron that's been transected in the axon, and it's built up by these microtubules. So you imagine then that microtubules are part of the stabilizing structure that support this beautiful architecture of the neuron. But what happens in multiple different neurodegenerative processes is that this microtubule can be disrupted. So here we have a single microtubule blown up and it's stabilized by these purple strands, these filaments called tau. And for some reason, it's not entirely clear at this point, we can have this tau have a confirmation change caused by a phosphate group attaching to it and a change in its structure. And as a result, these purple filaments then fall out of the structure of the microtubule and aggregate. Unfortunately, one thing that we've seen is that this abnormal tau called P-tau or phosphorylated tau can induce normal tau adjacent to it to also change in confirmation and aggregate into these clumps, which form the basis of a neurofibrillary tangle, which is an indication of a diseased cell. Unfortunately, one other characteristic of this P-tau is that it can transverse across and induce neighboring neurons to also change in confirmation and have this abnormal structure of tau. And that's one of the ways we believe that tau propagates in neurodegenerative diseases. This P-tau that I'm referring to is in multiple neurodegenerative processes, CTE being one of them, but also some forms of FTLD and of Alzheimer's disease as well. It's one of the two proteins associated with that. So CTE is not a new disease. It was first described by Harrison Martin in 1928 in JAMA. And between 1928 and 2008, there were 45 cases of CTE in those 80 intervening years. The vast majority of cases of CTE in the world's literature were from boxing up until that point. But there were a number of other cases that were also reported. Famously, a circus clown that was repetitively shot out of a cannon was subjected to CTE. So the common denominator between all these cases were histories of repetitive brain trauma. So between those 45 cases, between 1928 and 2008, there's been a significant advance, and largely that's been done by the work of the researchers at BU. And recently they announced that they surpassed 1,000 brain donors in their MTBI brain bank. The first 85 of these donors were published in Brain in 2013. The first 202 football players were published in JAMA in 2017. And there's been most recently 366 of these donors published in Active Neuropathologic just this year. So there's been a whole lot of focus on CTE more recently. And so in those 80 prevailing years, there hasn't been a whole lot of research done. And similarly, this is an indication of the publications really over the last year, and some of the key milestone publications that have, I think, spurred a lot of this increased focus and increased research. So what is the disease process? Well, here we have the brain of a 65-year-old gentleman who passed away that is stained such that brown, the p-tau that I referred to earlier shows up as brown, the regular cells here show up as purple. And even microscopically, then there's no brown that's visible in a normal 65-year-old brain. However, this is a 65-year-old former NFL player who played for 10 years in the NFL. And again, you don't need to bust out the microscope to determine there's significant and abnormal distribution of tau predominantly here in the medial temporal lobe, but really widespread throughout the cortex. And it seems to be focused in the depths of the sulci more than other areas in the brain. And microscopically, what we can see then is the characteristic lesion of CTE, which is the abnormal accumulation of p-tau in neurons surrounding blood vessels. So that is diagnostic specifically, it's pathognomonic, actually, of CTE. So this was first proposed by Dr. McKee in 2013. Now, the p-tau in CTE isn't just limited to the cortex, it can actually spread throughout the brain, including the sedentary scenario, which might explain some of the Parkinson's symptoms, but also throughout the brainstem and spinal cord. So there was a consensus conference in 2016 that brought together the leading tauopathists from across the country to validate the criteria. And these were subsequently updated in 2021. And so the latest criteria then, the major change of these criteria are that previously, that the phosphorylated tau, the p-tau aggregates had to be either in neurons or in astrocytes. But now we're increasingly realizing that it needs to be in the neurons to be diagnostic of CTE, because there's cases of misdiagnosis of CTE when there's just the p-tau in the astroglia, you have this potential age-related tau-astrogliopathy that can sometimes look like CTE if you don't restrict the p-tau aggregates diagnostically into neurons. So it's particularly important because a lot of the cases where there have been reports of CTE-like pathology in individuals who don't have history of repetitive head impacts, it's largely a misdiagnosis based on these new classification. And it's our tag that's being represented, not, or other processes, not CTE. In addition, in 2013, Dr. McKee proposed a staging criteria for CTE, where different levels of tau burden were associated with different stages of disease. And what you noted in stage one disease is that you have one or two foci of CTE predominantly in the frontal or parietal cortices. And in stage two, those foci might spread to the point of a half dozen to a couple dozen foci, but still predominantly in those cortices, very little temporal and medial temporal involvement. And that distinguishes what we see in stage three disease then, which is where you have a preponderance of tau deposition in the medial temporal cortex. And we'll talk about the clinical implications of this later in this talk. But by stage four disease, you have widespread deposition of tau. This earlier case might not look distinctly different from the stage three case that I just showed. But what's important here is actually that the neurofibrillary tangles have resulted in death of the neuron, and the neurons have been cleared. And so you have widespread atrophy. So when you look at it grossly from this view, it might not look distinctly different. But under the microscope, it's very, very different. Dr. McKee's staging criteria were validated by Dr. Olasko in active neuropathology last year, where he looked at a semi-quantitative tau burden across multiple different regions, and used a novel K-medioid cluster analysis to determine what were the optimal number of groupings for the pathology across these different regions, across all of the 366 donors that he studied here. And what he found actually was that although Dr. McKee proposed four stages, there were five optimal clusters for the tau pathology, where stage one disease largely lined up with cluster one, stage two with cluster two, stage three with cluster three, and really it was stage four that was divided between two potential clusters, cluster four and cluster five. So largely validating the criteria that Dr. McKee proposed seven years prior. So in about 60%, actually 52% of cases of CTE have beta amyloid deposition reported in them. And so this is a different stain where beta amyloid appears red. And it's important to note that when we're talking about 52% of CTE cases having beta amyloid, in the absence of other neuropathologic processes, this is what we're talking about by beta amyloid. So you might see that there's a few foci of beta amyloid distributed throughout this brain, but this on the contrary is a case of Alzheimer's and Alzheimer's certainly being characterized by that deposition of beta amyloid. You have much more beta amyloid spread throughout the brain. So when we talk