Validating the New Criteria for Preclinical Alzheimer's disease

描述(由申请人提供)：2010年，阿尔茨海默氏症协会(AA)、国家老龄研究所(NIA)和国家神经疾病和中风研究所成立了三个工作组，以修订自1984年以来一直采用的阿尔茨海默病(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南。该领域的大多数人认为，成功的AD疾病修饰治疗将要求在痴呆发作之前开始治疗，可能在明显的临床症状(即MCI)之前开始治疗。因此，验证新的临床前AD标准是一个主要的新的研究前沿。阿尔茨海默病的临床前阶段是由没有或只有微小的认知缺陷的异常AD生物标记物研究来定义的。目前，AD的生物标志物主要分为两类：1)脑淀粉样变性的生物标志物；2)神经元损伤的生物标志物。临床前标准描述了临床前AD的三个阶段，这三个阶段代表了更严重的疾病：阶段1-无症状的脑淀粉样变性。阶段2-淀粉样蛋白阳性加上突触功能障碍和/或早期神经变性的证据。阶段3-淀粉样蛋白阳性加上神经变性的证据加上轻微的认知症状。虽然制定新的标准本身就是一种进步，但仍有许多问题没有得到解决，主要的问题是：“标准是否有效？”此外，没有具体说明标准实施所需的许多问题。我们在这项拨款提案中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记物和认知测试制定ct点或阈值，以识别认知正常的老年受试者，这些受试者有异常的生物标记物值或轻微的认知缺陷。我们有五个具体目标：目标1：创建AD受试者(1a)和认知正常受试者(1b)的队列，这些受试者拥有全部5个生物标志物。目标2：为每个生物标记物制定切入点(目标2a)，评估同类生物标记物之间的一致性(目标2b)，并制定细微认知变化的切入点(目标2c)。目的3：使用目标2的发现来估计老年人群队列中处于临床前阶段的受试者的分布。AM 4：确定新的临床前AD标准的分期对进展为轻度认知障碍或痴呆的预测能力(目标4a)，并确定临床前AD的阶段与系列认知测试下降的相关性(目标4b)。目的5：根据临床随访和纵向认知测试，修订和重新估计处于临床前阶段的受试者的分布，并将其与目标2的横断面切点和目标3的临床前AD阶段的人群分布进行比较。

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.