Horizons of Hope for Treating Brain Injury

Cheryl L Wellington
University of British Columbia

November 18, 2010

 Synopsis and Learning Objectives

To identify the factors that limit recovery after brain injury

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

To review current clinical trials for brain injury treatments

To discuss new potential treatment options now in the research and

discovery phase
Traumatic Brain Injury is the leading cause of death
and disability in persons under 40 years of age
Traumatic Brain Injury is the leading cause of death
and disability in persons under 40 years of age

Despite this enormous unmet medical need, resources to support

research and discovery efforts to treat brain injury are extremely limited
Brain and Spinal Cord Injury Statistics
Causes of Brain and Spinal Cord Injury
What factors limit recovery after brain injury?
The bony skull has a fixed volume and a rough interior
surface
Brain edema causes increased intracranial pressure

Because the skull is a fixed volume, brain

swelling (edema) after injury increases pressure
on the brain and compromises brain function.
Post-trauma edema is a major source of
mortality after brain injury.
 Axons shear at the interface between gray and white
matter

Brain tissue contains gray and white matter.

Gray matter contains neuronal cell bodies and their

supporting glial cells and capillaries.

White matter contains bundles of myelinated axons.

Because gray matter and white matter are different

densities, movement of the brain causes shear forces
at the gray-white matter interface.

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

The peripheral and central nervous systems differ in their
ability to regenerate
Myelin produces factors that block neuronal regeneration

Myelin is the insulating sheath around

axons and essential for conduction of nerve
impulses.

In the peripheral nervous system, Schwann

cells and macrophages help to clear up
myelin debris after injury, allowing
peripheral neurons the chance to regrow.

In the central nervous system,

oligodendrocytes and microglia are far less
efficient in clearing myelin, leaving behind
barriers for neuronal regeneration.
Factors producing a hostile environment in the brain

Myelin associated proteins: These proteins are found in CNS myelin and inhibit
neuronal regeneration in the brain. They stabilizes the wiring of the developed brain
at 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 scars
that 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 and

regenerating neurons. Aging decreases baseline GAP-43 levels as well as the
ability to stimulate GAP-43 expression after injury.
Brain injury increases risk for dementia
Alzheimer’s Disease: the leading cause of dementia
Alzheimer’s disease is an irreversible, progressive brain
disease that slowly destroys memory and thinking skills.

Clinical features include a progressive memory loss,

language deterioration, disorientation, impaired
judgment, inability to perform everyday tasks, and
personality changes.

Alzheimer’s Disease is the most common cause of

senile dementia, and affects approximately 50% of the
population over 85 years of age.

Slide 4
Alzheimer’s Disease: the leading cause of dementia
Alzheimer’s disease is an irreversible, progressive brain
disease that slowly destroys memory and thinking skills.

Clinical features include a progressive memory loss,

language deterioration, disorientation, impaired
judgment, inability to perform everyday tasks, and
personality changes.

Alzheimer’s Disease is the most common cause of

senile dementia, and affects approximately 50% of the
population over 85 years of age.

In 2006, the global burden of AD was 26.6M. By 2050, this will

quadruple to over 100M, which is roughly one in 85 persons.

Slide 4
Modifiable Risk Factors for Alzheimer’s Disease

Patterson 15
et al (2008)
CMAJ 178: 548-556
Neuropathological hallmarks of
Alzheimer’s Disease

Neurofibrillary tangles are composed of

intranneuronal hyperphosphorylated tau
aggregated in a paired helical structure

Amyloid plaques consist primarily of

insoluble A! peptides that are
deposited between neurons

Amyloid is also commonly found in

cortical and leptomeningeal vessels
 The amyloid cascade hypothesis of
Alzheimer’s Disease
"-secretase
!-secretase #-secretase
AMYLOID PRECURSOR PROTEIN

CYSTEINE RICH ACIDIC GLYCOSYLATED A! CP

Soluble A!

Oligomeric A!

Amyloid
Fibrillar A!

