Chronic traumatic encephalopathy –neuropathology in athletes and war veterans

Nelli Lakis1, Robert J. Corona1, Gentian Toshkezi2, Lawrence S. Chin2

1Department of Pathology, SUNY Upstate Medical University, Syracuse, NY, USA, 2Department of Neurosurgery,SUNY Upstate Medical University, Syracuse, NY, USA

Objective: The neuropathologic findings of chronic traumatic encephalopathy (CTE) were first describedalmost 40 years after the first clinical reports. We reviewed the literature and describe the neuropatho-logical findings seen primarily in professional athletes and more recently, in war veterans.Methods: We reviewed the literature of CTE concentrating on references that focused on the correlation ofclinical findings with the neuropathologic changes. The pathobiology and proposed mechanisms of injuryare described. Diagnostic modalities and various diagnostic criteria of CTE are reviewed.Results: We are beginning to understand the neuropathologic basis of CTE, which appears to be aconsequence of repetitive mild brain injuries. There appear to be reproducible criteria for the post-mortemdiagnosis of CTE and the neuropathologic findings are becoming more widely accepted. More research isrequired to elucidate the risk factors that predispose athletes and war veterans to CTE. There is also a needfor more diagnostic markers and a method to assess CTE in patients prior to death. The neuropathologicfindings of a progressive tauopathy including the presence of numerous neurofibrillary tangles (NFTs), rareneuritic plaques, and widespread expression of TDP-43 (transactive response [TAR] DNA binding protein43) also require further study.Discussion: The potential prevalence of CTE, as well as the vulnerable populations involved, makesresearch into this topic crucial. Currently, a comprehensive neurological exam, neuropsychiatricassessment, and standard radiographic techniques such as conventional MRI are the mainstay ofdiagnosis. There is a pressing need for the prevention of CTE and the development of non-invasivediagnostic tests in order to develop therapies that may be of clinical use to athletes and blast injuryveterans during their lifetimes.

Keywords: Chronic traumatic encephalopathy, Tau proteinopathy, Neurofibrillary tangles, Concussion, Traumatic brain injury, Dementia

IntroductionTraumatic brain injury (TBI) is a major cause of

mortality and morbidity. The Centers for Disease

Control (CDC) estimates that 1.7 million people in

the United States sustain a TBI every year and in data

analyzed up until 2007, an annual average of 53 014

deaths from TBI occurred among US residents.

Elderly individuals are most likely to suffer hospita-

lizations and death from TBI primarily from falls

compared to adolescents and young adults, for whom

traffic crashes are the primary cause.1

The most recent definition of TBI has been proposed

in a position paper by the Demographics and Clinical

Assessment Working Group of the International and

Interagency Initiative toward Common Data Elements

for Research on Traumatic Brain Injury and Psy-

chological Health. They propose a definition for TBI as

‘an alteration in brain function, or other evidence of

brain pathology, caused by an external force’.2 Various

other groups have their own definitions including the

American Congress of Rehabilitation Medicine, the

CDC, and the World Health Organization (WHO).3

The CDC defines concussion as a condition of

temporary altered mental status as a result of head

trauma and proposes that the term ‘concussion’ be

replaced by the term ‘mild traumatic brain injury’

(mTBI). However, the term concussion is still used in

sport-related injury.4,5 Alteration in brain function is a

non-specific entity that can include loss or decreased

level of consciousness, mental state changes, memory,

and neurological deficits. External forces include the

head striking or being struck by an object, rapid

acceleration or deceleration of the brain, and exposure

to blast injury.3 By any of the definitions, TBI,

particularly moderate and severe, leaves individuals

with significant long-term neurobehavioral sequelae. A

meta-analysis of 15 case-control studies estimated that

individuals who suffered head injury with loss of

consciousness were at approximately 50% increased

Correspondence to: Lawrence S Chin, Department of Neurosurgery,SUNY Upstate Medical University, 750 E, Adams Street, Syracuse, NY13078, USA. Email: chinl@upstate.edu

290� W. S. Maney & Son Ltd 2013DOI 10.1179/1743132813Y.0000000177 Neurological Research 2013 VOL. 35 NO. 3

risk of Alzheimer’s type dementia compared with

others (pooled odds ratio (OR) 1.58 and 95%

confidence interval (CI) 1.21–2.06).6 The MIRAGE

study examined the effects of head injury on AD risk in

a large family study and found that the OR for

dementia after head trauma with loss of consciousness

was 4.0 (95% CI, 2.9–5.5) versus an OR of 2.0 (95% CI,

1.5–2.7) for head injury without loss of consciousness.7

Retrospective studies have recall bias as an inherent

flaw. A more convincing prospective study by Plass-

man et al. found a positive association between head

trauma and dementia. They identified 548 US Navy

and Marine veterans hospitalized for TBI during the

Pacific theater in World War II and compared them to

1228 veterans without head injury. From 1996 to 1997,

military medical records were abstracted to document

the occurrence and details of the closed head injury and

the entire sample was then evaluated for dementia and

AD. Using proportional hazards models, the authors

estimated the risk of dementia, specifically AD and

found that moderate head injury (hazard ratio

[HR]52.32; CI51.04–5.17) and severe head injury

(HR54.51; CI51.77–11.47) were associated with

increased risk of AD. No increased risk was evident

for veterans with mTBI and the authors were unable to

exclude various other confounders that may have

influenced the findings.8

From TBI to Chronic Traumatic Encephalopathy(CTE)It has been observed that multiple mTBIs of the sort

