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Scholarly Works (5 results)

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UC Riverside Electronic Theses and Dissertations (2014)

ABSTRACT OF THE DISSERTATION

Neuropathology Following Repeated Traumatic Brain Injury and the Influence of Inflammatory Status on Injury Outcome

by

Virginia Dorothy-Marie Donovan

Doctor of Philosophy, Graduate Program in Cell, Molecular, and Developmental Biology Program

University of California, Riverside, August 2014

Dr. Andy Obenaus, Co-Chairperson

Dr. Monica J. Carson, Co-Chairperson

Traumatic brain injury (TBI) is an increasing public health concern, accounting for approximately 30% of injury related deaths. Clinical and experimental studies have demonstrated that the brain remains vulnerable following TBI and subsequent injuries may worsen tissue damage. Following injury, microglia, the brain macrophage, have demonstrated both cytotoxic and cytoprotective functions. However, the role of microglial activation in injury progression and resolution is not understood. This dissertation examines the progression of tissue damage following repeated mild TBI (rmTBI) and investigates whether inflammatory status at the time of a moderate-to-severe injury influences outcome.

Using a novel rmTBI model, we found acute 2-fold increases in tissue damage on T2-weighted magnetic resonance imaging (MRI) when injuries were induced 7 (7D), but not 3 days (3D) apart. Furthermore, injuries 7D apart resulted in 2-fold more blood deposition, while those 3D apart showed more edema. Though sub-acute grey matter pathology was transient. We therefore assessed white matter, not directly underneath the impact, using diffusion tensor MRI and electron microscopy at sub-acute (14-day) and long-term (60-day) timepoints. At sub-acute times, we found that rmTBI 7D apart resulted in white matter changes localized to regions immediately adjacent to the impact sites. However, long-term assessment revealed that changes in white matter integrity within rmTBI animals became widespread.

The effect of inflammatory status on TBI induced hemispheric swelling and lesion pathology was tested 7D post injury. We compared MRI pathology with inflammatory molecule expression from naïve, wildtype (TBI; no pre-treatment), wildtype with LPS-challenge 24-hrs before TBI and TREM2KO animals. MRI showed an 80% reduction in hemispheric swelling within TREM2KO and LPS-challenged animals compared to wildtype. Reduced swelling coincided with a 2-fold increase in microglial expression of inflammatory genes compared to naïve animals. However, LPS-challenged and TREM2KO mice showed a reduced inflammatory response from wildtype. Furthermore, comparison of TREM2KO microglia with cortical tissue revealed an opposing number of expressed genes.

Overall, these studies demonstrate that (1) brain vulnerability is dependent on the time interval between and location of injuries, (2) rmTBI results in early white matter disruption that progresses long-term and (3) reduced swelling occurs during limited microglial activation.

