Handbook of Clinical Neurology, Vol.

167 (3rd series)

Geriatric Neurology
S.T. DeKosky and S. Asthana, Editors
https://doi.org/10.1016/B978-0-12-804766-8.00018-2
Copyright © 2019 Elsevier B.V. All rights reserved

Chapter 18

The long-term consequences of repetitive head impacts:

Chronic traumatic encephalopathy

MICHAEL L. ALOSCO1 AND ROBERT A. STERN1,2*

1
Boston University Alzheimer’s Disease and CTE Centers, Department of Neurology, Boston University School of Medicine,
Boston, MA, United States
2
Departments of Neurosurgery, and Anatomy & Neurobiology, Boston University School of Medicine, Boston, MA, United States

Abstract
Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to
repetitive head impacts (RHI). Although described in boxers for almost a century, scientific and public
interest in CTE grew tremendously following a report of postmortem evidence of CTE in the first former
professional American football player in 2005. Neuropathologic diagnostic criteria for CTE have been
defined, with abnormal perivascular deposition of hyperphosphorylated tau at the sulcal depths as the
pathognomonic feature. CTE can currently only be diagnosed postmortem, but clinical research criteria
for the in vivo diagnosis of CTE have been proposed. The clinical phenotype of CTE is still ill-defined
and there are currently no validated biomarkers to support an in-life diagnosis of “Probable CTE.” Many
knowledge gaps remain regarding the neuropathologic and clinical make-up of CTE. An increased under-
standing of CTE is critical given the millions that could potentially be impacted by this disease. This chap-
ter describes the state of the literature on CTE. The historical origins of CTE are first presented, followed by
a comprehensive description of the neuropathologic and clinical features. The chapter concludes with
discussion on future research directions, emphasizing the importance of diagnosing CTE during life to
facilitate development of preventative and intervention strategies.

Chronic traumatic encephalopathy (CTE) is a distinct
neurodegenerative disease associated with a history of
exposure to repetitive head impacts (RHI), such as those
incurred by contact sport athletes and military veterans
(McKee et al., 2013, 2016; Bieniek et al., 2015; Ling
et al., 2017; Mez et al., 2017; Tagge et al., 2018;
Falcon et al., 2019; Stern et al., 2019). Chronic traumatic
encephalopathy may be a major public health concern;
however, the epidemiology of CTE remains unknown
because this disease can currently only be diagnosed
postmortem using recently defined neuropathologic
diagnostic criteria (McKee et al., 2016). Chronic trau-
matic encephalopathy has indeed become well-defined
neuropathologically over the past decade, and clinical
research diagnostic criteria have also been proposed
(Stern et al., 2013; Montenigro et al., 2014). Despite
these advancements, research on CTE remains in its
infancy, and many knowledge gaps need to be addressed
given the millions of individuals who could potentially
be impacted by this devastating, but possibly prevent-
able, disease. The purpose of this chapter is to provide
a comprehensive review on the current state of the liter-
ature on CTE in order to convey what is currently known
and not known about CTE. We present the historical
origins of CTE briefly, followed by a detailed description
of its neuropathologic features. The role of RHI in the
development of CTE is discussed, and a review of the
clinical presentation and features of CTE is provided.
The chapter concludes with a discussion on directions
for future research.

*Correspondence to: Robert A. Stern, Boston University Alzheimer’s Disease and CTE Centers, Department of Neurology,
Boston University School of Medicine, 72 E. Concord St, Suite B7800, Boston, MA 02118, United States. Tel: +1-617-358-5375,
Fax: +1-617-358-6544, E-mail: bobstern@bu.edu
338 M.L. ALOSCO AND R.A. STERN
CHRONIC TRAUMATIC
ENCEPHALOPATHY: HISTORICAL
ORIGINS
The historical origins of CTE have been described in
detail by Montenigro et al. (2015). CTE dates back to
1928, when Harrison Martland introduced the term
“Punch Drunk” to describe his observation of a clinical
syndrome in prizefighters. The prizefighters exhibited
early onset behavioral disturbances, characterized by
Martland as “goofy,” “slug nutty,” and “cuckoo,” fol-
lowed by later onset “mental deterioration” (Martland,
1928). Following Martland’s paper, numerous different
nosologic terms were used throughout the years to refer
to a constellation of behavior, mood, cognitive, and
motor symptoms found in boxers, including the well-
known term “dementia pugilistica,” which was coined
in a 1937 publication that simultaneously provided
neuropathologic support for the disease (Millspaugh,
1937). The term “chronic traumatic encephalopathy”
was designated in 1940 in the description of a profes-
sional boxer with chronic behavior/mood and cognitive
disturbances (Bowman and Blau, 1940). In 1949, British
neurologist Macdonald Critchley again used the term
CTE in the context of symptomatic boxers. Neuropatho-
logic research in the 1950s and 1970s began to provide
support for a relationship between boxing and damage
to regions of the brain, including the septum pellucidum,
periventricular gray matter, frontal and temporal lobes,
and substantia nigra, as well as cerebellar scarring and
neuronal loss (Brandenburg and Hallervorden, 1954;
Corsellis et al., 1973). Corsellis et al. (1973) observed
widespread p-τ neurofibrillary tangles (NFT) in the
cerebrum and brain stem in their case series study of
15 retired boxers. Notably, in the remote research show-
ing the long-term clinical consequences of boxing,
there is also mention of American football as a potential
source of chronic symptom sequelae (Osnato and
Giliberti, 1927; Carroll, 1936; Bowman and Blau,
1940; Martland, 1943).
It was not until 2005 that CTE became a societal
concern after neuropathologic changes consistent with
CTE were found in a former National Football League
(NFL) player. Mike Webster was a former lineman for
the Pittsburgh Steelers and Kansas City Chiefs who
experienced depression and memory problems after retir-
ing from football and was demented prior to his cardiac-
related death in 2002 at the age of 50 (Fainaru-Wada and
Fainaru, 2013). Neuropathologist Bennet Omalu and his
colleagues examined Webster’s brain at postmortem and
discovered it to be macroscopically normal, but micro-
scopically abnormal due to evidence of hyperpho-
sphorylated tau (p-τ). Omalu published this case in the
journal Neurosurgery in 2005, in an article entitled,
“Chronic Traumatic Encephalopathy in a National Foot-
ball League Player” (Omalu et al., 2005). Since that time,
CTE has increasingly become a household term due to
neuropathologic evidence of this disease in many ensu-
ing well-known American professional football players
(e.g., Junior Seau, John Mackey, Dave Duerson), as well
as an array of other modern day contact sport athletes
(e.g., ice hockey, soccer, boxing, rugby), soldiers
deployed to Iraq and Afghanistan, and civilians with
recurrent head trauma (McKee et al., 2013; Ling et al.,
2017; Lee et al., 2019).
NEUROPATHOLOGIC FEATURES OF
CHRONIC TRAUMATIC
ENCEPHALOPATHY
Corsellis et al. (1973) and Omalu et al. (2005) were
among the first to describe the neuropathologic features
of CTE. Through the case reports from Omalu (Omalu
et al., 2010a,b, 2011), and the extensive, ongoing studies
by McKee and colleagues at the Boston University (BU)
Alzheimer’s Disease and CTE Centers and the Veterans
Administration-BU–Concussion Legacy Foundation
(VA-BU-CLF) Brain Bank (McKee et al., 2013), the neu-
ropathologic descriptions of CTE have been refined.
Through an ongoing study funded by the National Insti-
tute of Neurological Disorders and Stroke (NINDS),
entitled, “Understanding Neurologic Injury in Traumatic
Encephalopathy (UNITE)” (PI: Ann McKee) (Mez et al.,
2015), neuropathologic diagnostic criteria for CTE have
been examined during a recent NINDS and National
Institute of Biomedical Imaging (NIBIB) sponsored con-
ference. A panel of seven neuropathologists with exper-
tise in neurodegenerative diseases, in general, and
tauopathies, in particular, convened to evaluate McKee
et al.’ (2013) neuropathologic criteria for CTE. Each
neuropathologist evaluated 25 selected cases of various
tauopathies, with CTE cases being representative of
the disease and being at least of moderate disease sever-
ity. There was good agreement for overall neuropatho-
logic diagnosis (k ¼ 0.67) and even better for CTE
diagnosis (k ¼ 0.78). The neuropathologic criteria agreed
upon for diagnosing CTE are presented in Table 18.1.
The conference led to a consensus agreement that CTE
is a “unique disease” caused, in part, by RHI, with the
pathognomonic lesion being the deposition of p-τ neuro-
fibrillary, astrocytic, and neuropil tangles around small
blood vessels in an irregular pattern at the depths of
the cerebral sulci (see Fig. 18.1)—a pattern unique from
any other tauopathy, including Alzheimer’s disease (AD)
and frontotemporal dementia (FTD). Recent work also
shows that the specific tau species of CTE is unique
(Falcon et al., 2019).
Table 18.1
Neuropathologic criteria for diagnosing chronic traumatic encephalopathy (McKee et al., 2016)

