Prevention and Treatment of the Effecfs of Repetitive Brain Trauma Concussion, PCS, CTE

Robert C. Cantu, MA, MD, FACS, FACSM, FAANS

Clinical Professor of Neurosurgery and Neurology Co-Founder, Medical Director Co-Founder-Clinical Diagnostics and Therapeutics Concussion Legacy Foundation Leader CTE-AD Center Boston University School of Medicine Member Independent Concussion Advisory Group World Rugby Medical Director and Director of Clinical Research Dr. Robert C. Cantu Concussion Center Senior Advisor, NFL Head Neck & Spine Committee Assoc. Chairman, Dept. of Surgery, Member, NFLPA Mackey-White TBI Committee Chief, Neurosurgery Service Director of Sports Medicine Senior Advisor Brain Injury Center Emerson Hospital, Concord, MA Children’s Hospital, Boston MA Medical Director VP and Chair Scientific Advisory Committee National Center for Catastrophic Sports Injury Research National Operating Committee on Standards for Adjunct Professor Athletic Equipment ( NOCSAE ) Dept. of Exercise and Sports Science, UNC Chapel Hill Disclosures

• Senior Advisor NFL Head Neck & Spine Committee • VP NOCSAE and Chair Scientific Advisory Committee • Co-Founder, Medical Director Concussion Legacy Foundation • Royalties Houghton Mifflin Harcourt • Legal Expert Opinion (NCAA, NHL etc.) Historical Definitions of concussion

• Persian physician Rhazes 10th century AD • before 1974: LOC • 1980’s - ~2000: altered brain function • Currently: any symptom Theories of Concussion

• Vascular; brief ischemia, decreased cerebral blood flow • Reticular: brainstem site, effect on the ARAS produces loss of consciousness • Centripetal: Stresses and strains maximal at the brains surface but when severe would make them way to the center of the brain and to the brainstem. • Pontine cholinergic system: activation of the inhibitory system in the dorsal pons • Convulsive: symptoms like those of a seizure but is a brainstem reflex Strain in the Brain: a restating of CTC

•The direction, type, rapidity and magnitude of head motions will determine the strains in the brain •A particular set of input variables will produce a particular and unique “strain field/time profile” •Certain “strain-field/time profiles” will result in clinically apparent symptoms (phenotypic presentation) and pathological alterations Visualizing a Concussion

• The brain is the consistency of custard or Jell-O • A concussion can occur due to linear acceleration where the brain slams into the rough interior of the skull Visualizing a Concussion

• A concussion can be caused by rotational forces, which twist the brain • Most concussions are caused by a combination of both forces Common Concussion Symptoms

From SCAT 3 POST-CONCUSSION SYNDROME

Physical • Up to 30% of concussive patients have persistent symptoms past the typical healing time-frame, including Vestibulo Emotion -ocular al physical, cognitive, and emotional symptoms, which can last for weeks to months. (Baker, et al, 2012; Mittenberg et al, 2001) Cognitive Sleep

Learning with Purpose

Diagnosis of Concussion

Balance Symptom Assessment Check List Eye(BESS EYE)

Eye Cognitive Tracking Assessment Smooth Persuit Saccadic Take away message 1: When diagnosing a concussion the more tools you use the more accurate you will be- there is no golden bullet except LOC Concussion was thought to be a Structural Injury as far Back as the Mid-Nineteenth Century

• James Crichton-Brown who was to found the Journal Brain in 1871 wrote: “Concussion is, of course, the most important element in the vast majority of cranial injuries, in relation to subsequent mental infirmity. ….Everything points to the conclusion that the evil of concussion really consists on what may be called dynamical changes in the nerve cells and their connecting fibrils.”

Crighton-Browne J. Cranial Injuries and Mental Disease. W Rid Lun Asy Med Rep.1:30-21;1871. Concussion was Thought to be a Structural Injury

Mott linked repetitive head trauma with structural changes. Other pathologists including Charles Cassasa, Michael Osnato and Vincent Giliberti and Harrison Martland talked of concussion hemorrhages.

