Traumatic brain injury (TBI) is a significant health concern affecting millions of individuals worldwide. Within the United States (U.S.), the Centers for Disease Control and Prevention report that 1.7 million individuals sustain a TBI annually, and 5.3 million individuals live with TBI-related disabilities. Consequently, TBI has been described as a “silent epidemic” for multiple reasons. First, epidemiological reports likely reflect an underestimation of incidence, particularly for milder forms of brain injury. Second, without an accurate incidence rate, it is impossible to identify the true public health and economic consequence of brain injury, including caregiver burden. Third, survivors of mild to moderate brain injury often display delayed and task-specific impairments making chronic, time-dependent reporting essential in documenting long-term effects of TBI. Finally, many post-injury problems are not visible, including cognitive and emotional impairment. Together, these points emphasize the many challenges that we face in attempting to improve recovery following TBI.
Inflammation following TBI is a complex and dynamic response of both the central and peripheral nervous systems, which is influenced by age, sex, injury location and severity, secondary injury cascades, and genetics. Inflammation occurs after all brain injuries and is considered to be an integral mediator of post-injury outcome. Excessive or chronic neuroinflammation is linked to progressive changes, including atrophy, neuronal loss, and axonal degeneration. TBI is not an isolated event within the inflammatory milieu. Accumulating data indicate that pre- and post-injury immune challenges may influence the immune response to brain injury and post-injury pathology and behavioral recovery.
Alzheimer's disease is a neurodegenerative disease that progresses from mild cognitive impairment to severe dementia over time and is characterized by key neuropathological impairments including extracellular accumulation of beta-amyloid (Aβ) protein in senile plaques and intracellular aggregation of MAPT in neurofibrillary tangles (NFTs). Increasing evidence implicates TBI as a risk factor for AD. Our research aims to define molecular mechanisms linking TBI to development of AD. We hypothesize that post-TBI inflammation is critical in this relationship. In addition, our data suggests that the presence of accumulating Aβ and MAPT alter the neuroimmune response to TBI.
The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease
Kokiko-Cochran & Godbout, 2018 Frontiers in Immunology, 9:672
Figure 1. Macrophage-related response to brain injury varies in response to previous, coincident, and subsequent immune stressors. Normal, age-related health burden is depicted with a solid black line and grey shading. A) TBI in the presence of pathological tau (solid blue line) results in an enhanced macrophage response to TBI that remains elevated at chronic post-injury time points. TBI in the presence of Aβ (solid red line) results in an acute blunted macrophage response that increases at chronic post-injury time points. TBI occurring in the absence of tau or Aβ (dotted black line) results in acute macrophage related neuroinflammation that subsides over time. B) Post-injury peripheral immune challenge (solid blue line) causes a hyper-active macrophage response correlating with behavioral dysfunction. Repetitive post-injury immune challenge (dotted blue line), similar to what is observed in repetitive TBI, increases macrophage-related neuroinflammation and correlates with the advanced neuropathology. Pre-injury peripheral immune challenge at sub-threshold levels (red line) attenuates the post-injury macrophage related inflammatory response to TBI. Single TBI (dotted black line) results in acute macrophage related neuroinflammation that subsides over time. Over time, macrophage related neuroinflammation increases with normal health burden.
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