Shape-based personalized AT(N) imaging markers of Alzheimer's disease

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Abstract The AT(N) framework of Alzheimer’s disease (AD) provides a systematic guidance to study AD based on quantitative measures of biological markers of β-amyloid (Aβ) plaques (A), neurofibrillary tau tangles (T), and neurodegeneration (N). Existing AT(N) imaging markers are typically defined as average measures of cortical regions determined a priori, which are insufficient to characterize the heterogeneous pathology and atrophy patterns of AD. To allow more personalized characterization of the AT(N) status of individual subjects, we will develop in this project novel imaging markers based on advanced shape analysis techniques. From the perspective of imaging marker development, challenges to study the heterogeneity of AD can arise from multiple sources. The first is the frequent existence of atypical AD pathology and brain atrophy patterns that deviate from canonical Braak stages. The second is the high variability of cortical anatomy and the resulting large variations of cortical thickness at so called “corresponding” locations of even healthy brains. The third is the current lack of understanding about the role of AT(N) imaging markers in characterizing the diverse disease trajectories in minority groups including African Americans and Mexican Americans. Building upon our extensive experience in brain shape analysis, we will develop tools to quantify the topographic pattern of cortical tau and Aβ pathology, build a personalized analysis framework for the early detection of localized brain atrophy, and apply these tools to the multi-ethnic cohort from the Health & Aging Brain Study – Health Disparities (HABS-HD) (n=3000) to characterize the heterogeneity of AT(N) imaging markers in diverse populations. There are three specific aims in our project: 1. To develop surface-based modeling of topographic patterns in tau and amyloid PET imaging for personalized subtyping and staging of AD pathology. 2. To develop personalized imaging measures of brain atrophy by resolving variability due to cortical folding and shape differences. 3. To characterize the impact of health disparity on disease staging and subtyping with personalized imaging markers. In summary, our main goal is to create novel computational tools for the creation of personalized AT(N) imaging markers and apply them to characterize the heterogeneity of AD pathology in the context of health disparity. All tools and imaging markers developed in this project will be distributed freely to research community, which we believe will greatly enhance the state-of-the-art in the subtyping and staging of AT(N) pathology in diverse populations.