• Mott FW. The Lettsomian Lectures on the Effect of High Explosives Upon the Central Nervous System: Lecture II. • Lancet.441-448;1916. • Cassasa CSB. Multiple Traumatic Cerebral Hemorrhages. Proc NY Path Soc.24:101-106;1924. • Osnato M, Giliberti V. Postconcussion Neurosis Traumatic Encephalitis. A Conception of Postconcussion • Phenomena. Arch Neurol Psych. 18:181-214;1927. • Martland HS. Punch Drunk. Jama.91:1103-1107;1928. ion hemorrhages. Take away message 2: Concussion is both a pathophysiologic metabolic as well as a structural injury In the early 1930’s concussion was discussed in a text entitled The Injured Workman by G F Walker. He stated concussions were common enough that “mental impairment of post traumatic origin is surely well-known to every practitioner in industrial districts.”

Walker GF. The Injured Workman. Bristol: John Wright & Sons Ltd; quotes on 41-47;1933. Take away message 3: Concussion in a small percent of cases can have permanent effects (prolonged PCS) Fixed Head vs Head That Can Move

• Tedeschi reported when 68 animals were divided into two groups in which half a moving head struck a stationary object and the other half a moving object struck a stationary head by a force of exactly the same momentum, it was clear the group in which the head was not able to move had less loss of consciousness (40% vs 73%) and less percentage chance of death (7% vs 17%).

Tedeschi CG. Cerebral Injury by Blunt Mechanical Trauma. Special Reference to the Effects of Repeated Impacts of Minimal Intensity; Observations on Experiment Animals. Arch of Neurol. And Psychiatry. 53:333- 354;1945.

Take away message 4: Concussion risk is reduced by decreasing the rapid movement of the head (head restraint, neck strength) It was also of interest in a group of animals that received sub concussive trauma that some animals that received repetitive sub concussive trauma (defined as head trauma of such minimal strength as to be insufficient to cause a loss of consciousness or delayed effect in a normal animal) had loss of consciousness as the number of sub concussive insults increased and that some had persistent deficits and some died. Those that received sub concussive repetitive head trauma in close approximation in time unconsciousness began to be seen as soon as the fifth sub concussive blow. It was also concluded that "when the repeated sub concussive blows were delivered in a short period, there was a somewhat higher incidence of ill effects then when the trauma was delivered at longer intervals”.

Evidence Based Cantu Revised Concussion Grading Guidelines

Grade 1 No LOC* PTA‡/PCSS‡‡ < 30 min (Mild)

Grade 2 LOC <1 min or PTA/PCSS > 30 min (Moderate)

Grade 3 LOC > 1 min or PTA > 24 hrs, PCSS > 7 days (Severe) *Loss of consciousness ‡Post-traumatic amnesia (antrograde/retrograde) ‡‡Post-concussion sign/symptoms

Cantu RC Post-tramatic (retrograde and anterograde) amnesia: pathophysiology and implications in grading and safe return to play. J of Athletic Training 36(3),2001 Concussion Definitions: Why we are seeing more concussions? Take away message 5: Concussions are not created equally, the duration of symptoms is > important than > proximity of concussions > than number NFL Funded UPMC Hosted

Michael “Micky” Collins, PhD Meeting Chair

Anthony P. Kontos, PhD David Okonkwo, MD, PhD Co-Organizer Co-Organizer Meeting Chairman

Anthony P. Kontos, PhD Anthony P. Kont

Cantu Concussion Center

Speech/ Physical Occupational Therapy Language Therapy Pathology

Neuropsychology Support Group/Yoga Medical Provider

Other: Psychiatry/ Optometry/ Ophthalmology ENT, Endocrinology Psychology Take away message 6: Concussion is treatable with therapies/pharmacology 1995

“I’ve found a disease that no one has ever seen before” Andre Waters Commits Suicide

• November 20, 2006

• “I think I lost count at 15.” He later added: “I just wouldn’t say anything. I’d sniff some smelling salts, then go back in there.”

