Sixth Annual Intensive Update in Neurology/media/Images/Swedish/CME1/SyllabusP… · “Punch Drunk” “Dementia Pugilistica” 1928 First reported by Harrison Martland in 1928

Sixth Annual Intensive Update in Neurology 9/15-16/2016

1

Football and the brainAnn C. McKee M.D.

Professor of Neurology and Pathology VA Boston Healthcare System

Boston University School of Medicine

Director of the CTE Program

Associate Director, Alzheimer’s Disease Center


2

“Punch Drunk” “Dementia Pugilistica” 1928First reported by Harrison Martland in 1928 in boxers

"nearly one half of the fighters who have stayed in the game long enough”

Martland (1928) Punch drunk. JAMA 91:1103–1107

“Chronic Traumatic Encephalopathy “ 1949, 1957Critchley M (1949) Punch-drunk syndrome: the chronic traumatic encephalopathy of boxers.

Hommage à Clovis Vincent. Paris.

Critchley M. Medical aspects of boxing, particularly from a neurological standpoint.

Br Med J 1957; 1: 357No. 4824.

FEBRUARY 12, 1916.

The Lettsomian LecturesON

THE EFFECTS OF HIGH EXPLOSIVES UPON

THE CENTRAL NERVOUS SYSTEM.

Delivered before the Medical Society of London

BY FRED. W. MOTT, M.D. LOND., F.R.C.P.

LOND., HON. LL.D. EDIN., F.R.S.,MAJOR R.A.M.C. (T.), 4TH LONDON GENERAL HOSPITAL; PATHOLOGIST TO

THE LONDON COUNTY COUNCIL ASYLUMS.

LECTURE I.

(Delivered (In lieb. 7th.)

MR. PRESIDENT AND GENTLEMEN,-Permit me tothank you for the great honour the Medical Societyof London has done me in asking me to give theLettsomian lectures this year. The society hasbeen fortunate in having had addresses and discus-sions on most of the medical and surgical problemsconcerning the war, with the exception of the effectsof high explosives upon the central nervous systemin the production of functional neuroses and

psychoses. As I have had the opportunity of

studying these effects I ventured to change the

subject which I at first contemplated.The employment of high explosives combined

with trench warfare has produced a new epochin military medical science. This war was recentlydescribed at a Labour Congress as a barbarous,unromantic, machine war. Yet in no war of the

past has individual courage and self-sacrifice shonewith greater lustre; for the contemptible little

army in the retreat from Mons fought against over-

whelming odds and covered itself with glory.Again, in the terribly anxious times when the

enemy tried to break through to Calais, whatcould have surpassed the courage and self-sacrificeof our men in the trenches on the Yser, or the

gallant stand of the Canadians when the Germans

sprang the gas upon us? Lastly, the landing ofthe Anzacs is one of the finest and most romantic

deeds in the history of war.

High explosives contained in huge shells have

played a prominent part in this war, and apartfrom the effects produced by direct material injuryto the central nervous system, there is the moral

effect of the continued anxious tension of what

may happen, which, combined with the terror

caused by the horrible sights of death and destruc-tion around, tends to exhaust and eventuallyeven shatter the strongest nervous system. To

live in trenches or underground for days or

weeks, exposed continually to wet, cold, and

often, owing to the shelling of the communication

trenches, to hunger, combined with fearful tensionand apprehension, may so lower the vital resistanceof the strongest nervous system that a shell burst-

ing near, and without causing any visible injury,is sufficient to lead to a sudden loss of conscious-

ness. So that in considering the effects of highexplosives it is absolutely necessary to take intoaccount the state of the nervous system of the

individual at the time of the " shock " caused bythe explosive. A neuro-potentially sound soldierin this trench warfare may from the stress of pro-

longed active service acquire a neurasthenic condi-tion, and it stands to reason that a soldier who hasbecome neurasthenic from a head injury or fromthe acquirement of a disease prior to his enlistmentwill not stand the strain as well as a neuro-

potentially sound man. Again, if in a soldier there

is an inborn timorous or neurotic disposition or aninborn germinal or acquired neuropathic or psycho-pathic taint causing a lOClt8 minoris resistentiae

in the central nervous system, it necessarilyfollows that he will be less able to withstand the

terrifying effects of shell fire and the stress of

trench warfare. Thus, whether a tendency to a

neurasthenic condition has been acquired or is

more or less inborn, an emotional experience suchas fright is more liable to develop the symptoms ofa functional neurosis or psychosis.

