Molecular and Cellular Neuroscience 66 (2015) 81–90

Contents lists available at ScienceDirect

Molecular and Cellular Neuroscience

journal homepage: www.elsevier.com/locate/ymcne

Post-traumatic neurodegeneration and chronic

traumatic encephalopathy
Daniel H. Daneshvar a,b,c, Lee E. Goldstein a,b,c,d,e,f,g,h,i,j, Patrick T. Kiernan a,b,c,
Thor D. Stein a,b,d,k, Ann C. McKee a,b,c,d,k,⁎
a
Boston University Chronic Traumatic Encephalopathy Program, Boston University School of Medicine, 72 E. Concord St., Boston, MA 02118, USA
b
Boston University Alzheimer's Disease Center, Boston University School of Medicine, 72 E. Concord St., Boston, MA 02118, USA
c
Department of Neurology, Boston University School of Medicine, 72 E. Concord St., Boston, MA 02118, USA
d
Department of Pathology and Laboratory Medicine, Boston University School of Medicine, 72 E. Concord St., Boston, MA 02118, USA
e
Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, 72 E. Concord St., Boston, MA 02118, USA
f
Department of Neurosurgery, Boston University School of Medicine, 72 E. Concord St., Boston, MA 02118, USA
g
Boston University Photonics Center, Boston University, 1 Silber Way, Boston, MA 02115, USA
h
Department of Biomedical Engineering, Boston University, 1 Silber Way, Boston, MA 02115, USA
i
Department of Electrical and Computer Engineering, Boston University, 1 Silber Way, Boston, MA 02115, USA
j
Department of Mechanical Engineering, Boston University, 1 Silber Way, Boston, MA 02115, USA
k
VA Boston Healthcare System, 150 South Huntington Avenue, Jamaica Plain, MA 02130, USA

a r t i c l e i n f o a b s t r a c t

Article history: Traumatic brain injury (TBI) is a leading cause of mortality and morbidity around the world. Concussive and
Received 2 February 2015 subconcussive forms of closed-head injury due to impact or blast neurotrauma represent the most common
Accepted 5 March 2015 types of TBI in civilian and military settings. It is becoming increasingly evident that TBI can lead to persistent,
Available online 7 March 2015
long-term debilitating effects, and in some cases, progressive neurodegeneration and chronic traumatic enceph-
alopathy (CTE). The epidemiological literature suggests that a single moderate-to-severe TBI may be associated
Keywords:
Traumatic brain injury
with accelerated neurodegeneration and increased risk of Alzheimer's disease, Parkinson's disease, or motor neu-
Chronic traumatic encephalopathy ron disease. However, the pathologic phenotype of these post-traumatic neurodegenerations is largely unknown
Axonal injury and there may be pathobiological differences between post-traumatic disease and the corresponding sporadic
Brain trauma disorder. By contrast, the pathology of CTE is increasingly well known and is characterized by a distinctive pattern
Posttraumatic neurodegeneration of progressive brain atrophy and accumulation of hyperphosphorylated tau neurofibrillary and glial tangles, dys-
Motor neuron disease trophic neurites, 43 kDa TAR DNA-binding protein (TDP-43) neuronal and glial aggregates, microvasculopathy,
Tau protein myelinated axonopathy, neuroinflammation, and white matter degeneration. Clinically, CTE is associated with
Concussion
behavioral changes, executive dysfunction, memory deficits, and cognitive impairments that begin insidiously
Blast and impact neurotrauma
and most often progress slowly over decades. Although research on the long-term effects of TBI is advancing
quickly, the incidence and prevalence of post-traumatic neurodegeneration and CTE are unknown. Critical
knowledge gaps include elucidation of pathogenic mechanisms, identification of genetic risk factors, and clarifi-
cation of relevant variables—including age at exposure to trauma, history of prior and subsequent head trauma,
substance use, gender, stress, and comorbidities—all of which may contribute to risk profiles and the develop-
ment of post-traumatic neurodegeneration and CTE. This article is part of a Special Issue entitled 'Traumatic
Brain Injury'.
Published by Elsevier Inc.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
1.1. Acute mild TBI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
1.1.1. Concussive and subconcussive injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
1.1.2. Blast injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82

Abbreviations:TDP-43, 43 kDa TAR DNA-binding protein; AD, Alzheimer's disease; APOE ε4, apolipoprotein ε4; Aβ, beta-amyloid; CSF, cerebrospinal fluid; CTE, chronic traumatic enceph-
alopathy; p-tau, hyperphosphorylated tau; mTBI, mild traumatic brain injury; NFTs, neurofibrillary tangles; PHF-tau, paired helical filament-tau; PET, positron emission tomography; PCS,
post-concussion syndrome; TBI, traumatic brain injury.
⁎ Corresponding author at: VA Boston Healthcare System, Boston University School of Medicine, Professor of Neurology and Pathology, Director, CTE Program, Associate Director,
Alzheimer's Disease Center, 150 S. Huntington Avenue, Boston, MA 02130, USA.

http://dx.doi.org/10.1016/j.mcn.2015.03.007
1044-7431/Published by Elsevier Inc.
82 D.H. Daneshvar et al. / Molecular and Cellular Neuroscience 66 (2015) 81–90

1.1.3. Juvenile head trauma syndrome and second impact syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83

1.2. Chronic effects of traumatic brain injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
1.2.1. Cognitive deficits and mood disturbances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
1.2.2. Alzheimer disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
1.2.3. Parkinson disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
1.2.4. Amyotrophic lateral sclerosis or motor neuron disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
2. Chronic traumatic encephalopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
2.1. Clinical symptoms of CTE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
2.1.1. CTE and PTSD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
2.2. Neuropathology of chronic traumatic encephalopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
2.2.1. Gross pathologic features of CTE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
2.2.2. Microscopic pathology of CTE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
2.2.3. TDP-43 pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
2.2.4. Axonal pathology and neuroinflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
2.2.5. Amyloid-β peptide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
2.2.6. Lewy bodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
2.3. Chronic traumatic encephalopathy and co-morbid disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
2.3.1. CTE with motor neuron disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
3. Future areas for research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
3.1. Potential risk factors for CTE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
4. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88

1. Introduction as experimental studies in gyrencephalic piglets demonstrate greater

1.1. Acute mild TBI
1.1.1. Concussive and subconcussive injury
Concussive and subconcussive injuries are thought to be produced
by rapid acceleration and deceleration of the head (Meaney et al.,
1995). Rapid linear or angular acceleration, deceleration or rotational
forces cause the brain to deform, stretching individual neurons, glial
cells and blood vessels and altering membrane permeability. Although
all cell compartments are affected by the injury, blood vessels and
axons are especially vulnerable as they often extend long distances
within the nervous system. In addition to structural deformation, trau-
matic acceleration–deceleration forces produce a rapid influx of calci-
um, efflux of potassium, release of neurotransmitters, and alterations
in the function of cellular sodium–potassium (Na +–K +) pumps.
