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Current Evidence of Chronic Traumatic Grant funding, salary/employment, consulting fee, Encephalopathy Disclosures honorarium or equity Abbott Diagnostic Laboratories Continuing Legal Education in MN, NY Hennepin County Medical Center Hennepin Health Foundation Integra Corporation ö Intellectual Property Islamic Medical Association of North America related to concussion Medtronic Corporation and brain injury Minnesota Brain Injury Alliance assessment National Football League ö Intellectual Property National Neurotrauma Society Uzma Samadani MD PhD FACS related to assessment of North American Brain Injury Society dementia after brain Oculogica Inc Rockswold Kaplan Endowed Chair Traumatic Brain Injury Research injury Steven and Alexandra Cohen Foundation for Veteran Post ö Intellectual Property Traumatic Stress and Traumatic Brain Injury Hennepin County Medical Center related to treatment of Texas, Minnesota, and Wisconsin High School Coaches intracranial hemorrhage Associations Associate Professor Neurosurgery, University of Minnesota United States Veterans Administration and Office of Research and Development Staff Neurosurgeon, Minneapolis VAMC USA Football

What Do These Men Have In Common?

Franklin D. Roosevelt in Groton Dwight D. Eisenhower John F. Kennedy enjoyed playing Nixon (top center) seen Gerald Ford played on two national Jimmy Carter played under- School’s 1899 football team, sitting kicking a football at West touch football with family and here as a member of the championship football teams at 140 lb. football at second from left, first row. Point. 1912. friends. He also played football at Whittier (California) squad, Michigan. He played center for the Annapolis.He was a sprint the Dexter School in Brookline, also played college football University of Michigan Wolverines . football played for the Navy Mass. and at the Choate Hall prep Midshipmen. Franklin D. Roosevelt Dwight D. Eisenhower John F. Kennedy Richard Nixon Gerald Ford Jimmy Carter school in Wallingford.

Reagan poses as Notre Dame George H. W. Bush pictured Pictured above, Bill Clinton George W. Bush went to the Obama was a star basketball player, Trump , who attended the New football star George Gipp, whom above, playing football in 1980. reaching for the ball at a game Phillips Academy in Andover, winning the state championship in York Military Academy, was a George W. Bush Barack Obama Donald Trump Ronald Reagan George H. W. Bush Bill Clinton Reagan played in the 1940 film He also captained the football in South Carolina. He played Massachusetts, where he was an 1979. Also, in the White House member of the varsity soccer, Knute Rockne All American. team at Yale from 1964-68). touch football when growing all-around athlete, playing Concussion Summit, he recounts his baseball and football teams. up. baseball, basketball and football. early days when he played football.

Why is concussion/brain injury so hard to diagnose and define? How do we diagnose and classify these? No two recoveries are the same (functional plasticity, resilience) What are the long-term consequences?

Scalp Injury Prognosis Best Skull Injury

Compressive Lesions Epidural / Subdural Spinal Cord Injury = Paralysis Inner Ear Injury - Dizziness Subarachnoid Hemorrhage/IVH

Diffuse Axonal Injury=CTE

Anoxic Brain Injury= Permanent Neuro Deficit Endocrine Dysfunction= Cortical Spreading Depression= Depression, Suicidality Headache, Seizures, Stroke Worst Genetic and environmental contributors to recovery (COMT, BDNF, ApoE, RAR)

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Why is concussion/injury so hard to diagnose and Neither imaging nor loss of consciousness tell the whole story define? Some people with brain injury were never “hit” in the head… Inflammation/edema •Primary blast injury: transmission of the blast Diffuse axonal injury pressure wave to the brain. Endocrine dysfunction •Secondary blast injury: penetration of Spreading depolarization (CSD) projectiles through the skull and into the Iron toxicity brain. Physiologic Hypoxic/anoxic Injury •Tertiary blast injury: acceleration and TBI Astroglial scarring (blast) deceleration effects, for example, if the casualty is thrown against fixed surfaces. •Quaternary blast injury: thermal, chemical, and other injuries to the head, including the Structural TBI face, scalp, and respiratory tract.