experienced by professional athletes such as boxers

and football players are associated with a distinct

clinical–pathological entity known as CTE. The recent

observation that the same phenomenon may be

occurring in war veterans as a consequence of blast

injuries has brought this topic to the forefront of

public health concerns.9,10 Chronic traumatic ence-

phalopathy has a specific pattern of neurodegenera-

tion which researchers have spent decades attempting

to elucidate.11,12 There is currently no consensus base

for diagnosing CTE partly due to the paucity of

prospective studies that follow-up patients with

clinical symptoms of CTE that then show autopsy-

confirmed CTE.

The long-term impact of repeated concussion in

football players was based on media reports that

these former football players suffered from depres-

sion and early onset dementia. A study sponsored by

the National Football League (NFL) demonstrated

that former players in the age group of 30–49 years

presented with dementia symptoms at an incidence of

1.9%, or two times higher than the same age matched

population. Once over 50 years of age, the incidence

of dementia symptoms is 6.1% higher in former

football players or five times higher than national

average.4 The CDC have published mortality data

from 3439 NFL players with at least five pension-

credited playing seasons from 1959 to 1988. This

study was undertaken to analyze neurodegenerative

causes of death, specifically AD, Parkinson’s, and

amyotrophic lateral sclerosis (ALS). Comparisons

were made using standardized mortality ratios

(SMR) from the US population. The results showed

that while there is an overall decrease in player

mortality (SMR 0.53, 95% CI 0.48–0.59), neurode-

generative diseases contributed to mortality both as

an underlying cause of death and a multiple cause of

death (MCOD). Using MCOD rates for both ALS

(SMR 4.31, 95% CI 1.73–8.87) and AD (SMR 3.86,

95% CI 1.55–7.95), the authors concluded that the

mortality of this cohort is four times that of the

general US population.13 While these findings are

concerning, this study is unable to address death

caused by CTE since as a pathologic entity it is a

relatively new diagnosis and is not listed as a cause of

death. It is also unable to attribute causation and

elucidate why the risk is increased in professional

football players.

Many other studies have shown that repetitive

concussions increase the risk of consecutive concus-

sions and lower the threshold for brain injury.14

Sport-related concussions occur from a direct or

indirect blow to the head that results in an alteration

of mental status with or without loss of conscious-

ness. This is a complex pathophysiological process

that affects the brain and results in impairment of

memory, attention, cortical functions, and the ability

to process information, as a result of the biomecha-

nical forces. These symptoms usually resolve in 7–

10 days. The incidence of concussion in young

athletes is reported to be 3–6%, but as many as 50%

of high school athletes who have concussion fail to

report it as an injury.15 Statistics shows that sport-

and recreation-related concussions are increasing

from 300 000 annually a decade ago to four million

annually at present.16 Recent reports suggest that

5% of high school and college football players sustain

at least one concussion during a single football

season.17 This number may again be underestimated

due to under-reporting by concussed athletes. Epide-

miological data has shown that 17% of the indivi-

duals with mTBI develop progressive long lasting

symptoms with features of CTE. Severe dementia

occurs in 6% of subjects exposed to multiple con-

cussions.18 The severity and the frequency of repeti-

tive injury that initiates the exact pathological change

that leads to CTE is currently unknown.5,11,19,20

Computer-based tests have been developed to assess

neurocognitive performance among athletes. The

baseline neurocognitive test for post-concussion was

first introduced in 1987 and a legislation has been

Lakis et al. Chronic traumatic encephalopathy

Neurological Research 2013 VOL. 35 NO. 3 291

implemented in 14 states that allow school districts to

create concussion programs.21

Chronic Traumatic Encephalopathy – ClinicalThe phenomenon of CTE was originally described in

professional boxers by Harrison S Martland in

1928,22 and was called ‘punch drunk’ syndrome. He

described early symptoms of staggering and disequi-

librium, associated with mental confusion and signs

of slowed muscular movement. Millspaugh later in

1937 coined the term ‘dementia pugilistica’ (DP),23

and Courville introduced the term ‘psychopathic

deterioration of pugilist’.24 In 1967, A H Roberts

was appointed to conduct a study on professional

boxers to determine the late neurological sequelae.

He interviewed and examined 250 retired boxers. He

acknowledged a wide spectrum of clinical presenta-

tions yet ascribed the diagnosis of traumatic ence-

phalopathy to a composite clinical syndrome

involving cerebellar, pyramidal, and extrapyramidal

systems. He did not include dementia or neuropsy-

chiatric manifestations in his evaluation so he may

have underestimated the prevalence of CTE in this

population.25

CTE – NeuropathologyCTE pathology reports have lagged behind the

clinical reports (see Table 1 for summary of neuro-

pathologic findings of CTE in chronologic order includ-

ing case reports up to the time of publication26–32).

