Traumatic Brain Injury (TBI) is a leading cause of death and disability worldwide and a risk factor for later development of Alzheimer?s Disease (AD.) TBI causes increased axonal production and rapid brain deposition of amyloid ? a pathologic hallmark of AD. Persistence of amyloid in the brain after TBI may underlie TBI as a risk factor for AD. For this project, using Positron Emission Tomography (PET), we will measure the amount of amyloid in the brain immediately (within 14 days) following moderate or complex mild TBI and again one year later. We hypothesize that brain amyloid will be reduced/cleared over the recovery period. Critically, we will assess the presumptive mechanism by which amyloid is cleared from the brain using a new dynamic PET method we developed. This method quantifies the rate and magnitude of radiotracer removal from the brain?s ventricles, providing a measure of cerebrospinal and interstitial fluid (CSF/ISF) clearance we have termed vCSF-clearance. In animal models, CFS/ISF clearance via the recently-described brain glymphatic system has been shown to be critical for clearing the brain of waste products including amyloid, and to be diminished after TBI. Our preliminary data in humans show that vCSF-clearance is inversely proportional to the amount of amyloid present in the brain and can differentiate patients with AD ? long considered a disorder of amyloid clearance ? from controls. For this five year longitudinal study, we will test the hypothesis that post injury vCSF-clearance predicts the reduction in amyloid lesions over one year. We will also determine if vCSF-clearance predicts cognitive, functional and symptomatic outcome from TBI, and assess the relationship between vCSF- clearance and blood levels of brain proteins such as neurofilament light protein (NfL) which are used as biomarkers of TBI severity, but which also depend upon clearance mechanisms to travel from brain to blood. Results from this project will provide novel information about the contribution of vCSF-clearance to amyloid removal after TBI relevant to TBI recovery as well as to the longer term risk of neurodegeneration after TBI.

Public Health Relevance

Traumatic Brain Injury (TBI), a leading cause of disability worldwide, causes rapid brain deposition of amyloid (the toxic protein present in the plaques of Alzheimer's Disease) and this may explain why TBI is a risk factor for the later development of Alzheimer's Disease. This project applies Positron Emission Tomography (PET) to 1) measuring amyloid in the brains of patients following TBI and 2) measuring the brain?s ability to clear toxic proteins like amyloid from brain cerebrospinal fluid (CSF) using a new PET method we developed. We will test the hypothesis that CSF clearance predicts the reduction in the amount of amyloid present in the brain one year after TBI and will also examine whether CSF clearance is relevant to recovery (cognitive, functional and symptomatic) from TBI.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
High Priority, Short Term Project Award (R56)
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Acute Neural Injury and Epilepsy Study Section (ANIE)
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Bellgowan, Patrick S F
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Weill Medical College of Cornell University
Schools of Medicine
New York
United States
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