about there being beta amyloid, this is what we're talking about in the absence of other neuropathologic processes. And it's certainly very difficult to conflate with what you see in Alzheimer's disease. And in fact, there are other distinctions between CTE and Alzheimer's disease. And so this is a really remarkable application by a colleague, John Cherry, that was published in Active Communications this year. And here he found that there are differences in the type of the tau that's in each of the, between the CTE and Alzheimer's disease, and also the regional distribution of that tau, where you have more of the tau involved in region CA2, 3, and 4 in late stage CTE compared to Alzheimer's disease. And what that basically means is that the tau regionally within the architecture of the hippocampus is more lateral and a little more ventral as well. So it's basically a different part of the hippocampus. And so that distinguishes, in large part, based on the location of the CTE lesion, the tau lesions in late CTE versus Alzheimer's disease. Another remarkable publication by John Cherry in 2016 looked at inflammation and its relationship with the P-tau CTE. And he found that there's a co-localization of inflammation with tau. So this is in red is inflammation and in green is tau. And so inflammatory microglia or in the microglial processes are in fact adjacent to the P-tau pathology, indicating that there might be some relationship between those two. And a really interesting study out of the UK a few years ago looked at computational modeling of the human brain to determine if there was some explanation for the regional distribution of the P-tau pathology in a CTE brain compared to other neurodegenerative processes. And what was found here is that a hit to the head predominantly induces trauma-induced tissue strain at the steps of the sulci, which is where we see the P-tau pathology in CTE as well. So that might perhaps be a mechanistic explanation for why there's a difference. Similarly, there's a publication out of also the UK that was published in Science in 2019 that found that the tau structure in CTE is distinct from other neurodegenerative processes. There's a whole lot more exciting information, but unfortunately we don't have enough time to dive into all of it, but I'd be happy to take questions on it after the talk. With that, this work wouldn't be possible without a whole lot of other people, but I will hand it over to Dr. Stern. So Dr. Stern was a mentor of mine for 15 years, very, very proud to have worked with him for some time. And he's not only that, but not only an incredible mentor, but he's the lead principal investigator for the Diagnose CTE study, which he's going to be talking about, which is the largest study looking at CTE in living individuals. And with that, I'll give it over to Dr. Stern. Hi, I'm Bob Stern. It's an honor to be able to be speaking with you today at this symposium on repetitive head impacts and chronic traumatic encephalopathy. I'm going to be speaking with you today about risk factors for CTE. Here are some disclosures. And, you know, that's what we kind of think of when initially thinking about CTE. Those big hits, those hits that result in symptomatic concussions. People talk about concussions all the time, concussion this, concussion that. Well, you know what, here's another disclosure. I'm not very concerned about symptomatic concussions when it comes to risk for later life cognitive and neuropsychiatric decline, as well as neurodegenerative disease, such as chronic traumatic encephalopathy. What do I mean by that? Well, let's talk about that bigger issue called repetitive head impacts. Repetitive head impacts include that very kind of smaller number, very tiny number of moderate to severe traumatic brain injuries. And by a small number, I mean in comparison to things like concussions or the MTBIs that can occur so often in contact and collision sports. But concussions really are just scratching the proverbial surface of the iceberg. What lay underneath are what we refer to as subconcussive impacts. Well, these are impacts to the brain with adequate force to have an effect on neuronal functioning, including a neurometabolic cascade, neuroimmune response, breakdown of the blood-brain barrier, release of toxic proteins, but no immediate symptoms of concussion. Some sports and some positions within sports are indeed very prone to these types of hits. Think of those linemen. Every play of every game and every practice, they're hitting those helmets against each other with those skulls inside and the brain surrounded by cerebrospinal fluid. So how do we even measure these subconcussive impacts? Well, the common way, especially in football, is to put these accelerometer gizmos inside the helmets. And using these types of helmet accelerometers, there have been many, many studies over the past decade or more. Where in one study, high school football players, not NFL, but high school football players received an average of over 650 hits to the head in excess of 15g of force in just a single season. And one player in that study had over 2200 hits. Studies with college players, the numbers of hits over a threshold of 15 or 20g are even higher. And now there's been growing evidence, more and more and more, that even after just one season, repetitive subconcussive trauma can lead to cognitive changes, physiological changes to the brain, metabolic changes, and indeed structural changes to the brain. And it affects even young players, youth players. Here's a study of just kids aged 8 to 12, where prior to a season, they were given MRIs. Then during the season, anyone who had a symptomatic concussion was removed from the study, but they all had accelerometers in their helmets so you could measure the number of subconcussive hits. And then after the season, they received another MRI, and indeed, these 8 to 12-year-olds showed a significant change in the integrity of the white matter of their brains just over a single season. And so the question for me, because I'm not a concussion person or acute brain trauma person, I'm a neurodegenerative disease researcher and clinician. And so the question is, do repetitive concussive and subconcussive head impact exposure lead to later life cognitive and neuropsychiatric decline and neurodegeneration? Well, one way we've gone about doing this to examine this is to come up with an estimate of a cumulative amount of head impact exposure. This was led by an MD-PhD student of mine from Montenegro several years ago. And in this, without going into all the detail, we came up with an algorithm using a whole bunch of previously reported data, helmet accelerometer data, and took the positions and levels of play, and then came up with each person's individual cumulative head impact index. Based on their own history. And we found a dose-response relationship between the estimated cumulative number of head impacts and later life cognitive, mood, and behavioral impairment. And this was in former high school players and former college football players. And with each additional 1,000 hits, the risk of later life impairments increased significantly. This is for clinically elevated depression measures, and showing the relationship, this kind of stepwise dose-response relationship between the amount of cumulative hits and the risk for depression. This is for cognitive impairment, clinically relevant cognitive impairment, and the relationship with cumulative head impacts. But we've also looked at this CHI index and measures of neurodegeneration. In this case, it's former NFL players. And the more the repetitive head impact exposure, the more, the higher the plasma levels of total tau. Total tau is viewed as a