Journal of Clinical Neuroscience 41 (2017) 24–29

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Journal of Clinical Neuroscience

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

Review article

Chronic Traumatic Encephalopathy: The cellular sequela to repetitive

brain injury
Alexander R. Vile a,⇑, Leigh Atkinson b
a
James Cook University College of Medicine and Dentistry, Australia
b
Wesley Pain and Spine Centre, Brisbane, QLD, Australia

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

Article history: This review aims to integrate current literature on the pathogenic mechanisms of Chronic Traumatic
Received 12 January 2017 Encephalopathy (CTE) to create a multifactorial understanding of the disease. CTE is a progressive neu-
Accepted 6 March 2017 rodegenerative disease, classed as a tauopathy, although it appears the pathogenic mechanisms are more
complex than this. It affects those with a history of repetitive mild traumatic brain injury. Currently, there
are no treatments for CTE and the disease can only be affirmatively diagnosed in post mortem.
Keywords: Understanding the pathogenesis of the disease will provide an avenue to explore possible treatment
Chronic Traumatic Encephalopathy
and diagnostic modalities. The pathological hallmarks of CTE have been well characterised and have been
CTE
Tau
linked to the pathophysiologic mechanisms in this review. Human studies are limited due to ethical
Immune excitotoxicity implications of exposing subjects to head trauma. Phosphorylation of tau, microglial activation, TAR
Mild traumatic brain injury DNA-binding protein 43 and diffuse axonal injury have all been implicated in the pathogenesis of CTE.
TAR DNA-binding protein 43 The neuronal loss and axonal dysfunction mediated by these pathognomonic mechanisms lead to the
Diffuse axonal injury broad psycho-cognitive symptoms seen in CTE.
Ó 2017 Elsevier Ltd. All rights reserved.

1. Introduction This is accompanied by marked atrophy of the temporal and fron-

Chronic Traumatic Encephalopathy (CTE) is a progressive neu-
rodegenerative disease, pathologically marked by tauopathy of
the brain. The disease was first described by Martland (1928),
who introduced the term ‘‘punch drunk” to medical literature to
describe a collection of symptoms, including Parkinsonism, mental
confusion and psychiatric illness among retired boxers [1]. Epi-
demiological evidence has established repetitive head trauma as
the aetiology of the disease, with the disease most prominent in
boxers and American football players [2,3]. Based on a 2013 case
series of 68 patients, the largest to date, McKee et.al. established
a pathological grading system of I–IV, with this correlating with
the severity of symptoms. To summarise macroscopically, milder
cases are marked by cavum septum pellucidum and mild enlarge-
ment of the frontal and temporal horns of the lateral ventricles,
accompanied by microscopic neurofibrillary tangles located
perivascular and at the depths of cerebral sulci [2]. These two
microscopic findings are what distinguish CTE from other tauopa-
thies [2,4]. Neurofibrillary tangles then spread from the depth of
the sulci and perivascular to the adjacent superficial cortical layers.
⇑ Corresponding author at: 8 Rivergum Place, Fig Tree Pocket, Queensland 4069,
Australia.
E-mail address: vile.alex07@gmail.com (A.R. Vile).
tal lobes, diencephalon and brainstem, with depigmentation of the
locus coeruleus and substantia nigra [2,5–7]. Axonal pathology in
the early stages is defined by distorted axonal varicosities, pro-
gressing to axonal loss in the cortex, subcortical white matter,
and deep white matter tracts of the diencephalon in later stages
[2]. Tar-DNA-binding protein (TDP-43) pathology is seen through-
out all stages, though not in all patients, but is universal by stage
IV, with 10% of patients also developing a motor neuron disease
indistinguishable from Amyotrophic Lateral Sclerosis [2]. Neuronal
and axonal loss leads to the symptomatology, shown in Table 1.
Despite having characterised the pathological hallmarks of the dis-
ease, the pathophysiological events leading to these hallmarks
remain poorly understood. This review aims to integrate current
understanding of the multiple mechanisms involved in the patho-
genesis of CTE to create a multifactorial model of understanding
the disease.
2. Pathogenesis of CTE
Much of the information regarding the pathogenesis of CTE has
been derived from animal studies. Whilst the pathological hall-
marks of the disease have been well characterized in humans,
the pathogenesis has been defined to a lesser extent due to the eth-
ical implications of exposing human subjects to head trauma. It is

http://dx.doi.org/10.1016/j.jocn.2017.03.035
0967-5868/Ó 2017 Elsevier Ltd. All rights reserved.
 A.R. Vile, L. Atkinson / Journal of Clinical Neuroscience 41 (2017) 24–29 25

