The pathology of traumatic brain injury in experimental models includes acute inflammatory reaction, blood brain barrier disruption, hemorrhage, demyelination, axonal transection and chronically with axonal neuronal loss and gliosis. Stem cell (SC) therapy is a potential treatment either as replacement therapy or via paracrine effect with release of growth factors and anti-inflammatory cytokines for TBI injury. We reported on a longitudinal study in a mild TBI rat model based on MRI and correlated to histology over 2 months. We reported that diffusion tensor imaging (DTI) axial diffusivity and fractional anisotropy (FA) were sensitive to axonal integrity, whereas radial diffusivity showed significant correlation to the myelin compactness. We also observed that FA was correlated with astrogliosis in the gray matter, whereas mean diffusivity was correlated with increased cellularity and magnetization transfer ratio (MTR) demonstrated a strong correlation with both axon and myelin integrity. We also were able to demonstrate that in rats with mild ventriculomegaly (MVM) demonstrated insignificant changes in FA, suggesting less axonal injury compared to normal rats following mild TBI. The MVM animals had significant increase in MTR compared to normal rats following mild TBI. On histological examination, limited axonal injury with significant increase of microgliosis and astrogliosis in MVM brains compared with normal animals. MVM rats exhibited greater inflammation following TBI compared to normal rat brains. These results indicated the importance of using MRI to screen for brain abnormalities in experimental animals used in TBI studies and that the variation observed in TBI studies may be due to the variability in response to induced trauma as a result of structural morphology The relationship between changes in diffusion tensor imaging (DTI) and magnetization transfer imaging (MTI) and the underlying pathologies is still relatively unknown.We investigated the radiological-pathological correlation between these imaging techniques and immunohistochemistry using a closed head rat model of TBI. TBI was performed on female rats followed longitudinally by magnetic resonance imaging (MRI) out to 30 days postinjury, with a subset of animals selected for histopathological analyses. A MRI-based finite element analysis was generated to characterize the pattern of the mechanical insult and estimate the extent of brain injury to direct the pathological correlation with imaging findings. We observed that DTI axial diffusivity and fractional anisotropy (FA) were sensitive to axonal integrity, whereas radial diffusivity showed significant correlation to the myelin compactness. FA was correlated with astrogliosis in the gray matter, whereas mean diffusivity was correlated with increased cellularity. Secondary inflammatory responses also partly affected the changes of these DTI metrics. The magnetization transfer ratio (MTR) at 3.5ppm demonstrated a strong correlation with both axon and myelin integrity. Decrease in MTR at 20ppm correlated with the extent of astrogliosis in both gray and white matter. Conventional T2-weighted MRI did not detect abnormalities following TBI, DTI and MTI afforded complementary insight into the underlying pathologies reflecting varying injury states over time, and thus may substitute for histology to reveal diffusive axonal injury pathologies in vivo.

Agency
National Institute of Health (NIH)
Institute
Clinical Center (CLC)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIACL090020-08
Application #
9549520
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Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
2017
Total Cost
Indirect Cost
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Clinical Center
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Tu, Tsang-Wei; Ibrahim, Wael G; Jikaria, Neekita et al. (2018) On the detection of cerebral metabolic depression in experimental traumatic brain injury using Chemical Exchange Saturation Transfer (CEST)-weighted MRI. Sci Rep 8:669
Dean, Dana D; Frank, Joseph A; Turtzo, L Christine (2017) Controlled Cortical Impact in the Rat. Curr Protoc Neurosci 81:9.62.1-9.62.12
Tu, Tsang-Wei; Williams, Rashida A; Lescher, Jacob D et al. (2016) Radiological-pathological correlation of diffusion tensor and magnetization transfer imaging in a closed head traumatic brain injury model. Ann Neurol 79:907-20
Tu, Tsang-Wei; Lescher, Jacob D; Williams, Rashida A et al. (2016) Abnormal Injury Response in Spontaneous Mild Ventriculomegaly Wistar Rat Brains: A Pathological Correlation Study of Diffusion Tensor and Magnetization Transfer Imaging in Mild Traumatic Brain Injury. J Neurotrauma :
Turtzo, L Christine; Budde, Matthew D; Dean, Dana D et al. (2015) Failure of intravenous or intracardiac delivery of mesenchymal stromal cells to improve outcomes after focal traumatic brain injury in the female rat. PLoS One 10:e0126551
Turtzo, L Christine; Lescher, Jacob; Janes, Lindsay et al. (2014) Macrophagic and microglial responses after focal traumatic brain injury in the female rat. J Neuroinflammation 11:82
Tu, Tsang-Wei; Turtzo, L Christine; Williams, Rashida A et al. (2014) Imaging of spontaneous ventriculomegaly and vascular malformations in Wistar rats: implications for preclinical research. J Neuropathol Exp Neurol 73:1152-65
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Turtzo, L Christine; Budde, Matthew D; Gold, Eric M et al. (2013) The evolution of traumatic brain injury in a rat focal contusion model. NMR Biomed 26:468-79
Budde, Matthew D; Frank, Joseph A (2012) Examining brain microstructure using structure tensor analysis of histological sections. Neuroimage 63:1-10

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