Brain Aging and Alzheimer's Biomarker Classification Using Amyloid PET, tau PET, and Neurodegeneration on MRI: Developing the ATN system

项目总结/摘要 从AG 041851的第一个周期中获得的中心见解是，淀粉样变性升高与淀粉样变性的结合， 和神经退行性变大大增加了临床正常和轻度 受损的人;并且，一个新的发现是异常生物标志物类别的定义，其特征在于 在不存在淀粉样蛋白的情况下，阳性神经变性/神经元损伤生物标志物。我们把这个类别 疑似非阿尔茨海默病病理生理学（SNAP），假设其代表常见的非AD 病理学-例如，脑血管病、路易体病等两种现代诊断分类 系统存在阿尔茨海默病（AD）;国家老年人协会研究所（NIA-AA） 国际工作组（IWG）。这两个标准中的任何一个都没有涉及SNAP，但大约有1/4的 临床正常（CN）和轻度认知障碍（MCI）的老年人属于这一类。此外，本发明还提供了一种方法， NIA-AA和IWG标准都不包括用于分类的τ PET。我们最近领导了一个大型国际活动 一组高级研究人员提出了一种新的AD生物标志物描述性分类方案 （附录）。7种最广泛的AD生物标志物用于创建3类生物标志物 这就是所谓的ATN系统。在ATN系统中，淀粉样蛋白生物标志物是淀粉样蛋白PET和 CSF Aβ42（由A表示）; tau生物标志物是tau PET和CSF p tau（由T表示）;以及， 神经变性/神经元损伤生物标志物是FDG PET、解剖MRI和CSF t tau（用N表示）。 个人被分为积极或消极的三个类别，导致八种可能的 生物标记状态（例如，A-T-N-、A+T+N-等）。NIA-AA和IWG标准都没有将个人分类为 这种方式，也没有解决八种不同的ATN生物标志物排列的含义。 这一更新补助金的目的将集中在理解个人分类的影响， 这八个ATN课程。我们将使用淀粉样蛋白PET来定义A，tau PET来定义T，以及MRI皮质厚度 定义N。鉴于目前强调的是临床上无症状或有非常早期症状的个体 对于认知障碍，我们将集中研究基线时CN和MCI的个体。我们的目标是： 目的1：创建年龄在30-90岁的CN和MCI个体的完全成像的基于人群的队列， 基线淀粉样蛋白PET、tau PET和MRI研究，每15个月进行一次临床随访。 目的2：确定临床和人口统计学特征（例如，年龄、性别、载脂蛋白E、 脑血管疾病和基线认知表现）在八种ATN生物标志物状态之间变化。 目的3：估计八种ATN生物标志物状态的年龄和性别特异性患病率。 目的4：确定八种ATN生物标志物状态与认知或临床 结果以及是否存在协变量（例如，年龄、性别、APOE和脑血管疾病）改变 认知能力下降

PROJECT SUMMARY / ABSTRACT Central insights gained from the first cycle of AG041851 were that the combination of elevated amyloidosis and neurodegeneration greatly increased risk of clinical progression among both clinical normal and mildly impaired persons; and, a novel finding was the definition of an abnormal biomarker category characterized by positive neurodegeneration/neuronal injury biomarkers in the absence of amyloid. We labeled this category suspected non-Alzheimers pathophysiology (SNAP) on the assumption that it represented common non-AD pathologies - e.g., cerebrovascular disease, Lewy body disease, etc. Two modern diagnostic classification systems exist for Alzheimers disease (AD); the National Institute on Aging-Alzheimers Association (NIA-AA) and the International Working Group (IWG). SNAP is not addressed by either of these criteria, yet roughly ¼ of elderly clinically normal (CN) and mild cognitive impairment (MCI) persons fall into this category. In addition, neither the NIA-AA nor the IWG criteria include tau PET for classification. We recently led a large international group of senior investigators in proposing a new, descriptive classification scheme for AD biomarkers (Appendix). The seven most widely regarded AD biomarkers are used to create a 3-class biomarker classification scheme called the ATN system. In the ATN system, amyloid biomarkers are amyloid PET and CSF Aβ42 (denoted by A); tau biomarkers are tau PET and CSF p tau (denoted by T); and, neurodegeneration/neuronal injury biomarkers are FDG PET, anatomic MRI, and CSF t tau (denoted by N). Individuals are classified as positive or negative in each of the three categories leading to eight possible biomarker states (e.g., A-T-N-, A+T+N-, etc.). Neither the NIA-AA nor the IWG criteria categorize individuals in this way and neither addresses the implications of the eight different ATN biomarker permutations. The aims of this renewal grant will focus on understanding the implications of categorizing individuals into these eight ATN classes. We will use amyloid PET to define A, tau PET to define T, and MRI cortical thickness to define N. Given the current emphasis on individuals who are clinically asymptomatic or have very early signs of cognitive impairment, we will concentrate on individuals who are CN and MCI at baseline. Our aims are: Aim 1: To create fully imaged population-based cohorts of CN and MCI individuals aged 30–90 with baseline amyloid PET, tau PET, and MRI studies who will be followed clinically with visits every 15 months. Aim 2: To determine how clinical and demographic characteristics (e.g., age, sex, APOE, indicators of cerebrovascular disease, and baseline cognitive performance) vary across the eight ATN biomarker states. Aim 3: To estimate the age and sex specific prevalence rates of the eight ATN biomarker states. Aim 4: To determine the associations between the eight ATN biomarker states and cognitive or clinical outcomes and whether covariates (e.g., age, sex, APOE, and cerebrovascular disease) modify rates of cognitive decline.