Table 1 notion that hyperphosphorylated tau causes neuronal death, as

Symptomatology of CTE [8]. indicated by genetic studies implicating tau as the sole cause of
Cognitive features Behavioural Mood Motor neuronal death in Fronto-temporal dementia and parkinsonism
features features features linked to chromosome 17, another tauopathy [24]. Based on the lit-
Memory impairment Physical violence Depression Ataxia erature, the argument presented in this review is that tau oligo-
Executive Verbal violence Hopelessness Dysarthria mers are the more toxic of the two, yet NFTs represent an
dysfunction adaptive response to prevent the development of toxic oligomers,
Impaired attention Explosivity Suicidality Parkinsonism
Dysgraphia Loss of control Anxiety Gait
but ultimately lead to neurodegeneration [22,25]. The aforemen-
Lack of insight Short fuse Fearfulness Tremor tioned has been difficult to study given tau does not readily aggre-
Preservation Impulsivity Irritability Masked gate into filaments within an ideal time frame for culture studies or
facies within an animal’s short lifespan, though it is thought that the
Language difficulties Paranoid delusions Apathy Rigidity
hyperphosphorylation of tau leads to a toxic gain of function with
Dementia Aggression Loss of Weakness
interest a loss of function, with this accounting for neuronal death. How-
Alogia Rage Labile Spasticity ever, it is not certain whether this toxicity is exerted by NFTs or oli-
emotions gomers [22,25]. Case control studies from the 1970s and 1980s,
Visuospatial Inappropriate Fatigue Clonus correlated the severity of cognitive impairments in humans to
difficulties speech
the extent of NFT formation, which intuitively indicated its role
Cognitive Boastfulness Flat affect
impairment in neurodegeneration [26–28]. This older paradigm has been chal-
Reduced intelligence Childish behaviour Insomnia lenged in a review by Crespo-Biel (2012), which show memory def-
Socially Mania icits preceding NFT pathology, indicating a toxic intermediate in
inappropriate
the tau phosphorylation cascade is likely to blame for neuronal
Disinhibited Euphoria
behaviour damage [29].
Psychosis Mood swings Studies into the mechanism by which these tau oligomers cause
Social isolation Prolix cells death are limited. One study has implicated tau oligomers in
interfering with anterograde axonal transport system protein kine-
sin, leading to an inability to maintain axons and axonal degener-
not yet clear the degree to which these studies are applicable on ation [30]. This would explain the milder cognitive impairments
humans, but they do provide a model for the disease. Phosphory- seen early in the disease, without the presence of pathological hall-
lated tau deposition, TAR DNA-binding protein 43 (TDP-43), micro- marks. Neuronal loss can be explained by the resultant deaf-
glial activation and diffuse axonal injury have been implicated in ferentation leading to a lack of survival signalling, known as
the pathogenesis of CTE. anterograde transneural degeneration [31]. Some studies have
addressed the role of caspase activation in tauopathy, however
the findings of these studies are inconsistent. Active caspases have
2.1. Tau phosphorylation been identified using fluorescent antibody tagging in neurons con-
taining NFT’s and shown to cause apoptosis in cultured hippocam-
Phosphorylation of tau has been suggested to play a major role pal neurons [32–34]. However, other studies have argued against
in the pathogenesis of CTE. The notion that tau has been implicated this theory, suggesting apoptosis was not an important contribut-
as a pathogenic mechanism has arisen in rat studies, in which ing factor to neuronal death, rather caspases cleaving tau increases
injection of oligomeric tau into the brains on healthy rats produced its fibrillogenicity [35,36]. Given either it appears the activation of
measureable behavioural symptoms, likened to that of CTE in caspases is pathogenic.
humans (Table 1) [9]. It has been hypothesized that the phospho- Additionally, other studies have associated tau with increased
rylated tau found in CTE cause neuronal death in a similar mecha- cell cycle proteins, proposed to cause differentiated neurons to
nism to those found in Alzheimer’s disease (AD), as the tau re-enter the cell cycle leading to their death [37,38]. It has also
isoforms found in CTE match those of AD [10,11]. Normal tau is been suggested that tau may lead to membrane permeability