THE EFFECTS OF HIGH EXPLOSIVES UPON THE

CENTRAL NERVOUS SYSTEM.

The effects of high explosives upon the centralnervous system fall into three groups. 1. Imme-

diately fatal either from pieces of shell, stones,rocks, or portions of buildings striking the indi-

vidual, causing instant death, or the person maybe buried from the explosion of a mine. Again,instant death must have occurred in groups of men

from the effects of shell fire and yet no visible

injury has been found to account for it. This

matter I shall discuss more fully later.2. In Group 2 we can place those cases in which

the detonation of high explosives has caused woundsand injuries of the body, including the central

nervous system, which have not been immediatelyfatal. The number of these cases which do not

exhibit any of the functional disorders and disturb-

ances characteristic of what is termed " shellshock

"

without visible injury, although such

individuals have received most serious and fatal

wounds from exploding shells, leads one to con-

sider that in a large proportion of cases of shellshock without visible injury there are other factorsat work in the production of the nervous symptomsbesides the actual aerial forces generated by theexplosive.

3. The third group includes injuries of the centralnervous system without visible injury, and to this

group I shall give especial attention, as it is the oneof which I have had most experience. I include

the functional neuroses and psychoses because

although there may be no discoverable lesion in a

" psychic trauma," yet so complex is the structureof the human central nervous system, and so subtilethe chemical and physical changes underlying itsfunctions, that because our gross methods of

investigating dead material do not enable us to saythat the living matter is altered, yet admitting that

every effect owns a cause, a refractory phase in

systems or communities of functionally correlatedneurons must imply a physical or chemical changeand a break in the links of the chain of neurons

which subserve a particular function. As we know,one of the peculiarities of the functional neuroses isnot only the sudden manner in which an emotionalshock may engender a loss of function, but likewisethe sudden manner in which it may be unexpectedlyrestored by a sudden stimulus of the most varied

kind, provided there is an element of surprise.That is, attention is for a moment taken off its

guard. I am referring especially to mutism. The

causes of shock to the nervous system by highexplosives may be considered under the headingsof physical trauma-concussion or " commotio

cerebri" by direct aerial compression or by theforce of the aerial compression blowing the personinto the air or against the side of the trench or

dug-out; or by blowing down the parapet or roofon to him causing concussion, or a sandbag hittinghim on the head or spine might easily causeconcussion without producing any visible injury.

G

No. 4824.

FEBRUARY 12, 1916.

The Lettsomian LecturesON

THE EFFECTS OF HIGH EXPLOSIVES UPON

THE CENTRAL NERVOUS SYSTEM.

Delivered before the Medical Society of London

BY FRED. W. MOTT, M.D. LOND., F.R.C.P.

LOND., HON. LL.D. EDIN., F.R.S.,MAJOR R.A.M.C. (T.), 4TH LONDON GENERAL HOSPITAL; PATHOLOGIST TO

THE LONDON COUNTY COUNCIL ASYLUMS.

LECTURE I.

(Delivered (In lieb. 7th.)

MR. PRESIDENT AND GENTLEMEN,-Permit me tothank you for the great honour the Medical Societyof London has done me in asking me to give theLettsomian lectures this year. The society hasbeen fortunate in having had addresses and discus-sions on most of the medical and surgical problemsconcerning the war, with the exception of the effectsof high explosives upon the central nervous systemin the production of functional neuroses and

psychoses. As I have had the opportunity of

studying these effects I ventured to change the

subject which I at first contemplated.The employment of high explosives combined

with trench warfare has produced a new epochin military medical science. This war was recentlydescribed at a Labour Congress as a barbarous,unromantic, machine war. Yet in no war of the

past has individual courage and self-sacrifice shonewith greater lustre; for the contemptible little

army in the retreat from Mons fought against over-

whelming odds and covered itself with glory.Again, in the terribly anxious times when the

enemy tried to break through to Calais, whatcould have surpassed the courage and self-sacrificeof our men in the trenches on the Yser, or the

gallant stand of the Canadians when the Germans

sprang the gas upon us? Lastly, the landing ofthe Anzacs is one of the finest and most romantic

deeds in the history of war.