These trauma-induced alterations in neuronal homeostasis result in
large increases in glucose metabolism and are collectively referred to
as the “neurometabolic cascade of concussion” (Giza and Hovda, 2001,
2014). Post-concussive hypermetabolism in the setting of decreased ce-
rebral blood flow produces a disparity between glucose supply and de-
mand or a cellular energy crisis (Giza and Hovda, 2001). Pathological
studies show that multifocal axonal injury, microhemorrhage, loss of
microvascular integrity, and neuroinflammation occur after concussion
(Blumbergs et al., 1994; McKee et al., 2014; Oppenheimer, 1968). The
astrocytosis is most severe in the cerebral white matter and brainstem
white matter tracts and clusters of activated microglia are most promi-
nent in the white matter around small vessels. Perivascular hemosiderin,
hematoidin-laden macrophages and vascular inflammation may also be
present after concussion, indicating microvascular damage and breach
of the blood–brain barrier. In addition, focal perivascular accumulations
of hyperphosphorylated tau (p-tau) and hyperphosphorylated TDP-43
(p-TDP43) occasionally occur after concussive injury (McKee et al.,
2013, 2014).
The severity of the axonal injury and microvasculopathy generally
parallel the severity of the TBI, with mild injury producing only micro-
scopic axonal damage and rare microhemorrhages, and moderate to se-
vere TBI producing more severe axonal injury with grossly visible
petechial hemorrhages. The degree of axonal injury after traumatic
impact may also vary with the direction of the head impact rotation,
behavioral abnormalities and more persistent axonal injury in piglets
exposed to sagittal versus axial rotational injury (Sullivan et al., 2013).
The axonal injury produced by mild TBI (mTBI) is multifocal, with a ten-
dency to be most severe in the corpus callosum, fornix, parasagittal
white matter and cerebellum, and within these areas, more pronounced
around small blood vessels (McKee et al., 2014).
These axonal changes likely contribute to the severity of symptoms
after mTBI and are major contributors to the development of post-
concussion syndrome (PCS). Acceleration–deceleration injury also causes
tau protein, normally associated with microtubules in axons, to become
abnormally phosphorylated, misfolded, aggregated and cleaved, all of
which generate neurotoxic tau peptide fragments (Amadoro et al.,
2006; Chen et al., 2010; Kanaan et al., 2011; Khlistunova et al., 2006;
McKee et al., 2013; Zilka et al., 2006). It is not clear how these acute alter-
ations develop into a progressive neurodegeneration after repeated injury
in some individuals, however traumatically-induced microvasculopathy
with breach of the blood brain barrier and release of normally excluded
systemic proteins, such as proinflammatory cytokines or other factors
may play a critical role. In addition, recent evidence indicates that a
brain-wide network of paravascular channels, the “glymphatic” pathway,
facilitates the clearance of interstitial solutes, including tau and beta amy-
loid (Aβ), from the brain. Experimentally in mice after acute TBI, the
glymphatic pathway is functionally impaired, an impairment that persists
for one month post injury and enhances the development of neurofibril-
lary pathology and neurodegeneration in post-traumatic rodent brain.
Chronic impairment of glymphatic pathway function after repetitive TBI
may be a key factor promoting tau aggregation and the onset of neurode-
generation (Iliff et al., 2014).
1.1.2. Blast injury
Blast injuries resulting from improvised explosive devices have
become an increasingly important form of TBI in civilian and military
populations. Recent estimates indicate that 10–20% of the 2.5 million
U.S. military service members deployed to Iraq and Afghanistan are
affected by TBI and the majority of these injuries are associated with
blast exposure (The CDC et al., 2013). Individuals exposed to blast are
susceptible to neurological injury with acute and long-term neuropsy-
chiatric and cognitive consequences. Military personnel exposed to re-
petitive mTBI from explosive blast (Goldstein et al., 2012; McKee and
 D.H. Daneshvar et al. / Molecular and Cellular Neuroscience 66 (2015) 81–90
Robinson, 2014; Omalu et al., 2011) show neuropathological changes of
early stage CTE, axonopathy, microvascular damage, astrocytosis and
activated microgliosis at autopsy (Goldstein et al., 2012). Clinical symp-
toms experienced after blast neurotrauma include progressive affective
lability, irritability, distractibility, executive dysfunction, memory dis-
turbances, and cognitive deficits. Four of the five veterans exposed to
blast who showed changes of early stage CTE at autopsy were also diag-
nosed with posttraumatic stress disorder (PTSD) during life suggesting
that PTSD and CTE might be biologically and pathologically intercon-
nected (McKee and Robinson, 2014). The focal p-tau changes associated
with blast neurotrauma share features of early CTE reported in young
American football and soccer players, boxers, head-bangers and others
(Geddes et al., 1999; Goldstein et al., 2012; McKee et al., 2013, 2014).
However, pathologies associated with blast exposure other than tau ac-
cumulation, including axonal injury and microvascular damage, most
likely are important contributors to the clinical and behavioral abnormal-
ities observed after blast injury. It is worth noting that laboratory mice ex-
posed to a single experimental blast also demonstrate brain pathology,
physiologic and functional changes very similar to those found after
human blast injury—including myelinated axonopathy, focal
microvasculopathy, neuroinflammation, neuronal loss, phosphorylated
tau proteinopathy, electrophysiological abnormalities, behavioral impair-
ments, and cognitive deficits (Goldstein et al., 2012). An independent rep-
lication study reported brain tau proteinopathy that persisted for at least
one month after exposing mice to a single blast (Huber et al., 2013).
Blast injuries represent a wide range of heterogeneous injuries and
are often complicated by other types of TBI, including closed-head
impact injury (Nakagawa et al., 2011). The occurrence of microscopic
neuropathology related to military blast exposure was first reported in
deceased World War I infantry soldiers by Sir Frederick Mott (Mott,
1916, 1919). While blast-induced brain pathology has been repeatedly
reported in humans and experimental animals, the origins of these inju-
ries are only recently beginning to be understood (Goldstein et al.,
2014). Kinematic analysis of high-speed videographic records obtained
in a military-relevant blast neurotrauma mouse model has shown that
blast winds with velocities of more than 330 miles/h—greater than the
most intense wind gust ever recorded on earth—produce rapidly oscil-
lating inertial forces on the head that induce injurious shearing forces
in the brain (Goldstein et al., 2012). An important point is that blast
winds, not blast waves, are responsible for the resulting cerebral injury,
whereas the acoustic blast wave produces little deformation of brain
tissue as a consequence of rapid shockwave pressure equilibration
(Goldstein et al., 2012). Blast injuries may also produce diffuse or focal
hemorrhage and edema as blood vessels and brain tissue rapidly
contract and expand several times within the fraction of a second fol-
lowing transit of the blast shock wave. Some of the traumatic effects
of blast exposure can be mitigated by immobilizing the head during
blast exposure.
