What is the evidence for chronic concussion-related
changes in retired athletes: behavioural,
pathological and clinical outcomes?
Paul McCrory,1Willem H Meeuwisse,2,3Jeffrey S Kutcher,4Barry D Jordan,5
▸ Additional data are
published online only. To view
this file please visit the journal
For numbered affiliations see
end of article.
Dr Paul McCrory, The Florey
Institute of Neuroscience and
Mental Health, Heidelberg,
VIC 3084 Australia;
Received 25 January 2013
Accepted 26 January 2013
To cite: McCrory P,
Meeuwisse WH, Kutcher JS,
et al. Br J Sports Med
Objective The purpose of this paper was to review the
current state of evidence for chronic traumatic
encephalopathy (CTE) in retired athletes and to consider
the potential differential diagnoses that require
consideration when retired athletes present with
cognitive and psychiatric problems.
Data sources MEDLINE, CINAHL, EMBASE, Mosby’s
Index, PsycEXTRA, PsycINFO and Scopus. Key words
included CTE, dementia pugilistica, punch drunk
syndrome, traumatic encephalopathy, CTE, repetitive
head injury, sports concussion, multiple concussions,
chronic concussions, subconcussive blow and sports-
related traumatic brain injury.
Results At present, there are no published
epidemiological, cross-sectional or prospective studies
relating to modern CTE. Owing to the nature of the
published studies, being case reports or pathological
case series, it is not possible to determine the causality
or risk factors with any certainty. As such, the
speculation that repeated concussion or subconcussive
impacts cause CTE remains unproven. The extent to
which age-related changes, psychiatric or mental health
illness, alcohol/drug use or coexisting dementing
illnesses contribute to this process is largely unaccounted
for in the published literature.
Conclusions At present, the interpretation of causation
in the modern CTE case studies should proceed
cautiously. The causal assumptions require further
prospective or longitudinal studies on the topic.
Considerable attention surrounds the potential for
long-term problems in athletes with high exposure
to head impacts during a career in collision sport.1
There is evidence2–4supporting an association
between long-term cognitive, neurobehavioural,
psychiatric problems and participation in sport.5
Given that sports-related concussion is a common
injury and that concussive or subconcussive blows
to the head or body are an inevitable consequence
of sports participation, if a causal relationship
between these impacts and later-life neuropsychi-
atric disease exists, then potentially an enormous
number of retired athletes would be at risk.6Based
on the published case studies, however, one esti-
mate is that fewer than 4% of retired US profes-
sional football players may be at risk for this
condition7rather than all exposed athletes, raising
the issue that this may not be a part of impact
exposure but rather due to other as yet unidentified
A recent report by McKee et al8has suggested
that chronic traumatic encephalopathy (CTE) may
represent a unique tauopathy with characteristic
pathological stages; however, the published meth-
odology does not allow a causal relationship to be
determined between concussion or subconcussive
impacts being a risk factor for CTE.
The purpose of this paper was to review the
current state of evidence for CTE in retired athletes
and to consider the potential differential diagnoses
that require consideration when retired athletes
present with cognitive and psychiatric problems.
Articles were retrieved via online database search-
ing, hand-searching reference lists and cited refer-
ence searches. The online databases of MEDLINE,
CINAHL, EMBASE, Mosby’s Index, PsycEXTRA,
PsycINFO and Scopus were searched. Key words,
MeSH terms and combinations of these were used
to systematically search the databases. Key words
included CTE, dementia pugilistica, punch drunk
syndrome, traumatic encephalopathy, CTE, repeti-
tive head injury, sports concussion, multiple con-
cussions, chronic concussions, subconcussive blow
and sports-related traumatic brain injury (TBI).
CLINICAL SYNDROMES OF LONG-TERM
PROBLEMS FOLLOWING CONCUSSION
The clinical characterisation of the presentations of
athletes with chronic postconcussive symptoms is
poorly defined and may reflect intrinsic differences
(eg, genetic) between individuals rather than the
oversimplified understanding that these syndromes
are due to concussive or subconcussive trauma
alone. In some cases, the persistent ‘postconcussive’
symptoms may, in large part, be due to unrecog-
nised depression or anxiety,9which may be labelled
as ‘overtraining’ or even athlete ‘burnout’.10
If we assume concussion is the acute clinical syn-
drome with 90–95% of cases recovering in less
than 10 days, then there is a small group where
prolonged postconcussive symptoms exist, that is,
where the symptoms persist more than 10 days
after a single episode of acute concussion (5–10%
of cases) but full recovery eventually ensues usually
within a matter of weeks.11The clinical and neuro-
psychological features are those of a resolving acute
injury and perhaps this entity should be considered
as part of the acute syndrome.
