chronic traumatic encephalopathy: what we...
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Chronic Traumatic Encephalopathy:What We Know
July 11, 2019
D.H. Daneshvar, M.D., Ph.D.Stanford University | Boston University
2
Neurodegenerative disease and TBI
Head Trauma
Alzheimer’s disease
Parkinson’s disease
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
18Daneshvar et al., 2011b, Kroshus et al., 2014
Concussion Epidemiology – Trainer Data
• Athletic trainer data shows that around 5% of football players suffer concussions each year
Source: Head Games: Football’s Concussion Crisis
Powell et al (1999)
Guskiewicz et al (2000)
Guskiewicz et al (2003)
McCrea et al (2002)
Zemper (2003)
Gerberich et al (1983)
Source Level Incidence
High School
HS/College
NCAA
HS/College
HS/College
High School
3.6 %
5.6 %
6.3 %
3.8 %
4.1 %
2.4 %
Concussion Legacy Foundation, 2012
Concussion Epidemiology – Athlete Data
• Surveys of athletes show that around 50% of football players suffer concussions each year
Langburt et al (2001)
Delaney et al (2002)
Delaney et al (2000)
Woronzoff (2001)
Moreau (2005)
McCrea et al (2004)
High School
College
CFL
College
High School
High School
47.2 %
70.2 %
47.8 %
61.2 %
65.2 %
15.3 %**
Source Level Incidence
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
Harrison S. Martland
(1883-1954)
First full time paid pathologist Newark city Hospital, 1909-1927Chief Medical examiner Essex county
• First described in boxers by Martland in 1928Martland HS: Punch drunk.
JAMA 91:1103–1107, 1928
Primary Trauma Source 45
Boxing 39
Soccer 1
Battered spouse 1
Head banging behavior 2
Circus clown 1
Epilepsy 1
• As of 2008, there were only 45 cases of CTE in the medical literature. All had histories of repetitive brain trauma
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
Medulla Cord
MidbrainPons
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
Mez and Daneshvar et al., 2017
• 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
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 Sxand 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• Robert Stern, PhD• Robert Cantu, MD• Chris Nowinski, PhD• Jesse Mez, MD, MS• Neil Kowall, MD• Andrew Budson, MD• Christine Baugh, PhD, MPH• Michael Alosco, MD• Yorghos Tripodis, PhD • Lee Goldstein, MD, PhD
• Doug Katz, MD• Michael McClean, ScD • Victor Alvarez, MD • Thor Stein, MD, PhD • Julie Stamm, PhD • Bobak Abdolmohammadi• Lauren Murphy • Patrick Kiernan • Lisa McHale
• 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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