Required for diagnosis of CTE

The pathognomonic lesions consists of p-τ aggregates in neurons, astrocytes, and cell processes around small vessels in an irregular
pattern at the depths of the cortical sulci
Supportive neuropathologic features of CTE
P-τ-related pathologies

1. Abnormal p-τ immunoreactive pretangles and NFTs preferentially affecting superficial layers (layers II–III), in contrast to layers
III and V as in AD
2. In the hippocampus, pretangles, NFTs, or extracellular tangles preferentially affecting CA2 and pretangles and prominent
proximal dendritic swellings in CA4. These regional p-τ pathologies differ from the preferential involvement of CA1 and
subiculum found in AD
3. Abnormal p-τ immunoreactive neuronal and astrocytic aggregates in subcortical nuclei, including the mammillary bodies and
other hypothalamic nuclei, amygdala, nucleus accumbens, thalamus, midbrain tegmentum, and isodendritic core (nucleus basalis
of Meynert, raphe nuclei, substantia nigra, and locus coeruleus)
4. P-τ immunoreactive thorny astrocytes at the glial limitans most commonly found in the subpial and periventricular regions
5. P-τ immunoreactive large grain-like and dot-like structures (in addition to some threadlike neurites)
Non-p-τ related pathologies

1. Macroscopic features: disproportionate dilatation of the third ventricle, septal abnormalities, mammillary body atrophy, and
contusions or other signs of previous traumatic injury
2. TDP-43 immunoreactive neuronal cytoplasmic inclusions and dot-like structures in the hippocampus, anteromedial temporal
cortex, and amygdala
Age-related p-τ astrogliopathy that may be present; nondiagnostic and nonsupportive

1. Patches of thorn-shaped astrocytes in subcortical white matter

2. Subependymal, periventricular, and perivascular thorn-shaped astrocytes in the mediobasal regions
3. Thorn-shaped astrocytes in amygdala or hippocampus

Table borrowed from McKee, A.C., Cairns, N.J., Dickson, D.W., et al., 2016. The first NINDS/NIBIB consensus meeting to define neuropatho-
logical criteria for the diagnosis of chronic traumatic encephalopathy. Acta Neuropathol 131: 75–86 under the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/legalcode).
No text changes were made, but the title was changed and the format of the table was revised.

