Football and the brain

Transcription

1 Football and the brain Ann C. McKee M.D. Professor of Neurology and Pathology VA Boston Healthcare System Boston University School of Medicine Director of the CTE Program Associate Director, Alzheimer s Disease Center 1

2 Shell Shock 1916 Frederick Mott The Lettsomian Lectures The Lettsomian Lectures ON FEBRUARY 12, FEBRUARY 12, is an inborn timorous or neurotic is an inborn disposition an timorous or neurotic disposition or an inborn germinal or acquired inborn neuropathic or psychopathic taint causing a loclt8 minoris resistentiae psycho- germinal or acquired neuropathic or in the central pathic taint causing a loclt8 minoris nervous ON system, it resistentiae in necessarily the central nervous THE EFFECTS OF HIGH EXPLOSIVES UPON follows that he will be less able to withstand the system, it necessarily THE EFFECTS OF HIGH terrifying EXPLOSIVES effects UPON of shell follows fire and that the he stress will ofbe less able to withstand the THE CENTRAL NERVOUS SYSTEM. trench warfare. Thus, whether terrifying a tendency effects to of a shell fire and the stress of Delivered THE CENTRAL NERVOUS SYSTEM. before the Medical Society of London neurasthenic condition has trench been acquired warfare. or Thus, is whether a tendency to a more or less Delivered before the Medical Society of inborn, an London emotional neurasthenic experience condition such has been acquired or is BY FRED. W. MOTT, M.D. LOND., F.R.C.P. as fright is more liable to develop more or the less symptoms inborn, ofan emotional experience such LOND., HON. LL.D. BY EDIN., FRED. F.R.S., W. MOTT, M.D. a functional LOND., neurosis F.R.C.P. or psychosis. as fright is more liable to develop the symptoms of MAJOR R.A.M.C. (T.), 4TH LONDON GENERAL HOSPITAL; PATHOLOGIST TO LOND., HON. LL.D. EDIN., THE THE LONDON COUNTY COUNCIL ASYLUMS. EFFECTS F.R.S., OF HIGH EXPLOSIVES a functional UPON neurosis THE or psychosis. MAJOR R.A.M.C. (T.), 4TH LONDON GENERAL HOSPITAL; CENTRAL PATHOLOGIST NERVOUS TO SYSTEM. THE THE LONDON COUNTY COUNCIL ASYLUMS. EFFECTS OF HIGH EXPLOSIVES UPON THE LECTURE I. The effects of high explosives upon the central CENTRAL NERVOUS SYSTEM. (Delivered (In lieb. 7th.) nervous system fall into three groups. 1. Immediately I. fatal either from pieces The of effects shell, of stones, high explosives upon the central MR. PRESIDENT AND GENTLEMEN,-Permit LECTURE me to thank (Delivered (In you for the great honour the Medical Society lieb. rocks, 7th.) or portions of buildings nervous striking system the fall individual, causing instant me todeath, diately into three groups. 1. Imme- of London has done me in MR. asking PRESIDENT me to AND give GENTLEMEN,-Permit the or the fatal person either mayfrom pieces of shell, stones, Lettsomian lectures this thank year. you The for the society great has honour be buried the Medical from the Society explosion rocks, of a or mine. portions Again, of buildings striking the individual, in been fortunate in having of had London addresses has and done discussions on most of the medical and me in instant death asking me to must have give theoccurred causing groups of men instant death, or the person may Lettsomian surgical lectures problems this from the year. The effects of shell fire and society has be buried yet no from visible the explosion of a mine. Again, concerning the war, with the been exception of the effects fortunate in having had injury has been found to account for it. This addresses and discussions most of the system matter I shall discuss more instant death must have occurred in groups of men of high explosives upon the central nervous medical and surgical problems from fully later. the effects of shell fire and yet no in the visible production of functional neuroses and 2. In Group 2 we can place those cases in which concerning the war, with the exception of the effects injury has been found to account for it. This psychoses. As I have had the opportunity of the detonation of high explosives has caused wounds of high explosives upon the central nervous system matter I shall discuss more studying these effects I ventured to change the and injuries of the body, including the central fully later. subject which I at first contemplated. in the production of functional nervous system, neuroses which and have not 2. In been Group immediately 2 we can place those cases in which The employment of high psychoses. explosives As I combined have had fatal. the The opportunity number of of these the cases detonation which of do high not explosives has caused wounds with trench warfare has studying produced these a effects new epoch I ventured exhibit