REVIEW

CURRENT
OPINION Chronic traumatic encephalopathy: understanding
the facts and debate
Christian LoBue a,b, Jeff Schaffert a, and C. Munro Cullum a,b,c

Purpose of review
Chronic traumatic encephalopathy (CTE) is hypothesized to be a progressive neurodegenerative disease
leading to dementia after repetitive head impacts. This review summarizes the recent evidence on CTE to
highlight the facts currently known and the areas that remain poorly understood.
Downloaded from http://journals.lww.com/co-psychiatry by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8K2+Ya6H515kE= on 03/16/2022

Recent findings
Increasing evidence suggests that many of the prior assertions about CTE in relation to repetitive head
trauma are premature. First, CTE lesions have been observed in individuals with no history of head
trauma/impacts. In addition, attempts to characterize possible clinical markers of CTE have had several
shortcomings, notably an absence of detailed clinical assessments during life, vague/nonspecific symptom
reports, and crude methodology. Moreover, recent studies demonstrate that current CTE pathological
criteria have limitations and are in need of refinement/validation.
Summary
CTE is still in the early stages of research as a neuropathological condition and no specific clinical criteria
exist. Claims about CTE being a progressive disease entity and caused exclusively by head trauma/
impacts are not well supported at present. Such assertions may have impeded our understanding of the
frequency and significance of this disorder. Refining diagnostic criteria to reduce ambiguity in classifying
cases will be essential before risk factors and/or possible clinical markers may be identified.
Keywords
concussion, dementia, traumatic brain injury, traumatic encephalopathy

INTRODUCTION 12 years and older (N ¼ 127) [4]. However, several

A diagnosis of chronic traumatic encephalopathy other studies have failed to support an association
(CTE) currently requires postmortem identification between age when beginning sport and the later
of a solitary phosphorylated tau aggregate in an development of cognitive/behavioral symptoms
& &

irregular pattern in neurons, astrocytes, or cell pro-
cesses around small blood vessels at the depths of
cortical sulci [1]. To date, it appears that only approx-
imately 300 cases with CTE have been reported in the
scientific literature. Dementia has been attributed to
the presence of CTE lesions based on a wide-array of
cognitive, behavioral, and emotional symptoms
described by next of kin in several CTE convenience
samples [2,3]. Brain injury and repetitive head
trauma, so-called ‘subclinical’ impacts received dur-
ing contact sport, have been claimed to lead to the
development of CTE and consequently dementia [3].
There are even reports that earlier participation in
contact sport is associated with an earlier develop-
ment of symptoms believed to relate to CTE. A recent
study of former professional football players with
CTE (N ¼ 211) suggested symptoms reportedly began
13 years earlier for those who started playing before
the age of 12 years (N ¼ 87) compared with those
[5,6 ,7 ]. Nonetheless, the claims about CTE have
made their way into public awareness and become
widely accepted, persuading many to focus on ways
to avoid developing CTE and/or seek restitution
because of an assumed relationship between CTE
and head trauma. For example, the public’s percep-
tion of CTE has contributed to some parents restrict-
ing their children from playing certain sports, local
agencies limiting sports programs to those age
12 years and older, and class action lawsuits being
a
Department of Psychiatry, bDepartment of Neurological Surgery, and
c
Department of Neurology and Neurotherapeutics, University of Texas
Southwestern Medical Center, Dallas, Texas, USA
Correspondence to Christian LoBue, PhD, 5323 Harry Hines Blvd.,
Dallas, TX 75390-8846, USA. Tel: +1 214 648 4604;
fax: +1 214 648 4660; e-mail: Christian.lobue@utsouthwestern.edu
Curr Opin Psychiatry 2020, 33:130–135
DOI:10.1097/YCO.0000000000000580

www.co-psychiatry.com Volume 33  Number 2  March 2020

Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.


