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

使用淀粉样蛋白 PET、tau PET 和 MRI 神经变性进行脑衰老和阿尔茨海默病生物标志物分类：开发 ATN 系统

• 批准号: 9308121
• 负责人: CLIFFORD R. JACK
• 金额: $ 73.24万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9308121
• 关键词: Address; Adopted; Age; Aging; Alzheimer' s Disease; Alzheimer' s Disease Pathway; Amyloid; Amyloidosis; Anatomy; Biological; Biological Markers; Categories; Cerebrovascular Disorders; Cessation of life; Characteristics; Classification; Classification Scheme; Clinic; Clinical; Clinical assessments; Cognitive; Collection; Data; Dementia; Deposition; Development; Diagnostic; Elderly; Frequencies; Functional disorder; Future; General Population; Grant; Grouping; Image; Impaired cognition; Impairment; Individual; International; Label; Lewy Body Disease; Magnetic Resonance Imaging; Modernization; National Institute on Aging; Nerve Degeneration; Neuronal Injury; Outcome; Paper; Participant; Pathology; Persons; Positioning Attribute; Positron-Emission Tomography; Prevalence; Publishing; Research; Research Infrastructure; Research Personnel; Scheme; System; Testing; Thick; Tracer; Visit; aged; aging brain; base; clinical risk; cognitive performance; cognitive testing; cohort; falls; fluorodeoxyglucose positron emission tomography; follow-up; imaging biomarker; insight; mild cognitive impairment; novel; population based; sex; tau Proteins; tau-1; working group

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.

项目概要/摘要 从 AG041851 第一个周期中获得的核心见解是，淀粉样变性升高的组合 神经退行性疾病大大增加了临床正常和轻度患者临床进展的风险 受损人群；并且，一项新的发现是异常生物标志物类别的定义，其特征是 在没有淀粉样蛋白的情况下，神经变性/神经元损伤生物标志物呈阳性，我们将其标记为此类。 怀疑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) 系统已存在；国家老龄化研究所 - 阿尔茨海默病协会 (NIA-AA) 和国际工作组 (IWG) 并未通过这两个标准中的任何一个来解决，但大约有 1/4。 此外，临床正常（CN）和轻度认知障碍（MCI）的老年人也属于这一类。 NIA-AA 和 IWG 标准均不包括 tau PET 分类。我们最近领导了一项大型国际研究。 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）七种最受广泛关注的 AD 生物标志物用于创建 3 类生物标志物。 称为 ATN 系统的分类方案 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（用A表示）；tau生物标志物是tau PET和CSF p tau（用T表示）； 神经退行性变/神经元损伤生物标志物包括 FDG PET、解剖 MRI 和 CSF t tau（用 N 表示）。 个体在三个类别中的每一个中被分为积极或消极，导致八种可能的情况 生物标志物状态（例如，A-T-N-、A+T+N- 等）。NIA-AA 和 IWG 标准均未对个体进行分类。 这种方式并没有解决八种不同 ATN 生物标志物排列的影响。 这笔续签赠款的目的将侧重于了解将个人分类为以下类别的含义： 我们将使用淀粉样蛋白 PET 来定义 A、tau PET 来定义 T 和 MRI 皮质厚度。 定义 N。考虑到目前对临床无症状或有早期症状的个体的重视 对于认知障碍，我们将重点关注基线为 CN 和 MCI 的个体。我们的目标是： 目标 1：创建基于人群的完全成像的 30-90 岁 CN 和 MCI 人群队列 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。 目标 2：确定临床和人口特征（例如年龄、性别、APOE、指标 脑血管疾病和基线认知表现）在八种 ATN 生物标志物状态中各不相同。 目标 3：估计八种 ATN 生物标志物状态的年龄和性别特定患病率。 目标 4：确定八种 ATN 生物标志物状态与认知或临床之间的关联 结果以及协变量（例如年龄、性别、APOE 和脑血管疾病）是否会改变发生率 认知能力下降。