any to of change the functional the and disorders injuries and disturbances characteristic of what contemplated. nervous is termed system, " shell which have not been immediately of the body, including the central in military medical science. subject This which war I was at first recently described at a Labour Congress as a The employment barbarous, of shock high explosives " without combined visible injury, fatal. although The number suchof these cases which do not unromantic, machine war. with Yet in no of the individuals have received most trench warfare has produced a new epoch exhibit serious any of and the fatal functional disorders and disturbances characteristic of what is past has individual courage and self-sacrifice shone wounds from in military medical science. This exploding shells, leads one to consider that in a war was recently with termed " shell greater lustre; for the contemptible little described at a Labour large Congress as a proportion of cases of shell barbarous, shock " without visible injury, although such army in the retreat from Mons fought against overwhelming odds and covered itself with war glory. at work in the production of the of individuals the nervous have symptoms received most serious and fatal shock without visible injury there are other factors unromantic, machine war. Yet in no Again, in the terribly past anxious has individual times when courage the besides and self-sacrifice the actual shone aerial forces wounds generated from exploding by the shells, leads one to consider that in a large proportion of cases of shell enemy tried to break with through greater to Calais, lustre; what for explosive. the contemptible little could have surpassed the army courage in the and retreat self-sacrifice from Mons 3. fought The third against group overwhelming the odds Yser, and or covered the nervous itself system with without glory. visible at work injury, the and production to this of the nervous symptoms includes shock injuries without of the visible central injury there are other factors of our men in the trenches on gallant stand of the Canadians Again, in when the the Germans terribly anxious group I times shall give when especial the attention, besides as the it is actual the one aerial forces generated I include by the the Anzacs is one of the finest and most romantic could have surpassed the courage and self-sacrifice 3. The third group includes injuries of the central although there may be no discoverable lesion in a nervous system without visible injury, and to this High explosives contained in huge shells have " psychic trauma," yet so complex is the structure gallant stand of the Canadians of the when human the central Germans nervous group I shall give especial attention, as it is the one system, and so subtile from the effects produced sprang by direct the gas material upon injury us? the Lastly, chemical the landing physical of of changes which underlying I have had its most experience. I include to the central nervous the system, Anzacs there is one is the of moral the finest functions, and most that romantic because our the gross functional methods neuroses of and psychoses because Punch Drunk Dementia Pugilistica 1928 sprang the gas upon us? enemy Lastly, tried the to landing break of of which I through to have had Calais, what most explosive. experience. the functional neuroses and psychoses because deeds in the history of war. of our in the trenches on the Yser, or the played a prominent part in this war, and apart effect of the continued deeds anxious in the tension history of of what war. investigating dead material First reported by Harrison Martland 1928 in boxers High explosives contained in huge although do not enable there us shells have may to saybe no discoverable lesion in a may happen, which, combined with the terror that the living matter is altered, " psychic yet admitting played trauma," that yet so complex is the structure caused by the horrible sights of a death and destruction around, tends to prominent part in every this effect owns war, and a apart cause, a of the refractory human phase central in nervous system, and so subtile from exhaust and the effects produced eventually by systems or direct material communities of injury the functionally chemical correlated and physical changes underlying its even shatter the strongest nervous to the central system. nervous system, there is the moral functions, that because our gross methods of effect of the continued anxious tension of what "nearly one half of the fighters who have may happen, which, stayed To neurons must imply a physical or chemical change live in trenches