PROJECT SUMMARY / ABSTRACT CSF drainage pathology, a potential new Alzheimer's disease (AD) therapeutic target, has been hypothesized as impaired in AD and demonstrated in AD models. There is no non-invasive technique to measure the brain CSF clearance (BCC) in humans. Low molecular weight PET tracers such as 18F-MK6240, 18F-THK5351 and 11C-PiB, like other ISF solutes, rapidly enter and clear the brain. They can freely pass the BBB, distribute into brain and ISF spaces, and move into the ventricular CSF through the glymphatic system. We have developed a method to use radiotracer clearance from brain as a biomarker for glymphatic clearance. Our recent paper and preliminary dynamic PET studies demonstrate that radiotracer distribution in ventricular CSF from 35 to 60 minutes (vCSF-AUC) is a valuable marker to estimate BCC. Our preliminary data demonstrate that after controlling for blood tracer levels, vCSF-AUC are highly reproducible within subjects across tau and amyloid PET tracers and achieve 90% accuracy for group separation between normal and impaired subjects. BCC correlated inversely with brain amyloid deposition, cognitive performance and cortical thickness even after controlling for confounds. These observations justify our proposed 2-year longitudinal study to evaluate the vCSF-AUC as a global predictor of Aβ deposition. Secondarily, we will examine the clearance deficit in early stages of AD and association with features of neurodegeneration (atrophy and cognitive function). This study is a novel attempt to improve our understanding of a proposed mechanism for AD. We anticipate this project will facilitate research into the development of risk factors, epidemiology, prevention and treatment of AD.

PROJECT NARRATIVE Aβ deposited in brain is considered due to an Aβ clearance failure in Sporadic Alzheimer's Disease (AD), but the contribution of glymphatic pathology to this clearance deficit has not been tested in humans. We invented and replicated a non-invasive PET technique to image the brain CSF clearance (BCC). We propose a longitudinal study of elderly normal control and MCI subjects to examine the clearance deficit in early stages of AD and association with brain Aβ burden and features of neurodegeneration (atrophy and cognitive function).