measure of overall neurodegeneration or injury. In this case, we did it with cerebrospinal fluid total tau, thought to be a better measure marker of overall neurodegeneration. And here, again, we found this pretty important relationship between CSF total tau, and the chi index. In this study, it was a measure of corpus callosum microstructural integrity and plasma total tau. And we found the relationship between the chi and the integrity, meaning in this case, it's inverse of the corpus callosum. In this, another study led by Mike Olasko, the relationship with the overall amount of white matter signal abnormalities on MRI was significant and pretty strong between the cumulative head impact index and the white matter abnormalities. In a study of ours that we've published in the New England Journal a couple of years ago, we were looking at measures of aberrant tau, tau, not total tau, but tau associated with tauopathies, phosphorylated tau, as measured by a PET scan called Flortausapir, the tracers Flortausapir. And what we found was that former NFL players compared to controls had elevations in tau, the P tau, in a few different areas that we might've expected it in CTE, as you heard from Dr. Daneshmar earlier. But what I'm wanting to show you here is this bottom row that shows that the amount of abnormal tau detected on this PET scan was significantly associated with the total years of playing football. So in this group of former NFL players, the more years of playing football, the more the abnormal tau uptake on this PET scan. So what about CTE pathology per se? What's very important to understand is that CTE pathology does not seem to occur without a history of repetitive head impact exposure. In one very important study at the Mayo Clinic, 1,700 male brains in their brain bank were examined for CTE neuropathology using the NINDS criteria that you heard about by Dr. Daneshmar. And CTE was found in only 21 brains. However, all of the people whose brains showed CTE had reported while they were alive that they had played some form of amateur contact sport, predominantly football. One third of all contact sport athletes in the entire brain bank had changes of CTE. And CTE wasn't seen in any of the matched controls without a contact sport history. And CTE wasn't seen in people with a history of a single traumatic brain injury. And what we're seeing more and more is that the greater the exposure, the overall exposure to repetitive head impacts, the greater the risk for CTE neuropathology. This was a study led by Jesse Mez from our group that showed that the duration of American football play across different levels of play was directly associated with the odds of having CTE pathology. In other words, the more years of football played, the more chance of having CTE pathology after death. With the odds of having CTE doubling for every 2.6 years of football play. And because this was a biased sample from a brain bank, everything was done to try to address all the potential types of selection biases. And so epidemiologists and biostatisticians were involved with this to conduct multiple simulation analyses to address potential selection biases. And even after conditions of extreme selection bias, the odds ratio between the relationship of duration of football play and CTE remained the same. All right, so then you already heard about the recent study looking at the relationship between our old traumatic encephalopathy syndrome criteria to detect the clinical syndrome during life and then later post-mortem CTE pathology. Dr. Katz presented some of this and then how it translated into decision-making for our more recent NINDS study. Consensus Diagnostic Criteria for Traumatic Encephalopathy Syndrome. And one of the key messages here is that within football at least, there were two different levels that seemed to predict a greater risk for having CTE pathology. With the biggest risk found in people who played 11 or more years of tackle football. There's nothing. Oh my gosh. So what about those kids? Does it matter when people start hitting their heads? Well, this has been the focus of our group for a while now where we refer to it as the age of first exposure to repetitive head impacts. Trying to answer the question, what if any of the long-term consequences of repetitive head impacts that occur during critical periods of the brain's development? This isn't any kind of new concept. Think about long-term consequences of other childhood exposures, like cigarette smoking, lead exposure, alcohol, even childhood adversity and disparities. In this case, it's important to understand that there are indeed these incredible milestones of neurodevelopmental maturation between the ages of nine and 12. I won't go into all the details here, but several studies have pointed to all these things that occur during these very important years where a lot of people start participating in activities that involve repetitive head impact exposure, such as tackle football. And so our first paper that we published in this was looking at the age of first exposure in former NFL players and later life cognitive impairment. Sorry, and what we found was indeed that people who started to play football before age 12, compared to those who started at age 12 or older, had significantly worse cognitive functioning on standardized neuropsychological tests. But what about potential impact on the structures of the brain instead of just functioning? Well, we have a whole series of papers that looked at the age of first exposure to football and various structural changes, including altered corpus callosum white matter microstructure, smaller thalamic volumes, cortical thickness. But those types of studies with former NFL players have lots of limitations. These were all people in middle age who played through intense levels of professional football. What about people who only played through high school or college? Well, Michael Osco led this effort to examine people who just played through high school, just played through college, and some professional. And what was found was that the people who played tackle football before age 12 had three times the odds of having clinically elevated depression scores, two times the odds of having problems with behavioral regulation, apathy, and executive functioning. And this was independent of the total number of years played or at what level played. What about, however, the relationship between age of first exposure and actual CTE pathology? Well, in another study, we found that it was not associated with the CTE pathology per se in terms of severity. But of all the people with CTE post-mortem, every one year younger the participants started to play tackle football predicted earlier cognitive symptom onset by almost two and a half years, earlier behavior and mood symptoms by two and a half years, and age of first exposure before age 12 predicted earlier cognitive and behavioral mood onset by over 13 years. And finally, in the folks who wound up having dementia, younger age of first exposure corresponded to earlier functional impairment onset. And so there are many, many more questions remaining, though, about risk and resilience for CTE and for cognitive and behavioral abnormalities associated with CTE, such as questions like, are American football players at greater risk than other contact and collision sport athletes? Are women at similar risk? What about in soccer? Is heading the ball an important risk factor? Well, these things need to be answered further. There's been some study, but more needs to be done. But what about answering the question, why do some people develop CTE pathology, the tauopathy, and others do not? Even if they have the same repetitive head impact