PROJECT SUMMARY/ABSTRACT Repetitive concussive and subconcussive brain trauma, as experienced in contact sports and military deployment, has been linked to devastating neurodegenerative disease in the long term, such as chronic traumatic encephalopathy (CTE) and Alzheimers disease (AD), but the mechanisms linking them remain largely elusive. It is well known that TBI can acutely induce increases in beta amyloid protein via axonal damage and there is evidence that this can evolve into amyloid plaques, but the magnitude, duration and implications of this increase have not been well studied in living humans, especially in mild TBI which is the most common form. The consequences of induced toxic amyloid species are worrisome, especially considering recent evidence that beta amyloid might directly stimulate production of tau protein via the adrenergic system, illustrating a new pathway through which amyloid may result in neurotoxicity even if its elevation is modest and subsequently cleared by normal physiological processes or pharmacological interventions. While this has enormous implications for AD research, it also raises the tantalizing possibility that amyloid is an important factor in the risk of neurodegeneration following TBI, perhaps including the mildest forms to which young athletes and service members are frequently exposed. Fortunately, there are robust and sensitive ways to measure beta amyloid in the living brain. In Aim 1, we will employ the most validated, quantitative PET/MR imaging techniques (11C-PiB with arterial input function and compartmental modeling) to sensitively measure brain levels of amyloid in college contact-sport athletes before and after a season of play. Our primary hypothesis is that global cortical amyloid distribution volume will be higher after the season. In Aim 2, we will explore relationships of this measure with related measures of traumatic axonal injury of associated white matter (using fractional anisotropy with DTI MRI, acquired simultaneously to PET), plasma biomarkers, and objective exposure variables measured by accelerometer. Although this is a preliminary mechanistic study, it could lead to vital new directions for diagnostic and preventative approaches across the full spectrum of TBI severity.