1.1.3. Juvenile head trauma syndrome and second impact syndrome
In children and young adults, minor brain trauma can occasionally
produce catastrophic, often fatal, cerebral edema and coma. If the neu-
rological deterioration occurs after a single TBI, it is referred to as juve-
nile head trauma syndrome (McQuillen et al., 1988). The neurological
collapse may be immediate or delayed, occurring after a “lucid interval”.
Juvenile head trauma syndrome is thought to represent rapid vasodila-
tion and redistribution of blood into the brain parenchyma after impact
injury, a process that may involve a functional age-related channelopa-
thy. Some individuals with juvenile head trauma syndrome have a mu-
tation in the calcium channel subunit gene (CACNA1A) associated with
familial hemiplegic migraine (Kors et al., 2001). Occasionally, juvenile
head trauma syndrome develops in a young athlete who experiences
two head injuries, with the second injury occurring before complete re-
covery from the first impact, similar to second impact syndrome (SIS)
(McQuillen et al., 1988).
83
SIS occurs when an individual sustains an initial mild head injury or
concussion, then suffers a second head injury before the symptoms as-
sociated with the first injury have cleared, the condition is associated
with rapid diffuse cerebral swelling and neurological deterioration
(Cantu, 1998; Cantu and Gean, 2010; Logan et al., 2001; Miele et al.,
2004; Mori et al., 2006; Saunders and Harbaugh, 1984). Typically, the
second injury is only a minor blow to the head, and there is no immedi-
ate loss of consciousness. However, within minutes of the injury, severe
cerebrovascular engorgement, cerebral edema and brain herniation de-
velop, associated with precipitous collapse. All reported cases of SIS
have involved young athletes, predominantly males (90%) ranging in
age from 10–24 years, mean age 17.9 years (Mori et al., 2006). Most
affected athletes were American football players, usually at the high
school level, but younger players and collegiate athletes have also
been reported. SIS has also occurred in association with boxing, karate,
skiing and ice hockey. It is thought to result from an abrupt posttrau-
matic loss of cerebral blood flow autoregulation and catecholamine
release that produce a rapid increase in intracranial blood volume and
catastrophic cerebral edema (Clifton et al., 1981; Lam et al., 1997). The
relationship of SIS to juvenile head trauma syndrome is uncertain, and
both may be manifestations of the same underlying pathophysiology.
1.2. Chronic effects of traumatic brain injury
A single moderate to severe TBI with loss of consciousness (LOC) is
associated with a 2–4 fold increased risk of dementia in later life
(Institute of Medicine Committee on Gulf War and Health: Brain
Injury in, 2008; Shively et al., 2012). The dementia is most often catego-
rized as probable or possible Alzheimer's disease (AD) using validated
clinical criteria, but few studies included neuropathological verification,
and clinical overlaps between AD, CTE and other post-traumatic
neurodegenerations are known to occur (Stern et al., 2013). Studies
also support a link between a remote single TBI and Parkinson's disease
(PD) and amyotrophic lateral sclerosis (ALS), although the pathological
features of traumatically induced PD and ALS may differ considerably
from the sporadic versions of these neurodegenerations (Daneshvar
et al., 2013; Kenney et al., 2014).
1.2.1. Cognitive deficits and mood disturbances
Retired professional football players who sustained 3 or more con-
cussions were found to report more cognitive symptoms including a
threefold increase in significant memory impairment, and a fivefold
increase in diagnosed mild cognitive impairment compared to retired
players without a history of concussion (Guskiewicz et al., 2005).
Other studies found cognitive deficits on neurological and neuropsycho-
logical examination in retired NFL athletes (Ford et al., 2013; Hart et al.,
2013; Randolph et al., 2013), that were associated with white matter
pathology on DTI and FLAIR imaging and alterations in regional cerebral
blood flow (Hampshire et al., 2013; Hart et al., 2013). A study of fifteen
retired professional football players with a history of concussions and
free of co-morbid conditions showed that there were decreases in frac-
tional anisotropy and increases in mean and radial diffusivity in the
frontal–parietal tracts and corpus callosum on DTI compared to an age
and education matched control group (Tremblay et al., 2014). Further-
more, these changes significantly correlated with a decline in episodic
memory decline. Retired NFL players with only mild deficits in execu-
tive functioning showed hyperactivation and hypoconnectivity of the
dorsolateral frontal and frontopolar cortices on fMRI (Hampshire et al.,
2013). Clinical and functional impairments in cognition have also been
correlated with the frequency of head impacts in high school and
collegiate football players wearing helmet-mounted accelerometers
(Breedlove et al., 2012; McAllister et al., 2012; Talavage et al., 2014), al-
though not all helmet sensor studies have supported this relationship
(Broglio et al., 2011; Gysland et al., 2012).
Brain trauma experienced in sport has also been linked to distur-
bances in mood. Retired professional football players who experienced
84 D.H. Daneshvar et al. / Molecular and Cellular Neuroscience 66 (2015) 81–90
three or more concussions reported a threefold increase in diagnosed
depression (Guskiewicz et al., 2007). A follow up survey administered
nine years later provided further evidence for a dose–response relation-
ship between self reported concussions and depressive symptoms later
in life (Kerr et al., 2012). Neuropsychological assessment in former pro-
fessional football players has confirmed the relationship between in-
creased self reported concussions and depression (Didehbani et al.,
2013). Depression in these athletes is also associated with increased
fractional anisotropy on DTI, as well as white matter abnormalities on
structural imaging (Hart et al., 2013; Strain et al., 2013).
1.2.2. Alzheimer disease
In a meta-analysis of 15 case–control studies, males who had a single
head injury associated with loss of consciousness (LOC) had a 50% in-
creased risk of AD dementia (Fleminger et al., 2003). In a recent study
of older veterans, a history of TBI was associated with a 60% increase
in the risk of developing dementia and an accelerated age of onset by
2 years (Barnes et al., 2014). In the MIRAGE study, head injury increased
the risk of AD and the magnitude of the risk was proportional to the se-
verity of the head trauma and heightened among first-degree relatives
of AD patients (Guo et al., 2000). A longitudinal study involving World
War II Navy veterans also demonstrated increased risk for AD in
late life with increasing TBI severity (Plassman et al., 2000). Veterans
with severe TBI with loss of consciousness (LOC) or prolonged post-
traumatic amnesia (PTA) were 4 times more likely to have AD, whereas
veterans with moderate TBI were twice as likely to have AD in late-life
compared to controls (Plassman et al., 2000). No increased risk was
found for veterans who had a mTBI (LOC or PTA less than 30 min).
