The Contribution of Fibrinogen to Inflammation and Neuronal Density in Human Traumatic Brain Injury

Traumatic brain injury (TBI) is a leading cause of death and disability, particularly among the young. Despite this, no disease-specific treatments exist. Recently, blood-brain barrier disruption and parenchymal fibrinogen deposition have been reported in acute traumatic brain injury and in long-term survival; however, their contribution to the neuropathology of TBI remains unknown. The presence of fibrinogena well-documented activator of microglia/macrophagesmay be associated with neuroinflammation, and neuronal/axonal injury. To test this hypothesis, cases of human TBI with survival times ranging from 12h to 13 years (survival <2 months, n=15; survival >1 year, n=6) were compared with uninjured controls (n=15). Tissue was selected from the frontal lobe, temporal lobe, corpus callosum, cingulate gyrus, and brainstem, and the extent of plasma protein (fibrinogen and immunoglobulin G [IgG]) deposition, microglial/macrophage activation (CD68 and ionized calcium-binding adapter molecule 1 [Iba-1] immunoreactivity), neuronal density, and axonal transport impairment (beta-amyloid precursor protein [beta APP] immunoreactivity) were assessed. Quantitative analysis revealed a significant increase in parenchymal fibrinogen and IgG deposition following acute TBI compared with long-term survival and control. Fibrinogen, but not IgG, was associated with microglial/macrophage activation and a significant reduction in neuronal density. Perivascular fibrinogen deposition also was associated with microglial/macrophage clustering and accrual of beta APP in axonal spheroids, albeit rarely. These findings mandate the future exploration of causal relationships between fibrinogen deposition, microglia/macrophage activation, and potential neuronal loss in acute TBI.