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 生物标记物可检测的病理生理变化在临床症状出现前几十年就开始了。这项临床前研究 一个人有AD的神经病理，但还没有表现出临床症状的阶段，对 对患者和照顾者进行潜在的干预和及时的诊断。临床前阶段目前仅为 可用昂贵的或侵入性生物标记物检测。因为目前的认知测量对 阿尔茨海默病的临床前阶段，特异性低，个体受教育程度和性别差异大 文化暴露，迫切需要开发敏感、低成本和高可获得性的认知标记物 在不同的老年人中及早发现。这个项目的主要目标是调查新奇的心理语言学 现有认知测试数据的度量可以准确地识别AD早期阶段的人。语义学 流利的任务--在一分钟内命名尽可能多的动物--测试语义记忆，这是最早的认知领域之一 在AD中受到损害。传统上，语义流畅度是根据条目的总数来评分的。然而，在那里 是这项任务项目级别的丰富信息，因为单词是在语义网络中组织的，该网络 在AD期间变得脆弱，特别是对于联系较差和不经常使用的单词。这些特点 可以用新的心理语言学度量来捕捉语义网络中的单词，例如词汇频率， 在我们的语言中，‘狗’是一个出现频率很高的词，而不是‘鬣蜥’。九种新的项目级心理语言学 语义流畅性的衡量标准已被选择用于：调查非痴呆患者的AD成像生物标志物 成人与心理语言测量有关(目标1，K99)；估计语义损伤的暂时性 AD连续体(目标2，R00)；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，R00)。因为人口统计学与心理语言学的关系 指标还没有被很好地理解，这个项目努力解构文化和人口对这些指标的影响 为了最大限度地发挥其在不同老年人早期诊断中的潜在效用。该项目将 使用高级统计分析来调查来自三个不同类型的大型纵向队列的数据 参与者和英语、西班牙语和荷兰语的语义流畅度数据。这份K99/R00提案奠定了 为一个独立的研究计划奠定基础，该计划专注于正常衰老和跨年龄的语义处理 公元连续体。拟议的项目将为申请者提供1)计算方面的新培训 语义学和结构方程建模，2)有生物标志物数据成像经验，3)有较强的 文化神经心理学基础。这些经历将补充申请人的强大背景 神经语言学和流行病学。拟议的研究结果有可能转化为 我们可以在教育、语言和文化上不同的人之间使用的临床工具，以完善谁 选择以进行干预试验。

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.