CTE in Athletes 1

Chronic Traumatic Encephalopathy in Athletes

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 CTE in Athletes 2

Chronic Traumatic Encephalopathy in Athletes

Introduction
Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease that
results from either single or repetitive closed-head injuries, making it a long-term consequence
associated with many sports or military combat; there is no treatment, as the only way to
definitively diagnose the condition is through a post-mortem examination of the brain (Saulle &
Greenwald, 2012). Dr. Harrison Martland, a medical examiner, first noticed this condition in
1928 while performing autopsies on boxers who had displayed certain symptoms in life,
including the well-known “punch drunk” symptoms – later to be recognized as a form of
dementia (i.e., dementia pugilistica); in the 1960s, the condition was renamed CTE, as it was not
exclusive to boxers, but also presented in other athletes (Saulle & Greenwald, 2012). In fact,
CTE is now closely linked to athletes participating in very physical contact sports such as
football, boxing, soccer, hockey, and even professional wrestling (Saulle & Greenwald, 2012).
Epidemiology and Risk Factors
One of the most common neurologic disorders is concussion or mild traumatic brain
injury (mTBI), which accounts for roughly 90% of all sustained brain injuries sustained; these
are frequently found in athletes, with yearly estimates in the U.S. reporting roughly 1.6 million to
3.8 million sport-related concussions (Saulle & Greenwald, 2012). In fact, sports-related head
injuries comprise 20% of all TBI cases within the country (Saulle & Greenwald, 2012). In high
school football, players sustain an average of 24 head impacts per game, each exceeding 14 g-
force; this has also been found in collegiate hockey players, suggesting that many different sports
players and athletes endure hundreds of significant head impacts per season (Broglio et al.,
2013). Even though it can be difficult to obtain accurate prevalence estimates due to difficulties
making definitive diagnoses, recent studies found CTE to be present in 87% of deceased football
players, including 99% of ex-National Football League (NFL) Players (Mez et al., 2017). The
disease burden’s magnitude has been connected to the level of play; for example, mild CTE was
found in high school athletes, while the most severe cases were in NFL players (Mez et al.,
2017). Furthermore, NFL players faced a three times higher risk of mortality due to
neurodegenerative causes compared to the general population and were four times more likely to
be diagnosed with Amyotrophic Lateral Sclerosis (ALS) or Alzheimer’s; additionally, those over
50 years of age were five times more likely to have dementia (Lehman et al., 2012).
 CTE in Athletes 3

Tharmaratnam et al. (2018) explain that the most essential risk factor for CTE is a history
of brain trauma, as over 32% of contact sport athletes have shown clinical presentations of this
condition, while patients with no prior brain trauma are not at risk. Therefore, contact sports are
a predisposing risk factor in CTE development. However, although exposure is necessary for this
condition to occur, it is not sufficient – not all those with a history of repetitive head impact
exposure get CTE (Baugh et al., 2014). In fact, there are several other risk factors for CTE,
including military service (especially those who have seen combat) and old age (Saulle &
Greenwald, 2012). The incidence of this condition may also be due to numerous other factors,
such as duration of play, position, sport, age of first exposure (AFE), and even genetics
(specifically, ApoE3 and ApoE4 alleles) (Tharmaratnam et al., 2018). In duration of play,
athletes are more likely to experience head trauma the longer they are involved in the sport. In
fact, 61% of NFL players are estimated to have experienced at least one concussion within their
careers, while having three or more is associated with an increased risk for prolonged CTE
symptoms (Tharmaratnam et al., 2018). AFE to contact football has also been linked with
neurological and psychiatric dysfunction later in life, especially for children younger than 12
years of age; this is because the volumes of both gray and white matter peak during this stage of
development, with both the amygdala and hippocampus maturing neurologically (Uematsu et al.,
2012). Therefore, when the brain is subjected to trauma – such as through tackle football or other
physical contact sports – it can predispose a person to future cognitive dysfunction, including
CTE (Tharmaratnam et al., 2018).
There may also be lifestyle comorbidities linked to contact sport athletes and even
military veterans who have seen combat; these include alcohol or recreational drug abuse or even
performance enhancing drugs, which can cause both neuropsychiatric difficulties and personality
changes (Baugh et al., 2014). However, since there are confirmed CTE cases of patients who did
not suffer these comorbidities, they are not causative factors (Baugh et al., 2014). Finally,
genetics can play a role. The apolipoprotein (ApoE) ε4 allele is a 34-kDa glycosylated protein
implicated as the brain’s primary source of cholesterol transport for neuronal repair
(Tharmaratnam et al., 2018). It is a profound predictor of sporadic Alzheimer’s, with reports
linking it to head injuries with an extensive range of negative outcomes, from poor cognitive
performance to prolonged recovery (Baugh et al., 2014). In football players, its presence has
been linked to longer recovery times from neurotrauma, increased injury severity, and greater
 CTE in Athletes 4