In addition to the acute syndrome, a number of
distinct but as yet poorly defined clinical subsets
exist that may shed light on the process of recovery
Scan to access more
McCrory P, et al. Br J Sports Med 2013;47:327–330. doi:10.1136/bjsports-2013-0922481 of 5
from concussive injury. These subsets are based on clinical
experience and are not supported by hard scientific evidence at
this time. Nevertheless, it may be useful to consider the full
spectrum of presentations of athletes with persistent or perman-
ent symptoms and the terminology of these states.
▸ Prolonged postconcussive symptoms as discussed above.
▸ Persistent postconcussion symptoms after one or more
concussions where recovery is slow and may take months
to years.12The DSM-IV criteria for Post Concussion
Syndrome is invoked only if the symptoms last beyond
3 months. Approximately 80% of such patients recover
fully with time.13Cognitive testing reveals mainly atten-
tional deficits, and structural neuroimaging is normal.
▸ Permanent PCS—as per above, but these individuals do
not recover fully, and this has been estimated at between
10% and 20% of all cases of persistent concussion symp-
toms. Functional MR and/or electrophysiological change
may be present, but normal structural neuroimaging is
▸ Proposed CTE where chronic cognitive and/or neurobeha-
vioural dysfunction exists and a pathological diagnosis is
subsequently confirmed.3 6It is worth noting that there
are cases where the clinical phenotype is the same as
pathologically confirmed CTE cases; however, no neuro-
pathological change is demonstrated at autopsy.8
As well as these broad categories, there are other athletes who
de novo manifest mental health issues (depression, anxiety,
suicide) or neurobehavioural problems in the absence of persist-
ent or prolonged concussive symptoms dating from the time of
an injury. Whether these represent a variant of the subsets above
or simply reflect the high incidence of such disorders in society
remains to be elucidated. The risk factors for such complications
following concussion remain unclear, although they may be
related to repeated concussions, at least in retrospective
surveys.2 15Prospective studies of head-injured individuals, with
neuropathological and clinical verification, are needed to
improve understanding of head trauma as a risk factor for
As well as clinical symptoms, there is some limited objective
evidence of persistent neurophysiological, cognitive16and radio-
logical17deficits up to 30 years following concussion.
PHYSIOLOGY OF CONCUSSION
Understanding the pathophysiology of concussion would be
expected to lead to an improvement in the assessment of deficit
and recovery following injury, and to facilitate the accurate clas-
sification of severity. For example, little is known about the ana-
tomical localisation of common clinical features such as
headache, loss of consciousness (LOC), difficulty with concen-
tration, sleep disturbance and fatigue. Moreover, it is currently
unknown whether mild TBI reflects a single clinical entity with
a linear spectrum of injury or even distinct injury subtypes. It is
hoped that this understanding may give some insight into
whether in vivo diagnosis of CTE is possible.
In animal models following acute injury, the release of neuro-
transmitters and ionic fluxes occurs (known as the ‘neurometa-
bolic cascade’),18which in turn leads to changes in cell
membrane function. Animal studies suggest that, during the
glucose metabolic depression phase (1–10 days postinjury), the
brain is more vulnerable to repeat injury.18Changes in the intra-
cellular fluid status or the presence of axonal swelling may be
detected using imaging techniques such as advanced diffusion
weighted imaging (DWI), which also allow mapping of white
matter fibre tracts in the central nervous system.19Preliminary
studies have demonstrated DWI changes in the acute setting fol-
lowing mild TBI in a small cohort of adolescent patients with
normal CT scans as well as in a cohort of asymptomatic profes-
example, functional MRI (fMRI) have demonstrated changes in
brain function following sport-related TBI.21The main limita-
tion of this technique is that it only reveals regions of the brain
that are active in the specific cognitive task being studied.
