Traumatic brain injury (TBI) is an all too common cause of morbidity and mortality, an event that is especially tragic in young people with many years of life ahead that can be affected. A great deal of research is being conducted in areas such as brain injury prevention, neurotrauma monitoring, neuroprotective agents, and rehabilitation. Moreover, the molecular underpinnings of cell death following brain trauma continue to be elucidated. Although much of the focus of this research is on the acute time period surrounding an injury, recent work is concerning for the fact that processes harming the brain after a trauma may continue to be deleterious even years after the initial insult. Specifically, in a recent report by Johnson et al. inflammation and white matter degeneration were detected at increased rates vs controls up to 2 decades after only a single brain injury (Johnson VE, Stewart JE, Begbie FD, et al. Inflammation and white matter degeneration persist for years after a single traumatic brain injury. Brain. 2013;136(1):28-42).
It has been observed for some time that survivors of TBI are particularly prone to dementia. Indeed, Alzheimer-like histopathology can be observed in the brains of these individuals. Despite an understanding that chronic inflammation and white matter injury have a role in diseases like Alzheimer disease, very little is known about its role in propagating the events of TBI after the acute injury. To study these phenomena, Johnson et al evaluated brain tissue samples from TBI survivors and age-matched controls. First, immunohistochemistry for evidence of activated microglia, a hallmark of inflammation in the brain, was performed. Whereas controls and acute injuries were similar in demonstrating a relative lack of microglial activation, subacute (2 weeks to 9 months) and long-term (>1 year) survivors of TBI showed evidence of increased microglial density and activation. Specifically, in the subacute and long-term survivors, this immunohistochemistry revealed extensive regions of activated ameboid microglia at significantly higher proportions to quiescent microglia. Next, specimens were subjected to immunohistochemistry for amyloid precursor protein to evaluate for axonal pathology. As expected, axonal pathology was most abundant in the acute phase after injury. Although this diminished over time, there remained a significantly increased abundance of amyloid precursor protein detected at the subacute and long-term times vs controls. This observation suggested that ongoing axonal damage is a feature the persistent effects of TBI.
Interestingly, these investigators also identified a distinct distribution and morphological pattern of axonal injury after the acute phase of injury. Specifically, axonal bulbs had a unique granular morphology when compared to the acute period or with ischemia-associated injury. This appeared consistent from 3 months all the way to 18 years after a single trauma. To inspect the integrity of the white matter, luxol fast blue staining was performed. This revealed diminished overall staining for myelin in TBI vs controls as well as evidence of phagocytosis of myelin fragments by microglia. Finally, Johnson et al measured the thickness of the corpus callosum after injury. With survival greater than 1 year, the thickness of the corpus callosum with meaningfully decreased vs controls and acutely injured individuals. Taken together, these observations in the long-term phase after TBI indicate that white matter disruption similar to that seen in neurodegenerative disorders continues to be a detectable phenomenon long after the initial injury.
These findings of inflammation and white matter degeneration have several important implications to both clinicians and scientists addressing TBI. First, it indicates that the pathological events of TBI can continue for many years after the initial injury. This suggests that the active treatment of TBI may need to be life-long. It also highlights another series of molecular pathways that can serve as a target of treatment. For example, therapies that limit microglial activation following TBI could limit white matter damage and prevent cognitive decline. Finally, the similarities between neurodegenerative diseases and the chronic phase of trauma could allow for an improved study of these pathologies and facilitate crosstalk between investigators in both fields. Although our understanding of the role of inflammation in TBI is still primitive, this work serves to highlight the fact that TBI is a chronic disease and decreasing the brain’s intrinsic inflammatory mechanisms could limit long-term sequalae and preserve neurological function.