11/2/2014

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Chronic Traumatic Encephalopathy:

What We Think We Know

and What We Need to Know Next

Robert A. Stern, PhD

Professor of Neurology, Neurosurgery,

and Anatomy & Neurobiology

Director of Clinical Research, BU CTE Center

Director, Clinical Core, BU Alzheimer’s Disease Center

Boston University School of Medicine

Disclosures • Psychological Assessment Resources,

Inc. (Royalties for Published Tests))

• Athena Diagnostics (Consultant)

• Eisai (Funded Research Investigator)

• Lilly (Funded Research Investigator)

• Janssen Alzheimer’s Immunotherapy

(Consultant)

• Avid Radiopharmaceuticals (Funded

Research Investigator)

Concussion

• Definition: Concussions occur from forces applied

directly or indirectly to the skull that result in the

rapid acceleration and deceleration of the brain.

The sudden change in cerebral velocity elicits

neuronal shearing, which produces changes in

ionic balance and metabolism. When accompanied

by clinical signs and symptoms, changes at the

cellular level are commonly referred to as mild

traumatic brain injury, or concussion. (Broglio,

Cantu, Gioia, et al., 2014)

• Does not require LOC; <10%

• It is NOT a bruise to the brain

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Neurometabolic Cascade of

Concussion (Giza & Hovda, 2001) The abnormalities

occur at the neuronal,

molecular, and

metabolic levels.

Dramatic ion channel

changes: Potassium

efflux and Calcium

influx.

Requires tremendous

energy to restore to

homeostasis

Concussions may

be the Tip of the

Iceberg

Repetitive Brain Trauma

Symptomatic mTBI/Concussion

Subconcussive

(asymptomatic) Trauma

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Subconcussive Blows

• Impact to brain with adequate g force to

have an effect on neuronal functioning but

No Immediate Symptoms.

• Some sports and positions very prone

– Football linemen may have 1000-1500 of

these hits per season, each at 20-30 g.

• Double the number for the athletes who plays both

offense and defense

– Soccer heading = ~15 g also 1000+ per

season.

Subconcussive Force

• “Two players who collide at full speed

helmet-to-helmet are essentially

experiencing the same forces to their

heads that one of them would feel had he

had a 16-pound bowling ball dropped on

his head from a height of 8 feet.”

– University of Nebraska physicist Timothy

Gay

• Car going 35 mph into a brick wall = 20 g

Force (g) = Mass x Acceleration

•Athletes are getting bigger

and faster!

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Subconcussive Blows • Broglio and colleagues (2011) found that

high school football players received, on

average, 652 hits to head in excess of 15 g

of force. One player received 2,235 hits!

• Growing evidence that even after one

season, repetitive subconcussive trauma

can lead to cognitive, physiological, and

structural changes. – Talavage et al., 2011

– McAllister et al., 2012

– Koerte et al., 2012, 2014

– Pasternack et al., 2014

Even Today’s Helmets Cannot

Fully Protect Against Concussions

or Subconcussive Trauma

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Long-Term Consequences of

Repetitive Head Impacts in Boxers • Punch Drunk: Martland, 1928

• Traumatic Encephalopathy: Parker, 1934

• Dementia Pugilistica: Millspaugh, 1937

• Chronic Traumatic Encephalopathy:

Critchley, 1957 (and earlier)

• Psychopathic Deterioration of the Pugilist:

Courville, 1962

• Chronic Traumatic Brain Injury: Jordan, 1997

• Chronic Traumatic Encephalopathy: Omalu et al.,

2005 – First American Football Player (2002)

• Traumatic Encephalopathy: Victoroff, 2013

Chronic Traumatic Encephalopathy

(CTE)

• Neurodegenerative disease, similar to

Alzheimer’s disease but is a unique

disease neuropathologically and clinically.

• Believed to be caused, in part, by

repetitive brain trauma, including

concussions and subconcussive blows.

• The repetitive trauma appears to start a

cascade of events in the brain that

eventually leads to progressive

neurodegeneration.

Chronic Traumatic Encephalopathy

(CTE)

• Not prolonged post-concussion syndrome.

• Not the cumulative effect of concussions.

• The disease appears to begin earlier in

life, but the symptoms begin years or

decades after the brain trauma and

continue to worsen.

• Though, in individuals with Persistent or

Chronic Post-Concussion Syndrome,

there may not be a noticeable delay in

symptoms due to cross-over.