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

17 TBI
 The amyloid cascade hypothesis of
Alzheimer’s Disease
"-secretase
!-secretase #-secretase
AMYLOID PRECURSOR PROTEIN

CYSTEINE RICH ACIDIC GLYCOSYLATED A! CP

Lipidated apoE Soluble A!

A! degradation
Oligomeric A!

Amyloid
Fibrillar A!

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

17 TBI
 Amyloid precursor protein levels are increased
after axonal injury

Increased APP levels are a hallmark of axonal damage

This can result in A! deposits or neurofibrillary

tangles that are nearly indistinguishable from those
found in Alzheimer’s Disease

18
Normal NFL player 1 NFL player 2 AD patient
Current clinical treatments for brain injury
 Hyperventilation, mannitol, barbituates and
corticosteroids are not effective for brain injury
e of evidence for eVectiveness of five interventions for severe head injury 731

Experiment Control RR RR
Study n /N n /N (95%Cl Fixed) (95%Cl Fixed)
Hyperventilation v control
Muizzelaar 9/36 14/41 0.73 (0.36–1.49)
Subtotal (95%Cl) 9/36 14/41 0.73 (0.36–1.49)
2
! 0.00 (df = 0) Z = 0.86

Mannitol v control
Sayre 5/20 3/21 1.75 (0.48–6.38)
Subtotal (95%Cl) 5/20 3/21 1.75 (0.48–6.38)
2
! 0.00 (df = 0) Z = 0.85

Barbiturates v control
Eisenberg 23/37 19/36 1.18 (0.79–1.75)
Ward 14/27 13/26 1.04 (0.61–1.76)
Subtotal (95%Cl) 37/64 32/62 1.12 (0.81–1.54)
2
! 0.14 (df = 1) Z = 0.70

Steroids v control
Alexander 16/55 22/55 0.73 (0.43–1.23)
Braakman 44/81 47/80 0.92 (0.70–1.21)
Cooper 26/49 13/27 1.10 (0.69–1.77)
Dearden 33/68 21/62 1.43 (0.94–2.19)
Faupel 16/67 16/28 0.42 (0.24–0.71)
Gaab 19/133 21/136 0.93 (0.52–1.64)
Giannotta 34/72 7/16 1.08 (0.59–1.98)
Grumme 38/175 49/195 0.86 (0.60–1.25)
Hernesniemi 35/81 36/83 1.00 (0.70–1.41)
Pitts 114/201 38/74 1.10 (0.86–1.42)
Ransohoff 9/17 13/18 0.73 (0.43–1.25)
Saul 8/50 9/50 0.89 (0.37–1.12)
Zagara 4/12 4/12 1.00 (0.32–3.10)
Subtotal (95%Cl) 396/1061 296/836 0.95 (0.84–1.07)
2
! 16.88 (df = 12) Z = 0.89

Roberts et al (1998) J Neurol

0.5 0.7 1 1.5 2
Favours treatment Favours control
Neurosurg Psychiatry 65: 729-733
Summary relative risks for death at the end of the study.

MANNITOL participants.17 18 The pooled relative risk for

 Moderate hypothermia may be effective for
severe brain injury

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

This treatment should be commenced as soon as possible after injury (e.g., in the emergency
department 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.

Maximal benefit occurred with a long-term or goal-

directed cooling protocol, in which cooling was
continued for at least 72 hours and/or until stable
normalization of intracranial pressure for at least 24
hours was achieved.

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

 Progesterone is a potent neuroprotective agent

Emory researchers concluded in an earlier three-year clinical

trial conducted in 100 patients that giving progesterone to
trauma victims shortly after a brain injury appears to be safe
and may reduce the risk of death and long-term disability.
That clinical trial was called ProTECT II (Progesterone for
Traumatic 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 suffering
from traumatic brain injuries. Results also showed a 50 percent reduction in mortality in
patients who were treated with progesterone. The treatment improved functional
outcomes and reduced disability in patients with moderate, but not severe, brain injury.