or underground for days or and a break in the links of weeks, exposed continually to wet, cold, and combined with the terror game long enough investigating the chain of dead neurons which subserve material do not enable us to a particular function. that the living As matter is altered, yet admitting that say we know, often, owing to the shelling of the communication one of the peculiarities of the functional neuroses is caused by the horrible sights of death and destruction lower around, the vital tends resistance to exhaust shock may and engender eventually a loss of systems function, or but communities likewise of functionally correlated every effect owns a cause, a trenches, to hunger, combined with fearful tension not only the sudden manner in which an emotional refractory phase in and apprehension, may so a physical or chemical change and a break in the links of the chain of neurons weeks, exposed continually to wet, cold, and which subserve a particular function. As we know, ness. So that in considering the effects often, owing to the of shelling high That of the is, communication attention is for a one moment of the taken off its peculiarities of the functional neuroses is explosives it is absolutely necessary to take into guard. I am referring especially to not mutism. The only the sudden manner in which an account the emotional state of the nervous system of the so lower the vital resistance a individual at the time of the " shock loss of " caused function, but likewise by of the strongest nervous system that a ing shell burst- the sudden manner in which it near, and without causing of physical any visible trauma-concussion injury, may be or " commotio unexpectedly in this trench warfare may from the stress of restored by a prolonged active service acquire is sufficient a neurasthenic to lead to condi- a sudden force of loss the of aerial conscious- compression kind, blowing provided the person there is an element of surprise. or sudden by the stimulus of the most varied tion, and it stands to reason ness. that a soldier who has into the air or against the That side of is, the attention trench or is for a moment taken off its or from guard. I am referring especially to mutism. The the acquirement of a disease prior to his enlistment on to him causing concussion, or a causes sandbag of shock hitting to the nervous system by high of the strongest nervous even system shatter that a the shell strongest bursting near, and without causing live any trenches visible or injury, underground restored by for a sudden days stimulus or of the most varied the nervous sudden manner system. in which Martland (1928) Punch drunk. JAMA 91: To neurons it may be must unexpectedly imply is sufficient to lead to a sudden loss of conscious- kind, provided there is an element of surprise. trenches, to hunger, combined with fearful tension causes of shock to the nervous and apprehension, may shock system by high explosives may be considered under may the engender headings Chronic Traumatic the explosive. Encephalopathy A neuro-potentially sound soldier 1949, 1957 cerebri" by direct aerial compression So that in considering the effects of high become neurasthenic from a explosives head it injury is absolutely dug-out; or necessary to by take blowing intodown the parapet or roof account the state of the nervous system of the will not stand the strain Critchley M (1949) Punch-drunk syndrome: individual as well the at as chronic the a time neuropotentially sound man. Again, if in a soldier there concussion without of the him traumatic " on shock the " caused head or by spine encephalopathy of boxers. the explosive. explosives might easily cause may be considered under the headings A neuro-potentially sound soldier producing any visible of physical trauma-concussion injury. or " commotio No G this trench warfare may from the stress of prolonged active service acquire a neurasthenic condi- force of the aerial cerebri" by direct aerial compression or by the Hommage à Clovis Vincent. tion, and it stands to Paris. compression blowing the person reason that a soldier who has into the air or against the side of the trench or become neurasthenic from a head injury or from dug-out; or by blowing down the parapet or roof the Critchley M. Medical aspects of boxing, particularly acquirement of a disease prior to his enlistment on to him will not stand the strain a neurological standpoint. causing concussion, or a sandbag hitting as well as a neuropotentially sound man. Again, if in a soldier there concussion without producing any visible injury. him on the head or spine might easily cause No G Br Med J 1957; 1: 357 2