involved in stabilizing microtubule fibrils by binding to tubulin, changes, leading to mitochondrial dysfunction, raised intracellular
facilitating neurite outgrowth [12]. Ca2+ and reactive oxygen species production. This idea is based on
Immuunohistochemical studies have ascertained that phospho- the propensity for oligomers of beta amyloid and alpha-synuclin to
rylation of tau occurs following mild traumatic brain injury [13]. form pores in lipid membranes [39]. Oligomerization is a charac-
The phosphorylation of tau arises from an imbalance between teristic shared by tau. There is evidence for mitochondrial dysfunc-
kinases and phosphatase activity. The signalling pathways that tion in tauopathy mice models, indicating this theory may be
activate kinases following head trauma are yet to be ascertained, plausible, but requires more evidence for affirmation [40]. Strongly
but the levels of active extracellular signal regulated kinases 1 supported by the evidence presented is the idea that tau effects
and 2, cycline dependant kinase 5, glycogen synthase kinase 3- neurons on two levels – synaptic and axonal dysfunction and neu-
beta, protein kinase C, c-jun kinase and Akt are all increased fol- ronal loss, and this is what leads to physco-cognitive symptoms
lowing head trauma [14–19]. One if not multiple are likely are seen in CTE patients [41].
involved in the phosphorylation of tau. Hyperphosphorylation Neurons can survive for decades with NFTs [42]. By forming
causes dissociation of tau from tubulin, rendering microtubules these large fibrillary aggregates the cell is protected from the
dysfunctional. This exposes further phosphorylation sites leading immediate cytotoxic effects of oligomers, allowing to the compro-
to a state of hyperophosphorylation [20]. In this state tau is insol- mised neuron to maintain itself [43]. However, as these NFTs grow,
uble, so translocates to the neuron soma [21,22]. Accumulation of they have been reported to decrease the number of cell organelles,
insoluble tau leads to the formation of tau oligomers [21,22]. inhibit proteasome activity, and also impair anterograde axonal
Sequestration of oligomers and post translational modifications transport, all of which may negative alter cell homeostasis leading
lead to neurofibrillary tangle formation (NFT), the pathological to cell death [44–46].
hallmark of CTE [22,23]. The progressive neurodegeneration in CTE can be explained by
Whether tau oligomers or NFTs are the source of neurotoxicity the transmission of tau oligomers between neurons. In rat models
is an area of intense research. However, what is clearer is the where tau is overexpressed, it has been observed to be secreted
26 A.R. Vile, L. Atkinson / Journal of Clinical Neuroscience 41 (2017) 24–29
[47]. Likewise Kfoury et al. was able to demonstrate that both
secretion of tau and uptake into cultured cells [48]. The notion that
this applies to humans is supported by the finding of higher levels
of tau in the cerebrospinal fluid of Alzheimer’s disease patients
when compared with healthy controls [49]. It is suggested that
uptake from the extracellular space is mediated by micropinocyto-
sis. Santa-Maria et al. and Wu et al. found tau aggregates to co-
localise with dextran, a maker for fluid phase endocytosis, indict-
ing this as a possible route of uptake [50,51]. A process that is pos-
sibly stimulated by the interaction between tau and heparin
sulfate proteoglycans, as was found by Hall et al. [52].
2.2. TAR DNA-binding protein 43 proteinopathy
TAR DNA-binding protein 43 (TDP-43) proteinopathy, is univer-
sal by late stage CTE [2]. Overexpression of TDP-43 leads to translo-
cation from the nucleus to the cytoplasm, leading to neuronal
death [53]. Injection of TDP-43 into the cytoplasm of neurons, also
produces marked neuronal death, supporting the idea that translo-
cation is associated with its pathogenicity [54]. TDP-43 expression
is upregulated in mild traumatic brain injury, which is the under-
lying aetiology of CTE, in addition to axotomy [55–57]. Following
translocation, TDP-43 undergoes post-translational modification,
causing it to become hyperphosphorylated, ubiquinated and
cleaved, which causes aggregation [58–61].
Numerous putative TDP-43 kinases have been identified,
though Casein Kinase 1d appears to be one of the more promising
of effectors, given its ability to replicate pathological phosphoryla-
tion of Ser 409/410 and downstream pathological alterations in cell
lines [62–64]. However, the relationship of these kinases to head
trauma remains to be determined.