Another imaging modality, Functional Connectivity, is able to
detect realtime resting state networks and may provide an alter-
native to fMRI for identifying brain subregions and networks
that are affected in mild TBI.22Other techniques such as MR
spectroscopy (MRS) allow the detection of metabolic distur-
bances following mild TBI through the measurement of intracel-
lular metabolites. Preliminary studies in a small cohort of
collegiate athletes suggest a role of mitochondrial dysfunction in
the postinjury metabolic depression.23Other studies using MRS
have also demonstrated that the N-acetylaspartate/creatine ratio
(which reflects neuronal cell damage) is related to injury severity
and outcome even when white matter appears normal on
DEMENTIA RATES IN THE GENERAL POPULATION
Given that cognitive impairment is one of the key features of
the proposed CTE, it is important to understand the risk of this
in similar age groups in the general population. The reported
incidence and prevalence rates of dementia vary according to
the population studied, and prevalence approximately doubles
every 5 years from the age of 65 years. The incidence of demen-
tia (all causes) in the 30-year-old to 64-year-old group is 54/
100 000, and for the 45-year-old to 64-year-old group, it is
Whether mild, or repetitive mild TBI (mTBI) increases an
individual’s risk for developing Alzheimer’s disease (AD) has
been a long-standing topic of contention. While mixed results
have been reported regarding the association between moderate
and severe TBI and AD, the association between mTBI and AD
appears to be less strong. For example, in a systematic review,
Bazarian et al26concluded that there was limited support for
the notion that mTBI (with LOC) results in an increased risk for
later life AD. Further, the authors also concluded that there was
insufficient evidence to determine whether an association
between mTBI (without LOC) and AD exists.
DEPRESSION IN THE GENERAL POPULATION
Depression and cognitive impairment are both common condi-
tions in older age, and they frequently occur together.
A US-based epidemiology study examining major depression
reported that the incidence of this disorder in men aged 25–34,
35–44 and 45–54 years was 12.3%, 11.0% and 8.6%, respect-
ively.27This is much higher among individuals with dementia,
where it has been reported that 25–50% of all patients with
dementia will develop depression at some point over the course
of their illness.28 29
DEPRESSION, COGNITIVE IMPAIRMENT AND
NEURODEGENERATIVE DISEASES IN FORMER ATHLETES
In a study of retired National Football League (NFL) players,
responses to questions regarding clinical depression revealed
that 269 (11.1%; 95% CI 9.9% to 12.3%) of 2434 respondents
reported a previous diagnosis of clinical depression. In compari-
son to retired NFL players with no history of concussion,
retired players with a history of one or two previous
2 of 5McCrory P, et al. Br J Sports Med 2013;47:327–330. doi:10.1136/bjsports-2013-092248
concussions were 1.5 times more likely to be diagnosed with
depression, while those with a history of three or more previous
concussions were found to be three times more likely to be diag-
nosed with depression.15
The results of a screening survey of 513 retired NFL players
(average age=61 years) reported that 35% produced scores sug-
gesting a possibly mild cognitive impairment.2In another recent
study of former NFL players, the death rate from neurodegen-
erative diseases was three times greater than that of the general
population, although the number of cases in this study was
small. More specifically, the rates of diagnosis of AD and amyo-
trophic lateral sclerosis (ALS) were found to be four times
higher in former NFL players than the general population.30Of
the 334 former athletes in this cohort, seven (2.1%) had ALS
listed on their death certificates. This issue of ALS is in keeping
with the TDP43 tauopathy seen in CTE cases.31
BRAIN PATHOLOGY IN NORMAL AGEING
The Honolulu-Asia Aging Study provides a unique longitudinal
model of ageing and disease and offers considerable insight into
what may be considered normal ageing from a pathological
standpoint.32From 1991 to 1993, 3 yearly follow-up clinical
and formal neuropsychological examinations have been con-
ducted in 3508 men who were free of dementia and a total of
593 standardised brain autopsies have been conducted.32
Postmortem brain examination demonstrated diverse path-
ology, even in individuals clinically diagnosed as ‘pure AD,’ with
fewer than 50% demonstrating the typical pathological features
of AD. Furthermore, neuropathological abnormalities were also
observed in approximately 40% of neuropsychologically normal
patients.32–34Similarly, disparity between clinical presentation
(ie, living diagnosis) and postmortem neuropathology has also
been demonstrated in other ageing study samples.35 36It is now
clear from these ageing studies that postmortem findings may
not represent pathology and may not equate to clinical sympto-
mology or a syndrome37and may be seen in cognitively normal
older adults. Whether the ‘gold standard’ of neuropathology in
neurological disease is true has been recently questioned.38
THE ‘CLASSIC’ SYNDROME OF CTE IN PROFESSIONAL
In 1928, Dr Harrison Martland first described the ‘punch
drunk’ or CTE state in retired boxers.39The incidence of classic
CTE has proven difficult to establish, due, in the main, to a lack
of prospective studies. Roberts,40who randomly sampled 250
retired boxers from a cohort of 16 781 UK boxers registered
between 1929 and 1955, reported that in 37 boxers (17%) clin-
ically demonstrable lesions of the nervous system were present.
