Delayed Increases in Microvascular Pathology after Experimental Traumatic Brain Injury Are Associated with Prolonged Inflammation, Blood–Brain Barrier Disruption, and Progressive White Matter Damage

Abstract

Traumatic brain injury (TBI) is a significant risk factor for chronic traumatic encephalopathy (CTE), Alzheimer's disease (AD), and Parkinson's disease (PD). Cerebral microbleeds, focal inflammation, and white matter damage are associated with many neurological and neurodegenerative disorders including CTE, AD, PD, vascular dementia, stroke, and TBI. This study evaluates microvascular abnormalities observed at acute and chronic stages following TBI in rats, and examines pathological processes associated with these abnormalities. TBI in adult rats was induced by controlled cortical impact (CCI) of two magnitudes. Brain pathology was assessed in white matter of the corpus callosum for 24 h to 3 months following injury using immunohistochemistry (IHC). TBI resulted in focal microbleeds that were related to the magnitude of injury. At the lower magnitude of injury, microbleeds gradually increased over the 3 month duration of the study. IHC revealed TBI-induced focal abnormalities including blood-brain barrier (BBB) damage (IgG), endothelial damage (intercellular adhesion molecule 1 [ICAM-1]), activation of reactive microglia (ionized calcium binding adaptor molecule 1 [Iba1]), gliosis (glial fibrillary acidic protein [GFAP]) and macrophage-mediated inflammation (cluster of differentiation 68 [CD68]), all showing different temporal profiles. At chronic stages (up to 3 months), apparent myelin loss (Luxol fast blue) and scattered deposition of microbleeds were observed. Microbleeds were surrounded by glial scars and co-localized with CD68 and IgG puncta stainings, suggesting that localized BBB breakdown and inflammation were associated with vascular damage. Our results indicate that evolving white matter degeneration following experimental TBI is associated with significantly delayed microvascular damage and focal microbleeds that are temporally and regionally associated with development of punctate BBB breakdown and progressive inflammatory responses. Increased understanding of mechanisms underlying delayed microvascular damage following TBI could provide novel insights into chronic pathological responses to TBI and potential common mechanisms underlying TBI and neurodegenerative diseases.

Temporal and Spatial Changes in the Pattern of Iba1 and CD68 Staining in the Rat Brain Following Severe Traumatic Brain Injury

“…Future studies are needed in order to test the connection between methamphetamine's effect on Iba1 + cells and neurogenesis within the dentate gyrus. Our data supports a recent finding by Glushakova et al [38] that Iba1 and CD68 immunoreactive cells increase in white matter tracts, specifically the periventricular white matter, up to 3 months post-TBI, presumably accompanying the expansion of microbleeds reported in their study. In support of this idea, we observed autofluorescent erythrocytes 48 hours after injury within the periventricular white matter at similar locations where the greatest Iba1 labeling was seen at 2 weeks post TBI.…”

Blood-Brain Barrier Disruption Is an Early Event That May Persist for Many Years After Traumatic Brain Injury in Humans

“…deposition around callosal blood vessels ipsilateral to controlled cortical impact in mice at 3 months survival from injury (49). Consistent with observations in animal models, evidence of acute BBB permeability following severe TBI in humans is provided by reports of elevations in CSF to serum albumin quotient (50)(51)(52)(53) and in serum S100² levels (50-53) after injury.…”

Erythropoietin regulates immune/inflammatory reaction and improves neurological function outcomes in traumatic brain injury

“…The microglia, inherent immune‐related cell in brain, is also rapidly activated (Cunningham et al., 2014; Glushakova, Johnson, & Hayes, 2014). Both of these partially contribute to brain edema and cognitive deficits after TBI (Xu et al., 2012).…”