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

多PI奖的紧急竞争性修订补编RO1AG058162，题为： 从血液动力学数据中提取基于模型的脑血管标志物 无创、便携、廉价的MCI或轻度AD的诊断和预测 疾病进展“ 项目总结 拟议的对当前多重PI的紧急竞争性修订补充的目标 RO1AG058162奖是将当前计划的范围扩大到包括以下方面 我们目前研究的一组志愿者脑血流的心肺调节 队列(30名AD患者、30名MCI患者和30名认知正常的对照组)以及30名 新入院寒战康复者对心肺调节的研究 新冠肺炎对心肌梗死和AD患者心肺功能的调节作用 控制和脑血流灌注。后一个问题在临床上已经变得非常重要。 正在进行的新冠肺炎大流行是因为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 一些严重的新冠肺炎患者出现很低的血氧饱和度而没有 正常预期的呼吸急促(暂称为“无症状性低氧血症”)。 这一拟议的扩大当前多PI方案的范围将进一步加强 主要目的是关于一类新的脑血管标志物在脑血管疾病诊断中的潜在用途 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)。获得这些标记的手段是非侵入性的， 价格低廉，便于携带，因此可用于初级保健环境中的筛查。这个 最近有希望为这类新的脑血管标记物提供科学依据 我们小组的结果以及越来越多的证据表明MCI/AD与 脑血管工作中的许多失调，这些都表明脑血管 调节失调是与阿尔茨海默病相关的最早和最强烈的病理因素 进展，证实了脑血管失调的假说。 目前的研究计划和扩大其范围的提议将实现可靠的 通过我们新的综合方法对脑血管调节障碍进行量化 分析脑血流动力学和心肺功能的预测性动力学模型 通过使用动态关系的投入-产出预测模型进行监管 心搏间期脑血流速度或脑组织氧合变化之间的关系 对动脉血压、呼气末二氧化碳数据、血氧饱和度、 心率和(扩大拟议订正补编的范围) 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 随后被用于计算脑血管调节动力学的标记。 这些基于模型的标记物将与已建立的基于MRI和基于PET的标记物进行评估 生物标志物，以及神经心理测试数据，提供了非侵入性， 廉价而灵敏的检测脑血管紊乱的方法 拟议补充材料)MCI或轻度AD早期的心肺功能失调， 以及许多严重的新冠肺炎病例，其令人费解的临床表现为“沉默” 低氧血症“被认为是住院重症新冠肺炎患者的高死亡风险。

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.