Fig. 18.1. Pathognomonic lesion of chronic traumatic encephalopathy. No changes were made to the illustration; however, minor
changes were made for brevity to the below legend. (A) Perivascular p-τ lesion at the sulcal depths. (B–F) Multiple perivascular
foci in the cortex in CTE. (G) The p-τ aggregates in CTE are rounded structures in the neuropil that are most dense in the areas
surrounding the vessel. (H) The rounded p-τ immunoreactive cell processes are more densely distributed than those found in argyr-
ophilic grain disease. Figure borrowed from McKee, A.C., Cairns, N.J., Dickson, D.W., et al., 2016. The first NINDS/NIBIB con-
sensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy. Acta Neuropathol 131:
75–86 under the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/legalcode).
340 M.L. ALOSCO AND R.A. STERN
McKee et al. (2013) proposed a 4-stage classification
system to grade the pathologic severity and progression
of p-τ in CTE, with stage I being the least severe and
stage IV being the most severe. As described in the fol-
lowing text, the stages are accompanied by progressively
worsening macro- and microscopic brain changes, axo-
nal pathology, chronic neuroinflammation, and 43 kDa
TAR DNA-binding protein (TDP-43) abnormalities.
MACROSCOPIC PATHOLOGY IN CTE
Gross pathology is unremarkable in stage I CTE. In stage
II, various macroscopic pathologies are present, includ-
ing mild enlargement of the lateral ventricles, mild
enlargement of the third ventricle, sharp concavity of
the third ventricle, cavum septum pellucidum, and pallor
of the locus coeruleus and/or substantia nigra. In stage III
CTE, there is mild cerebral atrophy and dilation of the
lateral and third ventricles. Approximately 40% of stage
III cases exhibit septal abnormalities (e.g., cavum sep-
tum, septal perforations), nearly 60% have moderate
depigmentation of the locus coeruleus, and 40% of the
brains show mild pallor of the substantia nigra. Thus,
neurotransmitter dysfunction or loss is clear and is added
to the other atrophic and connectivity losses. In addition,
atrophy of the mammillary bodies and thalamus, thinning
of the hypothalamic floor and corpus callosum, and con-
vex contour of the medial thalamus may be present. In
stage IV CTE, there is marked shrinkage of the cortex,
white matter, medial temporal lobe (MTL), thalamus,
hypothalamus, and mammillary bodies. A majority of
stage IV CTE brains exhibit pallor of the locus coeruleus
and substantia nigra, in addition to enlargement of the
lateral ventricles, enlargement or sharp concavity of
the third ventricle, and septal abnormalities.
MICROSCOPIC PATHOLOGY IN CTE
P-τ
Stage I CTE involves focal perivascular epicenters of
p-τ NFT and astrocytic tangles at the sulcal depths,
particularly in the superior, dorsolateral, and inferior
frontal cortices. In stage II, p-τ NFT become dispersed
throughout the cortex and extend into the superficial
layers of the cortex adjacent to the perivascular epicen-
ters formed in stage I CTE. There are moderate NFT
densities in the nucleus basalis of Meynert and locus
coeruleus. P-τ NFT spread further throughout the
cerebral cortex in stage III, and appear in the MTL
(e.g., hippocampus, entorhinal cortex, amygdala), olfac-
tory bulb, mammillary bodies, diencephalon, brainstem,
and spinal cord. In stage IV, p-τ is widely dispersed
throughout the cortex, MTL, diencephalon, basal
ganglia, brainstem, and spinal cord.
Axonal pathology
There is axonal injury, axonal degeneration, myelinated
fiber loss, and white matter atrophy in every stage of
CTE. Axonal pathology corresponds to the progression
of neural degeneration. In stages I and II, there are scat-
tered and distorted axonal varicosities in the frontal and
temporal cortices, as well as in the subcortical white mat-
ter and deep white matter tracts of the diencephalon. As
pathologic severity advances (stages III and IV), there is
striking axonal loss and distorted axonal profiles in the
cortex and subcortical white matter pathways, as well
as white matter macrophages and p-τ abnormalities.
TDP-43
TDP-43 is an RNA-protein (Sephton et al., 2011, 2012)
that binds to tau (Sato et al., 2009) and influences tau
isoform expression (Morales et al., 2009). Stage I CTE
cases often have TDP-43 neuritic thread and dot-like
inclusions in the subcortical white matter and fornix.
TDP-43 inclusions are present in stage II and III CTE
cases and are located in the subcortical white matter,
brainstem, or MTL (stage II), as well as in the cerebral
cortex (stage III). By stage IV, TDP-43 immunopositivity
can be widespread throughout the cerebrum, MTL,
brainstem, diencephalon, basal ganglia, and occasion-
ally, the spinal cord.
b-Amyloid
The presence of b-amyloid neuritic plaques is a hallmark
pathology of AD, and is part of the diagnostic criteria for
AD as per both the National Institutes of Aging (NIA)-
Reagan Institute and the NIA-Alzheimer’s Association
guidelines (Newell et al., 1999; Montine et al., 2012).
Unlike AD, b-amyloid peptide deposits are not a consis-
tent pathologic feature of CTE, and if present, they are dif-
fuse and dense core plaques (McKee et al., 2013). In a
2015 study, b-amyloid was found in 52% of former con-
tact sport athletes and military veterans with neuropatho-
logically confirmed CTE and was associated with older
age and the apolipoprotein E (APOE) E4 allele (Stein
et al., 2015b); carriers of this allele are known to have
greater accumulation of b-amyloid than noncarriers.
b-amyloid deposition may thus occur at an accelerated
rate in the presence of CTE pathology.
COMORBID NEUROPATHOLOGY
CTE is frequently comorbid with other neurodegenera-
tive diseases, including Lewy body disease (LBD),
AD, motor neuron disease (MND), and frontotemporal
lobar degeneration (FTLD) (McKee et al., 2013; Mez
et al., 2017). The presence of one disease may increase
 THE LONG-TERM CONSEQUENCES OF REPETITIVE HEAD IMPACTS
risk for another, possibly due to the interaction between
various proteins (e.g., tau, a-synuclein) (Jellinger, 2012;
Stein et al., 2014). The comorbidity between CTE and
AD is noteworthy given the extant research associating
traumatic brain injury (TBI), in particular moderate
and severe TBI, with increased risk for AD (Fleminger
et al., 2003). Autopsy and in vivo positron emission
tomography (PET) studies have linked moderate to
severe TBI with increased b-amyloid burden (Johnson
et al., 2012; Scott et al., 2016). It has been theorized that
CTE is and has been clinically misdiagnosed as AD in the
setting of TBI or recurrent head trauma (Lehman et al.,
2012) given that most studies examining the association
between TBI and AD risk have been without neuropath-
ologic confirmation of AD as the etiology. Notably, rel-
ative to a non-TBI AD group, AD subjects with a history
of TBI have been shown to exhibit clinical features con-
sistent with CTE and have lower amyloid angiopathy at
autopsy (Sayed et al., 2013). Recent studies that have
included autopsy and/or in vivo biomarker evidence of
AD have also failed to find an association between
TBI and AD pathology (Crane et al., 2016; Weiner
et al., 2017; Sugarman et al., 2019).
A subset of CTE cases exhibit motor neuron symp-
toms (e.g., muscle weakness, atrophy, spasticity, and fas-
ciculations) that mimic Amyotrophic Lateral Sclerosis
(ALS) (McKee et al., 2010, 2013). CTE subjects with
comorbid MND die at a younger age (CTE stages II–III),
and MND in CTE may be a consequence of TDP-43 pro-
teinopathy in the brain and spinal cord (McKee et al.,
2010, 2013). To a lesser extent, CTE also cooccurs with
FTLD. CTE has also been characterized as an FTLD
subtype due to the nature (e.g., tau and TDP-43 proteins)
and topographic deposition of pathology (e.g., fronto-
temporal) in CTE (McKee et al., 2010). Finally, recent
work suggests dot-like lesions as a possible significant
feature of CTE, which may have implications for argyr-
ophilic grain disease and Parkinson’s disease dementia
(Armstrong et al., 2017).
THE ROLE OF REPETITIVE HEAD
IMPACTS IN CHRONIC TRAUMATIC
ENCEPHALOPATHY
Repetitive head impacts refer to the cumulative lifetime
exposure of an individual to recurrent concussive (or
mild TBI) and subconcussive injuries (Montenigro
et al., 2016). RHI can also include recurrent moderate
and severe TBIs, but the majority of all head trauma is
mild in nature. CTE has been studied and characterized
largely in the context of exposure to sport-related concus-
sive and subconcussive head impacts, and to a lesser
extent, head trauma in military veterans. In the following
text, we first define concussion and subconcussive injury
341
and describe their associated prevalence and symptom
phenotype. Evidence supporting RHI as a necessary
risk factor for CTE is then presented, and possible
mechanisms for this relationship are discussed.
REPETITIVE HEAD IMPACTS:
TERMINOLOGY AND PREVALENCE
Concussion
Concussion, a mild TBI subtype, is a complex patho-
physiologic process affecting the brain secondary to
biomechanical forces induced from direct or indirect
blows to the head (McCrory et al., 2013). An estimated
1.6–3.8 million concussions occur from sports and recre-
ational activities each year in the United States (Langlois
et al., 2006). The true prevalence of concussion is likely
much greater, given that many or most are not reported.
Sport-related concussion rates are highest in American
football, but are prevalent in other contact sports as well
(e.g., ice hockey, lacrosse, soccer) (Daneshvar et al.,
2011). Additionally, mild TBI is common in military per-
sonnel. In 2014, the Department of Defense estimated the
number of new worldwide medical diagnoses of TBI
in veterans to be approximately 25,044, with just over
20,000 being mild (Defense and Veterans Brain Injury
Center, 2015). Typical classification criteria for concussion