cognitive deficits, with worse clinical outcomes compared to carriers of other isoforms
(Tharmaratnam et al., 2018). However, there has not yet been a confirmed associated between
the ApoE genotype and CTE pathology, and more recent research shows that the allele variation
found in CTE cases is not any more than in the general population (Maroon et al., 2015).
Neuropathology
Although there is much currently known about CTE’s neuropathology, thanks to
numerous postmortem neuropathologic assessments that have been conducted with retrospective
clinical interviews with family members, there is little available evidence on the pathobiological
mechanisms underlying the condition (Baugh et al., 2014). The neuropathology can be
categorized into four separate stages, based on condition severity: 1) perivascular foci of
hyperphosphorylated tau (p-tau) immunoreactive astrocytic tangles and neurofibrillary tangles
(NFT); 2) irregular cortical distribution of p-tau immunoreactive NFT and astrocytic tangles with
a predilection for the depth of cerebral sulci; 3) clusters of subpial and periventricular astrocytic
tangles in the cerebral cortex, basal ganglia, diencephalon, and brainstem; and 4) NFT in the
cerebral cortex located preferentially in the superficial layers (McKee et al., 2013).
CTE is characterized by p-tau protein deposition as NFT, starting peri-vascularly and at
cortical sulci depths; in later stages, p-tau pathology becomes more extensive, especially in the
medial temporal lobes and white matter, resulting in gliosis and neuronal loss (Saulle &
Greenwald, 2012). The disease is distinguished from other similar tauopathies – such as Lewy
body, Alzheimer’s, and Parkinson’s – by the p-tau NFT’s irregular and perivascular nature, not
to mention its inclination for sulcal depths as well as marked periventricular and subpial
involvement (Saulle & Greenwald, 2012). In about 80% of cases, TAR DNA-binding protein 43
(TDP-43) is present; early stages show few TDP-43 positive neurites in the medial temporal
lobe, cortex, and brainstem, while later stages present with both intraglial and intraneuronal
inclusions in the frontal subcortical white matter and fornix, brainstem, and medial temporal lobe
(Saulle & Greenwald, 2012). In most cases, there are no beta amyloid 1–42 (Aβ1–42) positive
neuritic plaques (Saulle & Greenwald, 2012). However, axonal injury is common, ranging from
multifocal axonal varicosities (early stage) to severe axonal loss (later stages); macroscopic
analysis typically shows some enlargement of either the lateral ventricles or third ventricle, with
or without mild septal abnormalities, in stages one and two (Saulle & Greenwald, 2012). In
advanced stages of the disease, both the lateral and third ventricles are significantly enlarged,
 CTE in Athletes 5

along with the septal perforations and cavum septum pellucidum; additionally, there may be
changes in pallor associated with the substantia nigra and locus coeruleus (Saulle & Greenwald,
2012). There is usually profound medial temporal lobe or global atrophy in severe cases.
Clinical Presentation
In patients where CTE is suspected, there are usually symptoms ranging from poor mood
and unfavorable behaviors to cognitive declines and motor dysfunctions; clinical presentations
typically begin roughly eight to 10 years after the repetitive mild traumatic brain injury or trauma
exposure (McKee et al., 2013). However, about a third of athletes become symptomatic when
they retire, while half occur within four years; this latency period is believed to result from tau
propagation from focal to widespread areas, resulting from progressive axonal disruption
(Kriegel et al., 2018). Although there can be symptom overlap between CTE and acute
concussive injury (i.e., post-concussion syndrome), CTE is distinct in that a history of repeated
brain trauma is required (McKee et al., 2013). There are four possible domains into which
symptoms may be categorized: mood, behavior, cognition, and motor. Patients may display
irritability, depression, or hopelessness (mood) as well as aggression, impulsivity, or explosivity
(behavior); there may be memory impairment, executive dysfunction, and dementia (cognitive)
as well as ataxia, parkinsonism, and dysarthria (motor) (Baugh et al., 2014). Four diagnostic
subtypes are based on these clinical features: “Definite,” Probable,” “Possible,” and
“Improbable” (Fesharaki-Zadeh, 2019). It is important to note that neurological changes,
especially dementia and parkinsonism, are usually only in later stages as CTE progresses
(McKee et al., 2013). Chronic headaches are also present in some cases (Baugh et al., 2014).
One area that remains contentious is the link between suicide and CTE. Omalu et al.
(2018) found a strong association between the two, suggesting that suicidal behavior’s etiology
in this population might be in part due to tauopathy; this occurs in the limbic brain nuclei, where
there are both NFT and neuritic threads. Another study by Maroon et al. (2015) reported that
suicide prevalence in the CTE population was 11.7%, which is significantly higher than the
general population, which was only 1.5%; furthermore, accidental deaths in those with CTE was
found to be 17.5%, which is again much higher than 4.8%, the incidence in the general
population. Nonetheless, some note that this link between disease progression and suicide still
remains unclear. For example, other research shows that professional football players do not
 CTE in Athletes 6

have a higher risk of suicide than the general population, but instead a lower standard mortality
rate (SMR) (Lehman et al., 2016).
There are two distinct clinical presentations of CTE. The first initially presents with
mood and behavioral symptoms earlier in life, around 35 years of age on average; it then
progresses to include cognitive symptoms at later stages (Stern et al., 2013). The second starts
with cognitive impairment later in life, with patients averaging about 60 years of age, with
disease progression including behavioral and mood symptoms (Stern et al., 2013). Years ago,
many CTE cases reported more motor symptoms, which led to two different clinical distinctions:
“classic” and “modern” (Baugh et al., 2014). This is because most cases in the early years of this
diagnostic discovery were boxers, while football players are now more common; each athlete has
different head trauma exposure, which may be the underlying reason for the differences in
presentation. Boxers experience proportionally more rotational acceleration than football players,
with the greatest stress impacts on the midbrain structures – which is a known brain area related
to parkinsonian features; boxers’ brains also show more cerebellar scarring (Baugh et al., 2014).
There is also a subset of cases associated with motor neuron disease (MND), known as CTE-
MND (McKee et al., 2013).
Diagnosis
A definitive CTE diagnosis can only be confirmed with a post-mortem autopsy and
immunohistochemistry for p-tau, which can isolate distinct features to distinguish it from other
tauopathies (Tharmaratnam et al., 2018). The National Institute of Neurological Disorders and
Stroke/National Institute of Biomedical Imaging and Engineering (NINDS/NIBIB) consensus
panel has identified key preliminary findings of CTE, which can be used to confirm diagnosis
based on macroscopic and microscopic abnormalities (McKee et al., 2016). These criteria are
related to the four stages of CTE, allowing clinicians to determine the severity of disease. These
include the presence of one or two focal perivascular CTE lesions in the cerebral cortex at sulci
depths (indicating stage one), while less than three CTE lesions in multiple cortical regions and
superficial NFTs along both the sulcal wall and gyral crests indicate stage two; in stage three,
there are multiple CTE lesions with widespread cortical NFTs in the medial temporal lobes
(McKee et al., 2016). Finally, the fourth stage involves the same criteria as stage three, with
additional features such as widespread astrocytic p-tau pathology, neuronal loss, and gliosis
(McKee et al., 2016). There are also different symptoms that patients present with, depending
 CTE in Athletes 7