Notably, the oldest boxers in this cohort fought in the late
1800s, in an era where bare-knuckle championships were still
conducted, frequent fights occurred even when boxers were
concussed and there was little medical supervision or weight
matching of boxers; however, only 11 of the 37 cases were ela-
borated on in this study. A close analysis of the clinical details
raises suspicion regarding the certainty of the diagnosis of CTE
in most cases.41
In the published cases, cognitive deterioration was typically
detected 10–20 years subsequent to cessation of exposure to
repetitive head trauma (ie, postretirement).6Interestingly, in all
cases where details were provided, the physical signs but not the
cognitive deficits progressed postretirement. There are two dis-
tinct clinical syndromes that have been demonstrated in this
data set; the first (which occurs in approximately 70% of cases)
includes dysarthria, pyramidal problems and cognitive deficits.
As the disease manifests clinically, these cognitive abnormalities
include difficulties in memory, information processing speed,
insight and orientation. The second clinical syndrome (in
approximately 30% of cases) includes dysarthria and pyramidal
problems, but with intact cognitive abilities.40 42–44Movement
disorders were reported to be present in approximately two in
every five reported cases.3
One of the difficulties of ascribing the clinical syndrome
solely to boxing is the presence of comorbidities plus risk
factors for other conditions that may also result in cognitive
deterioration. A case report of a champion boxer with cognitive
decline highlights these issues of multifactorial causation of cog-
The neuropathological features of classic CTE have been
described in detail46and typically result in a cavum septum pel-
lucidum with septal fenestration; cerebellar scarring involving
Purkinje cell loss and thinning of the granular layer; degener-
ation of the substantia nigra and locus caeruleus; and diffuse
neurofibrillary tangles (NFT) involving the medial temporal
region, uncus, amygdala, hippocampus, parahippocampal gyrus
and fusiform gyrus along with the more lateral temporal, insular
and frontal cortices. The extent of neuropathology appears
to be positively correlated with the level of exposure.46
Roberts et al44examined 14/15 brains originally described by
Corsellis et al,46as well as six additional boxers’ brains using
immunocytochemistry, and 19/21 cases also demonstrated wide-
spread diffuse amyloid deposits.
Recently, a propagation model of neurodegeneration has been
proposed, suggesting that tau positive NFT phosphorylation
may progressively spread from one neuron to adjacent neurons
in the absence of ongoing triggering factors.47–50The implica-
tion of this finding is that the neuropathological findings may
differ or progress in different stages of the condition. This
finding may help resolve the differences between reports of spe-
cific sites of tau positive NFT deposition in CTE and other
studies that suggest widespread changes.
THE ‘MODERN’ SYNDROME OF CTE IN FOOTBALLERS
Recent publications3 51on CTE in retired athletes have intro-
duced a number of conceptual changes in the clinical fea-
compared with the classic entity described by Roberts40and
Corsellis et al46in their boxing subjects.
53and outcomes, and also the neuropathology, as
PUBLISHED MODERN CTE CASES
A number of cases of CTE in retired athletes have been pub-
lished. The index case was reported by Omalu and colleagues in
2005, with additional cases reported subsequently.4 51 54–56
Recently, the Boston University group published their experi-
ence of CTE, with 80 athlete brain donors (22 of whom were
also military veterans) with a history of repetitive brain injury,
and they found that 80% of these cases demonstrated the char-
acteristic pathology for CTE.8
Signs and symptoms
The modern CTE description suggests that symptoms such as
gait disorders, speech slowing and extrapyramidal signs may be
present; however, neuropsychiatric and behavioural symptoms
tend to predominate early.57The most common symptoms
reported are mood disorder (mainly depression), paranoia, agi-
tation, social withdrawal, poor judgement and aggression.
