Understanding the Neuroanatomical Abnormalities of Repetitive Head Impacts - PROJECT SUMMARY Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease defined by the widespread accumulation of hyperphosphorylated tau (p-tau) in perivascular spaces and by regional brain atrophy. Athletes engaged in contact or collision sports, like American football players, are at a heightened risk for developing neurological disorders including CTE given their extensive exposure to repetitive head impacts (RHI). The neuropathology of CTE at postmortem is well established, however, there are currently no biomarkers available to diagnose CTE during life. There is only a classification of clinical symptoms associated with presumed CTE, called Traumatic Encephalopathy Syndrome (TES), in which the diagnosis is solely based on exposure to RHI and core clinical features of cognitive impairment and/or neurobehavioral dysregulation. Therefore, there is an immediate need to develop precise methods that can either support the clinical diagnosis of TES or detect and diagnose CTE during an individual's lifetime, enabling the development of suitable treatments and interventions. Thus, the primary objective of the current proposal is to study the long-term consequences of RHI in former athletes, particularly, former American football players. We will leverage data from the NINDS-funded Diagnostics, Imaging, And Genetics Network for the Objective Study and Evaluation of CTE (DIAGNOSE CTE) Research Project (U01NS093334), which includes behavioral, neuroimaging, and fluid biomarker data from 180 former American football players (60 former college players, and 120 former professional players) and a control group of 60 unexposed asymptomatic controls who are age-matched and have no history of RHI exposure or traumatic brain injury. We will utilize structural magnetic resonance imaging (MRI) to investigate neuroanatomical changes linked to neuropathological alterations observed in CTE at post-mortem. This investigation includes examining morphological changes in the sulci, ventricles, and gray/white matter. Furthermore, we will investigate aspects of the brain's waste clearance pathway by identifying changes and associations in structures important for this function such as the ventricles, choroid plexus, and perivascular spaces. This investigation provides insights into the accumulation of p-tau in perivascular spaces, a hallmark of CTE typically reported in post- mortem cases. In our design, we will include factors likely to contribute to worse outcomes within our neuroimaging measures by attempting to find associations with age, exposure factors (age of first exposure to football, total years playing football, and estimates of head impact), known contributors of CTE pathology (global p-tau aggregation), and TES diagnosis. Ultimately, understanding the presentation of neuroanatomical abnormalities and underlying mechanisms relating to p-tau accumulation could lead to supportive features for TES and possible biomarkers for the early detection of CTE during life.
