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

 描述（由申请人提供）：我们在此提出一项新的研究，直接解决阿尔茨海默病（AD）研究中两个最令人烦恼的问题：（1）早期AD如何开始偏离正常的认知老化？(2)临床研究环境中的生物标志物研究是否可推广到一般人群？本项目将研究在体内脑成像的两个神经病理学标志的AD在老年人证明临床前认知能力下降。具体而言，我们将使用匹兹堡化合物-B（PiB）-PET对淀粉样蛋白-β（Aβ）斑块沉积进行成像，并使用[F-18]AV-1451对聚集的tau病理进行成像。我们将这些成像工具应用于精心挑选和特征化的一组招募的参与者，利用基于人群的研究中4-8年的连续年度认知数据来定义临床前认知下降。结果将是一个独特的嵌套病例对照设计， 在临床正常认知状态的限制下的“下降者”和“非下降者”。这种来自母研究的个体差异特征使我们能够通过基线和30个月随访PET成像以及持续的年度临床认知监测来探索早期AD轨迹和正常老化轨迹之间的差异。我们将测试早期AD与正常衰老变异通路的三种竞争模型，并对以下因素之间的关联和时间顺序进行特定假设：1）临床前下降，2）Aβ沉积，3）近中和新皮质tau沉积，以及4）进展为MCI。此外，使用母研究中8年前测量的AD的已知流行病学痴呆风险因素（生活方式、健康史、认知储备和血管），我们将建立基线时临床前Aβ和tau病理学存在的预测模型，以及它们在2.5年内的动态变化率。最后，我们将评估研究结果的概括性和外部效度（即，与PET成像结果的风险保护相关性）回到最初的较大人群队列（N=1982），使用倾向加权模型。该项目将推进与年龄相关的认知衰退过程如何与AD的发展交叉的知识。研究结果将有助于阐明AD早期病理事件的顺序，从而为干预时机的预防策略提供信息。从研究结果的推论将概括超出高度选择的诊所或便利样本典型的神经影像学研究，到目前为止，一个更社会经济包容性的代表老年人。

 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.