3 Clinicopathological Series of 15 boxers with CTE Corsellis, Bruton, Freeman-Browne 1973 Psychological Medicine, 1973, 3,

4 Chronic Traumatic Encephalopathy 2005, 2006 Mike Webster Omalu, DeKosky et al. 2005, 2006 Death at 52 years Behavioral and mood disorders Cognitive loss Parkinsonism 4

5 Control Bedford CTE VAMC Control Stage IV CTE p-tau pathology Paul Pender World Champion boxer, Marine Died at age 73 Severe Dementia Paul Pender 5

6 February 2008 Paul Pender No p-tau 45 yo NFL 73 yo Boxer/Vet 6

7 Chronic Traumatic Encephalopathy cases at VA Boston/BUSM 48 other cases in the worlds literature 39 boxers (76%) 5 American football players (10%) 7

8 Brain Atrophy Pathology of CTE Hyperphosphorylated tau (P-tau) Normal CTE 8

9 Gross Characteristics: Cerebral Atrophy Severe II and III ventricular dilation 9

10 Cavum septum pellucidum 10

11 Thinning of the posterior corpus callosum Marked medial temporal atrophy 11

12 Atrophy of the thalamus, hypothalamus and mammillary bodies Septal fenestrations 12

13 Abnormalities of septum pellucidum 13

14 pallor of the substantia nigra 14

15 CTE Hyperphosphorylated tau protein (p-tau) 15

16 p tau CONTROL CTE frontal cortex nucleus basalis insula amygdala temporal cortex entorhinal 16

17 Hypothalamus Mammillary bodies Deep Nuclei Thalamus 17

18 Brainstem Substantia Nigra Locus coeruleus 18

19 McKee et al cases of CTE Neuropathological Criteria for CTE P-tau lesions 1. Perivascular 2. Focal distribution at depths of sulci 19

20 Why is tau protein deposited in those brain regions? Sulcal depth and perivascular area are regions of physical stress concentration Cloots et al Annals of Biomedical Engineering, Vol. 36, No. 7, July 2008 Cloots et al.j Mechanical Behavioral Biomedical Materials 2012 (41-52) 20

21 February 25-6, 2015 Sixth Annual Intensive Update in Neurology 9/15-16/2016 NINDS/NIBIB Consensus Meeting to Evaluate Pathological Criteria for the Diagnosis of CTE Nigel Cairns, Ph.D., Rebecca Folkerth, MD, Wayne Gordon PhD, C. Dirk Keene, M.D., Irene Litvan, PhD, Ann McKee, MD, Daniel Perl, M.D., Thor Stein M.D., Ph.D., William Stewart, M.D., Jean Paul Vonsattel, M.D., Dennis Dickson, M.D, Patrick Bellgowan, MD, Debra Babcock,PhD, Walter Koroschetz, MD 21

22 NINDS/NIBIB Consensus Meeting to Evaluate Pathological Criteria for the Diagnosis of CTE In 2014, the NINDS/NIBIB launched a major effort to define the neuropathological characteristics of CTE. First objective: evaluate the preliminary consensus criteria for the neuropathological diagnosis of CTE Is CTE is a distinct tauopathy that can be distinguished from other tauopathies? 22

23 Methods: The study design was based on previous successful NIHsponsored consensus conferences for other tauopathies, specifically PSP and CBD 25 cases of various tauopathies: CTE (with and without Aß) Alzheimer s disease Progressive Supranuclear Palsy Corticobasal Degeneration Argyrophilic Grain disease Primary age-related tauopathy Guamanian Parkinson s Dementia Complex No clinical or demographic information was provided to the neuropathologists including no information regarding the subjects age, gender, clinical symptoms or athletic exposure, no information on gross neuropathology. 23

24 Seven neuropathologists evaluated the digitized slides independently: Nigel Cairns, Ph.D. Dennis Dickson, M.D Rebecca Folkerth, MD Washington University, St Louis Mayo Clinic, Jacksonville Brigham and Womens, Boston C. Dirk Keene, M.D Univ Washington, Seattle Daniel Perl, M.D. Thor Stein M.D., Ph.D. Jean Paul Vonsattel, M.D. USUHS, Washington Boston Univ, Boston Columbia Univ, New York and submitted their diagnostic evaluations prior to the conference. 24