upon the stage. Patients with CTE are usually asymptomatic in stage one, although they can
suffer from mild short-term memory deficits, depressive symptoms, or even mild aggression;
mood and behavioral symptoms may be noticed in stage two, including behavioral outbursts and
more severe depressive symptoms (McKee et al., 2016). Stage three is indicated by further
cognitive deficits, such as executive functioning impairment, memory loss, visuospatial
dysfunction, and apathy; finally, advanced language deficits and psychotic symptoms – such as
motor deficits, parkinsonism, and paranoia – are seen in stage four (McKee et al., 2016).
Unfortunately, diagnosis of CTE – as well as a deeper understanding of this condition’s
clinical presentation – has been limited, especially since retrospective reviews of case reports
(incorporating family interviews) have historically been the only method available to clinicians
and researchers (Baugh et al., 2014). However, in vivo diagnosis while patients are still living
would provide much more knowledge on the issue. There is currently new research being
conducted on the use of neuroimaging techniques, such as 2-(1-{6-[(2-[F-18] fluoroethyl)
(methyl)amino]-2-naphthyl}ethylidene) malononitrile-positron emission tomography ([F-18]
FDDNP PET), for preliminary pre-mortem diagnosis (Omalu et al., 2018). Still, more research is
needed on this diagnostic tool, as well as ways to treat (or at least prevent) CTE in athletes.
Therefore, a literature review will be conducted on CTE and the current treatment and/or
management options that are available.
Literature Review
The purpose of this literature review is to evaluate current evidence on CTE, including
in-vivo diagnostic techniques used to identify patients while they are still living, so treatments
may be incorporated. Unfortunately, as CTE is incurable, prevention is the primary means by
which to reduce its incidence within the country. Available management strategies will also be
reviewed for athletes who present with these symptoms, categorizing these treatments by which
symptoms they alleviate – mood, behavior, cognition, or motor.
Search Strategy
An advanced search was conducted using three databases: PubMed, Cochrane, and
Medline. Search terms were (“chronic traumatic encephalopathy” OR “punch drunk syndrome”
OR “CTE” OR “chronic traumatic brain injury” OR “chronic head trauma” OR “dementia
pugilistica”) AND (“athletes” OR “American football players” OR “boxers) AND (“in-vivo
studies” OR “pre-mortem diagnosis”) AND (“management” OR “treatment” OR “prevention”).
 CTE in Athletes 8

Inclusion criteria included peer-reviewed original research studies and other published reports
within the last ten years (2010–2020); however, as the references sections for articles were
perused, any other potential studies that were relevant – even if they were earlier – were
incorporated into the literature review. Additionally, only English language studies were
included, although results were not restricted by location.
Synthesis of Literature
These peer-reviewed articles will be synthesized, identifying essential content in the
literature. Themes will be determined regarding CTE’s pre-mortem clinical diagnosis (including
in-vivo biomarkers) and treatment/management strategies that are currently available, including
any areas of research that are needed in the future. This will identify a gap in research that
requires further exploration.
Clinical Diagnosis. There are several crucial studies regarding how to develop reliable
biomarkers for CTE during life, even though a definitive diagnosis must still be based upon post-
mortem neuropathologic examination (Baugh et al., 2014). Three groups of researchers have
proposed preliminary clinical and/or research diagnostic criteria (Victoroff, 2013; Jordan, 2013;
Montenigro et al., 2014). All three are similar, following the National Institutes on Aging (NIA)
Alzheimer’s Association clinical diagnostic criteria, where probable and possible cases are
distinguished by various symptoms (Baugh et al., 2014). All patients must have a history of brain
trauma, exhibiting symptoms consistent with CTE’s clinical presentation, which are not likely
explained by other conditions (Baugh et al., 2014). Even though both behavioral and cognitive
disturbances are required for diagnosis, the groups do not agree on the significance of motor
features, with Jordan (2013) expressing the believe that they are necessary, while both
Montenigro et al. (2014) and Victoroff (2013) have suggested they are of less importance for
diagnosis.
In fact, according to Montenigro et al. (2014), it would be better to use the term
Traumatic Encephalopathy Syndrome (TES) for those with repetitive brain injuries, reserving
CTE for postmortem neuropathologic diagnoses. They presented four proposed subtypes: 1) TES
behavioral/mood variant (i.e., depressed or volatile), 2) TES cognitive variant (based on
neuropsychological testing), 3) TES mixed variant (both behavioral/mood and cognitive
features), and 4) TES dementia (Montenigro et al, 2014). Symptoms must persist for at least one
year, with repetitive hits to the head during sports as the primary source of neurotrauma
 CTE in Athletes 9

