AMYLOID IMAGING IN THE ADULT CHILDREN STUDY

我们假设阿尔茨海默病（AD）有一个临床前阶段，其中脑淀粉样蛋白水平升高和β-淀粉样蛋白沉积物的积累预示着神经元功能障碍，细胞丢失和痴呆的逐渐发作。虽然淀粉样蛋白在脑损伤发生中的确切作用尚不清楚，但明确淀粉样蛋白斑块沉积的确切时间对于充分理解AD的生物学起源和设计适当的干预措施非常有帮助。 该项目将使用一种新的方法对人脑中的淀粉样蛋白斑块进行体内成像。PIB由匹兹堡大学开发，[11 C]PIB在体外制剂中对淀粉样蛋白斑块具有非常高的亲和力，并在淀粉样蛋白沉积的转基因小鼠模型中快速结合淀粉样蛋白斑块。我们已经实施了这种方法，并证明了更大的皮层摄取在老年人诊断为DAT与非痴呆对照组相比。在该项目中，将招募240名年龄在45岁至74岁之间的参与者，并使用PET和[11 C]PIB进行基线成像，以计算淀粉样蛋白斑块结合。在每十年（45 - 54岁、55 - 64岁和65 - 74岁）中，将研究40名至少有一名生物学父母患有DAT（发病年龄或AAO <80岁）的参与者和40名父母均未患有DAT（父母必须> 70岁）的参与者。此外，我们将在三年间隔后对[11 C]PIB受试者进行重新成像，以确定这两个队列中淀粉样蛋白结合的纵向过程。通过这些数据，我们将实现四个具体目标：1）在01 - 03年，我们将测量和比较120名父母患有DAT的ACS参与者和120名父母不患有DAT的参与者的皮质[11 C]PIB摄取。2）我们将皮质[11 C]PIB摄取与认知表现的具体测量相关联，包括学习效果的存在和程度，和人格测量。3)我们将检测皮质[11 C]PIB摄取与CSF生物标志物之间的相关性（项目2），以及皮质[11 C]PIB摄取与神经解剖学生物标志物之间的相关性（项目4）。4)在第4年和第5年，我们将分别对第1年和第2年入组的受试者重复PET [11 C]PIB成像。通过比较大脑皮层 [11 C]PIB摄取在这两个不同的时间点相隔三年，我们将能够纵向评估ACS队列，以确定[11 C]PIB结合的自然史及其临床前检测AD的潜力。

We hypothesize that Alzheimer's disease (AD) has a preclinical stage in which elevated levels of brain amyloid protein and accumulation of beta-amyloid deposits foreshadow the gradual onset of neuronal dysfunction, cell loss and dementia. While the exact role of amyloid in the initiation of brain damage is still unclear, it is clear that clarifying the exact timing of amyloid plaque deposition that precede AD would be extremely helpful in fully understanding the biological origins of AD and to assist in the design of appropriate interventions. This project will use a new method for the in vivo imaging of amyloid plaques in the human brain. Developed at the University of Pittsburgh, [11C]PIB has very high affinity for amyloid plaques with in vitro preparations and binds rapidly to amyloid plaques in a transgenic mouse model of amyloid deposits. We have implemented this method and demonstrated much greater cortical uptake in older participants diagnosed with DAT compared with nondemented control participants. In this project, 240 participants between the ages of 45 and 74 y will be recruited and undergo baseline imaging with PET and [11C]PIB for calculation of amyloid plaque binding. In each decade (45 - 54 y, 55 - 64 y, and 65 - 74 y) 40 participants with at least one biologic parent with DAT (age at onset, or AAO, <80y) and 40 participants whom neither parent has/had DAT (parents must be >70y) will be studied. In addition, we will re-image subjects with [11C]PIB after a three year interval to determine the longitudinal course of amyloid binding in these two cohorts. With this data we will achieve four specific aims: 1) In Years 01 - 03, we will measure and compare cortical [11C]PIB uptake in 120 ACS participants with a parent with DAT and in 120 participants without a parent with DAT. 2) We will correlate cortical [11C]PIB uptake with specific measures of cognitive performance, including presence and magnitude of learning effects, and with personality measures. 3) We will test for correlations between cortical [11C]PIB uptake and CSF biomarkers (Project 2), and between cortical [11C]PIB uptake and neuroanatomic biomarkers (Project 4). 4) In Years 04 and 05, we will repeat PET [11C]PIB imaging on participants enrolled in Years 01 and 02, respectively. By comparing the cortical [11C]PIB uptake at these two different time-points three years apart, we will be able to assess the ACS cohorts longitudinally to determine the natural history of [11C]PIB binding and its potential for preclinical detection of AD.