exposure history, so are there genetics at play? At increased risk or decreased risk? And the role of cognitive reserve that our group has published a couple of papers now on, indicating that people who have this cognitive reserve, increased cognitive reserve, seem to have a greater protection of showing the changes of CTE pathology. And what is the role of race and associated disparities in social determinants of health? We've begun to look at this and have published on this already, but there's so much more that now needs to be examined. And what can and should be done now to increase resilience to, or possibly even prevent the symptoms of CTE? I won't go into the detail of this, but I wanted to just tell you that we're doing a couple of exciting studies. This one called the Diagnose CTE Research Project that you can read about in this recently published paper in Alzheimer's Research and Therapy, where we're looking at a whole bunch of former football players, both college and NFL players across the state of California, the severity of symptoms from asymptomatic to dementia. We're doing a whole lot of things with them. PET scans, MRIs, CSF collection, blood collection, all types of examinations using our traumatic encephalopathy syndrome criteria, and then following people four years later. Well, we completed all of our baseline evaluations around two weeks before lockdown. I was pretty lucky. In another study of ours, recently funded called HITS. Well, this was a little prescient in terms of when we submitted it. We actually submitted this study on February 5th of 2020, and it is for a fully online study in collaboration with Dr. Mike Weiner at UCSF and the Brain Health Registry that he oversees. And what this is is a longitudinal cognitive neuropsychiatric and dementia assessment of both female and male contacted collision sport athletes, including both soccer and American football. And the idea is to really examine the specific risk factors and resilience factors that can lead to later life problems in cognition, behavior, mood, and functioning. So what to do? Well, what if we could learn from our animal friends? Maybe we could start some efforts to prevent. With that, I just want to thank my wonderful collaborators at BU and elsewhere, and thank you very much for paying attention, and I look forward to answering some questions. Thank you. Thank you very much, Dr. Stern, for that incredible talk. Very excited to introduce our next participant as well. And so with that then, I'd like to introduce Dr. Doug Katz. He's a brilliant neurologist and researcher studying brain injury for over three decades. And in addition, the past president of the American Congress for Rehabilitation Medicine. So just a remarkable speaker, but he's also here to talk to us about the new criteria that he helped lead for diagnosing traumatic encephalopathy syndrome. Hello, I'm Doug Katz. I'm a neurologist from Boston University School of Medicine, and I'm delighted to be participating in this symposium on CTE with my colleagues. And I want to briefly talk to you about the clinical features of CTE that we now refer to as traumatic encephalopathy syndrome, TES, and the recently published NINDS consensus diagnostic criteria for TES. I have no significant financial disclosures related to this presentation. Now, the clinical features of CTE have been reported by a number of investigators, including these publications by some of my colleagues at Boston University at the CTE Center, including Bob Stern and Anne McKee. And these clinical features can be summarized as changes in emotional and behavioral control and changes in cognitive functioning that progress and can lead to functional decline and dementia. There may be associated motor impairment, including Parkinsonian signs. And the natural history may vary with differing patterns of onset and varying prominence of emotional and behavioral abnormalities versus cognitive abnormalities. And the presentation may relate in part to whether clinical problems present earlier or later in life. Now, there have been several previously proposed diagnostic criteria before the recently published NINDS consensus criteria, but none of these have been validated and their accuracy has not been established. And these include the Montenegro et al. criteria published in 2014, which came out of the BU CTE Center and have been used in a couple of studies, including the UNITE clinical pathologic study, a large study led by Anne McKee, and the large multicenter study, Diagnose CTE, that's led by Bob Stern. Now, earlier this year, I'm having a little trouble advancing. Earlier this year, Jesse Mez, as lead author from our BU CTE Center, published a study looking at the validity of the previous 2014 TES criteria in 336 consecutive brain donors to the UNITE clinical pathologic study and found that the sensitivity of these 2014 TES criteria was high, but the specificity was fairly low, meaning that almost no one who did not meet the 2014 clinical criteria for TES had a pathologic diagnosis of CTE, false negatives, but a bunch who met the 2014 clinical criteria of TES did not actually have CTE by the consensus pathologic criteria, false positives. So we now have retired these 2014 criteria, and we now have these NINDS consensus diagnostic criteria for TES published earlier this year in the journal Neurology. Now, this project is a part of Bob Stern's Diagnosed CTE Multicenter Study funded by NINDS, and one of the objectives of that study is to develop evidence-informed expert consensus diagnostic criteria for TES, the clinical disorder associated with neuropathologically diagnosed CTE. Now, the effort involved a distinguished expert panel from 11 academic centers from around the country representing multiple disciplines and areas of expertise, including neuropsychology, neurology, psychiatry, neurosurgery, and physical medicine and rehabilitation, and Bob Stern, myself, Ross Savant were part of that panel. The panel met in person in April 2019 in Phoenix, Arizona for the first live consensus conference and then continued the work online after that. Now, the panel was presented with evidence to inform the process, and this included reliability and validity data on the previous 2014 TES criteria, similar to what I just mentioned in the paper before. There was a presentation of a systematic review of CTE literature to date that had both clinical information and pathologically confirmed CTE and included some 40 papers and 229 cases, and they were presented clinical pathologic data from the UNITE study to examine how well certain clinical variables predicted pathologically diagnosed CTE. We went through a modified Delphi process to achieve agreement, and here we are gathered for the live meeting in Phoenix, Arizona, in April 2019. Now to show you some of the evidence presented to the expert panel, it included sources of exposure to repetitive head impacts in published cases, and you can see here that the overwhelming majority of published cases involve American tackle football, followed by boxing, and both of these together account for some 90% of the cases in the published literature. And evidence was presented regarding the amount of exposure, and at this point it's only available on American football players in this paper from the VU Unite study with Jesse Mez as lead author. It showed that with a pathological diagnosis of CTE, those who had that diagnosis at autopsy in the study, they were one-tenth as likely to have played football for less than four and a half years, and ten times as likely to have played for greater than 14 and a half years. And it turned out that 11 years of play maximized the sensitivity and specificity for predicting pathologically