Posterior Cingulate Perfusion and Alzheimer Disease Risk

后扣带回灌注与阿尔茨海默病风险

• 批准号: 8195978
• 负责人: Sterling C Johnson
• 金额: --
• 依托单位: WM S. MIDDLETON MEMORIAL VETERANS HOSP
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8195978
• 关键词: Address; Adult; Advisory Committees; Affect; Age; Aging; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease risk; Blood; Brain; Cells; Censuses; Cerebrovascular Circulation; Cerebrum; Cognition; Cognitive; Complex; Data; Deltastab; Dementia; Disease; Early Diagnosis; Early identification; Early treatment; Economic Burden; Elderly; Enrollment; Event; Exhibits; Face; Family; Family history of; Functional Magnetic Resonance Imaging; Functional disorder; Funding; Genetic Status; Health Services Accessibility; Healthcare Systems; Image; Impaired cognition; Individual; Intervention; Longevity; MRI Scans; Magnetic Resonance Imaging; Measures; Memory; Methods; Modeling; Nerve Degeneration; Neurodegenerative Disorders; Neuropsychological Tests; Oxygen; Participant; Patients; Pattern; Perfusion; Population; Prevalence; Public Health; Publications; Publishing; Recording of previous events; Recruitment Activity; Registries; Research; Research Priority; Resources; Rest; Risk; Risk Factors; Sampling; Scanning; Series; Signal Transduction; Spin Labels; Symptoms; Syndrome; System; Testing; Time; Veterans; Wisconsin; Work; apolipoprotein E-4; base; blood flow measurement; blood oxygenation level dependent response; burden of illness; cingulate cortex; cognitive change; cognitive function; cohort; executive function; experience; follow-up; gray matter; health care delivery; improved; ischemic lesion; meetings; memory recognition; middle age; mild neurocognitive impairment; morphometry; neuropsychological; pre-clinical; public health relevance; relating to nervous system; research and development; statistics; white matter

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.

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。本次更新申请继续关注临床前 AD 中的 PCC。在之前 VA 的资助下，我们使用功能性 MRI (fMRI) 来研究元认知和情景记忆过程中的大脑活动，并使用激活健康 PCC 的范式。我们发现 PCC fMRI 活性受到 AD 危险因素的影响，包括轻度认知障碍、载脂蛋白 e4 (APOE4) 遗传状态和 AD 父母家族史 (PFH)。然而，功能磁共振成像很复杂，更简单、更广泛使用的扫描类型可能更理想。在此应用中，我们将检查高危人群的静息脑血流量 (CBF) 或灌注。假设：总体假设是，在患有 AD 危险因素（包括认知能力下降、APOE4 状态和 PFH 状态）的中年人中，PCC 会表现出 CBF 降低，并且在两年的随访期内 CBF 降低将与认知相关和功能磁共振成像信号。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) 的无创灌注 MRI 方法的最新进展，以确定有 AD 风险的无症状人群是否表现出与危险因素状态或相关的 CBF 定量减少。观察到认知能力下降。这将把之前使用 ASL 进行的 AD 和 MCI 研究扩展到一个独特的、重要的 preMCI 队列中无症状的高危人群，该队列患有 AD PFH，并且每 4 年接受一次详细的认知测试。目标 1：确定 PCC 中 CBF 的基线或纵向下降是否可以解释记忆功能的纵向下降。该项目的这一部分将为我们提供独特而难得的机会来检查健康的中年晚期大脑从正常到 MCI 的纵向变化。目标 2：确定 PCC 中 CBF 的减少是否发生在认知能力下降之前，以及这种 CBF 的减少是否可能归因于 AD 风险因素。目标 3：检查 PCC 中识别记忆过程中的 fMRI 信号与 CBF 之间的关系，并检查可能导致不同 CBF 模式的认知概况。目标 4：检查先前收集的数据中的长期认知衰退（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 名受试者作为样本，这是一个由 1,200 名参与者组成的大队列，并进行纵向跟踪。我们将从该注册表中选择合适的受试者进行 ASL 和功能磁共振成像扫描。我们将使用基于体素的多变量统计的统一方法检查 PCC 中的 CBF 和 fMRI 活动，以确定认知能力下降、APOE4 和 PFH 危险因素与脑血流量之间的关系。对退伍军人的意义：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 AD 早期检测方法，以表征痴呆症状出现之前的大脑变化，以便更早开始干预措施。 公共卫生相关性： 退伍军人管理局研究与发展办公室已将“老龄化”和老龄化问题指定为其研究重点之一。随着退伍军人人口老龄化，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。需要找到方法来消除衰老综合症的歧义，例如早期 AD 造成的认知困难。 AD 的早期识别和治疗可以延长稳定的认知功能，并减轻 VA 和公共医疗保健系统因 AD 患病率随年龄增长而增加的经济负担。根据2000年的人口普查，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1680万退伍军人都比较年轻。这意味着超过 1/3 的退伍军人年龄超过 65 岁。随着人口老龄化（尽管年轻退伍军人的数量现在也在增加）和平均寿命的延长，这些数字预计还会增加，从而使 AD 和相关神经退行性疾病的患病率增加疾病成为一个日益严重的问题。在最近发布的总统工作组改善我国退伍军人的医疗保健服务中，第五章强调了退伍军人管理局系统面临的一个重要问题：通过退伍军人管理局获得医疗服务的日益增长的需求与满足这一需求的财政资源之间的不匹配。早期识别 AD 和其他痴呆症将有助于减少这种差异，并减轻这种疾病给美国和退伍军人管理局医疗保健系统带来的总体经济负担。