PCBIC 2010 Cheryl Wellington: Horizons of Hope for Treating Brain Injury

8/7/2019 PCBIC 2010 Cheryl Wellington: Horizons of Hope for Treating Brain Injury

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Cheryl L WellingtonUniversity of British Columbia

November 18, 2010

Horizons of Hope for Treating Brain Injury


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To identify the factors that limit recovery after brain injury

To understand how brain injury is a risk factor for dementia, even decadesafter injury

To review current clinical trials for brain injury treatments

To discuss new potential treatment options now in the research anddiscovery phase

Synopsis and Learning Objectives


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Traumatic Brain Injury is the leading cause of deathand disability in persons under 40 years of age


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Traumatic Brain Injury is the leading cause of deathand disability in persons under 40 years of age

Despite this enormous unmet medical need, resources to supportresearch and discovery efforts to treat brain injury are extremely limited


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Brain and Spinal Cord Injury Statistics


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Causes of Brain and Spinal Cord Injury


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What factors limit recovery after brain injury?


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The bony skull has a fixed volume and a rough interior

surface


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Brain edema causes increased intracranial pressure

Because the skull is a fixed volume, brainswelling (edema) after injury increases pressureon the brain and compromises brain function.Post-trauma edema is a major source ofmortality after brain injury.


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Brain tissue contains gray and white matter.

Gray matter contains neuronal cell bodies and theirsupporting glial cells and capillaries.

White matter contains bundles of myelinated axons.

Because gray matter and white matter are differentdensities, movement of the brain causes shear forcesat the gray-white matter interface.

This can stretch, twist, or rupture axons after injury.

Axons shear at the interface between gray and white

matter


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The peripheral and central nervous systems differ in their

ability to regenerate


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Myelin is the insulating sheath aroundaxons and essential for conduction of nerveimpulses.

In the peripheral nervous system, Schwanncells and macrophages help to clear upmyelin debris after injury, allowingperipheral neurons the chance to regrow.

In the central nervous system,oligodendrocytes and microglia are far lessefficient in clearing myelin, leaving behindbarriers for neuronal regeneration.

Myelin produces factors that block neuronal regeneration


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Factors producing a hostile environment in the brain

Myelin associated proteins: These proteins are found in CNS myelin and inhibitneuronal regeneration in the brain. They stabilizes the wiring of the developed brainat the expense of regenerative capacity.

NOGO

Myelin-associated glycoprotein (MAG)

NI-35 and NI-250

Glial Scarring: Inflammation at the site of injury leads to the formation of glial scarsthat contain chondroitin sulfate proteoglycans that inhibit neuronal regeneration.However, glial scarring may help to reseal the blood brain barrier and promote blood

flow to the injured region.

GAP-43: GAP-43 is a protein found in the growth cones of developing andregenerating neurons. Aging decreases baseline GAP-43 levels as well as theability to stimulate GAP-43 expression after injury.


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Brain injury increases risk for dementia


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Alzheimers disease is an irreversible, progressive braindisease that slowly destroys memory and thinking skills.

Alzheimers Disease: the leading cause of dementia

Slide 4

Alzheimers Disease is the most common cause ofsenile dementia, and affects approximately 50% of thepopulation over 85 years of age.

Clinical features include a progressive memory loss,language deterioration, disorientation, impairedjudgment, inability to perform everyday tasks, andpersonality changes.


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Alzheimers disease is an irreversible, progressive braindisease that slowly destroys memory and thinking skills.

Alzheimers Disease: the leading cause of dementia

Slide 4

Alzheimers Disease is the most common cause ofsenile dementia, and affects approximately 50% of thepopulation over 85 years of age.

Clinical features include a progressive memory loss,language deterioration, disorientation, impairedjudgment, inability to perform everyday tasks, andpersonality changes.

In 2006, the global burden of AD was 26.6M. By 2050, this willquadruple to over 100M, which is roughly one in 85 persons.


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Modifiable Risk Factors for Alzheimers Disease

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Patterson et al (2008)

CMAJ 178: 548-556


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Neuropathological hallmarks ofAlzheimers Disease

Neurofibrillary tangles are composed ofintranneuronal hyperphosphorylated tauaggregated in a paired helical structure

Amyloid plaques consist primarily ofinsoluble A! peptides that aredeposited between neurons

Amyloid is also commonly found incortical and leptomeningeal vessels
http://www.ahaf.org/alzdis/about/plaques_tangles.jpghttp://www.ahaf.org/alzdis/about/plaques_tangles.jpg


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The amyloid cascade hypothesis ofAlzheimers Disease

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Increasing A! production, or failing to degrade A!, initiates the amyloid cascade

Failure to remove A! may underlie most cases of AD and dementia following TBI

CYSTEINE RICH ACIDIC CPA!

!-secretase

"-secretase

#-secretaseAMYLOID PRECURSOR PROTEIN

Soluble A!

Oligomeric A!

