Imaging Beta-Amyloid Clearance Mechanisms in the Aging Brain

Summary/Abstract Function of the P-glycoprotein (P-gp) efflux pump at the blood-brain barrier (BBB) is reduced in Alzheimer’s disease (AD). Evidence suggests that cerebrospinal fluid (CSF) and interstitial fluid (ISF) flow, i.e., brain fluid dynamics (BFD), are also reduced in AD. P-gp function and BFD are both likely critical contributors to the clearance of beta-amyloid (Ab), and intriguing evidence suggests that P-gp and BFD have complementary, possibly dependent roles in the clearance of Ab. However, it is not known where in the AD pathophysiological spectrum P-gp function and BFD become critically reduced. It is further not established if reduced P-gp function and BFD are initiating factors of impaired Ab clearance and therefore Ab plaque deposition. These physiologic and biomechanical processes remain largely unexamined in vivo in humans, particularly early in the AD pathophysiological spectrum. Our preliminary data demonstrate that ventricular CSF dynamics are associated with Ab plaque deposition and are likely reduced prior to cognitive decline. The overarching goal of this study is to further understanding of the relationships between P-gp function, BFD, and Ab plaque deposition in the earliest AD pathophysiological stages, prior to the onset of dementia. To achieve this goal, we will leverage ongoing longitudinal neuroimaging studies of aging and AD to recruit non-demented older adults with known levels of Ab plaque load from existing 11C-PiB PET imaging. We will examine (1) P-gp function from (R)-11C-verapamil and 15O-H2O PET imaging; (2) ventricular CSF influx from 15O-H2O PET imaging; and (3) brain fluid pulsatility at physiologic relevant frequencies, including cardiac, respiratory, and vasomotion using a novel 7T MRI fast echo- planar imaging (EPI) sequence. We will examine these PET and 7T MRI neuroimaging markers both cross- sectionally and longitudinally relative to Ab plaque load and status from 11C-PiB PET imaging. Cross-sectionally, we hypothesize that P-gp function will be associated with BFD (ventricular CSF influx and brain fluid pulsatility) and that P-gp function and BFD will be reduced in non-demented participants with significant Ab plaque deposition (Ab+) relative to those without (Ab-). Longitudinally, we hypothesize that neuroimaging markers of P- gp function and BFD will predict future Ab deposition. These proposed findings will potentially identify PET and 7T MRI neuroimaging markers of P-gp function and BFD as earlier indicators of risk of AD than Ab PET imaging. These findings, in turn, may identify P-gp function and BFD as therapeutic targets for the prevention of Ab plaque deposition and therefore the onset of AD-related cognitive decline.