Pathology Grand Rounds: January 26, 2023, David S. Priemer, MD

January 27, 2023

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Chronic Traumatic Encephalopathy in Military Service Members, by David S. Priemer, MD

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00:00It is my pleasure to introduce
00:02today's grand round speaker,
00:03Doctor David Premer.
00:05The doctor Premer got his undergraduate
00:08degree in kinesiology from the
00:10University of Illinois in Chicago.
00:12Got his MD from Saint Louis University
00:14School of Medicine where he realized
00:16early on that he wanted to do pathology.
00:18His training there included a post
00:20sophomore year in pathology and he
00:21also received while he was there the
00:23Henry J Pinkerton Award for Outstanding
00:25Achievement in the study of Pathology.
00:28He did his training in residency.
00:31Actually, he was here.
00:31The last time he was here
00:33in New Haven was in 2015,
00:34where he interviewed for a position here.
00:36But alas, he decided instead to go to the
00:39Indiana University School of Medicine,
00:41where he did atomic pathology and neuropath.
00:44His training while he was there included
00:46three months at the New York City
00:49office of the Chief Medical Examiner,
00:51and while a resident,
00:52he received the Resident Award
00:54for Excellence in teaching.
00:56Once he finished his residency,
01:002019,
01:00he spent a year as an instructor in
01:02the division of autopsy pathology
01:03at the Johns Hopkins University
01:05School of Medicine and unique
01:06position as far as I know.
01:08And there he worked with Jody
01:10Hooper and worked very closely,
01:11among other things,
01:13on the research autopsy program.
01:16That was one of the one of
01:17the best in the country,
01:18my opinion.
01:19He's now an assistant professor of pathology
01:21at the Uniformed Services University,
01:24Edward A.
01:24Bear School of Medicine.
01:26And he's the clinical director of
01:28the Department of Defense Brain
01:29Tissue Repository and works with the
01:31Henry M Jackson Foundation for the
01:33Advancement of Military Medicine.
01:35He's an active neuropathologist
01:37and signs out.
01:38He has privileges at the Walter
01:40Reed National Medical Center and
01:41he's heavily involved with teaching
01:43pathology to the medical students.
01:45He's giving talks across the country,
01:47and in his early career he's
01:51already gotten a book chapter in
01:5328 peer reviewed publications,
01:55including a first author.
01:56Publication last year and the New England
01:59Journal of Medicine on today's topic.
02:03I've had the privilege of working
02:04with him on the autopsy committee of
02:07the College of American Pathologists
02:08where he is the editor for the
02:11autopsy continually education series.
02:12And I think David's work really
02:15demonstrates the power of applying a
02:17solid background in anatomic pathology
02:20along with information technology and
02:22and and sort of molecular technology
02:24to a large well curated tissue back.
02:28So today he's going to speak to us
02:31on chronic traumatic encephalopathy.
02:33And military service. It's all yours.
02:40Alrighty, thank you Harry
02:42for those really kind words.
02:45It's sounds a lot nicer than I think
02:47I almost deserve at this point,
02:50but thank you very much.
02:52I want to thank all of you for
02:53attending my talk and inviting
02:55me here to to speak today.
02:56I'm doctor David primer.
02:58As Harry said,
02:59I'm an assistant professor of pathology
03:01at the Uniformed Services University,
03:02the Human Neuropathology clinical
03:04director at the Department of Defense,
03:06USU brain Tissue repository where our.
03:09Primary focus is as a tissue bank
03:11studying a TBI or traumatic brain
03:14injury in the military population.
03:16And today I'm going to talk to you
03:18about our experience with chronic
03:20traumatic encephalopathy, or CTE,
03:22specifically in military personnel.
03:28Ohh, here we go.
03:30This is my required disclaimer.
03:32None of my opinions are are
03:33necessarily those of the federal
03:35government or its affiliates.
03:36I do not have any conflicts
03:39of interest to disclose.
03:40These are some objectives
03:42which we will cover today.
03:44And to begin this talk,
03:45I want to give a rather a comprehensive
03:48history of chronic traumatic
03:50encephalopathy from its inception
03:52about 100 years ago to modern day.
03:55And like I said the timeline of
03:58product traumatic encephalopathy it
03:59takes place or it has taken place
04:01now over the course of approximately
04:03100 years and and it's outlined in
04:06detail here and what we'll go over
04:09this timeline and it really begins in
04:111928 with Doctor Harrison Martland.
04:14Who is a pathologist and
04:16a clinician in Newark,
04:18NJ who described a A syndrome
04:21in a professional boxers,
04:24particularly the brawling type,
04:25professional boxers,
04:26numerous heavy knockouts over their
04:28long careers that he called the Punch
04:31Drunk syndrome and he character,
04:33and this is a clinical designation he
04:35he characterized early symptomatology,
04:37those in post fight and in the weeks
04:39and months following a hard fight,
04:42symptoms of unsteady gait disequilibrium.
04:44And oftentimes the the patient
04:46would appear as though they are
04:49intoxicated or slug nutty as he
04:51referred to it in his in his paper
04:54OK and he characterized late stage
04:56symptomatology in these patients as
04:58well typically years after retirement
05:00from their long boxing careers.
05:02And he described a combinations
05:04of of various motor,
05:06cognitive and behavioral symptomatology.
05:08The motor symptomatology not infrequently
05:11included tremors or Frank Parkinsonism.
05:14The.
05:14Cognitive symptomatology not
05:16infrequently included frank dementia.
05:19And so he postulated at the time,
05:20in 1928,
05:21that this may actually represent a
05:24chronic neurodegenerative disease
05:26in the boxing community and that
05:28we should study this further.
05:30So moving forward into the 1930s and 40s,
05:34more clinicians and researchers
05:35came out with further clinical
05:37descriptions of this phenomenon,
05:39including now a famous doctors mill Spa,
05:41Harry Parker, McDonald,
05:43Critchley,
05:43who all described similar phenomenon
05:46in the brains of former boxers,
05:48however they were as a collective.
05:50Somewhat adverse to using the term
05:53punch-drunk to to describe these patients.
05:56And so here even doctor Millspaugh refers
05:58to punch drunk as a derisive connotation.
06:00And so new nomenclature started to emerge,
06:03dementia pugilistica and now as
06:06we know today,
06:07traumatic encephalopathy or
06:09chronic traumatic encephalopathy.
06:11But keep in mind at this point in time,
06:14all of this research is based on
06:16clinical assessments of current and
06:18former boxers at this point in time.
