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

项目总结 检测阿尔茨海默病(AD)和轻度认知障碍(MCI)的早期征兆 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以及 从目前可用的治疗计划中获得最大利益。然而，由于两国之间的巨大差异， 认知损害的表现，临床前的认知变化与年龄相关的认知变化是无法区分的 拒绝。尽管使用神经心理学、体液和影像生物标记物的综合方法具有相对 提高了AD的及时诊断，这些生物标志物的测量成本高昂，技术含量高- 依赖，使这些技术不切实际地在不同环境中的许多老年人中使用。此外, 通过使用神经心理学电池评估认知功能仍然是临床上的黄金标准 干预效果的试验和评价。因此，识别对1)敏感的早期检测器是至关重要的 阿尔茨海默病的病理，2)对未来认知变化的强烈预测，以及3)跨不同领域的可访问性和可行性 设置。根据我们最近的发现，这些发现确定了言语运动控制的措施是对 索引神经退行性疾病的早期阶段，如肌萎缩侧索硬化症和原发进行性疾病 失语症，我们建议评估言语标记作为一种替代或补充和生态有效 识别因阿尔茨海默病而出现认知障碍风险的成年人的策略。言语生产是其中之一 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结合 这些都会随着年龄的增长而变化。我们假设与年龄相关的言语变化的速度 成人的运动控制会受到阿尔茨海默病的遗传易感性的影响。此外，我们假设 在认知要求高的言语任务中诱发的言语测量可以区分载脂蛋白Eε4的携带者(即 已知增加阿尔茨海默病风险的主要基因)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关节运动学 与神经成像相结合，追求三个目标。在目标1中，我们将确定老化对语音的影响 载脂蛋白ε4阳性(ε4)和载脂蛋白ε4阴性(ε4-)基因型在性别和性别上匹配的成年人的运动控制 教育。在目标2中，我们将确定与年龄相关的脑结构和静息状态的功能基础 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 根据霍普金斯学习测试的量化结果，声学/运动学测量可以预测两年内的认知变化。 修订了ε4和ε4组的高考成绩和连线测验分数，2)如果言语和认知发生变化 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关键信息 关于可以有效地结合到神经心理测试中以优化语音运动控制的措施 阿尔茨海默病临床评价。

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.