and mild TBI include post-injury confusion, disorientation,
or loss of consciousness (LOC)  30 min; a Glasgow Coma
Scale score of 13–15; and/or posttraumatic amnesia <24 h
(Kay et al., 1993). Absence of structural brain alterations
on standard CT or magnetic resonance imaging (MRI) is
characteristic of concussion and mild TBI.
Concussion symptoms typically fall into three
domains: neurologic, behavioral, and psychiatric
(Ponsford et al., 2000; McCrory et al., 2013). Neurologic
symptoms can include headache, dizziness, sensitivity to
light and noise, tinnitus, and vision disturbances. Cog-
nitive problems can appear immediately after the con-
cussion, such as difficulties in attention, psychomotor
speed, and memory. Behavioral and psychiatric symptoms
commonly involve depression, insomnia, fatigue, and irri-
tability. A majority of symptomatic concussions resolve
in days to weeks (Belanger and Vanderploeg, 2005;
McCrory et al., 2013), but in some cases, symptoms
may persist for up to 3 months following the injury
(Ponsford et al., 2000; Belanger et al., 2005; Iverson,
2005). In a small subset of individuals, psychologic, cog-
nitive, and somatic symptoms following concussion can
last 1 year or longer (Katz and DeLuca, 1992; Dikmen
et al., 2001; Bigler, 2008; W€aljas et al., 2015; Losoi
et al., 2016). Recurrent concussive injuries may increase
risk for more severe future concussive injuries, exacerbate
symptom presentation, and delay recovery (Collins et al.,
2002; Guskiewicz et al., 2003; Iverson et al., 2004).
342 M.L. ALOSCO AND R.A. STERN
Subconcussive injury
A subconcussive injury involves a direct or indirect blow
to the head that results in the transfer of mechanical energy
to the brain at a force sufficient to injure axonal integrity,
but does not result in overt clinical symptoms of concus-
sion (Dashnaw et al., 2012; Bailes et al., 2013; Belanger
et al., 2015; Erlanger, 2015). The threshold intensity level
of impact that causes neuronal damage but does not result
in clinical symptoms remains unknown. Subconcussive
events are common in the setting of contact sports, and
helmet-based accelerometer studies estimate that amateur
high school football players average 600 subconcussive
impacts with a seasonal linear acceleration of 16,746.1g
each season, an estimate that increases to over 1000 at
the collegiate level (Crisco et al., 2010; Broglio et al.,
2011; Gysland et al., 2012). Although subconcussive head
impacts do not result in immediate symptoms, repetitive
subconcussive blows registering greater than 14.4g on
helmet accelerometer sensors have been linked with
pre- to postseason cognitive decline, functional brain
alterations, and white matter changes in high school foot-
ball players (Davenport et al., 2014; Talavage et al., 2014;
Abbas et al., 2015). Additional studies of hockey (Koerte
et al., 2012a) and soccer players (Koerte et al., 2012b,
2015a; Lipton et al., 2013) have demonstrated altered
white matter integrity and brain biochemistry associated
with subconcussive exposure.
REPETITIVE HEAD IMPACTS
Recurrent concussion is a component of RHI, but it
is the numerous lifetime subconcussive head impacts
that appear to play a prominent role in the pathogenesis
of CTE. For example, 16% of neuropathologically
confirmed cases of CTE have no history of reported
concussions, but did have significant subconcussive
exposure (Stein et al., 2015a). Furthermore, McKee
et al. (2013) concluded that family-reported number of
concussions was unrelated to CTE pathologic stage,
yet all 68 cases diagnosed with CTE had a history of sub-
concussive trauma. Of the 68 individuals diagnosed with
CTE 64 were contact sport athletes. (The remaining four
were three military veterans, and one individual with a
history of self-injurious head banging.) These included
50 football players (34 professional), 5 ice hockey
players (enforcers), 7 professional and 1 amateur boxer,
and 1 professional wrestler. The 18 age- and gender-
matched controls without history of RHI exposure were
absent CTE neuropathology. Considering that many pro-
fessional athletes begin contact sport participation as
youth, they likely experience thousands of lifetime subcon-
cussive head impacts. Moreover, longer duration of expo-
sure to RHI (as operationalized by years of football play)
is associated with worse CTE neuropathologic severity
(McKee et al., 2013; Alosco et al., 2018a,b).
Bieniek et al. (2015) reviewed medical records of
>1700 brain donation cases from the Mayo Clinic brain
bank to ascertain history of amateur contact sport partic-
ipation. The authors evaluated the brains of 66 donors
identified to have had exposure to contact sports in high
school or college (34 played American football) for evi-
dence of CTE pathology, and applied the staging system
proposed by McKee et al. (2013). The authors found that
21 of the 66 former contact sport athletes exhibited neu-
ropathologic changes consistent with the disease (e.g.,
perivascular cortical p-τ). Remarkably, CTE pathology
was not present in 198 age- and disease-matched men
and women without exposure to contact sports, including
33 with a single TBI sustained from nonathletic causes
(e.g., falls, motor vehicle accidents). Ling et al. (2015)
also examined 268 neurodegenerative and control cases
from the Queen Square Brain Bank for Neurological
Disorders for evidence of CTE pathology. CTE neuropa-
thology was found in 11.9% of neurodegenerative disor-
ders and 12.8% of elderly controls. Of these cases, 93.8%
had a history of TBIs, 34% had a history of participation
in contact sports, and 18.8% were military veterans.
Research has also found evidence of CTE (and other
neurodegenerative disease pathologies) in former soccer
plays without a known history of concussion, suggesting
a possible link between repetitive subconcussive injuries
from routine heading and long-term neurologic disorders
(Ling et al., 2017).
REPETITIVE HEAD IMPACTS AND CTE:
POTENTIAL MECHANISMS
The mechanisms underlying the association between
RHI and CTE are not currently known and are likely
multifaceted. The acceleration and deceleration of the
head during concussion can result in shearing and
tensile forces on long fibers, such as axons and blood
vessels, and cause traumatic axonal injury and an
array of neurometabolic pathophysiologic changes
(e.g., ionic flux and glutamate release, neuroinflamma-
tion, altered neurotransmission, microvasculopathy)
(Maxwell et al., 1997; Medana and Esiri, 2003; Giza
and Hovda, 2014). Areas of the brain that are susceptible
to axonal direction and/or tissue-density change (e.g.,
around small blood vessels, gray–white matter interface)
are most sensitive to the biomechanical rotational
forces of concussion (Oppenheimer, 1968; Povlishock,
1993; Blumbergs et al., 1994; Gaetz, 2004; Cloots
et al., 2011; McKee et al., 2014). Experimental studies
in animals demonstrate that axonal injury and vascular
disruption following RHI is most severe at focal stress
points such as the perivascular regions and depths of
cortical sulci (Smith et al., 1999; Cloots et al., 2008).
 THE LONG-TERM CONSEQUENCES OF REPETITIVE HEAD IMPACTS
RHI-related axonal injury may also contribute to the tau
protein, a stabilizer of axonal microtubules, becoming
abnormally misfolded, phosphorylated, and aggregated
and cleaved, leading to neurotoxic tau fragments and
neuronal death (McKee et al., 2013, 2014, 2015;
Mouzon et al., 2014).
It is unclear how the acute pathophysiologic changes
associated with RHI (e.g., axonal injury, neuroinflamma-
tion, blood–brain barrier breach, disruption of tau) tran- and CTE, see Goldstein and colleagues (2014).
sition to the progressive neural degeneration observed in
CTE. Blaylock and Maroon (2011) theorized that it may
involve chronic immunoexcitotoxicity activity. In a nor-
mally functioning individual, microglia aid in immune
defense of the central nervous system and serve to
decrease neuroinflammation and repair neuronal func-
tion. However, activated microglia in the presence of
brain pathology can be neurodestructive and remain so
for a prolonged period of time. As hypothesized by
Blaylock and Maroon (2011), an initial head injury
activates (or primes) microglia, and the microglia remain a combination of behavior (e.g., aggression, explosivity),
activated for extended periods of time. Subsequent head
injuries cause the microglia to become hyperactive,
resulting in massive releases of immune cytokines and
excitotoxin neurochemicals (i.e., glutamate). The white
matter degeneration (gliosis) (Blaylock and Maroon,
2011; Smith et al., 2013), and chronic astrocytosis and
microgliosis that may occur during RHI exposure can
also lead to glutamate accumulation (Ojo et al., 2013;
Mannix et al., 2014). Glutamate continues to be released
as microglial activation and axonal injury persist
with each subsequent head injury. The result is chronic
immunoexcitotoxicity that could precipitate neural
degeneration. Some of these neuroinflammatory and
vascular-based mechanisms were recently supported
by an experimental study (Tagge et al., 2018).
MILITARY VETERANS AND CHRONIC
TRAUMATIC ENCEPHALOPATHY
A majority of neuropathologically diagnosed cases of
CTE have been former contact sport athletes, but military age ¼ approximately 35 years old) and (2) later-life onset
veterans may also be at risk. McKee et al. (2013) found
16 of 21 military veterans with CTE were also contact
sport athletes (8 former NFL players) and 9 of the vet-
erans saw combat (4 in Iraq and Afghanistan, 1 in Gulf
War, 2 in Vietnam, and 2 in World War II), and 3 were
exposed to blast. A history of blast exposure in military at death, and neuropathologic stage. There was a sig-
veterans is of particular concern in terms of CTE risk.
Postmortem analysis of a sample of five brains of US
male military veterans with history of blast exposure
revealed the presence of the pathognomonic CTE lesion