06:20No brain was actually examined
06:22of a former boxer,
06:24and it actually took almost 50 years
06:27since Doctor Martin's first description
06:29of the Punch drunk syndrome for
06:32there to be a definitive report that
06:34described relatively unique pathology
06:36in the brains in the brains of former boxers.
06:39And that is the paper by Doctor
06:41Nick dorsalis,
06:41the aftermath of boxing,
06:43in which he reports a constellation
06:46of neuropathology in the
06:48brains of 15 former boxers,
06:50most of which were.
06:52Professional boxers and again,
06:53it includes relatively unique
06:55gross findings coincident with
06:57microscopic findings. A grossly Dr.
06:59Corsellis made the observation that
07:01these former boxers frequently had a
07:04defects in their separate glycinin,
07:06whether that be cavum, septum,
07:07pellucidum, or fenestrations or
07:09tears in the septum, and so on.
07:11He additionally noted atrophy in the in
07:13the hypothalamus and mammillary bodies
07:15that not infrequently contributed to
07:17some dilatation of the third ventricle
07:19as opposed to the lateral ventricles.
07:22As well as depigmentation of the
07:24pigmented nuclei in the brainstem.
07:26And the microscopy is where
07:28it really got interesting.
07:29He noted neurofibrillary pathology,
07:31neurofibrillary tangles to high
07:33degrees in the cerebral cortex,
07:35and mesial temporal structures
07:37like hippocampus,
07:38and in the pigmented brain stem nuclei.
07:40But he noted these in the absence
07:42of evidence of senile plaques
07:44in the majority of cases,
07:45and in those cases that did
07:47have senile plaques,
07:47the tangle pathology far was
07:49far out of proportion to what
07:52the the plaque pathology was.
07:54And so ultimately he concludes
07:56that these changes.
07:57Have no particular connection
07:59with Alzheimer's disease,
08:00and in fact the alteration that links
08:02this condition with repeated head
08:04injury is the curious way in which
08:06neurofibrillary tangles develop in
08:07the absence of neuritic plaques,
08:09therefore not Alzheimer's disease.
08:10And his final statement is he knows of
08:13no other condition that has the same
08:15combination of neuropathologic findings.
08:17And so it is with this paper that
08:20the neuropathology of CTE starts
08:22to 1st emerge in the early 1970s.
08:24OK, however, at this time.
08:27A chronic traumatic encephalopathy
08:29is a rather obscure disease.
08:30It's thought to be rare,
08:32and it's thought to be more or
08:34less unique to former boxers.
08:37And from a research standpoint,
08:39this disease kind of lays low
08:41for a long time.
08:42It's dormant for for several decades.
08:45But that all changes in 2005 when
08:48CTE meets the NFL with now with
08:51the now famous case report that was
08:53published by Doctor Bennett Omalu,
08:55who is a neuropathologist and
08:57forensic pathologist. Pittsburgh.
08:58At the time,
08:59he received the brain of a former
09:01high profile NFL athlete and he
09:04diagnosed changes of chronic traumatic
09:06encephalopathy in this brain and
09:08of course urged the community to
09:10study football players further.
09:12And as many in the audience know,
09:14this resulted in a rather
09:18significant public interest.
09:20And so ultimately also in the
09:23creation in 2008 of the Boston
09:26University CTE Center and Brain Bank,
09:28which has been headed this entire
09:30time by Doctor Ann McKee,
09:31who's pictured on the left.
09:33And it's really doctor Mickey's
09:34work and the worker for colleagues
09:36and receiving numerous brains
09:38from former football players,
09:39particularly professional football players,
09:41and has found that a very high percentage,
09:44approaching 100% of former NFL players
09:47have CTE pathology. That is not.
09:50Visible in age match controls.
09:53OK.
09:53And so the result of this,
09:54as you can imagine and as many of you know,
09:57was an absolute media firestorm.
09:58Innumerable magazine articles,
10:01online articles,
10:02newspaper articles that continue
10:04to this day publish books,
10:06Hollywood movies and then ultimately a
10:09congressional hearings with NFL leadership
10:11in front of the House Judiciary Committee.
10:14So you see on the top left there's
10:16the NFL commissioner Roger Goodell
10:17speaking to the house and then
10:20finally the NFL concussion settlement.
10:23Which as of October of 2022 has officially
10:26paid over $1 billion to former NFL players
10:30and their families regarding this disease.
10:33However, moving forward to today,
10:36we have found CTE pathology not
10:38only in former boxers and in former
10:41football players of of all levels,
10:43but we have also found CTE and other
10:46combative sports to think about MMA,
10:47think about wrestling, and yes,
10:49I also mean so-called professional
10:51wrestling WWE type stuff.
10:53CTE exists in that population.
10:55It's been found in rugby players,
10:56hockey players and now more recently from
10:59a because of FIFA just kind of came up.
11:01It's been found in soccer players
11:03and as well as baseball players
11:06outside of contact sports.
11:07CTE pathology has been identified in the
11:10setting of repetitive impact head trauma
11:12in rare cases of domestic violence.
11:14And we're still learning a lot about that
11:17particular community with regard to CTE.
11:19It has emerged in epileptic patients.
11:21It has emerged in neurodevelopmental.
11:24Disabled individuals with headbanging
11:26behaviors and then very interestingly
11:29CTE or CTE like pathology has also
11:31been identified in circumstances and
11:34associated with individual as opposed to
11:37repetitive individual severe head trauma.
11:39And probably the most interesting of
11:42these from I guess from my perspective
11:44is a study that identified CTE like
11:47pathology immediately adjacent to
11:49lobotomy sites in the brains of
11:52formerly institutionalized individuals.
11:54OK.
11:54And so this pathology has been
11:56identified in many circumstances?
11:58And so,
11:59even though it started out as kind of
12:00this clinical phenomenon in the 20s,
12:02thirties and 40s,
12:03CTE today is a neuropathological
12:05entity that currently can only be
12:07diagnosed on the basis of postmortem
12:10examination of tissue.
12:11OK.
12:12And this diagnosis is achieved by
12:15the by discovering the presence or
12:17absence of what we refer to as the
12:21path in a monic lesion of for CTE.
12:23And that lesion is accomplished,
12:25that you find that lesion through
12:27immunohistochemistry for phosphorylated Tau,
12:29and I'll read it out.
12:31Tau aggregates in neurons with
12:32or without astrocytes,
12:33at the depth of a cortical sulcus,
12:35around a small blood vessel deep
12:37in the parenchyma,
12:38and not restricted to subpial or
12:40superficial readings of the sulcus.
12:42So Long story short,
12:44Perry Vascular pattern of
12:46neurofibrillary pathology and the
12:47depth of a cortical sulcus in the
12:49deep layers of the cerebral cortex.
