Dmitriy Yablonskiy, PhD - US grants

A fundamental discovery of modern human brain imaging with positron emission tomography (PET) that blood flow to activated regions of the normal human brain increases substantially more than oxygen consumption has lead to a broad discussion in the literature concerning possible mechanisms responsible for this phenomenon. It is well known that oxygen delivery is not the only function of systemic circulation. Additional roles include delivery of nutrients and other required substances to the tissue, waste removal, and temperature regulation. Among these other functions, the role of regional cerebral blood flow in local brain temperature regulation has received scant attention. Heat in the brain is produced mostly due to oxidative metabolism. It is removed chiefly by blood flow. The balance between heat production and removal in resting state maintains brain temperature at a constant level. However, a local increase in the blood flow and metabolism during brain functional activity can locally destroy this balance and alter brain temperature in the region of functional activity and surrounding tissue. This is an important issue since temperature substantially changes (by about 8 percent per each degree of centigrade) rates of metabolic reactions, the affinity of hemoglobin for oxygen, and, consequently, may affect brain performance - both healthy and diseased. This proposal seeks to provide data extending our understanding of the relationship between physiologic and metabolic control in nervous system. The major goals of this grant application are: To develop MR techniques that allow simultaneous monitoring of changes in brain temperature and oxidative metabolism. The proposed work includes implementations of MR techniques, development of biophysical models of brain temperature regulation and mathematical algorithms based on Bayesian probability theory for data processing. To measure by means of MR the spatial distribution in the changes of human brain temperature and the corresponding changes in oxygen metabolism during functional activation in a series of healthy subjects; to determine the range of these changes and their dependence on stimulus strength and duration. To determine the consequences of the disproportionate increase in blood flow compared to oxygen consumption, which occurs during functional activation, on brain temperature regulation. The potential implications of these results are significant. A powerful tool presents itself for analysis of the coupling of metabolic and physiologic control and for elucidation of details of the fundamental Blood Oxygenation Level Dependent contrast in MR.

[unreadable] DESCRIPTION (provided by applicant): Emphysema is a major medical problem in the US and worldwide. Diagnostic methods for the evaluation of emphysema should be sensitive to regional lung structure at the alveolar level. Diffusion MRI with hyperpolarized 3He gas that evaluates the 3He-gas ADC (apparent diffusion coefficient) can provide this sensitivity. It offers information on lung microstructure and function not provided by traditional imaging modalities and pulmonary function tests. With 3He diffusion MRI, alveolar size and the integrity of alveolar walls can be evaluated, even though the alveoli are too small to be resolved by direct imaging. This points to the large potential for clinical application of ADC measurements with hyperpolarized 3He gas. However, until recently it was not clear what specific features of lung structure are probed by 3He gas ADC measurements. Recently we proposed a theoretical model based on a large body of histology data that provides this explanation. However, substantial questions must be answered if we are to understand the 3He ADC measurement and optimally exploit its diagnostic potential. In this proposal we will extend our mathematical model that relates anisotropic ADC measurements in lung to lung microstructural parameters. The mathematical model is based on a realistic structure of lung at the acinar level described in terms of acinar airways covered with alveolar sleeves. The theory of gas diffusion in lung is based on our key concept of anisotropic diffusion in lung acinar airways. We will conduct sophisticated multi-dimensional MR experiments on sacrificed mice with healthy lungs to test the fundamental feature of our mathematical model, the anisotropy of ADC. We will develop further and test our new diffusion 3He MRI technique for tomographic "lung biopsy" on a canine model of emphysema with physiology similar to human and establish a quantitative relationship between the severity of emphysema as determined by CT and the 3He anisotropic diffusivities. We will use 3He diffusion and ventilation MRI together with CT to study normal human subjects and patients with emphysema. Inter-comparison of these three techniques will establish quantitative relationships between CT, lung ventilation and anisotropic ADC measurements and will open up possibilities for new interpretations of results obtained by each modality. The potential implications are significant. A comprehensive clinical picture of emphysema progression, from initial onset of the alveolar deformation to the final stage, characterized by dramatic loss of lung function, will be established. New methods will be sensitive enough to allow early diagnosis of emphysema that will improve patient treatment.

