Although Alzheimer's Disease (AD) is an aggressive and devastating dementia that has an increased frequency with age and is one of the most common neurodegenerative diseases, it is remarkably difficult to diagnose with certainty, particularly in the earliest stages when significant presymptomatic changes are happening in specific cognitive and memory centers of the patients'brains. Several other neurodegenerative dementias have similar symptoms and conclusive diagnosis requires a postmortem neuropathological exam. The two hallmark defects of AD are senile plaques (SP) and neurofibrillary tangles (NFT). If one or both of these defects could be imaged in the living patient during the earliest disease stages, it would benefit both clinical treatment regimens and basic research. To develop a method for such imaging studies, radiochemists have tried to model candidate tracers for neuroimaging on fluorescent dyes that bind to the beta-pleated sheet structures of the amyloid fibrils of SP. Several classes of tracers have met with a measure of success but lack a high signal-to-noise ratio and only one is labeled with 18F, a positron emitting isotope with a long enough halflife (110 minutes) to permit transportation to institutions lacking a cyclotron facility. We propose to develop a high-affinity, fluorinated radioligand for [3-amyloid that can be used as a radiotracer for PET neuroimaging. Analogs of several divergent prototypes from two different laboratories will be tested in both in vitro and in vivo assays for [3-amyloid binding in SP of AD brain tissue. In addition, we will determine the diagnostic specificity of ligand binding for two major subtypes of frontotemperal dementia classified according to deposits of ubiquitin versus tau. Finally, we will determine the aggregation state and peptide/protein composition of the binding site in AD brain tissue using photoaffinity labeling and affinity purification techniques combined with western blotting and mass spectroscopy.
Amyloid imaging agents developed through this project could provide reliable premortem diagnosis of AD, the ability to monitor disease progression, and an index for the evaluation of therapeutic efficacy. If such agents have higher signal-to-noise ratios than current radiotracers, then lower levels of amyloid could be detected in AD patients and therefore the onset of amyloidosis could be detected earlier. This could open a window on the initial stages of AD when the neurodegenerative processes are believed to begin and when it is probably most useful to intervene with novel therapies to preserve as much brain tissue as possible.