exposure; however, athletes may also have a history of four documented mild TBIs or
concussions, or two moderate/severe TBIs (Montenigro et al, 2014). They must have played the
sport for at least six years, including college level or higher for two; these sports may include
football, hockey, boxing, wrestling, or soccer (Montenigro et al, 2014). Furthermore, diagnostic
criteria requires a minimum of two supportive features: 1) impulsivity (e.g., substance abuse,
excessive gambling or shopping, and increased sexual activity); 2) anxiety (e.g., anxious mood,
agitation, excessive fears, or obsessive/compulsive behaviors); 3) apathy (e.g., loss of motivation
or interest in things that were once pleasurable); 4) paranoia; 5) suicidality (thoughts or
attempts); 6) significant headache (at least one per month for six months); 7) motor signs (e.g.,
bradykinesia, dysarthria, dysgraphia, rigidity, tremor, gait disturbance, or falls); 8) documented
decline (i.e., progressive decline in functioning); or 9) delayed onset (i.e., usually at least two
years after exposure) (Montenigro et al, 2014). Unfortunately, these measures should not be used
as a clinical diagnosis, but for research purposes only.
In-Vivo Biomarkers. There are four research groups that have suggested a reliable way to
differentiate between CTE and Alzheimer’s cases using negative amyloid PET imaging in the
presence of positive tau PET imaging (Baugh et al., 2012; Jordan, 2013; Small et al., 2013; Riley
et al., 2015). The PET ligand 18F-FDDNP has been studied, since it binds to both tau and amyloid
(Small et al., 2013). In fact, it has been shown to be an archetypal tau ligand, displaying an
imaging pattern with increased signal intensity in the medial temporal and frontal lobes, which is
a topographical distribution consistent with CTE (Omalu et al., 2018; Barrio et al., 2015). Small
et al. (2013) researched 18F-FDDNP’s use in five retired NFL players with histories of mood and
cognitive symptoms, analyzing PET signals in both subcortical and cortical regions, then
comparing them to the control group (Small et al., 2013). They found that players had higher
signals in brain areas that produce tau deposits after trauma, including all subcortical regions as
well as the amygdala; these findings suggest that 18F-FDDNP may offer a way to identify
neurodegeneration before death in these athletes (Small et al., 2013). Unfortunately, a limitation
of the study was that its nonspecific binding suggests that the signal cannot be attributed only to
the presence of tau – meaning diagnosis must still be confirmed through postmortem
examination (Small et al., 2013). Nonetheless, Chien et al.’s (2013) study confirmed the potential
use of the tau-specific PET ligand to measure tau in vivo, helping clinicians identify the
biomarkers for CTE.
 CTE in Athletes 10

Diffusion tensor imaging (DTI) is another method that allows for the identification of
persistent changes in white matter integrity after head impact exposures, which can be beneficial
in CTE diagnosis (Koerte et al., 2012; Bazarian et al., 2014). For example, in Bazarian et al.’s
(2014) study, they examined a single football season that included repetitive head impacts
(RHIs) without clinically-evident concussions, finding that multiple helmet impacts resulted in
white matter changes – diagnosed through DTI – which persisted after six months of no-contact
rest. Therefore, they determined that white matter in the brain did not recover, potentially
explaining how cumulative changes occur that can lead to CTE (Bazarian et al., 2014). This DTI
could be used in players with suspected CTE, examining their white matter changes.
The in-vivo diagnostic test Magnetic Resonance Spectroscopy (MRS) measures regional
cerebral blood flow, glucose metabolism, and brain metabolite concentrations that typically
occur after mild traumatic brain injury (mTBI) (Lin et al., 2012). These neurometabolites,
including N-acetyl aspartate (NAA), choline (Cho), and glutamine/glutamate (Glx), are shown to
have similar changes on MRS imaging to CTE pathological changes, although not specific
(Alosco et al., 2017). Unfortunately, other studies have shown that there is only partial
comparability, noting gender bias and inconsistently applied age-matched controls; furthermore,
ante- and postmortem research in MRS use is still necessary (Ruprecht et al., 2019; Alosco et al.,
2017). Cerebrospinal fluid (CSF) markers have also been useful for Alzheimer’s diagnosis, and
since CSF p-tau levels have correlated with brain levels of p-tau NFT deposition, these CSF
protein measures may be useful CTE biomarkers; it may also help to differentiate CTE from
other neurodegenerative diseases (McKhann et al., 2011). Potential biomarkers of traumatic
brain injury include glial fibrillary acidic protein (S100B), microtubule associated protein-2
(MAP-2), and brain-derived neurotrophic factor (BDNF) (Wang et al., 2018). By using these
biomarkers with diagnostic imaging, such as MRI and PET, future research may find ways to
ensure early diagnosis and monitor progression in those with CTE, while also developing more
effective therapeutic interventions (Tharmaratnam et al., 2018).
Prevention. Since CTE is so difficult to definitively diagnose, as well as the fact that it is
an untreatable neurodegenerative disease, treatment methodologies focus on preventive measures
(Saulle & Greenwald, 2012). These predominantly preventative treatment approaches’ main
objective is to target and relieve TBI’s harmful neurobiological outcomes, preventing them from
pathologically developing and manifesting as neurodegeneration (Milani & Jadavji, 2017). This
 CTE in Athletes 11

