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Introduction: Traumatic Brain Injury
– Sports related TBI
Incidence
Severity, symptoms
Chronic traumatic encephalopathy CTE
– Drugs for TBI
Synaptogenesis, Angiogenesis, Neurogenesis
Evidence from exercise
Animal models
– mild TBI associated and chronic loss of brain tissue
Critical review of Zhou et al. (2013)
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TBI in the USA
1.7 Million/year
29% of all ER visits
Incidence ‘bathtub’
function.
52,000
Deaths
275,000
Hospitalizations
1,365,000 ER Visits
??? Receiving other/no care
2002-2006 Faul et al. (2010)
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TBI in the USA
Causes
– Also vary with age
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Sports related TBI
CDC estimates 300,000 sports related TBIs
each year.
– However, only included TBIs with loss of
consciousness.
– LoC only account for 8-19.2% of of sports related
TBIs.
– Therefore, ~1.6-3.8 million sports related TBIs each
year.
– Athletes tend to under-report: Even this estimate
may be low!
Langlois et al. (2006)
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Sports concussion
 Recent attempts to define
sports-related subclassification of mild TBI
(e.g. Cantu Grading,
American Academy of
Neurology)
 Often no loss of
consciousness.
 Post-traumatic amnesia and
mental status can appear
normal within minutes.
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Sports concussion
Most athletes report complete resolution within 510 days.
‘Post-Concussive Syndrome’ refers to
complaints that persist weeks to months – more
common with multiple events.
– According to ICD-10 and DSM-IV mild TBI can occur
without loss of consciousness, but PCS requires LoC.
– While some individuals who claim chronic problems
may be malingering, others with legitimate problems
may not get appropriate compensation.
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Return to play
Strong reasons to halt play after mTBI:
– Concussion leaves one susceptible to another,
especially if second impact occurs before
symptoms resolve.
– Progressive process: smaller impacts cause the
same symptom severity (Zurich statement).
– Repeated concussions may increase the risk in
later life for dementia, Parkinson's disease, and/or
depression.
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Return to play
 McCrea et al. (2003) examined 1631 collegiate football players – carefully
evaluated 94 who suffered concussion (and 56 controls) 3hr, 1,2,3,5,7,90
days post injury. Cognitive deficits cleared in 5-7 days, balance deficits 3-5
days. Verbal processing resolved over 7 days.
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Return to play
 Quigley’s rule (Schneider, 1973) termination of
contact sports after 3 concussions, regardless of
severity
 Zurich Statement (2008) provides graduated return
of activities, typically over one week (table 1), with
recognition of modifiers (table 2).
 Section 4.2 same day return to play when concussion
management team available (professional sports)
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Second Impact Syndrome
 SIS refers to fatal injury that results occurs if two mild
TBIs occur in short succession (Buzzini & Guskwicz,
2006; Solomos 2002).
 Possible mechanism: first injury impairs vascular
regulation (Hovda et al., 1999).
 SIS also referred to as diffuse cerebral swelling (DCS)
 SIS very rare (17 documented cases), so remains
controversial (McCory 2001), unlikely well documented
vulnerability to subsequent non-fatal mild TBI.
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Chronic traumatic encephalopathy
 “Punch drunk syndrome” (Martland 1928)
 “Dementia Pugilistica” (Lampert and Hardman,
1984)
 CTE (Modern)
– Professional US Football conservatively 3.7% incidence
(Gavett et al., 2011). Some evidence for wrestling, hockey.
– Main symptoms typically years after career.
– Histological signs can be seen early in life, e.g. University
player Owen Thomas who committed suicide at 21 years
old.
– Seen in animals and humans with single blast exposure.
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CTE, McKee et al 2013
 Recent histological study of 85 men (1798yo) with history of repetitive mild TBI
and 18 controls: 68/85 had evidence of
CTE.
– 63% CTE only
– 16% Lewy Body disease
– 12% motor neuron disease
(Lou Gherig’s, ALS)
– 11% Alzheimers
– 6% Frontotemporal degeneration
 Authors suggests progression of
tau abnormalities
Lou Gherig
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Histological Biomarkers for CTE
Tau-positive neurofibrillary tangles (NFTs) in
the neocortex, concentrated around
penetrating parenchymal vessels
Neuropil (cortical) threads
Neocortical diffuse amyloid plaques, with or
without neuritic plaques
Sparing of the hippocampus
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AD vs CTE (McKee et al., 2013)
AD
Neurofibrillary
tangles
(expressing
amyloid, red),
normal sulcal
depth.
No clustering of
tangles near blood
vessels
Diffuse tau
CTE
Clumps of tau,
large sulci
Clustering of
tangles near blood
vessels
Tau mostly in
superficial layers
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CTE : McKee et al., 2013
 Currently CTE diagnosed at autopsy. Symptoms very similar
to Alzheimer’s disease
– Depression, anger around 35 yo
 Of 36 former athletes, 6 committed suicide
– Mental decline around 59 yo
– General symptoms








Recurrent headaches
Dizziness
Mood disorders (depression)
Aggression
Impaired judgment and impulse control
Parkinsonian movement disorders
Progressive dementia
Very strong association with ALS
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Genetic Risk Factors
 ApoE E4 a strong risk factor for
Alzheimer’s disease.