DESCRIPTION (provided by applicant): Substantial progress has been achieved in recent years in understanding the underlying biophysical nature of the MR BOLD signal. Most efforts have been directed toward study of dynamic changes in the BOLD signal during changes in brain activity. At the same time, very little attention has been paid to the nature of BOLD contrast in the resting state of the brain. Such an understanding is crucial to deciphering the consequences of baseline state impairment by diseases of the brain such as stroke, Alzheimer's disease, Huntington's disease, and other neurological disorders. It can also be of great importance for evaluation of hypoxia within tumors of the brain and other organs. We have developed a quantitative biophysical model of BOLD contrast (qBOLD) in MRI that analytically connects BOLD MRI signal to hemodynamic parameters, such as deoxygenated blood volume (DBV) and oxygen extraction fraction (OEF). Our preliminary MR-measured hemodynamic parameters obtained on healthy human subjects are in a good agreement with previous determinations. To date, the most accepted in vivo measurement of OEF in clinical neurological research uses [15O] tracers and PET. To make our qBOLD- based MR technique a working tool for research and clinical applications, direct comparisons between qBOLD and PET are required. We propose to conduct these comparisons in normal healthy subjects and in subjects with a Moyamoya syndrome. This rare disorder is characterized by an obliterative vasculopathy of the large arteries at the base of the brain leading to regionally increased OEF. If we find high correlation between our MR estimates of OEF and PET measures of OEF in both healthy and pathologic conditions, we will have completed an important step in validating our qBOLD approach for neurological disease research. Normal human subjects will also be recruited to undergo both PET and qBOLD MR measurements during visual activation is known to decrease regional OEF. These data will provide complementary information with a range of OEF values not seen in the resting state. The determination that the qBOLD technique yields estimates of OEF during visual activation that are highly correlated to PET measures will be additional justification for use of our new MR method in neurological investigation of brain hemodynamics. We expect our qBOLD model will provide adequate basis for data analysis. However, we will also perform quantitative evaluation of the model limitations and will further refine the model to investigate possibility of improvements in OEF and DBV quantification. The overarching goal of this proposal is to develop a new MR-based method for the quantitative in vivo evaluation of brain hemodynamics in health and disease. When fully implemented, this will provide an extraordinary tool for cognitive studies and clinical diagnosis, one that is much more widely available to clinicians and researchers than is oxygen-15 based PET for the measurement of brain hemodynamics. The overarching goal of this proposal is to develop a new Magnetic Resonance Imaging -based method for the quantitative in vivo evaluation of brain hemodynamics in health and disease. When fully implemented, this will provide an extraordinary tool for cognitive studies and clinical diagnosis, one that is much more widely available to clinicians and researchers than is oxygen-15 based Positron Emission Tomography for the measurement of brain hemodynamics and metabolism.

DESCRIPTION (provided by applicant): Emphysema is a major medical problem in the US and worldwide. In this grant application we propose to develop non-invasive lung morphometry as an improved diagnostic of this debilitating disease. Our technique is based on diffusion MRI with hyperpolarized 3He gas and allows in vivo 3D tomographic estimation of the lung alveolar surface area, alveolar density, and acinar airway radii - parameters that have been used by lung physiologists for decades as the gold standard for quantifying emphysema but were previously only measurable through invasive lung biopsy. As part of the previous grant period, we obtained in vivo lung morphometry data on 30 subjects with known smoking histories in the early stages of emphysema. This data revealed very specific changes in lung morphometry which were not appreciated with conventional clinical tests, suggesting that our technique is a very sensitive tool for detecting early changes in the lung microstructure. The main goal of this Renewal Application is to extend the diagnostic potential of the in vivo lung morphometry technique for identifying structural changes in lung parenchyma to all stages of emphysema. To achieve this goal we will: (i) extend our current mathematical model of gas diffusion in lungs by incorporating the effects of progressive lung tissue destruction on 3He gas diffusion;(ii) non-invasively establish the baseline parameters of lung microstructure in healthy human subjects without smoking histories over a range of age categories;(iii) non-invasively characterize the changes in lung microstructure for subjects in the initial through advanced stages of emphysema;(iv) validate our technique against direct morphometric measurements. Overall, we propose to further develop and validate our advanced MRI techniques for imaging of the human lung as superior, specific characterization of emphysematous changes in lung, and apply these techniques to advance our understanding of the microstructural changes that occur in emphysema, across a wide range of age and disease stages. A comprehensive picture of the changes in lung microstructure at the alveolar level with emphysema progression will be elucidated, from the initial onset of alveolar deformation to the advanced stages, characterized by a dramatic loss of lung function. Our novel methods are sufficiently sensitive to allow early detection and diagnosis of emphysema, providing an opportunity to improve patient treatment outcomes, and have the potential to provide safe and non-invasive in vivo biomarkers for monitoring drug efficacy in clinical trials. PUBLIC HEALTH RELEVANCE: The main goal of this study is to further develop our advanced MRI technique for imaging of the human lung - in vivo lung morphometry - as a superior, more sensitive characterization of emphysematous changes, and apply this technique to advance our understanding of the changes in lung alveoli and airways that occur in emphysema, across a wide range of ages and disease stages. This technique is based on diffusion MRI with hyperpolarized 3He gas. The results will provide new clinical insights into emphysema progression, from the initial onset of the alveolar deformation to the final stages, characterized by dramatic loss of lung function.

