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。 公共卫生相关性： 退伍军人事务部研究和发展办公室已将“老龄化”和老龄化问题定为其研究重点之一。随着退伍军人人口的老龄化，与老龄化相关的问题，包括痴呆症，将继续成为公共卫生负担。需要方法来消除诸如认知困难的老化综合征与早期AD的歧义。AD的早期识别和治疗可以延长稳定的认知功能，并减轻VA和公共医疗系统的经济负担，这些经济负担与AD随年龄增长而增加的患病率相关。根据2000年人口普查，退伍军人总数为2650万，其中970万退伍军人年龄在65岁以上，而1680万退伍军人年龄均较年轻。这意味着超过三分之一的退伍军人超过65岁。这些数字预计将随着人口老龄化而增加（尽管年轻退伍军人的数量现在也在增加），平均寿命增加，使AD和相关神经退行性疾病的患病率成为一个日益严重的问题。在最近出版的总统工作队，以改善医疗保健提供给我们国家的退伍军人，面临的VA系统的一个重要问题是在第五章中强调：之间的不匹配日益增长的需求获得保健通过VAH，和财政资源，以满足这一需求。早期识别AD和其他痴呆症将有助于减少这种差异，并减轻这种疾病对美国和VA医疗保健系统的总体经济负担。

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. PUBLIC HEALTH RELEVANCE: The Office of Research and Development of the VA has designated "aging" and problems of aging as one of its research priorities. With the aging veterans population, problems associated with aging, including dementias, will continue to be a public health burden. Methods are needed for disambiguating aging syndromes such as cognitive difficulties from early AD. Early identification and treatment of AD may prolong stable cognitive function and reduce the financial burden to VA and public healthcare systems associated with the increasing prevalence of AD with age. From the 2000 Census, there were 26.5 million total veterans, 9.7 million veterans are over age 65, while 16.8 million veterans are all younger. This means that more than 1/3rd of veterans are over 65. These numbers are expected to increase as the population ages (though the number of young veterans is now increasing, too), and average lifespan increases, making prevalence of AD and related neurodegenerative disease a growing problem. In the recently published President's Task Force To Improve Health Care Delivery to Our Nation's Veterans, an important problem facing the VA system is highlighted in Chapter Five: the mismatch between increasing demand for access to care through the VAH, and financial resources to meet this need. Early identification of AD and other dementias will serve to reduce this discrepancy and to relieve the overall economic burden of this disease to the U.S. and the VA health care system.