The overall goal of this project is to employ magnetic resonance imaging (MRI) in a novel manner to study the integrity and dynamics of the microvascular cerebral blood vessels in elderly subjects at risk for developing AD. Specifically, I will evaluate the affect that brain amyloid, a major pathologic component of AD, has on the reactive capacity of the cerebral microvasculature (i.e. cerebrovascular reserve) - a fundamental process in brain health, brain reserve and cognitive efficiency. Furthermore, I will evaluate the affect that co-existing cardiovascular risk factors, a major cause of health problems worldwide, have on the relationship between brain amyloid and cerebrovascular health. I hypothesize that cerebral amyloid will attenuate the ability of the cerebral microvessels to react appropriately to stimulus. This results in a chronic state of functional, neuronal hypoperfusion and contributes to cognitive failure. Furthermore, I hypothesize that differences in cerebrovascular reactivity between individuals will manifest as differences in cognitive performance. Lastly, I postulate that the relationship between cerebrovascular reactivity and brain amyloid will be partially modified by the presence of cardiovascular and cerebrovascular disease. This work will advance our understanding of two highly prevalent disorders, cerebrovascular and cardiovascular disease, and how these could be targeted in the treatment and prevention of AD and progressive cognitive decline in aging. The objective of this application is to evaluate a surrogate of small vessel cerebrovascular disease and cerebrovascular compliance, CVR, in the presence of cerebral amyloid using magnetic resonance imaging (MRI) in a population of cognitively normal and mild cognitive impaired subjects with cerebral amyloidosis. I will fulfill this by studying a unique population that have cognitive tests, amyloid PET scans and markers of cardio and cerebrovascular disease by employing a CO2 -hypercapnia measure of CVR. I will assess the independent contribution of cardio-and cerebrovascular disease, and cerebral amyloid on CVR. I will plan to recruit 50 subjects from two existing, federally funded projects, of ongoing longitudinal studies focusing on predictors of cognitive decline. Additionally, I will utilize a noel post-mortem pathologic- MRI/PET scan study to better explore the underlying relationship of microvascular pathology to the alterations identified with MRI measures of CVR. With the use of pilot funding we have completed 10 subjects thus far demonstrating feasibility as well as providing preliminary data to support the aims of this study. My long term goal is to identify critical elements in the relationship between cerebrovascular disease, cerebral amyloid and cognitive decline in order to improve the understanding of this complex, yet vital, connection and improve strategies for treatment and prevention of AD. This K23 investigation will help me to develop the skills, methodologies, and theories needed to pursue a career in clinical translational research investigating cerebrovascular cofactors associated with the expression of AD, particularly using multimodal brain imaging. By leveraging the resources at the University of Pittsburgh to acquire this critical knowledge base, I will be well positioned to gain the necessary expertise in brain imaging, pathology and vascular biology to move to the next step of independent research in vascular contributions to cognitive aging and AD. I am uniquely qualified to succeed in clinical research based on my clinical expertise, affiliation with the Alzheimer Disease Research Center (ADRC), recent publications and as site PI of an international, multisite biomarker study of familial Alzheimer Dementia. I will build on this promising early career through the five year career development plan proposed in this application. Mentors include Oscar Lopez MD, Co-Director of the ADRC and leader in research on cognitive aging; William Klunk MD, PhD, co-Director of the Alzheimer Disease Research Center and co-inventor of the amyloid tracer PiB; Milos Ikonomovic MD, leader in amyloid PET to pathology correlations; Alberto Vazquez, PhD, and expert in neuro-vascular and neuro- metabolic imaging of normal brain function with extensions to neurological pathologies, especially Alzheimer's disease; John Detre MD (consultant) co-inventor of ASL-MRI; as well as local ASL imaging expert, Tae Kim PhD, vascular biologists Jeffrey Isenberg, MD, MPH, and imaging biostatistician Dana Tudorascu, PhD. Through a combination of close mentorship, utilization of a unique cohort of study participants, specialized weekly lab meetings, and advanced imaging programs here, as well as structured didactic courses in neuroimaging and multivariate statistics, I will pursue expertise in multimodal neuroimaging. By the completion of this study I will possess the necessary expertise in multi-modal imaging focusing on vascular interactions in AD and cognitive aging. This work will serve as the foundation to move forward in independent research focusing on identifying mechanisms of neurovascular unit dysfunction in AD and related neurodegenerative disorders.

Public Health Relevance

The objective in this application is to evaluate a surrogate of small vessel cerebrovascular disease and cerebrovascular compliance, cerebrovascular reactivity (CVR), in the presence of cerebral amyloid using magnetic resonance imaging (MRI) in a population of cognitively normal and mild cognitive impaired subjects. The application will investigate whether the normal physiologic response to hypercapnia- cerebral arterial dilatation- is affected by fibrillar amyloid, cerebrovascular/cardiovascular disease and whether alterations in CVR account for differences in cognitive performance- functioning as a measure of cerebrovascular reserve. The outcomes of this study could lead to further investigations into vascular contributions to cognitive aging and Alzheimer's dementia, as well as lead to preventative and treatment targets in both.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Mentored Patient-Oriented Research Career Development Award (K23)
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Neuroscience of Aging Review Committee (NIA)
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Hsiao, John
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Washington University
Schools of Medicine
Saint Louis
United States
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Bateman, Randall J; Benzinger, Tammie L; Berry, Scott et al. (2017) The DIAN-TU Next Generation Alzheimer's prevention trial: Adaptive design and disease progression model. Alzheimers Dement 13:8-19
McDade, Eric; Bateman, Randall J (2017) Stop Alzheimer's before it starts. Nature 547:153-155
Tang, Mengxuan; Ryman, Davis C; McDade, Eric et al. (2016) Neurological manifestations of autosomal dominant familial Alzheimer's disease: a comparison of the published literature with the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS). Lancet Neurol 15:1317-1325