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

 ProTECT II

• 100 adult trauma patients admitted within 11 h of injury with a Glasgow

Coma Score of 4-12
• 77 randomized patients received progesterone, 23 received placebo
• Progesterone was mixed with intralipid and delivered IV in 6 infusions
over 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 improvement
in the Disability Rating Scale compared to placebo,

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

 ProTECT II Outcomes
Progesterone for Acute Traumatic Brain Injury Wright et al

Table 5. Outcome variables 30 days postinjury.

Progesterone Group Placebo Group
n!77 n!23
Outcome Variables 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 Score–Extended (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.

No discernible harms were noted in the 77 patients who Scale scores can miss clinically important findings that may
Neurosteroids

Neurosteroids are synthesized in the central and

peripheral nervous system, especially in
myelinating glial cells, from cholesterol or steroidal
precursors imported from peripheral sources.

Several of these steroids accumulate in the brain

after local synthesis or after metabolism of adrenal
steroids or gonadal steroids, especially
testosterone.
Neurosteroid functions

Neuroactive steroids (or neurosteroids) rapidly

alter neuronal excitability through interaction with
neurotransmitter-gated ion channels.

In addition, these steroids may also exert effects

on gene expression via intracellular steroid
hormone receptors.

Neurosteroids have a wide range of potential

clinical applications from sedation to treatment of
epilepsy and traumatic brain injury. Ganaxolone,
an analog of the endogenous neurosteroid
allopregnanolone, is under investigation for the
treatment of epilepsy.
New treatment options in research and discovery
 The role of ApoE in Brain and Spinal Cord
Injury
• ApoE is highly induced after brain injury, where it participates in neuronal
repair and synaptogenesis

• In humans, apoE4 is associated with worse prognosis after TBI and SCI,
similar to its adverse effect on Alzheimer’s 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 Alzheimer’s Disease brain

• Antecedent TBI increases risk of Alzheimer’s Disease later in life

28
ApoE is the major apolipoprotein in the brain
Lipid transport is highly induced after Injury

Figure 5: A model for lipid transport in the central nervous system.

After injury discoidal particles

remove excess lipids from
Astrocytes and microglia degenerating axons.
secrete discoidal,
immature lipoproteins.

These discoidal particles are

remodeled into mature spheres
CSF Lateral Ventricles by lecithin:cholesteryl acyl trans-
ferase for maximum transport
efficiency.

Interventricular
Foramen
Third
Ventricle Cerebral
Aqueduct
Fourth
Ventricle
Mature particles supply
neurons and glia with
lipids and are found in CSF. During reinnervation mature
lipoproteins supply neurons
with necessary lipids.
 Discoveries from the Wellington lab

• Current research shows that how much cholesterol is on

apoE 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

31
The ABCA1-apoE pathway and A! clearance
LXR agonists reduce A! and improve memory in AD mice

• Symptomatic Tg2576 mice were treated with

TO901317 for 7 days

• Treated mice showed a selective reduction in

hippocampal A!42 levels

• TO901317 treatment reverses the deficit in

contextual fear conditioning

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

The LXR agonist GW3965 improves cognitive function
after TBI

34
 Summary

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

Brain injury is a risk factor for dementia, as the injured brain can accumulate
amyloid plaques and neurofibrillary tangles very similar to those found in
Alzheimer’s Disease

Current clinical trials for brain injury treatments include hypothermia and
progesterone

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

Cheryl Wellington
James Donkin Wolf Tetzlaff
Sophie Stukas
Jonathan Collins
Veronica Hirsch-
Reinshagen David Holtzman
Jianjia Fan
Dhananjay Namjoshi Centre for Drug Research and
Anna Wilkinson Development
Jeniffer Chan
Michael Oda

Alzheimer’s Society of Canada/AstraZeneca

Canadian Institutes of Health Research
Pacific Alzheimer’s Research Foundation
Alzheimer’s Drug Discovery Foundation