that was indistinguishable from CTE neuropathology in
age- and gender-matched contact sport athletes with a
history of RHI (Goldstein et al., 2012). CTE neuropa-
thology was present for one military veteran who had
343
only one exposure to blast and was without any previous
or postmilitary service TBI history. Single blast exposure
and CTE pathology has also been observed in mice
(Goldstein et al., 2012). Multiple exposures may be
occurring within a single blast due to cycles of oscilla-
tion in head acceleration–deceleration, known as the
“bobblehead effect” (Goldstein et al., 2012). For a com-
prehensive review on blast exposure in military veterans
CLINICAL PRESENTATION OF CHRONIC
TRAUMATIC ENCEPHALOPATHY
Clinical presentation
POSTMORTEM RETROSPECTIVE DATA
McKee et al. (2013) provided an initial description of
the clinical symptoms associated with CTE that included
mood (e.g., depression, suicidal ideations), and cognitive
symptoms (e.g., executive dysfunction, episodic mem-
ory impairment). These findings were consistent with
earlier reports of boxers (Mawdsley and Ferguson,
1963; Corsellis et al., 1973). Stern et al. (2013)
conducted a comprehensive study to better delineate
the clinical nature and course of symptoms in CTE.
Retrospective next-of-kin telephone interviews were
conducted for 36 male contact sport athletes (29 football
players, 3 professional ice hockey players, 1 professional
wrestler, and 3 boxers) who donated their brain to
the VA-BU-CLF Brain Bank, were neuropathologically
diagnosed with CTE, and were without any other
significant comorbid neuropathology. Next-of-kin
interviews were conducted blinded to the neuropathol-
ogy of the brain donor, and neuropathologists were
blinded to all clinical data. The results revealed two
distinct clinical presentations: (1) initial onset of behav-
ioral (e.g., explosivity, impulsivity, aggression) or
mood (e.g., depression) changes at a young age (mean
(mean age ¼ approximately 60 years old) of cognitive
impairment, particularly in episodic memory and execu-
tive function. The subjects with initial behavior or mood
symptoms were combined into a single behavior/mood
group due to similarities in age of symptom onset, age
nificant delay (years to decades) between end of RHI
exposure and symptom onset. All subjects demons-
trated cognitive impairment at some point, but the cog-
nitive subgroup was less likely to have a history of
behavioral/mood symptoms and usually developed
dementia (i.e., cognitive impairment significant enough
to impact functional independence). The cognitive
subgroup was more advanced in disease severity.
344 M.L. ALOSCO AND R.A. STERN
In the study by Stern et al. (2013), none of the subjects
had motor features as an initial presenting feature, and
overall, motor symptoms were not common. This is in
contrast to the earlier reports on boxers who described
motor features to be a prominent symptom (Mawdsley
and Ferguson, 1963; Corsellis et al., 1973) and, as previ-
ously described, the established comorbidity of MND
and CTE. Although unclear, boxers may be more prone
to develop parkinsonism due to the angular acceleration
and torsional focal stress placed on the brainstem and cer-
ebellum, which is different from the transverse and linear
acceleration and deceleration biomechanical forces in
football (Viano et al., 2005; Beitz, 2014). Consistent with
this notion, McKee et al. (2013) observed that motor
symptoms and cerebellar pathology were more prevalent
in former boxers relative to former football players.
Motor impairment may be an initial presenting symptom
in boxers due to earlier degeneration of brain regions like
the substantia nigra. In contrast, motor symptoms in foot-
ball players might not manifest until later in the disease
course in the context of widespread neural degeneration.
IN VIVO RESEARCH
Chronic traumatic encephalopathy cannot currently be
diagnosed during life partially due to the lack of vali-
dated biomarkers. However, in vivo research has been
examining the clinical phenotype of subjects presumably
at high risk for CTE (e.g., former NFL players). These
studies corroborate behavioral/mood and cognitive
impairment as core features of CTE. In an independent
study at the University of California, San Francisco,
Gardner et al. (2015) conducted a case series study of
14 symptomatic, former professional male American
football players presenting to an academic memory
clinic. Three of the subjects exhibited delayed-onset
behavioral/mood symptoms (e.g., anxiety, depression,
irritability, impulsivity), and five had delayed-onset pro-
gressive cognitive symptoms (e.g., memory impairment,
executive dysfunction), one of whom displayed an initial
motor symptom onset with cognitive symptoms emerg-
ing 5 years later. There was also a third phenotype that
included five football players who exhibited chronic
postconcussive symptoms (e.g., headache, forgetfulness,
concentration difficulties, depression, apathy) that
began during their playing career. Neuropsychologic
testing of all subjects revealed verbal and visual memory
impairment and executive dysfunction to be common
and most prominent in the cognitive group. All of the
behavior/mood subjects had an elevated Geriatric
Depression Scale score, whereas only 17% of the cogni-
tive/motor group showed clinically meaningful symp-
toms of depression. Cognitive impairment, dementia,
and depression have also been found in other samples
of former NFL players relative to demographically-
matched controls (Hart et al., 2013), and executive
dysfunction has been reported in a sample of active
and former college and professional football players
(Seichepine et al., 2013).
CLINICAL RESEARCH DIAGNOSTIC
CRITERIA
Three different author groups (Jordan, 2013; Victoroff,
2013; Montenigro et al., 2014) have proposed similar
clinical research diagnostic criteria that are compared
in detail elsewhere (Baugh et al., 2014). The primary dif-
ference among the criteria is the central role of motor fea-
tures for the clinical diagnosis of CTE in the Jordan
(2013) criteria, whereas motor symptoms are supportive
features of CTE in the other criteria. Montenigro et al.
(2014) coined the nosology “Traumatic Encephalopathy
Syndrome (TES)” to refer to the clinical syndrome asso-
ciated with CTE (as well as other possible etiologies with
brain trauma exposure) and suggested to reserve the term
“CTE” for the postmortem diagnosis. The TES diagnos-
tic criteria are based on a systematic review of the clinical
features of 83 neuropathologically confirmed CTE cases
in the literature. The TES diagnosis requires a history of
multiple impacts to the head, such as multiple mild, mod-
erate, and/or severe TBIs, or exposure to concussive and
subconcussive events. Exposure sources could include,
but are not limited to, contact sports, military service,
domestic violence, and/or head-banging, among others.
Consistent with Stern et al. (2013), Montenigro et al.
(2014) found three core clinical features to most com-
monly emerge during the years to decades after RHI
exposure, with the presence of one or more of the follow-
ing three core clinical features necessary for diagnosis:
(1) behavioral symptoms primarily characterized by
aggression and impulsivity; (2) mood dysfunction
characterized by depression and related symptoms
(e.g., hopelessness, suicidality); and (3) cognitive diffi-
culties that involve cognitive decline and impaired cog-
nitive test performance (i.e., 1.5 SD below the normative
mean) in attention, executive function, and/or episodic
memory. These core features comprise four distinct
diagnostic TES variants: TES behavioral/mood variant
(TES-BMv), TES cognitive variant (TES-COGv), TES
mixed variant (TES-MIXv), and TES dementia
(TES-D). TES-D requires a progressive course of cogni-
tive core features and evidence of functional impairment.
There must also be a minimum of two of the following
supportive features: impulsivity, anxiety, apathy, para-
noia, suicidality, headache, motor signs, documented
decline (decline in function, symptoms, or signs based
on formal measurement), or delayed onset (at least
2 years after RHI exposure). Modifiers include the
 THE LONG-TERM CONSEQUENCES OF REPETITIVE HEAD IMPACTS
presence of motor features (e.g., dysarthria, dysgraphia,
bradykinesia) and the nature of the clinical course
(stable, progressive, unknown/inconsistent).
A separate diagnostic classification for “Possible
CTE,” “Probable CTE,” and “Unlikely CTE” is included
in the TES criteria and is based on the presence of poten-
tial biomarkers, which, when validated, indicate the
degree to which the underlying etiology of the clinical
presentation of TES is due to the CTE pathophysiologic
process. The TES diagnosis can be designated in the
presence of other neurodegenerative conditions other
than CTE who meet the requisite exposure and symptom
criteria. It is therefore critical that research identify and
validate in vivo biomarkers to facilitate the diagnosis
of “Probable CTE.”
POTENTIAL BIOMARKERS OF CTE
The use of biomarkers has become the gold standard for
diagnosing “Probable AD” during life (Jack et al., 2011;
McKhann et al., 2011), and a similar approach is being
adopted in CTE. The Montenigro et al. (2014) TES clin-
ical research criteria proposed the following biomarkers
to designate “Probable CTE”: Cavum septum pelluci-
dum, normal b-amyloid cerebrospinal fluid (CSF) levels,
elevated CSF p-τ/τ ratio, negative amyloid imaging, pos-
itive tau imaging, cortical thinning, and cortical atrophy.
Although limited, the extant research on the potential
utility of these biomarkers in CTE, as well as others that
have been identified since the proposal of TES, are dis-
cussed in the following text. Of note, in order to provide
robust support for potential biomarkers of CTE, we lay