12:52And So what you're seeing on
12:53the image here is a single what?
12:54You would call CTE lesion.
12:57And as it stands today,
12:59one lesion 1 sulcal depth with this
13:02pathology equals a diagnosis of CTE.
13:04OK and that and so it can go on
13:07a diagnostic report as CTE.
13:09And in cases where an individual may be
13:12or pathologist may be concerned about CTE,
13:15consensus sampling currently recommends
13:16a minimum of five sampling of
13:19five minimal cortical regions
13:20to discover CTE pathology
13:22including frontal frontal lobe,
13:24temporal lobe, mesial temporal lobe
13:25with hippocampus and amygdala.
13:26Right lobe occipital lobe.
13:30And in in in efforts to discover
13:31a path in demonic lesion.
13:33However when it comes to actually
13:36staging the pathology for CTE we're
13:38still in pretty early phases in
13:40terms of assessing the severity.
13:43There have been two staging
13:44criteria that were proposed.
13:46The first proposed staging
13:47criteria was a four stage McKee
13:49staging scheme from one to four.
13:51This is kind of the most famous
13:53one that you see pop up and and
13:56articles and this was proposed
13:58in 2015 and then a more recent.
14:00A criteria proposal was a made
14:02by a consensus in 2021 which is
14:04a two state system which is kind
14:07of algorithms out to the right
14:09here which characterizes CTE as
14:11either low or high severity.
14:13However at this point in time it is
14:16very important to stress that these
14:18that these staging criteria for
14:19the severity of CTE are proposed.
14:22They are an experimental phases
14:23and I'm not sure how near they
14:25are to clinical validation,
14:27probably not too close and.
14:30So at this point in time,
14:32it remains pretty difficult to
14:34correlate any degree of CTE pathology
14:36definitively with the clinical
14:38phenotype or in other words to predict,
14:41to predict whether or not a certain
14:43degree of CTE pathology may even
14:45correspond to clinical symptoms.
14:47And this is very challenging
14:48from our perspective,
14:50particularly in cases where we
14:52have very mild pathology and
14:54it's very difficult to ascribe
14:56a symptomatology to that.
14:58However,
14:58the clinical pursuit of a diary
15:01of a clinical diagnosis of CTE
15:03has been an aggressive one,
15:05and probably the most notable
15:07aspect of this has been the the
15:09designation of a new clinical term,
15:11traumatic encephalopathy syndrome.
15:13This is a syndrome that is proposed
15:16to be the clinical syndrome that
15:18corresponds to underlying CTE.
15:20Pathology was coined in 2014,
15:22and in 2021 a multidisciplinary
15:25consensus panel met together to define.
15:28Experimental criteria for this syndrome
15:30and they characterize it as follows.
15:33They progressive course of cognitive
15:35impairment and or neurobehavioral
15:37dysregulation associated with a
15:38confirmed history of quote substantial
15:40exposure to repetitive head impacts.
15:42That is quote not fully accounted
15:45for by other disorders,
15:46but not accounted for by Alzheimer's disease,
15:48neuropsychiatric disease or other disorders.
15:51And simultaneously they proposed an
15:53algorithm by which they hope to be
15:56able to predict underlying CTE pathology.
15:59On the basis of clinical information,
16:01OK, all these are also experimental.
16:03Time will tell whether or not these
16:06criteria and whether or not this
16:08algorithm actually ends up being
16:10predictive of underlying CTE.
16:12OK.
16:13So now with all of that said,
16:15what does this have to do with
16:17military service members?
16:18What is the history of traumatic
16:20brain injury in the military?
16:22Well as it pertains to our current
16:25understanding and our current
16:27experience with TBI in the military?
16:30That history all begins in World
16:32War One with the
16:34advent of TNT and widespread use
16:36of high explosives and more.
16:38So in 18 in the 1860s TNT was was
16:41discovered or synthesized and it
16:43was first used as a drying agent.
16:45Nobody intended it for it to be
16:48explosive until in the early 1900s
16:50of Germans actually discovered
16:52that it was explosive and started
16:54putting it into artillery shells.
16:56And of course this was right before
16:58World War One and so World War One.
17:00Became the first major war in which
17:02we had massive or widespread use of
17:05millions of high explosive artillery shells.
17:08And kind of the culmination of this,
17:10or if you had to give one anecdote of this,
17:12would be the Battle of Verdun,
17:14which is the longest battle of World War One.
17:16Lasted 10 months talking about 306,000
17:21soldiers died in this battle and over
17:2540 million rounds of high explosive
17:27artillery were used in just this one battle.
17:30OK, and so while many soldiers,
17:33particularly because protective equipment
17:35had not evolved to manage high explosives
17:38while many soldiers died from this exposure,
17:41many socials,
17:42many soldiers also survived this
17:45high intensity blast exposure.
17:47And many service members who had survived the
17:50started to develop chronic persistent neuro
17:54behavioral and cognitive manifestations.
17:56OK, including persistent headaches,
17:58concentration issues,
17:59memory issues, sleeping.
18:02Issues impulsivity.
18:03Operative issues and even suicidality.
18:06And because this was a brand
18:08new phenomenon at the time,
18:09in their medical charts they were
18:12characterized as having quote not
18:14yet diagnosed comma neurologic or
18:16NYDN or or characterized by the
18:18new late term of shell shock, OK.
18:21And this affected a huge proportion of the
18:24military personnel on both sides of the war.
18:27And as an example of this,
18:28it affected over 100,000 British
18:30military service members,
18:31which amounted to about 10%.
18:34Of the British military force.
18:36And so as you can imagine,
18:39the British Government was actually
18:41quite interested in research,
18:43diagnosis,
18:43management and prevention
18:44of what is now shell shock.
18:47And So what they did is they commandeered
18:50the services of a number of psychiatric
18:52research hospitals in the UK,
18:54most notably the Maudsley Hospital,
18:57which is,
18:57which is in London still there today.
18:59Picture at the top and or that's yeah,
19:02that's the Mosley hospital and
19:03then below the Moss.
19:04White Hospital and Mcgall and these two
19:07hospitals are very interesting to look at,
19:09juxtaposed next to each other because
19:11in many ways they were competing
19:14institutions with incongruent views
19:15in regards to what is shell shock.
19:18So at the Maudsley Hospital,
19:20this hospital was directed
19:21by Doctor Frederick Mott,
19:22who was trained in neurology
19:24and neuropathology.
19:25And he and his staff largely looked
19:28at physicians like Charcot and
19:30Alzheimer for their inspiration,
19:32for their clinical management and
19:34for their diagnostic techniques.