? DESCRIPTION (provided by applicant): Chronic obstructive pulmonary disease (COPD) has become the third most common cause of death in the U.S., and the number of COPD-associated deaths has doubled over the past 20 years. Age, environmental, and genetic factors affect COPD development and progression. While studies of COPD have evaluated different aspects of lung physiology, pathology, and function very little in vivo information exists on the structure and the role of the acinar airways, even though these airways represent 95% of the lung volume and function as the major gas-exchanging unit. This proposal has an overarching goal of developing a new understanding of the effects of aging, cigarette smoking, and COPD on the lung, by measuring and differentiating all aspects of the structural changes in acinar airways among these conditions. We also aim to understand the interplay between disease of small conducting airways and changes in the structure of acinar airways in regions of gas trapping which are thought to be early events leading to emphysema. Building on our prior discovery of anisotropic 3He gas diffusion in acinar airways, we developed and validated the innovative imaging technique of lung morphometry with hyperpolarized 3He magnetic resonance imaging (MRI) that provides unique in vivo quantitative information on the structure and spatial distribution of acinar airways for this study. We will combine 3He morphometric data with quantitative CT data to obtain unique information on parenchymal (alveolar walls including capillaries) and non-parenchymal (non-capillary vessels, etc.) lung tissue, as well as on disease of small conducting airways. Our Specific Aims focus on establishing quantitative relationships between structural alterations in acinar and small airways and declines in lung function: Aim 1: Identify and compare structural mechanisms of the progressive deterioration in lung function associated with aging in healthy never-smokers and healthy smokers, and differentiate contributions of acinar and small airway disease, by using quantitative metrics determined by MRI-based in vivo lung morphometry and quantitative CT. Aim 2: Identify the structural mechanisms of the progressive deterioration in lung function associated with smoking-related COPD, and differentiate the mechanisms of age-related structural changes in the acinar and small airways (in healthy never-smokers and healthy smokers) from those due to COPD, by using quantitative metrics determined by MRI-based in vivo lung morphometry and quantitative CT. We expect to develop a new approach for assessing the effects of aging and COPD on lung structure and function, provide a new understanding of how aging, cigarette smoking, and emphysema cause lung acinar structural changes and associated deterioration in lung function, and propose novel targets for preventing and treating the major public health problem of COPD.

This grant application addresses a significant health problem - Alzheimer?s disease (AD) - that affects ~5.3 million people in the US and 20-30 million worldwide. As the population ages, these numbers are anticipated to rise, stimulating an intense search for disease prevention and treatment therapies as well as for biomarkers allowing early identification of AD. The latter is very important due to the existence of a long pre-symptomatic period that can be used for the initiation of prevention trials of disease-modifying therapies in asymptomatic individuals, with the goal of preventing cognitive decline as opposed to treating of symptoms that are already present. The main goal of this study is to provide a groundwork for using the innovative MRI-based Gradient Echo Plural Contrast Imaging (GEPCI) technique for in vivo identifying early pathological changes in the AD brain. This technique, GEPCI, developed in our laboratory, provides surrogates for quantitative assessments of changes in the brain tissue structure at the cellular level and has been already successfully applied to evaluating tissue damage in multiple sclerosis and some psychiatric diseases. Our preliminary data, obtained on well-characterized research participants recruited from studies of aging and dementia at the Washington University Knight Alzheimer?s Disease Research Center, allowed us to demonstrate for the first time that in vivo MRI-based measurements obtained on a clinical MRI scanner can provide information on brain amyloid-? accumulation in human participants, and to distinguish between healthy control, preclinical and mild AD stages. Based on these results, we plan to achieve the following Specific Aims: 1. Our Aim 1 is to develop a readily available, non-invasive quantitative in vivo MRI-based biomarker that can serve as a surrogate for amyloid-? accumulation in the brain (a primary role of A? in the development of Alzheimer's disease is now almost universally accepted). 2. Our Aim 2 is to establish specific quantitative and spatial patterns of GEPCI metrics abnormalities that would distinguish between normal brain, preclinical AD, and very mild AD. 3. Our Aim 3 is to establish the effect of early AD-related brain tissue damage (defined by GEPCI surrogate biomarkers) on cognitive performance and to test the hypothesis that the GEPCI metrics and/or changes in GEPCI metrics can be predictors of the disease progression. 4. Our Aim 4 is to validate GEPCI measurements against direct neuropathology. The overarching goal of this proposal is to establish GEPCI as an in vivo non-invasive MRI technique available in a conventional clinical setting for screening population for preclinical AD pathology and clinical drug trials. GEPCI data are quantitative, reproducible and MRI scanner independent, thus allowing multi-center applications. The non-invasive nature of our approach is especially important since most of currently available biomarkers for identifying AD ?are invasive, to one degree or another (NIH PAR-15-359)?.