The first neuropathologic description was performed

by Corsellis et al. in 1973, almost 40 years after the

clinical syndrome had been described. He examined

the brains of 15 retired boxers, correlating ante-

mortem clinical symptoms recounted by surviving

family members with neuropathologic examinations.

The examined brains showed diffuse cerebral atro-

phy with enlarged lateral ventricles and a fenestrated

cavum septum pellucidum. The fornices had atro-

phied and the corpus callosum was significantly

thinned out. The cerebellum showed marked scar-

ring particularly in the tonsillar regions with

demyelination and loss of Purkinje cells. They also

described neurofibrillary tangles (NFTs), and aggre-

gates of misfolded, hyperphosphorylated tau protein

in the substantia nigra. No Lewy bodies were found

ruling out Parkinson’s disease. The NFTs were

spread diffusely throughout the cerebral cortex, with

preferential deposition in the medial temporal gray

matter. Extensive neuronal loss was also seen.

Neuritic AD plaques were rarely identified, with

the exception of one patient. The authors correlated

the neurological findings of memory loss, for

example, with the structural changes, such as

disruption of the limbic pathways.12

Omalu et al., reported a case of CTE in a

professional wrestler who died in 2007 (article

published 2010). Professional wrestling is a contact

sport, with an integral risk for players to sustain

repeated TBIs. This wrestler was a 40-year-old

Caucasian male, who had suffered at least 15 blows

to the head during his career. He presented with

mental problems at the age of 36 years and was

severely depressed until his demise. He hung himself

after killing his wife and son and a complete autopsy

and neuropathologic examination was performed.

The brain showed no atrophy and no recent or

remote contusions or necrosis. There was mild to

moderate neocortical neuronal dropout. There were

no diffuse or amyloid neuritic plaques in any regions

of the brain examined. The authors identified sparse

to frequent, randomly distributed NFTs and ghost

tangles in the neocortex, subcortical ganglia, and

brainstem nuclei including the substantia nigra. This

led them to the diagnosis of a diffuse cerebral

tauopathy consistent with CTE.33

In 2009, McKee et al. reviewed 48 cases of

neuropathologically verified CTE and documented

the detailed findings of CTE in three professional

athletes of their own (Cases 1–3). This was the first

paper to classify CTE as a distinct entity. Of the 51

patients with neuropathologically confirmed CTE, 46

(90%) were athletes, 39 boxers, five football players,

one wrestler, and one soccer player. Presenting

symptoms included memory loss, irritability, violent

abusive outbursts, confusion, cognitive deficits, head-

aches, slurred speech, and Parkinsonism. In 30%,

‘mood disturbance’ was the most significant symp-

tom; most commonly depression. The disease pro-

gression was slow with a range from 2–46 years with

a median time to diagnosis of 18.6 years. Movement

abnormalities were eventually reported in 42% of the

subjects and included Parkinsonism, staggered, slo-

wed and shuffling gait, dysarthric speech, ataxia, and

dysphagia. When broken down by respective profes-

sions, boxers appeared to have the most longstanding

disease, were frequently demented, and often mis-

diagnosed as having AD.34

Memory deficits appear to be a major clinical

presenting symptom of CTE. A meta-analysis of

eight studies with 614 individuals with a history of

mTBI found evidence to suggest that repeat brain

trauma is associated with an inability to recall new

information.35 Guskiewicz et al. investigated the asso-

ciation between previous head injury and the like-

lihood of developing mild cognitive impairment (MCI)

in a group of retired professional football players with

previous head injury exposure. They found a signifi-

cant association with three or more reported concus-

sions, a fivefold prevalence of MCI diagnosis and a

threefold prevalence of reported significant memory

problems compared with retirees without a history of

concussion.36 Functional magnetic resonance imaging

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292 Neurological Research 2013 VOL. 35 NO. 3

Table 1 Summary of major neuropathologic findings of CTE

Authors, year, patients Major neuropathologic findings

Corsellis et al.,12 1973, 15 retired boxers Characteristic findings: enlarged lateral ventricles,fenestrated cavum septum pellucidum, and thinnedcorpus callosum. Neurofibrillary tangles spreaddiffusely throughout the cerebral cortex and brainstem.Rare senile AD plaques identified.

Roberts et al.,26 1990, Archival formalin-fixed material from14/15 cases of dementia pugilistica (DP) originally reportedby Corsellis et al. and an additional four professional boxersand two amateur boxers plus 20 AD cases and 20 Controls

Found that all cases of DP with substantial tangleformation showed evidence of immunoreactivebeta-amyloid plaques.

Hof et al.,34 1992, three retired professional boxers and eightcases of AD

Observed that neurofibrillary tangles (NFTs) wereconcentrated in the superficial layers of the neocortexin Chronic traumatic encephalopathy (CTE), versusAD where they predominated in the deep layers.