diagnosed CTE. Now with regard to clinical cognitive features in cases with confirmed CTE in the literature, at least half the cases had memory impairment, impaired attention and concentration, or executive dysfunction or some form of dementia. With regard to behavioral features, in published cases, the most frequent problems occurred in at least 40% of cases, including violent, explosive, or impulsive behavior. And with regard to mood and emotional features, at least 30% of cases in the published literature included depression, anxiety, hopelessness, or apathy. However, the panel considered that these problems are relatively common in the general population, which lessened their value as core clinical features. And some motor features were relatively common, including those categorized as gait and balance problems, Parkinsonism, and dysarthria. Now the panel achieved consensus on the criteria, requiring at least 80% agreement for the components of these new NINDS criteria. And here's a summary of the criteria. The diagnosis of TES involves a stepwise process that includes first determining if there's substantial exposure to repetitive head impacts, followed by determining the presence of what are the core clinical features that we arrived at for the syndrome, cognitive impairment involving at least episodic memory or executive function problems, or neurobehavioral dysregulation, or both of these. And there must be a progressive course. The third step involves ruling out other disorders that might fully account for these core clinical features. And if these three are met, a diagnosis of TES is made. And the next step is to determine levels of functional dependence and dementia based on a structured scale. Now, a little more detail on these steps in the criteria. Exposure to repetitive head impacts does not necessarily have to involve concussion or more severe TBI. And there was not enough evidence to date to support TBI without a history of repetitive head impacts for the diagnosis of TES or CTE. Threshold for substantial exposure could only be established for American football and was set at at least five years of organized play, including at least high school play or beyond. Thresholds could not be established for other sources of exposure, including other contact sports, military service, or other sources of exposure to repetitive head impacts. Now, regarding the clinical features, they must be established by self-informant or clinician's report and represent a change from baseline. Cognitive impairment must involve deficits in episodic memory and or executive functioning. And if formal neuropsychological testing is available, represent at least one and a half standard deviations below estimated premorbid functioning. And neurobehavioral dysregulation must represent poor regulation or control of behavior or control of emotions and behaviors such as explosiveness, impulsivity, rage, violent outbursts, and the like. And there must be evidence of a progressive course of core clinical features over at least a year after exposure to repetitive head impacts. Now, in addition to these primary criteria for TES, the criteria also offered this schema for provisional levels of certainty for CTE pathology, mainly as a case identification guide for researchers, not for clinical use. So based on various combinations of clinical core criteria, levels of exposure, and combinations of a set of supportive features, the level of certainty for CTE pathology can reach these four levels of increasing certainty, suggestive of CTE, possible CTE, probable CTE, and definite CTE. Definite levels require pathologic evidence, at this point only available at autopsy, and higher levels of certainty require some cognitive impairment, exposure to contact sport for a greater number of years, and combinations of criteria that include additional supportive features. Now, these additional supportive features did not have the specificity to be part of the core clinical features, but added to them can improve diagnostic specificity, and these include delayed onset, motor signs, including Parkinsonian signs, and psychiatric or psychiatric features. And combinations of these various supportive features or the presence of neurobehavioral dysregulation in addition to cognitive dysfunction, or greater levels of functional impairment can determine these levels of certainty for CTE pathology. And now, in the future, we anticipate adding biomarkers to increase specificity for CTE, such as tau PET scanning and structural neuroimaging and fluid biomarkers, but we felt that these were not yet ready for inclusion in these criteria. So in conclusion, these NINDS consensus criteria for TDS were developed through a modified Delphi process involving a multidisciplinary panel of experts. The criteria are meant primarily for research settings to facilitate investigations into the clinical features associated with CTE pathology, and caution is advised in using and communicating these diagnoses of TDS in clinical and medical legal settings, avoiding any equivalence with a diagnosis of CTE, which is a pathologic diagnosis. Diagnosis of TDS requires substantial exposure to repetitive impacts, the clinical core features of cognitive impairment, memory or executive, and or neurobehavioral dysregulation, a progressive course, and the core features cannot be fully accounted for by other disorders. And we presented these provisional levels of certainty for CTE pathology, suggested, as possible, probable, definite, based on exposure, thresholds, core and supportive features, and levels of functional dependence, and these are really meant for research use. And we fully anticipate that these criteria will be updated and improved with revisions as more clinical pathologic information becomes available, and incorporating in vivo diagnostic biomarkers as these are refined and validated, and the criteria themselves as they are evaluated and validated with future study. Thank you so much for your attention. Thank you very much for that incredible talk, Dr. Katz. Next we'll be hearing from Dr. Zafont, Dr. Zafont, in addition to being a world-renowned expert in traumatic brain injury, and chair of rehab at Harvard Medical School, and president of Spaulding Rehab Hospital, as well as my boss. He's a, as I said, world-renowned expert in traumatic brain injury and author of the textbook Brain Injury Medicine, which we all have to read to become brain injury certified docs. With that intro, take it away, Dr. Zafont. Thank you for having me today. Our next topic is, if we have someone who we believe has traumatic encephalopathy syndrome or TS, how can we think about treatment paradigms? These are my disclosures. The only one of which is related is that I am the PI of the Football Players Health Study at Harvard. So people are connected, and they're connected in interesting and multiple different ways. Many of those connections play into our own perceptions and function for us to think about more clearly how we might mitigate parts of people's symptomatology. Because we know right now there is no direct tau antibody treatment or other for us to begin to aggressively treat the primary disease process itself. The other thing for us to remember is that we don't know how much of the symptomatology is being caused by the tau itself or other comorbids that may have been a life in sport or other entity that may have caused some of this vulnerability. So if we think about it, right, in part, we think about these number of factors that may relate to decline, some of which are brain aging related, some of which are circulatory, some of which are joint degeneration, all of which seem to take diseases of aging and move them earlier in life. That can