Evidence suggests that appropriate rehabilitative interventions can reduce functional impairment after TBI [52
]. In order to demonstrate the efficacy of clinical interventions, research must identify the biological, clinical, and neurological indices that are sensitive to the detection of functional impairments after TBI [55
]. We explored the feasibility of identifying plasma protein species that might be useful as clinically accessible surrogate biological indices of TBI. Our antibody array studies identified three candidate TBI protein biomarkers: MCP-1, present at higher levels, as well as IGFBP-3 and EGFR, present at lower levels, in plasma of chronic TBI cases. Moreover, we demonstrated that a three-biomarker panel using all three biomarkers provides a potential criterion for segregating TBI and control cases with 85% accuracy, 91% sensitivity, and 78% specificity. Our evidence tentatively implicates the value of this three-biomarker panel as a biological surrogate for improved TBI detection and more sensitive outcome measures for clinical trials.
Consistent with previous research, our findings suggest that MCP-1 plays a role in post-TBI clinical impairments. Elevated expression of MCP-1 in the brain has been observed following TBI [47
] and in response to neurodegenerative disorders [56
]. Moreover, MCP-1 is known to promote inflammatory responses and processes leading to degradation of the axonal myelin sheath [64
]. Using an independent ELISA assay, we confirmed elevated plasma MCP-1 concentrations in TBI cases from both civilian and veteran cohorts.
TBI cases in both the civilian and veteran study cohort were characterized by a long interval between injury and participation in the study (mean ± SD interval of 13.2 ± 12.7 years and 3.9 ± 1.4 years for the civilian and the veteran cohorts, respectively) ( and ). Thus, upregulation of plasma MCP-1 contents among TBI cases is not an acute post-injury response, but more likely reflects a long-term consequence of TBI.
Our observation that plasma MCP-1 contents correlated with the severity of head injury but not measures of TBI symptoms suggests that plasma MCP-1 is a marker of injury per se
rather than a marker of a specific injury-related impairments. Recent reports from our group [68
] and from others [69
] have demonstrated reduced FA, implicating impaired axonal pathways in the brains of TBI patients. In our present study, we found a significant correlation between elevated plasma MCP-1 contents and increasing white matter damage in the frontal cortex, as assessed by DTI FA. Our evidence suggests that elevated plasma MCP-1 concentration following TBI may provide a “window into the brain” that is associated with changes in axonal integrity in the brain, particularly in the frontal cortex.
Both TBI and MCI subjects may be at elevated risk for AD dementia. We found significantly elevated MCP-1 expression in the postmortem frontal cortex of MCI cases, suggesting that induction of MCP-1 following TBI might be a potential “predisposition” factor that imposes higher risk for AD or accelerated aging. As we schematically illustrated in , we propose that TBI resulting from either mechanical injuries or blast injuries results in a cascade of biological responses that lead to aberrant biochemical, structural, and/or functional changes in the brain that remain many years post-injury. While mechanisms underlying these pathological modifications are not well defined, it is possible that these changes in the brain may contribute to a chronic clinical course of TBI and/or increased risk for neurodegenerative disorders. Our data presented here suggest that chronic elevation of MCP-1 following TBI may contribute to demyelination processes that, over time, may reduce resilience of the brain to subsequent neurodegenerative insults leading to AD or other neurodegenerative disorders.
Fig. 6 Proposed mechanisms by which TBI may increase risk for Alzheimer’s disease and other neurological disorders. Schematic represents an overview of a proposed model by which TBI exposure may mechanistically increase subsequent risk for Alzheimer’s (more ...)