19:35And it was it was largely the view of
19:37the Maudsley Hospital that shell shock
19:40was an organic neurologic disorder
19:42related to physical changes in the
19:44brain caused by blast or some other
19:47battlefield exposure in contrast.
19:49The mall,
19:49the mall side hospital,
19:51was largely oriented towards psychiatry,
19:53particularly Freudian and Jungian psychiatry,
19:55for their diagnosis and management,
19:57and they largely considered shell
19:58shock to be a functional disorder,
20:00psychiatric disorder related to battlefield
20:03stresses and emotional disturbances.
20:06And so while this debate was raging on,
20:09the burden that these now 100,000
20:12plus service members was beginning
20:14to impose on the British government,
20:17particularly as it related to Pensioning.
20:19Expenses was beginning to mount.
20:22How do you deal with this this phenomenon?
20:25And so this resulted in the formation
20:27of the War Office Committee of
20:29inquiry into the causation and
20:31prevention of quote shell shock.
20:33And in this committee they heard testimony
20:35from physicians and scientists from
20:37both ends of the shell shock debate.
20:40But the opinion that tended to stick
20:43most concernedly to the to the committee
20:46was that shell shock was a sign of
20:48weakness and lack of character.
20:50And this was kind of a.
20:50Pervasive opinion about shell shock
20:52at the time,
20:53if not disguised malingering
20:55innovation of duty.
20:57When it came to the point where
20:59one neurologist who testified
21:00openly stated that frankly,
21:02he was not prepared to draw a distinction
21:05between cowardice and shell shock.
21:07OK.
21:07And this is the opinion that the
21:08the War Office committee stuck with.
21:10And so ultimately they concluded
21:12that no case of psychoneurosis
21:13or of mental breakdown even when
21:15attributed to shell explosion or
21:17the effect thereof should even be
21:18classified as a battle casualty.
21:20So they were not and that cleaned
21:23up a lot of pensioning concerns on
21:25on the prevention of shell shock.
21:27They recommended that we must simply
21:29promote more morale amongst military units,
21:31organize more recreational activities and
21:34that will prevent shell shock and as.
21:372 military recruitment officers.
21:38They promoted a study,
21:40a more intensive study of character
21:42for potential military recruits so as
21:44to prevent the recruitment of those who may,
21:46who are weak of character and may
21:48suffer from shell shock later.
21:50More controversial statements,
21:51particularly from a modern lens,
21:53start to emerge when,
21:54as it pertains to the treatment
21:55of shell shock.
21:56Quote,
21:56No soldier should be allowed to
21:58think that loss of nervous or mental
22:00control provides an honorable Ave.
22:02to escape from the battlefield
22:04he discharged to be pensioned.
22:06Quote when evacuation of the base
22:08from Shell shock is necessary,
22:10shell shock cases should be treated
22:12in a separate hospital or in separate
22:14sections of a hospital and not with
22:16the quote ordinary sick or wounded patients.
22:19So these were not regarded as sick
22:21or wounded patients at all.
22:22And then finally nail on the coffin.
22:24The term shell shock should be eliminated
22:26from the official medical nomenclature.
22:29This is near the end of the report.
22:31And so with this war
22:33report as the foundation,
22:34the term Shellshock was in fact discontinued
22:37in use from from Western medicine.
22:40But that didn't mean the phenomenon stopped.
22:42OK,
22:42so it just kept on persisting with
22:45different names in World War Two
22:46and Korea syndrome such as battle
22:48fatigue, combat fatigue,
22:50Combat Stress reaction emerged in Vietnam.
22:53That Vietnam syndrome all
22:55very similar clinical entities
22:57and at that time in the 70s,
23:00while the fields of neurology and
23:03psychiatry are starting to really
23:05diverge as distinctive subspecialties,
23:07this whole issue of shell shock
23:10became Vietnam syndrome was
23:12largely delicated to schists,
23:14and in the DSM three put under the
23:16umbrella of what became post Traumatic
23:18stress disorder, or PTSD. OK.
23:20And so now going all the way until today,
23:24we are familiar with the fact that a TBI,
23:28particularly so-called mild TBI,
23:29which you know, if you can read this here,
23:32the DoD defines mild TBI to include any
23:34loss of consciousness less than 30 minutes.
23:38So I will let you decide whether
23:40a 29 minute loss of consciousness
23:42constitutes mild, but that is what it is.
23:46But we understand that TBI is amongst
23:48the most common if not the most common.
23:50Injury in Modern Warfare.
23:52And and on top of that,
23:54many military recruits are quite
23:57active people and they sustained
23:59significant impact type TBI in their
24:01civilian life at very high frequencies.
24:04But regardless of that,
24:05many service members who are exposed
24:07to combat and particularly to high
24:09explosives are still reporting
24:11the very similar neuropsychiatric
24:13symptomatology that we have been
24:15seeing for the last 100 years,
24:16combinations of physical,
24:18cognitive and very importantly
24:20behavioral and emotional symptomatology
24:22such as depression.
24:23Anxiety,
24:23agitation and so on.
24:25And so it should come as no surprise
24:27that psychiatric arrangements are also
24:29very prevalent in the military population,
24:31particularly now this diagnosis of PTSD.
24:35And sympatric disease may or may
24:37not be but frequently is comorbid
24:39or associated with TBI from
24:41battlefield experiences.
24:42And as you can see the the the
24:45symptomatology attributed to that
24:46this kind of post blast TBI syndrome
24:49overlaps significantly with the
24:50symptomatology that is now in the
24:53current DSM defining PTSD creating
24:55a rather significant diagnostic
24:58dilemma for these patients.
25:00And so collectively mild TBI and
25:03PTSD are now referred to as the.
25:05Both signature injuries of Modern
25:07Warfare and because service
25:09members who who have these,
25:11who have this symptomatology,
25:13who *** **** imaging,
25:14frequently have negative head imaging
25:16and no evidence of anatomic disease.
25:18By neuroradiology,
25:19these are called the Ford
25:21invisible wounds of war.
25:22So we've gone from shell shock
25:24to the invisible wounds of war.
25:26OK.
25:26And very quickly I wanted to also
25:29mention the the concern of suicide in
25:31the military is as many of you are
25:34probably also familiar with suicide is
25:36a major issue in the military community.
25:39So just as an example,
25:40only amongst active duty service members
25:42in the post 911 era every single year
25:45the rate of suicide has been going on.
25:48So for example for example 18.5 for
25:50100,000 and 2014 now most recently in
25:53the newest data from 202136 out of 100.
25:56Causing our committing suicide.
25:58So in the post 911 era,
26:00over 30,000 active duty service
26:02members have committed suicide and
26:04this is in comparison to only
26:067000 who actually died in combat.
