Validating the New Criteria for Preclinical Alzheimer's disease

描述（由申请人提供）：2010年，阿尔茨海默病协会（AA），国家老龄化研究所（NIA）和国家神经疾病和中风研究所组成了三个工作组来修订自1984年以来一直使用的阿尔茨海默病（AD）诊断指南。临床前工作组为尚未正式定义的疾病阶段制定了指导方针。该领域的大多数人认为，成功的AD疾病修饰治疗需要在痴呆发病之前开始治疗，也许在明显的临床症状（即MCI）之前开始治疗。因此，新的临床前AD标准的验证是一个重要的新研究前沿。阿尔茨海默病的临床前阶段是通过异常的阿尔茨海默病生物标志物研究来定义的，没有或只有轻微的认知缺陷。目前，AD主要有5种生物标志物，可分为两类：1)脑Ab淀粉样变性生物标志物和2)神经元损伤生物标志物。临床前标准描述了临床前阿尔茨海默病的三个阶段，这些阶段代表着疾病逐渐发展到晚期：阶段1 -无症状脑淀粉样变性。第2期：淀粉样蛋白阳性加上突触功能障碍和/或早期神经退行性变的证据。第3期-淀粉样蛋白阳性加上神经退行性变的证据加上微妙的认知症状。虽然新标准的制定本身就是一种进步，但仍有许多问题没有解决，主要问题是：“这些标准是否有效？”此外，没有具体说明实施这些标准所必需的许多问题。我们的总体目标是评估新的NIA-AA临床前AD标准的有效性。实施和评估标准有效性的必要第一步是为不同的生物标志物和认知测试制定ct点或阈值，以识别具有异常生物标志物值或细微认知缺陷的认知正常老年受试者。我们有五个具体目标：目标1：创建一个具有所有5种生物标志物的AD受试者（1a）和认知正常受试者（1b）的队列。目标2：为每个生物标志物（Aim 2a）开发切点，评估同类生物标志物（Aim 2b）之间的一致性，并为细微的认知变化开发切点（Aim 2c）。目的3：利用目的2的结果来估计老年人群队列中处于临床前阶段的受试者分布。目的4：确定临床前AD新标准的阶段对轻度认知障碍或痴呆进展的预测程度（Aim 4a），并确定临床前AD阶段与系列认知测试成绩下降的关系（Aim 4b）。目的5：根据临床随访和纵向认知测试，修订切点并重新估计临床前阶段受试者的分布，并将其与Aim 2的横断面衍生切点和Aim 3的临床前AD阶段人群分布进行比较。

DESCRIPTION (provided by applicant): In 2010, the Alzheimer's Association (AA), National Institute on Aging (NIA) and National Institute of Neurological Disorders and Stroke formed three workgroups to revise diagnostic guidelines for Alzheimer's disease (AD) that had been employed since 1984. The preclinical workgroup devised guidelines for a stage of the disease that had not yet been formally defined. Most in the field believe that successful disease modifying treatment of AD will require that treatment begin prior to onset of dementia and perhaps prior to overt clinical symptoms (i.e. MCI). Thus, validation of the new preclinical AD criteria is a major new investigational frontier. The preclinical phase of AD is defined by abnormal AD biomarker studies with no, or only subtle, cognitive deficits. At present, there are five major AD biomarkers which fall into two classes: 1) biomarkers of brain Ab amyloidosis and 2) biomarkers of neuronal injury. The preclinical criteria describe three stages of preclinical AD that represent incrementally more advanced disease: Stage 1 - Asymptomatic cerebral amyloidosis. Stage 2 - Amyloid positivity plus evidence of synaptic dysfunction and/or early neurodegeneration. Stage 3 - Amyloid positivity plus evidence of neurodegeneration plus subtle cognitive symptoms. While formulation of the new criteria alone represents an advance, there were many issues left unaddressed, the major one being: "Are the criteria valid?".In addition, many issues necessary for operationalization of the criteria were not specified. Our overall goal in this grant proposal is to assess the validity of the new NIA-AA preclinical AD criteria. A necessary first step in operationalizing and assessing the validity of the criteria is to develop ct-points or thresholds for different biomarkers and cognitive tests to identify cognitively normal elderly subjects with abnormal biomarker values or subtle cognitive deficits. We have five Specific Aims: Aim 1: To create a cohort of AD subjects (1a) and cognitively normal subjects (1b) who have all 5 biomarkers. Aim 2: To develop cut-points for each biomarker (Aim 2a), evaluate the agreement between biomarkers of the same class (Aim 2b) and develop cut-points for subtle cognitive change (Aim 2c). Aim 3: To use the findings from Aim 2 to estimate the distribution of subjects that fall into preclinical stages in an elderly population-based cohort. Am 4: To determine how well the stages of the new criteria for Preclinical AD predict progression to mild cognitive impairment or dementia (Aim 4a) and to determine the association of the stages of Preclinical AD with decline on serial cognitive testing (Aim 4b). Aim 5: To revise cut-points and re-estimate the distribution of subjects that fall into preclinical stages based on clinical follow-up and longitudinal cognitive testing and compare these with cross-sectionally derived cut-points from Aim 2 and the population distribution of Preclinical AD stages from Aim 3.