can be difficult in contact sports such as football or even hockey, as hard hits and head collisions
are part of the game. Therefore, Saulle and Greenwald (2012) recommend a multifaceted
approach, where coaches, referees, team physicians, administrators, and players work together to
reduce the chance of head trauma. Coaches must be aware of how multiple hits have a
cumulative effect on the brain, so they should restrict how much time is spent in practice and
drills using full contact; they must also teach players safe techniques for hitting and tackling,
emphasizing the importance of controlled play (Saulle & Greenwald, 2012). Players themselves
must understand the dangers – both short- and long-term – of head trauma, protecting themselves
while playing as well as ensuring the seek help for any injuries they do sustain; they should
never attempt to hide any symptoms (especially of potential brain injuries), but instead go to
either their coach or team physician immediately (Saulle & Greenwald, 2012).
Referees must endeavor to establish a safe playing environment, upholding the
prearranged rules that were created to protect players, while the team physician should remove
any players from play that may be at increased risk, appropriately managing their mTBI until
they can return to the game (which itself must be based on certain criteria) (Saulle & Greenwald,
2012). Since it can be difficult to identify a player’s individual cognitive level (baseline) for
physicians to compare after an injury has occurred, it is recommended that neuropsychological
testing be undertaken prior to sports participation, so athlete’s cognitive function can be properly
assessed (Saulle & Greenwald, 2012). This gives the physicians a baseline with which to make
more accurate comparisons. Finally, administrators also have a crucial role; they establish
policies that penalize athletes for reckless or dangerous hits, not to mention setting equipment
standards for the various leagues (Saulle & Greenwald, 2012). For example, the NFL has
recently implemented various safeguards to prevent head injuries and subsequent CTE in its
players; these include restricting contact practices with tackles to once per week as well as
penalizing direct head impacts with disciplinary action and/or substantial fines (NFL, 2020).
There have also been updated concussion protocols and return-to-play guidelines instituted,
helping to ensure players who have suffered concussions abide by these return-to-play guidelines
after brain trauma (NFL, 2020).
Saulle and Greenwald (2012) explain that another aspect of prevention is improving
athletes’ protective equipment. This includes helmets and mouth guards, which function very
well in protecting players from severe head injuries; however, helmets must fit correctly and be
 CTE in Athletes 12

appropriately strapped into place, not to mentioned lined with the necessary padding to protect
the head and brain (Daneshvar et al., 2011). A recent study compared football helmets over a 40
year period (from 1970 to 2010), finding that newer helmets were both heavier from the extra
padding as well as longer, higher, and wider; these bigger helmets were better at absorbing
forces and impacts, meaning that the latest protective equipment is far superior to outdated
materials (Viano & Halstead, 2012). However, players may feel a false sense of protection while
wearing their helmets, encouraging them to be more reckless and violent (Saulle & Greenwald,
2012). Coaches must therefore ensure players understand the risks, even when wearing
protective equipment. Furthermore, trainers and strength coaches should emphasize neck
strength, as this can help to minimize head injuries, especially in younger athletes (Daneshvar et
al., 2011).
MINO +NAC. Even though these methods can help prevent injuries, athletes and
professional sports teams desire medical therapies that can reduce the damage after a head injury;
one of these is the use of beta-amyloid-lowering medications, which has shown promise in
rodent models, improving outcomes following TBI (DeKosky et al., 2010). Additionally,
scientists are examining how important the timely treatment of TBI is as a method for reducing
the likelihood of CTE development (Fesharaki-Zadeh, 2019). For example, both tauopathies and
neuroinflammation have a synergistic effect, with hyperphosphorylated tau’s secretion believed
to active both astrocytes and microglia, subsequently resulting in pro-inflammatory cytokine
production (Fesharaki-Zadeh, 2019). As TBI results in inflammation, anti-inflammatory agents
including minocycline (MINO) with N-Acetylcysteine (NAC) can be administered in acute to
subacute time windows after these brain injuries; this new therapeutic regimen has shown
promise in several studies (Sangobowale et al., 2018; Haber et al., 2017).
In Sangobowale et al. (2018), the researchers found that MINO 45 mg/kg plus NAC 150
mg/kg synergistically improved cognition and memory, modulated inflammation, and helped to
remyelinate damaged white matter (by preventing oligodendrocytes loss) when first dosed one
hour after controlled cortical impact (CCI). However, even if the first dose is not given until 12
hours after injury, there were still benefits, including reduced gray matter injury in the
hippocampus, preserving myelin in multiple white matter tracts; these improvements were seen
even at half doses (Sangobowale et al., 2018). These results were corroborated in Haber et al.
(2017), where researchers found that MINO plus NAC synergistically improved both memory
 CTE in Athletes 13