emphasis on studies that included populations presum-
ably at high risk for CTE, such as former (i.e., nonactive)
professional contact sport athletes. Comprehensive
reviews of neuroimaging findings in the setting of acute
and chronic RHI are provided elsewhere (Ng et al., 2014;
Koerte et al., 2015b).
Structural neuroimaging
CAVUM SEPTUM PELLUCIDUM
A cavum septum pellucidum (CSP) is a consistent neu-
ropathologic feature of CTE and represents a deviation
of the embryologic fluid space between the leaflets of
the septum pellucidum. A CSP can be observed on con-
ventional MRI. A recent study of 72 former NFL players
and 14 former professional noncontact sport athletes who
underwent high resolution 3T MRI showed that the for-
mer NFL players had a higher rate of CSP, greater CSP
length, and greater ratio of CSP length to septum length
(Koerte et al., 2016). Greater length of the CSP predicted
worse performance on a list learning and word reading
task. High rates of CSP on MRI was also found in another
345
sample of former American professional football players
(Gardner et al., 2016), and 12 of the 14 former profes-
sional football players from the Gardner et al. (2015) case
series study had a CSP.
MICROSTRUCTURAL CHANGES
Diffusion tensor imaging (DTI) is an MRI technique
sensitive to water diffusion within brain tissue. It is com-
monly used to assess microstructural axonal integrity
because water movement is directionally dependent on
the fiber tracts in white matter (Ng et al., 2014). There
is significant white matter pathology in every stage of
CTE, and DTI may be a useful tool to detect CTE-related
white matter pathology due to its sensitivity to axonal
injury in concussion (Shenton et al., 2012). Many studies
have demonstrated reduced microstructural white matter
integrity in active contact sport athletes (Zhang et al.,
2003; Chappell et al., 2006; Koerte et al., 2012b;
Lipton et al., 2013; Bazarian et al., 2014), and only lim-
ited research has examined RHI exposure and long-term
white matter changes. Reduced white matter integrity in
the frontal lobe predicted severity of depressive symp-
toms in a sample of 26 former NFL players (Strain
et al., 2013). White matter integrity of the frontal lobe
and its subcortical connections may be of particular inter-
est given the frontal distribution of pathology in CTE and
the frontal-mediated symptoms observed in this disease.
There is also support in the animal literature for long-
term white matter injury subsequent to repetitive cortical
impacts (Donovan et al., 2014).
CORTICAL ATROPHY AND THINNING
High resolution T1 volumetric MRI may help to identify
p-τ-related neuronal loss in CTE. In the Gardner et al.
(2015) case series study, seven of the nine former
American professional football players exhibited cortical
atrophy to a greater proportion than expected for their
age. Shrinkage and thinning of frontotemporal regions
and aspects of the MTL (e.g., hippocampus) is likely
in CTE given these brain regions are affected by p-τ in
the early stages of CTE and modulate clinical functions
impaired in CTE (e.g., episodic memory impairment,
executive dysfunction, depression, aggression, impulsiv-
ity). Most compelling evidence supporting this notion
can be found in a recent study by Goswami et al.
(2016). In that study, the uncinate fasciculus differ-
entiated former professional football players with a
history of multiple concussions from healthy controls
(Goswami et al., 2016). The former professional foot-
ball players with a history of concussion manifested
thinner anterior temporal lobes, and there was an
inverse correlation between orbitofrontal cortex thick-
ness with aggression and task errors on a go/no-go task
346 M.L. ALOSCO AND R.A. STERN
(suggestive of impulsivity). There was also a negative
correlation between axial diffusivity and error rates
and aggression, and elevated resting state functional
connectivity between the anterior temporal lobe and
the orbitofrontal cortex. Former NFL players have also
been shown to exhibit greater right hippocampal atrophy
relative to age-matched healthy controls (Coughlin et al.,
2015). Singh et al. (2014) also found that college football
players with and without a history of concussion exhib-
ited smaller hippocampal volumes relative to healthy
controls, and there was an inverse relationship between
years of football played and left hippocampal volume.
Players with a concussion had a smaller hippocampus
than those without such history.
Functional neuroimaging
NEGATIVE AMYLOID AND POSITIVE TAU
PET imaging is a nuclear medicine functional neuroim-
aging technique that detects g rays emitted from radio-
labeled tracers injected into the body, which are
captured in a PET scanner and the data used to construct
three-dimensional images. It is often used to examine
brain tissue metabolic activity using 18Fluorodeoxyglu-
cose (FDG) as a tracer of glucose utilization. Three
PET ligands that bind to b-amyloid have recently been
developed and approved by the Food and Drug Admin-
istration (e.g., 18F-Florbetapir) (Landau et al., 2013), and
used as part of the diagnostic process for AD, as well as
for the detection of preclinical AD (Beach et al., 2014;
Pietrzak et al., 2015). Minimal to no uptake of the amy-
loid tracer would rule out AD as an etiology. Given that
b-amyloid is not a consistent feature of CTE, amyloid
PET imaging may be key for the differential diagnosis
between CTE and AD in vivo; that is, absence of
b-amyloid plaques (as determined by negative amyloid
PET) would be suggestive of CTE in a symptomatic indi-
vidual who does not meet diagnostic criteria for another
disease or disorder. In recent years, several groups
have been developing ligands that bind to p-τ for use
in humans (Harada et al., 2016). The PET ligand
18
F-AV1451 has an affinity to bind to p-τ selectively over
b-amyloid and may have key diagnostic utility in tauopa-
thies, such as CTE (Gandy and DeKosky, 2014). As an
example, a case study found negative 18F-florbetapir
and positive 18F-AV1451 PET imaging in a former
NFL player who had a clinical profile similar to AD,
but the combination of these biomarker findings ruled
out AD as the likely etiology (Mitsis et al., 2014). Flor-
tauciper and florbetapir PET were recently examined in a
sample of 26 symptomatic former NFL players and
31 same-age asymptomatic controls without a history
of TBI or contact sport participation (Stern et al.,
2019). On average, flortaucipir SUVR was higher in for-
mer NFL players compared to the controls in the bilateral
superior frontal lobes, bilateral medial temporal lobes,
and the left parietal lobe. The SUVRs in these regions
were further associated with years of American football
play. However, tau deposition did not correspond to cog-
nitive or neuropsychiatric tests. Notably, only 1 of the
31 former NFL players had a positive florbetapir PET.
The PET ligand 18F-FDDNP also targets p-τ, but
unlike 18F-AV1451 (and other similar recent ligands)
18
F-FDDNP is an old ligand that binds to both p-τ and
b-amyloid, as well as other proteins, and thus lacks spe-
cific diagnostic accuracy. Nevertheless, Small et al.
(2013) found that FDDNP-PET signals were higher in
a sample of five symptomatic former NFL players rela-
tive to demographically matched controls, specifically
in multiple subcortical regions and the amygdala. That
same group reported 18F-FDDNP PET results in former
American professional football players that the authors
(Barrio et al., 2015) stated were consistent with CTE
neuropathology, though the pattern of findings was not
consistent with those described by McKee et al. (2013,
2015). Finally, PET ligands that target TBI-related
neuroinflammation (e.g., translocator protein, TSPO)
may also have clinical utility in CTE (Coughlin
et al., 2015).
HYPOMETABOLISM AND IMPAIRED NEURAL ACTIVITY
FDG-PET and other neuroimaging methods [e.g., arterial
spin labeling (ASL), single photon emission computed
tomography (SPECT), and functional MRI (fMRI)]
examine cerebral blood flow (CBF) and metabolism pat-
terns that are distinct across neurodegenerative disorders.
These tools may be useful to detect unique patterns of
metabolic abnormalities in CTE. Peskind et al. (2011)
found FDG-PET hypometabolism in the MTL, cerebel-
lum, vermis, and pons in a sample of Iraq war veterans
exposed to repeated blast exposures. In another study
of war veterans, repeated blast exposure subjects exhib-
ited greater hypometabolism in the right superior parietal
lobe relative to subjects exposed to blunt injury (Mendez
et al., 2013). ASL-related findings in cognitively
impaired former NFL players relative to controls also
showed regional blood flow differences in the left
temporal pole, inferior parietal lobule, and superior
temporal gyrus that corresponded to neuropsychologic
test performance (Hart et al., 2013).
Another useful fMRI biomarker is blood-oxygen-
level dependent (BOLD) fMRI, which indirectly exam-
ines neural activity through measurement of changes in
CBF via contrast between oxygenated and deoxygenated
blood. BOLD fMRI findings in a sample of former NFL
players has raised the possibility that recurrent concus-
sions may be associated with later-life functional ineffi-
ciencies in relational memory neural networks (Ford
et al., 2013). fMRI could be an important tool to better
 THE LONG-TERM CONSEQUENCES OF REPETITIVE HEAD IMPACTS
understand the neural substrates of clinical impairment in
CTE, and much more research that uses fMRI in living
subjects at high risk for CTE is needed.
NEUROCHEMICAL ALTERATIONS
Magnetic resonance spectroscopy (MRS) is a safe,
nonradioactive, advanced neuroimaging method that
examines physiologic metabolism in vivo. MRS mea-
sures neurometabolic markers indicative of neuronal loss
(N-acetyl aspartate; NAA), excitotoxicity, gliosis, neu-
roinflammation (glutamate-glutamine; Glx, myo-