High explosives contained in huge shells have

played a prominent part in this war, and apartfrom the effects produced by direct material injuryto the central nervous system, there is the moral

effect of the continued anxious tension of what

may happen, which, combined with the terror

caused by the horrible sights of death and destruc-tion around, tends to exhaust and eventuallyeven shatter the strongest nervous system. To

live in trenches or underground for days or

weeks, exposed continually to wet, cold, and

often, owing to the shelling of the communication

trenches, to hunger, combined with fearful tensionand apprehension, may so lower the vital resistanceof the strongest nervous system that a shell burst-

ing near, and without causing any visible injury,is sufficient to lead to a sudden loss of conscious-

ness. So that in considering the effects of highexplosives it is absolutely necessary to take intoaccount the state of the nervous system of the

individual at the time of the " shock " caused bythe explosive. A neuro-potentially sound soldierin this trench warfare may from the stress of pro-

longed active service acquire a neurasthenic condi-tion, and it stands to reason that a soldier who hasbecome neurasthenic from a head injury or fromthe acquirement of a disease prior to his enlistmentwill not stand the strain as well as a neuro-

potentially sound man. Again, if in a soldier there

is an inborn timorous or neurotic disposition or aninborn germinal or acquired neuropathic or psycho-pathic taint causing a lOClt8 minoris resistentiae

in the central nervous system, it necessarilyfollows that he will be less able to withstand the

terrifying effects of shell fire and the stress of

trench warfare. Thus, whether a tendency to a

neurasthenic condition has been acquired or is

more or less inborn, an emotional experience suchas fright is more liable to develop the symptoms ofa functional neurosis or psychosis.

THE EFFECTS OF HIGH EXPLOSIVES UPON THE

CENTRAL NERVOUS SYSTEM.

The effects of high explosives upon the centralnervous system fall into three groups. 1. Imme-

diately fatal either from pieces of shell, stones,rocks, or portions of buildings striking the indi-

vidual, causing instant death, or the person maybe buried from the explosion of a mine. Again,instant death must have occurred in groups of men

from the effects of shell fire and yet no visible

injury has been found to account for it. This

matter I shall discuss more fully later.2. In Group 2 we can place those cases in which

the detonation of high explosives has caused woundsand injuries of the body, including the central

nervous system, which have not been immediatelyfatal. The number of these cases which do not

exhibit any of the functional disorders and disturb-

ances characteristic of what is termed " shellshock

"

without visible injury, although such

individuals have received most serious and fatal

wounds from exploding shells, leads one to con-

sider that in a large proportion of cases of shellshock without visible injury there are other factorsat work in the production of the nervous symptomsbesides the actual aerial forces generated by theexplosive.

3. The third group includes injuries of the centralnervous system without visible injury, and to this

group I shall give especial attention, as it is the oneof which I have had most experience. I include

the functional neuroses and psychoses because

although there may be no discoverable lesion in a

" psychic trauma," yet so complex is the structureof the human central nervous system, and so subtilethe chemical and physical changes underlying itsfunctions, that because our gross methods of

investigating dead material do not enable us to saythat the living matter is altered, yet admitting that

every effect owns a cause, a refractory phase in

systems or communities of functionally correlatedneurons must imply a physical or chemical changeand a break in the links of the chain of neurons

which subserve a particular function. As we know,one of the peculiarities of the functional neuroses isnot only the sudden manner in which an emotionalshock may engender a loss of function, but likewisethe sudden manner in which it may be unexpectedlyrestored by a sudden stimulus of the most varied

kind, provided there is an element of surprise.That is, attention is for a moment taken off its

guard. I am referring especially to mutism. The

causes of shock to the nervous system by highexplosives may be considered under the headingsof physical trauma-concussion or " commotio

cerebri" by direct aerial compression or by theforce of the aerial compression blowing the personinto the air or against the side of the trench or

dug-out; or by blowing down the parapet or roofon to him causing concussion, or a sandbag hittinghim on the head or spine might easily causeconcussion without producing any visible injury.

