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

项目总结 在先兆中检测阿尔茨海默病(AD)和轻度认知障碍(MCI)的早期迹象 AD阶段对于具有成本效益的临床试验、开发有针对性的干预措施变得越来越重要 战略，并从目前可用的治疗计划中获得最大利益。然而，由于 认知损害的表现有实质性差异，临床前认知改变不明显 与年龄相关的认知能力下降有明显区别。尽管综合运用神经心理学，流体， 而成像生物标记物相对提高了AD的及时诊断、测量这些生物标记物 昂贵且高度依赖技术，这使得这些技术在许多老年人中使用不切实际 在不同的环境中。此外，通过使用神经心理学来评估认知功能 电池仍然是临床试验和干预效果评估的黄金标准。因此，至关重要的是 识别1)对AD的病理敏感的早期检测器，2)强烈预测未来AD的变化 认知，以及3)在不同的环境中可获得和可行的。根据我们最近的发现，这些发现已经 确定言语运动控制的措施是对神经退行性变早期阶段进行索引的有力辅助 疾病，如肌萎缩侧索硬化症和原发性进行性失语，我们建议评估 语音标记作为识别高危成年人的替代或补充和生态有效的策略 由阿尔茨海默病引起的认知障碍。言语产生是人类最复杂的运动之一 行为，因为它依赖于认知、感觉和运动过程的紧密结合，这些过程都受到 随着年龄的增长而改变。我们假设年龄相关的言语运动控制的改变率 成年人可能会受到遗传易感性的影响而患上阿尔茨海默病。此外，我们还假设， 在认知要求高的言语任务中诱发的言语可以区分载脂蛋白Eε4的携带者(即 已知会增加AD风险的基因)来自非携带者，以及基线语音、声学和运动学测量 可以预测以后的认知衰退。拟议的研究将创新性地使用声学和发音 运动学与神经成像相结合，追求三个目标。在目标1中，我们将确定老化的影响 载脂蛋白ε4阳性(ε4)和载脂蛋白ε4阴性(ε4-)基因匹配成年人的言语运动控制 在性和教育方面。在目标2中，我们将确定大脑结构和静息状态与年龄的功能基础- ε-4和ε-4-型成人言语测量的相关变化最后，在目标3中，我们将确定 1)基线语音声学/运动学测量是否可以预测两年后的认知变化 由霍普金斯学习测验修订(HVLT-R)和连线测验(TMT)得分；以及2)如果言语和认知 变化是通过大脑结构和功能的改变来调节的。这项研究的结果将提供 有关语音运动控制措施的关键信息，可以有效地合并到 神经心理测试，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; 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.