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

项目概要 检测前驱期阿尔茨海默病 (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变得越来越重要，开发有针对性的干预措施 策略，并从当前可用的治疗计划中获得最大利益。然而，由于 认知障碍的表现存在显着差异，但临床前认知变化并不明显 可以从与年龄相关的认知能力下降中看出。尽管使用神经心理学、液体、 影像学生物标志物相对提高了AD的及时诊断，这些生物标志物的测量 价格昂贵且高度依赖技术，使得这些技术对于许多老年人来说不切实际 跨越不同的设置。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 识别早期检测器，这些检测器 1）对 AD 病理敏感，2）强烈预测未来的变化 认知，3) 在不同的环境中均可访问且可行。根据我们最近的调查结果， 确定言语运动控制措施可以作为神经退行性疾病早期阶段的有力辅助手段 肌萎缩侧索硬化症和原发性进行性失语症等疾病，我们建议评估 言语标记作为识别处于危险中的成年人的替代或补充且生态有效的策略 因 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结合，而这些过程都受到 随着年龄的增长而变化。我们假设言语运动控制的年龄相关变化率 成年人可能会受到遗传易感性的影响而患 AD。此外，我们假设测量 在认知要求较高的言语任务中引发的言语可以区分 APOE ε4 的携带者（即主要的 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，我们将确定衰老的影响 对 APOE ε4 阳性 (ε4 ) 和 APOE ε4 阴性 (ε4-) 基因型匹配的成人言语运动控制的影响 在性和教育方面。在目标 2 中，我们将确定年龄相关的大脑结构和静息态功能基础。 具有 ε4 和 ε4- 基因型的成年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内的认知变化（量化） 根据霍普金斯学习测试修订版 (HVLT-R) 和越野测试 (TMT) 分数； 2）如果言语和认知 变化是通过大脑结构和功能的改变来介导的。这项研究的结果将提供 有关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.