Molecular imaging in the brain is complicated by the combined requirements for blood-brain barrier permeability, high target specificity, and rapid clearance. We present four technologies that address these obstacles, with application to Alzheimer's and other diseases.
First, we develop a Monte Carlo simulation platform for comprehensive study of fluorophore and imaging parameters. We determine the optimal fluorophore properties for amyloid imaging in transgenic mouse models, and find that improvements in contrast ratio and fluorophore emission wavelength would significantly improve current detection capabilities. Different measurement configurations are tested and we propose a region-based measurement that accurately predicts amyloid content in different brain regions.
Second, we demonstrate optical property imaging across the whole mouse. Optical properties impact the tomographic forward model and can vary by orders of magnitude. Our Rytov-based approach performs well for a range of optical property perturbations in simulations and mice. Fluorescence tomography of indocyanine green is performed in mice using forward matrices that incorporate optical property heterogeneities.
Third, we use fluorescence lifetime imaging to multiplex 2 or 3 fluorophores in vivo. Fluorescence lifetime is a characteristic decay property which is a photophysical identifier. We use asymptotic lifetime fitting to separate fluorophores in vitro and in vivo; recovered 3D localizations correspond well with known biodistributions and post-mortem organ analysis. Furthermore, lifetime multiplexing allows in vivo measurement of inflammation in stroke and background autofluorescence reduction when imaging fluorescent proteins.
Fourth, we show that low-power focused ultrasound in the presence of microbubbles may be used to deliver fluorophores and immunotherapeutics locally in transgenic Alzheimer's model mice. When administered concurrent with ultrasound exposure, fluorophores (Trypan blue) and antibodies are delivered at high levels (17x and ∼ 3x, respectively) to the treated brain regions, with minimal histological tissue damage. Ultrasound-enhanced delivery is possible with MRI guidance or on a simple benchtop system.
In summary, this dissertation demonstrates: new simulation methods for systematically studying molecular imaging problems, in vivo optical property imaging, lifetime-based contrast-enhancement and fluorophore multiplexing, and a localized delivery technique for CNS targets. These technologies will have an important impact on the molecular imaging of Alzheimer's and other disease processes.