–
–
–
–
E2: reduced AD risk
E3: normal AD risk
E4 single copy: x1.75 risk
E4 two copies: x8 risk
 May also be involved with sportsrelated dementia:
– Jordan et al. (1997) boxing exposure
and E4 interacted to predict dementia.
– Kutner et al. (2000) cognitive effects in
US Football players with E4.
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Summary of Sports-related TBI
 Sports related mTBI very common. Boxing, football,
ice hockey, soccer (also equestrian, rugby and
gymnastics).
 Reported incidence increasing (better awareness).
 Both acceleration/deceleration impacts as well as
rotational shearing of white matter.
 Typically not visible with neuroimaging
 Basal forebrain, medial temporal lobes, white matter.
 Typically 5-10 day recovery
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Break
-Pause
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Potential for treating TBI
How can we reduce the consequences of TBI?
Neurogenesis (Chapter 20)
Xiong et al. (2010) review restorative
treatments.
Xiong et al. (2013) describe animal models of
TBI.
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Can drugs treat TBI? (ch 20)
 Primary Injury
– Direct due to mechanical forces - contusion, damaged blood
vessels, axonal shearing.
 Secondary Injury
– Cascade of metabolic cellular(e.g. increased Ca,Na
decreased K) and molecular events leading to tissue damage.
– e.g. Glutamate toxicity, perturbed calcium homeostatis,
increased free radicals lipid peroxidation, mitochondrial
dysfunction (due to Ca), inflammation, apoptosis (programmed
cell suicide) and diffuse axonal injury.
– Initial contusion hours/days: swollen, days-weeks: shrunken
(pyknosis: nucleus shrinks) and resorbed GM and WM.
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Acute and chronic injury
Primary and secondary
Xiong, Mahmood & Chopp (2010)
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Protecting people from TBI
Both Primary and Secondary Injury
– Prevention: seatbelts, helmets
Secondary injury
– Time window to intervene with processes
Some studies suggest long term functional and
structural changes take place up to 1 year post injury.
Drugs taken after injury may help minimize extent of
injury (neuroprotection) and aid in compensation
(neurorestoration).
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Neuroprotection versus neurorestoration
Neuroprotective therapies aim to block the
molecular cascade of injury following traumatic
brain injury (TBI).
– These approaches aim to minimize size of injury.
– To date, human clinical data disappointing.
Alternatively, neurorestoration therapy aims to
aid recovery via neurogenesis, axonal
sprouting, synaptogenesis, oligodendrogenesis
and angiogenesis
Xiong, Mahmood & Chopp (2013)
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Mechanisms for restoration
Adult CNS has limited capacity to regenerate
after injury (Xiong et al., 2010).
– Neurogenesis
– Angiogenesis
– Axonal sprouting
Glial responses
Synaptic plasticity appears dominant mode of
adaptation in adult brain (includes biochemical
changes and synaptogenesis)
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Neurogenesis
Adults develop new neurons in and around the
hippocampus.
TBI induces neurogenesis in mice (Kernie et
al., 2001)
Wang et al (2001) report
Metformin promotes mouse
neurogenesis and enhances
spatial learning
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Neurogenesis (ch 20)
 In chapter 20, Wojtowicz suggests
–
–
–
–
Hippocampal neurogenesis first described in 1962 (Altman)
‘Use it or lose it’ seems to apply
Some initial examples of adult neurogenesis in other brain regions.
The authors suggest that neurogenesis may be different for lab animals
versus those in natural environment.
 Weak evidence: they compare across species (rats vs squirrels)
 Studies within species (rats, Epp et al., 2009) does not support this claim
 Unlike embryonic neurogenesis, adult neurogenesis appears to be
limited (Kriegstein and Alvarez-Buylla, 2009):
–
–
–
–
–
Only adds to existing cortical layers
Only limited brain areas (hippocampal, olfactory bulb)
New cells migrate through existing layers
Derived from specialized glial rather than stem cells
Only generates specific types of neurons
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Angiogenesis
 Vasculature can grow to provide more nutrients.
 Most prior research has focused on drugs that impair
angiogenesis (to treat tumors)
 Meng et al. (2011) note EPO given 24 hours after TBI
increase angiogenesis and hippocampal
neurogenesis in rats.
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Axonal Sprouting (Axonal Remodeling)
Regeneration of axons well known in peripheral
nervous system.
Recently: CNS axonal sprouting may be involved
with motor recovery after TBI (Smith et al., 2007;
Oshima et al., 2009)
Inosine infused into ventricles
may aid this
(Smith et al., 2007)
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Glial responses to TBI
 Gliosis common after injury
 Whereas adult neurogenesis is focal/limited,
glial responses widespread/robust.
 Astrocytes react to TBI, with response graded
by injury severity. Both beneficial and
detrimental consequences
– Detrimental: numerous studies (e.g.
