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the role of the K
ATP
channel in vascular dysfunction targeted by either
L-arginine or L-lysine following repetitive mild TBI.
Adult male Sprague Dawley rats were subjected to repetitive mild
TBI using impact-acceleration injury. Pial vascular function was as-
sessed through the use of cranial windows. Pial arteriolar K
ATP
channel function was assessed following repetitive mild TBI by
measuring vascular reactivity to topical application of pinacidil, a
K
ATP
channel opener. We then evaluated the protective effects of
intravenous administration of L-arginine and L-lysine on repetitive
mild TBI by measuring vascular reactivity following the topical ap-
plication of Acetylcholine.
Following repetitive mild TBI, the pial arterioles failed to dilate to
pinacidil implicating the K
ATP
Channel. Acetylcholine induced vas-
cular reactivity was also impaired after repetitive mild TBI; however,
protection occurred with L-arginine (5 mg/kg) administration, with the
best results achieved when L-arginine was administered prior to the
second/repetitive injury. Comparable cerebrovascular protection was
not achieved with the same concentration of L-lysine; however, higher
doses of L-lysine (20 mg/kg) proved protective.
Collectively, these studies demonstrate that repetitive mild TBI
impairs cerebrovascular reactivity via K
ATP
channel dysfunction.
Additionally, this impaired vasoreactivity could be maximally pre-
served with the early use of L-arginine administration, suggesting its
potential therapeutic utility. The enhanced benefits achieved with low
dose L-arginine in comparison to L-lysine, may be explained by the
fact that L-arginine also acts as precursor of nitric oxide in addition to
its K
ATP
channel function.
Supported by NIH Grant HD055813.
Keywords: ATP-sensitive potassium channel, L-arginine, L-lysine,
repetitive mild traumatic brain injury, vascular reactivity
T1-20
ADVANCED DIFFUSION MRI-BASED RADIOLOGICAL-
PATHOLOGICAL CORRELATIONS IN CHRONIC TRAU-
MATIC ENCEPHALOPATHY
Laurena Holleran
1
, Joong Hee Kim
1
, Mihika Gangolli
1
, Thor Stein
1
,
Victor Alvarez
2
, Ann McKee
2
, David L. Brody
1
1
Washington University St. Louis, Department of Neurology, St.
Louis, USA
2
Boston University, CTE Center, Boston, USA
Chronic traumatic encephalopathy (CTE) is a progressive degenera-
tive disorder associated with repetitive traumatic brain injury (TBI).
Post-mortem studies report hyperphosphorylated tau pathology in
CTE, most notably in perivascular, periventricular and sulcal depth
grey matter as well as axonal injury. Currently a diagnosis of CTE is
restricted to post-mortem neuropathological analysis. However, ad-
vanced neuroimaging methods, such as diffusion MRI, may provide
the necessary microstructural information to differentiate CTE related
pathology. We are in the process of testing this hypothesis using
diffusion MRI acquired from
ex vivo
brain samples to determine the
sensitivity and specificity of the radiological-pathological relationship
in CTE.
Cortical and hippocampal samples of 2 CTE pathology, 2 non-CTE
pathology, and 2 control formalin fixed post-mortem brains were
obtained from BU CTE Center brain bank. Diffusion MRI data was
acquired using the 11.74 T MRI scanner at Washington University.
MRI sequence acquisition was optimized to produce high spatial
resolution data with 250
·
250
l
m voxel dimensions in 500
l
m slices
and calculation of traditional diffusion tensor and non-tensor based
methods, including diffusion kurtosis imaging (DKI) and generalized
q-space imaging (GQI) parameters. Following MRI acquisition tissue
blocks were serially sectioned at 50
l
m thickness and tested for
phosphorylated tau immunoreactivity using AT8 monoclonal anti-
body. Mounted tissue sections were co-registered with diffusion MRI
data to quantify the relationship between diffusion parameters and
positive tau staining. Initial analyses show that diffusion MRI pa-
rameters significantly differ between regions of dense tauopathy
compared to normal cortical tissue. Differences in diffusion MRI
parameters, indicative of microstructural abnormalities were also
detected in white matter adjacent to cortical tau pathology.
The results of this study indicate that advanced diffusion MRI has
the potential to detect microstructural alterations related to hyper-
phosphorylated tau pathology and adjacent axonal abnormalities seen
in CTE. The long-term goal is to advance future non-invasive methods
of accurately diagnosing CTE during life.
Keywords: Chronic Traumatic Encephalopathy, diffusion MRI, Tau
Pathology, Radiological-Pathological Correlation
A-9