Chronic Traumatic Encephalopathy: What We Know July 11, 2019 D.H. Daneshvar, M.D., Ph.D. Stanford University | Boston University
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Neurodegenerative disease and TBI Alzheimer’s disease Parkinson’s disease Head Trauma Amyotrophic lateral sclerosis Chronic traumatic encephalopathy Daneshvar et al., 2015a
Concussion Legacy Foundation, 2013
Concussion Legacy Foundation, 2013
Concussion Legacy Foundation, 2013
Concussion Legacy Foundation, 2013
Concussion Legacy Foundation, 2013
Concussion Legacy Foundation, 2013
Concussion Legacy Foundation, 2013
Concussion Legacy Foundation, 2013
Concussion Legacy Foundation, 2013
Concussion Legacy Foundation, 2013
Concussion Legacy Foundation, 2013
Diagnosing Concussions is Problematic • Often rapid onset and resolve spontaneously • Changing definitions and guidelines means many coaches, athletic trainers, and other sports professionals not up to date on proper concussion identification and treatment • Additionally, symptomatic impacts may only represent subset of the problem Daneshvar et al., 2011b, Kroshus et al., 2014 18
Concussion Epidemiology – Trainer Data • Athletic trainer data shows that around 5% of football players suffer concussions each year Source Level Incidence High School 3.6 % Powell et al (1999) HS/College 5.6 % Guskiewicz et al (2000) NCAA 6.3 % Guskiewicz et al (2003) HS/College 3.8 % McCrea et al (2002) HS/College 4.1 % Zemper (2003) High School 2.4 % Gerberich et al (1983) Source: Head Games: Football’s Concussion Crisis Concussion Legacy Foundation, 2012
Concussion Epidemiology – Athlete Data • Surveys of athletes show that around 50% of football players suffer concussions each year Source Level Incidence High School 47.2 % Langburt et al (2001) College 70.2 % Delaney et al (2002) CFL 47.8 % Delaney et al (2000) College 61.2 % Woronzoff (2001) High School 65.2 % Moreau (2005) High School 15.3 %** McCrea et al (2004) Concussion Legacy Foundation, 2012
Asymptomatic impacts may have consequences • Symptomatic impacts (i.e. concussion) may only reflect part of the problem – Some athletes may experience 1000-1500 hits per season (>10g, median ~25g; Martini, 2013) • Impact to brain with adequate g force to have an effect on brain cell functioning but no immediate symptoms – Neuropsych (Gysland, 2012; McAllister, 2012a) – fMRI (Talavage, 2013; Breedlove 2012) – DTI (McAllister, 2012b)
History of CTE • First described in boxers by • As of 2008, there were only 45 Martland in 1928 cases of CTE in the medical Martland HS: Punch drunk. literature. All had histories of JAMA 91:1103 – 1107, 1928 repetitive brain trauma Primary Trauma Source 45 Harrison S. Martland Boxing 39 (1883-1954) Soccer 1 First full time paid pathologist Battered spouse 1 Newark city Hospital, 1909-1927 Chief Medical examiner Essex county Head banging behavior 2 Circus clown 1 Epilepsy 1 McKee et al., 2009
Current Status of the Brain Bank • Over 700 brains of former athletes, veterans, and individuals otherwise exposed to repetitive head impacts • Published first 85 donors in Brain in 2013 • Published first 202 football players in JAMA in 2017 (177 with CTE) and first 246 in Annals of Neurology in 2018 (211 with CTE)
24 Concussion Legacy Foundation, 2013
McKee et al., 2013
Substantia Nigra Locus coeruleus Cord Medulla Pons Midbrain McKee et al., 2013
Stage I McKee et al., 2013
Stage II McKee et al., 2013
Stage III McKee et al., 2013
Stage IV McKee et al., 2013
Beta-amyloid deposition Stein et al., 2015
Normal CTE AD McKee et al., 2010
Progressive? • Although clinical symptoms appeared to be slowly progressive in most individuals diagnosed with CTE, CTE may not progress, or may not progress at the same rate, in all individuals with the disease. • Significant difference in age at death between stages (p<0.0001) – Stage 1: Age 44 +/- 21 – Stage 2: Age 52 +/- 19 – Stage 3: Age 64 +/- 14 – Stage 4: Age 74 +/- 8 McKee et al., 2013; Mez and Daneshvar, et al., 2017
Symptoms and Stage • Significantly more likely to have cognitive symptoms and dementia with advanced stage • No differences in behavior/mood symptoms (>88% of all stages) • Significantly associated with highest level of play, duration of play • No differences based on concussion number • No differences based on age of first exposure • No differences based on position Mez and Daneshvar et al., 2017
