Alzheimer neuroimaging-biomarkers in pre-clinical cognitive decline from a population-based study

 描述(申请人提供)：我们在这里提出了一项新的调查，直接解决了阿尔茨海默病(AD)研究中最令人头疼的两个问题：(1)早期AD是如何开始偏离正常认知老化的？(2)临床研究环境中的生物标记物研究是否适用于普通人群？该项目将研究老年性痴呆的两个神经病理特征的活体脑成像，以证明临床前认知能力下降。具体地说，我们将使用匹兹堡化合物-B(PIB)-正电子发射断层扫描技术来成像淀粉样β蛋白(Aβ)斑块沉积，并使用[F-18]AV-1451来成像聚集的tau病理。我们将把这些成像工具应用于一组精心挑选和确定特征的招募参与者，利用一项基于人群的研究中4-8年的连续、年度认知数据来定义临床前认知下降。其结果将是一种独特的嵌套病例对照设计 在临床正常认知状态范围内的“衰退者”和“非衰退者”。这项来自父母研究的个体差异表征使我们能够通过基线和30个月的随访PET成像以及持续的、年度的临床认知监测来探索早期AD轨迹和正常衰老轨迹之间的差异。我们将测试三种相互竞争的早期AD和正常衰老变异通路的模型，具体假设它们之间的关联和时间顺序：1)临床前下降，2)β沉积，3)近侧和新皮质tau沉积，以及4)进展为轻度认知障碍。此外，使用8年前在父母研究中测量的AD的已知流行病学痴呆症危险因素(生活方式、健康史、认知储备和血管)，我们将建立预测模型，以预测基线是否存在临床前Aβ和tau病理，以及它们在2.5年期间的动态变化率。最后，我们将使用倾向加权模型评估研究结果的概括性和外部有效性(即，与PET成像结果的风险保护关联)回到原始的较大人群队列(N=1982)。这个项目将促进人们对与年龄相关的认知衰退过程如何与阿尔茨海默病的发展相交的认识。研究结果将有助于阐明AD早期的病理事件顺序，从而为干预时机的预防策略提供信息。研究结果的推论将超越神经成像研究中典型的高度精选的临床或便利样本，推广到更具社会经济学包容性的老年人代表。

 DESCRIPTION (provided by applicant): We propose here a novel investigation that directly addresses two of the most vexing questions in Alzheimer Disease (AD) research: (1) How does early AD start to diverge from normal cognitive aging? (2) Are biomarker studies in clinical research settings generalizable to the general population? This Project will investigate in vivo brain imaging of the two neuropathological hallmarks of AD in older adults evidencing pre-clinical cognitive decline. Specifically, we will use Pittsburgh Compound-B (PiB)-PET to image amyloid-beta (Aβ) plaque deposition, and [F-18]AV-1451 to image aggregated tau pathology. We will apply these imaging tools to a carefully selected and characterized group of recruited participants, leveraging 4-8 years of serial, annual cognitive data from a population-based study to define pre-clinical cognitive decline. The result will be a unique nested case-control design of `decliners' and `non-decliners' within the constraints of clinically normal cognitive status. This individual-difference characterization from the parent study allows us to probe the divergence between early-stage AD trajectories and normal-aging trajectories, with baseline and 30-month follow-up PET imaging, and continued, annual clinical-cognitive monitoring for incident MCI. We will test three competing models of early-AD vs. normal-aging-variant pathways with specific hypotheses about associations and temporal order among: 1) pre-clinical decline, 2) Aβ deposition, 3) mesial and neocortical tau deposition, and 4) progression to MCI. Further, using known epidemiologic dementia risk factors for AD measured 8 years earlier in the parent study (lifestyle, health-history, cognitive reserve, and vascular), we will build predictive models for presence of preclinical Aβ and tau pathology at baseline, as well as their dynamic rate of change over 2.5 years. Finally, we will evaluate generalizability and external validity of study results (i.e., risk-protective associations with PET-imaging outcomes) back to the original larger population cohort (N=1982), using propensity-weighted modeling. This Project will advance knowledge of how the processes of age-related cognitive decline intersect with the development of AD. Findings will help elucidate the sequence of pathologic events early in AD and thereby inform prevention strategies regarding the timing of interventions. Inferences from study results will generalize beyond highly selected clinic or convenience samples typical of neuroimaging studies, to date, to a more socioeconomically inclusive representation of older adults.