Areza-Fegyeres et al.,27 2007, Case report of a 61-year-oldex-boxer who presented with a three-year history of progressivememory decline and clinical course very similar to ADwithout Parkinsonism, pyramidal, or cerebellar symptoms

Characteristic findings: cavum septum pellucidumwith multiple fenestrations, numerous NFTs in thecerebral isocortex and hippocampus, and rareAD plaques.

Nowak et al.,28 2009, Case report of a former world boxingchampion whose progressive cognitive decline could beascribed to DP, cerebral infarcts, and Wernicke–Korsakoffsyndrome

Observed numerous NFTs, rare neuritic plaques,multiple cerebral infarcts, fenestrated septumpellucidum, atrophic and gliotic mamillary bodies,and pale substantia nigra and locus ceruleus.Concluded that dementia in retired boxers could bedue to several factors such as DP, multiple cerebralinfarcts, and Wernicke–Korsakoff syndrome.

McKee et al.,11 2009, 51 patients with neuropathologicallyconfirmed CTE, 46 athletes, 39 boxers, 5 football players,1 wrestler, and 1 soccer player (48 reviewed cases andthree cases of their own)

First paper to classify CTE as a distinct entity, namelya progressive tauopathy with or without Parkinsonismand attendant neuropsychiatric manifestations.

King et al.,29 2010, Neuropathological examinations of 59cases of various neurodegenerative conditions of whichthere were three cases of DP

Described an abnormal widespread expression ofTDP-43 (transactive response [TAR] DNA bindingprotein 43) expression in both the limbic system andneocortex in the three cases of boxing-related CTE.Pattern of distribution of TDP-43 inclusions from theDP cases most closely resembled that in FTLD-TDPleading the researchers to postulate a sharedpathogenic mechanism between the two conditions.

Omalu et al.,30 2010 June, Clinical history and neuropathologicalexaminations of five cases of professional American contactsport athletes who committed parasuicides and suicides

Immunohistochemical analyses showed widespreadcerebral tauopathy and NFTs without neuritic amyloidplaques. Documents the role of forensic pathologistsin emerging disease surveillance of CTE in professionalathletes.

Omalu et al.,31 2010, Case report of CTE in a retired 44-year-old NationalFootball League (NFL) player with a premortem history of cognitiveand neuropsychiatric impairment, including depression and suicide

Diffuse cerebral tauopathy with NFTs and neuritic threads.

Omalu et al.,33 2010, Case report of CTE in a 40-year-old professionalAmerican wrestler after killing his wife and son and committing suicide

Diffuse, sparse to frequent tau-immunoreactiveNFTs and neuropil threads in the neocortex, subcorticalganglia, and brainstem nuclei and the substantia nigraand mild to moderate neocortical neuronal dropoutwithout any amyloid plaques.

McKee et al.,32 2010, Clinical findings and neuropathological findingsin 12 cases of CTE; three of which had progressive motor neurondisease (MND)

Found widespread TDP-43 in the frontal and temporalcortices, medial temporal lobe, basal ganglia,diencephalon, and brainstem.In the three cases of MND, there were abundantTDP-43-positive inclusions and neurites in the spinalcord leading the authors to postulate a pathologiclink between CTE, FTD, and MND.

Omalu et al.,62 2011, Case Report of a 27-year-old marine whohad committed suicide

Multifocal, frequent NFTs and neuritic threads in thesulcal depths of the frontal cortex, parietal cortex,temporal cortex, occipital cortex, and cingulate cortex.First case of documented CTE in a war veterandiagnosed with post-traumatic stress disorder (PTSD).

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Neurological Research 2013 VOL. 35 NO. 3 293

(fMRI) has also provided evidence supporting this

phenomenon. Kasahar et al. studied nine chronic-stage

patients with TBI and nine age-matched healthy

controls. They examined functional connectivity of the

brain regions critical to working memory performance

using psychophysiological interaction analyzes and

found that patients with TBI made a greater percentage

of errors than controls. The fMRI data showed that in

the case group, activation of the left inferior parietal

gyrus was significantly reduced and activation of the

right inferior frontal gyrus was significantly increased

compared to controls. They concluded that abnormal

functional connectivity between these two regions that

mediate memory might underlie the observed working

memory deficits that occur in patients after TBI.37

Patients with CTE also tend to present with

behavioral and psychiatric complaints such as depres-

sion, mood swings, explosive outbursts, disinhibition,

risky behavior, even suicide, and early death.38 The

clinico-pathologic basis for this may be the tau

abnormality distribution in what is the ‘emotional’

