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Sprague-Dawley rats (male, 300–350 g), were anesthetized and
secured on a platform that was accelerated vertically at 700, 2800 or
4000 Gs after detonation of a small explosive positioned under the
platform. Blast and sham animals were subjected to behavioral testing
to assess for hippocampus-dependent working-memory and anxiety-
like behavior using Y-maze and Plus-maze tests for up to 30 days
post-injury, or euthanized at 30 min, 1 or 7 days post-trauma. All
animals were euthanized by transcardial perfusion and, brain tissue
processed for immunostaining.
We observed a significant increase of cleaved-caspase-3 immuno-
reactive cells in different brain regions of blast-rats, including the
hippocampus, amygdala and cerebellum, starting 30 min post-injury.
These cells were mostly neurons. This observation was substantiated
by the presence of TUNEL-positive cells in those brain sections and
reduced purkinje cells density in the cerebellum. Furthermore, im-
munostaining for F4/80 showed increased numbers of infiltrated in-
flammatory cells (macrophage/microglia), predominantly within
perivascular and periventricular areas. Animals exposed to 2800G-
blast intensity all survived but exhibited significant deficits in
hippocampus-dependent working-memory and anxiety-like behavior,
as indicated by ANOVA and post-test analysis. Furthermore, 67% of
animals subjected to 4000G-blast force died within 4 hours post-blast
due to pulmonary hemorrhage.
These findings suggest that our model may be important to further
close the gap in understanding the pathophysiology of blast induced-
TBI that closely reflects real under-vehicle blast scenarios.
Grant-support: US-Army-W81XWH-13-1-0016; US-Air-Force-
FA8650-11-2-6D04
Keywords: Blast-TBI, Neuronal loss, Inflammation, Neurobeha-
vioral deficits
B7-10
ASSOCIATION BETWEEN APOE GENOTYPE AND NEURO-
DEGENERATIVE PATHOLOGIES AFTER TRAUMATIC
BRAIN INJURY
Patricia Washington
1
, Victoria Johnson
2
, Jennifer Hay
3
, James
Nicoll
4
, Douglas Smith
2
, William Stewart
3
1
Columbia University, Pediatrics and Critical Care Medicine, New
York, USA
2
University of Pennsylvania, CBIR, Philadelphia, USA
3
Southern General Hospital, Department of Neuropathology, Glas-
gow, UK
4
Southampton General Hospital, Department of Cellular Pathology,
Southampton, UK
Traumatic brain injury (TBI) is recognized as a risk factor for neuro-
degenerative disease; specifically chronic traumatic encephalopathy
(CTE). A hallmark pathology of CTE is abnormal accumulation of
hyperphosphorylated tau, with many cases also showing pathologies in
amyloid-beta. However, these pathologies are not ubiquitous after in-
jury. APOE genotype is recognized to influence acute post-TBI pa-
thology and is also suggested to influence longer-term clinical outcome.
This pilot study was designed to investigate the association between
APOE genotype and neuropathology after TBI. Cases with a history of
single moderate/severe TBI and survival ranging from 28d to 47 years
(n
=
59) were selected from the Glasgow TBI Archive, together
with age-matched controls with no history of TBI (n
=
69). Im-
munohistochemistry for both amyloid and tau was performed and assessed
using standardized semi-quantitative grading protocols. APOE genotype
was determined using established techniques. Approximately half of TBI
and control cases contained amyloid plaques, tau-immunoreactive neu-
rofibrillary tangles or both pathologies. Notably, these pathologies
were detected in TBI cases at younger ages and in wider distribution
than in non-injured controls, with incidence increasing with age—
such that
*
90% of TBI cases over age 60 displayed some pathology.
Regarding genotype, the APOE-
e
4 allele was associated with in-
creased incidence of amyloid pathologies in both control and TBI
cases. However, no association was found between APOE genotype
and tau pathologies, with or without history of TBI. These preliminary
data support previous observations that, for a proportion of patients,
TBI survival is associated with the development of more extensive tau
and amyloid pathologies when compared to age-matched controls.
Further, for the first time, we provide evidence that this late post-TBI
pathology may be influenced by genotype, with the development of
amyloid pathologies after single moderate/severe TBI apparently
influenced by possession of the APOE-
e
4 allele.
Keywords: APOE, Amyloid, Tau, CTE, Human
C1 Poster Session V - Group C: Cognition
C1-01
SYMPTOMATIC, PSYCHIATRIC, BEHAVIORAL AND COG-
NITIVE OUTCOMES IN BLAST EXPOSED VETERANS
Weiya Mu
1
, Namhee Kim
1
, Molly Zimmerman
1
, Andrew
McClelland
2
, Roman Fleysher
1
, Mark Wagshul
1
, Eva Catenaccio
1
,
Tamar Glattstein
1
, Malka Zughaft
1
, Michael Lipton
1,2
1
Albert Einstein College of Medicine, Gruss Magnetic Resonance
Research Center, Bronx, USA
2
Montefiore Medical Center, Radiology, Bronx, USA
Blast-related mild traumatic brain injury (mTBI) is highly prevalent
among OEF/OIF combat veterans. Because many studies employ con-
trols with different baseline characteristics than the blast-exposed sub-
jects, it remains largely unexplored to what extent findings might be
attributable to baseline characteristics. We therefore recruited close male
relatives to assess outcomes in a cohort of blast-exposed combat veterans.
Twenty male OEF/OIF veterans with history of combat blast exposure
and 19 matched male close relatives (53% siblings) underwent assess-
ment of multiple TBI outcomes, including PCS, depression, anxiety,
stress, PTSD, aggression and cognitive function. Demographics and
medical history were compared using unpaired T- and Fisher’s exact
tests. The outcome measures were assessed with linear regression, ad-
justing for age, education and employment. False discovery rate (FDR;
a
<
0.05) was used to account multiple comparisons. Z scores were cal-
culated to classify subjects as clinically impaired based on Z
< -
1.5.
Veteran and family groups were similar based on demographic, SES,
medical history and substance use. Veterans reported worse health re-
lated quality of life (p
=
1.7e-7), PCS (p
=
1.0e-6), and sleep quality
(p
=
7.7e-6). They exhibited much greater depression (p
=
0.0004), anx-
iety (p
=
0.0002), stress (p
=
0.0001) and PTSD (p
=
4.0e-5) compared to
siblings. Veterans also endorsed aggression (p
=
0.013), and performed
worse in measures of attention (p
=
0.007) and working memory
(p
=
0.0003). All results survived FDR correction. Compared to norma-
tive data, veterans had worse symptomatic, psychiatric and cognitive
outcomes. Veterans demonstrated excess PCS, psychiatric and cognitive
morbidity in the context of an extremely well-matched control sample,
which accounts an array of measured (e.g., education, age, race, SES,
substance use) and unmeasured (heritability, genetics, social and geo-
graphic background) variables. These findings support the relationship of
blast to morbidity, suggesting it is not explained by baseline factors, and
should inform future studies of combat TBI and TBI in general.
Keywords: Blast, Veterans, Chronic mTBI, Psychosocial outcomes,
Family member controls
A-71