Abstract
Although concussion is now recognized as a major health issue, its non-lethal nature has limited characterization of the underlying pathophysiology. In particular, potential neuropathological changes have typically been inferred from non-invasive techniques or post-mortem examinations of severe traumatic brain injury (TBI). Here, we used a swine model of head rotational acceleration based on human concussion to examine blood–brain barrier (BBB) integrity after injury in association with diffuse axonal injury and glial responses. We then determined the potential clinical relevance of the swine concussion findings through comparisons with pathological changes in human severe TBI, where post-mortem examinations are possible. At 6–72 h post-injury in swine, we observed multifocal disruption of the BBB, demonstrated by extravasation of serum proteins, fibrinogen and immunoglobulin-G, in the absence of hemorrhage or other focal pathology. BBB disruption was observed in a stereotyped distribution consistent with biomechanical insult. Specifically, extravasated serum proteins were frequently observed at interfaces between regions of tissue with differing material properties, including the gray–white boundary, periventricular and subpial regions. In addition, there was substantial overlap of BBB disruption with regions of axonal pathology in the white matter. Acute perivascular cellular uptake of blood-borne proteins was observed to be prominent in astrocytes (GFAP-positive) and neurons (MAP-2-positive), but not microglia (IBA1-positive). Parallel examination of human severe TBI revealed similar patterns of serum extravasation and glial uptake of serum proteins, but to a much greater extent than in the swine model, attributed to the higher injury severity. These data suggest that BBB disruption represents a new and important pathological feature of concussion.
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The authors thank Kathryn Wofford for assistant with kinematic measurements. Research reported in this publication was supported by the Department of Defense Grant W81XWH-13-1-0052, and the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under award numbers R01NS092398, R01NS094003 and R01NS038104, and the Department of Veterans Affairs under Merit Review number I01RX001097.
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401_2018_1824_MOESM1_ESM.tif
IgG Extravasation and Cellular Uptake Following Experimental Concussion. IgG extravasation was observed in a similar pattern and distribution to FBG shown at (a) the inferior aspect of the lateral ventricle and (b) a penetrating vessel at the cortical surface. (c) Cellular uptake of IgG was observed including cells with the morphological appearance of glia at the depth of a cortical sulcus and (d) cortical neurons. (e) Astrocytic (arrowhead) immunoreactivity for IgG was confirmed using triple labeling immunofluorescence with markers IgG (green), IBA-1 (red) and GFAP (purple). Note a cell with the morphological appearance of a neuron with no co-localization with glial marker is also shown (arrow). (f) Neuronal uptake was further confirmed with markers IgG (green) and MAP-2 (red) demonstrating co-localization. (g-i) Similar patterns of IgG (green) and FBG (red) extravasation were observed in double immunofluorescent labeling studies. Scale bars: (a-d) 25 μm, (e-i) 20μm (TIFF 10078 kb)
401_2018_1824_MOESM2_ESM.tif
Representative Examples of Semiquantitative Scoring for FBG Extravasation in Human Tissue. Representative examples (a) Minimal (score 1), (b) Moderate (score 2) and (c) Extensive (score 3) FBG extravasation in human postmortem material including the entire hemi-coronal section of the parasagittal cortex at the level of the mid-thalamus to include the cingulate gyrus and corpus callosum. Scale bars (a-c) 1mm (TIFF 2023 kb)
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Johnson, V.E., Weber, M.T., Xiao, R. et al. Mechanical disruption of the blood–brain barrier following experimental concussion. Acta Neuropathol 135, 711–726 (2018). https://doi.org/10.1007/s00401-018-1824-0
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DOI: https://doi.org/10.1007/s00401-018-1824-0