This presentation will summarize the discovery, development, and use of amyloid-beta (Ab) imaging agents in Alzheimer's disease (AD). Amyloids are proteins composed of different amino acids with variable molecular weights. Two defining characteristics of amyloid proteins are their propensity to aggregate (both in vitro and in vivo in different tissues in the body) and to form extended beta-pleated sheet structures that avidly bind fluorescent dyes such as Congo red and thioflavin-S. Aggregated amyloids accumulate both peripherally and in the brain and are associated with a variety of diseases such as systemic amyloidosis, AD, frontal temporal dementias, Parkinson's disease, and Huntington's disease. Historically, the clinical diagnosis of many of the amyloid-related diseases was confirmed in post-mortem tissue samples and utilized the location and concentration of the amyloid aggregates as definitive evidence of disease presence at the time of death.
A goal of researchers throughout the world was to develop methods capable of the definitive diagnosis of amyloid-related diseases prior to death in living human subjects. This would permit the identification of early stage disease cases in whom the natural history of disease progression could be defined, as well as assist in the evaluation of the efficacy of anti-amyloid therapeutics at different stages of disease. Non-invasive imaging methods, such as positron emission tomography (PET), could be utilized pre-mortem for this purpose, if suitable radiotracers for the different amyloids were developed and applied. The first reported amyloid imaging radiotracers were non-selective and bound with high affinity to a variety of different amyloids. The development of PET radiotracers that bound selectively to one type of aggregated amyloid over all other types is desirable, particularly in AD where both aggregated Ab (in the form of Ab plaques) and tau (in the form of neurofibrillary tangles) can be present. In the early 2000's, our research groups at the University of Pittsburgh identified the first selective amyloid PET radiotracer, carbon-11-labeled Pittsburgh Compound B (PiB), for imaging aggregated Ab. Thousands of research PiB PET imaging studies in normal elderly subjects, subjects diagnosed with mild cognitive impairment, and AD have been conducted worldwide, and the results of those studies will summarized. Subsequent development of longer-lived fluorine-18-labeled Ab PET radiotracers permitted their wider distribution and clinical use at a variety of PET imaging centers. Currently, Ab PET imaging is being used to understand the natural history of Ab deposition, to help define and identify pre-AD subjects, to assist drug development efforts in clinical trials, and to add an etiological component into the pre-mortem diagnosis of probable AD in research settings. The future uses and expansion of Ab PET imaging will likely be affected by the degree of success of plasma-based AD biomarkers, such as Ab40/42 and phospho-tau species.