inositol; mI), and axonal injury (choline; Cho) (Lin
et al., 2012; Ng et al., 2014), all of which are common
neuropathologic changes in CTE. Neurochemistry in
the posterior cingulate gyrus (PCG) was compared
between five former professional male athletes (three
of five being former NFL players) with RHI exposure
and five healthy controls without a history of RHI (Lin
et al., 2015). All professional male athletes were exam-
ined 3–25 years after their career and exhibited symp-
toms including, but not limited to, memory loss,
impaired judgment, aggression, and depression. Relative
to controls, RHI exposure was associated with 31%
higher Glx and 65% higher Cho levels in the PCG. In
a follow-up MRS study of 77 symptomatic former
NFL players and 23 asymptomatic controls without a
history of TBI or contact sport participation (Alosco
et al., 2019), there was lower NAA in the parietal white
matter among the former NFL players compared to con-
trols. Exposure to RHI (estimated by a cumulative head
impact index) was associated with lower creatinine in the
parietal white matter of the former NFL players.
Neurochemicals in the anterior cingulate gyrus that are
associated with neuroinflammatory processes were also
found to affect behavioral and mood functioning.
Other work has used MRS to examine neurochemical
concentrations in 11 former professional soccer players
exposed to subconcussive trauma aged between 40 and
70 years and 14 age- and gender-matched noncontact
former athletes. Former soccer players exhibited higher
Cho and mI concentrations in the PCG relative to con-
trols (Koerte et al., 2015a). Relative to former collegiate
athletes without a history of concussion, those with a
concussion history exhibit elevated mI in the medial tem-
poral lobe that correlated with worse visual memory
performance (Tremblay et al., 2013).
Fluid biomarkers
Fluid biomarkers are cost and time efficient alternatives
to neuroimaging. Fluid biomarkers are typically derived
from blood or CSF. For example, CSF levels of b-amy-
loid, p-τ, and total tau are known biomarkers of AD
(Kang et al., 2015; Olsson et al., 2016). Given the nature
of CTE neuropathology, normal b-amyloid CSF levels
347
and elevated CSF p-τ/τ ratio would theoretically be bio-
markers of CTE. There is a paucity, however, of in vivo
research examining whether fluid biomarkers can accu-
rately detect the long-term consequences of RHI expo-
sure, in general, or underlying CTE pathology, in
particular. Recent findings from Stern et al. (2016) sup-
port plasma exosomal tau as a potential biomarker for
CTE. Exosomes are nanovesicles released by cells
throughout the body into the extracellular environment.
Notably, they cross the blood–brain barrier and can be
isolated in blood. Exosomes carry the molecular cargo
of the cell from which it was derived, including tau, if
present. Plasma and serum exosomal p-τ and total tau
have both been shown to accurately detect AD
(Fiandaca et al., 2015). Stern et al. (2016) found that a
sample of 78 former NFL players exhibited higher levels
of plasma exosomal tau relative to 16 controls without RHI
exposure. Exosomal tau discriminated the former NFL
players from controls with 82% sensitivity, and 100%
specificity, and greater levels of exosomal tau in the
NFL group correlated with worse performance on neurop-
sychologic tests of memory and psychomotor speed. The
authors acknowledge that their findings are preliminary
and require refinement of the procedures, as well as repli-
cation and validation. Alosco et al. also found an associa-
tion between greater exposure to RHI (using a cumulative
head impact index) and higher levels of both plasma
(Alosco et al., 2016) and CSF (Alosco et al., 2018a,b) total
tau in a sample of symptomatic former NFL players. In
both studies, however, the fluid levels of total tau in the
former NFL players were not significantly different from
a group of aysmptomatic same-age individuals without a
history of TBI or contact sport participation.
RISK AND PROTECTIVE FACTORS
As previously highlighted, neuropathologic evidence
supports RHI as a necessary risk factor for CTE diagno-
sis, and we present research below that has examined
RHI exposure and later-life neurologic impairment in
living subjects. Because RHI exposure history alone is
not sufficient for the development of CTE, other risk
factors are believed to interact with RHI to either (1) con-
tribute to the development of CTE, and/or (2) contribute
to the symptom heterogeneity observed in CTE. Despite
the advancements of our understanding of the disease,
CTE risk factors remain poorly understood, and there
is limited research on this topic. A nonexhaustive list
of several potential targets is discussed later.
RHI exposure factors
Rapidly expanding research has sought to quantify RHI
exposure in living subjects, in order to examine directly
the relationship between RHI and later-life neurologic
consequences. Quantification of RHI exposure history
348 M.L. ALOSCO AND R.A. STERN
in living subjects is challenging because it involves
retrospective self-report of numerous ambiguous events
throughout one’s life. Research has relied on single, indi-
rect metrics of RHI (e.g., recurrent concussion history).
These metrics have been shown to be associated with
later-life clinical impairment (Guskiewicz et al., 2005,
2007; Wright et al., 2016), but do not account for subcon-
cussive events, perhaps the most important risk factor
for CTE.
Direct metrics that reliably quantify both concussive
and subconcussive trauma are beginning to be devel-
oped. Montenigro et al. (2016) recently created the
cumulative head impact index (CHII), a metric of cumu-
lative exposure to RHI from football. The CHII is based
on self-reported exposure and estimated quantitation of
head impacts from published helmet accelerometer stud-
ies. The CHII has been used to examine the relationship
between cumulative RHI exposure and later-life cogni-
tive, mood, and behavioral impairment in a sample of
former football players whose highest level of play
was either high school or college. The mean CHII was
7742 total impacts, and it strongly predicted later-life
clinical outcomes and outperformed other individual
metrics such as concussion history. There was also a
threshold of head impacts necessary for risk of cognitive
or neurobehavioral impairment. In addition to the CHII,
Wright et al. (2016) recently developed an index
comprised of concussion frequency, severity, and time-
frame, as well as metrics of cognitive reserve, and found
that this index successfully predicted global cognitive
ability in former professional American football players.
However, this index did not include estimates of subcon-
cussive brain trauma, among other limitations. Kerr et al.
(2015) proposed the Head Impact Exposure Estimate
(HIEE), which is a self-report estimate of a football
player’s total hours of contact exposure. The relationship
between HIEE and outcomes has yet to be determined
and that metric does not include helmet accelerometer
intensity estimates.
Early age of first exposure (AFE) to tackle football, or
RHI in general, may be involved in later risk for CTE.
Recent findings show that former NFL players who
began playing tackle football prior to age 12 exhibited
worse cognitive functioning (Stamm et al., 2015a) and
microstructural integrity of the anterior corpus callosum
(Stamm et al., 2015b) in middle age compared to those
who began playing at age 12 or older. Among autopsy
participants with neuropathologically confirmed CTE,
AFE to football was not associated with CTE pathologic
severity (Alosco et al., 2018a,b). However, younger AFE
was associated with earlier onset of cognitive and beha-
vioral/mood symptoms. In boys, the years between the
ages of 9 and 12 represent a period of time in which
the brain undergoes tremendous neurodevelopmental
maturation (e.g., Caviness et al., 1996; Epstein, 1999;
Giedd, 2008). It is hypothesized that RHI exposure dur-
ing this window of neurodevelopmental vulnerability
may disrupt normal brain development or result in a
lower threshold for later life cognitive and structural
brain pathology associated with CTE. Notably, research
in active football players suggests that the effects of RHI
from youth football may not be observed immediately or
even in young adulthood (Caccese et al., 2019) and thus
there appears to be a possible interaction with aging.
Other aspects of RHI exposure (e.g., specific types of
hits, such as rotational forces), the amount of rest
between hits may also be key in the pathogenesis of
CTE, and this awaits empirical testing.
Non-RHI exposure factors
GENETICS
McKee et al. (2013) found that, of the 68 contact sport
athletes and military veterans neuropathologically diag-
nosed with CTE, the proportion of those with at least one
APOE E4 allele was similar to the general population. In
contrast, Stern et al. (2013) found that relative to an
age-matched normative sample, there was a greater pres-
ence of APOE genotypes in their sample of contact
sport athletes with neuropathologically diagnosed CTE
and no other neuropathologic finding. There was a larger
proportion of E4 homozygotes in the CTE subjects with
cognitive impairment as the initial presenting symptom,
and not the behavioral/mood subgroup. Possession of
an APOE E4 allele has also been shown to exacerbate
clinical impairment in high exposure professional boxers
(i.e., 12 or more professional bouts) (Jordan et al., 1997),
professional football players (Kutner et al., 2000), and is
associated with increased risk for dementia following a
TBI (Mayeux et al., 1995). The APOE E4 allele is the
most important genetic risk factor for AD, and future
work will continue to examine its role in CTE, in addition
to other genes, such as the microtubule-associated
protein tau (MAPT) gene.
CEREBROVASCULAR DISEASE
