Friday, April 26, 2024
4/26/2024
ABSTRACT The overall goal of this proposal is to compare vascular markers between amnestic mild cognitive impairment (MCI) subjects with amyloid or Alzheimer’s disease (AD) pathology, and the newly identified MCI subjects with suspected non-amyloid pathology (SNAP-MCI). The innovation of this work is that we will explore vascular pathology and its role as a driver of cognitive deficits in this new cohort. Compared to the amyloid positive MCI subjects, SNAP-MCI subjects show similar neurodegeneration, similar amnestic symptoms, but normal amyloid accumulation in the brain. The higher burden of white matter hyperintensities in SNAP-MCI suggests vascular involvement in the disease mechanism. However, not much is known regarding vascular abnormalities in this group. To address this gap, we will compare cerebral blood flow (Aim 1) and cerebrovascular reserve (Aim 2) between cognitively normal older adults, amyloid positive MCI subjects, and SNAP-MCI subjects from the University of Washington AD Research Center (directed by primary mentor, Grabowski). We will then repeat these measurements after 18-24 months to track longitudinal changes (Aim 3). We will assess the co-localization of the vascular and amyloid pathologies using amyloid positron emission tomography (PET, Training Aim 4). We hypothesize that amyloid positive MCI subjects will have the lowest cerebral blood flow and vascular reserve due to the dual effects of amyloid and neurodegeneration. Importantly, the presence of vascular pathology in SNAP-MCI subjects will underline the role of a non-amyloid, vascular mechanism initiating dementia of Alzheimer type. We will apply arterial spin labeling magnetic resonance imaging (MRI) to estimate cerebral blood flow. We will use a breath-hold functional MRI paradigm, validated in our lab, to evaluate cerebrovascular reserve. In a subset of MCI subjects, we will perform dynamic PET imaging to determine R1, i.e., PET measure of CBF, and correlate it with our MRI measure of CBF. We will use the static Florbetapir 18F PET images for a semi-quantitative regional analysis of amyloid accumulation. The significance of this work is that it will enable us to identify vascular targets for early intervention. Our future work will focus on applying tau PET to determine neurodegeneration patterns that are specific to SNAP-MCI and their relation to vascular abnormalities. Candidate: The long-term goal of the candidate is to become a leader in AD imaging research. The candidate has a strong technical background in MRI physics, data processing, and analyses. She firmly believes that a multi-modal analysis is the key to bridge the systems-level MRI markers with the cellular level PET markers for a better understanding of AD mechanisms. To complement her technical background, she will take courses in neurology, allowing her to formulate and test well-informed hypotheses for degenerative disease mechanisms. She will secure new skills in static and dynamic PET analyses, as well as PET-MRI image fusion. She has provided a detailed plan for her research publications and first R01 submission. The candidate’s mentors will ensure that she is well-prepared to launch her independent career as an imaging research scientist.
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