and cognition in rats with mCCI; this medication protected resident oligodendrocytes,
modulating microglia/macrophages (MP/MG) activation. MINO has been approved as an
antibiotic for bacterial meningitis by the Food and Drug Administration (FDA, 2004). Therefore,
time sensitive protocol, similar to those for ischemic stroke, must be developed; these would
allow researchers to not only measure long-term outcomes in post-TBI recovery, but also help
prevent CTE development (Sangobowale et al., 2018).
Salsalate NSAID and Methylene Blue. Research has shown there is an inflammatory
cascade that leads to hyperphosphorylated p-tau accumulation, with acetylation considered to
start of the vicious cycle of repetitive damage and imperfect repair; this theory suggests a “two-
hit” mechanism of acetylation and phosphorylation that results in microtubule destabilization and
p-tau aggregation (Lucke-Wold et al., 2017). Therefore, it is recommended that pharmacological
therapies target the inhibition of ac-tau in the paired helical filament-6 (PHF-6) (Tharmaratnam
et al., 2018). One promising medication is salsalate, a non-steroidal anti-inflammatory drug
(NSAID) which decreases p-300 mediated acetylation of tau, enhancing cognition and reducing
brain atrophy (such as in the hippocampus) (Lucke-Wold et al., 2017). A similar study
corroborated these findings, with salsalate reducing MP/MG activation, thereby inhibiting
inflammatory pathways to the site of injury after TBI; this medication was able to induce genes
associated with neurogenesis and neuroprotection (including thyrotropin and oxytocin releasing
hormone), simultaneously improving functional recovery after injury (Lagraoui et al., 2017).
Another tau aggregation inhibitor is methylene blue (MB), which modulates acetylation activity
at K280/K281, where post-translational modification occurs before hyperphosphorylation of the
tau protein (Lucke-Wold et al., 2017). Lagraoui et al. (2017) mentioned the potential benefits of
MB, especially in combination with therapies that improve deacetylase activity (e.g., HDAC-6
and sirtuin-1) for potentiation and synergism.
Monoclonal Antibody Therapy. This form of immunotherapy an extremely promising
strategy for combating CTE, and perhaps the best candidate for future research (Breen &
Krishnan, 2020). Antibody therapeutic intervention should target tau accumulation in CTE, since
this is the most prominent feature of the condition; some studies have examined intracellular-
acting antibody treatments, since phosphorylated tau has intraneuronal localization in CTE,
although monoclonal antibody therapy (mAbs) is dependent on both receptor affinity and charge
(Sigurdsson, 2018). Therefore, extracellular mechanisms may be the better option, blocking
 CTE in Athletes 14

neuronal p-tau import (Nobuhara et al., 2017). It is preferred that tau protein’s pathogenic forms
be targeted with effective mAB immunotherapies, since tau has an essential role in promoting
microtubule transport assembly and axonal support (Nakamura et al., 2012). Unfortunately, there
are downfalls to mAB. One of the biggest challenges involves efficiently crossing the blood–
brain barrier (BBB) (Breen & Krishnan, 2020). To prevent the body’s immune system from
attacking these antibodies, they must first be humanized; however, this can decrease efficiency,
as tau’s charge and binding are altered (Congdon et al., 2019). There are currently no clinical
trials specifically for CTE, even though many explore these therapies on patients with
Alzheimer’s, which may be applicable to CTE’s tauopathy in the near future (Sigurdsson, 2018).
Methodology
Research Design
By reviewing the current literature and noting existing gaps, new research should be
conducted on mAbs and its uses on CTE’s tauopathy. Clinical trials are needed. Therefore, a
prospective study design will be used, which watches for outcomes, such as the development of a
disease, during the study period and relates this to other factors such as suspected risk or
protection factor. These are almost always cohort studies, which are ideal for this research,
facilitating the calculation of disease incidence in the exposure groups; this will allow for both
absolute and relative risk to be determined, as well as risk difference and attributable proportion.
These research designs are especially useful for examining the effects of unusual or rare
exposures, since investigators need to identify an adequate number of participants who have the
exposure; they work best for studying adverse effects of drugs or treatments. Cohort studies also
reduce the possibility for biased results stemming from impartial selection of comparison group
participants, as the specific outcome is not known at baseline when exposure status is
established.
As both extra- and intracellular pathways are involved in antibody-mediated clearance of
tau, it is crucial to understand the factors that impact these therapies’ efficiency and
effectiveness. These include the tauopathy being targeted, the stage of the disease, and the tau
antibody (charge, isotype, epitope, affinity, whole vs. fragment) (Sigurdsson, 2018). Therefore,
specific criteria will be used to determine the disease stage, with the intervention targeting the
tau antibody amino acids 294–305 linked to Keyhole Limpet Hemocyanin (KLH), which is a
highly immunogenic T-cell dependent antigen that is used in immunotoxicological studies
 CTE in Athletes 15

(Swaminathan et al., 2014). This proposed study will follow the guidelines established in the
clinical trial of Alzheimer’s patients by Novak et al. (2017).
Sample Population
For this research, the cohort study will include former NFL football athletes who played
for at least six years and have been retired for at least two years; other inclusion criteria include a
history of four documented mild TBIs or concussions or two moderate/severe TBIs. Participants
must be showing the early symptoms of Stage 1 CTE, including mild cognitive deficits and/or
behavioral changes. Clinical presentation criteria will utilize Montenigro et al.’s (2014) TES
subtypes, including behavioral/mood, cognitive, and mixed variants; those presenting with
advanced stages of dementia will be excluded. Symptoms may include impulsivity, anxiety,
apathy, paranoia, suicidality, significant headache, motor signs, documented decline, or delayed
onset; participants must have experienced these symptoms for at least one year (Montenigro et
al, 2014). Therefore, this study will focus on the second clinical presentation, with patients who
are, on average, 60 years of age or older; their disease progression will present with behavioral
and mood symptoms at later stages.
Methods
As this cohort study will be progressive, the cohort population will be followed over
time. Baseline data will be obtained on the TBI exposure, including data such as how long they
participated in football, how many head traumas and concussions they suffered, how long it has
been since they retired, and the symptoms they are exhibiting. Then, a sample subset (i.e.,
experimental group) will be administered the examined therapy, which is the vaccine AADvac-1,
a tau peptide mAbs which encompasses amino acids 294–305 linked to KLH. AADvac-1 is an
active vaccine that induces the immune response by targeting KLH in pathological tau forms,
impeding tau aggregation and reducing NFT formation (Huang et al., 2020). Next, a sub-
classification of the cohort will be selected for comparison (i.e., control group); these participants
will not receive the intervention. Both groups will be closely monitored, obtaining further
measurements of their conditions or symptoms. This is considered a randomized controlled trial
(RCT), as participants are randomly assigned to either the experimental or control group.
Participants will receive three subcutaneous doses of AADvac1 or placebo each month,
which will be blinded using masked vaccine kits to reduce bias; next, they will enter the open-
label phase, where everyone (both experimental and control groups) will receive three monthly
 CTE in Athletes 16

