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

Objective: The goal of this project is to develop blood and spinal fluid tests to diagnose a condition called chronic traumatic encephalopathy. These tests will be developed in mice for future use in people.

Rationale: Chronic traumatic encephalopathy can cause brain function to worsen over time in people who have had several concussions. At present, this condition cannot be diagnosed accurately during life. Patients may have progressively worsening memory loss, changes in personality, emotional imbalances, poor decision making, impulsive behavior, slurred speech, slowness and stiffness of movement, and other problems. However, common conditions like post-traumatic stress disorder, depression, drug and alcohol abuse, Alzheimer's disease, Parkinson's disease, and other types of dementia can cause many of the same symptoms, so symptoms alone are not enough to tell for sure.

Chronic traumatic encephalopathy has attracted substantial public attention due to cases in former National Football League players like Andre Waters, boxers like Sugar Ray Robinson, and hockey players like Derek Boogaard. Muhammad Ali may have chronic traumatic encephalopathy, but he is still alive so his condition not known for sure. Importantly, cases of military service-related chronic traumatic encephalopathy have been reported recently. One was a US Marine exposed to multiple blast-related injuries in Iraq who then deteriorated in terms of behavior and emotional control. This led to his suicide at age 27. At autopsy, the diagnosis of chronic traumatic encephalopathy was made. There are large numbers of military personnel who have sustained multiple brain injuries during the wars in Iraq and Afghanistan. Because of the time lag ranging from years to decades between concussions and deterioration, there may be many more cases in US military personnel recognized in the coming years.

At autopsy, the hallmark of chronic traumatic encephalopathy is clumping of a protein called tau inside of nerve cells in the brain. Our best idea about what causes chronic traumatic encephalopathy is that injury to the brain causes a small amount of tau clumping right away, and then the clumped tau inside of cells causes more clumping of tau in nearby cells. In this way, the tau clumping slowly makes its way through the brain, causing more and more brain regions to function poorly. We think that measuring tau clumping activity in the blood and spinal fluid could be a useful way to test for chronic traumatic encephalopathy.

Ultimate Applicability: Our vision is that anyone who has had three or more concussions would be tested for tau clumping activity. If the tests are positive, they would be offered a chance to take an investigational new treatment designed to prevent chronic traumatic encephalopathy. We and others have good candidates for new treatments that block tau clumping or prevent it from spreading, but we do not have a test that would tell us who to try them on.

What types of patients will it help, and how will it help them? If we had a blood or spinal fluid test for chronic traumatic encephalopathy, this could help US military personnel, athletes, and others with multiple concussions: (1) We could determine the cause of symptoms with greater certainty, ruling in or ruling out effects of trauma. (2) We could have a chance to test new treatments in the right people, ideally before symptoms become severe. (3) We could repeat the test over time to help tell whether the new treatments are affecting the disease.

What are the potential clinical applications, benefits, and risks? The applications include diagnostic testing, selecting good candidates to test new treatments, and following the effects of these treatments over time. The benefits would be that this could improve the accuracy of diagnoses and dramatically accelerate the time required to develop an effective treatment for chronic traumatic encephalopathy. There are no immediate risks of this proposed study involving mice, but ultimately testing in people would involve the risks of drawing blood, sampling spinal fluid, and possibly toxic side effects from new treatments. There could also be psychological and economic risks of false positives or false negatives.

What is the projected time it may take to achieve a patient-related outcome? This project using mice will take 4 years to complete. If it is successful, the next step will be to test blood and spinal fluid from people with multiple concussions, including both former athletes and military personnel over the subsequent 2-3 years. We could then start therapeutic trials in 6-7 years and hope to have one or more effective therapeutic 11-12 years from now.

Likely contributions of this study to advancing the field of TBI research: For this project, we will determine: (1) Whether tau clumping activity in the blood and spinal fluid can predict which injured mice will get tau clumping in the brain. T .......