Loss of Schematic diagram of the mechanisms of blast-related traumatic brain injury. Figure shows local effects (1–7) consciousness and systemic effects (8, 9) of primary blast injury, secondary blast injury (10–12), tertiary blast injury (13), quaternary blast injury (14), and portals for blast wave transmission to the brain (15, 16). (1) Acoustic impedance mismatch causes spallation. (2) Shock–bubble interaction. (3) Shear stress causing diffuse axonal injury. (4) Cavitation. (5) Skull deformation with elastic rebound. (6) Reflection of the blast wave within the skull. (7) Bobblehead effect of acceleration–deceleration. (8) Blood surge from the torso damages the microvasculature. (9) Air embolism from blast lung injury.(10) Penetrating fragments. (11) Compound fractured skull. (12) Intracerebral haemorrhage. (13) Contrecoup contusion. (14) Burns. (15) Blast wave transmitted through the orbits. (16) Blast wave transmitted through the nasal sinuses. Rosenfeld et al. Lancet Neurology Blast-related traumatic brain injury, 2013-09-01Z, Volume 12, Issue 9, Pages 882-893

Suicide Risk Is Increased After Concussion 235000 pts followed for 9 years: 31/100,000

>109,000 Swedes under age 25 with TBI compared to their siblings Increased risk: pension disability, psychiatric hospitalization and premature death Severity and number of injuries correlates with outcome

Lehman et al 2016 3439 NFL players from 1959-1988 seasons were studied (minimum of 5 Drugs are assessed by standardized mortality ratio (the seasons per player) Followed for 28.9 years after increase or decrease in mortality of a study cohort with retirement respect to the general population

If playing in the NFL (for a mimimum of 5 seasons) was Players retired-since 1987 treated like taking a drug: 6.1/100,000 Players retired- since 2005 It reduces standardized mortality 12.5/100,000 (measured 30 years later) by half! Take daily Average American man- since 2014 20.1/100,000 Saving 296 lives at the cost of 17 deaths

Since 2005, NFL players are 48% less likely to commit suicide than the general population Since 1987, NFL players are 70% less likely to commit suicide than general population!

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Suicide in the general population and Decrease in Youth Athletics NCAA athletes Compared to Youth Suicide Rate

NUMBER OF ATHLETIC PARTICPANTS (AGE 6-17) COMPARED TO NUMBER OF SUICIDES IN TOTAL US POPULATION 44,000 100000000 90000000 42,000 80000000 40,000 70000000 General Population 12.6 per 100,000 Published Oct 2015 60000000 38,000 50000000 18-22 year old non-college 12 per 100,000 40000000 9 year study 36,000 30000000

College students 7.5 per 100,000 of Number Suicides 3,773,309 participant seasons 34,000 20000000 10000000 NCAA Athlete 0.93/100,000 32,000 0

2009 2010 2011 2012 2013 2014 Number of Athletic Participants NCAA Football (male only) 2.25/100,000 Number of Suicides Athletic Participants Linear (Athletic Participants )

What is the Relationship Between Concussion and Dementia?

ö1/3 of Americans have had a concussion in their lifetime, 2/3 of these concussions are in males öDementia occurs about 63.5 per 1000 persons in the US 32 öAlzheimer’s twice as common in women vs men ö5 Million have Alzheimer’s – no reliable diagnostic, unknown öAn increase in sports participation (grades 7-12) leads to a cause decrease in depression by 25% öOther common types: vascular dementia, frontotemporal öSuicidal ideation decreases by 12% with an increase in sports dementia, normal pressure hydrocephalus participation

What are the risk factors for dementia?