37 HISTORY OF CTE

Journal of the American Medical Association 1928

ConcussionFoundation ConcussionFoundation ConcussionFoundation.orgConcussionFoundation.org @ChrisNowinski1@ConcussionLF

Babinski Cushing

Neurology Neurosurgery

Critchley Vincent

Establishes Neurosurgery in Europe.

Martland Parker Millspaugh Courville Jordan

1928 1934 1937 1962 1997 Psychopathic Chronic Punch Traumatic Dementia Located Deterioration Traumatic Drunk Encephalopathy Pugilistica In Holland of the Pugilist Brain Injury • Recently, we uncovered case reports of Punch-drunk football players (aka “stumblebacks”) in the early medical literature (1930s). • Notably, the clinical presentation in those cases was consistent with recent pathologically confirmed cases.

The Milwaukee Journal circa 1937

Part of the CTE Archive.org (CTEarchive.com)

Impact

Growth

Time VA-BU-CLF BRAIN BANK

• Founded in September 2008, the first center in the world dedicated to CTE research

• Pathological, clinical, and basic science research

• 500 brains donated, over 350 confirmed with CTE

ConcussionFoundation ConcussionFoundation ConcussionFoundation.orgConcussionFoundation.org @ChrisNowinski1@ConcussionLF Christopher Nowinski, a former professional Robert Cantu wrote the original, and wrestler and Harvard defensive tackle, was largely ignored, return-to-play guidelines in forced to retire at 24 with post-concussion the 1980’s. syndrome.

Researcher Ann McKee was invited to discuss her findings with the Robert Stern calls his group’s science “one piece NFL. “They were polite,” she says. “But it was falling on deaf ears.” of an incredibly complex puzzle.” ConcussionFoundation ConcussionFoundation ConcussionFoundation.orgConcussionFoundation.org @ChrisNowinski1@ConcussionLF BU CSTE 2008

Preclinical Studies of Mechanisms Boston University Center for the Study of Traumatic Encephalopathy

Goal: To study the long-term effects of mild traumatic brain injury 1. Mild Traumatic Brain Injury Brain Bank 2. Brain Donation Registry 3. Longitudinal Clinical Studies 4. Preclinical Studies of Mechanisms

Criticisms of the Neuropathology of CTE CTE IS NOT A UNIQUE TAUOPATHY AND CANNOT BE DISTINGUISHED FROM AGING AND AD DISPROVED BY NIH CONSENSUS MEETING AND SUBSEQUENT PUBLICATIONS Pathological Criteria for the Diagnosisof CTE the Pathologicalfor Criteria NINDS/NIBIB Consensus NINDS/NIBIB Is isCTE a distinct tauopathy that can be distinguished from other tauopathies? McKee et al. Acta Neuropathologica 2016 Neuropathologica Acta et al. McKee Meeting to Evaluate Evaluate to Meeting

February 25-6, 2015

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.”

Age related-tau astrogliopathy that may be present-non diagnostic, non supportive

• Patches of thorn-shaped astrocytes in subcortical white matter • Sub-ependymal, periventricular,perivascular thorn-shaped astrocytes in medial basal regions • Thorn-shaped astrocytes in amygdala and hippocampus CTE Questions

• What is the clinical presentation and course (based on objective, prospective examination)? • How can CTE be detected and diagnosed during life (biomarkers)? • How can CTE be treated?

Not So Quick! • The sample size (n=5) was very small. • FDDNP is a nonspecific PET ligand that binds to both amyloid and tau with no way of discerning which protein it is binding to. • There is evidence that FDDNP binds to other abnormal proteins, including all prion plaques, e.g., sporadic Creutzfeldt-Jacob disease (Bresjanak et al., 2003). • Authors stated: specific localization of FDDNP binding consistent with CTE, based on our group’s previous work. Not true. • They showed binding in several subcortical regions but not in the cortex, stating that it was consistent with our group’s findings. But…it does not fit what we would expect in CTE.

