Page 70 - NNS 2014 Program & Abstract Book

Traumatic and mild traumatic brain injury (mTBI) can lead to chronic
damage and result in permanent disability. mTBI is often undiagnosed
at early stages, thereby allowing patients to remain vulnerable to
multiple mTBI, a condition that is known to lead to irreversible long-
term damage. At present, there are no objective methods to diagnose
mTBI, with current diagnosis requiring negative results on a CT scan
plus assessment of cognitive and physical symptoms plus behavioral
changes. mTBI can lead to alterations in cell functions through bio-
logical processes including disruption of the blood-brain barrier
(BBB). Similar to the BBB, disruption of the blood eye barrier (BEB)
has also been observed and correlated to the severity of brain injury.
We hypothesize that biomarkers associated with the autoimmune re-
sponse initiated by mTBI permeate the BEB through the ciliary vas-
culature in the eye and result in subclinical changes in protein
concentration in the aqueous humor (AH) which can be a direct
measure of the damage associated with mTBI. In this study, we an-
alyzed AH protein concentration in two different murine brain injury
models including 1) a blast injury model in rats and 2) a repeated mild
diffuse injury model in mice. A significantly elevated protein con-
centration was measured in the AH ex vivo (p < 0.05) in injured ro-
dents compared to sham controls, supporting our hypothesis. We have
also developed and patented a novel optical system which can be used
to rapidly (< 30 sec) scan the anterior chamber of a subject’s eye to
determine ocular inflammation and quantify the concentration of
proteins in the AH. A prototype optical system has been tested in vitro
and in vivo in a non-human primate model to determine the ability to
measure small changes in AH protein concentrations and is currently
being clinically validated. Taken together, these findings may result in
an optical device that can rapidly and non-invasively diagnose mTBI
by quantifying the change in AH total protein concentration.
Key words
concussion, diagnosis, non-invasive, ocular
A4-05
SERUM MICRORNA SIGNATURES OF CLOSED HEAD IN-
JURY IN MICE: A POTENTIAL BIOMARKER FOR MILD
TRAUMATIC BRAIN INJURY
Chandran, R.1,3, Sharma, A.1, Balakathiresan, N.S.1, Bhomia, M.1,
Barry, E.S.2, Hutchison, M.A.2, Grunberg, N.E.2, Maheshwari, R.K.1
1Uniformed Services University of the Health Sciences, Department of
Pathology, Bethesda, Bethesda, USA
2Uniformed Services University of the Health Sciences, Department of
Medical and Clinical Psychology, Bethesda, USA
3Birla Institute of Technology and Science-Pilani, Department of
Biological Sciences, Pilani, India
To date, there is no clinically proven biomarker(s) available for di-
agnosis of mild traumatic brain injury (mTBI). Circulating micro-
RNAs (miRNAs) are fast emerging as noninvasive diagnostic
biomarkers for various diseases because of their specificity and sen-
sitivity. Our main objective of this study was to identify the mTBI
altered miRNA signatures in serum to use them as a reliable molecular
biomarker. In this study, we used a custom-made weight-drop device
to induce a single concussion to the left parietal lobe in mice. Dif-
ferent rod weights (246 and 333 g) and fall heights (2 and 3 cm) were
used to create four injury groups. Neurobehavioral Severity Scale-
revised, open field activity and acoustic startle response were studied
at 24 hours post injury. MiRNA expression profiling for serum col-
lected at 3 hours post injury were performed using TaqMan Micro-
RNA Array cards. Neurobehavioral tests showed transient behavioral
changes at 24 hours post injury. MiRNA profiling in serum showed
thirteen common miRNAs between the four injury groups. In silico
analysis indicated most of the thirteen miRNAs to be either of brain
origin or predicted to be involved in TBI pathophysiology. Network
analysis of thirteen miRNAs and their validated targets showed few of
them to have a direct correlation with axon guidance, depression and
sensorimotor impairment associated pathways. Brain related serum
miRNAs- miR-199-3p, miR-214 and miR-376a were validated. Al-
tered serum miRNAs expression at 3 hours post injury showed cor-
relation with TBI pathophysiology indicating their potential as a novel
molecular biomarker for mTBI. (Opinions expressed here are those of
authors and does not reflect views of USUHS, DMRDP or BITS
Pilani).
Key words
mild TBI, serum microRNAs, weight drop model
A4-06
MICROTUBULE-ASSOCIATED PROTEIN 2 (MAP2) CSF
BIOKINETIC CHARACTERISTICS ARE ASSOCIATED WITH
POOR OUTCOMES IN SEVERE TBI PATIENTS
Brophy, G.M.1, Papa, L.2 , Robertson, C.S.3 , Wang, K.K.4, Hannay,
H.J.5 , Heaton, S.4, Gabrielle, A.4, Schmalfuss, I.6, Hayes, R.L.7,
Robicsek, S.A.4
1Virginia Commonwealth University, Richmond, USA
2Orlando Regional Medical Center, Orlando, USA
3Baylor College of Medicine, Houston, USA
4University of Florida, Gainesville, USA
5University of Houston, Houston, USA
6University of Florida and NF/SG Veterans Administration, Gaines-
ville, USA
7Banyan Biomarkers Inc., Alachua, USA
MAP2 is a promising new candidate biomarker of dendritic injury;
however, most studies identify one point in time to determine asso-
ciations with outcomes. This study assesses the relationship between
the exposure and kinetic metrics of MAP2 in cerebral spinal fluid
(CSF) over time and clinical outcomes. This prospective observational
study was conducted in patients with severe TBI (GCS £ 8) requiring a
ventriculostomy. CSF samples were obtained every 6 hours on day 1,
then every 24 hours for up to 10 days post injury and analyzed for
multiple biomarkers using an ELISA; with MAP2 showing strong
correlations. Biokinetic parameters evaluated include area under the
curve (AUC), maximum concentrations (Cmax), time to maximum
concentration(Tmax), mean residence time (MRT) and half-life. Of
the 120 patients with kinetic metric results, 92 had outcome data
available for analysis. There were significant correlations between
increasing median AUC and Rotterdam scores predicting risk of
mortality (p < 0.001). When Marshall Classification was dichotomized
into I-II versus III-VI, the median AUC and Cmax were significantly
higher in the III-VI group (p < 0.001). Among patients with Marshall
Classification I-II versus III-IV, median AUCs were 116 vs 475 ng/
ml*hr(p = 0.001) and median Cmax was 2.4 vs 9.2 ng/ml(p = 0.001).
The median AUC for GOSe at 6 months in those with favorable versus
unfavorable outcome were 82 vs 323 ng/ml*hr (p = 0.007), the median
Cmax was 2.4 vs 8.7 ng/ml(p = 0.005), the median MRT was 52 vs 69
hr (p = 0.056). MAP2 exposure and biomarker kinetic metrics over the
10 day study time period show significant correlations with prognostic
imaging classifications and poor clinical outcomes in severe TBI
patients.
Key words
biomarker, MAP2, TBI
A-38