or ‘visceral’ brain; that is the amygdalo-hippocampal-

septo-hypothalamic-mesencephalic brain or the Papez

circuit.39,40 The early involvement of memory may be

linked to the early involvement of the hippocampi,

entorhinal cortex, and medial thalamus.41

Microscopically, McKee et al. describe neuronal loss

and gliosis in the hippocampus, substantia nigra, and

cerebral cortex. Other areas susceptible to neuronal

loss are the mammillary bodies, medial thalamus, locus

ceruleus, and nucleus accumbens.11

Chronic traumatic encephalopathy has been classi-

fied as a neurodegenerative tauopathy; a tauopathy

associated with amyloid deposition and prominent

Parkinsonism.42 Tauopathies are characterized by tau

proteins dissociating from microtubules, which are

then hyperphosphorylated and aggregate to form

NFTs. The process by which NFTs cause neuronal

toxicity and death is not known.38 In CTE, the tau-

immunoreactive neurofibrillary pathology is irregular

and multifocal in distribution and often extremely

dense in the superficial layers of the cortex; namely

layer II and the upper third of Layer III. The

superficial and usually perivascular distribution is

in stark contrast to AD in which the NFTs are

preferentially located in deeper layers V and VI and

are much less dense.34 In CTE, tau-immunoreactive

protoplasmic astrocytes are interspersed throughout

the superficial cortical layers composed primarily of

globular neurites that look like accumulated plaques.

The corpus callosum, subcortical white matter such

as the extreme and external capsule, anterior and

posterior commissures, thalamic fasciculus, and

fornix also show neuropil neurites (NNs) and astro-

cytic tangles. This unique pattern of tau pathology

was seen in all three cases described by McKee et al.

with increasing severity from Cases 1–3. In specific,

Case 2 and Case 3 both showed extensive, dense

NFTs in the hippocampi, entorhinal cortex, and

amygdala.11

Immunohistochemical study does show that the tau

protein tangles in CTE are indistinguishable from the

tangles found in AD and both are composed of the six

identical brain tau isoforms.43 Chronic traumatic

encephalopathy is neuropathologically similar to other

neurodegenerative diseases such as progressive supra-

nuclear palsy, post-encephalitic Parkinsonism, amyo-

trophic lateral sclerosis/Parkinson’s-dementia complex

of Guam (ALS/PDC), corticobasal degeneration, and

frontotemporal dementia with parkinsonism linked to

chromosome 17 (FTDP-17).44–47 These entities all

display accumulations of hyperphosphorylated tau

protein. Neurofibrillary tau pathology in CTE and

ALS/PDC of Guam is found in the medial temporal

lobe, cerebral cortex, and spinal cord. Chronic

traumatic encephalopathy, ALS/PDC, and PSP all

preferentially involve the superficial cortical layers and

accumulation of tau-immunoreactive astrocytes.44

Chronic traumatic encephalopathy is different in that

its cortical involvement is irregular and patchy,

aggregating most densely at sulcal depths and having

a preponderance for perivascular, periventricular, and

subpial areas. The most unique feature of CTE is its

predilection for subcortical and brainstem structures.

Beta-amyloid deposition is not always seen in CTE

brains. Of the 51 brains examined by McKee et al.

diffuse plaques were found in 22 (44%) of the cases,

neuritic plaques in 13 (27%), and amyloid angiopathy

in three (6%).11 In contrast, it has been observed that

patients that die immediately after a TBI show diffuse

beta-amyloid plaques in up to 30% of cases. Multiple

cortical areas were examined from 152 patients after

a severe head injury with a survival time of between

4 hours and 2.5 years. Immunostaining with an

antibody to beta-amyloid protein confirmed the

original observation that 30% of cases of head injury

have beta-amyloid protein deposits in one or more

cortical areas. It was also observed that beta-amyloid

precursor protein (beta-APP) immunoreactivity was

increased in the perikarya of neurons in the vicinity of

beta-amyloid protein deposits. This appears to

support the idea that beta-amyloid protein is part

of an acute phase response to neuronal injury in the

brain and may contribute to the pathogenesis of

AD.25 Beta-amyloid accumulation has been observed

in surgically excised post-trauma brain tissues imme-

diately after surgical excision. The authors also

observed that NFTs were more likely to result from

chronic pathologic processes versus acute processes.48

Johnson et al. in a recent autopsy study, identified 39

patients who had a history of a single TBI and long-

time survival (1–47 years survival post-TBI) and

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294 Neurological Research 2013 VOL. 35 NO. 3