Other studies indicate that while moderate–severe TBI increases the
risk for dementia age groups older than 55 years, mTBI increases the
risk of dementia only among individuals older than 65 years (Gardner
et al., 2014).
Other studies have also suggested that TBI precipitates an earlier
onset of AD. In the Northern Manhattan study, a history of head injury
with LOC was associated with earlier onset of AD dementia, whereas
mTBI was not significantly associated with earlier onset of AD dementia,
and those with severe TBI were at significantly increased risk for AD
Fig. 1. Atypical AD-like neurodegeneration, Lewy body disease, and axonopathy in a 62 year old woman 11 years after a single severe TBI.
(Schofield et al., 1997). Reanalysis of the Rochester Epidemiology Pro-
ject data also indicated that the age of onset of AD among AD patients
with head injury was 8 years earlier than the expected time of onset
predicted by a life-time method based on 689 AD patents without
head injury in the same cohort (Guo et al., 2000). Nordstrom et al.
evaluated the risk of young onset of dementia (dementia before the
age of 65 years) after TBI in a cohort of more than 800,000 young men
followed for over 3 decades. They found a strong dose–response associ-
ation between TBI and young onset dementia, with more severe or more
frequent TBI associated with increasing risk (Nordström et al., 2014).
Most case control and longitudinal epidemiologic studies of demen-
tia after TBI use only clinical criteria to diagnose AD. Recent clinical
studies show that CTE and other post-traumatic, neuropathologically
verified degenerations share considerable clinical features with AD
and may be incorrectly diagnosed as probable AD. There have been
only a few reports of head injury that used neuropathological confirma-
tion of the AD diagnosis. Jelling and colleagues examined the incidence
of AD pathology in 55 consecutive autopsy cases with a history of single
TBI. They found definite or probable AD in 21.8% that was significantly
higher than the 14% expected in an age-matched general population
(Jellinger et al., 2001).
The pathological link between Alzheimer's neurodegeneration and
TBI may be related to the accumulation of Aβ and tau proteins after
trauma. Aβ plaques and intra-axonal Aβ deposits have been found
in approximately one third of TBI subjects dying shortly after injury
(DeKosky et al., 2007; Gentleman et al., 1997; Ikonomovic et al.,
2004), even in young subjects (Horsburgh et al., 2000), and may contin-
ue to accumulate chronically (Johnson et al., 2010). Murine models also
show transient elevation of amyloid precursor protein (APP), and intra-
axonal Aβ deposits after acute TBI (Chen et al., 2004). Neuropathological
analysis of 18 cases of fatal TBI showed widespread axonal injury, accu-
mulation of neurofilament protein, amyloid APP, Aβ and alpha-
synuclein in axonal bulbs and varicosities (Uryu et al., 2007). p-Tau pro-
tein was also found to accumulate in both axons and neuronal cell bod-
ies (Uryu et al., 2007). p-Tau immunoreactive neurofibrillary tangles
(NFTs) have been observed in young individuals dying weeks to months
after their last concussion (McKee et al., 2014). An autopsy study of 32
 D.H. Daneshvar et al. / Molecular and Cellular Neuroscience 66 (2015) 81–90
long-term single TBI survivors (age range: 19–60 years, mean 48 years,
93% male, survival 1–47 years, mean 8.4 years after TBI) found wide-
spread Aβ plaques and p-tau NFTs in one third of subjects. NFTs were
particularly increased in subjects under the age of 39 years compared
to age-matched controls. The NFTs were described as superficial and
slightly clustered at sulcal depths suggesting that a single, moderate to
severe traumatic injury may promote the development of an atypical
AD-like neurodegeneration (Johnson et al., 2010). In an individual
case report, a 62 year old woman developed progressive dementia
and parkinsonism 11 years after a severe motor vehicle accident; at
autopsy, her brain showed multiple neurodegenerative processes
including atypical AD, Lewy body disease, axonopathy and TDP-43
proteinopathy (Fig. 1). A strikingly similar case was reported by Kenney
and colleagues (Kenney et al., 2014). The subject was a 75-year-old man
who developed a rapidly progressive dementia 12 years before death
and 25 years after a moderate to severe TBI. Neuropathological exami-
nation revealed atypical AD with hippocampal sparing and severe
white matter degeneration. These reports suggest that moderate–se-
vere TBI may generate unique neurodegenerative processes with clini-
copathological phenotypes unlike sporadic disease (Kenney et al.,
2014). It is also worth noting that many individuals who suffer TBI do
not develop dementia, as suggested by Gardner and Yaffe “post-TBI neu-
rodegeneration is a multifactorial process that is likely dependent upon
number, mechanics, and timing of TBIs, individual genetics, and many
other health-related, lifestyle, and environmental risk and protective
factors” (Gardner and Yaffe, 2014).
At autopsy, her brain showed multiple neurodegenerative processes
including widespread diffuse plaques in the neocortex (A, B (Aβ immu-
nostaining), C (Bielschowsky silver method)), Lewy body disease with
abnormally large Lewy bodies in the thalamus and mammillary bodies
(D, E, F (alpha-synuclein immunostaining)), axonopathy with extreme-
ly large axonal spheroids in the thalamus (G (SMI-34 immunostain), H
(AT8 immunostaining)), and an atypical distribution of p-tau NFTS
and dystrophic neurites (AT8 immunostaining) (I, locus coeruleus, J, K,
temporal cortex, L, median raphe), all calibration bars = 100 μm.
Several investigators have studied the relationship between inheri-
tance of an apolipoprotein ε4 (APOE ε4) allele and dementia after TBI.
In the Northern Manhattan population study, a history of TBI and inher-
itance of an APOE ε4 allele were associated with a 10-fold increased risk
of AD, while APOE ε4 in the absence of TBI resulted in only a 2-fold
increased risk (Mayeux et al., 1995). These results are in contrast to
findings in the MIRAGE study in which head injury increased the odds
of AD to a greater extent among those lacking the APOE ε4 allele com-
pared to those having one or two ε4 alleles (Guo et al., 2000).
There is also evidence that APOE ε4 is associated with deposition of Aβ
protein after head injury (Hartman et al., 2002). APOE ε4 has been associ-
ated with increased severity of chronic neurologic deficits in boxers with
high exposure to repetitive trauma compared to those without an APOE
ε4 allele (Jordan et al., 1997). In addition, inheritance of an APOE ε4 allele
is associated with longer periods of unconsciousness following severe
blunt traumatic injury as well as poorer functional outcome (Friedman
et al., 1999). Furthermore, Aβ deposition in CTE is associated with the
APOE ε4 allele and significantly increased in CTE compared to a normal
aging population (Thor Stein, personal communication).