G

“Shell Shock” 1916

Frederick Mott


3

Psychological Medicine, 1973, 3, 270-303

Clinicopathological Series of 15 boxers with CTECorsellis, Bruton, Freeman-Browne 1973


4

Mike Webster Death at 52 years

Behavioral and mood disorders

Cognitive loss

Parkinsonism

Chronic Traumatic Encephalopathy 2005, 2006

Omalu, DeKosky et al. 2005, 2006


5

CTEControl

Stage IV CTE

Paul Pender

Control

Paul Pender

World Champion boxer, Marine

Died at age 73

Severe Dementia

p-tau pathology

Bedford VAMC


6

Paul Pender

No p-tau 45 yo NFL 73 yo Boxer/Vet

February 2008


7

Chronic Traumatic Encephalopathy 2009

3 cases at VA Boston/BUSM

48 other cases in the worlds literature

39 boxers (76%)

5 American football players (10%)


8

Pathology of CTEBrain Atrophy

CTE

Normal

Hyperphosphorylated tau (P-tau)


9

Severe II and III ventricular dilationGross Characteristics: Cerebral Atrophy


10

Cavum septum pellucidum


11

Marked medial temporal atrophy

Thinning of the posterior corpus callosum


12

Septal fenestrations

Atrophy of the thalamus, hypothalamus and mammillary bodies


13

Abnormalities of septum pellucidum


14

pallor of the substantia nigra


15

Hyperphosphorylated tau protein (p-tau)CTE


16

amygdala

frontal cortex

p tau

nucleus basalis

insula

temporal cortex

CTECONTROL

entorhinal


17

Deep Nuclei

Thalamus

Hypothalamus

Mammillary bodies


18

Brainstem

Substantia Nigra Locus coeruleus


19

Neuropathological Criteria for CTE

P-tau lesions

1. Perivascular

2. Focal distribution at depths of sulci

68 cases of CTE

McKee et al 2013


20

Cloots et al Annals of Biomedical Engineering, Vol. 36, No. 7, July 2008

Cloots et al.J Mechanical Behavioral Biomedical Materials 2012 (41-52)

Sulcal depth and perivascular area are regions of physical stress

concentration

Why is tau protein deposited in those brain regions?


21

Fe

bru

ary

25

-6,

201

5

NINDS/NIBIB Consensus Meeting to Evaluate

Pathological Criteria for the Diagnosis of CTE 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


22

In 2014, the NINDS/NIBIB launched a major effort to define the

neuropathological characteristics of CTE.

First objective: evaluate the preliminary consensus criteria for the

neuropathological diagnosis of CTE

Is CTE is a distinct tauopathy that can be distinguished from

other tauopathies?

NINDS/NIBIB Consensus Meeting to Evaluate

Pathological Criteria for the Diagnosis of CTE


23

Methods: The study design was based on previous successful NIH-

sponsored consensus conferences for other tauopathies, specifically PSP

and CBD

25 cases of various tauopathies:

CTE (with and without Aß)

Alzheimer’s disease

Progressive Supranuclear Palsy

Corticobasal Degeneration

Argyrophilic Grain disease

Primary age-related tauopathy

Guamanian Parkinson’s Dementia Complex

No clinical or demographic information was provided to the neuropathologists–

including no information regarding the subjects age, gender, clinical symptoms

or athletic exposure, no information on gross neuropathology.


24

Seven neuropathologists evaluated the digitized slides independently:

Nigel Cairns, Ph.D. Washington University, St Louis

Dennis Dickson, M.D Mayo Clinic, Jacksonville

Rebecca Folkerth, MD Brigham and Womens, Boston

C. Dirk Keene, M.D Univ Washington, Seattle

Daniel Perl, M.D. USUHS, Washington

Thor Stein M.D., Ph.D. Boston Univ, Boston

Jean Paul Vonsattel, M.D. Columbia Univ, New York

and submitted their diagnostic evaluations prior to the conference.


25

Results

There was good agreement within the neuropathologists

who reviewed the cases (Cohen’s kappa: 0.67)

There was even better agreement between reviewers and

CTE diagnosis (Cohen’s kappa: 0.78) using the proposed criteria

for CTE .