The aforementioned is postulated to give TDP-43 a gain of func-
tion toxicity, though the mechanism by which causes cell death
has not been defined [58–61]. It has also been demonstrated that
loss of TDP-43 function can also lead to neuronal death, with this
possibly being linked to its protein mis-folding and aggregation
[65–67]. Cases control studies on Amyotrophic Lateral Sclerosis
with cognitive impairment, have shown altered tau metabolism
including hyperphospherylation and tau phosphatase resistance
concurrent with TDP-43 proteinopathy, suggesting TDP-43 ability
to modulate tau phosphorylation, which may be applicable to
CTE [68]. However the extent to which this applies to CTE is
debateable given that minimal co-localisation has been found
[69]. Similar to tau, TDP-43 has been shown to have prion like
seeding and propagation properties, with this again accounting
for the spread of TDP-43 throughout the brain [70].
2.3. Microglial activation and immunoexcitoxicity
Mechanical trauma and disruption to the blood brain barrier,
which occurs in mild traumatic brain injury ‘prime’ microglia. To
date no biochemical descriptors of microglia priming have been
identified, with morphological changes the only marker of micro-
glia priming. These morphological changes have been identified
in post mortem of long term survivors of traumatic brain injuries
[71,72]. When microglia remain primed, a second incidence of mild
traumatic brain injury, may fully activate the microglia, stimulat-
ing a release of toxic levels of pro-inflammatory cytokines,
chemokines, interferons, reactive oxygen species (ROS), and excito-
toxins; glutamate, aspartate, and QUIN [73–75]. The effects of
cytokines involved following brain injury were reviewed by Ziebell
and Morganti-Kossmann, and were found to inherently harmful to
the neurons [76]. Cytokines in combination with the effects of ROS
and excitotoxins lead to neurodegeneration, in what is termed
immune excitotoxicity [74,76].
In non-CTE affected brain the neuro-destructive actions of
microglia are self-limiting, as they switch to a neuro-reparative
mode following activation, secreting neurotrophic factors, to repair
inflicted damage [77]. Frequent incidences of mild traumatic brain
injury lead to persistent activation of microglia, not allowing them
to switch to neuro-reparative mode or repetition of the priming
effect, there is evidence for both occurring, with both leading to tis-
sue damage [78–83]. Activation time also increases with each inci-
dence of injury, and this leads to the chronic neuro-inflammation
and tissue injury seen in CTE [78–81]. This theory has been sup-
ported in humans by the higher incidence of translocator protein
(TSPO) levels, a marker of neuro inflammation in 9 retired NFL
players, with a history of repetitive head trauma, when compared
with 9 age matched healthy individuals, indicating a chronic
inflammatory response [84]. Additionally, excitotoxicity is
believed to play a role in tau hyperphosphorylation, likely through
CDK5 activation. In an in vivo mice model, kainic acid was used to
induce excitotoxicity, and this resulted in a dramatic activation of
CDK5 and tau hyperphosphroylation [85]. This likely occurs
through NMDA receptors, as NMDA receptor blockers have
decreased phosphorylated tau deposition [85]. The role of excitot-
cicity is also supported by the correlation between areas most
effected between the significant atrophy of the hippocampus,
entorhinal cortex and amygdala and their higher susceptibility to
excitotxicity [86]. Should the activation of kinases be proven to
be solely due to excitotoxins, this would represent a unifying
mechanism in the signalling cascade, and propose a mechanism
by which kinases become activated following head injury. This is
yet to be determined. Additionally, there is evidence to suggest
neuronal loss and misfolded proteins can further prime microglia
and this may perpetuate the disease process [87].
2.4. Diffuse axonal injury
In McKee et al. systematic review of the pathological findings
CTE, axonal degeneration was found to be common and is seen
on imaging studies of retired NFL players with CTE [2]. It is sug-
gested that axonal injury suffered in mild traumatic brain injury
is similar to that of diffuse axonal injury, just to a lesser extent
of that is seen in severe head trauma, given there are similarities
in axonal pathomorphology [88]. When the brain is subjected to
rapid acceleration, deceleration or rotational forces, such as that