Rodgers et al., 2013) find that antiinflammatory (that reduce glial response)
help recovery.
– Beneficial: Myer (2006) in mice with
moderate TBI, selective ablation of the
reactive astrocytes increased neuronal
degeneration by 60%
Astrocytes react to injury
Ren et al. (2013)
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Synaptic plasticity
 Existing synapses’ facilitory and inhibitory connections
strengthen and weaken over time.
 Dynamic and rapid method for learning and compensation
(Hebbian learning).
 Albensi et al. (2000) gave rats
cyclosporin A (a compound that
stabilizes mitochondrial function) 24
hours after TBI and found
normalized long-term potentiation
and normal long-term depression.
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Drug intervention
Multiple mechanisms of injury
– Cocktail of drugs may be required.
– Unfortunately, drug interactions make these
studies challenging
Example: EPO promising found promising for minimizing
ischemic stroke, but clinical studies found interaction
with tPA (clot busting agent).
Xiong, Mahmood & Chopp (2013)
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Animal models of TBI
Human injury very heterogeneous – hard to
conduct controlled studies.
Different forms of animal injury attempt to
mimic specific patterns of human injury.
Xiong, Mahmood & Chopp (2013)
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Animal models
Animal research can isolate effects, but some
choices may limit relevance:
– Many studies use prospective neuroprotective
agents where drug given prior to injury – limited
human relevance (Marklund & Hillered, 2011).
– Only examine single mechanism or measure in
isolation. Ignore interactions.
– Focus on only young adults, whereas most injuries
occur in children or elderly.
– Only examine acute time window.
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Exercise as guide for studies
 Exercise provides strong rationale for potential to influence brain
health (either through physical exertion or finding drugs to mimic
effects).
– Exercise strongly correlated with brain health. Understanding this
relationship may help identify drugs for TBI treatment.
– Exercise demonstrated to slow progression of Alzheimer’s Disease
(Radak et al., 2010) and rat TBI (Griesbach et al., 2004).
– Numerous studies have shown that exercise can promote synaptogenesis
(Dietrich et al., 2008) angiogenesis (p 420) and [hippocampal]
neurogenesis (p421).
– Focus on brain-derived neurotrophic factor (BDNF), involved in
hippocampal neuronal plasticity by facilitating long-term potentiation (LTP)
– While exercise may provide clues for drugs and be useful for TBI, it may
be initially deleterious for depression and cognitive function. Acute forced
exercise can increase TBI induced lesion size (Griesbach 2011).
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Break
Pause
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Zhou et al. (2013) Long term effects of mTBI
By definition, individuals with uncomplicated
mild TBI have no apparent injury visible with
neuroimaging.
Zhou et al. (2013) suggest that these
individuals actually show subtle atrophy when
observed a year post injury.
This could provide an important clue that many
common (low grade) concussions cause
permanent brain injury.
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Overview
Most imaging studies of mTBI acute, cross
sectional.
Longitudinal studies can control for individual
differences in brain size, and detect more
subtle effects.
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Methods
28 individuals with mTBI, 19 followed up 1 year
22 matched controls, 12 followed up at 1 year
Brain scans segmented into gray and white
matter.
Correlations between changes in clinical
scores and changes in brain tissue.
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Tissue Segmentation
 T1 scans show good contrast between gray, white matter,
CSF.
 Segmentation uses brightness and location of signal to
estimate regional tissue concentration.
 Any location is partitioned into GM+WM+CSF=1. Does not
‘know’ about injured tissue (contusion)
T1
GM
WM
CSF
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Results
Suggest longitudinal change.
Volume loss of 1-year
follow-up versus initial visit.
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Results
Global brain atrophy.
Regional medial differences in WM and GM
Volume loss of
mTBI 1 year post
injury versus
control subjects.
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Results
 WM volume in the left cingulate gyrus isthmus correlated with
clinical scores of anxiety (Spearman rank correlation r = 20.68,
P = .007) and postconcussive symptoms (Spearman rank
correlation r = 20.65, P = .01).
Anterior cingulate reduction
correlates with change in
California Verbal Learning
Test performance
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Critique
 Very small sample size – Effects small, population
heterogeneous.
 Is it possible that effects reflect acute contusion
rather atrophy?
– We do not have a true baseline scan. Swelling extends
days after injury
 pediatric swelling peaks 6 days post injury (Khoshyomn and
Tranmer, 2004).
– Initial MR ~23 days post injury (range 3-53).
 Huge range!
– All patients exhibited some PCS at that time (e.g. more
severe mild TBI).
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Conclusion
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–
–
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Fits with behavioral deterioration.
Promises non-invasive biomarker.
Larger study could help address robustness.
Better inclusion criteria could at least control for contusion
effects.
– Paradigm could be adapted to animal studies that could
acquire baseline image and control for individual variability
(e.g. it is possible that as a group people who have TBI
have poorer tissue integrity and cognitive performance than
those who do not).
– Be warned, correlations are not causal.