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

描述（由申请人提供）：我们要求对205名最初的中年晚期认知正常人进行为期五年的纵向研究，这些人具有载脂蛋白E 54等位基因（一种常见的迟发性阿尔茨海默病（AD）易感基因）的两个拷贝、一个拷贝和没有拷贝。在下一个资助期内，1）我们将继续表征和比较脑葡萄糖代谢率（CMRgl）的氟脱氧葡萄糖正电子发射断层扫描（FDG PET）测量，灰质密度、皮质厚度和全脑体积的磁共振成像（MRI）测量的基线测量和纵向变化，每两年对3554例纯合子、5054例杂合子和7554例非携带者进行临床评级和神经心理学测试，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在多大程度上预测随后的认知下降率和转化为轻度认知障碍（MCI）或可能的AD;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结果进行表征和比较，以进一步确定我们的研究结果与这一未充分研究的少数群体相关的程度。2)我们还将每两年获得匹兹堡化合物B分布体积比（PI B DV）的PET测量值，提供一个独特的机会来检测和跟踪处于迟发性AD遗传风险的三个水平的认知正常人中的一些最早的纤维状淀粉样蛋白沉积，表征这些个体中纤维状淀粉样蛋白沉积与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单独或与其他脑成像测量组合预测随后认知下降和转化为MCI和可能的AD的速率的程度。3)我们将使用我们提出的症状前脑成像内表型来评估AD风险的假定修饰因子，包括综合遗传风险评分和个体单核苷酸多态性（SNP），我们已经在一项独立资助的500，000 SNP全基因组关联研究中涉及了1000多例临床和神经病理学特征的AD病例和对照。4)我们将进一步完善，测试和建立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差异风险相关的大脑变化中的价值。5)最后，我们将继续分享我们的DNA、生物标本、数据和发现的核心资源，以支持其他研究人员和其他研究。这项研究最终旨在提供一种具有成本效益的方法来评估有前途的治疗方法，用于AD的一级预防。事实上，我们已经为此目的建立了一个新的非营利机构。

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.