1.2.3. Parkinson disease
In addition to AD, a link has been suggested between TBI and PD. In a
case–control study, data from the Rochester Epidemiology Project was
used to identify 196 subjects who developed PD and compared to con-
trols matched for age and gender. The frequency of head trauma was
significantly higher in PD cases compared to controls (OR 4.3). The OR
for PD was substantially increased (11.0) in subjects who experienced
mTBI with LOC or more severe TBI (Bower et al., 2003). Animal studies
have shown that the brains of aged TBI-injured mice develop a transient
increase in alpha-synuclein that is not found in sham-injured aged ani-
mals or TBI-injured young mice (Uryu et al., 2006). As parkinsonian
85
symptoms may result from neuronal loss in the substantia nigra associ-
ated with either accumulation of alpha-synuclein in Lewy bodies, as oc-
curs in PD, or p-tau inclusions in the form of NFTs, as occurs in CTE, AD
and many other tauopathies, it is likely that non-alpha synuclein pathol-
ogies contribute to the increased frequency of Parkinsonism following
TBI (Uryu et al., 2003).
1.2.4. Amyotrophic lateral sclerosis or motor neuron disease
ALS is a fatal progressive degeneration of motor neurons in the brain
and spinal cord. Ninety to 95% of ALS cases are sporadic; gene mutations
in copper/zinc superoxide dismutase 1, senataxin, dynactin, angiogenic,
and TAR-DBP (the gene for TDP-43 on chromosome 1) account for some
familial forms of the disease (Bruijn et al., 2004). ALS is pathologically
characterized by motor neuron loss and corticospinal tract degenera-
tion. Remaining motor neurons in sporadic ALS often have ubiquitin-
and TDP-43 immunoreactive inclusion bodies that appear either as
rounded or skein-like inclusions.
Although the etiology of sporadic ALS is unknown, it may involve in-
teraction between genetic and environmental risk factors. Many envi-
ronmental risk factors have been considered as possible triggers of
ALS neurodegeneration, including a history of trauma to the brain and
spinal cord (Chen et al., 2007; Schmidt et al., 2010; Strickland et al.,
1996). Recent literature points toward a trend not only between CNS
trauma and the development of ALS but also between a smaller number
of years between the last injury and ALS diagnosis, and older age at the
last injury and the development of ALS (Schmidt et al., 2010). In a case
control study of 109 cases of ALS and 255 controls, Chen et al. (2007)
found that having experienced repeated head injuries or having been
injured within the 10 years before diagnosis was associated with a
more than 3-fold higher risk of ALS, with a slightly elevated risk for
the interval 11 to 30 years. The authors also further performed a
meta-analysis of 8 previous ALS studies and estimated a pooled OR of
1.7 (95% CI, 1.3–2.2) for at least one previous head injury. Another
case–control study, which was not included in the meta-analysis, re-
ported an increased risk of ALS when the last head injury occurred at
an older age and closer to the time of diagnosis (Binazzi et al., 2009).
ALS incidence and mortality are also reported to be unusually high
among professional soccer players in Italy (Chio et al., 2005). ALS mor-
tality for Italian professional soccer players was increased 12-fold,
whereas mortality from other causes was generally lower or compara-
ble to that of the general population (Belli and Vanacore, 2005). Further-
more, an incidence study involving 7325 Italian professional soccer
players showed that the incidence of ALS was 6.5 times higher than ex-
pected (Chio et al., 2005). A study looking at cause of death in retired
NFL players who played for 5 years or more were found have a 4.31
higher risk of developing ALS and a 3.86 higher risk of developing de-
mentia compared to age and gender matched controls. Although the
death certificates indicated dementia and ALS, there was no neuropath-
ological verification of the neurodegenerative processes, and the actual
underlying diagnoses might well have included CTE and CTE with motor
neuron disease (CTE-MND) (Lehman et al., 2012).
Table 1
Characteristics of the hyperphosphorylated tau pathology in CTE.
Adapted from McKee et al., Brain 2013.
1. Perivascular foci of p-tau immunoreactive astrocytic tangles (ATs) and
neurofibrillary tangles (NFTs)
2. Irregular cortical distribution of p-tau immunoreactive NFTs and ATs with a
predilection for the depth of cerebral sulci
3. Clusters of subpial and periventricular ATs in the cerebral cortex, diencephalon,
and brainstem
4. NFTs in the cerebral cortex located preferentially in the superficial layers
86 D.H. Daneshvar et al. / Molecular and Cellular Neuroscience 66 (2015) 81–90
2. Chronic traumatic encephalopathy
2.1. Clinical symptoms of CTE
The symptoms of CTE are insidious, often first manifested as dis-
turbances in attention or concentration or depression that are occa-
sionally associated with headaches. Short-term memory difficulties,
aggressive tendencies, executive dysfunction and explosivity are
also frequent symptoms. Characteristically the first symptoms usual-
ly appear around ages 35–45 years, although the range is broad, from
24 years to 65 years (McKee et al., 2013). There is characteristically a
long latent period (mean 8 years, range 0–37 years) between the last
trauma and the development of symptoms (McKee et al., 2009),
however some athletes develop symptoms while playing that do
not improve once sports participation has stopped. In these individ-
uals, it is unclear if the symptoms represent prolonged post-
concussive symptoms or the early manifestations of CTE. Unlike
other neurodegenerative disorders, headache is a persistent and
early symptom in nearly half the individuals who develop CTE. The
headache may be migrainous or a constant dull pain.
Other personality and behavioral changes that are common in
individuals with early (Stage I or II) CTE are irritability, explosivity,
and erratic behaviors (McKee et al., 2013). Early-stage CTE is often
asymptomatic, and the symptoms that may be present, including head-
ache, loss of attention and concentration, depression and irritability are
non-specific (Daneshvar et al., 2011b). Subjects with Stage II CTE are
usually symptomatic and demonstrate short-term memory difficulties,
aggressive tendencies, difficulties with planning and organization,
mood swings and explosivity (McKee et al., 2013; Stern et al., 2013).
By Stage III disease, most subjects are considered cognitively impaired
and by Stage IV CTE, executive dysfunction and memory loss are usually
severe and most are demented. Other symptoms often include im-
pulsivity, suicidality, language difficulties, paranoia, and visuospatial
abnormalities; approximately one third are suicidal at some point in
their course. Gait disturbances, dysarthria, and Parkinsonism are
found in about 10% of individuals with CTE in association with late
stage disease.