25 Results There was good agreement within the neuropathologists who reviewed the cases (Cohen s kappa: 0.67) There was even better agreement between reviewers and CTE diagnosis (Cohen s kappa: 0.78) using the proposed criteria for CTE. 91.4% of the total responses correctly identified CTE 95.7% after the clinical information and gross neuropathological features were revealed 25

26 Pathognomonic Lesion of CTE In CTE, the tau lesion considered pathognomonic was an abnormal perivascular accumulation of tau in neurons, astrocytes, and cell processes at the depths of the depths of the cortical sulci in an irregular pattern. 26

27 Pathognomonic Lesion of CTE The panel also stated that: thus far, this pathology has only been found in individuals exposed to brain trauma, typically multiple episodes 27

28 Low power microscopic examination often a clue to the diagnosis 28

29 CTE: Perivascular accumulation of p-tau in NFTs, thorned astrocytes and dot-like structures 29

30 The hippocampal ptau pathology is distinctive from AD 30

31 The TDP-43 pattern is distinctive from other neurodegenerations 31

32 CTE is not ARTAG 32

33 Validation of pathological criteria for CTE CTE risk in amateur contact sport athletes Acta Neuropathologica, 2016 In a review of >1,700 male brains donated over 18 years to Mayo Clinic Brain Bank, researchers found CTE pathology in 32% of contact sport athletes 162 control brains without a history of brain trauma or contact sports yielded zero cases of CTE. 33 brains with a history of a single TBI, yielded zero cases of CTE. Additional evidence linking repetitive brain trauma to CTE 33

34 Russ Huber, MD PhD Perivascular ptau lesions depth of sulcus neurons and astrocytes vesselel GFAP astrocytes AT8 34

35 Characterization of Early Pathological Tau Conformations & Phosphorylation in Chronic Traumatic Encephalopathy Kanaan N, Cox K, Alvarez V, Stein T, Poncil S, McKee A. JNEN 2016 astrocytes perivascular lesions TNT TOC1 ps422 dotlike structures CTE is a distinctive tauopathy that can be distinguished from AD and age- related tauopathy by the nature and distribution of the pathology and by immunohistochemical and biochemical analyses. 35

36 Cis P-Tau Trans P-Tau Kondo et al Nature July

37 CTE: other pathology P-TDP-43 P-TDP-43 SMI-34 IBA1 axonal injury and neuroinflammation 37

38 Stein et al Acta Neuropathol May

39 Aß deposition in CTE Stein et al Acta Neuropathol May 2015 Aß deposition in 52% of CTE subjects - never before the age of 50 years Age is significantly associated with Aß in CTE ApoE4 allele is significantly associated with Aß plaques in CTE Aß occurs in CTE at earlier age and an accelerated rate compared to a normal aging population (p=0.025) Aß in CTE is significantly associated with dementia, Parkinsonism, and LBD pathology 39

40 IBA1 Microglial neuroinflammation contributes to tau pathology in CTE in CTE Jon Cherry and Thor Stein A 300 B 600 Iba1+ cell/ mm GFAP+ cell/ mm Control I II III IV 0 Control I II III IV Control Stage 1 Stage II Stage III Stave IV C D E F G 20x H I J K L 63x 40

41 ptdp43 pathology in CTE D Barnes, P Kiernan, V Alvarez, B Huber. A Dedeoglu, L Goldstein, N Kowall, T Stein, A McKee ptdp-43 inclusions are observed in most CTE There is a significant correlation between ptdp-43 score and: CTE stage Hippocampal sclerosis Aß plaques Clinical dementia In CTE, ptdp43 deposits are often found in the frontal cortex, medial temporal lobe and substantia nigra The morphology of ptdp-43 appears to be unique in CTE Hippocampal sclerosis in CTE correlates with CTE stage 10% of CTE cases have ALS 41

42 UNITE BRAIN BANK BRAIN DONORS Brain Donors # Boxing 16 American Football 225 Ice Hockey 17 Professional Wrestling 5 Rugby 7 Military Veterans* 25 (*also 60 Veteran-athletes) Soccer 5 Other Sport: amateur wrestling, baseball, bull riding, lacrosse, martial arts, water polo 10 Other: physical abuse, poorly controlled epilepsy, head banging 12 TOTAL

