Chronic Traumatic Encephalopathy: What We...

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