Quantitative Measurement of Cerebrovascular Permeability in Early Dementia

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DESCRIPTION (provided by applicant): This application proposes a training program to integrate the PI's previous research efforts into investigations of aging and Alzheimer's disease (AD). Much of Dr. Anderson's previous research has involved methodologies related to biomedicine, but has been done with only a basic understanding of the clinical needs and complexities. The proposed project would provide a broad experiential mentoring experience focused on clinical aspects of aging and AD, as well as added knowledge in vascular physiology and high field magnetic resonance imaging (MRI). The overall goal is to expand the PI's experience and training in biomedicine and bioimaging to position her for a career in biomedical research. Alzheimer's disease is the most common form of dementia in the elderly. Although traditionally considered a disease of neurofibrillary tangles and amyloid plaques, cerebrovascular structure and function is profoundly altered in AD and may contribute directly to oxidative stress, neuronal injury and death. Many older demented patients not meeting common pathological criteria for AD may have dementia on a microvascular basis that is not readily appreciated. Since vascular dysfunction often precedes cognitive impairment, understanding the role of vascular abnormalities in AD pathogenesis is critical to the rational treatment of the disease. Dynamic contrast-enhanced MRI (DCE-MRI) provides quantitative measures of vessel integrity in the living human brain. The long-term goal of this project is to quantify with high precision and accuracy the microvascular properties of the human brain along the healthy aging-AD continuum. The specific aims are to: (1) define the microvascular properties of the early AD and healthy aged brain; (2) define a 'microvascular permeability' network in early AD; and (3) examine the capillary integrity of white matter lesions in the healthy aged and mild AD brain. To maximize the spatiotemporal resolution, DCE-MRI studies will be performed at 7T. We anticipate that use of this ultra-high field will lead to substantial improvement in the precision and accuracy of pharmacokinetic parameters and the maps derived from them. These maps provide the key to translation of advanced MR techniques to the identification of new imaging biomarkers of incipient AD. PUBLIC HEALTH RELEVANCE: The proposed project will yield precise, accurate in vivo measures of vascular permeability and will map at high resolution the microvascular properties of the early Alzheimer's disease (AD) and cognitively unimpaired elderly brain. This knowledge could improve our understanding of the transition from healthy brain aging to dementia and suggest new imaging biomarkers of incipient AD.