KEY POINTS
 Neuropathological abnormalities may not be
associated with cognitive decline, and the scientific
community is moving towards isolating
neuropathological definitions from possible
clinical markers.
 Recent studies illustrate that ambiguity and lack of a
lower threshold in CTE pathological diagnostic criteria
can lessen reliability/validity in CTE diagnoses.
 The neuropathological changes associated with CTE
are not unique to individuals with a history of head
trauma/impacts.
 CTE often co-occurs in the context of other
neuropathological conditions.
 Refinement and validation of CTE pathologic diagnostic
criteria are needed before risk factors and/or clinical
markers can be appropriately studied.
filed against various organizations/institutions when
cognitive difficulties manifest years after contact
sports participation [8–10]. Although CTE is report-
edly associated with dementia and brain trauma,
there is significant disagreement within the scientific
community because of contradictory findings,
uncertainty about the sensitivity/specificity of CTE
pathological lesions, lack of scientific rigor in many
CTE studies, and overinterpretation of correlational
findings. The purpose of this review is to highlight
the current facts and topics of debate relating to CTE,
discuss recent scientific advances that serve to better
understand its implications, and underscore the need
for future research.
PROBLEM WITH DEFINING CHRONIC
TRAUMATIC ENCEPHALOPATHY AS A
NEURODEGENERATIVE DISEASE
Two opposing perspectives exist about CTE and
how to define it. Some believe CTE is a progressive
neurodegenerative disease with specific neuropath-
ologic findings and neurobehavioral correlates. The
flip side is that CTE is merely a neuropathological
condition with no relation to a clinical syndrome
or degenerative process. Assertions that CTE is a
neurodegenerative entity are based on retrospective
descriptions of a gradual decline in cognitive/
behavioral functioning from next of kin in those
identified with CTE postmortem [2]. Interestingly,
earlier diagnoses of dementia have become increas-
ingly common overall, with a push in the scientific/
clinical community to identify and track those who
are likely to manifest neurodegenerative disease.
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Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.
Chronic traumatic encephalopathy LoBue et al.
However, information from detailed clinical assess-
ments during life documenting a progressive
decline has yet to be published in those later rec-
ognized with CTE. This is a puzzling phenomenon
in today’s era, and allows for ambiguity in report-
ing the hypothesized clinical effects of CTE, as
inconsistencies between perceived impairments
and measured neuropsychological functioning
often exist. For instance, a recent study compared
neuropsychological functioning of former profes-
sional football/hockey athletes to age-matched
&
athletes from a noncontact sport [11 ]. Although
the football/hockey athletes rated themselves as
having impairments in cognitive functioning, this
was not actually substantiated with neuropsycho-
logical data. Furthermore, the largest systematic
study to date in individuals with possible CTE
was completed by Roberts nearly 50 years ago,
wherein he found many former boxers had motor
symptoms and cognitive deficits that did not prog-
ress [12]. Thus, assertions about CTE’s implications
during aging appear to be premature and based on
minimal evidence.
Doubt for CTE being a progressive neurodegen-
erative disease is further raised from the fact that
many individuals with CTE often have other co-
occurring neuropathological processes. Alzheimer’s
&
disease [13], Lewy body disease [14 ], cerebrovascu-
& &
lar changes [15 ], Creutzfeld–Jacob disease [16 ], and
other well known conditions have frequently been
found in individuals with CTE, which would be
expected to cloud a potential association CTE may
have with aging, if any. Oddly, the effects of these
processes have largely been downplayed or ignored
in many prior studies, with cognitive/behavioral
declines attributed to CTE rather than the other
and better understood comorbid pathological pro-
cesses. Ideally, a reversed approach should be taken,
wherein co-occurring processes are presumed to
carry the weight in producing cognitive deteriora-
tion in aging over that of CTE. A recent review by
&&
Brett et al. [17 ] detailed the lack of scientific rigor in
previous attempts to link CTE pathological changes
with a clinical presentation. The authors highlight
that previous studies relied on simple observations
that lacked appropriate statistical paradigms, cau-
tioning that these do not offer any information
about the sensitivity/specificity of CTE pathological
lesions in producing symptoms. There is a clear need
for a sophisticated attempt to correlate CTE patho-
logical changes with clinical assessments in individ-
uals with CTE alone, as well as in individuals with
CTE and co-occurring neuropathological processes.
Such an approach would avoid confirmatory bias
and allow for a more clear understanding of CTE’s
implications during aging.
www.co-psychiatry.com 131
Neurocognitive disorders
REASONS FOR DEFINING CHRONIC
TRAUMATIC ENCEPHALOPATHY AS A