ö Smoking ö High blood pressure 4265 older adults followed ö Diabetes ö Atrial fibrillation for 45190 years ö Sedentary lifestyle ö Genetics ö High fat diet / obesity ö Decreased level of education No association between a ö Frequent alcohol use (women) single brain injury ö Female gender ö Mild brain injury if over 65 years ö Low socioeconomic status (women) of age (men) and mild cognitive ö Sleep apnea ö Moderate or severe brain injury impairment, Alzheimers ö Hearing loss if over 55 (men) or other types of dementia ö Depression ö Decreased social contact

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What is Chronic Traumatic Omalu et al and McKee et al. presented Encephalopathy (CTE) new definitions for CTE in the 2000s:

ö ,

ö First discovered in 1928 in NJ boxers published in JAMA ö Found in 17% of living professional boxers in England, named CTE in 1969 ö Motor deficits, Dementia ö Pathology described in 1960’s and 1970’s at Queen’s Square, England

“CTE, as defined in America, is not a neurological entity, but Current Sports Medicine Reports: is a culture-specific social phenomenon.” Jim January/February 2014 - Volume 13 - Issue 1 - p 33–37 Andrikopoulos, British Medical Journal

February 2015: The feds step in to help define CTE: decide on 4 types but the condition may be clinically asymptomatic

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“the pathognomic “a substantial lesion consists of number of p-tau aggregates neurologically in neurons, unimpaired astrocytes and subjects even at a cell processes very old age around small display only sparse vessels in an to modest extent of irregular pattern neurodegenerative at the depths of pathology” the cortical sulci ”

Contact sport athletes, regardless of injury, are CTE is equally common in people with and at increased risk for “symptomless” CTE without clinical neurodegenerative symptoms

ö CTE prevalence in people with neurodegenerative diseases (11.8%) was the same as in controls (12.8%). ö Patients with CTE died at a mean age ö CTE pathology in 21/66 former of 81 years and that “most positive athletes; 3 had prior concussions. cases [were] likely to be clinically asymptomatic.” ö CTE not seen in 198 non-athletes, of whom 33 had documented ö CTE is found under the microscope in head trauma. equal proportions of healthy normal asymptomatic people as it is in ö There was no association people with dementia and other between clinical symptoms and diseases. CTE

-CTE is not the problem “The combined history of head -deposition of tau may injury and alcohol and/or drug be a response to injury abuse was a significant or opioids that is predictor of any CTE-like changes. Age was also a reparative or normal significant predictor; most with aging any CTE-like changes were >40 years old. CTE-like changes 71% NFL players have were not identified at sites of abused opioids contusion” n=111 subjects

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Does football increase risk of dementia? Rochester Epidemiology Project

From 1956-70

296 varsity football vs 196 wrestling, swimming, 438 Football Players and basketball athletes

followed for 50 years Football players more likely to have had a concussion

Same risk for No difference in likelihood dementia as of dementia, Parkinsonism or ALS members of chorus, >50 years after injury glee club or band

men who graduated from a Wisconsin high school in 1957: 834 played football 52 players; 29 controls 1858 did not Averaged 22 years of professional international rugby play 14 concussions on average At ages 54, 65, 72 – no difference in Average age of 54 years at assessment Cognition Depression Controls: higher CV disease Behavior/Anger/Anxiety/Alcohol abuse No differences in cognitive testing, general Kids who did high school football more likely to play sports at age 35 or mental health

So then why does this article about dementia feature a kid in a sports helmet?

IMPERFECT SCIENCE 1.) no controls (normal children change as they develop) 2.) ascertainment bias 3.) outcome measures assess risk of brain injury but not risk/benefit of sports

------$$$$ MOTIVATIONS Researchers are dependent on positive results and “real life application” for their livelihood!

Lots of people want to profit from “the worried well” and kids playing sports

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25 boys aged 8-13 studied with accelerometers A normal child has changes in brain structure and function as they grow and develop Change in FA plotted vs risk-weighted cumulative exposure Children learning to read activate different areas for speech as they progress… 1. There are no controls in this study

2. One outlier creates “significance”

3. We have no idea what the kids were doing with their accelerometers (?throwing them around)

4. We don’t know what the kids were doing outside of Monzalvo et al. Brain and Language, Volume 127, Issue 3, 2013, 356 - 365 football

What is an ascertainment bias?