of mild traumatic brain injury the brain elongates and deforms,
stretching the micro-architecture of the brain, including neurons,
glial cells and blood vessels. Animal studies have demonstrated
that areas that experience most stress are the depths of the cere-
bral sulci and perivascularly [89,90]. The stretch forces placed on
the axolemma increases its permeability leading to calcium influx.
Increased intracellular calcium induces calpain activation leading
to proteolysis of the axonal cytoskeleton and opening of the mito-
chondrial membrane permeability transition (MPT)-pore in axonal
mitochondria. This leads to proapoptotic substance release, such as
cytochrome C, leading to further degeneration of the axon
cytoskeletal network [91,88]. Microscopically, this is marked by
mitochondrial and axonal swelling due to ATP dependant ion
pump failure, which is seen in both mild traumatic brain injury
and diffuse axonal injury [92,88]. The highest concentration of
phosphorylated tau correlates to the areas of highest areas of
stress, being the perivascular regions and depths of cerebral sulci.
On the basis of evidence provided in this review this may be due to
a more pronounced activation of microglia at these sites.
2.5. Amyloid beta and Lewy body pathology
A 2015 study conducted by Stein et.al. found Ab pathology in
52% of 114 neuropathologically confirmed CTE cases, with a similar
 A.R. Vile, L. Atkinson / Journal of Clinical Neuroscience 41 (2017) 24–29
Fig. 1. Pathogenesis of CTE.
rate of 44% found by McKee et al. [2,93] When controlling for age,
beta amyloid pathology was of higher incidence, occurred at a
younger age and at a greater rate in CTE affected patients than in
the general population. It is possible that the presence of Ab repre-
sents the development of a co-morbid Alzheimer’s disease, though
the accelerated rate that occurs in CTE would suggest that the dis-
ease process of CTE is a possible modifying factor for Ab deposition.
Additionally, there were correlates between severity of Ab pathol-
ogy and CTE stage progression. This would indicate possible inter-
play between these factors and also a worse prognosis in those
with extensive Ab pathology. Of note, is the difference in Ab distri-
bution in CTE compared with AD, with CTE having less neuritic pla-
ques, but similar frequencies of diffuse plaques when compared to
AD. Given this CTE with Ab pathology is a likely subtype of CTE
with a faster clinical course [93]. Additionally, a-Synuclein-
positive Lewy bodies have been reported in approximately 20% of
CTE cases [2]. An explanation for this is provided in the evidence
that exists for the synergism between tau and alpha-synuclein
27
aggregation, with the two able to modulate each other’s aggrega-
tion to propagate themselves [94–97]. Such a theory also explains
higher frequency of Parkinsonism that occurs in individuals with
CTE [2].
3. Conclusion
The pathogenesis of the CTE is multifactorial and complex. Fig. 1
displays a proposed pathogenesis of CTE. Repetitive mild head
trauma has been established as a clear aetiology of the disorder.
This leads to microglial and kinase activation and diffuse axonal
injury. The phosphorylation of tau, a result of kinase phosphatase
imbalance, induced by the head injury, leads to hyperphosphoryla-
tion of tau, oligomer formation followed by sequestration into
NFTs. The mechanism by which tau causes neuronal death is yet
to be fully elucidated and appears to be multifactorial. Along with
diffuse axonal injury and the immunoexcitotoxicity that arises
from microglial activation, phosphorylated tau leads to axonal
28 A.R. Vile, L. Atkinson / Journal of Clinical Neuroscience 41 (2017) 24–29
degeneration and neuronal death, resulting in disruption of neural
circuitry. The disruption to neural circuitry is what underpins the
broad psycho-cognitive abnormalities seen in CTE (Table 1). Amy-
loid beta and Lewy bodies possibly modify factors to the diseases
course. Currently, there is no treatment for CTE. Given the inter-
relationship between phosphorylation of tau and other mecha-
nisms, kinase inhibition presents itself as a possible treatment
modality, and has shown success in Alzheimer’s disease, another
tauopathy [98]. Thus, this review has detailed the pathogenesis
of CTE, as well as linking the pathophysiology to the distribution
of pathological hallmarks, allowing future studies to utilise this
knowledge for the conception of treatment and diagnostic
modalities.
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