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，与“鬣蜥”相对，“狗”在我们的语言中使用频率很高。“九个新颖的项目级心理语言学 语义流畅性的指标已被选择：调查如何AD成像生物标志物在非痴呆症 成人与心理语言学措施（目标1，K99）;估计语义障碍的时间性， AD连续体（目标2，R 00）;并确定心理语言学措施的敏感性和特异性， 预测进展为临床AD（目标3，R 00）。由于人口统计学与心理语言学的关系 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对这些指标的影响。 指标，以最大限度地发挥其在不同老年人中的早期诊断的潜在效用。该项目将 采用先进的统计分析，调查来自三个大型纵向队列的数据， 参与者和语义流畅性数据在英语，西班牙语和荷兰语。此K99/R 00提案奠定了 一个独立的研究项目的基础，专注于正常老化和跨 AD连续体拟议的项目将为申请人提供1）计算方面的新培训 语义和结构方程建模，2）成像生物标志物数据的经验，以及3）强大的 文化神经心理学的基础这些经验将补充申请人的强大背景 神经语言学和流行病学拟议研究的结果有可能转化为 临床工具，我们可以使用在教育，语言和文化多样的个人，以完善谁， 选择进行干预试验。

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.' Nine novel item-level psycholinguistic metrics of semantic fluency have been selected to: investigate how AD imaging biomarkers in nondemented adults relate to psycholinguistic measures (Aim 1, K99); estimate the temporality of semantic impairment across the AD continuum (Aim 2, R00); and determine the sensitivity and specificity of psycholinguistic measures to predict progression to clinical AD (Aim 3, R00). 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. The project will employ advanced statistical analyses to investigate data from three large longitudinal cohorts with diverse participants and semantic fluency data in English, Spanish, and Dutch. This K99/R00 proposal lays the foundation for an independent research program focused on semantic processing in normal aging and across the AD continuum. The proposed project will provide the applicant with 1) new training in computational semantics and structural equation modeling, 2) experience with imaging biomarker data, and 3) a strong foundation in cultural neuropsychology. These experiences will supplement the applicant's strong background in Neurolinguistics and Epidemiology. 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.