be musculoskeletal, that could be dementia, that could be cardiorespiratory. And so among the things that we've considered is that a model for treatment could be an exposure or a series of exposures that result in pathologies. We have a lot of medical comorbidities, some of which are driven by the pathology, some of which are driven by a lifestyle that we all have. There are age-related factors, there are human cofactors such as genetics, and we have the functional decline in early loss of middle life. And an integrated way to think about this would be a unique lens, an integrated person's lens, that there are pre-injury factors, injury factors, and post-injury factors that go into cognitive, emotional, and physical disturbances that result in a series of concerns that either former players or others who may have TES experience. And this slide is adapted from the work of David Arsenagas and John Silver in our book. When we think about these kinds of things, we have to remember a few things, one of which is when you look at all-cause mortality among football players and compare it to a reasonably legitimate comparative population, which is Major League Baseball, which is quite different than the average population because here we avoid a little bit of the healthy worker bias. What we see is that all-cause mortality changes early in life for cardiovascular disease and later on in life for neurodegenerative disease, suggesting that vascular dysfunction, as one might expect, could be a significant issue for this population early on. When we also looked at people reporting a CTE diagnosis, one of the things we found was that there are high rates of comorbid disease paradigms. Those could be depression, obesity, pain medication use, hypertension, sleep apnea, high cholesterol, or low testosterone. And in this model by Askin, among the things to consider is that an abnormal end phenotype, so to speak, is really contributed to by multiple different processes. Those could be normal aging, anesthesia exposure, certainly repetitive brain trauma, but also sleep disorders or chronic pain use or psychosocial issues or regional issues and adjustment. Now what gives us an idea we might be able to impact outcomes? So this is a very interesting study by Isaacson, where they recruited clinical and preclinical Alzheimer's patients. And here what they did is they took a comprehensive look at these individuals and began to say, what can we do as an early preventative or early treatment group? And these treatments included medications, treatment for cognitive training related issues, vitamins, exercise, nutrition, stress reduction. And what they seem to be able to do is blunt the rapidity of the decline as would be expected in the clinically so-called treated group. Giving us a sense, along with this article recently in Dementia, that early interventions, especially these multiple domain interventions, could have an impact on early stage dementia. In this study that I have before you here, Sokov looked at 44 individuals in this 15-week multi-component dimensional intervention, and what they found was participants perceived the intervention as meaningly found positive and found a functional impact on their physical and social well-being. Now, there are a number of subcomponents that might be able to be addressed. Among them is dietary. It's an underappreciated thing when we think about brain health, but clearly a critical one. When we look at these kinds of things, among the things we really have done an inadequate job is defining the role of diet in brain health. It appears, however, that DASH, MIND, or Mediterranean diets seem to be associated with healthy dietary patterns and neurocognition. And when we look at Alzheimer's dementia, which is not in any way the same thing, but could be taken as a theoretical parallel to CTE backslash clinical TES, Alzheimer's dementia is associated with lower adherence to dietary guidelines, higher alcohol intake, we all know that's bad, lower vegetable intake, and poor executive function is associated with poor diet. And on your right, among the things we see is that dietary sodium apparently promotes cognitive impairment through tau phosphorylation. This is a very interesting entity that may enhance the propagation of phosphorylated tau, and it is a controllable variable, both for hypertension, as well as potentially cognitive decline. Now, everybody's on a dietary supplement. We know this. But what are the role of various diets? Ketone-based diets may have a benefit in Alzheimer's disease. Calorie restriction appears associated with improved cognition and anti-apoptotic function. Antioxidants, supplements, vegan diets all seem to focus on an anti-inflammatory impact. And the one that is people most obsessed with is fish oil. There is a clear importance of EPA and DHA. Higher omega-3s are associated with lower damage after stroke. And there is some work showing neurofilament light chain, which is a biomarker of chronic brain injury, may be lower among those taking higher dose fish oil. The evidence, however, is still out. Now, there is another entity that has been proposed to be a reparative or a mitigatory from Alzheimer's disease and is being even explored in long COVID-related cognitive impairment. And that's nicotinamide riboside. It reduces small vessel disease damage in mice. There's a clear reduction in brain inflammation, improves cognitive impairments in Alzheimer's disease mice models, and improves the elements of DNA repair, likely by mediating parts of the energetic function as well as beta secretase from an Alzheimer's disease perspective. Nicotinamide riboside also helps maintain blood-brain barrier integrity and changes to some extent gut microbiota in mice. One of the things that we were able to show is that weight gain early on in life and probably later as well is associated with bad things. So rapid elevated weight gain, we have to remember that many of these gentlemen eat 10, 12,000 calories a day in youth trying to gain or put on a lot of weight. And we see cardiometabolic disease, sleep apnea, and chronic pain is associated with early life weight gain, and even college to pro weight gain is associated with neurocognitive impairment. So that weight gain puts a substantial impairment onto people in a number of different ways, producing cardiac sleep and pain-related risks, as well as neurocognitive-related risks. When we look at weight loss, improved cardiopulmonary status, it has an impact on pain, as I said, but also results in enhanced resilience. And weight loss in Alzheimer's disease seems to be associated with changes in PET-based myomarkers and parallels mitigation of some elements of cognitive decline in a small study. One of the things that we all don't do enough of, or the vast majority of us don't do enough of is exercise. And exercise has a number of reparative qualities, but among that is a mitigation of some elements of inflammatory markers. So it's clear that exercise has an impact on the expression of IL-6, IL-1 beta and TNF that could impact cognitive disorders. It also obviously has an enhanced function on vascular function. This has been shown in the elderly. Indeed, another study has shown that fitter individuals may need lower gray matter blood flow, even among those with microvascular disease to have thicker cortices. And exercise is mediated in part through brain-derived neurotrophic factor, some of which may be responsive related to polymorphisms, specific genetic traits, and BDNF markers have an impact on depression, higher level functions, and connectivity in learning. And that, of course, has been demonstrated in this small study of those with diabetes, but in other entities, both in animal and