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

项目摘要 在前驱期检测阿尔茨海默病（AD）和轻度认知障碍（MCI）的早期体征 AD阶段对于成本有效的临床试验越来越重要，开发有针对性的干预措施 战略，并从目前可用的治疗计划中获得最大利益。但由于 认知障碍的表现存在实质性差异，临床前认知变化不 与年龄相关的认知能力下降。虽然使用神经心理学，流体， 而影像学生物标志物相对提高了AD的及时诊断， 昂贵且高度依赖技术，使得这些技术不适用于许多老年人 在不同的环境中。此外，通过使用神经心理学评估认知功能， 电池仍然是临床试验和评估干预效果的金标准。因此，关键是 识别早期检测器，其1）对AD的病理学敏感，2）对AD的未来变化具有强烈的预测性， 认知，以及3）在不同环境中可访问和可行。根据我们最近的发现， 确定了言语运动控制的措施，作为索引神经退行性疾病早期阶段的有力帮助。 疾病，如肌萎缩侧索硬化症和原发性进行性失语症，我们建议评估 语音标记作为识别风险成年人的替代或补充和生态有效策略 患上AD导致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整合，这些过程都受到 随着年龄的增长而变化。我们假设，年龄相关的言语运动控制的变化率， 成年人可能受到遗传易感性的影响而发展成AD。此外，我们假设， 在认知要求高的言语任务期间引发的言语可以区分APOE ε4的携带者（即，主要 已知增加AD风险的基因），以及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，追求三个目标。在目标1中，我们将确定衰老的影响 对APOE ε4阳性（ε4+）和APOE ε4阴性（ε4-）基因型匹配的成年人的语言运动控制的影响 在性和教育方面。在目标2中，我们将确定年龄的大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内的认知变化， 通过霍普金斯学习测验修订版（HVLT-R）和连线测验（TMT）评分;以及2）如果言语和认知 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 关于言语运动控制措施的关键信息，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; 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.