Jeffrey Petrella
As the global population ages, the incidence of Alzheimer disease (AD), now more than 30 million worldwide, is predicted to triple by the year 2050, creating an urgent need for developing therapeutics designed to slow or halt disease progression. The search for a cure continues, and our extensive, yet incomplete, understanding of its biology have led to many potential drug targets. Because of the cost and duration of trials designed to show a clinical benefit on cognition and function, there are limitations on the number of drugs that can be tested in large multicenter phase III trials, which can cost tens of millions of dollars and last up to a decade to test a single agent. Both the FDA and pharmaceutical industry are interested in a high-throughput approach aided by biomarkers, such as imaging, in smaller early-phase trials, to demonstrate that a drug is affecting its intended target. Such an approach is expected to significantly decrease the duration and number of subjects necessary to measure an effect, and greatly increase the rate at which candidate drugs can be brought to testing in larger phase III trials. While preclinical studies in animal models have been used for this purpose, imaging studies are an ideal means to demonstrate the potential for success of a given agent in humans.
Mild cognitive impairment (MCI) is a significant risk factor for development of AD, and is considered by many to be a pre-Alzheimer condition. While donepezil is one of a small handful of FDA-approved medications for symptomatic treatment of AD, its use in MCI is still under investigation. It is part of a class of drugs known as cholinesterase inhibitors, which enhance cognition by increasing levels of acetylcholine at the synapse. We were involved in a multicenter, double-blind, placebo-controlled trial to assess the effects of donepezil on cognition in MCI. We wanted to determine whether we could measure its effects on the brain in a small