Early Biomarkers of Alzheimer's Disease: Using Speech Markers to Detect Mild Cognitive Impairment

项目摘要 阿尔茨海默病（AD）和轻度认知障碍（MCI）的前驱期早期体征检测 AD对于具有成本效益的临床试验，开发有针对性的干预策略， 从现有的治疗计划中获得最大的益处。然而，由于在 认知障碍的表现，临床前认知变化与年龄相关的认知变化不可区分 下降尽管使用神经心理学、流体和成像生物标志物的组合方法相对具有优势， 改善了AD的及时诊断，这些生物标志物的测量是昂贵的和高度技术性的， 依赖性，使得这些技术在不同环境中的许多老年人中使用不切实际。此外，本发明还提供了一种方法， 通过使用神经心理学成套测验来评估认知功能仍然是临床的金标准。 试验和干预效果评价。因此，识别早期检测器是至关重要的：1）对 AD的病理学，2）强烈预测未来的认知变化，以及3）在不同的领域中可获得和可行 设置.根据我们最近的发现，已经确定言语运动控制的措施是一个强大的援助， 神经退行性疾病的早期阶段，如肌萎缩性侧索硬化症和原发性进行性硬化症， 失语症，我们建议评估的言语标记作为一种替代或补充和生态有效的 用于识别有发生AD所致认知障碍风险的成人的策略。言语产生是 人类最复杂的运动行为，因为它依赖于认知，感觉和运动过程的紧密整合 这些都是随着年龄的增长而变化的。我们假设年龄相关的言语变化率 成年人的运动控制可受到遗传易感性的影响而发展成AD。此外，我们假设， 在认知要求的言语任务期间引起的言语测量可以区分APOE ε4的携带者（即，的 已知增加AD风险的主要基因）和基线语音声学和运动学测量 可以预测以后的认知能力下降。拟议的研究将创新地使用声学和发音运动学 与神经影像学相结合，以实现三个目标。在目标1中，我们将确定年龄对语言的影响 APOE ε4阳性（ε4+）和APOE ε4阴性（ε4-）基因型在性别和 教育在目标2中，我们将确定年龄相关变化的脑结构和静息状态功能基础， ε4+和ε4-基因型成人的言语测量。最后，在目标3中，我们将确定1）基线语音是否 声学/运动学测量可预测两年内的认知变化，如霍普金斯学习测试所量化的那样， ε4+和ε4-组的修订（HVLT-R）和连线测验（TMT）评分，以及2）如果言语和认知发生变化 是通过改变大脑结构和功能来调节的。这项研究的结果将提供关键信息， 关于言语运动控制的措施，可以有效地纳入神经心理学测试，以优化 AD的临床评估。

PROJECT SUMMARY Detecting early signs of Alzheimer’s disease (AD) and mild cognitive impairment (MCI) during the prodromal stage of AD is becoming increasingly important for cost-effective clinical trials, developing targeted intervention strategies, and gaining maximum benefit from currently available treatment plans. However, because of substantial differences in the manifestation of cognitive impairment, preclinical cognitive changes are not discernible from age-related cognitive decline. Although a combined approach of using neuropsychological, fluid, and imaging biomarkers has relatively improved the timely diagnosis of AD, measurement of these biomarkers is expensive and highly technology- dependent, making these techniques impractical for use in many older adults across different settings. In addition, assessment of cognitive functions through the use of neuropsychological batteries remains the gold-standard in clinical trials and evaluation of intervention efficacy. Thus, it is critical to identify early detectors that are 1) sensitive to pathologies of AD, 2) strongly predictive of future change in cognition, and 3) accessible and feasible across diverse settings. Based on our recent findings, which have identified measures of speech motor control as a powerful aid in indexing early stages of neurodegenerative diseases such as amyotrophic lateral sclerosis and primary progressive aphasia, we propose assessment of speech markers as an alternative or complementary and ecologically valid strategy for identifying adults at risk of developing cognitive impairment due to AD. Speech production is one of humans’ most complex motor behaviors, as it relies on tight integration of cognition, sensory, and motor processes which are all subject to change with advancing age. We hypothesize that the rate of age-related changes in speech motor control of adults can be influenced by genetic susceptibility to develop AD. In addition, we hypothesize that measures of speech elicited during cognitively-demanding speech tasks can differentiate carriers of APOE ε4 (i.e., the major gene known to increase AD risk) from noncarriers and that baseline speech acoustic and kinematic measures can predict later cognitive decline. The proposed research will innovatively use acoustics and articulatory kinematics in combination with neuroimaging to pursue three Aims. In Aim 1, we will determine the effect of aging on speech motor control of adults with APOE ε4 positive (ε4+) and APOE ε4 negative (ε4-) genotypes matched in sex and education. In Aim 2, we will identify the brain structural and resting-state functional bases for age-related changes in speech measures of adults with ε4+ and ε4- genotypes. Finally, in Aim 3, we will determine 1) whether baseline speech acoustic/ kinematic measures predict cognitive change over two years, as quantified by Hopkins Learning Test- Revised (HVLT-R) and Trail Making Test (TMT) scores in ε4+ and ε4- groups and 2) if speech and cognitive changes are mediated through alterations in brain structure and function. The findings of this study will provide critical information about measures of speech motor control that can be efficiently incorporated into neuropsychological testing to optimize the clinical assessment of AD.