human models. Now, when we looked at hypertension and cardiovascular disease, this is actually the Weir unpublished report. What you see is that the rate of early life hypertension among former football players is actually pretty high. Later life, because we have selected out, this seems to be mitigated down because everybody else gets hypertension, but it's that early life hypertension that may be a substantial risk factor. Another risk factor that we tend not to think about as much as sleep apnea. Sleep apnea or sleep restlessness or sleep disturbance may be caused by many things. Pain may be one of them. Hypoxia related to sleep apnea may be one of them. And hypercarbia is associated with lower MOCA scores, Montreal Cognitive, and other markers of cognitive function. One of the critical things for us to remember is that sleep apnea or other entities of sleep disturbance may be associated with reduced G-lymphatic metabolic waste clearance in the brain, suggesting that sleep may be a critical important function that is more than just rest. It may be a function as a toxin clearer. And that element may have an important role, especially in those with neurodegenerative disease risk. The other thing that sleep could do is help us with the normal CSF fluid oscillations. And the loss of those oscillations may be a deleterious role in propagation of degenerative disease. And that sleep, especially obstructive sleep apnea, has been shown to result in reduced cerebral blood flow. Again, many of these formats tie in some way to reduced microvascular function and generalized neuroinflammation added upon by these various medical comorbidities that are treated. Now, one of the things we know from other groups of people is that social networks are critically important. This is work by Amr Touhan in multiple sclerosis. We've recently done this work with football players, but the closer you are tied to others, your links in a social network has a direct impact on your cognition and how well you do. And we all know this from both depression and other cognitive disorders. Being socially tied, being cognitively active is critically important and who you're tied to may have a predilection for your future function. Now, previously, Rachel Gashow in our group was able to show a connection between concussion score, especially for those who had a loss of consciousness and lower total testosterone and erectile dysfunction, suggesting that those with more significant numbers of injuries and those with more significant injuries had a greater level of neuroendocrine dysfunction as metricized by these two clinically important components. Now, we always worry about people being on opioid-related medications. This is a slide I borrowed with permission from Shali Rasheen, who was at the Brigham and Women's Hospital and Harvard Medical School. And what Shali's group here conveys to all of you is the high prevalence of low testosterone, sexual dysfunction, and osteoporosis in men treated with opioid analgesics. That could be methadone. That could be other entities as well where this seems to carry over as well. The lower testosterone findings, sexual dysfunction, and osteoporosis in a group of humans that should not have this really strongly ties to the negative effects of long-term opiate use. And pain itself, pain itself has a significant impact on neurocognition. It impairs neuroplasticity. It has a limited amount of resources. In other words, it dampens about other areas you might be able to co-recruit from, and it might be a mediator of pro-inflammatory factors. So if we look at this population of people, among the people we see are high rates of pain early in life, significant arthritis relationships in NFL retirees. If we look at this, men 30 to 49, and we look at NFL retirees, 41% may well have an arthritis diagnosis. And this is work from our own Adam 1040 where Adam was able to show significant early life hip and knee arthroplasty rates that vastly exceed the general known population. Now, expectations are an important thing as well. And what I mean by that is what we tell people can have an impact on their health. We've told everyone both through the media and otherwise that if you've been in a sport and you've hit your head, you're inexorably going to do badly. Clearly repetitive head trauma is a risk, but how we inculcate beliefs is also a risk. This is work by Rami Burstein who's at Harvard in Beth Israel. And in this, on the axes, what Rami did here is he looked at migraine related patients and labeled various migraine meds, in this case, Maxalt, and looked at the placebic response of Maxalt, suggesting that suggestion, what we tell people can have an important impact. Up is better, down is worse for our purpose on the Y-axis today. And what we see is when we tell people they're going to get no treatment, they get 15% worse. When they tell people, we're going to give you a placebo and it's labeled placebo, they get 15% better unbelievably. And when we label a placebo Maxalt, they get over 30% better. And we have Maxalt labeled placebo, they get 38% better. And we have Maxalt labeled Maxalt, they get way better. So there are astonishing effects that occur by expectation. And we have to be careful about that, especially in the nocebo way. And what I mean by that is that placebos and nocebos can have very important impact on self-belief, especially for restricted populations of people. This is work by Ted Kapchuck and investigators in Brazil, in which an open label placebo had a statistically significant impact on chronic low back pain. Lastly, I want to touch on the role of how we might intervene by enhancing resiliency. This is a colleague of ours who is part of the Football Players Health Study, Herman Taylor at Morehouse, in which in Atlanta, we are doing an intervention to teach goal-directed resistance training, which can impact chronic pain, skill building, and wellbeing to enhance pain mitigation. If we think about how we might enhance medications for cognition, among the things that we think about are those that have been used in other cognitive disorders, deniprazil, other acetylcholine esterase inhibitors, and memetine, all of which have not yet well been studied in this specific TES population. Others have tried to use or think about amantadine, a partial NMDA antagonist, and other stimulatory agents. One should do these types of things with great experience, counsel with others, and caution. And so when we think about all of this, we think about the brain. And so many things determine brain resilience, increased brain size, neuronal count, our education, our leisure activities, nutrition, and social stimulation. And there are things that impact negatively, repetitive brain injury, psychiatric illness, decreased activities, both cognitive and otherwise, malnutrition, a lack of education, and clearly loneliness. So in conclusion, many factors can impact outcome. It's likely that interventions might drift the trajectory. And we need to better understand, are there phenotypes that are more responsive? And is earlier treatment better? Thank you very much. And we're thrilled to take questions. Thank you very much for that wonderful talk, Dr. Svobod. I know we're running a few minutes over, but we'd be excited to take any questions if there are any. So in the chat, someone said that the cures of certain football positions are most associated with CTD. Dr. Stern, would you like to take that one? Yeah, well, originally we thought that it was going to be the linemen and linebackers that might be the greatest risk for CT pathology because they have the greatest number of overall hits based on the sensor data. It's not as clean cut as that. We have seen now CT across all