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Clinical Features

Three-Four Primary Domains

Two Subtypes? • Earlier reports of boxers suggested two

distinct subtypes of clinical presentation – Jokl & Guttman (1931)

– Soeder & Arndt (1954)

– Grahmann & Ule (1957)

– Mawdsley & Ferguson (1963)

– Corselis (1973)

• (1) Younger onset, with initial behavioral

and mood disturbance, but with minimal

cognitive and motor features

• (2) Older onset, with greater cognitive

impairment and, often, motor

disturbance

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Stern et al. (2013) Neurology

• 36 Neuropathologically-confirmed cases

of CTE (mean age = 56.8; SD = 21.9;

range = 17–98)

• All athletes (81% football)

• No comorbid findings

• Extensive semi-structured interviews

(psychological autopsy) and medical

record review; Blind to neuropath

findings

• 33 of 36 symptomatic

Stern et al. (2013) Neurology • Two different clinical presentations: one initially

exhibiting behavioral or mood changes, and the

other initially exhibiting cognitive impairment.

• The behavior/mood group demonstrated symptoms

at a significantly younger age than the cognition

group.

• Although almost all subjects in the behavior/mood

group demonstrated cognitive impairments at some

point, significantly fewer subjects in the cognition

group demonstrated behavioral and mood changes

during the course of their illness.

• Motor features relatively uncommon

Two Pathways to Symptoms?

• Stable or Progressive White Matter

Changes leading to mood/behavior

impairment

– Axonopathy of CTE or Distinct from CTE?

– Progressive degeneration secondary to

inflammation (Bigler, 2013)

• Progressive Tauopathy of CTE leading

to cognitive changes and dementia

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Traumatic Encephalopathy Syndrome (TES) Montenigro et al., Alz. Res. Ther. 2014

• We recently published proposed research

diagnostic criteria that incorporate Jordan’s

criteria for Possible/Probable CTE and

address many of the limitations of criteria

proposed by Victoroff for Traumatic

Encephalopathy.

• Our criteria are derived from previous

literature on CTE, as well as from the

specific findings from our studies of the

clinical presentation of neuropathologically-

confirmed cases of CTE.

Traumatic Encephalopathy Syndrome (TES) Montenigro et al., Alz. Res. Ther. 2014

• The term, “Traumatic Encephalopathy

Syndrome” (TES) was selected to describe

the clinical presentation of CTE as well as

other possible long-term consequences of

RHI (e.g., chronic or progressive

axonopathy without tauopathy), but is not

meant to include the acute or post-acute

manifestations of a single concussion, post-

concussion syndrome, or moderate-to-

severe TBI.

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Traumatic Encephalopathy Syndrome (TES) Montenigro et al., Alz. Res. Ther. 2014

• The Proposed Research Diagnostic Criteria for

TES include five General Criteria, three Core

Clinical Features, and nine Supportive Features,

that are used to define subtypes of TES, including:

– Behavioral/Mood Variant

– Cognitive Variant

– Mixed Variant

– TES Dementia

• The modifier, “Progressive Course,” “Stable

Course,” and “Unknown/Inconsistent Course” is

used to describe the clinical course, and if specific

motor signs are evident, the additional modifier,

“with Motor Features” is added.

Possible and Probable CTE Diagnostic Criteria

• Possible CTE – Meets classification for any TES subtype, Progressive Course, and

either

• has not undergone any potential biomarker testing;

• has had negative results on one or more biomarkers with the exception of

PET Tau Imaging (i.e., if a negative PET Tau Imaging finding, the current

classification would be “Unlikely CTE”); or

• Meets the diagnostic criteria for another disorder that could, on its own,

account for the clinical presentation.

• Probable CTE – Meets classification for any TES subtype, Progressive Course

– Does not meet diagnostic criteria for another disorder more consistently than

TES

– Has a minimum of one positive potential biomarker for CTE.

• Unlikely CTE – Does not meet TES diagnostic criteria and/or has had a negative PET Tau

Imaging scan.

CTE • Like Alzheimer’s and other

neurodegenerative diseases, CTE can

currently only be diagnosed

postmortem.

• Dr. Ann McKee has examined more

brains with CTE than any other

neuropathologist; BU CTE Center and

has the largest CTE brain bank (VA-BU-

SLI Brain Bank) in the world.

– >150 brains examined; 76 of 79 deceased

NFL players with CTE

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Brain 2013 Paper • Largest neuropathological case series of

CTE to date.

• Examined post-mortem brains obtained

from a cohort of 85 subjects with histories

of repetitive brain trauma.

