45 / 162
(taurine). These age-related differences in the cascade of cellular injury
mechanisms may contribute to the poor functional recovery of aged rats
after TBI. Our findings point to bioenergetic impairment, excitotoxicity,
and edema as potential therapeutic targets for improving recovery after
TBI in older individuals.
Keywords: Aging, Traumatic Brain Injury, Magnetic Resonance
Spectroscopy, Imaging, Biomarker, Secondary Injury
B1-07
EFFECT OF AGING ON HIPPOCAMPAL-DEPENDENT
COGNITION AND NEUROINFLAMMATORY RESPONSES
AFTER TRAUMATIC BRAIN INJURY
Austin Chou
1–3
, Josh Morganti
2,3
, Susanna Rosi
1–3
1
UCSF, Neuroscience Graduate Program, San Francisco, USA
2
UCSF, Brain and Spinal Cord Injury Center, San Francisco, USA
3
UCSF, Physical Therapy and Rehabilitation Science, San Francisco,
USA
Traumatic Brain Injury (TBI) is a powerful environmental risk factor for
the development of Alzheimer’s disease and dementia. Age is a signifi-
cant factor in both the risk and incidence of acquired brain injury. TBI
recovery and outcomes are worse in elderly patients with higher fatality
rates and greater severity of TBI-related disabilities. In animal models
recapitulating TBI, aging predisposes increases in neuronal loss, inflam-
mation, and motor dysfunction shortly after injury. However, long-term
cognitive outcomes of TBI in aging animals and underlying mechanisms
for age-related exacerbation of TBI have not yet been investigated. In the
current study, we characterized the effect of aging on long-term cognitive
deficits after TBI and on injury-induced neuroinflammatory responses.
TBI was generated through controlled cortical impact over the right pa-
rietal cortex in 3 and 22–24 month old male mice. Thirty days after injury,
hippocampal-dependent learning and memory functions were measured
using the radial arm water maze (RAWM), novel object recognition
(NOR), and contextual fear conditioning (CFC) assays. Our data dem-
onstrates that both age and TBI negatively affects hippocampal-depen-
dent learning and memory. Furthermore, aging worsens TBI-induced
hippocampal-dependent memory impairments in particular.
While aging increases both pro- and anti-inflammatory responses in
many inflammatory contexts, it is unclear if aging upregulates and
maintains pro-inflammatory responses or results in diminished anti-
inflammatory responses after TBI. We characterized the inflammatory
responses of the injured brains of young and old animals by quanti-
tative PCR at acute and sub-chronic time points after a TBI. Our
results demonstrate that 24 hours post-injury, there was increased
inflammatory responses in old animals. At 7 days after injury, there
was a significant decrease in anti-inflammatory responses in old ani-
mals compared to the young. This suggests an imbalance in the reg-
ulation of inflammation in the aging brain which may sustain a pro-
inflammatory environment after injury.
Keywords: Hippocampal-dependent memory, Novel Object Re-
cognition, CCI, Mice, Neuroinflammation
B1-08
MW151, A SMALL MOLECULE INHIBITOR OF NEUROIN-
FLAMMATION, PREVENTS CLOSED HEAD INJURY IN-
DUCED COGNITIVE DEFICITS IN APP/PS1 KI MICE
Adam Bachstetter
1
, Scott Webster
1
, D. Martin Watterson
2
, Linda
Van Eldik
1
1
University of Kentucky, Sanders-Brown Center on Aging, Lexington, USA
2
Northwestern University, Department of Pharmacology, Chicago, USA
Epidemiological studies have associated increased risk of Alzheimer’s
disease (AD) related clinical symptoms with a medical history of head
injury. Currently, little is known about pathophysiology mechanisms
linked to this association. Persistent neuroinflammation is one out-
come observed in patients after a single head injury. Neuroin-
flammation is also present early in relevant brain regions during AD
pathology progression. In addition, previous mechanistic studies in
animal models of either traumatic brain injury or AD link neuroin-
flammation as a contributor to neuropathology and cognitive impair-
ment seen in each respective model. This raises the possibility that
selective targeting of the dysregulated cytokine response, a compo-
nent of the neuroinflammation that contributes to neuronal dysfunc-
tion, may be a useful therapeutic approach. MW01-2-151WH
(MW151) is a novel, CNS-penetrant small molecule drug that se-
lectively restores injury- or disease-induced overproduction of
proinflammatory cytokines towards homeostasis. We have previously
reported that MW151 administered post injury is efficacious in a
closed head injury (CHI) model of diffuse TBI in mice. Therefore, we
explored the potential interplay of neuroinflammatory responses in
TBI and AD by intervention with MW151 to attenuate the dysregu-
lated proinflammatory cytokine response seen in APP/PS1 knock-in
(KI) mice following a CHI. Based on prior work, showing a delayed
peak neuroinflammatory response at 7 days post injury (p.i), mice
received treatment every other day from day 7-to-27 p.i. In radial arm
water maze (RAWM) testing (day 29 and 30 p.i.), the APP/PS1 KI
mice
+
CHI
+
MW151 made significantly fewer errors than the APP/
PS1 KI mice
+
CHI
+
vehicle. Consistent with a link between neu-
roinflammatory responses and altered risk for AD-associated pathol-
ogy changes with head injury, our results show that intervention with
a small molecule experimental therapeutic (MW151) which selec-
tively attenuates proinflammatory cytokine production can improve
cognitive behavior outcomes.
Keywords: neuroinflammation, cytokines, astrocytes, microglia,
amyloid plaque
B1-09
WHO GETS HEAD TRAUMA OR RECRUITED IN MILD
TRAUMATIC BRAIN INJURY RESEARCH?
Harri Isokuortti
1
, Grant L. Iverson
2
, Anneli Kataja
3
, Antti Brander
3
,
Juha O¨ hman
4
, Teemu M. Luoto
5
1
University of Tampere, Medicine, Helsinki, Finland
2
Harvard Medical School, Physical Medicine and Rehabilitation,
Boston, USA
3
Tampere University Hospital, Radiology, Tampere, Finland
4
Tampere University Hospital, Neurosciences and Rehabilitation,
Tampere, Finland
5
Tampere University Hospital, Neurosurgery, Tampere, Finland
Background:
Outcome from mild TBI is heterogeneous in part due to
pre-injury individual differences that typically are not well described
or understood. Our objective was to provide a comprehensive de-
scription of the pre-injury health characteristics of a cohort of patients
who sustain head trauma and undergo evaluation in an emergency
department. The number of people with specific pre-injury health
problems, singly and in combination, was determined.
Methods:
Pre-injury health characteristics of all consecutive pa-
tients (N
=
3,023; average age
=
55.0 years, SD
=
24.0; male
=
56.4%)
who underwent head CT due to acute head trauma in the emergency
department of Tampere University Hospital, Finland between August
2010 and July 2012 were examined. Patients were screened to obtain a
sample of working aged adults with no pre-injury medical or mental
A-45