NEUROPATHOLOGICAL CONDITION ONLY
Defining CTE solely as a neuropathological condition
with no link to being a degenerative disease should
become the standard until robust evidence is avail-
able. Numerous case studies show that differences
exist between neuropathology and clinical presenta-
tions prior to death. For example, neuropathological
abnormalities at autopsy have been reported in as
many as 40% of cognitively normal older individuals
[18], including a small percentage (8%) of those
with severe Alzheimer’s neuropathology [19]. The
presence of phosphorylated tau aggregates, as seen
with CTE, have previously been posited to cause an
extremely wide-array of nonspecific symptoms,
but in some CTE cases, cognitive functioning has
even been reported to be normal [13,20]. Herein, a
causal relationship between phosphorylated tau and
cognitive/behavioral symptoms has not been estab-
lished. Interestingly, aging-related tau astrogliopathy
(ARTAG) is a neuropathological condition identified
within the past few years that commonly occurs in
aging brains, neurodegenerative disorders, and even
those with CTE [20]. However, although there have
been questions about cognitive decline with ARTAG,
it is currently only defined as a pathological entity
because of minimal evidence. It would seem reason-
able to treat CTE similarly, especially as there have
been prominent movements to separate pathological
definitions from possible clinical consequences for
other more common neuropathological conditions,
such as Alzheimer’s disease [21].
LACK OF A CLEAR NEUROPATHOLOGICAL
THRESHOLD FOR CHRONIC TRAUMATIC
ENCEPHALOPATHY
Classifying CTE using the pathological diagnostic
criteria developed in 2016 out of an initial consen-
sus meeting (the only such meeting to date) has
proved challenging and highlighted several impor-
tant limitations. For instance, several scientists have
&& &&
found ambiguity in classifying CTE [22 ,23 ,24],
owing to a lack of a clear threshold when small
amounts of phosphorylated tau are seen that do
not meet other criteria. As CTE is currently consid-
ered an ‘all-or-nothing’ diagnosis (present versus
absent), there is potential for CTE to be overdiag-
nosed in individuals with very few CTE-like lesions.
Along these lines, CTE has been reported to be
common in individuals with prior participation in
football, ranging from 64 to 99% of individuals who
played beyond the high school level (college, semi-
professional, and professional) [2]. Although these
percentages sound high (which likely have led many
132 www.co-psychiatry.com
Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.
to assume contact sports will result in CTE),
the frequency of CTE has been much lower in more
recent studies that more clearly document the
number of cases having some CTE features without
&&
meeting full neuropathologic criteria [23 ,24]. For
&&
example, a recent investigation by Bieniek et al. [23 ]
assessed CTE pathological lesions in 750 individuals,
300 of whom were blindly identified to be former
athletes of contact sports after reviewing public
records (online obituaries and high school year-
books). Less than 6% of all individuals were found
to have CTE pathological features, whereas less than
3% actually met full CTE neuropathological criteria.
Furthermore, among the 15 former athletes who
played football beyond the high school level, 7
had some CTE features, but only 3 were actually
diagnosed with CTE neuropathologically. CTE then,
appears to not only be far less common than previ-
ously suggested, but there is increasing data calling
into question when a neuropathological diagnosis of
CTE should be considered definite or meaningful.
Moreover, there has only been one reliability study of
the diagnosis of CTE, and notably, neuropathologists
disagreed in 22% of CTE cases considered being
&&
moderate/severe [25 ]. Taken together, refine-
ment/validation of CTE pathological criteria is
needed, wherein a lower bound threshold is devel-
oped, ambiguity is measured objectively, and robust
reliability studies are completed.
EFFECTS OF CHRONIC TRAUMATIC
ENCEPHALOPATHY VERSUS
ALTERNATIVE EXPLANATIONS
Clinical symptoms of ‘modern’ CTE (i.e. 2005
onward) have been reported to include depression,
anger/irritability, explosivity, suicidality, substance
use, apathy, headaches, motor abnormalities, and
cognitive decline based on postmortem case reviews
[2,13,26,27]. Four diagnostic frameworks have been
published (most recently in 2016), all of which
involve degrees of clinical certainty (e.g. possible,
probable, definite) based on clinical symptomatology
[28–31]. However, each of these include a wide range
of cognitive, psychiatric, and motor symptoms that
vary in specificity and the domains of cognitive
impairment, disease course, degree of head injury
exposure, and symptom duration required for diag-
nosis. Additionally, these criteria were developed
exclusively using retrospective descriptions from
next of kin in those with CTE pathological lesions,
which is problematic for a number of reasons. First,
many of CTE’s purported symptoms are broad and
highly nonspecific. It would seem that physical,
emotional, and/or cognitive ailments could be
attributed to CTE when other factors, including
Volume 33  Number 2  March 2020