26:08So an active duty soldiers four times
26:10more likely to have to die from their own
26:13hand than they are actually in combat.
26:15Shocking number.
26:16And this is only talking about active duty.
26:19When you include veterans who in
26:21the post 911 era have had an annual
26:24average suicide rate of 6000 per year,
26:27we're talking about anywhere between
26:30150,000 and 200,000 military suicides
26:32that have occurred since 2001.
26:36And ultimately,
26:37as as as one could think,
26:40the reasons behind this are very
26:43likely multifactorial pre-existing
26:45psychiatric disease readjusting
26:47to civilian life after combat.
26:50Depression or other or other issues
26:52related to public opinions about
26:54the wars they're in and so on.
26:56However,
26:57despite a lot of the recent interest in TBI,
27:00and particularly military TBI,
27:02the issue of military suicide has largely
27:06been one of a mental health issue,
27:09and most of the money has been dedicated
27:12to mental health research in this regard.
27:14However,
27:15with all of the stuff we've
27:17talked about in mind,
27:18a question may come here.
27:21Have we actually been missing an
27:23underlying pathology this entire time,
27:24or an underlying pathobiology?
27:27Do these soldiers have CTE?
27:30Is that the invisible wound?
27:32It's a legitimate question because if
27:34you look at the symptomatology of combat
27:37and blast exposed military personnel
27:39juxtaposed next to the symptomatology
27:42that has been described with CTE,
27:44there is a lot of overlap between
27:47these two clinical syndromes.
27:49There is one major difference that
27:51exists between the two and that is the
27:54the subject of latency or the topic
27:56of latency or the time of onset to
27:59symptomatology is kind of the classic
28:00history of CTE that an individual.
28:02Develop symptomatology usually
28:03in their retirement years.
28:05So classically an NFL player
28:06retires and then starts to develop
28:09neurocognitive symptomatology,
28:11whereas in the combat and
28:12blast exposed a service member.
28:14That symptomatology tends to develop right
28:16away with very little of any latent period,
28:19OK.
28:19However, nonetheless,
28:19there is a lot of overlap
28:21between these two phenomenon.
28:22The question remains and as we
28:25start to answer these questions,
28:27or we begin to and we begin
28:28to answer these questions,
28:30some familiar faces begin to emerge.
28:32In this conversation,
28:33OK,
28:34so both doctors have been Imola and
28:36Ann McKee jumped on this question and
28:39working separately between 2011 and 2014,
28:42both of them reported a total of 5 cases
28:46of CTE and former military personnel
28:49who were blast exposed and symptomatic.
28:52And a couple of interesting
28:54conclusions came from this.
28:55Repetitive TBI can sometimes
28:56provoke the development of CTE,
28:58as has been demonstrated in veterans
29:00of the Iraq and Afghanistan
29:02conflicts exposed to blast.
29:04Although the neurobiological effects of
29:06blast neurotrauma are complex or more
29:08complex than TBI from other causes,
29:10such as a boxing punch for example,
29:12the mechanisms involved put these
29:15individuals at risk for CTE.
29:17However,
29:17the fine print of these five
29:19cases is that four of these five
29:22cases were of contact sports,
29:24athletes and or individuals who had
29:26some sort of a major impact TBI event.
29:29At least one, but oftentimes multiple in
29:31their civilian life unrelated to sports.
29:33They would get into bar fights.
29:35And things like that with orbital fractures,
29:37and that's in their history.
29:38And the remaining case simply neglected to
29:41affirm or deny that type of information.
29:44But nonetheless, these five cases
29:46were lumped together with roughly
29:48about a dozen and 1/2 pre-existing
29:50cases that were in the literature of
29:53athletes who were military personnel,
29:55who were included in athlete studies.
29:56But ultimately all to start building the
29:59case that I that a military career and
30:02blast exposure is a risk factor for CTE.
30:05OK, and so what's the result of this?
30:07We get another media firestorm,
30:10not directed toward the NFL,
30:11but now with regard to the military,
30:14that ultimately culminates in a
30:1760 minutes piece entitled Combat
30:19Veterans are coming home with CTE.
30:22And so we begin to see that the lay media,
30:25the public and then eventually the
30:27medical community and military community
30:29begin to accept that a military career,
30:32particularly blast exposure,
30:33actually represents a risk factor for CTE.
30:37And this got to the point where
30:39the new criteria for traumatic
30:41encephalopathy syndrome,
30:42remember the clinical syndrome that's
30:44supposed to correspond to CTE includes
30:47military service with multiple blast
30:50exposures as a known risk factor for CTE.
30:53And so at this point I will remind you
30:56that all of this is based on five cases
30:58and and five imperfect cases from what
31:01I would from what I would surmise.
31:04And so the question becomes have
31:06we actually done our diligence?
31:08Where is the large scale data
31:10that supports military service as
31:12a risk factor for CTE,
31:13whereas the large scale and experimental
31:15data that supports that blast exposure,
31:17which is a totally different
31:19type of TBI than an impact,
31:21is a risk factor for CTE.
31:23It's not there at this point.
31:25And so in comes the DoD USU
31:28brain tissue repository.
31:29We were started in 2012 and we're
31:31now in a state-of-the-art lab space.
31:33We are the only brain bank in the
31:36world that is exclusively dedicated
31:37to the study of military brain health,
31:40primarily TBI military service members.
31:43We accept postmortem brain donations
31:44from anyone who is actually
31:46who served in the military,
31:48regardless of branch,
31:49regardless of symptomatology,
31:50regardless of of exposures,
31:52and regardless of cause and manner of death,
31:55OK.
31:55Each brain receives a comprehensive
31:57neuropathologic examination
31:58by a trainer of pathologists,
32:00including myself and my team and
32:03ultimately towards our goal of studying
32:05the the brain health of the warfighter.
32:08OK.
32:08And so at this point in time,
32:10as of this month,
32:12we have 315 brains in our repository
32:15with a rather unique collection
32:17in regards to age or average age
32:20is 48 years across a very broad
32:22age range of 18 to 103 years 98.
32:26Percent of our our our brain
32:28donations are from military.
32:29We have a small number of civilian controls,
32:31pretty even distribution of active
32:34duty and retired distribution
32:35across all military branches,
32:37and as you can imagine a diversity
32:40of various exposures and factors.
32:42So 10% of our brain donations are
32:44from special forces operators.
32:46Very importantly,
32:47this is a critical subgroup because these
32:50individuals are heavily combat exposed,
32:52heavily blast exposed, a subgroup 27.