Recent case series of athletes with neuropathologically confirmed
CTE suggested that there are three distinct presentations of CTE: one
with a younger age at onset that presents as behavioral disturbances
(e.g., impulsivity, violence) or mood changes (e.g., depression, hopeless-
ness), another that manifests later in life as cognitive impairment
(e.g., episodic memory deficits, executive dysfunction), and a mixed
presentation that presents with both behavioral, mood and cognitive
symptoms (Montenigro et al., 2014; Stern et al., 2013). Demented sub-
jects with neuropathologically diagnosed with Stage IV CTE often meet
clinical criteria for AD established by the National Institute on Aging-
Alzheimer's Association (NIA-AA) Workgroup and the NINCDS-ADRDA
(Stern et al., 2013). Current research is focused on delineating aspects of
the clinical presentation that could help distinguish CTE from AD, in addi-
tion to the history of neurotrauma (Montenigro et al., 2014).
In CTE, the severity of cognitive impairment is most likely associated
with several pathologies, including neuroinflammation, axonal, neuro-
nal and synapse loss and the accumulation of toxic aggregates of tau
and TDP proteins. The severity of the tau pathology almost certainly
contributes to cognitive decline and behavioral changes, as has been
shown for AD (McKee et al., 1991), however, there is also substantial
axonal pathology and neuroinflammation in CTE that might contribute
to the development of personality and behavior changes, especially in
early stages of disease when the accumulations of p-tau are minimal.
Other contributors to clinical symptoms include accumulations of
toxic forms of pTDP-43. Although the clinical symptoms of CTE often
begin with behavior and personality changes in a person's thirties or
forties similar to frontotemporal lobar degeneration (FTLD), the
clinical course of CTE is considerably slower and often spans three
or four decades.
2.1.1. CTE and PTSD
The clinical course of CTE (and some TBI) frequently overlaps with
posttraumatic stress disorder (PTSD). All 3 conditions are characterized
by neuropsychiatric symptoms indicative of frontal lobe dysfunction
including alterations in working memory, planning, multitasking, com-
plex decision making, judgment, empathy, executive function, impulsivi-
ty, emotional lability, and disinhibition, as well as changes in personality
and social behavior. Some individuals diagnosed with PTSD have neuro-
pathological changes of CTE at autopsy (Goldstein et al., 2012), and it is
possible that CTE, axonal injury and neuroinflammation may underlie
some of the symptoms that are associated with PTSD.
2.2. Neuropathology of chronic traumatic encephalopathy
Like many neurodegenerative diseases, CTE can only be diagnosed
definitively at post-mortem neuropathological examination (McKee
et al., 2009, 2013; Stern et al., 2013) and no consensus criteria or bio-
markers of disease currently exist that can be used to aid in the clinical
diagnosis of CTE (Stern et al., 2013). Corsellis, Bruton, and Freeman-
Browne described the clinical symptoms and neuropathological find-
ings in 15 former boxers (Corsellis et al., 1973). They noted a reduction
in brain weight, enlargement of the lateral and third ventricles, thinning
of the corpus callosum, cavum septum pellucidum with fenestrations,
and scarring and neuronal loss of the cerebellar tonsils. Using histolog-
ical stains including silver stains they also described neurofibrillary
degeneration of the substantia nigra and cerebral cortex, often in the ab-
sence of senile plaques. Subsequent studies using immunocytochemical
techniques determined that many of the original cases from Corsellis
showed widespread diffuse Aβ deposits. Recent analysis over 140
cases of CTE from the VA-BU-SLI CTE Brain Bank determined that 67%
of CTE cases have no evidence of Aβ deposition either as diffuse or neu-
ritic senile plaques or amyloid angiopathy. Furthermore, Aβ deposition
in this large series was significantly associated with age at death, and no
subjects less than 50 years demonstrated Aβ deposition as diffuse or
neuritic plaques.
2.2.1. Gross pathologic features of CTE
The most commonly observed gross pathologic features of CTE are
generalized cerebral atrophy, with a tendency to affect the frontal, tem-
poral and medial temporal lobes most severely, thalamic, hypothalamic
and mammillary body atrophy, enlargement of the lateral and third
ventricles, thinning of the corpus callosum, cavum septum pellucidum,
septal fenestrations, and pallor of the substantia nigra and locus
coeruleus (Daneshvar et al., 2011b; McKee et al., 2009, 2010). Cerebellar
scarring, a feature recorded often in early reports of boxers, is not a com-
mon feature of CTE in modern day athletes, although there is often mi-
croscopic evidence of p-tau neurodegeneration in the dentate nucleus
of the cerebellum and roof of the fourth ventricle.
2.2.2. Microscopic pathology of CTE
2.2.2.1. Hyperphosphorylated tau (Table 1). CTE is a tauopathy, and mi-
croscopically there are widespread deposits of p-tau protein as NFTs
throughout the brain (McKee et al., 2009, 2013). Tau in CTE is similar
biochemically to tau in AD. It is composed of both 3- and 4-
microtubule binding repeat tau, with a ratio of 4 versus 3 microtubule
binding repeat tau of ~ 1 (although the pattern of neuronal 4R tau in
CTE differs from AD) and six abnormally phosphorylated tau isoforms
(McKee et al., 2013; Stern et al., 2013). Two microscopic features unique
to CTE, not found in another tauopathy, are that the tau pathology in CTE
is 1) perivascular 2) irregularly distributed in the depths of cortical sulci.
The early p-tau deposition of CTE affects the cerebral cortex, primarily
the frontal, temporal, septal and insular neocortex, although the ento-
rhinal and parahippocampal cortex may occasionally be affected in
young subjects. Unlike the early stages of AD, however, the hippocam-
pus is spared in early phases of CTE. Abnormal p-tau astrocytes are
 D.H. Daneshvar et al. / Molecular and Cellular Neuroscience 66 (2015) 81–90
also commonly found in the subpial region at the sulcal depths. There
may be scattered tau deposition in the ependyma lining the ventricles
and on the lateral surface of the brainstem. Scattered tau positive axonal
varicosities and neuropil threads are found in the subcortical and deep
white matter.
2.2.2.2. Stages of CTE: evolution of p-tau pathology.
Stage I: In Stage I CTE, tau is found in focal, perivascular clusters as
NFTs and dystrophic neurites, often at the sulcal depths of
frontal, septal or temporal cortex. The surrounding cortex is
typically unremarkable although rare NFTs may be found in
the deep nuclei, such as the locus coeruleus.