compared their brains to uninjured age-matched

controls. They stained the brains for beta-amyloid

plaques and NFTs. Observers were blinded to demo-

graphic and clinical information and the NFTs and

beta-amyloid plaques were both semi-quantitatively

assessed. The results showed NFT pathology spread

out across a wider age spectrum following TBI than in

controls. The observers reported NFTs in 18 of 39

cases (46%) and 16 of 47 (34%) controls. The authors

note that these numbers did not reach statistical

significance; however, when analyzed with respect to

age, all controls that had NFTs were over 60 years of

age. More importantly, the authors described NFTs

following TBI in the superficial cortical layers,

clustering at the sulcal depths, in the cingulate gyrus

and extending through the superior frontal gyrus and

insular cortex. Conversely in controls, NFTs were seen

mostly within the transentorhinal cortex and CA1 of

the hippocampus.49 This pattern is what has been

previously described as ‘normal aging’ NFTs.50–52 The

authors concluded that NFTs were more prevalent in

younger subjects following a single TBI and that the

extent of NFTs was significantly greater in the cases

versus the controls. Beta-amyloid plaques were found

in equal incidence in both cases and controls. The

extent of the plaques differed in that those following

TBI were moderate or high versus the controls in

which they were sparse. This observation did not reach

statistical significance, but there appeared to be a trend

towards wider distribution and greater plaque density

following TBI. Cases had beta-amyloid plaques

distributed relatively evenly throughout all layers of

the cortex or beta-amyloid plaques in isolated clusters

scattered throughout the cortex with areas free of any

plaque pathology. Cases post-TBI were more likely to

have widespread plaques across an entire cortical

region, particularly extending from the cingulate gyrus

to the superior frontal gyrus. Plaques could also be

observed in the entorhinal cortex, the fusiform gyrus,

and the inferior temporal gyrus while relatively sparing

the hippocampus and subiculum.

The nature of the plaques was also found to be

different. In seven of the 11 (64%) beta-amyloid

plaque-positive cases, the plaques were predomi-

nantly fibrillar or displayed a mixed diffuse/fibrillar

pattern while all 13 beta-amyloid plaque-positive

controls had diffuse plaques with very few fibrillar

plaques identified.49 Tau pathology in this cohort was

not uniform but it did appear to be ‘superficial’,

further supporting that CTE following multiple TBI

or even a single injury may be of the same

pathological process versus AD, where the deep

cortical layers are mainly affected.11,34,53 The authors

also found that following TBI glial cells immunor-

eactive for tau were observed more frequently in

regions were NFTs had already been identified. This

finding may have implications for further research on

the mechanism of tau accumulation and clearance.49

Tau pathology may be found in white matter and it

is generally less severe than in adjacent gray matter. It

is usually of the dot-like or spindle-shaped tau-positive

neurites. These are distinct from the thread-like

neurites found in AD, and suggest that they may be

of axonal origin. The NNs in CTE are usually shorter

and less prominent than those in AD and are not

related to senile plaques.54 McKee et al. also describe

vascular abnormalities that include small arterioles

with thick hyalinized walls and hemosiderin-laden

macrophages. In two of their cases (Case 1 and Case 3)

they found myelin loss and axonal damage in the

corpus callosum and subcortical fronto-temporal

lobes and perivascular hemosiderin deposition.11

Saing in 2011 published a detailed paper on the

clinical and neuropathological findings of a retired

boxer who had findings consistent with CTE. He was

55 years old and had the clinical signs and symptoms

of predominantly frontal lobe deficits. His brain was

compared to matched controls from the University of

California Irvine Alzheimer Disease Research Center

(UCI-ADRC) Tissue Repository. Gross examination

of his brain revealed no obvious atrophy, minimal

atherosclerosis, and no leptomeningeal pathology.

Coronal sections revealed an absent septum pelluci-

dum and moderately severe ventricular enlargement

with thinning of the corpus callosum. There was an

irregular 0.4 cm infarct within the medial pallidal

segment and moderate depigmentation in the sub-

stantia nigra and the locus ceruleus. Within the gray

matter, significant beta-amyloid plaque pathology

was seen, in the form of diffuse mild-to-moderate

neuritic plaques distributed in the middle frontal,

rostral and caudal cingulate cortices. Tau pathology

was extensive and frontal white matter showed

evidence of glial tau inclusions. Cerebrovascular

pathology was minimal with patchy amyloid angio-

pathy. The clinical and pathological findings led the

authors to diagnose DP.18

Postulated Mechanisms of InjuryThe mechanisms of cerebral injury are thought to be

due to the acceleration–deceleration forces.55,56 The

severity of brain damage is proportional to the

severity of the generating forces, and depends on

the direction from which these forces are applied.

There is evidence that lateral forces can cause more

damage than front-back forces of the same degree.

Repetitive TBI can cause neuronal loss via necrosis

initiated from the immediate release of excitatory

transmitters such as glutamate and/or focal ischemic

changes and breakdown of the blood–brain barrier

with inflammatory processes that release cytokines,

all initiating and maintaining necrotic and apoptotic

Lakis et al. Chronic traumatic encephalopathy

Neurological Research 2013 VOL. 35 NO. 3 295

death cascades that can cause a diffuse, delayed cell

death.11 A concussive force produces a wave in the

lateral ventricles, which may produce a shearing force

on the septum pellucidum. This may explain the

fenestrations seen grossly on CTE brains. The

patchiness of the NFTs in CTE may be due to the

location where the blow was physically received on

the head, either the side or the top. Ischemia has been

postulated as a cause especially as the tau pathology

is concentrated within the deep sulci.11 Blood–brain

barrier damage and release of neurotoxins may

explain the perivascular tau-immunoreactive NFTs,

tau-positive glia and NNs.57 Chronic traumatic

encephalopathy related to repetitive mTBI continues

to progress decades after the activity causing the

original TBI has ceased. Once these pathologic

cascades are initiated, they continue to execute their

effect and the longer the patient’s lifetime, the worse

the symptom progression.11,18

Chronic Traumatic Encephalopathy and BlastInjuryThe predominance of mood and neuropsychiatric

symptoms has rekindled the interest in an organic

cause for the deficits identified in war veterans.