Assuming that the subjects you are performing research on are representative of the general population

“This study had several limitations. First, a major limitation is ascertainment bias Example: associated with participation in this brain donation program. Although the criteria for participation were based on exposure to repetitive head trauma rather than on clinical signs of brain trauma, public awareness of a possible link between 110/111 patients that I see with headache have repetitive head trauma and CTE may have motivated players and their families bleeding or a tumor in the brain with symptoms and signs of brain injury to participate in this research. Therefore, caution must be used in interpreting the high frequency of CTE in this sample, and estimates of prevalence cannot be concluded or implied from this sample.

93 former football players studied --problems: ascertainment bias - no controls

45 former NFL players studied - Ascertainment bias can be used to demonstrate either side!

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Age at first Study of 42 former exposure to NFL players: tackling does not result in No controls increased risk of Ascertainment neurocognitive deficits bias

American Journal of Sports Medicine February 2016

Brain injury is complex, with multiple causes (not just football) and pathophysiologies and treatment of Better Classification of Brain Injury a “single pathology” especially one with dubious connection to Begins With Multi-Modal symptoms is unlikely to be successful. Assessment

When you can’t accurately measure and classify a problem, Objective physical measures: don’t count on being able to treat it! eye tracking serum markers radiographic measures

Blood-based Biomarkers Biomarker Concentrations

Type Time UCH-L1 GFAP S100B

0-6 hours TBI pt. 9498 23 3380 post-injury

24 hours TBI pt. 738 498 201 post-injury

2 weeks TBI pt. 178 20 66 post-injury Average 91 12 71 Control

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TBI pt. CONTROL Eye Tracking

Stimulus: short video rotating around screen

Camera: track eye movemen ts Eye Tracking Eye

Operator Screen: view output

S100B Hierarchical Approach to Classification

Eye Tracking MRI Spontaneous Bleed Anoxia Diffuse Axonal UCH-L1 Injury CT-positive TBI CT-negative TBI Algorithm Control GFAP CT Blood-based biomarkers Molecule: https://commons.wikimedia.org/wiki/File:Protein_UCHL1_PDB_2etl.png

Webster H. Pilcher Duke Samson Mitchel S. Berger Kim J. Burchiel Joseph C. Maroon M.D., Ph.D. M.D. M.D. M.D., F.A.C.S. M.D. Colgate University Stanford University Harvard College University of California Davis University of Indiana Chairman of Neurosurgery at Lois C.A. and Darwin E. Chairman, Department of Chairman Emeritus of the Vice Chair, the University of Rochester Smith Distinguished Chair in Neurological Surgery. Berthold Department of Neurological UPMC Community Medicine. Medical Center in Rochester, Neurological Surgery, and Belle N. Guggenhime Surgery at Oregon Health & University of Pittsburgh University of Texas New York Endowed Chair, University of Science University (OHSU). Medical Center, and the Heindl Southwestern Medical Center California, San Francisco Scholar in Neuroscience.

Julian E. Bailes Robert E. Harbaugh M.D. M.D., FAANS, FACS Louisiana State University Lebanon Valley College Chairman of the Department of Chair, Department of Neurosurgery at the North Shore Neurosurgery, Penn State University Health System Institute of the Neurosciences.

