CTE - Boston Children`s Hospital

CTE
Neurodegeneration associated with Repetitive Head Injury
Ann C. McKee M.D.
Professor of Neurology and Pathology VA Boston Healthcare System
Boston University School of Medicine
Director of the CTE Center
Associate Director, Boston University Alzheimer’s Disease Center
No disclosures
What is CTE?
“Punch Drunk”
“Dementia Pugilistica”
1928
First reported by Harrison Martland in 1928 in boxers
Punch drunk. JAMA 91:1103–1107, 1928
"nearly one half of the fighters who have stayed in the game long enough”
“Chronic Traumatic Encephalopathy “
Critchley M (1949) Punch-drunk syndromes:
the chronic traumatic encephalopathy of boxers.
In: Hommage à Clovis Vincent. Paris.
Dementia Pugilistica
Chronic Traumatic Encephalopathy
Neuropathological Criteria for CTE
(McKee et al., Brain 2013)
P-tau lesions
1. Perivascular
2. Focal distribution at
depths of sulci
McKee et al Criteria for CTE
1. Perivascular foci of p-tau immunoreactive neurofibrillary tangles, astrocytes and
neurites in the neocortex
2. Irregular distribution of p-tau lesions at the depths of cerebral sulci
3. NFTs located preferentially in the superficial layers of cortex (a feature often most
pronounced in temporal lobe)
NINDS/NIBIB Consensus Meeting to Evaluate
Pathological Criteria for the Diagnosis of CTE
February 25-27, 2015
http://www.ninds.nih.gov/research/tbi/ReportFirstNIHConsensusConference.htm
Nigel Cairns, Ph.D., Rebecca Folkerth, MD, Wayne Gordon PhD, C. Dirk Keene, M.D.,
Irene Litvan, PhD, Ann McKee, MD, Daniel Perl, M.D., Thor Stein M.D., Ph.D., William
Stewart, M.D., Jean Paul Vonsattel, M.D., Dennis Dickson, M.D, Patrick Bellgowan, MD,
Debra Babcock,PhD, Walter Koroschetz, MD
8 expert neuropathologists: Nigel Cairns, Dennis Dickson, Rebecca
Folkerth, C. Dirk Keene, Daniel Perl, Thor Stein, William Stewart,
Jean Paul Vonsattel
independently analyzed digitized images of pathological slides from
25 cases completely blinded to any clinical or demographic data. The
neuropathologists submitted their diagnostic evaluations prior to
attending the conference.
Cases included: Alzheimer’s disease
Progressive supranuclear palsy
Primary age-related tauopathy
Corticobasal degeneration
Guamanian Parkinson Dementia Complex
Argyrophilic grain disease
CTE
The results showed that there was substantial agreement between
reviewers (overall kappa: 0.67) and substantial agreement between
reviewers and CTE diagnosis (overall kappa: 0.78) using the
proposed criteria (McKee et al, Brain, 2013)
Criteria for CTE
THE PATHOGNOMONIC LESION
The feature considered the most specific for CTE, that distinguished the
disorder from the other tauopathies, was the distinctive distribution of tau
aggregates.
“In CTE, the tau lesion considered pathognomonic was an abnormal
perivascular accumulation of tau in neurons, astrocytes, and cell processes
at the depths of the depths of the cortical sulci in an irregular pattern.”
Criteria for CTE
THE PATHOGNOMONIC LESION
The panel also stated that:
“ thus
far, this pathology has only been found in individuals
exposed to brain trauma, typically multiple episodes”.
Future directions
These criteria are the beginning of the process of fully characterizing
the pathology of CTE, and this was the first of a series of consensus
conferences that will take place funded by NINDS.
It is also important to understand that correlation between clinical
symptoms and future brain health with the signature pathologic feature
of CTE (irregular foci of abnormal tau immunoreactive neurons and
astrocytes in a perivascular distribution at the depths of cortical sulci)
is not yet known.
