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

项目摘要/摘要 从AG041851的第一个周期中获得的中心见解是，升高的淀粉样变的组合 在临床正常和轻度患者中，神经变性大大增加了临床进展的风险 一个新的发现是定义了一个异常生物标记物类别，其特征是 在没有淀粉样蛋白的情况下，阳性的神经变性/神经元损伤生物标志物。我们给这个范畴贴上标签 疑似非阿尔茨海默病病理生理学(SNAP)，假设它代表常见的非AD 病理学--例如，脑血管疾病、路易体病等。两种现代诊断分类 阿尔茨海默病(AD)系统已经存在；国家老龄研究所-阿尔茨海默病协会(NIA-AA) 和国际工作组(工作组)。Snap不符合这两个标准中的任何一个，但大约 老年临床正常(CN)和轻度认知障碍(MCI)就属于这一类。此外, 无论是NIA-AA标准还是IWG标准都不包括tau PET进行分类。我们最近领导了一家大型国际公司 高级研究小组提出了一种新的AD生物标志物描述性分类方案 (附录)。七个最广泛被认为的AD生物标记物被用来创建一个三级生物标记物 分类方案称为ATN系统。在ATN系统中，淀粉样生物标记物是淀粉样PET和 脑脊液Aβ42(表示为A)；tau生物标记物是tau PET和脑脊液p tau(表示为T)；以及， 神经变性/神经元损伤的生物标记物是FDGPET、解剖MRI和脑脊液t tau(用N表示)。 在这三个类别中，每个人都被归类为积极或消极，这导致了八种可能的情况 生物标志物状态(例如，A-T-N-、A+T+N-等)。NIA-AA和IWG的标准都没有将个人归类为 这两种方式都没有解决八种不同的ATN生物标志物排列的含义。 这项续期拨款的目的将集中在了解将个人归类为 这八个ATN类。我们将使用淀粉样蛋白PET来定义A，使用tau PET来定义T，并使用MRI皮质厚度 定义N鉴于目前强调的是没有临床症状或有早期体征的人 对于认知障碍，我们将集中在基线为CN和MCI的个体。我们的目标是： 目标1：创建30-90岁的CN和MCI人群的完全成像人群队列 基线淀粉样蛋白PET、tau PET和MRI研究将每15个月进行一次临床随访。 目标2：确定临床和人口学特征(例如，年龄、性别、载脂蛋白E、 脑血管疾病和基线认知能力)在八种ATN生物标志物状态中各不相同。 目的3：评估8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的关系 结果以及协变量(例如，年龄、性别、载脂蛋白E和脑血管疾病)是否会改变 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.