Stage II: In Stage II CTE, multiple discrete clusters of perivascular p-tau
NFTs are found in the sulcal depths, most commonly in fron-
tal, temporal, parietal, insular and septal cortices. NFTs are
also found in the superficial layers of adjacent cortex sur-
rounding the epicenters. The nucleus basalis of Meynert
and locus coeruleus show NFTs as well. Rare NFTs may be
found in entorhinal cortex, amygdala, hippocampus, thala-
mus, substantia nigra, and dorsal and median raphe nuclei
of the midbrain.
Stage III: In Stage III CTE, the medial temporal lobe structures including
the hippocampus, entorhinal cortex, and amygdala show neu-
rofibrillary degeneration, and there is widespread involvement
of the frontal, temporal parietal, insula and septal cortices.
Moderate densities of NFTs are found in olfactory bulbs, hypo-
thalamus, thalamus, mammillary bodies, substantia nigra and
dorsal and median raphe nuclei.
Stage IV: In Stage IV CTE, there are dense NFTs in widespread regions of
the brain, with prominent neuronal loss and gliosis of the neo-
cortex and increasing p-tau in astrocytes. There is prominent
neuronal loss in CA1 of the hippocampus and subiculum, cere-
bral cortices and increasing myelinated fiber and axonal loss in
the white matter. Severe p-tau pathology is found in the cere-
bral cortex, diencephalon, basal ganglia, and brainstem, white
matter tracts and spinal cord. Primary visual cortex is spared.
2.2.3. TDP-43 pathology
The majority of CTE cases also demonstrate TDP-43 immunoreactive
intraneuronal and intraglial inclusions and neurites (McKee et al.,
2010). The pathology ranges from cytoplasmic neuronal inclusions
that partially co-localize with p-tau inclusions to glial inclusions and
abnormal neurites (McKee et al., 2010). TDP-43 immunoreactivity
increases with the degree of tau pathology, and is found in nearly all
Stage IV cases as TDP-43 positive rounded and threadlike neurites,
intraglial and intraneuronal inclusions. Cases with the most severe
TDP-43 deposition show dense accumulations of TDP-43 inclusions
and neurites in all layers of the neocortex, particularly layer II, as well
as occasional TDP-43-positive inclusions in the dentate fascia of the hip-
pocampus, a distribution pattern that overlaps with the distribution
of TDP-43 found in frontotemporal lobar degeneration with TDP-43
(FTLD-TDP) (Cairns et al., 2007).
TDP-43 is an RNA-binding protein that regulates RNA metabolism
(Sephton et al., 2010, 2012) and binds to tau (Sato et al., 2009). Dysreg-
ulation of TDP-43 may influence tau isoform expression and the devel-
opment of tau pathology (Morales et al., 2009). Diseases caused by
abnormal TDP-43 metabolism have shown altered tau metabolism
including hyperphosphorylation, tau phosphatase resistance, and depo-
sition of p-tau intracellular aggregates (Strong and Yang, 2011). In ex-
perimental in mouse models of TBI, either from controlled cortical
impact or blast injury, elevated breakdown fragments of TDP-43 are
found (Yang et al., 2014). In addition, TDP-43 and its 35 kDa fragment
levels are elevated in the cerebrospinal fluid (CSF) of patients with
severe TBI.
87
2.2.4. Axonal pathology and neuroinflammation
In addition to p-tau pathology, axonal pathology is also present at all
stages of CTE and progresses with CTE severity. In the earliest stages of
disease, distorted axonal varicosities are found in the cortex, subcortical
white matter, and deep white matter tracts of the diencephalon. By
Stage III CTE, severe axonal loss and pathological profiles are found in
the subcortical white matter, and are most severe in the frontal and
temporal lobes. In advanced CTE, there is widespread axonal loss with
frequent severely distorted axonal profiles widely distributed in the
subcortical white matter (McKee et al., 2013).
In addition to degeneration of myelinated axons, neuroinflamma-
tion is a consistent feature of CTE, perivascular clusters of activated mi-
croglia are found throughout the subcortical white matter in early stage
CTE, in later stage disease, dense activated microglia are found through-
out the gray and white matter. A robust astrocytosis also found in the
white matter of early stages of CTE, in more advanced disease, generalized
astrocytosis is found throughout the gray and white matter.
2.2.5. Amyloid-β peptide
Aβ containing plaques, especially diffuse Aβ plaques, are present in
some cases of CTE, although they are not a consistent feature of CTE,
are not found in early stage disease, and are significantly associated
with age at death (McKee et al., 2013). Compared to a normal aging
population, Aβ deposition occurs at an earlier age and at an accelerated
rate in CTE, and is associated with increased clinical and pathological se-
verity (Thor Stein, personal communication).
2.2.6. Lewy bodies
Alpha-synuclein positive Lewy bodies are found in approximately
20% of CTE cases, and are significantly associated with the age of the
subject at death (McKee et al., 2013).
2.3. Chronic traumatic encephalopathy and co-morbid disease
Like most other neurodegenerative diseases (Gorell et al., 1994;
Jicha and Carr, 2010; Kalaria, 2000; Sonnen et al., 2007; Waite et al.,
1997), CTE is associated with the development of other neuro-
degenerations, especially as a function of increased age (Hazrati et al.,
2013; McKee et al., 2010, 2013). Of 142 neuropathologically confirmed
cases of CTE, 15 (10.56%) had coexistent motor neuron disease (MND), 15
(10.56%) AD, 10 (7.04%) Lewy Body disease, 4 (2.82%) frontotemporal
lobar degeneration (FTLD), and 7 (4.93%) had two or more of these
comorbidities; 89 (63.16%) cases were diagnosed only with CTE.
2.3.1. CTE with motor neuron disease
Approximately 10–13% of individuals with CTE develop a progres-
sive motor neuron disease (MND) that is clinically indistinguishable
from sporadic ALS (McKee et al., 2010, 2013). Typically, individuals
with CTE and MND present with motor weakness, atrophy and fascicu-
lations and develop mild cognitive and behavioral symptoms several
years after the onset of their motor disorder. Among the 142 neuro-
pathologically confirmed cases of CTE, there were 16 individuals who de-
veloped a progressive motor neuron disease (MND) (11.4%) (McKee et al.,
2013, 2014). Most subjects presented with motor weakness, atrophy and
fasciculations and developed mild cognitive and behavioral symptoms
several years after the onset of motor symptoms. The mechanisms under-
lying the development of MND after trauma remain unknown but p-tau
lesions are frequently found in early CTE, and electrophysiological abnor-
malities have been found in the motor cortex after concussion in young
athletes (Pearce et al., 2014) in retired athletes (De Beaumont et al.,
2013). Furthermore, there is recent evidence suggesting that lesions to
the motor cortex induce amyotrophic lateral sclerosis (Rosenbohm
et al., 2014). Multiple experimental models of TBI in mice have demon-
strated increased fragmentation of TDP-43 and relocation of TDP-43
from its normal position in the nucleus to the cytoplasm where it is asso-
ciated with degeneration (Moisse et al., 2009a,b; Yang et al., 2014).
