Posterior Cingulate Perfusion and Alzheimer Disease Risk

描述（由申请人提供）： 近年来，通过我们实验室和其他人的工作，越来越清楚的是，后扣带皮层（PCC）在阿尔茨海默病（AD）的早期受到影响。此次更新申请继续关注临床前AD中的PCC。在之前的VA资金支持下，我们使用功能性MRI（fMRI）来研究元认知和情景回忆过程中的大脑活动，使用激活健康PCC的范例。我们发现PCC的fMRI活性受AD的危险因素影响，包括轻度认知功能障碍、载脂蛋白e4（APOE 4）基因状态和AD的父母家族史（PFH）。然而，fMRI是复杂的，更简单，更广泛使用的扫描类型可能更理想。在这个应用中，我们将检查处于危险中的人的静息脑血流量（CBF）或灌注。假设：总体假设是，PCC将在具有AD风险因素（包括认知下降、APOE 4状态和PFH状态）的中年成人中表现出CBF降低，并且在两年随访期间CBF降低将与认知和fMRI信号相关。研究设计：这个为期4年的项目将利用称为伪连续动脉自旋标记（ASL）的非侵入性灌注MRI方法的最新进展，以确定无症状AD风险人群是否表现出与风险因素状态或观察到的认知下降相关的定量CBF下降。这将把先前的AD和MCI研究与ASL一起扩展到一个独特的、重要的preMCI队列中的无症状风险人群，该队列具有针对AD的PFH，并且每4年进行一次详细的认知测试。目的1：确定记忆功能的纵向下降是否可以通过PCC的基线或CBF的纵向下降来解释。该项目的这一组成部分将使我们有独特而难得的机会来检查大脑从正常到MCI的纵向变化，在其他方面健康的中年晚期成年人中。目标2：确定PCC中CBF的降低是否发生在认知能力下降之前，以及此类CBF降低是否可归因于AD风险因素。目标3：探讨再认记忆过程中的fMRI信号与PCC中CBF的关系，以及可能导致不同CBF模式的认知特征。目的4：在先前收集的数据中检查长期认知能力下降（4年）和PCC BOLD反应。方法：为了实现这些目标，我们将从威斯康星州AD预防登记处（WRAP）招募200名受试者，这是一个由1,200名参与者组成的大型队列，他们将接受纵向随访。我们将从该登记研究中选择适当的受试者进行ASL和fMRI扫描。我们将使用基于体素的多变量统计的统一方法来检查PCC中的CBF和fMRI活动，以确定认知下降、APOE 4和PFH危险因素与脑血流量之间的关系。对兽医的意义：全国超过三分之一的退伍军人年龄超过65岁，迫切需要更好的早期检测AD的方法来表征痴呆症状发作前的大脑变化，以便干预措施可以更早开始。

DESCRIPTION (provided by applicant): In recent years, through the work of our lab and others, it has become increasingly clear that the posterior cingulate cortex (PCC) is affected early in Alzheimer's Disease (AD). This renewal application continues to focus on the PCC in preclinical AD. With prior VA funding, we used functional MRI (fMRI) to study brain activity during metacognition and episodic recollection using paradigms that activate the healthy PCC. We have found that PCC fMRI activity is affected by risk factors for AD including mild cognitive impairment, apolipoprotein e4 (APOE4) genetic status, and parental family history (PFH) of AD. However, fMRI is complex, and a simpler, more widely available type of scan may be more ideal. In this application, we will examine resting cerebral blood flow (CBF) or perfusion in people at risk. HYPOTHESIS: The overall hypothesis is that the PCC will exhibit reduced CBF in middle-aged adults with AD risk factors including cognitive decline, APOE4 status, and PFH status and that reduced CBF over a two-year follow-up period will be related to cognition and fMRI signal. STUDY DESIGN: This 4-year project will capitalize on very recent advances in a noninvasive perfusion MRI method known as pseudo-continuous arterial spin labeling (ASL) to determine if asymptomatic people at risk for AD exhibit quantitative CBF decrements associated with risk factor status or observed cognitive decline. This would extend prior AD and MCI research with ASL to asymptomatic people at risk in a unique, important preMCI cohort that has PFH for AD and that undergoes detailed cognitive testing every 4 years. AIM 1: To determine whether longitudinal decline in memory functioning is explained by baseline or longitudinal decline in CBF in the PCC. This component of the project will allow us the unique and rare opportunity to examine the brain with regard to longitudinal change from normal to MCI in otherwise healthy, late middle-aged adults. AIM 2: To determine whether reductions in CBF in the PCC occur prior to cognitive decline, and whether such CBF reductions may be attributable to AD risk factors. AIM 3: To examine the relationship between fMRI signal during recognition memory and CBF in the PCC, and also to examine cognitive profiles that may result in different CBF patterns. AIM 4: To examine the long-term cognitive decline (4 years) and PCC BOLD response in data previously collected. METHODS: To accomplish these aims, we will recruit a sample of 200 subjects from the Wisconsin Registry for AD Prevention (WRAP), a large cohort of 1,200 participants who are followed longitudinally. We will select appropriate subjects from this registry for ASL and fMRI scanning. We will examine CBF and fMRI activity in the PCC using a unified approach with voxel-based multivariate statistics to determine the relationship between cognitive decline, APOE4, and PFH risk factors and cerebral blood flow. SIGNIFICANCE FOR VETERANS: More than one-third of the nation's veterans are over age 65, and better methods for early detection of AD are urgently needed to characterize brain changes prior to dementia symptom onset so that interventions can begin sooner.