doses of AADvac1. One endpoint will be all-cause treatment-emergent adverse events, with
separate analyses for other adverse reactions, such as injection site reactions. Participants were
considered responders if they displayed a positive IgG titre against the tau peptide component of
AADvac1 at least once; this determined the vaccine’s safety.
Scales that can be used include the Glasgow Coma Scale score, which measures severe,
moderate, and complicated mild TBI. However, since there are numerous outcome measures that
can be examined in patients with TBI and CTE, other measurement tools will also be integrated.
The Extended Glasgow Outcome Scale (GOS-E) will measure global functional measure, the
Controlled Oral Word Association Test will be used for neuropsychological measures, while
both the Digit Span Test and Processing Speed Index will measure information-processing speed
(Bagiella et al., 2010). Furthermore, both the Trail Making Test and the Stroop Color-Word
Matching Test will be used to assess executive functions, while the California Verbal Learning
Test–2 will measure episodic memory (Bagiella et al., 2010).
Researchers will accurately measure how long the participants take the medication, what
dosage and specific regimen, as well as any noted side effects or symptoms. Outcome measures
will then be calculated, with data gathered and analyzed to compare the groups. As baseline data
will be obtained for each participant, this will allow pretest-posttest analysis to also be
conducted; therefore, there will be comparisons not only between the two groups (experimental
vs. control), but also for each person’s individual changes. Outcomes that will be measured
include improvements in overall functioning, including episodic memory and executive
functions, as well as the speed at which they process information.
Discussion
Through the literature review and proposed research, even though CTE is potentially
devastating neurodegenerative disease, there are ways to address it, helping improve patients’
health outcomes and quality of life. First, however, it must be accurately diagnosed while the
patients are still alive, which can be difficult; historically, CTE’s definitive diagnosis came only
upon postmortem autopsies. One area of interest involves the use of in-vivo biomarkers. For
example, the PET ligand 18F-FDDNP binds to both tau and amyloid; it can help clinicals
diagnose CTE, as the imaging pattern shows signal changes in the brains of those with this
condition. By visualizing these increased signals, it can support a clinical diagnosis (even though
it is not a definitive one, as confirmation at death is still needed). Furthermore, DTI can also be
 CTE in Athletes 17

used to identify brain changes after these head traumas, since helmet impacts during football
cause alterations in white matter, which remain even after some time has gone by. Another
diagnostic test is MRS, which measures neurometabolites – which occur with head trauma and
mTBI – as well as regional cerebral blood flow and glucose metabolism; unfortunately, it has the
same downfalls as 18F-FDDNP and DTI, meaning they are not conclusive. However, by
combining them with CSF protein measures – which themselves are beneficial CTE biomarkers
– ensure earlier diagnosis of CTE may be made, allowing clinicians to monitor the disease’s
progression more effectively.
A primary intervention that researchers stress is the importance of prevention in CTE. If
those involved in high-risk sports (such as football) utilize a multifaceted approach, multiple
head traumas – and subsequently, its neurological damage – can be significantly reduced.
Therefore, it is crucial for not only coaches and administrators, but also players to work toward
preventing brain injuries and exposure to head trauma. One method is for coaches to restrict how
much time players spend participating in full-contact practice and drills, ensuring they utilize
safe techniques for hitting and tackling. Furthermore, administrators can set up policies that
punish athletes for reckless or dangerous play, whether through fines or disciplinary action; they
should establish equipment standards, concussion protocols, and return-to-play guidelines. Those
in change should also mandate that all players undertake neuropsychological testing before being
allowed to play, so team physicians have documentation on their cognitive function, which can
be used for comparison after head injuries.
However, one of the most powerful stakeholders is the player. It is their life (both
quantity and quality) that is on the line; therefore, they should abide by all policies for safe play,
not to mention alerting team physicians to any potential brain injuries they may incur. Hiding
injuries has long been considered a way of life for athletes, as they overcome any and all aches
and pains to continue the game; unfortunately, this sports culture has disastrous outcomes on
players. Rather than seeking help immediately, they pretend everything is alright, which makes
any possible therapeutic interventions a moot point. Since players may not always do what is
best for their health (and the same can be said for coaches and administrators in professional
sports, as they have a lot riding on these games), it is absolutely crucial to ensure that at least the
athletes’ protective equipment is in excellent condition, using the latest technologies to guarantee
optimal protection. Helmets and mouth guards should be correctly worn by all players. Even
 CTE in Athletes 18