91.4% of the total responses correctly identified CTE

95.7% after the clinical information and gross neuropathological

features were revealed


26

Pathognomonic Lesion of CTE

“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.”


27

Pathognomonic Lesion of CTE

The panel also stated that:

“ thus far, this pathology has only been found in individuals

exposed to brain trauma, typically multiple episodes”


28

Low power microscopic examination

often a clue to the diagnosis


29

CTE:

Perivascular accumulation of p-tau in NFTs,

thorned astrocytes and dot-like structures


30

The hippocampal ptau

pathology is distinctive from AD


31

The TDP-43 pattern is distinctive

from other neurodegenerations


32

CTE is not ARTAG


33

Validation of pathological criteria for CTE

CTE risk in amateur contact sport athletes

• In a review of >1,700 male brains donated over 18 years to Mayo

Clinic Brain Bank, researchers found CTE pathology in

32% of contact sport athletes

• 162 control brains without a history of brain trauma or contact

sports yielded zero cases of CTE.

• 33 brains with a history of a single TBI, yielded zero cases of CTE.

• Additional evidence linking repetitive brain trauma to CTE

Acta Neuropathologica, 2016


34

GFAP AT8

Perivascular ptau lesions depth of sulcus

neurons and astrocytes

Russ H

ub

er,

MD

PhD

vesselel

astrocytes


35

CTE is a distinctive tauopathy that can be distinguished from AD and

age- related tauopathy by the nature and distribution of the pathology and by

immunohistochemical and biochemical analyses.

Characterization of Early Pathological Tau Conformations & Phosphorylation

in Chronic Traumatic Encephalopathy

Kanaan N, Cox K, Alvarez V, Stein T, Poncil S, McKee A. JNEN 2016

TNT TOC1 pS422

astrocytes

perivascular lesions

dotlike structures


36

Cis P-Tau

Trans P-Tau

Kondo et al Nature July 2015


37

CTE: other pathology

P-TDP-43

P-TDP-43

SMI-34 IBA1

axonal injury and neuroinflammation


38

Stein et al Acta Neuropathol May 2015


39

Aß deposition in CTE

• Aß deposition in 52% of CTE subjects - never before the age

of 50 years

• Age is significantly associated with Aß in CTE

• ApoE4 allele is significantly associated with Aß plaques in

CTE

• Aß occurs in CTE at earlier age and an accelerated rate

compared to a normal aging population (p=0.025)

• Aß in CTE is significantly associated with dementia,

Parkinsonism, and LBD pathology

Stein et al Acta Neuropathol May 2015


40

Con

trol I II III IV

0

100

200

300

Iba

1+

ce

ll/ m

m2 2

Con

trol I II III IV

0

200

400

600

GF

AP

+ c

ell/

mm

A B

2

C D E F G

H I J K L

20x

63x

Control Stage 1 Stage II Stage III Stave IV

IBA

1

Microglial neuroinflammation contributes to tau pathology

in CTE in CTE Jon Cherry and Thor Stein


41

D Barnes, P Kiernan, V Alvarez, B Huber. A Dedeoglu, L Goldstein, N Kowall, T Stein,

A McKee

•pTDP-43 inclusions are observed in most CTE

•There is a significant correlation between pTDP-43 score and:CTE stageHippocampal sclerosisAß plaquesClinical dementia

•In CTE, pTDP43 deposits are often found in the frontal cortex, medial temporal lobe and substantia nigra

•The morphology of pTDP-43 appears to be unique in CTE

•Hippocampal sclerosis in CTE correlates with CTE stage

•10% of CTE cases have ALS

pTDP43 pathology in CTE


42

Brain Donors #

Boxing 16

American Football 225

Ice Hockey 17

Professional Wrestling 5

Rugby 7

Military Veterans* 25 (*also 60 Veteran-athletes)

Soccer 5Other Sport: amateur wrestling,

baseball, bull riding, lacrosse,

martial arts, water polo 10

Other: physical abuse, poorly

controlled epilepsy, head banging 12

TOTAL 322

UNITE BRAIN BANK BRAIN DONORS


43

CTE Diagnoses # CTE # Evaluated

Boxing 14 16

American Football 156 189

Ice Hockey 9 14

Professional Wrestling 2 4

Rugby 2 5

Military Veterans* 9 (*46 Veteran-athletes) 23 (*53 Veteran-athletes)

