PROJECT SUMMARY/ABSTRACT Traumatic Brain Injury (TBI) is a leading cause of death and disability and a risk factor for later development of Alzheimer's Disease (AD.) This project focuses on brain cerebrospinal/interstitial fluid systems essential for clearing the brain of waste and toxins, including the glymphatic system, as important to the pathophysiology of both TBI and AD. We will use neuroimaging to measure brain fluid clearance after TBI. Our preliminary results suggest that TBI causes significant reduction in clearance. In this project, we will confirm these results using additional clearance measurement methods, and determine if lower post-injury clearance is associated with worse cognitive, functional and symptomatic recovery from TBI. We will also use neuroimaging (Positron Emission Tomography - PET) to measure brain amyloid-β (Aβ) – a hallmark pathologic feature of AD – as soon as possible after TBI. Studies in animals and our preliminary data in humans indicate that Aβ is released after TBI and deposits rapidly in the brain, but after a variable period of time, is usually no longer present. We hypothesize that the rate of brain fluid clearance will predict the change in brain Aβ over one year after TBI. Poor clearance and persistent Aβ may explain (in part) why TBI is a risk factor for AD. In addition, monitoring these processes after TBI will provide information relevant to understanding AD in general, since this same pathophysiology – poor clearance leading to Aβ deposition – occurs in AD, but slowly over decades, making it more difficult to study. We will conduct a five year longitudinal study which will recruit subjects within hours after moderate or complex-mild TBI from a network of busy NYC emergency rooms. Neuroimaging, blood draw for TBI biomarkers and detailed cognitive/clinical assessment will be performed as soon as possible (<14 days) after injury and repeated at one year. Because there is no current gold standard for measuring brain fluid clearance in humans, we use a panel of complementary PET and MRI neuroimaging methods to estimate fluid flow, mixing and clearance through interconnected fluid-filled spaces in the brain. This includes a PET method we developed that measures the rate of radiotracer egress from the ventricle. Integrating measures from these multimodal methods will provide greater insight into human fluid clearance than could be achieved with any single modality, and will also provide information about the relative accuracy/predictive ability of each measure that can inform design of future studies. Results from this project will provide novel information about brain fluid clearance after TBI that is also relevant to AD, and that can inform targeted therapies to enhance TBI recovery and reduce future risk of neurodegeneration.