Recent articles in Science and Nature, postulate a

link between blast injuries and neurodegenerative

processes.9,10 The wars of Afghanistan and Iraq have

increased the awareness of TBI. The rate of TBI

among military personnel has increased substantially

during these wars owing to high rates of exposure to

explosive munitions and the higher survival rates

because of improved body armor, surgical care, and

rapid evacuation. The Department of Defense (DoD)

and Department of Veterans Affairs (VA) also offer

comprehensive screening programs and may be

identifying TBI with a much higher frequency than

in previous wars and have led to it being described as

the ‘signature injury’ of current military operations.58

Blast injury has its own mechanisms that contribute

to the severity of TBI. Explosive content, explosive

amount, distance from blast, and environmental

barriers all contribute to the ‘amount’ of TBI suffered

by a veteran.59 There are four basic mechanisms of

blast injury. Primary injuries are due to high-order

explosive overpressurization shock waves moving

through the body from solid and liquid phases into

gas-filled organs, such as the lungs, gastrointestinal

tract, and middle ear. Secondary injuries are due to

bomb shrapnel propelled by the explosion. Tertiary

injuries result from the blast wind throwing the

victim. These secondary and tertiary injuries are

mechanical injuries and therefore similar to TBI

sustained in the more classic falls and motor vehicle

accidents. Quaternary injuries include burns, crush-

ing injuries, and respiratory injuries.58 Shear and

stress waves from the primary injury could also

potentially cause TBI directly through concussion,

hemorrhage, edema, or diffuse axonal injury but

these findings remain controversial.60 Functional

magnetic resonance imaging studies have been used

to compare task responses in 15 subjects with mild,

chronic blast-related TBI and 15 subjects who had

not experienced a TBI or blast exposure while

deployed. The limitations of the study are the paucity

of numbers and the inability to closely match for

combat exposure. However, the authors reported that

TBI subjects had slightly slower responses during

fMRI and increased somatic complaints and symp-

toms of post-traumatic stress disorder (PTSD) and

depression. Traumatic brain injury subjects also

showed higher activation during stimulus–response

activities within the anterior cingulate gyrus, medial

frontal cortex, and posterior cerebral areas involved

in visual and visual–spatial functions.61

The overlap of symptoms that military personnel

share with athletes who have CTE diagnosed at

autopsy has led to the postulation that combat veterans

diagnosed with neurologic and/or neuropsychiatric

conditions such as depression or PTSD may actually

have CTE. In support of this, Omalu et al. in a recent

paper report the case of a 27-year-old marine who had

committed suicide and had evidence of CTE on

autopsy. In a previous paper in 2010, Omalu et al.

had defined CTE as a ‘progressive neurodegenerative

syndrome caused by single, episodic, or repetitive blunt

force impacts to the head and transfer of acceleration-

deceleration forces to the brain’. The marine was an

Amphibious Assault Vehicle Crewman and had served

two deployments to Iraq. He reported multiple

exposures to mortar blasts and improvised explosive

device (IED) blasts less than 50 m away from him. He

was court-martialled twice during his second deploy-

ment for ‘acting out’, insubordination, and violence.

After his deployment, he returned to the US and

played football in a base league during which he

again suffered a hit on the side of the head without

loss of consciousness and he was never evaluated or

diagnosed with concussion. His colleagues noticed

that he was confused and disoriented and he reported

residual headaches and memory problems after this

episode.

Neuropsychological screening showed that he

forgot dates and conversations, was grumpy with

his family and lost his temper frequently. He had

trouble falling asleep, was irritable, uncomfortable

with crowds, had exaggerated startle reactions,

anhedonia, withdrawal and lack of engagement with

his family. From a general cognitive standpoint he

was found to be in the high average range for his age

and gender. His final diagnoses were an axis 1 of

PTSD with hyperarousal including irritability and

Lakis et al. Chronic traumatic encephalopathy

296 Neurological Research 2013 VOL. 35 NO. 3

insomnia with numbing and continuous alcohol

abuse. He was found hanging from a staircase by a

leather belt noose in his residence after his parents

had not heard from him for 2 days.

Gross neuropathological exam showed diffuse

parenchymal edema with very focal decompositional

change, without atrophy of the subcortical ganglia,

hippocampus, or thalamus, or any other gross

parenchymal gray or white matter lesions. In summary

the brain appeared normal as pertains to any acute or

chronic cerebral cortical contusional or ischemic

necrosis or hemorrhagic changes.

