Abstract / Project Summary: Alzheimer's disease (AD) is an irreversible brain disease that affects tens of millions of people in the world. Unfortunately, there is currently no cure for AD except symptoms release treatments. Even with advanced knowledge of AD accumulated over the past several decades, many clinical trials aiming to intervene at the causative pathological elements have failed to produce disease-altering effects. One reason is that there are no suitable biomarkers for early diagnosis and accurate differentiation of AD patients into different subtypes that could benefit from certain treatment regimes. Molecular imaging such as PET and SPECT have the ability to provide biomarkers that permit spatial assessment of pathophysiological molecular changes in AD and lead to the development of interventions personalized to an individual's molecular risk and disease pathology profile. It can also objectively evaluate and follow up therapeutic responses. Even though SPECT is more widely available than PET and has the potential to perform dual-isotope imaging, brain SPECT imaging is rarely used both in clinics and research for AD due to the poor sensitivity and spatial resolution of the current clinical SPECT system. The goal of this proposed project is to develop an ultrahigh-resolution single-photon emission microscopy imaging system for brain SPECT. The goal is to provide a spatial resolution of a few hundred microns while maintaining a sensitivity that is close to a PET system. This system will lead to dynamic SPECT images with a superior spatial resolution that is better than PET, as well as an opportunity to perform simultaneous multiple- isotope/tracer imaging that can be applied to develop biomarkers of diagnosis and disease progression in Alzheimer's disease, mild cognitive impairment (MCI) and other neurodegenerative diseases.