• Evidence of CTE in 68 subjects: all males,

ranging in age from 17 to 98 years (M=60)

– 64 athletes

– 21 military veterans (86% also athletes)

– 1 individual with head banging behavior

CTE Neuropathology • Characterized by abundance of a misfolded,

hyperphosphorylated form of the

microtubule-associated protein (MAP) tau:

– Neurofibrillary tangles and astrocytic tangles

• Widespread distribution with early

perivascular distribution and at the depths of

cortical sulci

• Later widespread distribution; “prion

spread”?

• Very little, if any beta amyloid; if exists, only

diffuse plaques

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Unique Pathology of CTE

Perivascular

Depths of the Sulci

Hyperphosphorylated tau protein as neurofibrillary tangles

Superficial Layers NFTs

CTE

vs

AD

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John Grimsley - Died at Age 45

• Houston Oilers 1984-1990;

Miami Dolphins 1991-1993;

Linebacker; Pro-Bowl, 1988

• At least 8 concussions during

NFL career.

• Hunting/Fishing guide post NFL

• For the 5 years prior to death at

age 45, he experienced

worsening memory and

cognitive functioning, as well as

increasing “short fuse.”

• Died of gunshot to chest while

cleaning gun. Not suicide.

Grimsley - Neuropathology

65 yr old healthy

control

Grimsley 45 yr

old CTE

73 yr old boxer with

dementia and CTE

Photoscan

Microscope

Tom McHale

Died at age 45 • Nine-year NFL veteran lineman

• Tampa Bay Buccaneer

• No reported concussions, but as

lineman had routine subconcussive

blows

• Cornell University graduate, successful

restaurateur post NFL, husband and

father of three boys

• Died due to drug overdose after a multi-

year battle with addiction.

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McHale - Neuropathology

Photoscan

Microscope

Dave Duerson – Age 50 November 28, 1960 – February 11, 2011

Duerson’s Clinical History

• Successful businessman post NFL

• ~5 years prior to death, he had

worsening short-term memory

difficulties

• Increasingly out of control:

– Short fuse, hot tempered, physically

abusive, verbally abusive; lost business,

marriage

• Committed suicide Feb 2011, shooting

self in chest to avoid hurting brain.

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Not Just Football

• We have found CTE in >70

individuals, including mostly football

players, but also:

– Boxers

– Pro Hockey Players – Enforcers

• Reggie Fleming

• Bob Probert

• Derek Boogaard

– Major League Baseball

• Ryan Freel

Ryan Freel – Age 36

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Ryan Freel

Suicide at age 36

Barry (Tizza) Taylor – Age 77

Australian Rugby Player Competitive Rugby for 19 years

235 games for Manly Rugby Union, an

Australian professional team near Sydney

Tizza Taylor – Age 77 Cognitive Problems in 50’s

Severe Dementia in 60’s

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Soccer Patrick Grange – 29 yo with “ALS”

Started heading at age 5

College and Semipro Soccer

CTE-Motor Neuron Disease

UPenn Football Co-Captain (Lineman)

Played since age 9; NO Concussions

Owen Thomas

Owen Thomas

Suicide at Age 21

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Suicide Caused by CTE?

• Unlikely

• Suicide is, tragically, too common in this

age group

• Complex, multifactorial causes to

suicide

• Thomas case showed us:

– Early evidence of CTE at just 21 years old

– Another case of CTE with no reported

concussions

Neuropathology of CTE

is Now Well-Described

• Postmortem description of CTE has

had a great impact on public policy

and awareness.

• However, the public thinks that the

science of CTE is far more

advanced than it is.

Time

Growth

Impact

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CTE Questions

• Is CTE Common?

–We just don’t know!

–76 of 79 Pro Football players in BU

Brain Bank have had CTE.

–Biased!!

–Need for longitudinal research with

large sample size

–UNITE study (McKee PI) U01 grant

funded by NINDS/fNIH/NFL

CTE Questions

• Why do some people get CTE and others do

not?

– all neuropathologically confirmed cases (>150)

have had h/o repetitive brain trauma

– repetitive brain trauma is a necessary but not

sufficient cause of CTE

– not everyone who hits their head will get it!

CTE Questions

• Analogy: Cigarette Smoking

– Not every cigarette smoker has long-term

pulmonary consequences

– Some develop emphysema

– Some develop cancer

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CTE Questions

• What are the risk factors?

– Genetics (e.g., APOE, MAPT)

– EXPOSURE Variables

• Severity and type of trauma; overall duration;

total amount of hits; amount of rest/time

between hits; age at first exposure to hits

ApoE ε4 as CTE Risk Factor? Stern et al., 2013, Neurology

• We examined ApoE genotypes in 36

neuropathologically-confirmed cases of CTE

without co-morbid disease.

