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

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。这个 在早期发现和预测症状出现方面存在知识差距。AD病理(淀粉样蛋白/tau蛋白)和 突触功能障碍比症状早几十年，为早期AD提供了机会之窗 侦测。目前AD的早期诊断依赖于昂贵的成像或侵袭性脑脊液(CSF) 淀粉样蛋白/tau的检测。我们的目标是识别非侵入性的生物标记物，通过简单的测试来填补这一空白 以淀粉样蛋白/tau生物标记物为基准。我们早期的研究定义了有症状前的AD：老年研究 参与者在多领域神经心理测验中被归类为认知健康(CH)。我们 根据回归得出的脑脊液A？42/Tau比值截断值将CH参与者分为两组 病理比例(CH-PAT)或正常比例(CH-NAT)的个体。4年后，40%的CH-Pat但 没有CH-NAT个体认知能力下降，这为评估Pre-NAT的生物标志物提供了一个强有力的队列 正常衰老引起的症状性AD(CH-PATS)(CH-NAT)。 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、潜意识处理和自主调节(CSA系统)对内部和 受突触功能障碍影响的神经振荡的外部刺激。CSA神经振荡 可通过非侵入性电生理方法检测：脑电和心电图，基准为淀粉样蛋白/tau。 据报道，个别CSA功能障碍出现在轻度认知障碍阶段，而CSA尚未出现 在有症状的阿尔茨海默病中进行了研究。 我们假设CsA系统的测量结合起来可以为出现症状前的患者提供可靠的生物标志物 广告。类似于揭示冠状动脉功能不全的压力测试，我们的认知挑战显示了CHPATS 低负荷挑战时有额部多动，高负荷时认知资源不足 挑战，对潜意识干扰的高反应性，以及过度活跃的自主神经调节。此外， 联合应用CsA生物标志物可提高对有症状前AD的检测。因此，我们假设神经 认知挑战期间的振荡将揭示症状前AD的执行功能改变， 与阈值下加工和自主神经功能受损相关，它们的 联合应用将提高对有症状前AD的检测和预测能力。 我们的具体目标将在新的队列中测试我们的假设，并测试CsA生物标记物识别CH-1的能力。 在一项为期2年的纵向研究中，PATS和预测下降。实现这种CSA方法将提供多个 新的翻译生物标记物用于表征有症状前的AD。这些生物标志物是非侵入性的， 以已建立的脑脊液生物标记物为基准。我们的研究解决了症状前期的一个重要缺口 AD的检测和AD症状发作的预测。

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.