• (18F) Florbetapir positron emission tomography (PET) imaging for amyloid plaques • (18F)-T807 PET imaging ligand that binds to tau, neurofibrilary tangles • 71 yo male, decade long NFL career ending 40 years before • Successful 20 year business career • History of progressive cognitive impairment

• (18F) Flurbetapir -, (18F) T708 + globus pallidus, putamen, and hippocampus (subcortical location) BU Researchers ID Possible Biomarker for Diagnosing CTE during Life MED’s Ann McKee calls findings a hopeful step hronic traumatic encephalopathy (CTE), a progressive degenerative brain disease found in people with a history of repeated head trauma, can currently be detected only after death, through an autopsy. Absent being able to diagnose the disease in living patients, researchers cannot develop treatments for CTE. In the past several years, scientists have taken small steps forward in identifying possible biomarkers for the disease, and now researchers from the Boston University School of Medicine and the VA Boston Healthcare System (VABHS) have discovered a new biomarker that may potentially allow the disease to be diagnosed in the living. In a study published Tuesday in the journal PLOS ONE, the researchers found that the biomarker, the protein CCL11, might also help distinguish CTE from Alzheimer’s disease, which often presents with symptoms similar to CTE and also can be definitively diagnosed only postmortem. The ability to diagnose CTE in the living would allow not only for the development of possible therapies to treat the disease, but also for research into prevention. “This is a step forward from our knowledge gained in understanding CTE from brain donations,” says study senior author Ann McKee, a MED professor of neurology and pathology, director of BU’s CTE Center, and chief of neuropathology at VABHS. “It’s a hopeful step. The whole point is to understand as much as we can from the individuals who’ve fallen, so we can apply it to our future veterans and athletes.” P-tau pathology of aging shares no microscopic features of CTE, even in mildest stages

• In CTE cortical sections show irregular distribution of p-tau pathology in a prominent perivascular location in neocortex with focal accentuation at depths of sulci, subpial clusters of p- tau also found at sulcal depths and superficial layers of cortex. Hippocampus and entorhinal cortex free of pathology in early stages. • In AD the NFT’s (p-tau pathology) is diffuse not irregular • not perivascular, not at depths of sulci or sub-pial regions, • in deep not superficial layers of cortex, • AB plaques are a requisite diagnostic feature and not found in early stage CTE and more than 50% of CTE cases overall. Distinct Tau immunoreactive NFTs Preferential involvement of the superficial cortical layers

I II III IV

V TAU

CONTROL CTE CTE Alzheimer’s CTE is entirely distinct from Alzheimer’s disease

no Aß, Normal no tau

tau CTE no Aß

tau Alzheimer’s and disease Aß Criticisms of the Neuropathology of CTE

• CTE is commonly seen with other neurodegenerative diseases obscuring any conclusions that can be drawn. • Co-morbidities are common, the rule, with all neurodegenerative diseases esp. with advanced age. • Suggests they including CTE share common etiological factors and these factors are enhanced with age CTE cannot be diagnosed during life, therefore, it is not a distinct neurodegeneration

• Nonetheless, the fact that we are unable to diagnose CTE with certainty during life does not diminish CTE as a distinct entity, a concept that also holds true for many neurodegenerations, including AD, Lewy body disease, Parkinsons disease and Frontotemporal Lobar degeneration.

• Research to develop biomarkers for CTE is underway in many laboratories (Chein et al., 2013; Xia et al., 2013), and hopefully, in the future there will be specific and sensitive blood and cerebrospinal fluid biochemistries and neuroimaging signatures that will enable in the diagnosis of CTE during life. Criticisms of the Neuropathology of CTE

Observational Science is poor science Observational science is not meant to be and end in in itself but is often the initial event leading to new scientific paradigms and expanding the frontiers of human disease. e.g. AIDS, Alzheimer’s disease, lung cancer etc. Prospective studies involving large numbers over decades need to be done. Chronic Traumatic Encephalopathy (CTE) is

• Progressive neurodegenerative disease. • Believed to be caused by repeated trauma to brain, including concussions and subconcussive blows. • Not prolonged post-concussion syndrome. • Not just the cumulative effects of concussions. • Symptoms often begin years or decades after the brain trauma and usually continues to worsen. Diagnosis of CTE During Life is Next Critical Step

• Determine the risk factors for CTE • repetitive brain trauma is a necessary but not sufficient cause of CTE • Differentiate between CTE and other causes of dementia, e.g., Alzheimer’s. • Prevention of suicide. • Understand the true prevalence of the disease. • Begin clinical trials for treatment and prevention Criticisms of the Clinical Aspects of CTE

There is no well-defined clinical phenotype The clinical picture has come from biased retrospective accounts provided by the affected individuals family and friends. There is marked overlap in clinical features between CTE and other neurodegenerative conditions, such as AD, and “normal healthy aging”.