43 CTE Diagnoses # CTE # Evaluated Boxing American Football Ice Hockey 9 14 Professional Wrestling 2 4 Rugby 2 5 Military Veterans* 9 (*46 Veteran-athletes) 23 (*53 Veteran-athletes) Soccer 3 5 Other Sport: amateur wrestling, baseball, bull riding, lacrosse, martial arts, water polo UNITE BRAIN BANK Dx: CTE 3 10 Other: physical abuse, poorly controlled epilepsy, head banging 1 11 TOTAL

44 Neuropathological Dx: CTE 184 Athletes Boxing Football Hockey Soccer Rugby MLB WWE MMA Total Pro Am NFL Sem Pro Coll HS/Y outh NHL Am Pro Am #CTE # evaluated % 78% 83% 28% 44

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46 CTE McKee et al, 2013, Brain 46

47 McKee et al, 2013, Brain Stages of Tau Pathology Age at Death Stage I mean age: years Stage II mean age: years Stage III mean age: years Stage IV mean age: years 47

48 Stages of Tau Pathology: NFL Age at Death Stage I mean age: 27.6 range: years Stage II mean age: 40.0 range: years Stage III mean age: 61.5 range: years Stage IV mean age: 75.0 range: years 48

49 143 cases of CTE in athletes: co-morbid neurodegeneration in 37% CTE+FTLD, 4, 3% CTE+LBD, 11, 8% CTE+Mul ple, 7, 5% CTE+Other, 2, 1% Pure CTE CTE+MND CTE+AD, 16, 11% CTE+MND, 15, 10% Pure CTE, 88, 62% CTE+AD CTE+LBD CTE+FTLD CTE+Mul ple CTE+Other 49

50 Michael Keck 25 yo college football player Mez et al, JAMA Neurology yrs football, 3 years division I, linebacker/ special teams Multiple concussions persistent vision changes, memory problems, confusion, difficulty sleeping and headaches Quit football after 3 yrs college. Continued to experience memory loss, disorientation, difficulty with attention, concentration and word finding, progressively worsened over the last 2 years of life Depression, impulsivity and severe anger Died at age 25 from a staph infection 50

51 Brain weight: 1480 grams 51

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53 Mez et al, JAMA Neurology 2016 Frontal, temporal, parietal cortex: AT8 (p-tau) 53

54 Michael Keck Stage II CTE PHF-tau 54

55 Tyler Sash 27 yo former NFL player 16 yrs football, 2 years NFL, safety and kick coverage 20 concussions symptoms from last concussion never completely resolved Subtle changes in his behavior in the NFL, more aggressive and anxious After NFL, impairment in attention, memory, executive function, shorter fuse, depression and apathy Narcotic use for chronic pain Death at 27 from accidental overdose 55

56 Tyler Sash 27 years old PHF-tau 56

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58 Death at age 50 years Dave Duerson 56 58

59 Stage III CTE 59

60 69 yo former NFL player 28 yrs football: 4 yrs high school, 4 years division 1 college, 15 years professional primarily as quarterback 500+ concussions, none with LOC Heavy alcohol use throughout life Age 55: brief episode of difficulty speaking, TIA Subtle episodic memory changes at age 60, often repeated himself c/o Headaches, increased sensitivity to light and noise, chronic pain and tinnitus Mood became more sullen and withdrawn, more anxious and he developed insomnia Brief cognitive eval at age 65: mild cognitive impairment Death at 69 from colon cancer 60

61 69 yo former NFL player Consensus panel clinical diagnosis: CTE with contributions from substance abuse 61

