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

阿尔茨海默病的早期生物标志物：使用语音标志物检测轻度认知障碍

• 批准号: 10457426
• 负责人: Marziye Eshghi
• 金额: $ 19.88万
• 依托单位: MGH INSTITUTE OF HEALTH PROFESSIONS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10457426
• 关键词: 3-Dimensional; Acoustics; Adult; Affect; Age; Age-associated memory impairment; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease pathology; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyotrophic Lateral Sclerosis; Anatomy; Apolipoprotein E; Biological Markers; Brain; Brain region; Clinical; Clinical Trials; Clinical assessments; Cognition; Cognitive; Cohort Studies; Complex; Data; Dementia; Detection; Diagnosis; Diagnostic; Early Intervention; Early treatment; Elderly; Electromagnetics; Evaluation; Frequencies; Functional disorder; Future; Genes; Genetic Predisposition to Disease; Genotype; Goals; Gold; Healthcare Industry; Human; Impaired cognition; Intervention; Learning; Liquid substance; Magnetic Resonance Imaging; Measurable; Measurement; Measures; Mediating; Mentored Patient-Oriented Research Career Development Award; Motor; Movement; Neurobehavioral Manifestations; Neurodegenerative Disorders; Neuropsychological Tests; Neuropsychology; Onset of illness; Patients; Performance; Primary Progressive Aphasia; Process; Production; Research; Rest; Risk; Sampling; Sensory; Sex Education; Signal Transduction; Speech; Speech Acoustics; Structure; Techniques; Technology; Testing; Time; Trail Making Test; Treatment Efficacy; Uncertainty; age effect; age related; base; blood oxygen level dependent; brain tissue; clinical diagnosis; cognitive ability; cognitive change; cognitive control; cognitive function; cognitive load; cognitive process; cognitive skill; cohort; cost effective; cost efficient; detector; diagnostic strategy; disease prognosis; early detection biomarkers; functional MRI scan; imaging biomarker; improved; indexing; innovation; insight; kinematics; mechanical properties; mild cognitive impairment; motor behavior; motor control; neural correlate; neurobiological mechanism; neuroimaging; normal aging; physical property; pre-clinical; research clinical testing; training opportunity; treatment planning

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.

项目摘要 检测阿尔茨海默氏病（AD）和轻度认知障碍（MCI）的早期迹象（MCI） 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 策略，并从当前可用的治疗计划中获得最大收益。但是，由于 认知障碍的表现存在实质性差异，临床前认知变化不是 从与年龄相关的认知下降中可见。尽管使用神经心理学，流体， 成像生物标志物相对及时提高了AD的诊断，测量这些生物标志物 是昂贵且技术高度依赖的，使这些技术不切实际地用于许多老年人 跨不同的设置。此外，通过使用神经心理学评估认知功能 电池在临床试验和干预效率的评估中仍然是金标准。那至关重要 确定1）对AD病理敏感的早期探测器，2）强烈预测未来的变化 认知和3）在潜水员环境中可访问和可行。根据我们最近的发现， 确定的语音运动控制量度是为神经退行性的早期阶段索引的强大帮助 肌萎缩性侧索硬化症和主要进行性失语症等疾病，我们提出评估 语音标记是一种替代或完善和生态有效的策略，以识别有风险的成年人 由于AD而发展的认知障碍。语音生产是人类最复杂的电动机之一 行为，因为它依赖于认知，感官和运动过程的紧密整合，这些过程都受 随着年龄的增长而变化。我们假设与年龄相关的语音运动控制变化率 成年人可以受到发展AD的遗传敏感性的影响。此外，我们假设 在认知言语任务期间引起的语音可以区分ApoEε4的载体（即主要 已知会增加非载流人的AD风险的基因和基线语音声音和运动学测量值 可以预测后来的认知下降。拟议的研究将创新使用声学和发音 运动学与神经影像结合实现三个目标。在AIM 1中，我们将确定衰老的影响 APOEε4阳性（ε4+）和APOEε4阴性（ε4-）基因型的成年人的语音运动控制 在性别和教育中。在AIM 2中，我们将确定年龄的大脑结构和静止状态功能基础 具有ε4+和ε4基因型的成年人语音测量的相关变化。最后，在AIM 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来的认知变化 通过霍普金斯学习测试重新定义（HVLT-R）和TRAIL制作测试（TMT）分数； 2）如果言语和认知 通过改变大脑结构和功能来介导变化。这项研究的发现将提供 有关语音运动控制度量的关键信息，可以有效地纳入 神经心理学测试以优化AD的临床评估。