The clinical phenotype of CTE is not yet well defined. The clinical presentation of CTE has come from retrospective analysis (Stern et al., 2013, McKee et al., 2013, Mez et al., 2013).

The suggestion that CTE is not itself a distinct neurodegenerative disease because its symptoms overlap with other neurodegenerative diseases is short sighted at best.

There is significant overlap in symptoms with all the neurodegenerative diseases Explosivity Disinhibition Paranoia

Depression Anxiety Suicidal ideation

Cognitive impairment Eric Pelly, 18 Years-Old

• Tau pathology pathognomonic but there is also breakdown of BBB, neuroinflammation, axonal degeneration, neuronal loss….

If history is any guide, our understanding of CTE will likely follow a similar trajectory to other neurodegenerative diseases, which underwent intense scrutiny, debate and revision before formal diagnostic pathological and clinical criteria were validated and agreed upon (Harciarek & Jodzio, 2005). Evidence that CTE is caused by trauma

In the case of trauma-associated human disease, it is not feasible to conduct experimental studies to provoke disease in human subjects and no direct determination of causality can be ethically conducted. As such, the determination that needs to be made is whether the preponderance of the evidence allows one to reasonably conclude that the disease is

associated with traumatic exposure, a constant of all reported cases.

There is substantial evidence using animal models in support of the association (Bailes & Mills, 2010; Bennett, Mac Donald, & Brody, 2012; Conte et al., 2004; Creed, DiLeonardi, Fox, Tessler, & Raghupathi, 2011; Genis, Chen, Shohami, & Michaelson, 2000; Goldstein et al., 2012; Huber et al., 2013; Jane, Steward, & Gennarelli, 1985; Kanayama et al., 1996; Kane et al., 2012; Lado & Persinger, 2003; Lifshitz & Lisembee, 2012; Mills, Bailes, Sedney, Hutchins, & Sears, 2011; Mills, Hadley, & Bailes, 2011; Mouzon et al., 2014; Nakajima et al., 2010; Ojo et al., 2013; Olsson, Rinder, Lindgren, & Stalhammar, 1971; Prins, Hales, Reger, Giza, & Hovda, 2010; Raghupathi, 2004; Shitaka et al., 2011; Shultz, MacFabe, Foley, Taylor, & Cain, 2012; Smith et al., 1999; Tran, LaFerla, Holtzman, & Brody, 2011; Uryu et al., 2002). Figure 1. Acute and chronic effects of close-head impacts Acute Pathology Chronic Pathology Gliding Contusion Neurofibrillary Tangles Vascular Neurofibrillary Injury Tangles

The VA-BU-CLF Brain Bank • Frontal parasagittal • Frontal parasagittal • Perivascular • Perivascular • Sulcal depth • Sulcal depth DoD SoS Conference Proceeding. Journal of Neurotrauma 2016 In the last several years multiple researchers have shown similar ultrastructural and functional brain alteration from multiple head blows without “recognized” Concussion symptoms

