Revision Supplement: Model-based cerebrovascular markers extracted from hemodynamic data for diagnosing MCI or AD and predicting disease progression

多PI合同RO 1AG 058162的紧急竞争修订补充，标题为： “从血液动力学数据中提取的基于模型的脑血管标记物， MCI或轻度AD的非侵入性、便携式和廉价的诊断以及 疾病进展” 项目摘要 当前多PI的拟议紧急竞争修订补充的目标 授予RO 1AG 058162的目的是扩大当前计划的范围，以包括以下方面 在我们目前的一组志愿者中， 队列（30名AD患者、30名MCI患者和30名认知正常对照）以及30名 新招募的Covid康复患者，以研究心肺调节 在MCI和AD患者中，以及COVID-19对心肺功能调节的影响 对照和脑灌注。后一个问题已经达到迫切的临床重要性， 由于观察到的基本功能障碍， 心肺化学反射似乎无法恢复体内平衡， 一些严重的Covid-19病例表现出非常低的血氧饱和度， 正常预期的呼吸急促（暂称为“无症状低氧血症”）。 这一扩大目前多PI计划范围的建议将进一步增强 主要目的是关于一类新的脑血管标志物的潜在效用， 改善轻度认知障碍（MCI）的诊断和疾病进展预测 和轻度阿尔茨海默病（AD）。用于获得这些标记物的手段是非侵入性的， 价格便宜，便于携带，因此可以在初级保健环境中用于筛查。的 最近有希望的研究为这类新的脑血管标记物提供了科学依据。 我们小组的研究结果以及MCI/AD和AD之间强相关性的越来越多的证据表明， 脑血管失调的工作，这表明，脑血管 调节异常是与AD相关的最早和最强的病理因素 进展，证实了脑血管失调的假设。 目前的研究计划和扩大其范围的建议将实现可靠的 通过我们的新的综合方法量化脑血管失调， 预测动态建模，分析脑血流动力学和心肺功能， 通过运用投入产出动态关系预测模型进行调控 心跳间脑血流速度或脑组织氧合的变化之间的关系， 对动脉血压、呼气末CO2数据、血氧饱和度 心率和（随着拟议修订补充的范围扩大） 呼吸频率、通气量和吸入气体（O2和CO2）。所获得的基于数据的模型 随后用于计算脑血管调节的动态标记。 这些基于模型的标志物将根据已建立的基于MRI和基于PET的 生物标志物，以及神经心理学测试数据，提供了非侵入性的承诺， 用于检测脑血管失调的廉价且灵敏的手段，并且（使用 在MCI或轻度AD的早期阶段的心肺功能失调， 以及许多严重的新型冠状病毒病例，其令人困惑的临床表现是“沉默”， 低氧血症”被认为是住院重症COVID-19病例的高死亡风险。

Urgent Competitive Revision Supplement to the multi-PI award RO1AG058162 entitled: "Model-based cerebrovascular markers extracted from hemodynamic data for non-invasive, portable and inexpensive diagnosis of MCI or mild AD and prediction of disease progression" PROJECT SUMMARY The goal of the proposed Urgent Competitive Revision Supplement to the current multi-PI award RO1AG058162 is to expand the scope of the current program to include aspects of cardio-respiratory regulation of cerebral perfusion in a subset of volunteers from our current cohort (30 AD patients, 30 MCI patients and 30 cognitively-normal controls) as well as in 30 newly recruited Covid-recovered patients in order to investigate the cardio-respiratory regulation in MCI and AD patients, as well as the effect of Covid-19 on the regulation of cardio-respiratory control and cerebral perfusion. The latter issue has attained urgent clinical importance during the ongoing Covid-19 pandemic because of the observed dysfunction of the fundamental cardio-respiratory chemoreflex that appeared unable to restore the homeostatic balance in some severe cases of Covid-19 presenting very low blood oxygen saturation without the normally expected tachypnea (termed tentatively “silent hypoxemia”). This proposed expansion of the scope of the current multi-PI program will further enhance the main objective regarding the potential utility of a new class of cerebrovascular markers for the improved diagnosis and prediction of disease progression in Mild Cognitive Impairment (MCI) and mild Alzheimer's Disease (AD). The means for obtaining these markers are non-invasive, inexpensive and portable, so that they can be used for screening in a primary-care setting. The scientific rationale for this new class of cerebrovascular markers is provided by recent promising results of our group and the mounting evidence of a strong correlation between MCI/AD and cerebrovascular dysregulation in the work of many others, which suggest that cerebrovascular dysregulation is the earliest and strongest pathologic factor associated with AD progression, corroborating the hypothesis of cerebrovascular dysregulation. The current research program and the proposed expansion of its scope will achieve reliable quantification of cerebrovascular dysregulation through our novel integrative approach of predictive dynamic modeling that analyzes the cerebral hemodynamics and cardio-respiratory regulation through the use of input-output predictive models of the dynamic relationships between changes in beat-to-beat cerebral blood flow velocity or cerebral tissue oxygenation in response to changes in arterial blood pressure, end-tidal CO2 data, blood oxygen saturation, heart rate and (with the expanded scope of the proposed Revision Supplement) changes in respiratory rate, ventilation and inhaled gases (O2 and CO2). The obtained data-based models are subsequently used to compute markers of the dynamics of cerebrovascular regulation. These model-based markers will be evaluated against established MRI-based and PET-based biomarkers, as well as neuropsychological test data, offering the promise of non-invasive, inexpensive and sensitive means for detecting cerebrovascular dysregulation and (with the proposed Supplement) cardio-respiratory dysregulation at the early stages of MCI or mild AD, as well as in many severe Covid-19 cases with the puzzling clinical presentation of “silent hypoxemia” that is recognized as high mortality risk for hospitalized severe Covid-19 cases.