Clinical Presentation of CTE • 36 male athletes, ages 17 to 98, diagnosed with CTE after death, and who had no other brain disease, such as Alzheimer’s. • The majority of the athletes had played amateur or professional football, with the rest participating in hockey, wrestling or boxing • Data suggests two presentations: – A younger age of presentation (34.5 years) with initial symptoms of behavioral (e.g., impulsivity, violence) and/or mood changes (e.g., depression, hopelessness) – An older age of presentation (58.5 years) with initial symptoms of cognitive impairment (e.g., episodic memory deficits, executive dysfunction) Stern, Daneshvar et al., 2013
Prevalence of CTE • 110 of 111 former NFL players studied had CTE – Represents 9.6% of all NFL players who died from 2/2008 to 5/2016 • Mayo study: 66 former CCS athletes and 198 NDD controls – 21 of 66 (32%) CCS athletes had CTE – No CTE in NDD controls • VITA study – No CTE in 310 controls Mez, Daneshvar et al., 2017; Binney et al., 2019; Forrest et al., 2019; Bieniek et al., 2015
Playing football before age 12 • 246 tackle football players (211 with CTE, 126 without comorbid neurodegenerative diseases) • Age of exposure not associated with CTE (or AD or LBD) • In those with CTE, every one year younger AFE to football predicted earlier cognitive symptom onset by 2.44 years (p<0.0001) and behavioral/mood symptoms by 2.50 years (p<0.0001) • AFE before 12 predicted earlier cognitive (p<0.0001) and behavioral/mood (p<0.0001) symptom onset by 13.39 and 13.28 years • Similar effects observed in the CTE only participants Alosco et al., 2018
Biomarkers to improve diagnosis • Brain and CSF biomarkers – CCL11, a protein linked to age-associated cognitive decline – 23 football players with CTE, 50 subjects with AD, and 18 controls – CCL11 levels significantly increased in DLFC in CTE (fold change = 1.234, p < 0.050) compared to AD and controls – CCL11 correlated with years of exposure to football ( β = 0.426, p = 0.048) independent of age ( β = -0.046, p = 0.824) – CSF CCL11 trended towards increase in CTE (p = 0.069), significant association with years of football ( β = 0.685, p = 0.040) independent of age ( β = -0.103, p = 0.716) Cherry et al., 2018; Lee et al., 2018
PET Imaging • To date, 7 studies: ~75 subjects • Most recently, 26 former NFL athletes with cognitive, behavioral, and mood Sx and 31 asymptomatic controls – Higher PHF tau levels than controls – No elevation in amyloid-beta – No relationship between PHF tau and neuropsych testing – Direct relationship between PHF tau and total years of play Stern et al., 2019
What do we know: Overall • At this time, CTE can only be definitely diagnosed postmortem • Nearly every individual diagnosed with CTE has had some history of head impacts: – From sports – From occupation, and – From other sources McKee et al., 2009; Daneshvar et al, 2015b; Mez, Daneshvar et al., 2017
Acknowledgements • • Ann McKee, MD Doug Katz, MD • • Robert Stern, PhD Michael McClean, ScD • • Robert Cantu, MD Victor Alvarez, MD • • Chris Nowinski, PhD Thor Stein, MD, PhD • • Jesse Mez, MD, MS Julie Stamm, PhD • • Neil Kowall, MD Bobak Abdolmohammadi • • Andrew Budson, MD Lauren Murphy • • Christine Baugh, PhD, MPH Patrick Kiernan • • Michael Alosco, MD Lisa McHale • Yorghos Tripodis, PhD • • Lee Goldstein, MD, PhD Our donors and their families
Thank you! Questions?
New Orleans Saints, 1987
HBO Real Sports, 2007
HBO Real Sports, 2007
Stage I • Headaches and issues related to attention and concentration McKee et al., 2013
Stage II • Symptoms expanded to include depression, explosivity and short-term memory impairment McKee et al., 2013
Stage III • Cognitive impairment and problems with executive functions, specifically planning, organization, multitasking and judgment McKee et al., 2013
Stage IV • Dementia (i.e., memory and cognitive impairments severe enough to impact daily living) in 90% of subjects McKee et al., 2013
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