Fibrillar A!Amyloid

GLYCOSYLATED


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The amyloid cascade hypothesis ofAlzheimers Disease

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Increasing A! production, or failing to degrade A!, initiates the amyloid cascade

Failure to remove A! may underlie most cases of AD and dementia following TBI

CYSTEINE RICH ACIDIC CPA!

!-secretase

"-secretase

#-secretaseAMYLOID PRECURSOR PROTEIN

Soluble A!

Oligomeric A!

Fibrillar A!Amyloid

A! degradation

Lipidated apoE

GLYCOSYLATED


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Amyloid precursor protein levels are increasedafter axonal injury

This can result in A! deposits or neurofibrillarytangles that are nearly indistinguishable from thosefound in Alzheimers Disease

Increased APP levels are a hallmark of axonal damage

Normal NFL player 1 NFL player 2 AD patient


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The best available evidence to date supports the use of early prophylactic mild-to-moderate hypothermiain patients with severe TBI (Glasgow Coma Scale score < or = 8) to decrease mortality and improverates of good neurologic recovery.

This treatment should be commenced as soon as possible after injury (e.g., in the emergencydepartment after computed tomography) regardless of initial intracranial pressure (ICP), or before ICP is

measured. Most studies report using a temperature of 32 degrees -34 degrees C.

Moderate hypothermia may be effective forsevere brain injury

Fox et al (2010) CJEM 12: 355-364

Maximal benefit occurred with a long-term or goal-directed cooling protocol, in which cooling wascontinued for at least 72 hours and/or until stablenormalization of intracranial pressure for at least 24

hours was achieved.


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Progesterone is a potent neuroprotective agent

Emory researchers concluded in an earlier three-year clinicaltrial conducted in 100 patients that giving progesterone totrauma victims shortly after a brain injury appears to be safeand may reduce the risk of death and long-term disability.That clinical trial was called ProTECT II (Progesterone forTraumatic brain injury -- Experimental Clinical Treatment).The current trial is named ProTECT III.

The earlier trial found evidence that progesterone is safe for use in patients sufferingfrom traumatic brain injuries. Results also showed a 50 percent reduction in mortality inpatients who were treated with progesterone. The treatment improved functionaloutcomes and reduced disability in patients with moderate, but not severe, brain injury.

Progesterone is a promising agent with proven effectiveness for brain injury.


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ProTECT II

100 adult trauma patients admitted within 11 h of injury with a GlasgowComa Score of 4-12

77 randomized patients received progesterone, 23 received placebo

Progesterone was mixed with intralipid and delivered IV in 6 infusionsover 3 days

Adverse events did not differ between progesterone and placebo groups Patients randomized to progesterone had a significant reduction in 30-

day mortality

Moderately injured patients (GCS 9-12) showed significant improvementin the Disability Rating Scale compared to placebo,

Wright et al (2007) Ann Emerg Med 49: 391-402.


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ProTECT II Outcomes

Table 5. Outcome variables 30 days postinjury.

Outcome Variables

Progesterone Group

n77

Placebo Group

n23

n Mean 95% CI n Mean 95% CI

Duration of coma, days

Severe (iGCS 4-8) 55 10.11 7.7-12.5 16 3.9 2.5-5.4

Moderate (iGCS 9-12) 20 4.1 1.4-6.8 7 6.1 0-13.2

Duration of posttraumatic amnesia, days

Severe (iGCS 4-8) 37 18.6 15.2-22.0 9 12.8 5.2-20.4

Moderate (iGCS 9-12) 15 10.7 6.2-15.3 3 18.3 0-46.9

Mortality

Severe (iGCS 4-8) 7 13.2% 6 40.0% RR 0.33 (0.13-

0.830)

Moderate (iGCS 9-12) 3 16.7% 1 14.3% RR 1.11 (0.14-9.41)All-cause mortality 10 13.0% 7 30.4% RR 0.43 (0.18-0.99)

Neurologic deaths 4 5.3% 4 17.4%

Nonneurologic deaths 5 6.6% 3 13.0%

Disability Rating Score (DRS)

Severe (iGCS 4-8)

Employ 46 2.7 2.5-2.9 9 2.4 1.9-2.9

Function 46 2.9 2.9-3.5 9 1.8 0.54-3.1

Total DRS 45 10.7 8.3-13.1 9 4.4 0.0-9.8

Moderate (iGCS 9-12)

Employ 15 1.8 1.2-2.4 6 3.0 2.0-3.96

Function 15 1.5 0.6-2.4 6 3.8 2.4-5.2

Total DRS 15 5.0 1.8-6.2 6 12.7 7.6-17.78

Dichotomized Glasgow Outcome ScoreExtended (GOS-E)

Severe (iGCS 4-8)

Dead/vegetative/severe 41 78.9% 11 73.3% RR 0.79 (0.29, 2.13)

Moderate/good 11 21.2% 4 26.7%

Moderate (iGCS 9-12)

Dead/vegetative/severe 8 44.4% 7 100% *

Moderate/good 10 55.6% 0 0.00%

iGCS, Index GCS score; RR, relative risk.

*No relative risk estimate, because of 0 cell; however, P.0202.

Wright et al (2007) Ann Emerg Med 49: 391-402.


