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

描述（由申请人提供）：我们要求对205名最初具有两拷贝、一拷贝和无拷贝载脂蛋白e54等位基因（一种常见的晚发性阿尔茨海默病（AD）易感基因）的认知正常的中老年患者进行为期5年的纵向研究。在下一个资助期内，1)我们将继续表征和比较基线测量和纵向变化，氟脱氧葡萄糖正电子发射断层扫描（FDG PET）测量葡萄糖的脑代谢率（CMRgl），磁共振成像（MRI）测量灰质密度，皮质厚度和全脑体积，临床评分和每两年对3554名纯合子，5054名杂合子和7554名非携带者进行神经心理学测试；进一步表征它们与54基因剂量的关系，并确定基线脑成像测量和纵向变化预测随后认知衰退和转化为轻度认知障碍（MCI）或可能的AD的比率的程度；我们将继续对来自拉丁裔社区的1554名携带者和3054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与这一未被充分研究的少数群体的相关程度。2)我们还将每两年获得匹兹堡化合物B分布体积比（PIB DV）的PET测量，提供一个独特的机会来检测和跟踪一些最早的纤维状淀粉样蛋白沉积，在认知正常的人中有三个水平的晚发型AD遗传风险，表征纤维状淀粉样蛋白沉积与这些个体的其他脑成像变化的关系。并最终确定纤维状淀粉样蛋白沉积的程度，单独或与其他脑成像测量相结合，预测随后的认知能力下降和转化为轻度认知障碍和可能的AD的速度。3)我们将使用我们提出的症状前脑成像内表型来评估AD风险的推定修饰因子，包括总体遗传风险评分和个体单核苷酸多态性（SNP），我们在一项独立资助的500000个SNP全基因组关联研究中涉及1000多个临床和神经病理学特征的AD病例和对照组。4)我们将进一步完善、测试和确立先进的基于体素的图像分析技术在异常早期发现和跟踪与阿尔茨海默病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DNA、生物标本、数据和发现等核心资源，以支持其他研究者和其他研究。这项研究的最终目的是提供一种具有成本效益的方法来评估有希望的阿尔茨海默病一级预防治疗方法。事实上，我们已经为此目的建立了一个新的非营利性研究所。

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.