Preclinical markers of Alzheimer's disease using psycholinguistic semantic measures

项目摘要 阿尔茨海默病（AD）的临床诊断是基于记忆障碍的核心标准，但 生物标志物可检测的病理生理学变化在临床症状出现前几十年就开始了。本临床前 阶段，其中有人患有AD的神经病理学，但尚未表现出临床症状，对于 为患者和护理人员提供潜在干预和及时诊断。临床前阶段目前仅 可以用昂贵的或侵入性的生物标志物检测到。因为目前的认知测量对 AD的临床前阶段，并且具有低特异性和关于个体的教育和 文化接触，迫切需要开发敏感，低成本和高访问认知标记， 在不同的老年人中早期发现。这个项目的主要目标是调查小说心理语言学 现有认知测试数据的度量可以准确地识别处于AD最早阶段的人。语义 流畅性任务-在一分钟内说出尽可能多的动物-测试语义记忆，这是第一个认知领域之一 在AD中受损。传统上，语义流畅性是通过项目总数来评分的。但 在此任务的项目级别上，单词是丰富的信息，因为单词是在语义网络中组织的， 在AD期间变得脆弱，特别是对于连接不良且不经常使用的单词。这些特质 可以用新颖的心理语言学度量来捕获语义网络中的词，例如词频， 例如，在一个实施例中，在我们的语言中，“狗”是一个高频词，与“鬣蜥”相反。本研究的K99阶段显示， 新的心理语言学项目级指标与记忆随着时间的推移而下降， 传统的神经心理学评分，与脑容量有关，超过了既定的遗传，主观， 和认知风险因素，并与8年来没有高风险个体的更多皮质变薄有关。 痴呆症的诊断在R 00阶段，心理语言学指标将被用来估计的时间性 AD连续体中的语义障碍（目标1），并确定 心理语言学指标预测进展为临床AD（目的2）。因为人口统计学的关系 心理语言学指标还没有得到很好的理解，这个项目致力于解构文化和人口统计学 这些指标的影响，以最大限度地提高其在不同的老年人早期诊断的潜在效用。 对于R 00目标，该项目将采用先进的统计分析来调查来自两个大型 来自一系列社会人口背景和语义流畅性数据的参与者的纵向队列 英语和西班牙语。R 00提案为一个独立的研究计划奠定了基础， 在正常老化和AD连续体中的语义处理。拟议研究的结果已 转化为临床工具的潜力，我们可以在教育，语言和文化上使用 不同的个体来细化选择谁进行干预试验。

PROJECT ABSTRACT The clinical diagnosis of Alzheimer’s disease (AD) is based on the core criterion of memory impairment, but biomarker-detectable pathophysiological changes start decades before clinical symptoms. This preclinical phase, in which someone has the neuropathology of AD but does not yet show clinical symptoms, is crucial for potential intervention and timely diagnosis for patient and caregiver. The preclinical phase is currently only detectable with expensive or invasive biomarkers. Because current cognitive measures are not sensitive to the preclinical phase of AD and have low specificity and large variation with regard to individuals’ educational and cultural exposure, there is a critical need to develop sensitive, low-cost, and high-access cognitive markers for early detection in diverse older adults. The primary goal of this project is to investigate if novel psycholinguistic metrics of existing cognitive test data can accurately identify people in the earliest stages of AD. The semantic fluency task—naming as many animals in one minute—tests semantic memory, one of the first cognitive domains to become impaired in AD. Traditionally, semantic fluency is scored by the total number of items. However, there is a wealth of information at the item-level of this task, because words are organized in a semantic network that becomes vulnerable during AD, specifically for words that are poorly connected and not often used. These traits of words in the semantic network can be captured with novel psycholinguistic metrics, such as lexical frequency, e.g., ‘dog’ is a high-frequent word in our language, as opposed to ‘iguana.’ The K99 phase of this study showed that novel psycholinguistic item-level metrics related to memory decline over time over and above other traditional neuropsychological scores, related to brain volume over and above established genetic, subjective, and cognitive risk factors, and related to more cortical thinning across eights years in high-risk individuals without a dementia diagnosis. In the R00 phase, psycholinguistic metrics will be used to estimate the temporality of semantic impairment across the AD continuum (Aim 1) and determine the sensitivity and specificity of psycholinguistic measures to predict progression to clinical AD (Aim 2). Since the relationship of demographics to psycholinguistic metrics is not well understood, this project strives to deconstruct cultural and demographic effects on these metrics in order to maximize their potential utility in early diagnosis among diverse older adults. For the R00 aims, the project will employ advanced statistical analyses to investigate data from two large longitudinal cohorts with participants from a range of socio-demographic backgrounds and semantic fluency data in English and Spanish. The R00 proposal lays the foundation for an independent research program focused on semantic processing in normal aging and across the AD continuum. The results of the proposed research have the potential to translate into a clinical tool that we can use across educationally, linguistically, and culturally diverse individuals to refine who to select for intervention trials.