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Neurosteroids

Neurosteroids are synthesized in the central andperipheral nervous system, especially inmyelinating glial cells, from cholesterol or steroidalprecursors imported from peripheral sources.

Several of these steroids accumulate in the brainafter local synthesis or after metabolism of adrenalsteroids or gonadal steroids, especiallytestosterone.


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Neuroactive steroids (orneurosteroids) rapidlyalter neuronal excitability through interaction withneurotransmitter-gated ion channels.

In addition, these steroids may also exert effects

on gene expression via intracellular steroidhormone receptors.

Neurosteroids have a wide range of potentialclinical applications from sedation to treatment ofepilepsy and traumatic brain injury. Ganaxolone,an analog of the endogenous neurosteroidallopregnanolone, is under investigation for the

treatment of epilepsy.

Neurosteroid functions
http://en.wikipedia.org/wiki/Allopregnanolonehttp://en.wikipedia.org/wiki/Allopregnanolonehttp://en.wikipedia.org/wiki/Ganaxolonehttp://en.wikipedia.org/wiki/Ganaxolonehttp://en.wikipedia.org/wiki/Traumatic_brain_injuryhttp://en.wikipedia.org/wiki/Traumatic_brain_injuryhttp://en.wikipedia.org/wiki/Epilepsyhttp://en.wikipedia.org/wiki/Epilepsyhttp://en.wikipedia.org/wiki/Sedationhttp://en.wikipedia.org/wiki/Sedationhttp://en.wikipedia.org/wiki/Steroid_hormone_receptorhttp://en.wikipedia.org/wiki/Steroid_hormone_receptorhttp://en.wikipedia.org/wiki/Steroid_hormone_receptorhttp://en.wikipedia.org/wiki/Steroid_hormone_receptorhttp://en.wikipedia.org/wiki/Gene_expressionhttp://en.wikipedia.org/wiki/Gene_expressionhttp://en.wikipedia.org/wiki/Ligand-gated_ion_channelhttp://en.wikipedia.org/wiki/Ligand-gated_ion_channelhttp://en.wikipedia.org/wiki/Neurotransmitterhttp://en.wikipedia.org/wiki/Neurotransmitterhttp://en.wikipedia.org/wiki/Neuronhttp://en.wikipedia.org/wiki/Neuronhttp://en.wikipedia.org/wiki/Steroidhttp://en.wikipedia.org/wiki/Steroid


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New treatment options in research and discovery


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The role of ApoE in Brain and Spinal CordInjury

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ApoE is highly induced after brain injury, where it participates in neuronalrepair and synaptogenesis

In humans, apoE4 is associated with worse prognosis after TBI and SCI,similar to its adverse effect on Alzheimers Disease risk

In mice, apoE deficiency is also associated with worse outcome from TBI.Mice expressing apoE4 respond worse to TBI than mice expressing apoE3.

In humans, TBI leads to amyloid deposits that are indistinguishable from

those in the Alzheimers Disease brain

Antecedent TBI increases risk of Alzheimers Disease later in life


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ApoE is the major apolipoprotein in the brain


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Discoveries from the Wellington lab

Current research shows that how much cholesterol is onapoE is key determinant of amyloid burden in AD mice

ABCA1 is the protein that moves cholesterol onto apoE in

the brain

ABCA1 activity influences amyloid burden in AD mice

Drugs that stimulate the ABCA1-apoE pathway stimulate A!

clearance and improve cognitive function in AD mice

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The ABCA1-apoE pathway and A! clearance


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LXR agonists reduce A! and improve memory in AD mice

Symptomatic Tg2576 mice were treated withTO901317 for 7 days

Treated mice showed a selective reduction inhippocampal A!42 levels

TO901317 treatment reverses the deficit incontextual fear conditioning

Riddel et al (2007) Mol Cell Neuroscience 34: 621-628


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The LXR agonist GW3965 improves cognitive functionafter TBI


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Summary

Factors that limit recovery after brain injury include the fixed volume of tehskull and several proteins found on myelin that block regrowth of neurons inthe brain and spinal cord

Brain injury is a risk factor for dementia, as the injured brain can accumulateamyloid plaques and neurofibrillary tangles very similar to those found inAlzheimers Disease

Current clinical trials for brain injury treatments include hypothermia andprogesterone

New potential treatment options now in the research and discovery phaseinclude ways to stimulate clearance of lipids and A! produced after injury,and ways to overcome the myelin block to neuronal regrowth in the brain


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Acknowledgements

Cheryl WellingtonJames DonkinSophie StukasVeronica Hirsch-ReinshagenJianjia Fan

Dhananjay NamjoshiAnna WilkinsonJeniffer Chan

Alzheimers Society of Canada/AstraZenecaCanadian Institutes of Health ResearchPacific Alzheimers Research FoundationAlzheimers Drug Discovery Foundation

Wolf Tetzlaff

Jonathan Collins

David Holtzman

Centre for Drug Research andDevelopment

Michael Oda

PCBIC 2010 Cheryl Wellington: Horizons of Hope for Treating Brain Injury

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