Cerebrovascular disease may interact with RHI to
contribute to the development of CTE. Pathologic corre-
lates of white matter signal abnormalities (WMSA) seen
on MRI (e.g., gliosis, axonal injury) are common and
persisting in former football and soccer players with
extensive RHI exposure, and may contribute to memory
loss, executive dysfunction, aggression, and depression
(Lin et al., 2015; Koerte et al., 2015a). Concussion
has been linked with cerebral hypoperfusion that may
persist (Wang et al., 2016), and boxers exhibit chronic
frontotemporal cerebral hemodynamic impairment
 THE LONG-TERM CONSEQUENCES OF REPETITIVE HEAD IMPACTS
(Bailey et al., 2013). The case series study by Gardner
et al. (2015) found that seven of nine former NFL players
had subcortical or periventricular WMSA. In addition to
RHI-related risk for WMSA, cardiovascular disease
(CVD) and its risk factors are prevalent in active and
former professional American football players (Tucker
et al., 2009; Pokharel et al., 2014; Stamm et al.,
2015a), and is a common cause of death within this pop-
ulation (Lehman et al., 2012). CVD risk factors (e.g.,
obesity) in former NFL players can reduce prefrontal
and temporal perfusion, which may underpin executive
and memory deficits (Willeumier et al., 2012).
AGE
Older age at death is associated with greater CTE patho-
logic severity (McKee et al., 2013). Those who develop
cognitive impairment as an initial presenting symptom
are typically older and have an advanced stage of CTE
(Stern et al., 2013). There is also neuropathologic evi-
dence of CTE in some younger individuals (e.g., in their
20s) who generally had predominantly behavioral/mood
symptoms, and died with early stage CTE because of
suicide, overdose, or incidental death. This subgroup
of individuals may have developed cognitive impairment
and more advanced CTE if they lived longer. In CTE,
age may be a modifier of disease progression vs a
pathogenetic mechanism.
COGNITIVE RESERVE
High cognitive reserve (e.g., as measured by greater
years of education, high occupational attainment) is a
known clinical modifier of neuropathology in neuro-
degeneration (Stern, 2012), and there is strong prelimi-
nary evidence for its protective effects in CTE. For
example, in the examination of the clinical presentation
of neuropathologically confirmed cases of CTE without
comorbid disease by Stern et al. (2013), two of three
asymptomatic subjects who had stage II CTE neuropa-
thology also had advanced graduate degrees. Recent data
also supports a cognitive reserve effect (operationalized
by academic achievement and occupational attainment)
in a sample of former professional American football
players (Wright et al., 2016). Higher cognitive reserve
has also been shown to attenuate cognitive dysfunction
and facilitate recovery following TBI (Kesler et al.,
2003; Schneider et al., 2014).
LIFESTYLE FACTORS
Poor diet, lack of physical activity, and substance abuse
behaviors can all increase vulnerability to neurode-
generation, although the specific contribution of these
factors to CTE remains unknown. Of note, a history of
349
anabolic steroid use is prevalent in contact sport athletes,
but has been shown to be unrelated to CTE neuropatho-
logic severity (McKee et al., 2013). Moreover, many
former American football players with neuropathologi-
cally confirmed CTE played well before the availability
and use of anabolic steroids or other performance
enhancing drugs. However, steroids are known to exac-
erbate neuropsychiatric symptoms, and a recent mouse
model study showed that repetitive TBI was associated
with axonal injury and microgliosis, and that these
pathophysiologic changes were exacerbated by andro-
genic–anabolic steroids (Namjoshi et al., 2016).
CONCLUSIONS AND FUTURE
DIRECTIONS
Chronic traumatic encephalopathy is a unique neurode-
generative disease associated with a history of exposure
to RHI. Neuropathologic and clinical research in CTE
has evolved rapidly over the past decade and has led to
improved understanding of this progressive and devas-
tating, but potentially preventable, brain disease. In par-
ticular, neuropathologic diagnostic criteria have been
developed and clinical research criteria for the in vivo
diagnosis of CTE have been proposed. The existing lit-
erature, however, is not without methodological limita-
tions, and there remain many questions and knowledge
gaps that need to be addressed. CTE research is of high
priority given the millions of individuals who could be
potentially impacted by this disease.
The majority of existing neuropathologic CTE
research is limited by ascertainment bias due to samples
consisting of brain donors with extreme RHI exposure
(e.g., professional contact sport athletes) and suspected
pathology, and who themselves or their family members
have agreed to brain donation. It is important to note that
the objective of current postmortem CTE research is to
neuropathologically define CTE and its clinicopatho-
logic correlates and not to determine epidemiology;
thus, recruitment of subjects at high risk for CTE is
essential. Although the study from the Mayo Clinic’s
large, unbiased brain bank (Bieniek et al., 2015), pro-
vides some initial evidence of the prevalence of CTE
neuropathology in individuals with a history of amateur
contact sports, large epidemiologic postmortem studies
are needed to determine the association between RHI
and CTE in former athletes, military veterans exposed
to blasts, as well as in nonathletic exposure to RHI
(e.g., work-related head trauma, domestic violence, falls
in elderly). Likewise, to date, nearly all neuropathologi-
cally diagnosed cases of CTE have been former male
football players. It will be important to examine larger
numbers of brains of other contact sport athletes exposed
to RHI, particularly former female athletes.
350 M.L. ALOSCO AND R.A. STERN
Refinement of the existing neuropathologic criteria
for CTE will be important for ex vivo differential
diagnosis from other neurodegenerative tauopathies.
Postmortem studies that implement control and neurode-
generative comparison groups will shed light on the
following: (1) the mechanisms of the spread of tau and
other proteins (e.g., b amyloid, TDP-43) involved in
CTE; (2) characterization of the extent and nature of
other pathologic aspects of CTE, including neuronal cell
loss, gliosis, and inflammation; (3) identification of the
involvement of other cortical and subcortical brain
regions involved in the pathogenesis of CTE; and (4)
whether RHI exposure and CTE pathology are associated
with an altered and accelerated development of a variety
of neurodegenerations. Validation of the McKee et al.
(2013) staging classification for the severity and progres-
sion of p-τ in CTE is also a target of future work.
The critical next step is to be able to diagnose CTE
during life, in order to facilitate clinical research on the
nature and course of symptoms, epidemiology, risk fac-
tors, and disease-specific mechanisms. Currently, the
diagnosis of “Probable CTE” is limited due to the lack
of validated biomarkers. This is problematic because
the clinical manifestations of CTE are somewhat similar
to other neurodegenerative diseases (e.g., AD, FTD), and
there is much symptom overlap with psychiatric disor-
ders (e.g., posttraumatic stress disorder, depression),
notably for CTE cases with predominantly behavioral/
mood symptoms. In addition, clinically differentiating
between CTE and persistent postconcussive syndrome
among young individuals with active or recently con-
cluded RHI exposure is challenging, as highlighted by
a recent published case report (Mez et al., 2016).
A grant was recently funded by NINDS for a 7-year,
multicenter study, entitled, “Diagnostics, Imaging,
and Genetics Network for the Objective Study and
Evaluation of Chronic Traumatic Encephalopathy
(DIAGNOSE CTE) Research Project” (PIs: Robert A.
Stern [Contact PI], Jeffrey Cummings, Eric Reiman,
Martha Shenton). That study is currently being con-
ducted with the primary objective of developing
identification of biomarkers that support the diagnosis
of “Probable CTE” during life. DIAGNOSE CTE will
include former athletes with high exposure to RHI
(former NFL players with and without symptoms),
medium exposure to RHI (former college football
players with and without CTE), and a control group
(asymptomatic same-age men without RHI exposure
or TBI). All subjects will undergo clinical examinations
(neurologic, motor, neuropsychologic, neuropsychiat-
ric, and functional assessments), extensive neuroimag-
ing (amyloid and tau PET, MRI, fMRI, DTI, MRS),
lumbar punctures (for CSF biomarkers), and blood
draws (for blood-based biomarkers, as well as DNA
extraction) at baseline and again at a 3-year follow-up.
In addition to biomarkers, DIAGNOSE CTE will refine
and validate clinical diagnostic criteria for CTE, and it
will examine various risk factors (e.g., genetics, life-
style) that interact with RHI to contribute to the patho-
genesis of CTE. Moreover, many of the subjects from
DIAGNOSE CTE will likely agree to brain donation,
which will generate research that can clarify the patho-
genetic mechanisms by which the acute neurologic
consequences of RHI transition to CTE. Simultaneous
to DIAGNOSE CTE, research from UNITE will con-
tinue to conduct clinicopathologic studies in subjects
with neuropathologically confirmed CTE that will help
to determine the pathologic differences in symptom pre-
sentation (e.g., behavior/mood symptoms vs cognitive
impairment). Once CTE can be diagnosed during life
and risk factors are identified, prevalence and incidence
of this disease can be determined, therapeutic targets can
be identified or developed, clinical trials can be initiated,
and clinical and policy-related issues can be addressed.
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