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James R. Kasser, MD Neil J. Cobelli, MD Abhinav Bobby Chhabra, Andrew N. Pollak, MD Todd J. Albert, MD Walter R. Lowe, MD Steven M Theiss, MD Thomas R. Thompson, MD Richard T. Laughlin, MD James P. Stannard, MD Lawrence G. Morawa, MD MD Surgeon-in-Chief; University Chairman James Lawrence Kernan Chairman, Department of Chairman of Orthopedics at Professor and Interim Chair Chair, Akron General Health Department Chair, Wright Hansjörg Wyss Distinguished Chair, Wayne State Orthopedic Surgeon, and Professor of Lillian T.Pratt Distinguished Professor and Chair in the Orthopedic Surgery at the University of Texas John D. Sherrill Chair of System's Department of State University Boonshoft Chair in Orthopedic Surgery University, Department of Boston Children’s Orthopedic Surgery, Professor and Chair of Department of Orthopedics, Weill Cornell Medical Health Science Center at Orthopedic Surgery, Orthopedic Surgery, School of Medicine’s Chairman, Department of Orthopedic Surgery, Wayne Hospital Albert Einstein College Orthopedic Surgery, University of Maryland – College Houston and the Head of University of Alabama Cleveland Clinic Department of Orthopedic Orthopedic Surgery, State University – School of of Medicine University of Virginia Health School of Medicine Orthopedic surgery at School of Medicine Surgery University of Missouri Health Medicine System Memorial Hermann-Texas – School of Medicine Medical Center and LBJ General Hospital.

Randall E. Marcus, MD Douglas R. Dirschl, MD Sanford E. Emery, MD, MBA Charles Cassidy, MD Joshua J. Jacobs, MD Harry E, Rubash, MD Eric Lindvall, MD Thomas R. Hunt, MD Eric Kropf. MD Felix H. Savoie, MD Norman E Walter, MD S. Terry Canale, MD Charles H. Herndon Lowell T. Coggeshall Professor and Chairman of the Orthopedist-in-Chief, Professor and Chairman, Emeritus Chief Professor and Chairman Professor of Orthopedic Department of Orthopedics at Professor and Chairman, Department of Orthopedic Chief of Orthopedic Surgery, Professor and Chairman, Chair Orthopedic Surgery Chairman of Orthopedic Dr. Walter is affiliated with Held roles as chair within Department of Orthopedic Department of Surgery West Virginia University Tufts University School of Surgery, Rush University University of California, San Joseph Barnhart Department and Sports Medicine and Surgery. Chief of Sports Genesys Regional Medical AAOS and POSNA, Surgery, Massachusetts Orthopedic Surgery, UH Chairman, Department of Medicine Medical Center Francisco – School of Medicine of Orthopedic Surgery, Director of Resident Medicine, Tulane School Center, Hurley Medical including COMSS Chair General Hospital Cleveland Medical Orthopedic Surgery and Fresno. Medical Director, Baylor College of Medicine Education and Research of Medicine Center and McLaren-Flint. and AAOS Board Member Center Rehabilitation Medicine, and President University Orthopedic Associates at Temple University UChicago Medicine

76% orthopedic chairs 86% neurosurgery chairs 90% TBI experts allowed their own children to play contact sports

suggesting that the more one understands brain injury the more likely they are to allow children to play contact sports

>70% pediatricians 9x and 28x more surveyed want to ban likely than college tackle football peers to have Only 5.4% feel comfortable played football! treating a child with PCS

BENEFIT RISK The children who choose to play football have an average BMI of 26.3 and thus are at highest risk for complications of obesity None High blood pressure Vascular disease Cancer Lung disease >1,000,000 American children play high school football (track 2 nd , b-ball 3 rd ) Seizures An additional >1,000,000 play Pop Warner or Headaches other league football Motor Disorders None Depression #1 participation sport in American high schools Executive Dysfunction Cognitive Delay If even half of those children became sedentary (rejected soccer, cross country and Reduces Obesity and Diabetes Brain or Other Injury other fall sport options) the resultant increase in Reduces Depression/SI sedentary lifestyle/obesity risks would be Reduces High Blood Pressure enormous (hypertension, diabetes, Reduces Heart Disease cardiovascular disease, 13 cancers, Reduces Stroke osteoporosis) Reduces Dementia Reduces 13 Types of Cancer Risk Complex Psychosocial Benefit BMI of 17-25 is considered healthy

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The obese child sees a greater The kids who are most cardiovascular likely to experience risk reduction medical benefit from than the lean playing football are child with those who may not aerobic interval have predilection for training other sports

Thank You!!

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