1. Talavage TM, Nauman E, Breedlove EL et al. Functionally –detected cognitive impairment in high school football players without clinically-diagnosed concussion. J Neurotrauma 2013;30:1-12 2. Bazarian JJ, Zhu T, Blyth B et al. Subject-specific changes in brain white matter on diffusion tensor imaging after sport-related concussion. Magn Reson Imaging 2012;30:171-180. 3. Shenton M et al . White matter integrity in the brains of professional soccer players without concussion. JAMA 2012; 308:1859- 4. Lipton ML. Soccer heading is associated with white matter microstructural and cognitive abnormalities. Radiology 2013;268:850-857. 5. Marchi N, Bazarian JJ, Puvenna V et al. Consequences of repeated Blood-brain Barrier Disruption in football players. Open Access March 2013. 6. Bourlas J, Stamm J, Baugh CM. Relationship between age of first exposure to tackle football and later life mood, behavior, and cognition. Pediatrics (submitted) 7. Singh R, Meier TB, Kuplicki R. Relationship of collegiate football experience and concussion with hippocampal volume and cognitive outcomes. Open Access 2014. 8. Bernick C (personal communication) Subconcussive Evidence

• Studies are finding short-term and long-term changes in brain microstructure and function even in the absence of “recognized” concussion 56 Rugby

The First NINDS/NIBIB Consensus Meeting to Define Neuropathological Criteria for the Diagnosis of Chronic Traumatic Encephalopathy

…..thus far, only been found in individuals who were exposed to brain trauma, typically multiple episodes.

Wrestling 21 of 66 contact sport athletes had CTE (32%) 43 football, 9 boxing, 8 baseball, 5 basketball, 1 wrestling, 1 MMA, 1 soccer No CTE Pathology in Any Control-32% Contact Athletes • Post-TBI neurodegeneration (CTE) very much exists, but under-recognised • Incidence unknown • Exposure levels required (concussive, sub-concussive) is unknown • Associated risk factors unknown • Clinical syndrome being defined • Diagnostic pathology criteria defined • Tau pathology pathognomonic, but also features pathologies in amyloid, TDP43 BBB, neuroinflammation, axonal degeneration, neuronal loss…. g

Conclusions Regarding Head Trauma and CTE

Although further research is needed to identify the critical variables essential to the development of CTE after RTBI including the role of genetics, inflammatory response, age, gender, and substance abuse , the preponderance of evidence supports the conclusion that CTE is directly associated with RTBI Conclusions Regarding Head Trauma and CTE

the disease is associated with traumatic exposure, a constant of all reported cases.

The NIH panel also stated that: “ this pathology has only been found in individuals exposed to brain trauma, typically multiple episodes” “There is absolutely no evidence to suggest a connection between the NFL and dementia.”

—Greg Aiello, NFL spokesman, April, 2007 94

The NHL’s CTE spin has spun out of control x

In the ongoing concussion lawsuit brought against the NHL by several former players, the NHL has sunk to a ridiculous new low. The history of science has been filled with infamous examples of skeptics voicing their dissent to the grind of human progress. Whether it be doubt that flight would ever be achieved or insistence that the Earth is flat instead of a globe, posterity records the stances of individuals which are now viewed as laughable. The NHL seems to have put itself in that company on the subject of chronic traumatic encephalopathy (CTE). These actions taken by the league are part of its attempts to derail a lawsuit brought against it by what could turn into a class of thousands of former players.

Recent evidence indicates:

• Developing brain is more vulnerable to poor outcome after TBI

(Giza 2005 Behavioral Brain Research) Recent evidence indicates:

• After TBI children vs adults have: Prolonged recovery rates

(Lovell 2004 AJSM) (Guskiewicz 2011 PM&R) (Field 2003 J Ped) (Anderson 2011 Brain) (Moser 2005 Neurosurgery) (Sim 2008 J Neurosurg) Recent evidence indicates:

• After TBI children vs adults have: Altered educational and social development

(Gioia 2009 BJSM) (Moser 2005 Neurosurgery) Recent evidence indicates:

• After TBI children vs adults have: Lower IQ and grade point average

(Anderson 2011 Brain) (Moser 2005 Neurosurgery) SEPTEMBER 19, 2017 Health A study, with some limitations, sees link between youth football and emotional issues in adulthood By Bob Tedeschi @bobtedeschi September 19, 2017

Ryan Kang/AP BOURLAS, AP, STAMM JM, BAUGH CM, DANESHVAR D H , BREAUD AH, ROBBINS CA, RILEY DO, MARTIN BM, MCCLEAN MD, AU R, GIOIA G , CHAISSON C E , OZONOFF A , M C K E E A C , NOWINSKI CJ, C A N T U R C , TRIPODIS Y, S T E R N R

