TRIAL DESIGN, DATA SHARING RISK MITIGATION, AND BASELINE CLINICAL AND COGNITIVE DATA FROM THE API AUTOSOMAL DOMINANT ALZHEIMER’S DISEASE COLOMBIA TRIAL

Abstract

Background: Specificity/sensitivity of amyloid PET ligands for cored neuritic plaques (CP) is high, however imaging-to-autopsy studies produced some false positive results. Thus, the contribution of diffuse plaques (DP) to amyloid PET signal needs to be investigated. High retention of [C-11]PiB and [F-18]Flutemetamol (Vizamyl) in striatum, where DP predominate, indicates these ligands also bind to diffuse amyloid. However, in cortical areas with mixed CP and DP, contribution of different plaque types to ligand binding is unclear.Methods: We used fluorescent derivatives of PiB (CN-PiB) and Flutemetamol (CN-Flute) applied to tissue sections from striatum (caudate, CD) and frontal cortex (FC) from 10 cases with definite AD. Fluorescent signal was analyzed relative to CP and DP, vascular amyloidosis, and neurofibrillary tangles. Percent area occupied by plaques and integrated density (combines plaque percent area coverage with fluorescent intensity) were calculated for each ligand. Confocal microscopy was used to obtain surface plots of intensity profiles and 3-D analyses of total fluorescence output from individual CP and DP. Results: Both CN-PiB and CN-Flute fluorescence was prominent in CP and vascular amyloidosis, and less so in DP, but was not present in neurofibrillary tangles. Percent area coverage of total plaques was similar in CD and FC for both ligands (CN-Flute: CD1⁄43.7960.64, FC1⁄45.8161.18, t-test p1⁄40.15; CN-PiB: CD1⁄43.1260.48, FC1⁄45.2562.20, t-test p1⁄40.08). In contrast, integrated density values were greater in FC compared to the CD for both ligands (CN-Flute: CD1⁄450246490.3, FC1⁄4117426568.2, ttest p<0.0001; CN-PiB: CD1⁄448466258, FC1⁄4124256551, t-test p1⁄40.002). Conclusions: [11C]PiB and [18F]Flutemetamol PET retention in vivo likely depends on both size and fibrillar density of CP and DP. For regions with comparable plaque burden, but with different involvement of CP and DP, the region with more CP yields greater integrated density signal for both ligands. In areas of mixed CP and DP, large swaths of DP could yield [11C]PiB and [18F]Flutemetamol PET retention levels comparable to brain regions with low CP frequency. Thus, amyloid PETmay reflect better NIA-AA 2012 AD neuropathology criteria that incorporate both CERAD (neuritic, CP) and Thal phases (all types of Ab plaques).