DRUG DISCOVERY

Traumatic Brain Injury —A Controversial and Deadly Epidemic
What is the definition of childabuse? To neuropathologist
Dr. Bennet Omalu, it is allowing
children to play football. In aninterview with ESPN writer
Kevin Seifert last August, Dr.
Omalu said, “I’ve always said
that every child who plays
football has a 100 percent riskof exposure to brain damage”(Seifert 2017).

Linking Football to Degenerative
Brain Disease and Mental Illness
Dr. Omalu knows firsthand how abusive
football can be to the brain. In 2002, hediscovered chronic traumatic encephalopathy(CTE) in a football player. CTE is caused byrepetitive insults to the brain, resulting in diffuse
accumulation of amyloid plaques throughout
the brain. These plaque deposits are also seenin patients with Alzheimer’s disease. In fact,many of the symptoms of CTE overlap
with Alzheimer’s disease.

Patients suffering from CTE may experience
the following symptoms, which can take up
to 10 years to manifest (McKee et al 2013):
Cognitive impairment
Impulsive behavior■■ Depression or apathy■■ Short-term memory loss■■ Loss of executive function■■ Emotional instability■■ Increased substance abuse■■ Suicidal thoughts and behavior■■■■

Traumatic Brain Injury — A Controversial and Deadly Epidemic

The player at the center of Dr. Omalu’s
discovery was Mike “Iron Mike” Webster
who played center for the Kansas City
Chiefs and Pittsburgh Steelers from 1974
to 1990. After retirement, Webster sufferedfrom amnesia, dementia, and depression.
Dr. Omalu’s discovery of the connection
between football and Webster’s severe
mental illness, as well as the national
football league’s (NFL’s) subsequent denialof that finding, was portrayed in the 2015
film Concussion.
In 2005, Dr. Omalu published his findings
based on Webster’s case in the journal
Neurosurgery in a paper titled “Chronic
Traumatic Encephalopathy in a National
Football League Player” (Omalu et al. 2005).
Dr. Omalu’s research sparked enormous
controversy in the NFL. In 2006, theleague’s traumatic brain injury (TBI)
committee requested the retraction of
Dr. Omalu’s paper, citing the researchas “completely wrong” and “a failure.”
Despite the pushback, Dr. Omalu continued
researching CTE in football players andpublished another study in 2006, whichshowed CTE in the brain of Terry Long,a former NFL player who suffered fromdepression and committed suicide in 2005
(Omalu et al. 2006).

It wasn’t until 2009 that the
NFL finally acknowledged
a possible link between
football and CTE.

This second study was also presented
to the league and was again met withsuspicion and ultimately complete denial.
The NFL’s TBI committee chair, Ira
Casson, told the press: “In my opinion,
the only scientifically valid evidence of
CTE in athletes is in boxers and in some
Steeplechase jockeys” (Ezell 2013). It wasn’t
until 2009 that the NFL finally acknowledged
a possible link between football and CTE.
Since that acknowledgement, the league
has continued to witness the tragedies ofsuicides in multiple players with confirmed
CTE: Junior Seau in 2012, who shot
himself in the heart to preserve his brain forresearch, and Aaron Hernandez, who wassentenced to life in prison and later hunghimself in his jail cell. Hernandez’s brain
revealed the worst CTE ever discovered
for someone his age. Other players who
have taken their own lives since 2009
include Shane Dronett, Dave Duerson,
Ray Easterling, Jovan Belcher, and Paul
Oliver — every one of them with evidenceof CTE.

2

A 2017 study in the Journal of the American
Medical Association (JAMA) revealed that110 out of 111 deceased former NFL players
who donated their brains to research had
developed CTE. It is important to note that
CTE is not the only brain injury that can
result from trauma to the brain. Commenting
on this study, Dr. Omalu said, “There has
been so much fascination with CTE that weare going the wrong way. CTE is just one
disease in a spectrum of many diseases
caused by brain trauma. If he doesn’t have
CTE, that doesn’t mean he doesn’t havebrain damage” (Seifert 2017).
Previously, CTE could be confirmed in thebrain only during an autopsy. In November
2017, a study published in Neurosurgery
revealed the first living patient to haveconfirmed CTE using brain scans (Omalu
et al. 2017). The study describes the brainscans of 14 former NFL players. The scansrevealed a distinctive pattern of tau buildup
in the brain, which is unique to CTE patients.
Upon the death of one of those players,
an autopsy was performed to confirm thediagnosis. Although further research needs
to be done to confirm the predictive validityof the brain scans for CTE diagnosis,
this is a promising step toward achieving
earlier diagnoses.