• Proportions of ApoE genotypes (i.e., ε4

homozygotes, combined ε4 homozygotes and

heterozygotes, and ε4 non carriers) in our CTE

sample were significantly different (p<.05) from

those found in an age-matched normative

sample.

• The relative proportions of ApoE genotypes in

our 10 subjects with dementia were not

significantly different from those seen in AD.

Age of First Exposure to Football Stamm et al., in press, Neurology

• Former NFL players (ages 40-69)

• Those who started playing before age 12

have greater current executive dysfunction

(WCST, p<.0001) and memory impairment

(NAB LL Long Delay, p = .015) than those

who began playing at age 12 or later

(controlling for total duration).

• But, is it CTE???

• Are there associated neuroanatomical

findings?

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Reduced Corpus Callosum

Integrity (FA) in Ss who Began

Football < 12 years old

Left panel depicts tractography of corpus callosum, subdivided into

five regions based on methods proposed by Hofer and Frahm. Right

panel: AFE<12 group has lower FA than AFE > 12 group.

Diagnosis of CTE During Life

is an Important Next Step • Differentiate between CTE and other causes

of cognitive and behavioral change, including

AD, FTLD, PTSD, and persistent/chronic

sequelae of previous repetitive or single mTBI

• Understand the true incidence and prevalence

of the disease

• Determine the risk factors (including genetic

and exposure variables) for CTE

• Begin clinical trials for treatment and

prevention

Biomarkers

Courtesy of Dr. Inga Koerte, PNL

Brigham & Women’s Hospital

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Step One • Develop a good acronym!

DETECT

Diagnosing and Evaluating

Traumatic Encephalopathy

using Clinical Tests

Step Two: Get a Grant “Chronic Traumatic Encephalopathy: Clinical

Presentation and Biomarkers”

Goal:

To Develop Biomarkers to Diagnose CTE

During Life Principle Investigator: R.A. Stern

NIH R01 Grants R01NS078337 and R56NS078337

funded by:

National Institute of Neurologic Diseases and Stroke

National Institute of Aging

National Institute of Childhood Health and Development

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DETECT - Underway

• 90+ former NFL players, ages 40-69, with highest

exposure to RBT, symptomatic

• 20+ same age elite non-contact sport athletes, no

brain trauma exposure

• Neuroimaging (MRI, DTI, SWI, FW, MRS, etc.) – Shenton and Lin (Harvard)

• Lumbar Puncture (CSF Tau, beta amyloid,

monoamines) – Trojanowski and Shaw (Penn); Mann (Columbia)

• EEG (BrainScope) – Prichep (NYU)

• Genetics (APOE, MAPT, MAOA-u)

• Clinical Exams (Neuro, Cognitive, Psych)

DETECT – CSF Proteins

Preliminary Findings

Analyte

CTL Mean

(SD)

NFL Mean

(SD)

Stat

(adjusted for

BMI) p-value

Total Tau 49.2 (3.6) 38.7 (2.2) 3.39 0.0664

p-Tau 16.9 (1.5) 19.5 (0.9) 3.44 0.0647

p-tau/t-tau 0.35 (0.04) 0.50 (0.04) 6.39 0.0120

MRI Volumetrics Shenton, Koerte, et al., BWH/PNL

• Bilateral cingulate gyrus volume and

bilateral amygdala volume were

significantly lower in former professional

football players (p = 0.03).

• Within the football group hippocampal

volume correlated with memory function

and cingulate gyrus volume correlated

with memory function and depression

scores

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R Hippocampus Volume and ROCF Visual

Memory Performance r=0.308, p=0.010

adjusted for age, BMI, education

Recent Cortical Thickness Findings:

Age x Thickness Interaction Koerte, Shenton, et al., BWH/PNL)

DTI: NFL Group Impaired WM

Microstructure (Koerte, Shenton, et al., BWH PNL

Altered white matter (WM) microstructure as investigated using DTI: Tract-

based spatial statistics (TBSS) revealed significantly decreased FA (p<0.0001)

as well as elevated Trace (p=0.0003) and RD (p=0.0001) in large parts of the

WM in both hemispheres, suggesting damage to the myelin sheath in former

professional football players

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Cavum Septum Pellucidum (CSP)

• CSP is common in individuals with

neuropathologically-confirmed CTE,

with increasing frequency of CSP in

worse neuropathological stages (McKee

et al., 2013, Brain).

Cavum Septum Pellucidum (CSP) Koerte, Shenton, et al., BWH/PNL

• MRIs from the DETECT cohort revealed a

significantly increased length of the CSP as well

as the ratio between CSP and septum length in

the NFL group compared to controls (p=0.029).

