Combined fMRI, structural MRI, 18MPPF PET & APOE to detect Alzheimer's risk

描述（由申请人提供）：这是我们之前名为“阿尔茨海默病早期诊断的功能性磁共振成像”（5 R01 AG013308-10）的R01的延续更新。拟议的第三个资助周期建立在该项目的最新发现和我们开发的海马结构和功能成像新技术的基础上。我们的数据支持结合遗传风险、结构和功能mri来识别阿尔茨海默病（AD）早期表现的实用性，并进一步表明载脂蛋白epsilon-4 （APOE-4）携带者的大脑变化可能比之前认为的要早得多。最近，我们的团队开发了高分辨率功能性核磁共振成像采集和分析的新技术，以及识别阿尔茨海默病受试者在很短时间内结构核磁共振成像变化的数学建模算法。此外，我们的研究小组最近使用了正电子发射断层扫描（PET），使用[18F]MPPF成像，一种测量海马（HC）、内吸皮层和杏仁核锥体细胞密度的配体；我们的初步数据显示[18F]MPPF结合在MCI和AD中降低，并且在健康对照中与记忆相关，提示其可能作为AD风险的独立评估。本研究建议在40-80岁AD和MCI高危人群的对照受试者中结合使用四种新的成像技术，两种结构成像技术（HC皮质厚度和HC径向萎缩）和两种功能成像技术（FMRI和[18F]MPPF），以确定在中老年至老年认知完整的高危受试者中，HC结构和功能是否存在与AD相似的细微纵向变化。我们将招募60名年轻（40-60岁）和36名年长（60岁以上）的对照者（各50%携带APOE-4）和35名轻度轻度认知障碍受试者，并使用这些新的成像方法和临床评估对他们进行为期两年半的随访。分析的重点将是对每项测量的单独变化率和组合变化率进行建模，目的是确定患AD风险最高的受试者。诊断和神经心理学评估将为基因型、家族史和短期大脑变化预测认知能力下降提供临床证实。通过结合这些不同的海马体结构和功能测量，我们的主要目标是开发一种方法来识别那些更有可能患AD的高危人群，并确定哪些新的成像技术提供了最理想和独立的预测未来衰退的方法。

DESCRIPTION (provided by applicant): This is a continuing renewal of our R01 previously titled "Functional MRl for Early Diagnosis of Alzheimer's Disease" (5 R01 AG013308-10). The proposed third grant cycle builds on recent findings from this project and new technologies we have developed for imaging hippocampal structure and function. Our data support the utility of combining genetic risk, structural and functional MRl to identify early manifestations of Alzheimer's disease (AD), and further suggest that brain changes may occur much earlier than previously thought in Apolipoprotein epsilon-4 (APOE-4) carriers. Recently, our group has developed new techniques in high-resolution functional MRl acquisition and analysis, and in mathematical modeling algorithms that identify structural MRl change in Alzheimer's disease subjects over very short time periods. In addition, our group has recently worked with positron emission tomography (PET) using [18F]MPPF imaging, a ligand that measures pyramidal cell density in the hippocampus (HC), entorhinal cortex and amygdala; our preliminary data show that [18F]MPPF binding is decreased in MCI and AD, and correlates with memory in healthy controls, suggesting its potential as an independent assessment of risk for AD. This grant proposes using a combination of four new imaging techniques, two structural (HC cortical thickness and HC radial atrophy), and two functional (FMRI and [18F]MPPF) in control subjects in the 40-80 range at-risk for AD and MCI patients, to determine if there are subtle longitudinal changes in HC structure and function similar to those seen in AD, in cognitively intact at-risk subjects in the late middle age to elderly range. We will recruit 60 younger (40-60) and 36 older (60+) controls, (50% of each with APOE-4), and 35 mild MCI subjects, and follow them for 21/2 years using these novel imaging measures and clinical assessments. Analyses will focus on modeling the rate of change of each measure alone and in combination, with the goal of identifying subjects at highest risk for developing AD. Diagnostic and neuropsychological evaluations will provide clinical corroboration that genotype, family history, and short-term brain changes predict cognitive decline. By combining these different measures of hippocampal structure and function, our primary goal is to develop an approach to identifying those at-risk who are more likely to develop AD, and to determine which of these novel imaging techniques provide the most optimal and independent predictors of future decline.