Microscopically, the frontal, parietal, temporal,

occipital, insular, and cingulate cortices showed the

expected columnar and laminar organization without

cortical disorganization or dysplasia. The periventri-

cular white matter revealed no leukomalacia or

subependymal astrogliosis; the substantia nigra, locus

ceruleus, and dorsal raphe nucleus were adequately

pigmented. No Marinesco bodies, pale bodies, or

Lewy bodies were seen. Immunohistochemical stain-

ing showed findings consistent with CTE. There were

frequent NFTs and neuritic threads found in sulcal

depths of the frontal cortex as well as in the parietal

cortex, temporal cortex, occipital cortex, and cingu-

late cortex. The frontal cortex contained the greatest

amount of tangles and threads as expected, as did the

entorhinal cortex, which showed moderate amounts

of flame-shaped NFTs and neural tangles. The

authors concluded that the gross, histological, and

immunophenotypical findings matched those they

had previously described in American athletes.62,63

Chronic Traumatic Encephalopathy and ApoEEpsilon4The correlation between ApoE epsilon4 genotypes and

CTE remains controversial. Established as a risk factor

for AD, it has not yet been accepted as a risk factor for

CTE.64,65 McKee et al. report 10 cases where ApoE

epsilon4 genotyping was included and they report that 5

out of the 10 cases carried at least one ApoE epsilon4

gene and one of their own cases was homozygous for

ApoE epsilon4.11 While evidence accumulates that

ApoE epsilon4 positive individuals suffer more from

TBI,66–68 contrary evidence supports the supposition

that severe TBI actually promotes AD in patients

lacking ApoE epsilon47,69 Whether a synergistic effect

exists between TBI and ApoE epsilon4 or no effect

exists, whether the two factors are indeed confounders

remains to be elucidated by further study.70

Chronic Traumatic Encephalopathy Diagnosisand Future ConsiderationsUnderstanding the neuropathologic basis of CTE is a

preliminary step. It is difficult at this stage to

definitively differentiate CTE from the other neuro-

degenerative disorders. In the workup of dementia,

patients are rarely asked about previous concussive

episodes. Patients who tend to present with chronic

headache and behavioral and psychiatric problems,

especially at a younger age, may benefit from being

diagnosed as having CTE. Nevertheless, CTE does

exist amongst older patients and the overlap between

the two diseases must be taken into account. Larger

prospective studies targeting vulnerable populations,

athletes, and war veterans need to be performed.38

There are also several non-invasive modalities that

may facilitate the diagnostic workup of CTE.

Magnetic resonance imaging (MRI) can help in the

diagnosis of CTE. In its least sophisticated form, it can

detect whole brain atrophy and fenestrations of the

cavum septum pellucidum.11 Resting state blood

oxygen level-dependent (BOLD) functional connectiv-

ity MRI (fcMRI) can determine differences between

AD and Lewy-body dementia.71 In a complex study of

high school football players, researchers used fMRI to

identify a group of multi-concussed athletes who had

no clinical symptoms of concussion but showed

neurophysiological disruptions of prefrontal cortex

and visual working memory. This suggests that

multiple concussions can cause sub-clinical changes

and alter function in the absence of any overt clinical

signs.72

Diffusion tensor (DT) imaging, a novel modality

that is sensitive to axonal injury allows the evaluation

of the effects of head trauma on white matter.

Matsushita et al. used DT imaging to investigate

where the white matter injury following mild to

moderate TBI is specifically located. DT imaging was

also used to examine the relationship between the

severity of the white matter lesion in the acute stage

of TBI and future cognitive function in the chronic

disease stage. Twenty cases and 27 matched controls

underwent conventional MR and DT imaging a

median of 3.5 days after injury. Eight different white

matter areas were studied, including the genu, stem,

and splenium of the corpus callosum and the corona

radiata, anterior limb of the internal capsule, poster-

ior limb of the internal capsule, frontal white matter,

and occipital white matter. The authors found that

DT imaging differences in the splenium and frontal

white matter in the acute stage of mild-to-moderate

TBI may be a useful prognostic factor for long-term

cognitive dysfunction.73

Magnetic resonance imaging susceptibility-weighted

imaging (SWI) is sensitive to brain micro-hemorrhages

that occur from head trauma.74 This is important

because abnormal tau proteins deposit perivascularly

and may be picked up by SWI before any clinical

symptoms are seen. SWI has been used in children to

predict future outcomes after TBI75 but the results in

adults have so far been inconclusive76 and more

research in this field is necessary.

Lakis et al. Chronic traumatic encephalopathy

Neurological Research 2013 VOL. 35 NO. 3 297

Magnetic resonance spectroscopy (MRS) may also

be used to measure human brain chemistry in vivo.

There have been a few studies that have measured

levels of glutamate, glutamine, and N-acetyl aspartate

in concussed athletes and they show that changes can

be documented, at least in the short term following

TBI but again, more and larger studies are required.77

ConclusionIn conclusion, prospective studies remain necessary at

this juncture in the research of CTE and its effects on

vulnerable populations. Currently, a comprehensive

neurological exam, neuropsychiatric assessment, and

standard radiographic techniques such as conven-

tional MRI are the mainstay of diagnosis. Novel

research into the pathophysiology as well as the use

of non-invasive imaging technologies may elucidate

this matter further and deepen our understanding of

what athletes and blast injury veterans are facing

from a neurological standpoint and help develop

therapies that may be of clinical use during their

lifetimes.

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