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11/2/2014
1
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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2
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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10
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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12
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
11/2/2014
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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?
11/2/2014
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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
11/2/2014
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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
11/2/2014
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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
11/2/2014
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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
11/2/2014
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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.
11/2/2014
25
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
11/2/2014
26
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
11/2/2014
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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
11/2/2014
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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
83
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