Development of In Vivo Biomarkers for Progressive Tau Pathology after Traumatic Brain Injury

Athletes in contact sports who have sustained multiple concussive traumatic brain injuries are at high risk for delayed, progressive neurological and psychiatric deterioration. This syndrome is termed chronic traumatic encephalopathy (CTE), and is also known as dementia pugilistica or punch drunk syndrome. US military personnel and others who have sustained multiple concussive traumatic brain injuries may also be at risk for this condition. Currently, there are no methods to identify progressive tau pathology in living humans. Hypothesis: Aggregated forms of hyperphosphorylated tau protein formed acutely in the setting of traumatic brain injury can seed further aggregation of intracellular tau in nearby cells, leading to delayed propagation of tau pathology and neurodegeneration. Objective: To develop standardized, high-throughput blood and cerebrospinal fluid assays for aggregated forms of tau responsible for propagation of tau pathology after traumatic brain injury. Progress to date: The major year 1 goal for the Brody lab was to determine which mouse model of experimental TBI and which human tau transgenic mouse line would be most useful for these experiments. We have determined that controlled cortical impact in 3xTg-AD mice will be optimal. The major year 1 goal for the Diamond lab was to refine and standardize the tau propagation assay. We have increased the sensitivity of the assay by nearly 1000 fold using a flow-cytometry based assay and established quantitative standard curves.
The original document contains color images.