TBI – Beyond CTE and Football
The established link between football andbrain damage is truly tragic. However, there
is a sport that has an even higher incidenceof TBI than football — girls’ soccer. A recent
study led by Dr. Wellington Hsu, professorof orthopedics at Northwestern University’s
Feinberg School of Medicine, reported
that 27% of all injuries in girls’ soccer are
TBI-related (compared to 24% in football)(Schallmo et al. 2017). The researchers
noted, “To our knowledge, this is the firststudy to report that concussions now
account for a higher proportion of injuries
in girls’ soccer than boys’ football. The
concussion rate for girls’ soccer is also
increasing rapidly and is now nearly tiedwith boys’ football and is threefold higher
than boys’ soccer.”
The Today Show interviewed Dr. Omalu
regarding the risk of TBI and various
sports. When asked about soccer he said,“Soccer is a high-dexterity, high visualspatial coordination sport. You need very
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Traumatic Brain Injury — A Controversial and Deadly Epidemic

According to the Centers for Disease Control, there were 2.5 million reported TBIs in the United States in 2010, resulting in direct andindirect costs of approximately $76.5 billion.

high levels of brain functioning to play it andchildren have not attained that level of brain
development. Soccer, as it’s played today,
should be played only by children who areabove the age of 12–14.” Dr. Omalu also
recommends eliminating heading the ball
until age 18 (Pawlowski 2017).

TBI Progression and Severity
TBI occurs in two phases: the primaryand secondary injuries. The primary injury
occurs at the moment of head trauma,
causing deformation of blood vessels,axons, glia, and neurons. This primary injury
is irreversible and preventive measures
such as helmets and airbags should be
employed. Secondary injury is potentiallyreversible and occurs over the course ofhours and days following the initial insult.
It involves a cascade of biochemical andphysiological responses to the primary injury
that can lead to severe brain damage anddeath (Plummer et al. 2016).
According to the Centers for Disease
Control, there were 2.5 million reported
TBIs in the United States in 2010, resulting
in direct and indirect costs of approximately$76.5 billion. The severity of a TBI may
range from mild (a brief change in mental
status or consciousness) to severe (anextended period of unconsciousness ormemory loss after the injury). A non-fatal
severe TBI may result in an extended periodof unconsciousness (coma) or amnesia
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after the injury. For individuals hospitalized
after a TBI, almost half (43%) have a related
disability one year after the injury.

Approximately 5.3 million
Americans are living with a
TBI-related disability
A TBI may lead to a wide range of shortor long-term issues affecting:
■■

■■

■■

■■

 ognitive function (for example, attention
Cand memory) otor function (for example, extremityM
weakness, impaired coordination andbalance) ensation (for example, hearing, vision,
S
impaired perception and touch) motion (for example, depression,E
anxiety, aggression, impulse control,
personality changes)

Approximately 5.3 million Americans areliving with a TBI-related disability, and theconsequences of severe TBI can affect
all aspects of an individual’s life. Thiscan include relationships with family andfriends, as well as their ability to work or be
employed, do household tasks, drive, or
participate in other activities of daily living(Bey and Ostick 2009).

Mild traumatic brain injury (mTBI) accounts
for more than 75% of all TBIs (McInnes etal. 2017). Along with impaired cognitive
function, mTBI causes an array of symptoms
that include headaches, fatigue, depression,anxiety, and irritability, collectively referred toas post-concussion syndrome (PCS). It takes
approximately three months for symptoms
to resolve in the majority of individuals.
However, some patients continue toexperience symptoms beyond the first year
after the injury. Those with such long-lasting
symptoms are said to experience persistent
PCS, which is estimated to impact 15% of
individuals with a first-time concussion.
mTBI produces more subtle deficits,
which can lead a patient or caregiver tounderestimate the seriousness of the injury
and return to an activity that may lead tocontinued exposure to further risk of mTBI.
Frequent repetitive TBI, such as that which
occurs over the course of a football player’s
career, leads to CTE. However, repetitive
mTBI can result in a much more acute,severe outcome. Repetitive mTBI that occurs
within hours, days, or weeks (second impact
syndrome or SIS) can cause diffuse cerebral
swelling, brain herniation, and even death.
SIS can occur with any two events involving
head trauma. While rare, it is devastating,since young, healthy patients can die withina few minutes (McInnes et al. 2017).

