Imaging Beta-Amyloid Clearance Mechanisms in the Aging Brain

摘要/摘要 阿尔茨海默病患者血脑屏障P-糖蛋白(P-gp)外排泵功能降低 疾病(AD)。有证据表明，脑脊液(CSF)和间质液(ISF)流动，即脑液 动力学(BFD)，在AD时也会降低。P-gp功能和BFD都可能是 β-淀粉样蛋白的清除，有趣的证据表明P-gp和BFD具有互补性， 在抗体清除过程中可能起依赖作用。然而，目前尚不清楚阿尔茨海默病的病理生理机制 频谱P-gp函数和BFD严重降低。如果P-gp功能减弱，则进一步不能确定 和BFD是抗体清除受损从而抗体斑块沉积的起始因子。这些生理上的 在人体内，特别是在AD早期，生物力学过程在很大程度上仍未得到研究 病理生理谱。我们的初步数据表明，脑室脑脊液动力学与 有抗体斑块沉积，在认知能力下降之前可能会减少。这项研究的首要目标是 进一步了解P-gp功能、BFD和抗体斑块沉积的关系 AD病理生理阶段，在痴呆症发作之前。为了实现这一目标，我们将利用正在进行的 招募抗体水平已知的非痴呆老年人的衰老和AD的纵向神经成像研究 现有的11C-PIB PET成像的斑块负荷。我们将研究(1)来自(R)-11C-维拉帕米的P-gp功能和 15O-H2O PET成像；(2)15O-H2O PET成像的脑室脑脊液流入；以及(3)15O-H2O PET成像时脑液的搏动性 生理相关频率，包括心脏，呼吸和血管运动，使用新的7T磁共振快速回声- 平面成像(EPI)序列。我们将检查这些PET和7T MRI神经成像标记物 与11C-PIB PET显像中抗体斑块负荷和状态的横断面和纵向相关。在横截面上， 我们假设P-gp功能与BFD(脑室脑脊液流入和脑液搏动性)有关。 在有显著抗体斑块的非痴呆参与者中，P-gp功能和BFD将会降低 沉积(Ab+)相对于不沉积(Ab-)。从纵向上看，我们假设P- GP功能和BFD将预测未来的抗体沉积。这些拟议的发现可能会确定PET和 7T MRI神经成像标记物P-gp功能和BFD可作为AD危险性的早期指标。 这些发现反过来可能确定P-gp功能和BFD作为预防抗体斑块的治疗靶点 沉积，从而导致与AD相关的认知功能下降。

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.