PET, APOE & the Preclinical Course of Alzheimer's Disease

描述(申请人提供)：我们请求五年继续支持对205名最初为中晚期、认知正常的人进行的纵向研究，这些人有两个副本、一个副本和没有副本的载脂蛋白E 54等位基因，这是一种常见的晚发性阿尔茨海默病(AD)易感基因。在下一个资助期间，1)我们将继续表征和比较基线测量和大脑葡萄糖代谢率(CMRg1)的纵向变化，磁共振成像(MRI)测量灰质密度、皮质厚度和全脑体积，临床评分和每两年一次的神经心理测试，包括35，54个纯合子，50，54个杂合子和75，54个非携带者，进一步描述它们与54个基因剂量的关系，并确定基线脑成像测量和纵向变化在多大程度上预测认知功能下降和转变为轻度认知障碍(MCI)或可能的阿尔茨海默病；我们将继续对来自拉丁裔社区的15 54名携带者和30 54名非携带者的相同测量进行表征和比较，以进一步确定我们的发现在多大程度上与这一研究不足的少数群体有关。2)我们还将每两年获取一次匹兹堡化合物B分布体积比(PIB DV)的PET测量，这将提供一个独特的机会来检测和跟踪认知正常人群中一些最早的纤维淀粉样蛋白沉积，包括晚发性AD的三个遗传风险水平，描述纤维淀粉样蛋白沉积与这些人中其他脑成像变化的关系，并最终确定纤维淀粉样蛋白沉积单独或与其他脑成像测量一起预测认知功能下降和转化为MCI和可能的AD的后续速率的程度。3)我们将使用我们提出的症状前脑成像内表型来评估AD风险的假定修饰物，包括总的遗传风险评分和单个单核苷酸多态(SNPs)，我们已经在一项独立资助的500,000个SNP全基因组关联研究中牵涉其中，该研究涉及1000多个临床和神经病理特征的AD病例和对照。4)我们将进一步提炼、测试和确定先进的基于体素的图像分析技术在异常早期检测和跟踪与AD的不同风险相关的大脑变化方面的价值。5)最后，我们将继续分享我们的核心资源，包括DNA、生物标本、数据和发现，以支持其他调查人员和其他研究。这项研究的最终目的是提供一种经济有效的方法来评估AD一级预防的有效治疗方法。事实上，我们为此成立了一个新的非营利性机构。

DESCRIPTION (provided by applicant): We request five years of continued support for the longitudinal study of 205 initially late-middle-aged, cognitively normal persons with two copies, one copy and no copies of the apolipoprotein E 54 allele, a common late-onset Alzheimer's disease (AD) susceptibility gene. During the next funding period, 1) we will continue to characterize and compare baseline measurements and longitudinal changes in fluorodeoxyglucose positron emission tomography (FDG PET) measurements of the cerebral metabolic rate for glucose (CMRgl), magnetic resonance imaging (MRI) measurements of gray matter density, cortical thickness and whole brain volume, clinical ratings and neuropsychological tests every two years in 35 54 homozygotes, 50 54 heterozygotes, and 75 54 non-carriers, further characterize their relationship to 54 gene dose, and determine the extent to which baseline brain-imaging measurements and longitudinal changes predict subsequent rates of cognitive decline and conversion to mild cognitive impairment (MCI) or probable AD; and we will continue to characterize and compare the same measurements in 15 54 carriers and 30 54 non-carriers from the Latino community to further establish the extent to which our findings are relevant to this understudied minority group. 2) We will also acquire PET measurements of the Pittsburgh Compound B Distribution Volume Ratio (PIB DV) every two years, providing a unique opportunity to detect and track the some of the earliest fibrillar amyloid deposition in cognitively normal persons at three levels of genetic risk for late-onset AD, characterize the relationship of fibrillar amyloid deposition to the other brain imaging changes in these individuals, and ultimately determine the extent to which fibrillar amyloid deposition, alone or in combination with other brain imaging measurements, predicts subsequent rates of cognitive decline and conversion to MCI and probable AD. 3) We will use our proposed presymptomatic brain-imaging endophenotype to evaluate putative modifiers of AD risk, including an aggregate genetic risk score and individual single nucleotide polymorphisms (SNPs) that we have implicated in an independently funded 500,000 SNP whole-genome association study of more than a thousand clinically and neuropathologically characterized AD cases and controls. 4) We will further refine, test and establish the value of advanced voxel-based image-analysis techniques in the unusually early detection and tracking of brain changes associated with the differential risk of AD. 5) Finally, we will continue to share our core resource of DNA, biological specimens, data and findings in support of other investigators and other studies. This study is ultimately intended to provide a cost-effective way to evaluate promising treatments for the primary prevention of AD. Indeed, we have established a new non-profit institute for this very purpose.