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

描述(由申请人提供)：这是我们的R01的持续续订，以前的标题是“用于阿尔茨海默病早期诊断的功能性MRL”(5 R01 AG013308-10)。建议的第三个赠款周期建立在该项目的最新发现和我们为成像海马体结构和功能而开发的新技术的基础上。我们的数据支持结合遗传风险、结构和功能MRL来识别阿尔茨海默病(AD)的早期表现，并进一步表明，在载脂蛋白epsilon-4(APOE-4)携带者中，大脑变化可能比先前认为的更早发生。最近，我们团队在高分辨率功能MRL采集和分析以及数学建模算法方面开发了新技术，这些算法可以在很短的时间内识别阿尔茨海默病受试者的结构性MRL变化。此外，我们的团队最近使用[18F]MPPF成像进行了正电子发射断层扫描(PET)，这是一种测量海马区(HC)、内嗅皮层和杏仁核中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中减少，并与健康对照组的记忆力相关，表明它可能作为AD风险的独立评估。这项拨款建议结合四种新的成像技术，在40-80岁AD和MCI患者的对照受试者中使用两种结构(HC皮质厚度和HC放射状萎缩)和两种功能(fMRI和[18F]MPPF)，以确定在认知正常的中老年高危受试者中，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名老年(60+)对照组(各50%患有APOE-4)和35名轻度MCI受试者，并使用这些新的成像方法和临床评估对他们进行21年半的跟踪调查。分析将侧重于对每项措施单独和组合的变化率进行建模，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提供临床证实，即基因型、家族史和短期脑部变化预测认知能力下降。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发展为AD的高危人群，并确定这些新的成像技术中的哪一种提供了对未来衰退最理想和最独立的预测因子。

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.