3

Traumatic Brain Injury — A Controversial and Deadly Epidemic

TBI Diagnosis
Neuroimaging (brain scan) in the form ofcomputed tomography (CT) is considered
the gold standard of TBI diagnosis. A
CT scan of the brain provides detailed
information about damaged brain
structures, including disruption of the blood
brain barrier. Another scanning technology,
magnetic resonance imaging (MRI), revealschanges in brain activity associated withtrauma. However, neither CT nor MRI ispractical for use in the field or on a repetitive
basis due to low accessibility, high cost, andradiation exposure.
Diagnosing the severity of the initial insult
as early as possible is critical in preparing
for the downstream effects of a secondary
injury. The only field-based assessment usedcurrently is the Glasgow Coma Scale (GCS),
which yields a score by assessing the eye
movement as well as the verbal and motor
response of the patient. The limitations of the
GCS are that it takes a skilled practitioner
to accurately perform the assessment, it issubjective (poor inter-assessor reliability), andlacks sensitivity when a patient is under the
influence of drugs, alcohol, or stress (factors
often related to TBI outside of sports). Thiscan lead to underestimating the severity of
the injury, thus risking inappropriate follow-up
and treatment.
The lack of TBI follow-up can result in “talkand die” syndrome, a term used to describe
the rapid deterioration of a head trauma
patient, typically due to epidural hematoma(bleeding in the brain). This was the ultimate
cause of the death of 45 year-old Natasha
Richardson, actress and wife of actor Liam
Neeson in March 2009. Richardson fell andhit her head while skiing on a beginner run
at Mont Tremblant in Quebec, Canada.
After her fall on a Monday morning, the ski
patrol attended to her, but it is reported
that she refused a doctor or ambulance.
She returned to her room at the resort,and was monitored by a ski instructor
and the manager of the hotel. Later thatafternoon, her condition deteriorated andan ambulance was called to take her tothe hospital. Unfortunately, by the time she
arrived, doctors could not stabilize her. By
Wednesday evening of the same week,
Richardson was dead. Had the severity ofher injury been detected on the mountain,4

she would have been rushed to the hospital
to relieve the pressure from the bleeding in
her brain, giving her a chance at survival.

Biomarkers in TBI
The current methods of TBI diagnosis are
inadequate, especially given how commonand debilitating the impact of the diseasecan be. Researchers have been striving
for a method of TBI detection that is
portable, openly accessible, and requires
little training and expertise to administer.
Experts in the field recognize that serumbased biomarkers represent the holy grailof potential TBI detection and prognosis(Figure 1, Table 1).
Unlike other diseases where specificbiomarkers that provide a definitive diagnosis
or severity for a disease have been identified(for example, HBA1c for diabetes), no suchdiagnostic biomarkers exist for TBI. For
years, researchers have studied dozens ofpotential biomarkers that show promise,
yet today there is still no FDA-approved
biomarker available for clinical use. Whileblood-based biomarkers afford optimal
convenience and accessibility in the field,
serum biomarker alterations may notcompletely reflect the biochemical changes
in the injured brain. This is because otherfactors, such as the integrity of the bloodbrain barrier and the release of biomarkers

Other TBI markers
 ytokines: IL-6, IL-10, IL-8, TNF-α
C
miRNA
■■ UA
■■ BDNF■■ Metabolomic profiling■■■■

Experts in the fieldrecognize that serum-based
biomarkers represent theholy grail of potential TBI
detection and prognosis.

Neuron cell body■■■■

UCH-L1
NSE

Axon
■■
■■
■■

SBDP
Tau
Neurofilaments

Myelin sheath
Dendrites■■

MBP

Axon terminals
Astroglial cell■■■■

S100-B
GFAP

Fig. 1. Prospective TBI Biomarkers. BDNF, brain-derived neurotrophic factor;
GFAP, glial fibrillary acidic protein; MBP, myelin basic protein; miRNA, microRNA;
NSE, g-enolase; SBDP, spectrin breakdown products; UA, uric acid; UCH-L1, ubiquitin
C-terminal hydrolase.

© 2018 Bio-Rad Laboratories, Inc.