88 D.H. Daneshvar et al. / Molecular and Cellular Neuroscience 66 (2015) 81–90
3. Future areas for research
Other than trauma, the risk factors for CTE remain unknown, but are
likely multifactorial. Genotypic, diagnostic, and prognostic markers are
urgently needed to assess CTE risk, resilience, and responsivity to treat-
ment in individuals at risk for the disease. Other factors such as gender,
age at first exposure, number, timing and severity of head injuries,
cognitive reserve and flexibility, substance use and neuropsychiatric co-
morbidities are likely modulators of CTE diathesis and disease progres-
sion. The contribution of these and other factors to CTE pathogenesis are
poorly understood, especially in the context of individual patients. At
present, CTE is a postmortem diagnosis. Consequently, clinicians are in
critical need of objective diagnostic biomarkers to enable reliable detec-
tion, staging, and tracking of CTE during life. Biomarkers are also needed
for assessment of presymptomatic, incipient, and prodromal disease.
Development of sensitive and specific diagnostics is essential for identi-
fication of individuals “at risk” who may benefit from early intervention
as emerging therapeutics become available. Moreover, reliable bio-
markers for CTE are required to monitor therapeutic and rehabilitative
efficacy, as well as to guide comprehensive multidisciplinary care
services for patients and their families. Understanding the mechanistic
underpinnings of CTE pathobiology is an essential prerequisite for de-
velopment of new treatments, diagnostics, and rehabilitative strategies
for this devastating disease. For this there is no substitute for “bench-to-
bedside” translational research (Goldstein et al., 2014).
3.1. Potential risk factors for CTE
Several studies indicate that the APOE ε4 allele may be associated
with a poorer prognosis in patients with severe TBI (Zeng et al., 2014).
Allelic variation in APOE in boxers and professional football players
has also been implicated in prolonged recovery time and poorer cogni-
tive outcome after a single TBI (Jordan et al., 1997). Several studies have
reported a higher than expected prevalence of APOE ε4 carriers and
homozygotes in individuals with neuropathologically confirmed CTE
(McKee et al., 2009, 2013; Stern et al., 2013). While no genes have
been established as risk factors for CTE, these findings suggest that
APOE ε4 may increase risk of developing CTE. Triple transgenic mice
crossed with the APOE ε4 genotype had more axonal injury after TBI
compared to triple transgenic mice crossed with APOE ε2 or APOE ε3, al-
though there was no significant effect on Aβ or p-tau deposition
(Bennett et al., 2013). Other candidate risk factor genes include MAPT
and TARDBP (Czell et al., 2013; Lee et al., 2013).
The discovery of highly-penetrant tau gene (MAPT) mutations in
rare families with FTLD demonstrated that tau dysfunction alone was
sufficient to cause neurodegeneration (Gasparini et al., 2007). Some
MAPT mutations, clustered around exon 10, influence splicing, which
leads to accumulation of tau having four microtubule binding domain
repeats (4R) over those with three (3R) (Vandrovcova et al., 2010).
MAPT also harbors a common genetic variation that is associated with
tauopathy. MAPT is contained within a ~900 kb ancestral genomic inver-
sion that defines two haplotypes, H1 and H2 (Stefansson et al., 2005).
These haplotypes are in complete linkage disequilibrium and do not re-
combine. Sporadic tauopathies such as progressive supranuclear palsy
and corticobasal degeneration as well as PD are associated with the H1
haplotype (Baker et al., 1999; Bekris et al., 2010; Di Maria et al., 2000).
It remains to be determined if the H1 haplotype pays a role in susceptibil-
ity for CTE.
Gender differences may play a role in the development of CTE. To
date, most neuropathologically confirmed cases have been identified
in men, largely reflecting the demographic of TBI. CTE has been docu-
mented in 2 women (reviewed in McKee et al., 2009), it if women are
as susceptible to CTE as men. Women appear to be at greater risk for
mTBI and PCS-related symptoms (Daneshvar et al., 2011b). These differ-
ences may based on hormonal differences, neck and muscle strength, or
simply more reporting of somatic symptoms (Daneshvar et al., 2011a).
Cognitive reserve and cognitive flexibility are thought to play a
significant role in the development and clinical course of CTE. In other
neurodegenerative diseases such as AD, cognitive reserve is considered
protective against clinical manifestations (Stern et al., 2013) and that
one can increase one's “reserve” and relative resistance with occupa-
tional and educational attainment (Stern et al., 2013). In diseases such
as AD and CTE, cognitive reserve provides an explanation for individual
differences in measured cognitive deficits despite similar degrees of
neuropathology (Stern et al., 2013).
4. Conclusions
TBI, particularly mTBI, has been largely overlooked as a major health
concern until very recently. It is increasingly clear that TBI is a process
and not a static injury, and that prolonged symptoms in TBI survivors
represent functional and structural damage. Moderate-to-severe TBI
may be associated with accelerated neurodegeneration and increased
risk of Alzheimer's disease, Parkinson's disease, and motor neuron dis-
ease, although it is if the pathologic phenotype of these post-traumatic
neurodegenerations differs from sporadic disease. While repetitive
mild TBI is associated with the development of a tauopathy, CTE, very
little is known about the pathogenetic mechanisms underlying the de-
velopment of a neurodegeneration after the acute insults. Effective
treatment of mTBI, concussion and subconcussion will need to address
the diagnosis and management of the acute injury as well as the long-
term progressive neurodegeneration that occasionally follow. Currently,
the best therapy is prevention and continued public education about
proper detection and management of the acute traumatic injuries.
Acknowledgments
We gratefully acknowledge the use of resources and facilities at
the Edith Nourse Rogers Memorial Veterans Hospital (Bedford,
MA). We also gratefully acknowledge the help of all members of
the Boston University and the Boston VA, and the individuals and
families whose participation and contributions made this work
possible. This work was supported by the Department of Veterans
Affairs; Veterans Affairs Biorepository (CSP 501); Translational
Research Center for Traumatic Brain Injury and Stress Disorders
(TRACTS) Veterans Affairs Rehabilitation Research and Develop-
ment Traumatic Brain Injury Center of Excellence (B6796-C);
National Institute of Neurological Diseases and Stroke 1U01NS086659-
01, National Institute of Aging Boston University Alzheimer's Disease
Center [P30AG13846; supplement 0572063345-5]; National Institute of
Aging Boston University Framingham Heart Study R01 [AG1649]; Sports
Legacy Institute; and National Operating Committee on Standards for
Athletic Equipment. This work was also supported by an unrestricted
gift from the National Football League, the Andlinger Foundation and
the WWE.
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