Project-3 Summary/Abstract: The main goal of this neuropathology-neuroimaging correlation study is to validate [C-11]PiB and [F-18]AV-1451 as selective positron emission tomography (PET) radiotracers for in vivo detection of fibrillar amyloid-β (Aβ) and Tau pathologies, respectively. In Project-3 (formerly Project-6), we propose to extend our investigation of pathological substrates and sensitivity thresholds of [C-11]PiB PET signal, and to advance further the neuroimaging field by characterizing both Aβ and Tau imaging ligands in the same subjects. We will first refine our threshold and correlation estimates in larger numbers of [C-11]PiB PET autopsy brains with a range of pathology load and clinical disease status. Using our established bank of autopsy brains from [C-11]PiB PET imaged subjects, and new brains we will resource, we can now address these issues over the spectrum of cognitive profiles, for the first time. We will use highly fluorescent derivatives of PiB (6-CN-PiB) and Congo red (X-34) to test our hypothesis that PiB signal is determined by both fibrillar content and percent area coverage of cored/neuritic and diffuse plaques, as well as by modified Aβ forms in plaques, specifically truncated, highly fibrillogenic pyroglutamate Aβ (Aim 1). The second major goal of this proposal is to determine the selectivity of AV-1451 for Tau pathology, in relation to PiB-relevant fibrillar Aβ aggregates in the same brain regions. We will compare [H-3]AV-1451 autoradiography signal to immunohistochemically-identified Tau and Aβ pathology and PiB labeling, in brains with different levels of Tau pathology defined by Braak staging (Aim 2a). Complementary biochemical studies will compare [H-3]AV-1451 binding to Tau and Aβ concentrations and [H-3]PiB binding levels in tissue homogenates from the same brain regions. We also propose the first imaging-to-autopsy correlation study of [F-18]AV-1451 (Aim 2b). To accomplish this, we will utilize new brains from control, MCI, and AD participants in the end-of-life GEMS cohort imaged with [F-18]AV-1451 and [C-11]PiB PET in Project 1. Our third goal is to examine the relation of [C-11]PiB and [F-18]AV-1451 retention levels (and Aβ/Tau measures postmortem) with synaptic density, reductions in which most closely parallel cognitive decline in AD (Aim 3). We will also determine if Tau and other coexisting pathologies (vascular, inflammation, TDP-43, α-synuclein) influence the relation between PiB measures and synapses/cognition or have an independent effect. Collectively, our studies will contribute to a better understanding of the pathological substrates of PiB and AV-1451 PET retention, their relationship with synaptic loss and cognitive decline, and the influence of vascular and inflammation pathology on these relationships in AD.