62 Brain weight: 1318 grams 62

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70 Olfactory bulb : AT8 70

71 AT8 Temporal pole Superior frontal Amygdala Septal cortex CA1 Hippocampus Amygdala Inferior frontal 71

72 Hippocampus CA1 CA4 72

73 Mammillary body Medial geniculate nucleus 73

74 Substantia nigra Locus coeruleus 74

75 Aß plaques: moderate diffuse plaques, sparse neuritic plaques 75

76 Ken Stabler: Pathological Diagnoses 1.CTE, Stage IV Septal fenestrations, mild generalized atrophy, most severe in frontal and temporal lobes Perivascular ptau immunoreactive neurofibrillary tangles and astrocytic inclusions concentrated at the depths of the cerebral sulci with severe involvement of the medial temporal lobe structures and brainstem Sparse TDP-43 neurites in CA1 hippocampus 2.Alzheimer s changes, insufficent for diagnosis Neuropathological change: Low (A3,B2,C1) NIA-Reagan: Low likelihood CERAD plaque density: sparse Mild CAA 3.Microinfarcts, Rolandic cortex 76

77 Ken Stabler Stage IV CTE 77

78 Aggregated tau stages I Neuroinflammation Microvasculopathy CTE II III IV Aß Neurodegeneration TDP-43..genetic susceptibility and resistance: MAPT, ApoE..other environmental exposures: steroids, drugs, alcohol PHF-tau Repetitive mild trauma Behavioral changes Age Memory loss/ Cognitive impairment Dementia 78

79 Possible mechanisms of tau spread? Prion protein templating Glymphatic channels Tau secretion Exosomes Other 79

80 What are the critical issues in CTE?: pathology and pathogenesis 1. How to detect, diagnose and monitor CTE during life 2. What mechanisms are involved in CTE pathogenesis? 3. Is CTE reversible? Can progression be halted? 4. What are the effects of gender? 5. What is the incidence and prevalence of CTE? 6. What are the genetic susceptibility factors? 7. What is the risk for CTE in amateur and professional sports and military service? 8. How does CTE contribute to other neurodegenerative pathologies? 9. Does trauma provoke other neurodegenerations besides CTE? 80

81 BU/VA CTE Program Jason Adams Victor Alvarez MD Kathryn Babcock Alexandra Bourlas Christine Baugh Andrew Budson MD Robert Cantu, MD FACS Kerry Cormier Dan Daneshvar, MD, PhD Brian Frye Matthew Jacobs Lee Goldstein MD PhD Bertrand R. Huber, MD, PhD Doug Katz, MD Patrick Kiernan Neil Kowall, MD Carol Kubilus Lisa McHale Jesse Mez, MD Phillip Montenigro Lauren Murphy Chris Nowinski David Riley Cliff Robbins Jon Cherry, PhD Dharmendra Goswami, PhD VA Boston/ Boston University/ CLF CTE Program Hyo Soon-Lee MD Todd Solomon, PhD Thor Stein, MD, PhD Robert Stern PhD Prince Williams Rhoda Au, PhD Other Institutions David Brody, Wash U Robert Brown MD, U Mass Nigel Cairns, PhD Wash U John Crary, MD, PhD Columbia Ramon Diaz-Arrastia, MD Dennis Dickson, MD Mayo Clinic Rebecca Folkerth, MD Brigham Garth Hall, PhD U Mass Lowell Laurena Holleran, Wash U Keith Johnson, MGH Dirk Keene, MD U Wash Alexander Lin, PhD, BWH Irene Litvan, MD UC San Diego Thomas Montine, MD, PhD U Wash Daniel Perl, MD USHS Michael Strong, MD Western William Stewart, Glasgow Jean Paul Vonsattel, MD Columbia BU Goldstein Lab Andrew Fisher, PhD Chad Tagge, PhD Juliet Montcaster, PhD Mark Wojnarowicz CLF Robert Cantu, MD FACS Chris Nowinski Boston VA (TRACTS) Regina McGlinchey, PhD William Milberg, PhD Terry Keane, PhD Lauren Radigan Meghan Robinson David Salat, PhD All the families who participated in our research 81

82 Thank you! Funding sources: Department of Veterans Affairs NINDS/ NIBIB/ NIA Department of Defense Andlinger Foundation WWE NFL NOCSAE 82