Traumatic Brain Injury — A Controversial and Deadly Epidemic

Table 1. Potential TBI biomarkers.
Cytokines
IL-6, IL-8, IL-10

TNF-α

The levels of interleukin-6 (IL-6), IL-8, and IL-10 are increased in CSF in response
to severe TBI. The magnitude of the increase correlates with patient outcome andblood brain barrier (BBB) dysfunction, as indicated by the CSF: serum albumin
ratio. However, these markers are not brain specific. They may be released into theperipheral tissues and slowly seep into the CSF (Neselius et al. 2012).
TNF-α is produced in the brain in response to various pathological processes suchas infectious agents (for example, human immunodeficiency virus (HIV) and malaria),
ischemia, and trauma (Feuerstein et al. 1994).

Cell Body Markers
Ubiquitin C-terminalhydrolase (UCH-L1)

g-enolase (NSE)

UCH-L1 is an abundant enzyme in the soma of neurons that cleaves ubiquitin. Its
levels correlate with the severity of TBI and patient outcome in some studies, but
the results are inconsistent in mTBIs. One study reported that serum UCH-L1 levels
can discriminate mTBIs from controls, whereas some studies were unable to show asufficient discriminating power between patients with mTBI and non-injured controls(Adrian et al. 2016).
In humans, early studies showed serum NSE to be elevated in mTBI patients
although subsequent reports indicate a lack of clinical relevance despite elevatedlevels (Kulbe and Geddes 2016).

Axonal Markers
Spectrin breakdown
products (SBDP)

Upon cellular injury, calpains and caspases (enzymes) cleave spectrin, a cytoskeletal
protein that maintains cell membrane integrity and cytoskeleton structure, to spectrin
breakdown products (SBDPs). SBDPs have been reported in the CSF early after
injury as well as in adults with severe TBI. SBDP levels significantly correlate with theseverity of injury and clinical outcome (Papa et al. 2015).

Tau

After TBI, tau is proteolytically cleaved (c-tau) and gains access to the CSF andserum. CSF levels of c-tau are significantly elevated in TBI patients, which correlatewith clinical outcome. Total tau protein may be indicative of axonal damage in graymatter neurons and has been found to be associated with the scale of injury insevere TBI (Papa et al. 2015).

Neurofilaments(NF-L, NF-H)

CSF measurements of NF-L are regarded as the most sensitive markers of axonal
injury. Phosphorylated NF-H has been found to be elevated in the CSF of adultpatients with severe TBI (Papa et al. 2015).

Myelin basic protein(MBP)

Increases in CSF MBP have been reported following an array of neurological insults
including TBI in adults and children (Su et al. 2012).

Glial Markers
S-100bGlial fibrillary acidic
protein (GFAP)

S-100b helps to regulate intracellular levels of calcium in astrocytes and isconsidered a marker of astrocyte injury or death. Because S-100b is also foundin non-neural cells such as adipocytes, chondrocytes, and melanoma cells, itscorrelation with TBI can be confounded by release from extracerebral tissues (Thelin
et al. 2017).
After brain damage, GFAP is released from degenerating brain cells into thesurrounding interstitial fluid and appears in the peripheral blood, likely throughdisruptions in the BBB. Elevated serum GFAP can provide diagnostic and prognostic
information in a range of neurological diseases including severe TBI (Lei et al. 2015).

Profiling Markers
microRNAs

Metabolomics profile

miRNAs can be detected in serum and can be an indicator of disease pathology inthe cell of origin, including neuronal cells. Serum miRNAs are relatively stable
at variable pH conditions and are resistant to repeated freeze/thaw cycles andenzymatic degradation, which make them a suitable biomarker candidate forTBI (Di Pietro et al. 2017).
The metabolic profile provides a window into the in vivo enzymatic activity of thebrain and body. Recent studies suggest that metabolomics has the potential for
diagnostic and prognostic characterization, monitoring, and identifying surrogate
markers of a broad spectrum of TBIs (Posti et al. 2017).

Other Novel Markers
Uric acid (UA)A recent study indicates a strong correlation between UA levels and patient
outcome, either in hospital or at six months after discharge (Hatefi et al. 2016).

Brain derived
neurotrophic factor(BDNF)

Assessment of BDNF levels within 24 hr of head injury can predict the severity andprognosis of TBI. Healthy people averaged 60 ng/ml of BDNF in their bloodstreams,
whereas patients with brain injuries average less than 20 ng/ml, and those withthe most severe TBIs average around 4 ng/ml. High levels of BDNF led to partial
recovery within six months of injury and low levels correlated with lingering
symptoms at six months (Korley et al. 2016).