Cognitive impairment tends to emerge as the major neuro-
psychiatric feature in the latter stages58 59and typically includes
McCrory P, et al. Br J Sports Med 2013;47:327–330. doi:10.1136/bjsports-2013-0922483 of 5
language, attention, information processing speed and executive
functioning.60These cognitive symptoms have been proposed to
progress in a somewhat predictable manner,3whereas the classic
CTE entity reported little progression of cognitive deficits.46
The reported neuropathological characteristics of both entities
(classic and modern CTE) appear to be more closely related and
share a number of common features such as fenestrated septum
pellucidum, cerebral atrophy, tau+NFT inclusion (although
found in greater amounts in modern CTE), β-amyloid depos-
ition (found in less amounts in modern CTE), reduced pigmen-
tation of the substantia nigra and locus caeruleus, and enlarged
ventricles. The qualitative description of modern CTE charac-
terises the neuropathological change as also including fronto-
temporal lobe atrophy with extensive tau pathology distributed
throughout the neocortex, medial temporal lobe, diencephalon,
brainstem and spinal cord. In the 51 cases reviewed by Gavett
et al7 61diffuse amyloid plaques were found in 24 (47%), neur-
itic amyloid plaques in 13 (27%) and amyloid angiopathy in
3 (6%). In the Boston study,8amyloid deposition was noted in
44% of the CTE cases.
Although a number of similarities in neuropathological find-
ings have been reported across the modern CTE cases, there are
also some important differences. McKee et al3have reported a
marked accumulation of tau-immunoreactive astrocytes, but
this has not been observed in any of the cases examined by
Omalu et al.62
Omalu et al63
phenomenon, with a propensity to lobar cortical distribution in
the absence of prominent periventricular topographic distribu-
tion, which has not been described in the McKee et al3cases.
A defining neuropathological feature of the modern CTE
entity is abundant filamentous tau lesions, of which the patterns
of expression are considered unique, occurring in the absence
(or at least relative scarcity) of β-amyloid deposits.3 8Prominent
filamentous tau inclusions and brain degeneration in the absence
of β-amyloid deposits are also considered the sine qua non of a
number of neurodegenerative tauopathies. It is worth noting
that a number of the degenerative tauopathies, such as behav-
ioural variant fronto-temporal dementia, share many of the clin-
ical and pathological features of ‘modern’ CTE.64–69
have reported the skip-
The recent autopsy cases differ from the classic CTE description
across a number of characteristics including age of onset, pro-
gression, assumed predominate (clinical) features and diagnostic
criteria. It has also been reported that these recent cases of
modern CTE, speculated to be a consequence of concussive and
subconcussive blows, are characterised by a distinct neuropatho-
logical profile3 61 63and manifest primarily as a tauopathy.8
Although many of the reported macroscopic neuropathological
features are common among the original and newer descriptions
of CTE, the different distribution of tau-immunoreactive astro-
cytes distinguishes the newer description with preferential
involvement of the superficial cortical layers occurring on a
background of relative scarcity of β-amyloid plaques.
At present, there are no published epidemiological, cross-
sectional or prospective studies relating to modern CTE. Owing
to the nature of the published studies, being case reports or
pathological case series, it is not possible to determine the caus-
ality or risk factors with any certainty. As such, the speculation
that repeated concussion or subconcussive impacts cause CTE
The extent to which age-related changes, psychiatric or
mental health illness, alcohol/drug use or coexisting dementing
illnesses contribute to this process is largely unaccounted for in
the published literature. In addition, consideration for the
potential genetic risk in those athletes with a family history of
neurodegenerative disease and the extent to which this contri-
butes to the clinical and pathological profiles also require
At present, the interpretation of causation in the modern CTE
case studies should proceed cautiously. The causal assumptions
require further prospective or longitudinal studies on the topic.
Ultimately, scientific research might establish that participation
in contact sports leads to a distinct neuropathological syndrome,
and this neuropathology causes psychiatric, cognitive and phys-
ical problems, but this cause and effect relationship remains to
be shown scientifically.
1The Florey Institute of Neuroscience and Mental Health, Heidelberg, Australia
2Faculty of Kinesiology, Sport Injury Prevention Research Centre, Calgary, Alberta,
3Faculty of Medicine, Hotchkiss Brain Institute, University of Calgary, Calgary,
4Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA
5Burke Rehabilitation Hospital, White Plains, New York, USA
6Neuropsychiatry Service, HNE Mental Health Service, Newcastle, New South Wales,
Competing interests See the supplementary online data for competing interests
Provenance and peer review Commissioned; internally peer reviewed.
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