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S04-02
PRECLINICAL MODELS OF CELLULAR THERAPY: IN-
FLAMMATORY RESPONSE
Pramod Dash
Univ. TX Med. School, Neurobiology & Anatomy, Houston, USA
Objective:
The proinflammatory environment after TBI leads to
breakdown of the blood-brain barrier (BBB) thereby worsening neu-
rologic and cognitive deficits. We have previously shown that intra-
venous administration of adult bone-marrow-derived stem cells can
reduce BBB permeability and this protective effect requires an intake
spleen. Recent studies have implicated vagus nerve regulation of
splenic alpha7 nicotinic receptor signaling in the regulation of sys-
temic inflammation. However, it is not known if this mechanism plays
a role in TBI-triggered inflammation and BBB breakdown.
Method:
Animals received controlled cortical impact injury and were
treated with various agents. Cytokine levels were measured by ELISAs
and blood-brain barrier permeability by Evans blue extravasation.
Results:
Using pharmacological and genetic approaches, we have
observed that blockade of alpha7 signaling exacerbates, while its acti-
vation attenuates inflammation and TBI-triggered BBB permeability.
To test the translation usefulness of our findings, we tested the efficacy
of galantamine administration. Post-injury intraperitoneal administra-
tion of galantamine reduced BBB permeability and improved outcome.
Conclusion:
Stimulation of nicotinic alpha7 receptors reduces in-
flammation and BBB permeability after experimental TBI. These
results support the translational relevance of our findings.
Keywords: nicotinic alpha7 receptor, vagus nerve, spleen, ga-
lantamine
S04-03
NEUROIMAGING AND FUNCTIONAL OUTCOMES AFTER
CELLULAR THERAPY FOR SEVERE ADULT TBI
Linda Ewing-Cobbs
, Jenifer Juranek
University of Texas Health Science Center at Houston, Pediatrics &
Children’s Learning Institute, Houston, USA
Despite numerous clinical trials, no pharmacotherapeutic interven-
tions have been shown to improve patient outcomes following severe
traumatic brain injury (TBI) in children or adults. We report longi-
tudinal clinical outcome data in adults with severe TBI enrolled in a
dose escalation trial examining impact of intravenous infusion of bone
marrow mononuclear cells (BMMNC). Neuroimaging and neu-
ropsychological outcomes were evaluated 1 and 6 months after injury
in three cohorts of five patients and a non-treated control cohort of
patients with Glasgow Coma Scale scores of 5 to 8.
Secondary aims of the trial examined whether BMMNC infusion
showed neuroprotective effects characterized by preservation of cor-
pus callosum structure on serial structural neuroimaging studies.
Fractional anisotropy from diffusion tensor imaging studies indexed
microstructural integrity of the entire corpus callosum. At 1 month
after injury, higher fractional anisotropy values were evident across all
treated groups. At 6 months after injury, well-preserved fractional
anisotropy values were demonstrated in low and middle dose groups.
The impact of BMMNC dose on neuropsychological outcomes was
also evaluated 1 and 6 months after injury. Outcome domains included
measures of functional, neuropsychological, and psychological health
status. The treated and nontreated groups showed improvement from the
1 to 6 month follow-up on the Glasgow Outcome Scale-Extended, Dis-
ability Rating Scale, and Mayo-Portland Adaptability Inventory. Glas-
gow Outcome Scale scores tended to improve in more patients receiving
low to mid doses of BMMNC infusion than in nontreated patients.
Long-term functional and cognitive outcomes were significantly related
to the integrity of callosal subregions. Six months after injury, fractional
anisotropy of the whole corpus callosum was significantly positively
correlated with the Glasgow Outcome Scale-Extended and neu-
ropsychological outcomes including processing speed, divided attention,
and fine motor speed and negatively correlated with the Mayo-Portland
Adaptability Index composite score. Greater preservation of callosal in-
tegrity was associated with better functional and neuropsychological
scores when assessed at the chronic stage of recovery from severe TBI.
Keywords: diffusion tensor imaging, functional outcome, neu-
ropsychological outcome, corpus callosum
S05 The Role of apoE and APOE Genotype in Outcome
after TBI
S05-01
APOE4 AS A RISK FACTOR FOR POOR OUTCOME AFTER
TBI - CLINICAL AND PRECLINICAL EVIDENCE
Mark Burns
Georgetown University, Department of Neuroscience, Washington, USA
The apoE protein is an important brain apolipoprotein whose primary
function is as a cholesterol transporter. There are 3 apoE isoforms, apoE2,
apoE3 and apoE4 – encoded for by polymorphisms in the APOE gene. The
APOE4 allele is best known as a genetic risk factor for the development of
Alzheimer’s disease, but it is also associated with poor outcome after TBI,
andmay be linked to the development of chronic traumatic encephalopathy
in athletes. This talk will critically assess the clinical and preclinical evi-
dence data supporting the link between APOE4 and TBI, and unpublished
data from humanized APOE mice will also be presented. This new data
will focus on mechanisms by which APOE4 can negatively impact out-
come after TBI including through aberrant amyloid clearance, increased
neuroinflammation and impaired closure of the blood brain barrier.
Keywords: apoE, amyloid, inflammation
S05-02
THE EFFECTS OF APOE GENOTYPE ON PROTEOMIC AND
LIPIDOMIC RESPONSE TO INJURY IN DIFFERENT MOUSE
MODELS OF TBI
Fiona Crawford
1,2
, Corbin Bachmeier
1,2
, Laila Abdullah
1,2
, Jon
Reed
1,2
, Cillian Lynch
1
, James Evans
1,2
, Gogce Crynen
1,2
, Benoit
Mouzon
1,2
, Venkatarajan Mathura
1,2
, Michael Mullan
1
1
The Roskamp Institute, Inc., The Roskamp Institute, Inc., Sarasota, USA
2
James A Haley Veterans Administration, James A Haley Veterans
Administration, Tampa, USA
Introduction:
We have used different laboratory models of TBI and
quantitative proteomics and lipidomics approaches to generate brain
proteomic and lipidomic profiles and identify cellular mechanisms that
are triggered in response to TBI. Moreover, we have carried out these
studies in mice transgenic for different isoforms of human APOE in
order to discriminate between the cellular mechanisms associated with
favorable (APOE3) versus unfavorable (APOE4) outcomes after TBI.
Methods:
We used the well characterized controlled cortical impact
(CCI) model administered with a moderate (1.3mm depth) or severe
(1.8mm) single injury in 6–8 month old APOE transgenic mice, and in
targeted replacement APOEmice we administered a repetitive mild TBI (r-
mTBI) model developed in house (Mouzon
et al.
2012) with a paradigm of
three hits per week for one month. Proteomic and lipidomic analyses
employed liquid chromatography-mass spectrometry (LCMS) approaches
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