32:56Percent have a history of
32:58contact sports participation,
33:0023% of a history of known or
33:03otherwise reported blast exposure,
33:0522% of our donations, unfortunately,
33:06our deaths by suicide.
33:0938% of our donations involve individuals with
33:12the diagnosed with a psychiatric diagnosis,
33:14PTSD being the most common and in addition,
33:1710% of our bank had a firm psychiatric
33:20symptomatology according to interviews,
33:22but never actually sought psychiatric care.
33:25And then finally 41% of our.
33:26Donations involve a history of
33:28alcohol or substance abuse.
33:30OK.
33:30And so as you can imagine,
33:31one of the founding questions,
33:33if not the preeminent founding question
33:35of our laboratory was the CTE question,
33:38is CTE common in military service members,
33:40is blast exposure risk factor for CTE,
33:43is shell shock,
33:44CTE is the invisible wound CTE.
33:46That's probably the biggest
33:48question of our laboratory.
33:49And after a decade of brain collection,
33:51it was decided that it was time to take
33:53the first major step in this regard.
33:55And so in the winter of 2021,
33:57we examined the 1st 225.
34:00Consecutive military brain donations in
34:02our bank for evidence of CTE pathology,
34:05and we were fortunate enough to be
34:07able to report these findings in
34:08a in a summer edition last June
34:10of of the New England in the New
34:12England Journal of Medicine.
34:12That's what I'm going to be going over now.
34:15OK.
34:15And so as far as methodology is concerned,
34:18each brain in our bank as I have
34:20said is extensively sampled and
34:21examined including with towel,
34:23towel immunostains for CTE.
34:25All slides are digitized.
34:26We're able to view them virtually
34:28or conventionally and we gather
34:30our histories retrospectively with
34:31semi structured interviews with
34:33next of kin and with available
34:35medical records including but not
34:36limited to autopsy reports,
34:38death certificates and so on.
34:39And so for this,
34:41for this study we reviewed all Tao
34:43Immunostain slides for all 225.
34:46Cases for CTE pathology according
34:48to the current criteria,
34:50that is one path that demonic lesion
34:52equals CTE and we did this completely
34:55blind to clinical information.
34:56We looked at the slides blind.
34:58We did not know prior neuropathology
35:00reports or any information about that.
35:02And only after we made diagnosis
35:04of CTE and non CTE cases did we
35:06unblind ourselves and begin to
35:08make comparisons between the CE
35:10and non CE population with regards
35:12to various clinical factors and
35:14with regards to various TBI.
35:16Exposures.
35:18So in this group 217 men,
35:20eight women,
35:20this kind of reflects the general
35:22distribution of our brain bank,
35:23average age of 48 years,
35:25active duty and retired military personnel,
35:289.2% special forces again
35:30important exposed subgroup,
35:32a 60 or 25% or 26.7% were former
35:36contact sports athletes of some kind
35:3944 or 19.6%. Additionally at some sort of
35:42a significant non sports related civilian
35:45impact TBI such as a skull fracture.
35:48From physical assault,
35:49intracranial bleeding from a
35:51motor vehicle accident, and so on.
35:54And then 21 or or or 45 or 20%
35:58had a reported history or known
36:00history of military blast exposure.
36:02So now as it pertains to psychiatric disease,
36:04alcohol, substance abuse and suicidality,
36:0739.1% of the cohort had diagnosed
36:09psychiatric disease,
36:09most commonly PTSD,
36:1243.1% had alcohol or substance abuse and
36:15then a 22.7 per a percent or 49% or 49.
36:18Total in the cohort had a history of
36:21suicide and these are very important
36:23numbers because they compare rather
36:25favorably or rather similarly to large
36:28scale epidemiologic data of of both
36:30active duty and retired military personnel.
36:33And so we thought that we really
36:34had a nice snapshot of military
36:36community with this group, OK.
36:38And so I'll remind you that the
36:41minimum consensus sampling protocol
36:42for CTE includes again a minimum
36:44of five cortex containing samples.
36:47We analyzed an average of 13.
36:49Cortex containing samples per case,
36:51and so we really oversampled looking for CTE,
36:54and we found CTE pathology to be an
36:57only ten of these 225 cases or 4.4% OK,
37:00and here's some examples of that.
37:03And this is a table that summarizes those
37:0610 cases. Don't worry about reading it.
37:07We are going to go over it.
37:09First thing I want to talk about
37:11is severity of those 10 cases.
37:135 cases or half had only barely
37:16diagnostic pathology,
37:17that is one single lesion.
37:19So here's one,
37:20here's an example of that single
37:22sulcal depth with one tile lesion.
37:24That's the only town in the entire case.
37:27So minimally diagnostic and that's a very
37:29highly questionable clinical significance,
37:31at least from the early perspective.
37:332 cases were observed and more
37:35elderly a service members who had
37:37a background of severe Alzheimer's
37:39disease neuropathology and so kind of
37:41assessing CTE severity in that context.
37:43It's very difficult and we kind of
37:46abstain from doing that and then
37:49finally the remaining 2 cases had.
37:51They had more than one CTE lesion,
37:53but to our perspective still
37:56relatively mild pathology.
37:57Again,
37:58this is admittedly in the absence
38:00of clinically validated criteria.
38:01So I don't exactly know what mild is,
38:04but more or less this is what we felt.
38:07As far as psychiatric disease,
38:08alcohol substance abuse,
38:10manner of death,
38:11despite our very large brain cohort,
38:14despite high rates of these clinical factors,
38:16it is precisely because we have so
38:18few CTE cases amongst all of this
38:20that we were we were unable to.
38:22Our study was underpowered to
38:24draw conclusions relating to these
38:26factors and and CTE.
38:27However, it was obvious to us,
38:29and I hope it's obvious to you,
38:30that CTE pathology did not correspond
38:32or coincide with the large majority of
38:35patients who suffered from any of these.
38:37Various factors. OK.
38:39Now finally,
38:40as it relates to traumatic brain
38:42injury and contact sports,
38:43probably the most significant finding
38:45in our study is that all 10 cases
38:48of CTE that we identified were
38:50informer contact sports athletes.
38:52So in other words,
38:5410 of 60 contact sports athletes had CTE,
38:570 of 165 without a contact
39:00sports history had CTE,
39:02and most of these also had an
39:04additional history of severe
39:05civilian impact TBI unrelated to.
39:07Sports again like motor vehicle accidents,
39:10physical assaults and so on.
39:12So as it pertains to blast,
39:14even though we had high amounts
39:15of exposure in our study,
39:17again our study was because
39:18it had so few CT cases,
39:20it was under power to draw
39:22definitive conclusions with
39:24regard to blast exposure and CTE.