Pathology of CTE
Brain Atrophy
Deposition of abnormal p-tau aggregates
“In CTE, the tau lesion considered pathognomonic is an:
abnormal perivascular accumulation of tau in neurons, astrocytes,
and cell processes in an irregular pattern at the depths of the cortical sulci”.”
http://www.ninds.nih.gov/research/tbi/ReportFirstNIHConsensusConference.htm
Pathology of CTE
Aggregation of Abnormal Proteins
P-TDP-43
P-TDP-43
SMI-34
IBA1
Axonal injury & loss
Neuroinflammation
Why is tau protein deposited in those brain regions?
Depth of sulcus and perivascular area are regions of physical
stress concentration
Cloots et al Annals of Biomedical Engineering, Vol. 36, No. 7, July 2008
Cloots et al.J Mechanical Behavioral Biomedical Materials 2012 (41-52)
Hammer injury to brain
Leestma, Forensic Pathology, 2008, second edition
mTBI BRAIN BANK
02/2008
12/2013
03/2015
LAST 15
MONTHS*
Boxing
American Football
2
12
14
2
1
128
183
55
Ice Hockey
0
8
11
3
Wrestling
Rugby
0
3
3
0
0
3
3
0
Military Veterans
0
Soccer
0
3
4
2
Other: physical abuse,
poorly controlled
epilepsy, head banging
0
16
21
5
3
185
255
70
Brain Donors
TOTAL
39 (27 ath) 59 (43 ath)
20 (16 ath)
*Supported by: NINDS and NIBIB Cooperative agreement, 1U01NS086659-01
McKee 2009;McKee 2010; McKee 2013a;McKee 2014a, b, c ;McKee 2015 a, b
mTBI BRAIN BANK: CTE
02/2008 12/2013
03/2015
# UO1 funding
Boxing
American Football
2
10
11
1
1
96
119
23
Ice Hockey
0
5
6
1
Wrestling
Rugby
0
2
2
0
0
1
1
0
Military Veterans*
0
Soccer
0
1
3
2
Other: physical abuse,
poorly controlled
epilepsy, head banging
0
5
5
0
3
125
152/215
27/30
TOTAL
*
28 (23 ath) 34 (29 ath)
6 (6 ath)
McKee 2009;McKee 2010; McKee 2013a;McKee 2014a, b, c ;McKee 2015 a, b
Neuropathological Dx: CTE
143 Athletes
Boxing
Football
Pro Am NFL CFL
#CTE 10 1
Hockey Soccer
SP
HS/Y
Coll
NHL Am
outh
Rugby
Pro
Am
MLB WWE MMA
Total
83
4
2
21
8
5
1
3
1
1
1
2
0
143
87
4
5
27
28
5
4
4
1
3
1
3
1
186
#
evalua 11
ted
2
95%
77% 29%
77%
McKee et al. 2009 ; McKee et al, 2010; McKee et al 2013a, McKee et al. 2013b
143 cases of CTE in athletes:
co-morbid neurodegeneration in 37%
CTE+FTLD,
4, 3%
CTE+Mul ple,
7, 5%
CTE+Other,
2, 1%
CTE+LBD,
11, 8%
Pure CTE
CTE+MND
CTE+AD
CTE+AD, 16,
11%
CTE+MND, 15,
10%
CTE+LBD
Pure CTE, 88,
62%
CTE+FTLD
CTE+Mul ple
CTE+Other
McKee et al, 2013, Brain
CTE
Age at Death
Stage I
mean age: 28.3 + 13 years
Stage II
mean age: 44.3 + 16 years
Stage III
mean age: 56.0 + 14 years
Stage IV
mean age: 77.4 + 12 years
For American football players: number years played, years since retirement, and age at death
significantly correlated with pathological stage of CTE
McKee et al, 2013, Brain
Stages of Tau Pathology
P-Tau
Death 10 days after 4th concussion
Stage I CTE
18 year old high school football and rugby player
P-Tau
Death 10 days after 4th concussion
Stage I CTE
Stage I CTE
25 yo college football player
• 16 year exposure to football, 3 years division I college FB
Linebacker and special teams
• Several severe concussions during college with persistent vision
changes, memory problems, confusion, difficulty sleeping and
debilitating headaches.
•
Quit football after 3 yrs. Continued to experience episodic memory
loss, disorientation, difficulty with attention and concentration and word
finding, progressively worsened over the last 18-24 months of his life.
• Also experienced depression, bouts of impulsivity and severe anger.
