A Multidimensional Alzheimer's Disease Brain Atlas

描述（由申请人提供）：这是一个为期10年的项目的竞争性更新，该项目为阿尔茨海默病（AD）提供了巨大的见解，这种疾病仅在美国每年就花费1130亿美元，尚无已知的治疗方法。该项目开发了AD的多维计算图谱。我们的5年工作计划提供了最强大的计算工具来跟踪阿尔茨海默病在症状出现前几年在活的大脑中出现和传播。我们将在图谱坐标框架中关联AD的3个视角-序列MRI，新型PET示踪剂和3D病理学。这将为科学家们提供有史以来最敏感的方法来衡量影响疾病进展的因素（药物治疗、遗传风险等），以及治疗如何有效地减缓向阿尔茨海默病的过渡。首先，我们通过一系列MRI的新分析绘制了AD的解剖轨迹（Aims 1,2）。我们检测大脑变化的工具（皮质厚度测绘，基于张量的形态测量）提供了疾病在活体大脑中传播的第一张延时地图。在这里，我们将它们应用于MCI受试者（在任何给定年份转换为AD的风险高出5倍），以确定即将发病的疾病的最佳预测因素，并预测特定认知领域的变化。这将通过更好地确定早期治疗的候选者，从而极大地推进药物试验，在不可逆转的损害发生之前，谁能受益最大。接下来，我们将使用新型PET示踪分子来重建阿尔茨海默病在活脑中形成和扩散的动态序列（Aim 3）。我们新开发的PET（正电子发射断层扫描）示踪化合物[18F]- fddnp被誉为阿尔茨海默病领域的一项突破，它可以可视化淀粉样斑块和神经原纤维缠结（nft），这些都是阿尔茨海默病的特征，以前只能在尸检中检测到。我们灵敏的基于表面的3D分析技术将绘制出衰老、轻度认知障碍和AD中斑块和纠缠积聚的时空轨迹，通过组间比较来识别预测即将发生的认知退化或向AD过渡的大脑变化；我们将把这些信号与萎缩率和皮质退化的MRI测量结果进行比较和关联，以创建疾病负担的MR-PET联合测量。我们将率先进行3D冷冻切片成像（每年3个受试者），以确定三维重建的缠结密度和β淀粉样蛋白在整个大脑中的分布如何与活体患者的成像测量相关联。这一基础数据将为AD社区提供资源，揭示其生理意义知之甚少的成像信号的细胞相关性。我们将绘制个体和人群的图谱，揭示预测结果的皮层变薄、斑块和缠结病理的群体模式。识别即将衰退和疾病发作的预测因素，我们的图谱将识别具有早期药物治疗新病理的候选人，并将存储统计数据，以量化治疗在高危人群中抵抗阿尔茨海默病的效果。我们将与100多个合作实验室共享所有图像、协议和算法。

DESCRIPTION (provided by applicant): This is a competitive renewal of a 10-year project that has provided enormous insight into Alzheimer's Disease (AD), a disease that costs $113 billion/yr in the U.S. alone, with no known cure. The project develops a multidimensional, computational atlas of AD. Our 5-year plan of work provides the most powerful computational tools to track AD emerging and spreading in the living brain - years before symptoms begin. We will correlate 3 perspectives on AD in an atlas coordinate framework - serial MRI, novel PET tracers, and 3D pathology. This will provide scientists will the most sensitive approach ever created to gauge which factors affect disease progression (drug treatment, genetic risk, etc.), and how effectively treatments slow the transition to AD. First, we chart the anatomic trajectory of AD with novel analyses of serial MRI (Aims 1,2). Our tools to detect brain changes (cortical thickness mapping, tensor-based morphometry) provided the first time-lapse maps of the disease spreading in the living brain. Here we apply them to MCI subjects (who are at five-fold higher risk of converting to AD in any given year) to identify the best predictors of imminent disease onset, and to predict changes in specific cognitive domains. This will greatly advance drug trials by better identifying candidates for early treatment, who can benefit most before irreversible damage sets in. Next, we will use novel PET tracer molecules to reconstruct the dynamic sequence of AD pathology as it builds up and spreads in the living brain (Aim 3). Hailed as a breakthrough in the AD community, our newly-developed PET (positron emission tomography) tracer compound, [18F]-FDDNP, visualizes amyloid plaques and neurofibrillary tangles (NFTs) - hallmarks of AD previously only detectable at autopsy. Our sensitive surface-based 3D analytic techniques will map the spatio-temporal trajectory of plaque and tangle build-up in aging, mild cognitive impairment, and AD, comparing groups to identify brain changes that predict imminent cognitive deterioration or transition to AD; we will compare and correlate these signals with MRI measures of atrophic rates and cortical degeneration to create joint MR-PET measures of disease burden. We will pioneer 3D cryosection imaging (in 3 subjects/year) to establish how 3D reconstructed maps of tangle density and betaamyloid distribution throughout the brain correlate with imaging measures from living patients. This groundtruth data will be a resource to the AD community, revealing the cellular correlates of imaging signals whose physiological meaning is poorly understood. We will map individuals and populations, revealing group patterns of cortical thinning and plaque and tangle pathology that predict outcomes. Identifying predictors of imminent decline and disease onset, our atlas will identify candidates with emerging pathology for early drug treatment, and will store statistical data to quantify how well treatments resist AD in those at risk. We will share all images, protocols, and algorithms with our 100+ collaborating laboratories.