39:26However, upon relative risk analysis,
39:29it became very clear to us that
39:32civilian impact TBI exposures
39:34particularly contact sports,
39:36new world numerically substantially more.
39:38Associated with CTE pathology
39:40than military exposures,
39:42especially blast exposure,
39:43which by far had the lowest
39:45association with CTE pathology
39:46and whose confidence interval for
39:48relative risk was on the low end,
39:50was the only one to dip below one.
39:52OK, so they wouldn't let us write.
39:54Statistically insignificant in the
39:55New England Journal of Medicine,
39:57but that's how I feel. OK.
39:59And So what does this all mean?
40:01We don't deny that certain perhaps
40:03unique military circumstances
40:05could predispose to CTE,
40:06but we demonstrate that CTE is
40:09uncommon and in large military cohort,
40:11despite high rates of exposures,
40:14CT does not coincide with the
40:16majority of psychiatric disease,
40:17suicidality and and and substance abuse.
40:20In the military context,
40:22when we identify CTE,
40:23it's oftentimes only minimally
40:25diagnostic and thus currently of
40:27questionable clinical significance.
40:29And we have only identified it in
40:30the setting of a history of contact
40:32sports and has the lowest numerical
40:34and blast has the lowest numerical
40:36association with CTE pathology.
40:37And so we actually don't believe that
40:40blast exposure is a risk factor for CTE.
40:43And just as an update,
40:44we now have 315 brains and we have
40:4713 cases of CTE in our repository,
40:49so that that rate has held true.
40:51And after now approaching 12 years,
40:54we have yet to see a single
40:55case of CTE in our repository in
40:57the absence of a contact.
40:59What's history?
41:00OK, and so now the question becomes,
41:03if all of this is not CTE?
41:07If the invisible wound is not CTE,
41:08what is it?
41:11And so that question is a question
41:13that remains unanswered and that
41:15is the ongoing mission of our
41:17brain bank to to decipher it.
41:19However,
41:19we do feel that we have made some
41:21pretty important discoveries in the
41:23particularly as it concerns chronic
41:26neuropathology following blast.
41:27And probably the most notable of
41:29these is our description of an
41:31entity which we've referred to as
41:33interface astroglial scarring.
41:34This is a pattern of glial scarring
41:37detectable by just a simple GFP that occurs.
41:40Long Junction points or interfaces between
41:42heterologous elements of the brain,
41:44so greater white matter junction,
41:45perivascular spaces,
41:47periventricular spaces,
41:48the PO parenchymal interface,
41:51and so on. And we noticed this.
41:55And we continue to note that most
41:57prominently in individuals who are
41:59symptomatic and heavily blastic,
42:00exposed and tend to not see it and
42:03controls without blast exposure.
42:04And when we do see it,
42:05this scarring pattern is widespread,
42:08certainly involves many.
42:09Brain regions and neural circuits
42:12that can implicate symptomatology
42:14in the war fighter after blast,
42:17and at the time we described it,
42:19it was certainly compatible with
42:22pre-existing a tissue data and other
42:26organs with how blast waves propagate
42:28and cause injury in those tissues.
42:30So it was compatible with the
42:32biodynamics of blast wave.
42:33However, nonetheless this diagnosis
42:35was understandably met with a
42:37lot of criticism in regards to
42:39its definitive relation.
42:40With blast, however,
42:41in the last year or so,
42:44or two years now,
42:45a couple of important studies have
42:47emerged supporting the fact that this
42:49pathology may actually be induced by blast.
42:52The first of which is this study
42:54that was published in the Journal of
42:56Neuropathology and Experimental Neurology,
42:58wherein a prospective blast model
43:01using ferrets was developed.
43:03And ferrets are a very important animal
43:06to consider here because unlike rodents,
43:09ferrets have gyros.
43:10Cephalic brains they have gyri and sulci.
43:13Ferrets have well delineated
43:14Gray white matter junction.
43:16Ferrets have anatomic complexity
43:18that is far closer to that of
43:20the human than a rodent,
43:22which has a license to phallic brain and
43:24an indistinct Gray white matter junction.
43:26And when ferrets were blasted and
43:28and and sacrificed and same for GFP
43:31and identical pattern of interface,
43:33glial staining was identified
43:35in those ferrets,
43:36as we have seen in our
43:38postmortem human tissues.
43:39Further pause this further,
43:41a study out of Michigan State and
43:44the Air Force actually engineered
43:47an artificial head model,
43:49polymer based model where polymers
43:51of different densities were used
43:52to construct a brain with jyri,
43:54with sulci, with Gray matter,
43:56with white matter encased in
43:58dura with CSF and ultimately
44:00encased in the skull and blasted.
44:03And they recorded the blast wave
44:06passing through this artificial
44:08brain and in this ultra.
44:09Slomo footage you can almost visualize
44:12where the strain is most maximum.
44:14So this is over the course of a very
44:16small duration of time and you can
44:18see right at the Gray white matter
44:20junctions you're you're seeing a lot
44:21of those forces take place and they
44:24actually calculated that the physical
44:26strain was highest at brain interfaces.
44:28Again compatible with what we
44:31were seeing in the human tissues.
44:34OK and more recently they have done they
44:37have used the same exact head model and.
44:39Impact TBI study or they they drop,
44:42they drop the head from the ceiling
44:44and they record it impacting
44:46with the floor and this video,
44:48I wish I could show it to you is
44:50completely different in terms of how
44:52that how that traumatic brain injury
44:54transfers through that artificial brain.
44:56OK.
44:56And so at this point in time,
44:58we are encountering this pattern
45:00of IS at increasing proportions
45:02in our brain bank and we believe that
45:04we have identified at least a subset of
45:07military personnel who may be predisposed
45:09or vulnerable to neuropsychiatric
45:11sequelae based on physical damage
45:13to the brain from the blast, OK.
45:16However, at this point,
45:18we definitely emphasize that
45:20this is a brand new diagnosis.
45:22We do not currently have an
45:24objective way to diagnose. Diagnosis.
45:26Therefore, at this point in time,
45:28it's difficult to quantify,
45:30even more difficult to associate
45:32with a clinical phenotype.
45:34And so a lot of work needs to be done here.
45:37Some of that work is ongoing,
45:38of course with aggression in a in a
45:40very recent paper published in Brain,
45:43along with our NEURORADIOLOGY
45:44colleagues at NIH,
45:46they have used a new imaging modality,
45:47AI based imaging modality and
45:50they have actually been able to.
45:53Discover a neuro radiologic signature
45:55using our ex vivo tissues for
45:57interface astroglial scarring.
45:59So they took our blocks,
46:00image them and you can almost do a heat
46:02map with the GFP saying and it's identical,
46:04OK?