Soccer 3 5Other Sport: amateur wrestling,

baseball, bull riding, lacrosse,

martial arts, water polo 3 10

Other: physical abuse, poorly

controlled epilepsy, head banging 1 11

TOTAL 201 280

UNITE BRAIN BANK Dx: CTE


44

Neuropathological Dx: CTE184 Athletes

Boxing Football Hockey Soccer Rugby MLB WWE MMA Total

Pro Am NFLSem

ProColl

HS/Y

outhNHL Am Pro Am

#CTE 11 3 90 9 48 6 6 3 3 1 1 1 2 0 184

# evaluated 12 4 94 11 58 26 6 8 5 1 4 1 4 1 235

96% 78% 83% 28%


45


46

CT

E

McK

ee e

t al, 2

013,

Bra

in


47

Stages of Tau Pathology Age at Death

Stage I

Stage II

Stage III

Stage IV

mean age: 28.3 + 13 years




McK

ee e

t al, 2

013,

Bra

in


48

Stages of Tau Pathology: NFL Age at Death

Stage I

Stage II

Stage III

Stage IV

mean age: 27.6

range: 23-35 years

mean age: 40.0

range: 25-70 years

mean age: 61.5

range: 40-89 years

mean age: 75.0

range: 60-84 years


49

143 cases of CTE in athletes: co-morbid neurodegeneration in 37%

PureCTE,88,62%

CTE+MND,15,10%

CTE+AD,16,11%

CTE+LBD,11,8%

CTE+FTLD,4,3%

CTE+Mul ple,7,5%

CTE+Other,2,1%

PureCTE

CTE+MND

CTE+AD

CTE+LBD

CTE+FTLD

CTE+Mul ple

CTE+Other


50

Michael Keck

25 yo college football player

• Quit football after 3 yrs college. Continued to experience memory loss,

disorientation, difficulty with attention, concentration and word finding,

progressively worsened over the last 2 years of life

• Depression, impulsivity and severe anger

• Died at age 25 from a staph infection

• 16 yrs football, 3 years division I, linebacker/ special teams

• Multiple concussions –

persistent vision changes, memory problems, confusion, difficulty

sleeping and headaches

Mez et al, JAMA Neurology 2016


51

Brain weight: 1480 grams


52


53

Frontal, temporal, parietal cortex: AT8 (p-tau)

Mez et al, JAMA Neurology 2016


54

Michael Keck Stage II CTE

PHF-tau


55

Tyler Sash

27 yo former NFL player

• 16 yrs football, 2 years NFL, safety and kick coverage

• 20 concussions –

symptoms from last concussion never completely resolved

• Subtle changes in his behavior in the NFL, more

aggressive and anxious

• After NFL, impairment in attention, memory, executive

function, shorter fuse, depression and apathy

• Narcotic use for chronic pain

• Death at 27 from accidental overdose


56

PHF-tau

Tyler Sash 27 years old


57


58

56

Death at age 50 years

Dave Duerson


59

Stage III CTE


60


• 28 yrs football: 4 yrs high school, 4 years division 1 college, 15

years professional primarily as quarterback

• 500+ concussions, none with LOC

• Heavy alcohol use throughout life

• Age 55: brief episode of difficulty speaking, “TIA”

• Subtle episodic memory changes at age 60, often repeated

himself

• c/o Headaches, increased sensitivity to light and noise, chronic

pain and tinnitus

• Mood became more sullen and withdrawn, more anxious and

he developed insomnia

• Brief cognitive eval at age 65: “mild cognitive impairment”

• Death at 69 from colon cancer


61


Consensus panel clinical diagnosis:

CTE with contributions from substance abuse


62

Brain weight: 1318 grams


63


64


65


66


67


68


69


70

Olfactory bulb : AT8


71

Septal cortex Inferior frontal

Superior frontalTemporal pole

Amygdala CA1 HippocampusAmygdala

AT

8


72

CA1 CA4

Hippocampus


73

Mammillary body Medial geniculate nucleus


74

Substantia nigra Locus coeruleus


75

Aß plaques: moderate diffuse plaques, sparse neuritic plaques


76

Ken Stabler: 1945-2015

Pathological Diagnoses

1.CTE, Stage IV

• Septal fenestrations, mild generalized atrophy, most severe in frontal and temporal lobes