    Cover page: Neuropathology Following Repeated Traumatic Brain Injury and the Influence of Inflammatory Status on Injury Outcome
    • Article
    • Peer Reviewed
    UC Irvine Previously Published Works (2014)
    Currently, there is a lack of computational methods for the evaluation of mild traumatic brain injury (mTBI) from magnetic resonance imaging (MRI). Further, the development of automated analyses has been hindered by the subtle nature of mTBI abnormalities, which appear as low contrast MR regions. This paper proposes an approach that is able to detect mTBI lesions by combining both the high-level context and low-level visual information. The contextual model estimates the progression of the disease using subject information, such as the time since injury and the knowledge about the location of mTBI. The visual model utilizes texture features in MRI along with a probabilistic support vector machine to maximize the discrimination in unimodal MR images. These two models are fused to obtain a final estimate of the locations of the mTBI lesion. The models are tested using a novel rodent model of repeated mTBI dataset. The experimental results demonstrate that the fusion of both contextual and visual textural features outperforms other state-of-the-art approaches. Clinically, our approach has the potential to benefit both clinicians by speeding diagnosis and patients by improving clinical care.
      Cover page: Visual and Contextual Modeling for the Detection of Repeated Mild Traumatic Brain Injury
      • Article
      • Peer Reviewed
      UC Irvine Previously Published Works (2012)
      Mild traumatic brain injury (mTBI) has become an increasing public health concern as subsequent injuries can exacerbate existing neuropathology and result in neurological deficits. This study investigated the temporal development of cortical lesions using magnetic resonance imaging (MRI) to assess two mTBIs delivered to opposite cortical hemispheres. The controlled cortical impact model was used to produce an initial mTBI on the right cortex followed by a second injury induced on the left cortex at 3 (rmTBI 3d) or 7 (rmTBI 7d) days later. Histogram analysis was combined with a novel semi-automated computational approach to perform a voxel-wise examination of extravascular blood and edema volumes within the lesion. Examination of lesion volume 1d post last injury revealed increased tissue abnormalities within rmTBI 7d animals compared to other groups, particularly at the site of the second impact. Histogram analysis of lesion T2 values suggested increased edematous tissue within the rmTBI 3d group and elevated blood deposition in the rm TBI 7d animals. Further quantification of lesion composition for blood and edema containing voxels supported our histogram findings, with increased edema at the site of second impact in rmTBI 3d animals and elevated blood deposition in the rmTBI 7d group at the site of the first injury. Histological measurements revealed spatial overlap of regions containing blood deposition and microglial activation within the cortices of all animals. In conclusion, our findings suggest that there is a window of tissue vulnerability where a second distant mTBI, induced 7d after an initial injury, exacerbates tissue abnormalities consistent with hemorrhagic progression.
        Cover page: Computational analysis reveals increased blood deposition following repeated mild traumatic brain injury
        • Article
        • Peer Reviewed
        UC Irvine Previously Published Works (2014)
        Mild traumatic brain injury (mTBI) is an increasing public health concern as repetitive injuries can exacerbate existing neuropathology and result in increased neurologic deficits. In contrast to other models of repeated mTBI (rmTBI), our study focused on long-term white-matter abnormalities after bilateral mTBIs induced 7 days apart. A controlled cortical impact (CCI) was used to induce an initial mTBI to the right cortex of Single and rmTBI Sprague Dawley rats, followed by a second injury to the left cortex of rmTBI animals. Shams received only a craniectomy. Ex vivo diffusion tensor imaging (DTI), transmission electron microscopy (TEM), and histology were performed on the anterior corpus callosum at 60 days after injury. The rmTBI animals showed a significant bilateral increase in radial diffusivity (myelin), while only modest changes in axial diffusivity (axonal) were seen between the groups. Further, the rmTBI group showed an increased g-ratio and axon caliber in addition to myelin sheath abnormalities using TEM. Our DTI results indicate ongoing myelin changes, while the TEM data show continuing axonal changes at 60 days after rmTBI. These data suggest that bilateral rmTBI induced 7 days apart leads to progressive alterations in white matter that are not observed after a single mTBI.
          Cover page: Repeated Mild Traumatic Brain Injury Results in Long-Term White-Matter Disruption
          • Article
          • Peer Reviewed
          UC Irvine Previously Published Works (2018)
          Recent data suggest that repairing the cerebral vasculature after traumatic brain injury (TBI) may help to improve functional recovery. The Wnt/β-catenin signaling pathway promotes blood vessel formation during vascular development, but its role in vascular repair after TBI remains elusive. In this study, we examined how the cerebral vasculature responds to TBI and the role of Wnt/β-catenin signaling in vascular repair. We induced a moderate controlled cortical impact in adult mice and performed vessel painting to visualize the vascular alterations in the brain. Brain tissue around the injury site was assessed for β-catenin and vascular markers. A Wnt transgenic mouse line was utilized to evaluate Wnt gene expression. We report that TBI results in vascular loss followed by increases in vascular structure at seven days post injury (dpi). Immature, non-perfusing vessels were evident in the tissue around the injury site. β-catenin protein expression was significantly reduced in the injury site at 7 dpi. However, there was an increase in β-catenin expression in perilesional vessels at 1 and 7 dpi. Similarly, we found increased number of Wnt-GFP-positive vessels after TBI. Our findings suggest that Wnt/β-catenin expression contributes to the vascular repair process after TBI.
            Cover page: Up-regulation of Wnt/β-catenin expression is accompanied with vascular repair after traumatic brain injury
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