Sandra A. Billinger, Ph.D. - US grants

DESCRIPTION (provided by applicant): The candidate for this Mentored Career Development Award has as long-term goals to: 1) increase her exposure, experience and credibility in vascular physiology as it relates to stroke;2) obtain formal and informal training experiences that are essential to developing a long-term plan of study in rehabilitation research;and 3) execute and expand her comprehensive training program into an independent research career and submit an R01 application. The candidate's immediate goals that support her long-term goals will be to focus on: 1) obtaining a better understanding of vascular physiology (through courses and lab experiences) to understand the mechanistic vascular changes that may occur as a result of an acute stroke;2) acquiring the essential skills to conduct experiments and data analysis for flow-mediated dilation (FMD), Doppler ultrasound and the specialized, vascular wall tracking software;3) understanding how aerobic exercise early in stroke rehabilitation reduces vascular dysfunction;and 4) gathering results and pilot data to become an independent investigator on an R01 submission. The mentorship, training plan and environment that the candidate will have access to are robust and will ensure successful career development. The mentors for this Career Development Award have the background and experience that is complementary to the candidate's and they are committed to helping her succeed and meet her goals. Dr. Billinger's mentors have experience and a track-record of NIH funding, numerous publications and a history of mentoring junior faculty/researchers. Each mentor uniquely contributes to the candidate's scientific and career growth towards independence. Dr. Nudo, the primary mentor, will help the candidate with understanding brain physiology, the cascade of cerebral cellular events that occur after stroke, grantsmanship, improving scientific writing skills for high-impact journal submissions and NIH grants, and conducting mechanistic, hypothesis driven research. Dr. Dengel, co-mentor, will be instrumental for learning how to perform FMD techniques, using Doppler ultrasound for vascular scanning and interpreting findings using electronic vessel-wall tracking software. Dr. Dawn, co-mentor, will provide lab experiences and research discussions on vascular physiology, blood flow, and autonomic control. He will facilitate a productive learning environment between the candidate and the vascular sonographers. Dr. Wood, co-mentor, will provide lab experiences and mentorship regarding vascular regulation and benchtop techniques for identifying mechanisms related to reduced blood flow, hypoxia and vascular dysfunction. Dr. Billinger will be using the ELISA techniques in Dr. Wood's lab for identifying the pro-inflammatory in plasma. Dr Rymer, co-mentor, will ensure access to the stroke patient population and resources to conduct the experiments at the hospital (St. Luke's Brain Institute). She has been part of several clinical trials and can assist the candidate with approaches and problem-solving on recruitment, consenting, and drop-outs. Research Plan: Individuals with chronic stroke demonstrate reduced blood flow in the hemiparetic limb. A better understanding of mechanistic factors that influence vascular regulation after stroke could lead to innovative rehabilitation strategies that diminish disability and improve functional outcomes. Pro-inflammatory markers are released after stroke as a result of the brain injury. The pro-inflammatory markers enter the peripheral vascular system within 24 hours post-stroke. Cytokines (TNF-a, IL-6) and vascular adhesion molecule (VCAM-1) are pro-inflammatory markers that, when present in the vascular system, can reduce production and/or release of nitric oxide, a potent vasodilator. Nitric oxide is needed for vessel dilation to occur in order to accommodate increased blood flow during periods of exercise. Although people post-stroke demonstrate altered vascular function, pilot work suggests exercise can improve blood flow in the hemiparetic limb. The candidate will recruit individuals after an acute stroke to examine the relationship between pro-inflammatory markers and vascular function (using flow-mediated dilation). Plasma samples will be analyzed to quantitatively determine the amount of pro-inflammatory markers in the plasma. Doppler ultrasound and specialized vessel wall tracking software will be used to assess vascular function. In the most innovative aspect of the project, the candidate will also explore the role of an aerobic exercise intervention during stroke rehabilitation. The candidate believes that the exercise intervention will down-regulate the effect of pro-inflammatory markers and improve vascular regulation. The candidate plans to use the results from these experiments as pilot data for a larger clinical trial. However, before a clinical trial is undertaken, it is important and essential that one understands the role of pro-inflammatory markers and vascular function during stroke recovery. PUBLIC HEALTH RELEVANCE: Stroke is a leading cause of death and disability for older adults in the United States with approximately 795,000 new or recurrent strokes occurring each year. Elevated levels of inflammatory markers have been predictive of poor outcomes after stroke. This project will explore the role of circulating inflammatory markers in the blood and the impact of these markers on vascular health. The candidate will also use an aerobic exercise intervention to evaluate whether exercise decreases the level of inflammatory markers in the blood and positively affects vascular function in stroke survivors. This study will further our understanding of the physiologic mechanisms that affect vascular function after stroke and lead to effective rehabilitation strategies in reducing disability from this devastating event.

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 multi-PI project is to establish proof of concept for the utility of a new class of cerebrovascular markers that may aid in 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 the recent promising results of our group and the mounting evidence of a strong correlation between MCI/AD and cerebrovascular dysregulation. A recently published retrospective study on a large cohort of 1,171 subjects from the ADNI database utilized multi-factorial data-driven analysis to assess the relation between MCI/AD disease progression and commonly used biomarkers (obtained from MRI/PET and plasma/CSF) and concluded that cerebrovascular dysregulation is the earliest and strongest pathologic factor associated with AD progression, corroborating the hypothesis of cerebrovascular dysregulation. Quantification of cerebrovascular dysregulation in that large-cohort study was achieved through analysis of ASL-MRI data of cerebral perfusion. We propose instead to explore a novel integrative dynamic modeling approach that analyzes the cerebral hemodynamics of persons with no cognitive impairment and MCI/AD patients with a methodology that yields input- output predictive models of the dynamic relationships between changes in beat-to-beat cerebral blood flow velocity (via Transcranial Doppler) or cerebral tissue oxygenation (via Near Infrared Spectroscopy) in response to changes in arterial blood pressure and end-tidal CO2 data. The obtained data-based models are subsequently used to compute markers of the dynamics of cerebrovascular regulation. Initial results of the advocated approach have achieved statistically significant delineation between 46 MCI patients and 20 age-matched controls on the basis of a model-based marker of dynamic vasomotor reactivity (DVR). Evaluation of the DVR marker against established MRI-based and PET-based biomarkers, as well as neuropsychological test data, from the larger cohort of the proposed project offers the promise of portable, non-invasive, inexpensive and sensitive means for detecting cerebrovascular dysregulation at the early stages of MCI or mild AD, and monitoring disease progression. Important co-variates of this study include age, gender, education, ApoE genotype, site and amyloid burden.

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.