MRS Biochemical Metabolites Dr. Alex Lin – Brigham & Womens Hospital

Controls Former

NFLers

statistically significant increases in glutamate/glutamine, choline,

phenylalanine, a fucoslyated species and myoinositol.

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Magnetic Resonance Spectroscopy (MRS) (Lin et al., BWH)

• We found group differences in brain

chemistry both in metabolite concentration

and brain region.

• In the posterior cingulate gray matter,

glutathione (GSH) was significantly reduced

(p<0.05), reflective of neuroinflammation,

whereas in parietal WM, glutamate (Glu) and

myo-inositol (mI) were significantly increased

(p<0.05), possibly reflecting glial activation.

The Next Important Step

Brain Tau Imaging • Over the past two years, three different

groups around the world have

developed new PET scan ligands which

specifically attach to the type of

abnormal tau found in CTE and which

do not appear to attach to other

proteins.

• These have now been used

successfully in humans, though are in

the very beginning phases of research.

The Next Important Step

Brain Tau Imaging

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Avid Radiopharmaceuticals

[F-18] T807

ex vivo T807 in CTE Brains

AT8

T557 (T807) immunostain of Tau Merge

Attardo G, Gomez F, Lin Y, et al. Detection of PHF-Tau Pathology

with [18F]T807 and T557 in Brain Sections from Alzheimer’s and

Non-Alzheimer’s Tauopathy Patients. European Journal of Nuclear

Medicine and Molecular Imaging 2014;41:S427

DETECT Study Sponsored by

Avid Radiopharmaceuticals

• T807 (AV 1451) PET Tau Imaging and

Florbetapir PET Amyloid Imaging added

to DETECT protocol.

• ~10 cases completed to date

• Preminary Findings

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DoD Grant Now Underway

DoD W81XWH-13-2-0064

Traumatic Brain Injury Research Award

“Tau Imaging of Chronic Traumatic Encephalopathy”

PI’s: Shenton and Stern

Hypothesized Differences in PET Ligands

between CTE, Alzheimer’s Disease Dementia,

and Controls CTE AD CNTL

Tau Ligand, [18F]-T807 + + - Aβ Ligand, [18F]-florbetapir - + -

Future Research • Another Acronym

• BRAIN-CTE

• Biomarkers, Risk, Assessment, and

Imaging Network for CTE

• Expand upon the preliminary work

conducted thus far:

– develop accurate objective biomarkers for CTE;

– validate clinical diagnostic criteria for CTE

– begin clinical trials for treatment and prevention

– examine risk factors (genetic and exposure) in

greater depth.

National Institutes of Health NINDS/NIA/NICHD R01 NS078337 and R56NS078337

Boston University Alzheimer’s Disease Center -NIA NIA P30 AG13846 supplement 0572063345-5

Boston University

Department of Veteran’s Affairs

NFL – Unrestricted Gift and Travel for study participants

NFL Players Association – Travel for study participants

JetBlue – Travel for study participants

Center for Integration of Medicine and Innovative

Technology (CIMIT) - Grant

NOCSAE – Grant

Weldon Worldwide Services – Ground transportation for study participants

Department of Defense PHTBI W81XWH-13-2-0064

BU CTE Clinical Research Funding

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Avid Radiopharmaceuticals - A division of Eli Lilly

Quanterix (Blood Biomarkers)

Exosome Sciences ( a division of Aethlon Medical)

(Blood Biomarkers)

BU CTE Clinical Research Funding

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Acknowledgments • Robert Cantu

• Ann McKee

• Chris Nowinski

• Martha Shenton

• Charles Adler

• Victor Alvarez

• Rhoda Au

• Christine Baugh

• Alexandra Bourlas

• Andrew Budson

• Patrick Curtis

• Dan Daneshvar

• Mike Devous

• Brandon Gavett

• Lee Goldstein

• Nate Fritts

• Inga Koerte

• Neil Kowall

• Alex Lin

• John Mann

• Mike McClean

• Lisa McHale

• Mark Minton

• Phil Montenigro

• Ofer Pasternack

• Kaitlyn Perry

• John Picano

• Leslie Prichep

• David Riley

• Eric Reiman

• Cliff Robbins

• Daniel Seichepine

• Leslie Shaw

• Julie Stamm

• Thor Stein

• Yorghos Tripodis

• John Trojanowski

• Ross Zafonte

• Sports Legacy Institute

• BU Alzheimer’s

Disease Center

• Bedford VAMC

• Boston VAMC

• And all the athletes,

veterans, and families

who participate in our

research