• He died at age 25 following a staph infection.
Brain weight: 1480 grams
Frontal, temporal, parietal cortex: AT8 (p-tau)
Stage II CTE
25 yo College Football Player
PHF-tau
Dave Duerson
Death at age 50 years
Football since at age 8 - 11-year NFL career
Post-NFL, successful businessman
Active in NFLPA; Benefits Board
Business and financial difficulties began in 2007
Personal difficulties in 2007
Increasingly out of control:
Short fuse, hot temper, physically and verbally
abusive
Long-standing complaint of headaches since
retirement NFL
Worsening short-term memory, word-finding and
vision difficulties
Self-inflicted gunshot wound, texted family to donate
brain to NFL brain bank
56
Stage III CTE
Stage III CTE
Diffuse axonopathy
SMI-31
TDP-43 Deposition
77 yo Australian Rugby Player
• Began playing rugby at age 13, played 6 years of U21 rugby,
and 10 years of senior rugby as flanker and breakaway (18 years).
•Age 54: Cognitive problems, memory loss, attention difficulties,
executive dysfunction, followed by depression and anxiety,
worsening explosivity and impulsivity.
• Age 65: physically and verbally abusive, with paranoia,
disinhibition and severe dementia
• Died at age 77 from myocardial infarction
77 yo Australian Rugby Player
Brain weight : 1030 grams
Barry “Tizza” Taylor
Stage IV CTE
PHF-tau
pTDP-43
Stage IV CTE
Clinical Presentations of CTE
36 athletes with pathologically confirmed pure CTE:
Behavioral and/or mood
Younger age at onset
(m 35 yrs)
Cognitive
Older age at onset
(m 59 yrs)
Indistinguishable from AD
Most subjects (86%) who present with behavioral/ mood symptoms
progress to have cognitive symptoms (m age death: 51 yrs)
Behavioral or mood symptoms less likely to develop (46%) in subjects
who present initially as cognitive impairment (m age death: 69 yrs)
Stern et al. Neurology 2013
Most common clinical features
(>70% of CTE cases )
COGNITIVE
BEHAVIORAL
MOOD
MOTOR
Memory
Physical
violence
Depression
Ataxia
Executive
dysfunction
Verbal violence Hopelessness
Dysarthria
Impaired
attention
Explosivity
Suicidality
Gait impairment
Dementia
Loss of control
Anxiety
Tremor
Cognitive
impairment
Short fuse
Irritability
Masked facies
Impulsivity
Apathy
Rigidity
Paranoia
Loss of interest
Rage
Fearfulness
Montenigro et al. Alzheimers Res Ther 2014
CTE: What are the Practice and Research
Gaps?
•
Incidence and prevalence of CTE: Epidemiological studies
•
Determination of Clinical Phenotype: Prospective longitudinal
studies
•
Diagnosis of CTE during life: Validated biomarkers studies
•Blood, CSF, saliva assays
•Neuroimaging: DTI & PET tau ligands
•
Determination of pathogenetic mechanisms and understanding the
relationship to concussion and subconcussion: Validated animal
models, better methods to quantitate trauma exposure during life,
better methods to diagnose CTE during life
•
Determination of genetic risk factors: large scale genetic studies
•
Treatment, comprehensive care, rehabilitation strategies
Relationship between concussion,
subconcussion and CTE is not clear
•
Concussion, subconcussion and post-concussion syndrome:
most likely reversible states of neuronal and axonal
derangement
•
CTE- a latent, progressive neurodegenerative disease.
•
Repetitive injury superimposed on unresolved injury may initiate
a series of metabolic and cytoskeletal disturbances that trigger a
pathological cascade leading to CTE in susceptible individuals
•
The number of concussions does not correlate with CTE or
predict CTE.
•
However, the severity of CTE is significantly associated with
length of exposure in American football, and it is likely that this
is a result of the cumulative effects of subconcussive injury
axonal injury: APP immunostain
neuroinflammation: microgliosis and astrocytosis
PHF-tau deposition
•
•
•
•
Axonal injury
Neuroinflammation
Microvascular dysruption/ loss of BBB/ microhemorrhage
Focal deposition of p-tau
Reversible or Progressive?