Relationship between age of first exposure to tackle football and later life mood, behavior, and cognition 92 male former foot ball players with history of no other contact sport taken from longitudinal examination to gather evidence of neurodegenerative

disease (LEGEND) study at BU-CSTE self report and online data collection through online questionnaires and telephone interview Bourlas, AP, Stamm JM, Baugh CM, Daneshvar DH, Breaud AH, Robbins CA, Riley DO, Martin BM, McClean MD, Au R, Gioia G, Chaisson CE, Ozonoff A, McKee AC, Nowinski CJ, Cantu RC, Tripodis Y, Stern R Relationship Between Age of First Exposure to Tackle Football and Later Life Mood, Behavior, and Cognition Conclusions and Relevance: First study to find an association between the age at which children begin playing tackle football and later-life mood, behavior, and cognitive dysfunction

➢ Conclusions and Relevance: 2nd study to find an association between the age at which children begin playing tackle football and later-life mood, behavior, and cognitive dysfunction • Age of First Exposure to American Football and Long-Term Neuropsychiatric and Cognitive Outcomes: Investigation in 214 Former Football Players

• Michael L. Alosco, PhD, 1,2 Alexandra P. Bourlas, MA, 1 Julie M. Stamm, PhD,1 Alicia S. Chua, MS,3 Christine M. Baugh, MPH,1,2,4 Daniel H. Daneshvar, MD, PhD,1 Clifford A. Robbins, BA,1,5 Megan Mariani, BS, BA,1 John Hayden, MS,1 Shannon Conneely, BA,1 Brandon E. Gavett, PhD,6 Rhoda Au, PhD,2,7 Alcy Torres, MD,8,9 Michael D. McClean, ScD,10 Ann C. McKee, MD, 1,2,11-13 Robert C. Cantu, MD,1,2,5,14,15 Jesse Mez, MS, MD,1,2 Christopher J. Nowinski, BA,1,5 Brett M. Martin, MS,1,16 Christine E. Chaisson, MPH,1,16 Yorghos Tripodis, PhD*,1,3 & Robert A. Stern, PhD*1,2,14,17 Translational Psychiatry 2017 KEY POINTS

• Question: Is younger age of first exposure (AFE) to American football associated with worse long-term neuropsychiatric and cognitive function? • Findings: Among 214 former amateur and professional football players, AFE to football before 12 corresponded with worse and >2X increased odds for clinically-meaningful impairments in reported behavioral regulation, depression, apathy, and executive function, compared to those who began playing ≥12. Effects were independent of duration of play, and were not level of play dependent. Significant relationships with clinical measures were present when AFE was examined as a continuous variable. • Meaning: Youth exposure to football may have long-term neuropsychiatric and cognitive consequences. Table 1. Sample Characteristics

Total Sample AFE <12 AFE ≥12 P (N = 214) (n = 101) (n = 113) Age, mean (SD) years 50.68 (13.33) 48.22 (10.87) 52.87 (14.91) 0.009 Race, n (%) White 192 (89.7) 92 (91.1) 100 (88.5) 0.53 Education, mean (SD) years 17.07 (2.27) 17.09 (2.38) 17.04 (2.19) 0.89 Learning disability, n (%) yes 19 (8.9) 10 (9.9) 9 (8.0) 0.62 Seasons of football play, median (IQR) 12.00 (9) 14.00 (10) 10.00 (8) <0.001

AFE to football, mean (SD) 11.12 (2.47) 8.98 (1.65) 13.04 (1.14) <0.001 Cumulative Head Impact Index,a mean (SD) 6969.09 (5230.11) 7112.57 (4705.24) 6838 (5683.59) 0.71

Highest level of football play, n (%) 0.54 High School 43 (20.1) 20 (19.8) 23 (20.4) College 103 (48.1) 51 (50.5) 52 (46.0) Professional 68 (31.8) 30 (29.7) 38 (33.6)

