Mechanism and Biomarkers of Degenerative Conditions After Repeated Mild Traumatic Brain Injury (rmTBI)

Background and Significance: Clinical observations and epidemiological studies have shown that individuals with traumatic brain injury (TBI) especially with repeated injuries have an increased risk to develop neurodegenerative disorders such as chronic traumatic encephalopathy (CTE). CTE is a progressive neurodegenerative disease that impairs memory, executive function, and attention, causing motoric imbalance, depression, anger, and suicide. Importantly, recent reports have shown that soldiers who suffered brain injuries from explosive blast may also develop CTE. Based on the large numbers of soldiers who have been exposed to blast, many of them repeatedly, the likelihood of large numbers of CTE cases in the coming years among military personnel is very high. The diagnosis of CTE is currently based on neurobehavioral tests, but cannot be confirmed until post-mortem neuropathology.

The exact pathomechanism of CTE is not known, and currently there is no early diagnosis and no specific treatment available. In vivo markers that can identify pathomechanisms, help monitor the progression of the disease, and identify potential targets to block or slow down the development of CTE would be of substantial value.

Hypothesis and Objective: We hypothesize that by using a combination of proteomics analysis of blood and brain regions, neurobehavioral monitoring, DTI, and neuropathology of the rodent model of repeated mild TBI (rmTBI) in a longitudinal study will help to identify the mechanism of CTE. Our objective is to establish blood-based proteomics to identify post-injury mechanisms that lead to CTE and to help identify potential targets for therapy.

Rationale: Determining the temporal pattern of changes in clinically relevant outcome measures, such as neurobehavior, MRI, serum biomarkers, in a high-fidelity animal model of CTE will identify the underlying mechanisms in an objective manner and help identify soldiers with increased vulnerability to additional exposures.

Research Area: Our proposed research directly addresses the research area of 'Identify and Characterize Mechanisms of Traumatic Brain Injury-Related Neurodegenerative Diseases.' We propose to identify the mechanism of CTE using our well-characterized animal model of mild, repeated blast-induced TBI. TBI, especially repeated mild injuries, have been identified as a main risk factor for developing CTE. CTE is emerging as a critical health issue both in the military and in the civilian population. We propose to employ a combination of highly sensitive and specific outcome measures including neurobehavioral assessments, proteomics (to monitor changes in protein biomarkers in serum and in specific brain regions) as well as DTI and histopathology. Importantly, our experimental approach mirrors and builds on and also extends currently used clinical assessments of TBI and CTE. Finally, it adds critically important novel data that can be easily translated into clinical practice.