1

Introduction: Traumatic Brain Injury

– Sports related TBIIncidenceSeverity, symptomsChronic traumatic encephalopathy CTE

– Drugs for TBISynaptogenesis, Angiogenesis, NeurogenesisEvidence from exerciseAnimal models

– mild TBI associated and chronic loss of brain tissueCritical review of Zhou et al. (2013)

TBI in the USA

1.7 Million/year29% of all ER visits

2

2002-2006 Faul et al. (2010)

Incidence ‘bathtub’ function.

TBI in the USA

Causes– Also vary with age

3

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!

4

Langlois et al. (2006)

Sports concussion

Recent attempts to define sports-related sub-classification 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.

5

Sports concussion

Most athletes report complete resolution within 5-10 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.

6

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.

7

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.

8

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)

9

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.

10

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.

11

CTE, McKee et al 2013

Recent histological study of 85 men (17-98yo) 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

12

Lou Gherig

Histological Biomarkers for CTE

Tau-positive neurofibrillary tangles (NFTs) in the neocortex, concentrated around penetrating parenchymal vessels

Neuropil (cortical) threadsNeocortical diffuse amyloid plaques, with or

without neuritic plaquesSparing of the hippocampus

13

AD vs CTE (McKee et al., 2013)

ADNeurofibrillary tangles (expressing amyloid, red), normal sulcal depth.No clustering of tangles near blood vesselsDiffuse tau

14

CTEClumps of tau, large sulci

Clustering of tangles near blood vessels

Tau mostly in superficial layers

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 headachesDizzinessMood disorders (depression)Aggression Impaired judgment and impulse controlParkinsonian movement disordersProgressive dementiaVery strong association with ALS

15

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 sports-related 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.

16

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 neuroimagingBasal forebrain, medial temporal lobes, white matter.Typically 5-10 day recovery

17

Break

-Pause

18

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.

19

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.

20

Acute and chronic injury

Primary and secondary

21

Xiong, Mahmood & Chopp (2010)

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).

22

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

23

Xiong, Mahmood & Chopp (2013)

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)

24

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 mouseneurogenesis and enhancesspatial learning

25

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

26

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

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.

27

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 ventriclesmay aid this (Smith et al., 2007)

28

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 anti-inflammatory (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%

29

Astrocytes react to injuryRen et al. (2013)

Synaptic plasticity

Existing synapses’ facilitory and inhibitory connections strengthen and weaken over time.

Dynamic and rapid method for learning and compensation (Hebbian learning).

30

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.

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).

31

Xiong, Mahmood & Chopp (2013)

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.

32

Xiong, Mahmood & Chopp (2013)

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.

33

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).

34

Break

Pause

35

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.

36

Overview

Most imaging studies of mTBI acute, cross sectional.

Longitudinal studies can control for individual differences in brain size, and detect more subtle effects.

37

Methods

28 individuals with mTBI, 19 followed up 1 year

22 matched controls, 12 followed up at 1 yearBrain scans segmented into gray and white

matter.Correlations between changes in clinical

scores and changes in brain tissue.

38

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)

39

T1 GM WM CSF

Results

Suggest longitudinal change.

40

Volume loss of 1-year follow-up versus initial visit.

Results

Global brain atrophy.Regional medial differences in WM and GM

41

Volume loss of mTBI 1 year post injury versus control subjects.

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).

42

Anterior cingulate reduction correlates with change in California Verbal Learning Test performance

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 injurypediatric 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).

43

Conclusion

– 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.

44