Title: Development of a Quantitative Iron Characterization System for Alzheimer's Using Computed Laminography X-ray Fluorescence Imaging (CL-XRFI) Project Summary/Abstract The discovery of ferroptosis has invigorated new therapeutics to prevent and/or alter pathological iron distribution in the brain correlated with Alzheimer?s disease (AD) and other neurodegenerative diseases. To efficiently evaluate new drug designs, techniques capable of directly imaging and quantifying the trace levels of iron in brain samples are required. Current approaches include LA-ICPMS and synchrotron microXRF, which each have their own drawbacks in terms of speed, quantification reliability, and accessibility. We propose to develop a scheme called computed laminography x-ray fluorescence imaging (CL-XRFI). In this novel system design, an x-ray beam is focused into a pencil-like beam incident upon a sample at a very low angle (3 degrees). A detector is placed parallel to the sample surface to maximize solid angle. Acquisition is similar in concept to absorption-based laminography, in which acquisition at multiple angles are taken for reconstruction of the signal origin. The system design is uniquely enabled by the company?s patented high brightness x-ray source and its proprietary x-ray optic technology that provides the large working distances necessary for the technique to work. The proposed Phase I 6-month project is a proof-of-principle demonstration of the sensitivity and throughput of a breadboard low angle incidence fluorescence system. The proposed Phase II 24-month project is to develop a complete prototype of the CL-XRFI.
This project proposes to develop a computed laminography x-ray fluorescence imaging (CL- XRFI) system for high sensitivity iron detection in brain samples. The development of the proposed system is needed for ongoing research on Alzheimer?s Disease (AD) and other neurodegenerative diseases, focused on the recently discovered ferroptosis pathway, an iron- induced cellular form of death. The system?s fast, high sensitivity, and high resolution analysis will provide efficient, quantitative understanding of how iron chelating and other ferroptosis- inhibiting drugs impact iron distribution in the brain, thus enabling faster drug time-to-market.