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from other injured organ systems, canconfound what is specifically happening in
the brain.
Cerebrospinal fluid (CSF) biomarkers havethe advantage of increased specificity
over peripheral blood markers due totheir increased proximity to the brain anddecreased susceptibility to the confounding
effects of factors outside the brain. However,
the CSF resides in a closed system aroundthe brain and spinal cord, making it
impractical for sampling in the field.
Biomarker research is itself difficult toperform. A researcher in an academic or
corporate setting may focus on a single
marker within a cascade of biologicalactivity that is likely dependent on upstream
and downstream markers outside of
their area of focus. Helping to solve thisproblem is a company called Amplion,
which has built a biomarker searchtool called BiomarkerBase, which uses
machine learning to immediately deliver
a comprehensive survey of the clinicalbiomarker landscape.

Machine Learning and thePromise for Biomarkers in TBI
Table 1 shows a myriad of attempts by
researchers to find a single biomarker
that can be used to detect TBI. However,none of them have shown results definitive
enough to warrant use in a clinical setting.
Advances in “-omic” profiling technologies
allow systematic analysis andcharacterization of alterations in genes,
RNA, proteins, and metabolites. These
technologies also offer the possibility of
discovering novel biomarkers and pathways
activated in disease or associated withdisease conditions.
Metabolomic profiling is one such approachthat may hold promise in TBI diagnosis,
prognosis, and screening. In a study out
of Western University in London, Canada,
plasma was isolated from 12 concussed
and 17 nonconcussed athletes and assayedfor 174 metabolites (Daley et al. 2016). Data
were analyzed using multivariate statisticalanalysis and machine learning. Applying
machine learning resulted in reducing thenumber of metabolites required to achieve
92% diagnostic accuracy from 174 to as
few as 17. Just as diagnostics for cancer
5Traumatic Brain Injury — A Controversial and Deadly Epidemic

in recent years have leveraged the powerof computers to make inferences amongenormous sets of clinical data and genomic
markers, the future of TBI detection may besolved in a similar fashion.

Motion as a Biomarker
A biomarker is typically thought of as ananalyte derived from serum, CSF, saliva,
tissue, or other biological substratethat can be sampled. By definition,
biomarkers are “objectively measured
indicators of normal biological processes,
pathogenic processes, or pharmacologicalresponses to a therapeutic intervention.”
They are “intended to substitute for aclinical endpoint (predict benefit or harm)
based on epidemiological, therapeutic,
pathophysiological, or other scientificevidence” (Biomarkers Definitions Working
Group 2001).
Therefore, could motion of the body besuch an indicator? With TBI, in fact, it
is. Motion itself is the primary cause of
TBI, inducing the mechanical insult thatdamages structures within the brain. Thatmotion, which occurs on impact, can bemeasured and an alert can be generated
when the motion increases above acertain threshold. Several companies havedesigned products, primarily for athletes,
which contain sensitive accelerometers that
attach to helmets to function in this way.
Some of these companies are Jolt Sensor,
X2 Biosystems, and the Shock Box.
Jan Medical has built a device called theBrainPulse, which uses highly sensitive
accelerometers placed on a headset todetect movement of the skull from bloodflow and pulse in the head. The movement
patterns are not only a result of the pulsatileblood flow into the brain but also physicalparameters of the brain tissue. Applying
machine learning to the data measured
by skull motion and disruptions of suchmotion allow patterns to be recognized andalgorithms to be developed that are specificto brain pathologies, including TBI. The
BrainPulse data, which are acquired withina few minutes, can aid in the diagnosisof these pathologies and enable triage ofpatients for adequate treatment.

6

Treating TBI
Despite improved supportive andrehabilitative care of TBI patients, no effective
drugs have been approved for reducing
TBI mortality and improving functional
recovery. This is because all phase II/III
TBI clinical trials so far have failed. Recent
preclinical data indicate the potential for
restorative therapies targeting multiple cells
to stimulate angiogenesis, neurogenesis,
axonal sprouting, and oligodendrogenesis,
with the goal of improving neurological
function after TBI (Xiong et al. 2015). Thereis also a compelling need to develop
novel therapeutics specifically designed tostimulate neuroplasticity, which subsequently
promotes neurological recovery after TBI.

Conclusion
TBI is an epidemic with significant healthand socioeconomic costs. Despite decadesof intense research, little progress has
been made in diagnostic, prognostic, andtreatment modalities for this indication. Thisreveals the extreme complexity of the central
nervous system and how it responds toinjury. Improvements in technology throughmachine learning and novel biomarkers showpromise in the search for valid, portable, andlow-cost diagnostic tools, which will hopefully
be on the sidelines and at accident scenes in
the foreseeable future.

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