Amyloid plaque has been the centerpiece of much research related to Alzheimer's disease (AD). In fact, several drugs in development that target these deposits have so far failed to produce a benefit for people with mild-to-moderate AD. A relatively new imaging modality called PIB-PET explains why and may be the key to developing the most effective treatments.

Two neuroscientists have reviewed 100 studies that used Pittsburgh compound B (PIB), which is injected into the brain of a live person via the bloodstream and then imaged using positron emission tomography (PET). What they have learned is, that treating AD "is turning out to be a much more complicated story," Gil Rabinovici, MD, assistant professor of neurology in the University of California, San Francisco Memory and Aging Center, told Medical Device Daily.

Until PIB-PET, the only way to examine the telltale plaques associated with AD was in the brains of cadavers. PIB, discovered about 10 years ago, opened the door to viewing the plaque in live people. Rabinovici and his colleague William Jagust, MD, of the Helen Wills Neuroscience Institute at the University of California, Berkeley, and Lawrence Berkeley National Laboratory (Berkeley), reviewed the studies and found that the amyloid hypothesis – that accumulation of amyloid-beta protein plaques in the brain is central to the development of the disease – is true.

But they also learned that by the time people have reached a state of even mild cognitive impairment, those amyloids have already reached a plateau. Drugs in development to treat plaque would be effective only if administered much earlier in a person's life.

"Amyloid isn't the whole story," Rabinovici said. "There are other things going on in the brain that lead to brain atrophy and clinical decline. This has enlightened our understanding between amyloid plaque and AD."

PIB-PET involves injecting the PIB tracer material into the brain via the bloodstream, and imaging the brain with PET. PIB binds to amyloid-beta protein plaques and sends a signal that is then detected by the PET scanner and translated into an image reflecting the quantity and distribution of amyloid in the brain.

"If amyloid treatments are to be helpful, they would need to be delivered in the presymptomatic phase," he said. "Even for people with mild memory problems, treating amyloid won't help. This has major implications in how we think about diagnosing AD, as well as preventive and therapeutic strategies."

In the studies surveyed, scientists complemented the PIB-PET investigations by using additional neuroimaging techniques such as magnetic resonance imaging or FDG-PET, which allowed them to measure the size of different brain structures, network connections or brain metabolism.

In 2006, the University of Pittsburgh (UP) first reported a study aimed at obtaining preliminary information on the performance of flourine-18 labeled Pittsburgh Compound B (F-18 PIB) to identify amyloid deposits in subjects with a diagnosis of AD. At the time, GE Healthcare (Waukesha, Wisconsin) reported a collaboration between radiochemists from the University of Pittsburgh and the company. GE Healthcare had licensed a number of compounds from UP in 2003, which ultimately led to this alliance (MDD, Nov. 30, 2006). Since then, numerous other research institutions have initiated PIB/AD related studies.

PIB-PET is currently used for research purposes only, due to its limited half life of 20 minutes. But other amyloid imaging agents are being developed for commercial use. Rabinovici discourages use of the current technology in cognitively normal individuals as a screening tool until effective and safe anti-amyloid therapies are available and the benefit of preventive treatment is demonstrated in clinical trials.

"Right now, there are at least three very promising PIB agents (with a longer half life) in clinical trials," he said. "If the FDA approves them there will be several options."

He said that the most obvious group on which to try the PIB-PET approach would be people with the specific amyloid precursor protein or anyone with a higher risk for developing AD. "If you can detect amyloid deposits in people in their 30s or 40s, they have very little to lose and this would be the proof of concept."

Rabinovici said that at some point PIB-PET will be ready to use as a tool to screen people who are genetically at risk for AD and those who have minimal symptoms. At that stage, anti-amyloid therapies would theoretically be effective to stall the full onset of disease.

Existing drugs, such as Aricept, Exelon and Razadyne, treat symptoms, but do not modify the biological progression of the disease.

Lynn Yoffee, 770-361-4789;
lynn.yoffee@ahcmedia.com