Pathology Grand Rounds: January 26, 2023, David S. Priemer, MD
January 27, 2023Information
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.