though this may give them a false sense of security, it is better than the alternative (i.e., no
protective equipment).
New medical therapies are currently being studied for TBI, which may help to reduce the
likelihood of CTE development. These include beta-amyloid-lowering medications as well as
MINO plus NAC, which are anti-inflammatory agents that can reduce neuroinflammation; this is
especially true when they are administered relatively soon after head injuries. Studies have
shown that the use of MINO 45 mg/kg plus NAC 150 mg/kg synergistically improved cognition
and memory in those with TBIs when given within the first 12 hours (although even better
results occur if it is administered within the first hour). This is because it prevents
oligodendrocytes loss through remyelinating damaged white matter while also reducing gray
matter injury. The FDA has approved MINO for use in humans; therefore, it is crucial to develop
a time sensitive protocol for use in players with brain trauma exposure. Another pharmacological
therapy is salsalate, which is an NSAID that targets the inhibition of ac-tau in PHF-6; this has
been shown to reduce MP/MG activation, thereby improving cognition and reducing brain
atrophy. In fact, it induced genes associated with neurogenesis and neuroprotection, allowing for
an enhancement in functional recovery after injury. MB also has shown promise. This is another
tau aggregation inhibitor which modulates acetylation activity at K280/K281; this intervention is
especially beneficial when combined with other therapies that improve deacetylase activity for
potentiation and synergism.
Finally, mAbs is a form of immunotherapy that is used to combat cognitive dysfunction
and brain changes in those with Alzheimer’s, making it a promising research avenue for CTE.
Antibody therapeutic interventions target tau accumulation, with both intracellular and
extracellular mechanisms as potential focuses. However, extracellular structures have been
shown to block neuronal p-tau import more effectively, helping to improve cognitive function in
those with brain injuries. Unfortunately, these medications must cross the BBB to be successful,
which can be difficult. Thankfully, there has been ongoing research into addressing this
complication. Ultrasound technology advancements – such as unilateral focused ultrasound
(FUS) – have been employed to aid immune response or drug delivery across the BBB; this
involves injecting preformed microbubbles using FUS, thus reducing any potential adverse
effects. This promotes the safe in vivo transfer of antibodies and other therapeutics across this
barrier. Therefore, the research proposal focuses on the use of the tau peptide mAbs, which is
 CTE in Athletes 19

introduced using the AADvac-1 vaccine. Clinical trials have already been conducted in patients
with Alzheimer’s; however, there has not been any trials on athletes with CTE. This gap in
current research should be addressed by future studies, as therapeutic interventions are necessary
to treat those with TBIs and head trauma.
Conclusion
CTE is a progressive neurodegenerative disease that is common in athletes, especially
those who have participated in physical contact sports such as football. In fact, millions of sport-
related concussions occur each year in the U.S., with a fifth of all TBI cases resulting from
sports-related head injuries. The condition results from either single or repetitive head injuries,
which can have a cumulative impact on the brain; unfortunately, there is currently no cure, and
difficulties in definitively diagnosing patients with CTE make successful interventions even
more challenging. This condition has gone by other names, including “punch drunk” (as it was
first seen in boxers) and dementia pugilistica. The severity of this disease is connected to the
level of play, with professional players being more at risk than those who only played in high
school.
For a diagnosis to be made in life, a history of brain trauma is required, although there
must be other criteria met, since not everyone with this history goes on to develop CTE. Many
may remain asymptomatic in earlier stages or have mild cognitive and/or behavioral issues,
while more behavioral outbursts are observed as the disease progresses. Memory loss and
executive functioning dysfunction, not to mention motor deficits, are associated with later stages.
Old age, genetics, military combat, or alcohol/substance abuse can be predisposing factors not
related to sports, while duration of play, position, sport, and AFE are variables in athletes.
Basically, the longer a person plays (including starting at an earlier age), the more likely they are
to experience head injuries that can result in CTE later in life. Furthermore, if players have the
ApoE ε4 allele, they may have much worse neurotrauma outcomes – including increased injury
severity, longer recovery times, and greater cognitive impairments – than those who do not have
this genetic variant. For a definitive diagnosis, the NINDS/NIBIB identified macroscopic and
microscopic abnormalities linked to CTE, which can be used in autopsy diagnoses to determine
the disease’s severity. Stage one includes one or two focal perivascular CTE lesions in the
cerebral cortex at sulci depths, while stage two is characterized by less than three of these
lesions, which are typically located in multiple cortical regions. Stage three involves multiple
 CTE in Athletes 20

CTE lesions with widespread cortical NFTs, while stage four also includes widespread astrocytic
p-tau pathology, neuronal loss, and gliosis.
As CTE is characterized by p-tau protein deposition as NFT, it becomes more extensive
in later stages and results in this neuronal loss. Considering clinical presentations in athletes,
symptoms can vary extensively, displaying changes in mood, behavior, cognition, and motor
functions. These may range from depression, irritability, and aggression to memory impairment,
executive dysfunction, and parkinsonism. Some patients have chronic headaches, while
increased risk of suicide has also been mentioned in relation to CTE, with some studies linking
the two while others refute this evidence. Furthermore, it is important for clinicians and
researchers to remember that there are two distinct clinical CTE presentations: 1) younger
patients with initial symptoms related to mood and behavioral (“classic”, primarily linked to
boxers), and 2) older patients with these early symptoms associated with cognitive impairment
(“modern”, primarily linked to football players).
Thankfully, research has been ongoing on methods to more conclusively diagnose CTE
while patients are living; this allows for them to receive treatment interventions that can alleviate
symptoms and possibly promote faster healing and recovery. The PET ligand 18F-FDDNP allows
clinicals to visualize the brain’s signal changes, while studies are also exploring the use of DTI
and MRS as possible diagnostic tools. Therapies that may help mitigate the harmful impacts of
this condition include anti-inflammatory agents such as MINO plus NAC, while
immunotherapies like mAbs can improve cognitive function in those with TBIs. However,
prevention is still the primary method for combating CTE. There must be changes in sports
culture, with coaches, team physicians, administrators, and players working together to
implement safe practices – ensuring there is adherence to these policies. In this way, athletes can
limit the number of brain traumas they are exposed to, while still playing the sport they love.
 CTE in Athletes 21

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