Neuropathology of Chronic Traumatic Encephalopathy (CTE) and Late Effects of Traumatic Brain Injury (TBI): Toward In-Vivo Diagnostics

The Brain Injury Research Center of Mount Sinai (BIRC-MS) is the lead center in this four-year, $6 million grant, funded in December 2013 by the Foundation for the National Institutes of Health and the National Institute of Neurological Disorders and Stroke. Collaborating sites in the study include the University of Washington, Group Health Research Institute, Oregon Health Sciences University, Martinos Imaging Center of Harvard/Massachusetts General Hospital, and the Uniformed Services University of the Health Sciences. The research agenda is multi-disciplinary in its approach and includes participants from neuropsychology, neuropathology, neuroradiology, geriatrics, neurology, biostatistics, and epidemiology.

While the media has paid much attention to CTE (chronic traumatic encephalopathy) in football players and boxers, not much is known about this disease. The current hypothesis is that repeated brain injuries trigger the development of CTE. However, it is not known why CTE develops in only a small number of athletes who have experienced many blows to the head over many years. And, since the number of people in the community who have experienced one or more brain injuries is far greater than the number of elite athletes who have experienced repetitive injuries, it is important to understand whether CTE can develop after these more common types of brain injury.

Our study’s general aim is to expand our understanding, in non-athletes, of CTE and other late effects of TBI. As the title for the project (“Toward In-Vivo Diagnostics”) implies, we hope to find a marker that allows diagnosis during life, when such knowledge could provide a basis for the development of better treatments.

CTE is thought to be a tauopathy, i.e., a neurodegenerative disease associated with the pathological aggregation of tau protein in the brain. There are many things we don’t know about CTE, such as the incidence and prevalence of the disease at a population level, the risk or protective factors for the disease, and the causal role of tauopathy on associated symptoms. Complicating the diagnosis of CTE is the fact that CTE, TBI, and Alzheimer’s disease have overlapping clinical features and postmortem pathologies. Thus, pre-mortem diagnosis of CTE is currently impossible. Further, the neuropathological consequences of a single mild TBI or even a moderate-severe TBI and their relationship with CTE and known dementias are unclear. Finally, our knowledge of CTE is limited by the fact that it has been described only in convenience samples of athletes with repetitive head trauma.

This project will leverage extensive resources from an ongoing study of brain aging; the study is a population-based prospective cohort study (Adult Changes in Thought [ACT], based at the University of Washington and Group Health Research Institute). The ACT study includes medical, behavioral, and genetic characterization of a cohort, 20 percent of whom have a history of mild-moderate TBI. In addition, a state-of-the-art neuropathology workup is undertaken upon death. An additional cohort of individuals with TBI will come from the BIRC-MS. All participants in the proposed study will undergo a uniform neurobehavioral assessment (chosen to maximize correspondence with existing large-scale TBI and dementia studies), an MRI scan, and genomic analysis. Those individuals who die during the course of the study and who consent to brain donation will undergo ex-vivo neuroimaging and extensive neuropathological exam using techniques designed to quantify tau and Aβ proteins.  

This project represents the most systematic and scientifically rigorous effort to date to develop a more complete understanding of the long-term clinical and neuropathological sequelae of single and multiple TBI. Further, only by examining postmortem pathology in a sample of individuals with varying levels of TBI exposure, who were well characterized prior to death, can postmortem pathology facilitate identification of in-vivo biomarkers that can act as diagnostic tools. We at the BIRC-MS are grateful to our research participants, whose contributions to our work allow us to advance science and improve clinical care for survivors of TBI.

Dr. Wayne Gordon is the Principal Investigator on this grant. Other principals at the BIRC-MS include Drs. Kristen Dams-O’Connor, Cheuk Tang, and Vahram Haroutunian. Principal Investigators at the collaborating sites include: Drs. Paul Crane, Eric Larson, Daniel Perl, Christopher Kroenke, and Bruce Fischl.