different positions and that includes quarterbacks, likely not the quarterbacks of today's era because they're so well-protected. They don't have many big hits or small hits and they don't practice with the rest of the team getting those hits along the way. But basically the way to think of it is the more hits people get, the greater the chance of having CT overall, but it's not as specific as one might think. Great response. Next question I see is, has anyone looked at victims of domestic violence or threepredative head trauma? So I'll take this one actually. This is a really important focus of research. At this point, the bulk of the donors to our brain bank have been due as a result of contact sports and to a lesser extent, military exposure simply by virtue of those being the most, the cohorts that we've, I think, been able to most actively reach out to and that have agreed to join their brains. There have been cases of victims of domestic violence in the global literature and we have a few of the thousand in our brain bank, but none of the individuals in our brain bank have CTE or have had CTE. There have been individuals globally that have. The next question is, why do you recommend caution in using TES in medical legal settings? Dr. Katz, would you like to take that one? Sure, sure. So the focus of developing these consensus criteria was really meant for research and that's, I think, fairly typical for consensus criteria, diagnostic criteria for other syndromes for a sort of start out that we want to sort of propose ways to research the diagnosis better in order to then develop more accurate, more specific consensus criteria in the future that can be used clinically with more confidence. So that was really the purpose of this was to really aim at researchers so that we could do better in the future for clinical use. And I think we know that when we put this out there and they're published, people are gonna use them clinically. So we wanted to be very cautious in using these both as clinicians and in the legal realm, but we know they're gonna be used and gonna be referred to. The other thing that we really tried to emphasize was the separation of these clinical criteria, which may have more or less specificity depending on how they're used for from the pathologic diagnosis of CTE. So we're not saying TES is CTE, but we're trying to identify the clinical criteria associated with pathologically diagnosed CTE. So as they get better, we think we will have more confidence in supporting them for clinical use and medical legal use. For now, there ought to be a lot of caution and explanation when the diagnosis is made if we're communicating these in the courtroom or to individuals with the disorder. Thank you for that, Dr. Katz. Our next question is for Dr. Zafant. Is there any evidence into the impact of breathing exercises such as diaphragmatic breathing, box breathing, nasal breathing, et cetera, for CT? Well, I've never been, want to make a controversial comment, but, and I wanna thank both Doug and Bob, as well as Dan for putting on this lovely symposia. You know, I think that there is value in breathing-based exercises from an anxiety-based perspective. And for calming symptomatology, we do see benefit from that and the literature's replete with that. I'm not sure I see a pathway for those breathing exercises to decrease the pathology associated with CTE. And I'm not sure I see a pathway for those exercises to mitigate at least all of the proposed criteria for TES. I do see them as a possible adjunct therapy for calming people with overt anxiety or possibly other behavioral syndromes linked to TES, either in parallel or TES alone. I'm not convinced we're gonna make much push against that symptom complex. Thank you. All right. And I think, unfortunately, since we're at 10 minutes over, we'll do one last question. I think that the question here is, is research going on with alcohol and opioid use and development of CTE? That's a great question. I'm happy to take it, but I think Dr. Stern, would you be comfortable to go on? I'll start. Please, you finish, I'm guessing. Yours is gonna be much more knowledge-based. There really isn't much of a mechanistic tie to think that opioid use and or alcohol use would lead to the misfolding and hyperphosphorylation of tau and then the spread thereafter. This population that we study of former athletes, there definitely is a greater use of alcohol and opioids. And the question is, what's chicken and what's egg in this case? We have looked in all of our studies at both opioid and alcohol and other substance use as risk factors for CTE pathology, as well as for TES-related symptomatology. And there isn't any kind of significant risk associated with it. Bob, I think we might, however, and I'm interested in what you and Doug and Dan think, if we had someone with probable and they're using alcohol or other substances, it's likely to make the situation further down the pathway worse. I was just speaking with- You didn't have to say that. I was just speaking with an individual right before this symposium who had excessive alcohol use, a former player, and I was saying exactly that, that we don't know if he has CTE, but no matter what, his excessive alcohol use right now is not going to help his brain, number one, and it's going to worsen some of the other symptoms, including lowering the threshold for anger and increasing depression and related symptoms. So it is such a complex issue, but overall, the big thing that, for me, would be a take-home from what you were just saying, Ross and Doug and Dan, throughout this, is we don't know if someone has CTE while they're living right now. Our TES diagnostic criteria can help us get a little bit closer to that, but we're not there yet. But the critical thing is to treat symptoms, that regardless of whether the person has CTE pathology, there is reason for hope for them by treating individual symptoms along the way, especially the ones that we think of as neurobehavioral dysregulation, but even the cognitive difficulties may have some appropriate treatments. The only thing I'll quickly add, which I think is exactly what I agree with everything so far, is that there's such an error-dependent relationship between these types of opioid use, alcohol use, where the older generations, they certainly weren't utilizing the same types of substances and the same frequencies at different generations. And one of the issues that CTE research has been confined, really, to the last decade. And so the two factors that we found that have been most associated with one's risk of having CTE and the pathology associated with that disease burden have been repetitive head impact exposure and age. And so when you're looking at, then, the potential confound between the era in which someone played and their age and these other substances, it becomes very problematic to look at these, but we haven't seen anything at this point. With that- You can talk about age as the greatest risk factor for any neurodegenerative disease, and because it's so conflated with era of play, that's what makes our job a little difficult. Yeah, pulling out our hair. So I want to thank the speakers for a wonderful series of talks. It's always great hearing all of you speak, and thank you so much for this session. We would love to sit this to the ground and answer more questions, but unfortunately, we're unable to. With that, thanks and take care. Thanks, Dan. Thank you all. Thanks, all. Everyone.

chronic traumatic encephalopathy

CTE

traumatic encephalopathy syndrome

TES

abnormal tau protein

pathologic diagnosis

neighboring neurons

risk factors

repetitive head impacts

age of first exposure

clinical features

diagnostic criteria