• Perivascular ptau immunoreactive neurofibrillary tangles and astrocytic inclusions concentrated at the depths of the cerebral sulci with severe involvement of the medial temporal lobe structures and brainstem

• Sparse TDP-43 neurites in CA1 hippocampus

2.Alzheimer’s changes, insufficent for diagnosis• Neuropathological change: Low (A3,B2,C1)• NIA-Reagan: Low likelihood• CERAD plaque density: sparse• Mild CAA

3.Microinfarcts, Rolandic cortex


77

Ken Stabler Stage IV CTE


78

Ag

gre

ga

ted

ta

u

AgeRepetitive mild trauma

DementiaMemory loss/

Cognitive

impairment

NeurodegenerationNeuroinflammation

Microvasculopathy

Behavioral changes

CTEII III IVIstages

…..other environmental exposures: steroids, drugs, alcohol

…..genetic susceptibility and resistance: MAPT, ApoE

PHF-tau

Aß TDP-43


79

Possible mechanisms of tau

spread?

• Prion protein templating

• Glymphatic channels

• Tau secretion

–Exosomes

• Other


80

What are the critical issues in CTE?: pathology and pathogenesis

1. How to detect, diagnose and monitor CTE during life

2. What mechanisms are involved in CTE pathogenesis?

3. Is CTE reversible? Can progression be halted?

4. What are the effects of gender?

5. What is the incidence and prevalence of CTE?

6. What are the genetic susceptibility factors?

7. What is the risk for CTE in amateur and professional sports and

military service?

8. How does CTE contribute to other neurodegenerative pathologies?

9. Does trauma provoke other neurodegenerations besides CTE?


81

BU/VA CTE ProgramJason Adams

Victor Alvarez MD

Kathryn Babcock

Alexandra Bourlas

Christine Baugh

Andrew Budson MD

Robert Cantu, MD FACS

Kerry Cormier

Dan Daneshvar, MD, PhD

Brian Frye

Matthew Jacobs

Lee Goldstein MD PhD

Bertrand R. Huber, MD, PhD

Doug Katz, MD

Patrick Kiernan

Neil Kowall, MD

Carol Kubilus

Lisa McHale

Jesse Mez, MD

Phillip Montenigro

Lauren Murphy

Chris Nowinski

David Riley

Cliff Robbins

Jon Cherry, PhD

Dharmendra Goswami, PhD

VA Boston/ Boston University/ CLF

CTE Program

All the families

who participated

in our research

BU Goldstein LabAndrew Fisher, PhDChad Tagge, PhDJuliet Montcaster, PhDMark Wojnarowicz

CLFRobert Cantu, MD FACSChris Nowinski

Boston VA (TRACTS)Regina McGlinchey, PhDWilliam Milberg, PhDTerry Keane, PhDLauren RadiganMeghan RobinsonDavid Salat, PhD

Hyo Soon-Lee MD

Todd Solomon, PhD

Thor Stein, MD, PhD

Robert Stern PhD

Prince Williams

Rhoda Au, PhD

Other InstitutionsDavid Brody, Wash U

Robert Brown MD, U Mass

Nigel Cairns, PhD Wash U

John Crary, MD, PhD Columbia

Ramon Diaz-Arrastia, MD

Dennis Dickson, MD Mayo Clinic

Rebecca Folkerth, MD Brigham

Garth Hall, PhD U Mass Lowell

Laurena Holleran, Wash U

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

Michael Strong, MD Western

William Stewart, Glasgow

Jean Paul Vonsattel, MD Columbia


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Funding sources:

Department of Veterans AffairsNINDS/ NIBIB/ NIA

Department of DefenseAndlinger Foundation

WWE NFL NOCSAE

Thank you !

Documents

Sixth Annual Intensive Update in Neurology/media/Images/Swedish/CME1/SyllabusP… · “Punch Drunk” “Dementia Pugilistica” 1928 First reported by Harrison Martland in 1928