46:05And so we are we are sooner rather
46:07than later going to be able to assess
46:10this disease in living patients.
46:12And so in closing,
46:12just as a way to close this out,
46:14I want to emphasize that our brain
46:16bank is the only one in the world
46:18that is studying the biology of
46:19last exposure and exclusively
46:21dedicated to military brain health.
46:22And of course,
46:24the availability of this collection
46:25provides for us a unique opportunity
46:27not only for this research but more
46:29broadly speaking toward an improved
46:31understanding of biology or the
46:33biologic underpinnings of of military TBI,
46:36particularly blast exposure.
46:37So I want to thank of course
46:41service Members and their families.
46:42Not for their donations.
46:43We wouldn't be able to do any
46:45of this without them.
46:46I want to give a special thanks to
46:48the special forces who recently
46:49had us visit Fort Bragg for kind
46:51of a day in the life of what they
46:54experienced just during training.
46:55And the amount of blast exposure
46:58that they sustained just during
47:00training operations is dramatic.
47:02And they do this day in and day
47:04out when they are not deployed and
47:06doing the and and blasting things
47:08and shooting things in real life.
47:10So I want to thank the team and
47:11all of our collaborators.
47:12I want to thank all of you
47:13for your attention today.
47:14These are my references.
47:16This is my dog, Peppa.
47:19And I'll I'm happy to take any questions.
47:26Questions from the audience mangine.
47:52We repeat the question for.
47:56OK. So the question was whether or
47:58not military helmets have protection
48:00against against blast injury.
48:02And the second question was whether or not
48:04we've had ferrets wear helmets when and not
48:07wear helmets with regard to blast exposure.
48:09I'll answer the second question first.
48:10No, that hasn't happened yet.
48:12It may. But the first question
48:14is kind of a more complex one.
48:16But interestingly,
48:17the answer to that question is also no.
48:20OK, the most recent helmet that has
48:24just been deployed to the US military.
48:27They spent something like $9 billion
48:30in development of this helmet.
48:32But the principal focus in the development
48:34of this helmet was to deflect bullets.
48:37They did not concern themselves largely with
48:39blast exposure and mitigating blast exposure.
48:42So even the most modern helmet of today
48:44is not designed to protect against blast.
48:47And so we're still a ways away
48:50from protective head equipment
48:52mitigating a blast exposure.
48:54Certainly our body armor has has
48:57resulted in far fewer deaths from
48:59blast exposure over time. And so on.
49:02World War One people were dying left
49:04and right from high explosive exposure.
49:05Now there are far less.
49:07Because of more modernized body armor,
49:09as far as helmets are concerned,
49:11we haven't gotten. Unfortunately.
49:16Work.
49:19Quick question,
49:20what is correctly if I mentioned that?
49:23But it seemed like a rainbow.
49:26Their military subset that have
49:29played confidence force, yeah,
49:31lower than grade in context.
49:35Previously reported. In other words,
49:39if you have that occur in the NFL,
49:40should do, then go into.
49:43Protect your head. So.
49:48So yeah, so the question was,
49:50we had 60 contact sports
49:52athletes in this study.
49:53Only ten of them had CTE and
49:55this rate is lower than what has
49:57been reported in other studies.
49:59That is some somewhat true.
50:02It really depends on what level of
50:04contact sports athletes you're looking.
50:05So if you go to the the study
50:08out of the BU group which is 101
50:11NFL brain something like that,
50:13they report CTE neuropathology
50:15at three different levels.
50:17NFL players, college players,
50:19high school athletes,
50:20they find that close to 100% of NFL players,
50:23if not 100% have CTE pathology,
50:2588% of college athletes have CTE
50:28pathology and then only 20% of high
50:31school football players have CTE pathology.
50:33OK and so.
50:34If you if you didn't have a
50:36very long career in football,
50:39your chances of having CD appear to
50:40be far lower than that and then we
50:42don't know what those rates are in
50:44other contact sports or what we are
50:46considering other contact sports now.
50:48And so I wasn't surprised to see
50:50this 10 of 60 because we have this
50:52myriad of different contact sports
50:54and different levels of participation.
50:57OK.
50:57And then and so considering that
50:59this is an active an active male
51:02population on that non active duty,
51:04I mean physically active population.
51:06This may actually be a as close
51:09of a representation of of the rate
51:11of CTE pathology and the active
51:13male community overall as we have.
51:15So I think that's that that kind of
51:18fits my perspective on that question.
51:20It really depends on duration of
51:21play and and and level you've
51:23reached in contact sports and so
51:24I'm not surprised by this rate.
51:29Yeah, we're, I think.
51:33I think you know, military for the
51:35most part it's it's an occupation and
51:38a lot of people don't have combat
51:40exposure or it's relatively minimal and.
51:43Uh, so we're dealing again,
51:45I think we're, we're as close as,
51:47as the literature has gotten to
51:49assessing CTE frequency in an active
51:51male population regardless of military.
51:54One other question.
51:55So the distribution.
51:58Change is fairly similar.
52:01And you know that that depth of
52:04salt patient you know as suggested
52:06by the biophysical model as
52:08suggested by the distribution of
52:10all IS and the distribution of.
52:14Tall.
52:16All sort of anatomically
52:17as some of the addition.
52:21Yeah, this is a spectrum of change.
52:25This perceived that this is sort of the
52:28the acute vision which compounded multiple
52:31times eventually leads to, you know.
52:36We also into. Maybe. I think.
52:40I think that the the jury is still
52:42out with regard to whether CTE cases
52:45have this background pathology.
52:47That hasn't been reliably demonstrated,
52:49at least to to me just yet.
52:51I will say in these IRS cases that.
52:56Negative. There is no topology in them,
52:58and the scarring does not
53:00favor soulful depth.
53:01It's more of a diffuse interface pattern,
53:05and so I think that question is reasonable.
53:07I think it's something that still
53:09may end up being the case, not sure,
53:11but at this point in time we are not
53:15seeing them coexist or at least match up,
53:17or at least match up.
53:20And so in that kind of vein,
53:22I also oftentimes get the question of,
53:24you know, you have a very young cohort.
53:27Could they just be developing CTE later
53:29and you're not getting that snapshot now?
53:32That's a frequent question I get.
53:34And my answer to that is that
53:37these people are symptomatic now.
53:39OK. And so their symptomatology,
53:42this invisible wound that they
53:43have now is not explainable?
53:50Ohh there are some check questions but
53:51they were popping up earlier. Oh, text no.
53:57Somebody's talking about an autopsy case.
54:02Any questions?
54:05Thank you very much.