Neuroimaging of Dedifferentiation and Memory Across the Lifespan

描述（由申请人提供）：本提案是对NOT-OD-058的回应，“NIH宣布为竞争性修订申请提供恢复法案资金。“它利用了新的神经成像技术（包括淀粉样蛋白成像），这些技术在最初应用时甚至还不适用于该项目。它将使雇用或维护共2.3全职人员：全职博士后的努力;全职研究助理，兼职实验室技术员，除了为德克萨斯大学西南医学院未充分利用的PET扫描仪的人员提供就业机会。在尸检中发现完全正常、健康的老年人以淀粉样蛋白沉积的形式表现出显著的神经病理学是很常见的。虽然淀粉样蛋白沉积是所有阿尔茨海默病（AD）患者的特征，但它也存在于许多正常成年人中，在轻度认知障碍（MCI）患者中观察到的水平高于正常人，并且是从MCI转化为AD的强预测因素。在过去，几乎不可能研究淀粉样蛋白沉积与健康成年人的认知和神经功能的关系，因为淀粉样蛋白沉积只能在尸检中测量。然而，最近已经开发出新的放射性示踪剂化合物，当注射到个体中时，其与他或她大脑中的淀粉样蛋白沉积物结合。我们建议增加淀粉样蛋白PET扫描和APOE-e4基因分型 （认知能力下降和阿尔茨海默氏病的一个已知的危险因素）到达拉斯寿命脑研究（DLBS），这是一项由美国国立卫生研究院资助的研究，全面描述了350名成年人的特征-从20年代到80年代，每十年有50名参与者-并包括认知功能，大脑结构和大脑功能的广泛测量。我们假设淀粉样蛋白是一个关键的起始事件，在认知正常的成年人的神经认知下降中起着核心作用。此外，由于DLBS是一个MERIT奖的P.I. Denise Park，我们有能力利用前五年的淀粉样蛋白测量来预测纵向随访时神经结构，功能和认知行为的轨迹。DLBS包括淀粉样蛋白数据，将提供我们认为是文献中正常认知老化的最完整表征，并允许测试关于淀粉样蛋白沉积的病理学如何影响健康，高度选择的成年人的大脑和行为的广泛假设。Avid Pharmaceuticals已同意免费为我们的研究提供配体（AV-45），因此只需要PET和人员费用，使大样本健康老年人的研究在经济上可行。目前，已发表的关于健康老年人淀粉样蛋白沉积的最大研究由43名参与者组成。这主要是由于用于测量淀粉样蛋白沉积的配体的成本和稀缺性。 公共卫生相关性：淀粉样蛋白沉积发生在一部分健康成年人的大脑中，并且总是发生在阿尔茨海默病患者的大脑中。我们终于可以用PET扫描来测量人体内淀粉样蛋白的沉积。我们建议在达拉斯寿命脑研究中增加淀粉样蛋白沉积的测量，这将提供迄今为止健康成人淀粉样蛋白沉积的最佳估计，并提供在阿尔茨海默病的早期诊断和干预中至关重要的基线信息。

DESCRIPTION (provided by applicant): This proposal is a response to NOT-OD-058, "NIH Announces the Availability of Recover Act Funds for Competitive Revision Applications." It utilizes new neuroimaging advances (including amyloid imaging) that were not even available to the project at the time of initial application. It will enable the hiring or maintenance of a total of 2.3 full time people: the effort of a full-time post-doc; a full-time research assistant, and a part-time laboratory technician, in addition to providing employment for personnel at an under-utilized PET scanner at the University of Texas Southwestern Medical School. It is quite common to find that entirely normal, healthy older adults show significant neuropathology at autopsy in the form of amyloid deposition. Although amyloid deposition is a characteristic feature of all patients with Alzheimer's Disease (AD), it is also present in many normal adults, is observed in individuals with Mild Cognitive Impairment (MCI) at a level higher than normals, and is a strong predictive factor in conversion from MCI to AD. In the past, it has been nearly impossible to study the relationship of amyloid deposition to cognitive and neural function in healthy adults, as amyloid deposition could only be measured at autopsy. Very recently, however, new radiotracer compounds have been developed that, when injected in an individual, bind to amyloid deposits in his or her brain. We propose to add an amyloid PET scan and genotyping of APOE-e4 (a known risk factor for cognitive decline and Alzheimer's disease) to the Dallas Lifespan Brain Study (DLBS), an NIA-funded study that fully characterizes 350 adults-50 participants at each decade from the 20's through the 80's-and includes extensive measurement of cognitive function, brain structure, and brain function. We hypothesize that amyloid is one critical, initiating event that plays a central role in neurocognitive decline in cognitively normal adults. Moreover, because the DLBS is a MERIT award to P.I. Denise Park, we have the ability to utilize the amyloid measures taken in the first five years to predict trajectories of neural structure, function and cognitive behavior at longitudinal follow-up. The DLBS, with the inclusion of the amyloid data, will provide what we believe to be the most complete characterization of normal cognitive aging in the literature, and allows for the testing of a broad range of hypotheses about how the pathology of amyloid deposition affects both brain and behavior in healthy, highly-selected adults. Avid Pharmaceuticals has agreed to provide the ligand (AV-45) to our study at no cost, so that only PET and personnel costs are requested, making the study of a large sample of healthy elderly financially feasible. At present, the largest published study of amyloid deposition in healthy older adults consists of 43 participants. This is largely due to the cost and scarcity of the ligands used to measure amyloid deposition. PUBLIC HEALTH RELEVANCE: Amyloid deposition occurs in the brains of a subset of healthy adults, and always occurs in the brains of individuals with Alzheimer's disease. We can at last measure amyloid deposition in vivo in humans with PET scanning. We propose to add measures of amyloid deposition to the Dallas Lifespan Brain Study which will provide the best estimate of amyloid deposition in healthy adults to date, and provide baseline information that will be critical in the early diagnosis and interventions for Alzheimer's disease.