D2-25
ELUCIDATING THE PATHOBIOLOGY OF IMPACT CON-
CUSSION IN A MOUSE MODEL OF MILD TRAUMATIC
BRAIN INJURY
Tagge, C.A.
1
, Fisher, A.M.
1
, Gaudreau, A.B.
1
, Wojnarowicz, M.W.
1
,
Minaeva, O.
1
, Moncaster, J.A.
1
, Casey, N.
1
, Stein, T.D.
1–3
, Moss,
W.C.
4
, Moir, R.D.
6
, Tanzi, R.E.
6
, Stanton, P.K.
5
, McKee, A.C.
1–3
,
Goldstein, L.E.
1,2
1
Boston University School of Medicine, College of Engineering,
Boston, USA
2
Boston University Alzheimer’s Disease Center, Boston, USA
3
Boston VA Healthcare System, Boston, USA
4
Lawrence Livermore National Laboratory, Livermore, USA
5
New York Medical College, Valhalla, USA
6
Massachusetts General Hospital, Charlestown, USA
We are investigating biomechanical and pathobiological determinants
that link traumatic brain injury (TBI) with chronic traumatic en-
cephalopathy (CTE), a tau protein neurodegenerative disease
(McKee, 2013). We reported the first case series of postmortem brains
from blast-exposed military veterans and compared results with brains
from young athletes with histories of impact-induced concussive head
injury (Goldstein, 2012). We found evidence of CTE neuropathology
in the blast-exposed veterans that was indistinguishable from the
neuropathology in the young athletes. Here we investigated concus-
sive impact TBI using a new murine model deployed without anes-
thesia. The new model system accurately recapitulates biomechanical,
pathophysiological, and clinical features of impact-induced TBI in
humans. Our impact concussion mouse model: (1) prevents mo-
mentary impact-related skull deformation (crush injury) evaluated by
two-axis high-speed videography, (2) induces acute lateralizing neu-
rological signs (Boston University Concussion Scale, BUCS-3R) that
resolve within 3 hours consistent with acute clinical concussion, (3)
produces persistent neuropathological, neurochemical, and neuro-
physiological changes in the brain that recapitulate chronic effects of
neurotrauma in humans. We used high-speed videography (capture
rate: 10
l
sec; 100 kHz) and kinematic analysis to show that this im-
pact TBI model accurately replicates head kinematics observed in our
blast TBI mouse model (Goldstein, 2012). Our results point to trau-
matic head acceleration as a major pathogenic contributor to acute and
chronic effects of neurotrauma resulting from impact or blast TBI.
These findings also provide insights into pathobiological responses
following impact-induced concussion that may trigger chronic se-
quelae, including CTE.
Key words
traumatic brain injury
D2-26
CORRELATING MECHANICAL STRAIN AND BIOLOGICAL
DAMAGE: AN
IN VIVO
, RODENT MODEL OF SPINAL CORD
INJURY
Bhatnagar, T.
1,4
, Liu, J.
4
, Yung, A.
3,4
, Kozlowski, P.
3,4
, Tetzlaff, W.
2,4
,
Oxland, T.
1,4
1
University of British Columbia, Departments of Orthopaedics and
Mechanical Engineering, Vancouver, Canada
2
University of British Columbia, Department of Zoology, Vancouver,
Canada
3
University of British Columbia, 7T MRI Centre, Vancouver, Canada
4
University of British Columbia, ICORD Research Centre, Vancou-
ver, Canada
Rodent models of acute spinal cord injury (SCI) are often used to in-
vestigate the effects of injury mechanism, injury speed and cord force
and displacement magnitude, on the ensuing cascade of biological
damage in the cord. However, due to its small size, experimental ob-
servations have largely been limited to the gross response of the cord in
SCI models. Therefore, the objective of this study was to determine
mechanical strain patterns within the spinal cord during injury, in order to
investigate the relationship between mechanical stimulus and biological
damage in acute SCI. We developed and validated a novel MRI-com-
patible test apparatus to impose an acute, sustained (30min.), cervical
SCI in an
in vivo
rodent model, inside of a 7T MR scanner. Twenty-four
rats (Sprague-Dawley,
*
300g) underwent either a contusion (n
=
12) or
dislocation (n
=
12) injury at the C5/6 level. Axial-slice MR image sets of
the cervical spinal cord (C2-C8) were acquired at ‘Pre-injury’ and
‘Sustained-injury’ time points (resolution: 0.14x0.14x0.5mm). The two
image sets were then registered, using a validated deformable registration
algorithm. The registration yielded a three-dimensional displacement
field that quantified the morphological change of the spinal cord due to
injury, on a voxel-scale. Determining the spatial derivatives of the dis-
placement field facilitated the calculation of mechanical strain (in 3D)
throughout the cervical spinal cord. The spinal cords were harvested,
sliced axially, and stained with NeuN to measure neuronal viability in the
ventral horns of the gray matter, after injury. A correlation analysis was
performed to determine how the NeuN data correlated with the me-
chanical strain measured in the ventral horns, over a region of
+
/- 3mm,
rostro-caudal, from the injury epicenter.
Key words
acute SCI, mechanical strain, spinal cord morphology
D2-27
CHALLENGES IN ASSESSING TAU IN A LARGE ANIMAL
MODEL OF TRAUMATIC BRAIN INJURY
McGuone, D.
, Smith, C., Costine, B.A., Duhaime, A.C.
Massachusetts General Hospital, Boston, USA
The tauopathies are a heterogeneous group of neurologic diseases
characterized by abnormally aggregated tau protein. Head injury is
considered an important potential cause of tauopathy, yet the mech-
anism of tau accumulation following injury is poorly understood.
Most work to date has been in rodent models. It is unclear if the
immature brain is selectively vulnerable to tauopathy after injury, and
the putative timeframe for pathologic tau accumulation after injury is
poorly defined. We evaluated hyperphosphorylated tau in a large
animal model with short survival times following cortical impact. We
describe the challenges in validating tau in this model.
Sixteen immature swine underwent scaled focal cortical impact using
a well-characterized contusion model. Animals were 5 days, 1 month or
4 months old at injury. Survival times were 1 week or 1 month. A
protocol for peroxidase immunohistochemistry was optimized for par-
affin embedded tissue using antibody to hyperphosphorylated tau
(AT8). Multiple whole-brain coronal slices were evaluated at the injury
site. Positive controls included human brain with Alzheimer disease and
tissue from a pig model of diffuse brain injury previously published
with tau positivity. Negative and sham controls were also used. Blinded
evaluation of a single case was performed by 4 neuropathologists.
Hyperphosphorylated tau was detected in axonal swellings in one
subject. Other subjects had focal or multifocal staining of neurons,
glia or neurites that was equivocally positive and difficult to interpret.
Review of a single blinded case by 4 neuropathologists yielded low
inter-rater reliability (50% agreement). Alternate methods to interro-
gate brain tissue for abnormal tau in this model are in progress
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