non-neurological explanations, may be the actual
source. Along these lines, depression is common in
middle-aged men and many stressful life events and
health problems may be associated with depression/
suicidality, suggesting a complex multifactorial psy-
chological process [32]. Second, a causal direction of
symptoms is unknown. For example, it is unknown if
depression/apathy is the result of CTE pathological
lesions, or related to potential functional decline,
adjustment to life stressors (e.g. retirement from
professional sports), or even other symptoms attrib-
uted to CTE (e.g. substance abuse). Though as it
stands currently, much of the research appears to
assume that any symptom found in those with
CTE pathological lesions is inevitably associated with
the neuropathology. In fact, a literature review on
numerous case series used to develop clinical criteria
consisted of at least 18 behavioral features, 16 mood/
psychiatric features, 12 cognitive features, and 10
motor features, encompassing 56 possible features
of CTE [30]. Others have suggested reasonable alter-
native explanations for these wide-ranging features.
A recent study found that 5% of middle aged men in
the general population often feel angry and 11%
endorsed they would hit someone if provoked, sug-
gesting that anger and aggression can also occur in
&&
middle-aged men [33 ], and may be even more
common in retired professional athletes who have
engaged in a lifelong history of aggressive sports.
Finally, the current hypothetical clinical framework
of CTE differs from historical observations of CTE in
two major ways. First, motor symptoms are often not
considered a core criterion in ‘modern’ CTE, found in
only about one-third of cases with CTE and never the
initial feature [26]. In contrast, motor abnormalities
were very frequent and often the initial presentation
in older reports of former boxers [34]. Second,
‘modern’ CTE has been posited as a progressive
tauopathy, which contrasts Roberts’ detailed 1967
in-vivo examination of boxers that suggested a stable,
nonprogressive course [12]. Importantly, no diagnos-
tic framework has been clinically accepted and there
has not been a single validation study to determine if
any of these clinical features are reliably associated
with CTE pathological lesions or differentiate CTE
from other neurodegenerative diseases.
CAUSE OF CHRONIC TRAUMATIC
ENCEPHALOPATHY
CTE is claimed to occur as a result of brain injury and
repetitive head impacts. Interestingly, a recent study
re-examined brain tissue from 14/15 retired boxers
previously described as having punch-drunk syn-
drome, one of the earliest descriptions of CTE
&
[35 ]. Only 7 of 14 cases were found to have CTE,
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Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.
Chronic traumatic encephalopathy LoBue et al.
which also co-occurred with ARTAG. On the basis of
the findings, it is reasonable to assume that brain
injury/repetitive head impacts alone may not be
sufficient to cause CTE. This position is becoming
well supported, as a growing number of case studies
are finding CTE in individuals with no history of head
trauma/impacts. For instance, a detailed review of
medical records and surveys with next of kin were
completed in a small sample with CTE to determine
&&
the frequency of head trauma [22 ]. Of the six cases
with CTE, only one had a history of head impacts.
Another study assessed for CTE among 18 former
military members between the ages of 32 and 94,
with 3 having a history of head trauma and/or blast
&&
exposure [36 ]. In this investigation, no cases were
identified as having CTE pathological lesions. An
increasing number of studies are also identifying
CTE pathological lesions in subjects with a wide-array
of neurological/psychiatric conditions and no
history of brain injury/repetitive head impacts,
including those with a history of alcohol use disorder
[24], opioid/other substance use [37], schizophrenia
with surgical leucotomy [38], temporal lobe epilepsy
[39], amyotrophic lateral sclerosis [40], and multiple
system atrophy as well as other neurodegenerative
disorders [41]. These findings illustrate that CTE does
not appear to be unique to brain injury and/or head
impacts, and further suggests that prior reports of
a clear link between CTE and head trauma were
premature. Thus, there is now mounting evidence
showing a disconnect between the public’s percep-
tion about developing CTE following participation in
contact sports and the actual data.
CONCLUSION
Recent studies demonstrate that CTE is currently
not well understood and remains in the very early
stages with regard to being a clinical condition.
Many claims about CTE, such as it being a progres-
sive neurodegenerative disease, an ‘all-or-nothing’
process, producing cognitive/behavioral changes,
and directly or solely tied to head trauma/impacts,
have generally not been well supported in the
scientific literature. In fact, such assumptions/
assertions may have impeded our understanding
of the significance of CTE pathological changes.
Moving forward, studies should revert to defining
CTE as a neuropathological condition and aim
efforts towards refining/validating diagnostic crite-
ria. Establishing criteria that are on a continuum,
similar to other well known neuropathological con-
ditions, and involving a lower bound threshold for
recognizing CTE is clearly needed to advance its
understanding. For example, moving to a scale com-
parable with what is now used in Alzheimer’s disease
www.co-psychiatry.com 133
Neurocognitive disorders
and Lewy body disease, such as a ‘no’, ‘low’, or ‘high’
likelihood for the presence of the condition [42],
would seem appropriate and likely yield a better
understanding of CTE in future research. Once this
stage has been reached, attempts to identify various
risk factors (genetic as well as environmental) that
may be related to CTE may yield greater success and
serve to further needed research in this area. Fur-
thermore, an updated framework for classifying CTE
may aid future efforts in characterizing the impli-
cations of CTE during aging. Much is still to be
learned about CTE, but efforts to re-focus on
enhancing reliability/validity of the pathological
diagnostic criteria is a critical first step.
Acknowledgements
None.
Financial support and sponsorship
Financial support for this work was provided in part by
the Texas Alzheimer’s Research and Care Consortium
(TARCC) and The Texas Institute for Brain Injury and
Repair (TIBIR) in the O’Donnell Brain Institute at UT
Southwestern Medical Center.
Conflicts of interest
There are no conflicts of interest.
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Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.
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