184 / 198
reduce the efficacy of rehabilitation and greatly increase the chances for
additional injury. Additionally, there is mounting evidence that TBI
itself may be a risk factor for the development of alcohol use disorders.
Finally, patients injured in childhood have poorer overall life outcomes
and a much greater likelihood of developing substance abuse disorders.
We used a standardized closed head injury to model mild traumatic
brain injuries. We found that mice injured during adolescence but not
during adulthood exhibited much greater alcohol self-administration in
adulthood. Further, this phenomenon was limited to female mice as
there was no effect of injury in males. Using behavioral testing, we
determined that increased drinking behavior is mediated by alterations
in the rewarding properties of alcohol and not sensory deficits from TBI.
Environmental enrichment administered after injury reduced axonal
degeneration and prevented the increase in drinking behavior. Ad-
ditionally, brain derived neurotrophic factor gene expression, which was
reduced by TBI, was normalized by environmental enrichment. Finally,
an analysis of human data indicated that girls injured during early ad-
olescence were much more likely to misuse alcohol as adults than were
girls injured during other developmental epochs. Together these results
suggest a novel model of alterations in reward circuitry following
trauma during development.
Keywords: Alcohol, Adolescent Injury, Environmental Enrichment,
BDNF, Inflammation, Concussion
S12-04
SINGLE EPISODE OF SEVERE AXONAL INJURY IN HU-
MANS IS ASSOCIATED WITH PATHOLOGY RESEMBLING
CHRONIC TRAUMATIC ENCEPHALOPATHY
Sarah Edgerton, Sharon Shively, Bao-Xi Qu, Diaz-Arrastia Ramon,
Daniel Perl
USUHS, CNRM, Bethesda, USA
Chronic traumatic encephalopathy (CTE) is a neurodegenerative
disorder associated with repetitive mild traumatic brain injury (TBI).
In CTE, abnormal
tau
proteins aggregate in a distinctive pattern of
neurofibrillary tangles (NFTs) and astrocytic tangles favoring sulcal
depths, perivascular regions and superficial neocortical layers. It has
been suggested that these
tau
aggregates develop following axonal
damage and/or impact-related mechanical stresses.
We analyzed postmortem brains from six schizophrenic patients who
had undergone prefrontal leucotomy prior to 1953 and then lived at least
another 40 years. Because leucotomy involves severing axons of the
prefrontal cortex, this procedure represents a single TBI with severe
axonal injury and no external cortical impact. We examined cortical
tissues at the leucotomy sites, prefrontal and caudal frontal cortices and
hippocampi. We compared these specimens to brains of six age-matched,
non-leucotomized schizophrenics. We conducted immunohistochemis-
try using antibodies against abnormal
tau,
b
-amyloid and astrocytes. We
performed APOE genotyping for the six leucotomy patients.
In all six leucotomy cases, prefrontal lesion sites revealed severe
white matter damage. Abnormal
tau
(NFTs and astrocytic tangles)
was detected in cortex adjacent to leucotomy sites, involving depths of
sulci, perivascular regions and superficial neocortical layers, but not in
prefrontal and caudal frontal cortices distant to the leucotomy lesions.
Similarly,
b
-amyloid plaques occupied the gray matter adjacent to the
lesion sites, but only in the three patients with APOE
e
4 haplotypes.
Non-leucotomized schizophrenic patients showed no significant pa-
thology.
Massive chronic axonal damage in white matter, as produced in
leucotomy, leads to abnormal
tau
in neurons and astrocytes in gray
matter adjacent to the lesion in the distinctive pattern resembling
CTE. These data suggest that chronic neuronal deafferentation alone
leads to abnormal
tau
accumulation. Because leucotomy lacks ex-
ternal cortical impact, the data suggest that selective accumulation of
tau
at depths of sulci may be related to underlying axonal damage
rather than mechanical stresses during TBI. Lastly, only patients with
the APOE
e
4 haplotype formed
b
-amyloid plaques.
Keywords: CTE, Axonal injury, tau, neuropathology
S12-05
TRAUMATIC AXONAL INJURY IN THE LIVING HUMAN
BRAIN: CONCORDANCE OF MICRODIALYSIS AND AD-
VANCED MRI APPROACHES
S Magnoni
2
, C Mac Donald
1
, TJ Esparza
1
, V Conte
2
, J Sorrell
1
, M
Macri
2
, G Bertani
2
, R Biffi
2
, A Costa
2
, B Sammons
1
, A Snyder
1
,
J Shimony
1
, F Triulzi
2
, N Stocchetti
2
,
David Brody
1
1
Washington University, Neurology, St. Louis, USA
2
Ospedale Maggiore Policlinico, Anesthesia-Intensive Care, Milano,
Italy
We performed microdialysis and diffusion tensor imaging in the same
cohort of 15 severe traumatic brain injury patients to assess axonal
injury with 2 complementary approaches. 100 kDa cut-off micro-
dialysis catheters were implanted at a median time of 17 h (13–29
hours) after injury in normal appearing (on CT scan) frontal white
matter in all patients. Diffusion tensor MRI scans at 3T were per-
formed 2–9 weeks after injury in 11 patients. Stability of diffusion
tensor imaging findings was verified by repeat scans 1–3 years later in
7 patients. An additional 4 patients were scanned only at 1–3 years
after injury. Imaging abnormalities were assessed based on compari-
sons with 5 controls (healthy subjects) for each patient, matched by
age and sex (32 controls in total).
We found that acute microdialysis measurements of the axonal
cytoskeletal protein tau in the brain extracellular space correlated well
with diffusion tensor MRI-based measurements of reduced brain
white matter integrity in the 1 cm radius white matter-masked region
near the microdialysis catheter insertion sites. Specifically, we found a
significant inverse correlation between microdialysis measured levels
of tau 13–36 hours after injury and anisotropy reductions in com-
parison with healthy controls (Spearman r
= -
0.64, p
=
0.006). Ani-
sotropy reductions near microdialysis catheter insertion sites were
highly correlated with reductions in multiple additional white matter
regions. We interpret this result to mean that both microdialysis and
diffusion tensor MRI accurately reflect the same pathophysiological
process: traumatic axonal injury. This cross-validation increases
confidence in both methods for the clinical assessment of axonal in-
jury. Future work will be required to determine the prognostic sig-
nificance of these assessments of traumatic axonal injury when
combined with other clinical and radiological measures.
Keywords: microdialysis, diffusion tensor imaging, tau
S13 Brain Injury: Effects on Physiology and Function
Beyond the Brain
S13-01
HEPATIC AND SPLENIC CONTRIBUTIONS TO TRAU-
MATIC BRAIN INJURY
Lee Shapiro
Texas A&M HSC, Surgery/Neurosurgery, Temple, USA
A-148