Does it depend on the amount of repeat injury?
Are there genetic risk factors for its development?
Additional environmental risk factors?
McKee et al, Acta Neuropathol 2014
Pathology of Concussion
Emerging research
• Increased Cerebral Vulnerability After
Repetitive mTBI
• Vulnerable period after mTBI
In animal models of mTBI:
Longhi et al (mice) 2005; Prins, Alexander,Giza and Hovda 2013
(mice); Huang et al 2013 (rats)
• Long-term effects of Subconcussion
HS football players: Talvage et al 2010, 2014; College football
players: Bazarian et al, 2014; Amateur soccer players/ headers:
Lipton et al 2013; Professional Soccer: Koerte et al 2012
CTE: Molecular Imaging
1. PHF-Tau ligands - new tau ligands that bond PHF-tau have shown promise in
PET studies in Alzheimer’s disease and tauopathy mouse models, will they detect CTE?
PHF-tau ligands:
[18F]-T807,T808: (Zhang et al, 2012, Xia et al, 2013, Chien et al, 2013)
C11PBB3: (Maruyama et al, Neuron 2013)
FDDNP: (Small et al, Am J Ger Psych 2013; Small et al, PNAS, 2015)
2. Neuroinflammation: microgliosis and astrocytosis
TSPO ligands (Coughlin et al, Neurobio Dis, 2015)
3. Absence of beta amyloid ~ 50% of cases
PIB, Florbetapir F18
4. TDP-43 ligands
Clinical Diagnosis: CTE
Abnormal uptake in SN,
globus pallidus, hippocampus,
T-807 signal overlaps with controls
a promising method in development
encephalopathy in a living brain
diagnosing or ruling out chronic traumatic
encephalopathy in a living brain,"
Mitsis et al, Transl Psychiatry 2014, 4, e441
Urgent need to help living athletes and other individuals who
are concerned that they have CTE
Urgent need to determine the relationship between concussion and the
development of long-term disabilities
Jim McMahon
Chicago Bears
Tony Dorsett
Dallas Cowboys
Brett Favre
Green Bay Packers
Ted Johnson
New England Patriots
Boston University CTE Program
Boston University ADC VA Boston
Supported by: NINDS and NIBIB Cooperative agreement
1U01NS086659-01
Chris Nowinski
VA Boston/ Boston University/ SLI
Chronic Traumatic Encephalopathy Program
BU/VA CTE Program
Victor Alvarez MD
Alexandra Bourlas
Christine Baugh
Robert Cantu, MD FACS
Kerry Cormier
Dan Daneshvar, MD, PhD
Brian Frye
Matthew Jacobs
Lee Goldstein MD PhD
Doug Katz, MD
Patrick Kiernan
Neil Kowall, MD
Carol Kubilus
Lisa McHale
Jesse Mez, MD
Philip Montenigro
Lauren Murphy
Chris Nowinski
David Riley
Cliff Robbins
David Salat, PhD
Hyo Soon-Lee MD
Todd Solomen, PhD
Thor Stein, MD, PhD
Robert Stern PhD
Prince Williams
Rhoda Au, PhD
Andrew Budson MD
Ben Wolozin MD, PhD
BU Goldstein Lab
Andrew Fisher, PhD
Chad Tagge, PhD
Juliet Montcaster, PhD
Mark Wojnarowicz
SLI
Robert Cantu, MD FACS
Chris Nowinski
Other Institutions
All the families
who participated
in our research
Nigel Cairns, PhD Wash U
John Crary, MD, PhD Columbia
Dennis Dickson, MD Mayo Clinic
Rebecca Folkerth, MD Brigham
Garth Hall, PhD U Mass Lowell
Keith Johnson, MGH
Dirk Keene, MD U Wash
Alexander Lin, PhD, BWH
Irene Litvan, MD UC San Diego
Thomas Montine, MD, PhD U Wash
Daniel Perl, MD USHS
Ismael Santa-Maria Columbia
Jean Paul Vonsattel, MD Columbia
Thank you !
Funding sources:
NINDS/ NIBIB/ NIA
Department of Veterans Affairs
Department of Defense
Andlinger Foundation
WWE NFL NOCSAE