Primary position, n (%)b -- Offensive Linemen 69 (32.7) 26 (26.3) 43 (38.4) Running Back 64 (30.3) 35 (35.4) 29 (25.9) Tight End 27 (12.8) 15 (15.2) 12 (10.7) Offensive Skill 51 (24.2) 23 (23.2) 28 (25.0) Defensive Line 72 (34.8) 30 (30.3) 42 (38.9) Linebacker 58 (28.0) 31 (31.3) 27 (25.0) Defensive Back 77 (37.2) 38 (38.4) 39 (36.1) ➢ Conclusions and Relevance: 3rd study to find an association between the age at which children begin playing tackle football and later-life mood, behavior, and cognitive dysfunction AGE OF FIRST EXPOSURE TO TACKLE FOOTBALL AND CHRONIC TRAUMATIC

ENCEPHALOPATHY

MICHAEL L. ALOSCO, PHD, 1 JESSE MEZ, MD, MS,1 YORGHOS TRIPODIS, PHD, 1,2 PATRICK T. KIERNAN,

BA, 1,3 BOBAK ABDOLMOHAMMADI, BA,1 LAUREN MURPHY, BA,1 NEIL W. KOWALL, MD, 1,4,5 THOR D.

STEIN, MD, PHD, 1,4-6 BERTRAND RUSSELL HUBER, MD, PHD, 1,5 LEE E. GOLDSTEIN, MD, PHD, 1,4,7,8

ROBERT C. CANTU, MD,1,9-11 DOUGLAS I. KATZ, MD,1,12 CHRISTINE E. CHAISSON, MPH, 1,13 BRETT

MARTIN, MS,1,13 TODD M. SOLOMON, PHD,1 MICHAEL D. MCCLEAN, SCD,14 DANIEL H. DANESHVAR,

MD, PHD,1,15 CHRISTOPHER J. NOWINSKI, PHD,1,10 ROBERT A. STERN, PHD,1,9,16 ANN C. MCKEE, MD1,4-6

ANNALS OF NEUROLOGY 2018 Age of First Exposure to Tackle Football and Chronic Traumatic Encephalopathy

• 246 tackle football players who donated brains-211 with CTE (126/211 without comorbid disease, 35 without CTE Results • Age of exposure not associated with CTE severity or Alzheimer’s disease • Of 211 with CTE every year younger participants began playing football predicted earlier reported cognitive symptoms onset by 2.44 yrs. and behavior/mood symptoms by 2.5 yrs. (p<0.0001) • Age of exposure before 12 predicted earlier cognitive and behavior/mood symptoms by 13 years (p<0.0001) Age of First Exposure to Tackle Football and Chronic Traumatic Encephalopathy

• Fourth paper from our BU group showing greater chance and in this case earlier onset of cognitive, behavior/mood symptoms in athletes who start playing tackle football under age 12.

Concussion, microvascular injury, and early tauopathy in young athletes after impact head injury and an impact concussion mouse model | Brain |

Blast-exposed mice also develop CTE neuropathology (tau proteinopathy, myelinated axonopathy, microvasculopathy,chronic neuroinflammation, and neurodegeneration)that recapitulates CTE in humans. • No correlation between concussion and CTE, + correlation with CHIE • Best evidence to date it is the hit, not concussion, that causes CTE • Traumatic head motion is the major contributor to acute & chronic effects of neurotrauma • Different types of neurotrauma, blast-impact, lead to similar CTE pathology • Currently no tools/techniques to diagnose/assess risk for CTE in living humans Impact

Growth

Time

BU CTE Center Funding National Institutes of Health NINDS/NIA/NICHD R01 NS078337 Boston University Alzheimer’s Disease Center -NIA NIA P30 AG13846 supplement 0572063345-5

Boston University School of Medicine Department of Veteran’s Affairs Sports Legacy Institute WWE NFL – Unrestricted Gift NFL Players Association – Travel for study participants JetBlue – Travel for study participants Center for Integration of Medicine and Innovative Technology (CIMIT) - Grant NOCSAE – Grant

Thank You!