Cognitive challenge to reveal systemic neurophysiology biomarkers in pre-symptomatic Alzheimer’s disease

认知挑战揭示阿尔茨海默病症状前的系统神经生理学生物标志物

• 批准号: 10573315
• 负责人: Xianghong Arakaki
• 金额: $ 73.19万
• 依托单位: HUNTINGTON MEDICAL RESEARCH INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-15 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10573315
• 关键词: Address; Affect; Aging; Alzheimer disease detection; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease pathology; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-Protein; Autonomic Dysfunction; Benchmarking; Biochemical; Biological Markers; Blood Pressure; Cerebrospinal Fluid; Classification; Clinical; Cognition; Cognitive; Color; Conscious; Coronary; Data; Dementia; Detection; Diagnosis; Disease Progression; Early Diagnosis; Elderly; Electrocardiogram; Electroencephalography; Electrophysiology (science); Entropy; Evaluation; Event; Executive Dysfunction; Functional disorder; Goals; Health; Hyperactivity; Image; Impaired cognition; Impairment; Individual; Information Systems; Knowledge; Longevity; Longitudinal Studies; Measurement; Measures; Methods; Modeling; Nervous System; Non-Invasive Detection; Participant; Pathologic; Reaction Time; Regulation; Reporting; Research; Resources; Role; Sensory; Short-Term Memory; Source; Staging; Stimulus; Stress Tests; Symptoms; Synapses; System; Systems Biology; Techniques; Testing; cognitive system; cohort; data reduction; density; distraction; effective therapy; executive function; heart rate variability; high risk; improved; mild cognitive impairment; nervous system disorder; neural; neurophysiology; normal aging; novel; predictive marker; response; source localization; subliminal influence; synaptic function; tau Proteins

The burden on Alzheimer’s disease (AD) is growing due to longer life span and lack of effective treatment. The knowledge gap exists for early detection and prediction of symptom onset. AD pathology (amyloid/tau) and synaptic dysfunction precedes symptoms by decades and offers a window of opportunity for early AD detection. Current early AD diagnosis depends on expensive imaging or invasive cerebrospinal fluid (CSF) detection of amyloid/tau. Our goal is to identify non-invasive biomarkers that fill this gap with simple tests benchmarked to amyloid/tau biomarkers. Our early studies defined pre-symptomatic AD: elderly study participants were classified as cognitively healthy (CH) in a multi-domain, neuropsychometric battery. We classify CH participants into two groups based on a regression-derived CSF Aß42/Tau ratio cutoff: CH individuals with pathological ratio (CH-PAT) or with normal ratio (CH-NAT). After 4 years, 40% of CH-PAT but no CH-NAT individuals declined cognitively, providing a strong cohort to evaluate biomarkers for pre- symptomatic AD (CH-PATs) from normal aging (CH-NATs). AD affects multiple nervous systems. Tightly related to our health, the interactions between conscious executive function, subliminal processing, and autonomic regulation (CSA system) respond to internal and external stimuli with neural oscillations that are affected by synaptic dysfunctions. The CSA neural oscillations can be detected by non-invasive electrophysiological methods: EEG and ECG, benchmarked to amyloid/tau. Individual CSA dysfunctions have been reported in the mild cognitive impairment stage, while CSA has not been studied in the pre-symptomatic AD. We hypothesized that CSA system measurements combine to provide robust biomarkers for pre-symptomatic AD. Analogous to the stress test to unmask coronary insufficiency, our cognitive challenge revealed CH-PATs had frontal hyper-activities with low load challenge and insufficient cognitive resources with high load challenges, hyperresponsivity to subliminal interference, and hyperactive autonomic regulation. Further, combined CSA biomarkers improve detection of pre-symptomatic AD. Therefore, we hypothesize that neural oscillations during cognitive challenge will reveal altered executive functions in pre-symptomatic AD, correlate with compromised subliminal processing and autonomic nervous function, and their combination will improve detection and prediction of pre-symptomatic AD. Our Specific Aims will test our hypothesis in a new cohort and test the ability of CSA biomarkers to identify CH- PATs and predict decline in a 2-year longitudinal study. Accomplishing this CSA approach will provide multiple novel translational biomarkers to characterize pre-symptomatic AD. These biomarkers are non-invasive, benchmarked to established CSF biomarkers. Our research addresses an important gap in pre-symptomatic AD detection and prediction of AD symptom onset.

由于寿命延长和缺乏有效治疗，阿尔茨海默病（AD）的负担正在增加。的 在早期发现和预测症状发作方面存在知识差距。AD病理学（淀粉样蛋白/tau）和 突触功能障碍先于症状出现数十年，并为早期AD提供了一个机会窗口 侦测目前早期AD诊断依赖于昂贵的成像或侵入性脑脊液（CSF） 检测淀粉样蛋白/tau蛋白。我们的目标是确定非侵入性生物标志物，用简单的测试填补这一空白 以淀粉样蛋白/tau生物标志物为基准。我们的早期研究定义了症状前AD：老年人研究 参与者在多领域神经心理测量组合中被分类为认知健康（CH）。我们 根据回归推导的CSF A β 42/Tau比值临界值将CH参与者分为两组：CH 具有病理比率（CH-PAT）或具有正常比率（CH-NAT）的个体。4年后，40%的CH-PAT， 没有CH-NAT个体的认知能力下降，提供了一个强有力的队列来评估前 症状性AD（CH-PATs）与正常老化（CH-NAT）的关系。 AD影响多个神经系统。与我们的健康密切相关，意识之间的相互作用 执行功能，阈下处理和自主调节（CSA系统）响应内部和 受突触功能障碍影响的神经振荡的外部刺激。CSA神经振荡 可以通过非侵入性电生理学方法检测：EEG和ECG，以淀粉样蛋白/tau为基准。 个体CSA功能障碍在轻度认知障碍阶段有报道，而CSA没有 在症状前AD中进行了研究。 我们假设CSA系统测量联合收割机为症状前的 AD.类似于暴露冠状动脉功能不全的压力测试，我们的认知挑战揭示了CH-PAT 低负荷时额叶过度活跃，高负荷时认知资源不足 挑战，对阈下干扰的过度反应，以及过度活跃的自主调节。此外，本发明还 组合的CSA生物标志物改善了症状前AD的检测。因此，我们假设， 认知挑战期间的振荡将揭示症状前AD中改变的执行功能， 与阈下处理和自主神经功能受损相关， 组合将改善症状前AD的检测和预测。 我们的具体目标将在一个新的队列中测试我们的假设，并测试CSA生物标志物识别CH-的能力。 在2年的纵向研究中预测PAT和下降。完成这种CSA方法将提供多个 表征症状前AD的新型翻译生物标志物。这些生物标志物是非侵入性的， 以确定的CSF生物标志物为基准。我们的研究解决了症状前的一个重要空白， AD检测和AD症状发作的预测。