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

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.