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， 狗是我们语言中使用频率很高的词，而不是鬣蜥。这项研究的K99阶段显示 这种新的心理语言学项目水平指标与记忆随着时间的推移而下降有关 传统的神经心理学评分，与脑体积有关，超过既定的遗传，主观， 和认知风险因素，并与高危个体8年来皮质变薄有关，没有 痴呆症的诊断。在R00阶段，将使用心理语言学度量来估计 跨AD连续体的语义损伤(目标1)并确定其敏感性和特异性 预测进展为临床阿尔茨海默病的心理语言学措施(目标2)。因为人口统计之间的关系 对心理语言学指标的理解不是很好，这个项目努力解构文化和人口统计 对这些指标的影响，以最大限度地发挥其在不同老年人早期诊断中的潜在效用。 对于R00目标，该项目将使用高级统计分析来调查来自两个大型 与来自一系列社会人口背景和语义流畅度数据的参与者进行纵向队列 用英语和西班牙语。R00提案为一个独立的研究计划奠定了基础，该计划专注于 正常衰老和跨AD连续体的语义加工。拟议的研究结果如下： 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，以完善谁来选择干预试验。

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.