Archief Roodbont

Pauline Anderson

Medscape Medical News 2008. © 2008 Medscape

November 13, 2008 — About 1 in 5 cognitively normal elderly people has signs of Alzheimer's-related amyloid plaques in the brain, which is about the same proportion as found in brains of deceased patients who were diagnosed with Alzheimer's disease (AD), a new study in the November issue of the Archives of Neurology has found.

In 1 of the first and largest studies of its kind, researchers used a novel amyloid-tracking agent called Pittsburgh Compound B (PiB) and positron-emission tomography (PET) to pick up areas of amyloid deposits in healthy living volunteers. In the past, it was only through autopsies that such plaque deposits could be detected.

"It's very revolutionary that we can reliably detect the pathology of AD in living people," said one of the investigators, Dr. William E. Klunk, MD, PhD, professor of psychiatry and neurology at the University of Pittsburgh School of Medicine, in Pennsylvania.

"Profound Implications"

These findings have "profound implications" for future preventive strategies and might lay the groundwork to possibly predict "fairly accurately" who will develop AD 5 to 10 years before the onset of symptoms, said the study authors.

"I see this as good news, bad news," Dr. Klunk told Medscape Neurology. The good news is that scientists are at a point where they can now screen people and detect amyloid in time to intervene with therapy. The bad news is that there isn't yet a proven therapy. "And as we sit here today, if we treat only people who have symptomatic Alzheimer's disease, we're already 10 years behind the pathology," he said.

For the study, investigators included 43 healthy cognitively normal subjects between the ages of 65 and 88 years. "It's important to note that this is a community-derived sample," said Dr. Klunk. "They're as representative of the typical elderly population as we could get."

These subjects underwent a battery of neurological and cognitive assessments as well as the PET PiB scanning. PiB is a derivative of an older dye that detects amyloid but only in autopsy tissue, as it can't enter the living brain. In a long and painstaking process, Dr. Klunk and his colleague Chester A. Mathis, PhD, professor of radiology at the University of Pittsburgh School of Medicine, modified that original compound to come up with an agent that not only can be used in a living brain but also is better at binding to amyloid.

Like Craft Glitter

Dr. Klunk likens the upgraded agent to craft glitter sprinkled over a paper dotted with glue. After turning the paper upside down, some of the glitter scatters but some sticks to the glue to create a pattern. "The paper is like the nonamyloid brain, the glue is like the amyloid in the brain, and the glitter is like PiB."

To help define amyloid positivity, an additional 19 cognitively normal subjects underwent the same diagnostic neuropsychological screening and PiB PET scanning. Using a complicated system of eliminating outliers, investigators came up with a cutoff for amyloid-positive status.

The PET scans used in the study concentrated on particular regions of the brain, including: frontal lobe, anterior cingulate gyrus (ACG), lateral temporal, mesial temporal, occipital, parietal, precuneus cortex (PRC)/posterior cingulate gyrus (PCG), sensorimotor cortices, and anterior-ventral stratum.

Equal Cognitive Performance

Of the 43 cognitively normal subjects, 9 (21%) showed early amyloid deposits in at least 1 area of the brain — about the same percentage as is found in postmortem studies. Investigators found no differences in cognitive performance or in demographics between the amyloid-positive and amyloid-negative groups.

Significantly, the investigators also noted that the amyloid deposition was primary in regions that ultimately develop heavy amyloid loads in AD patients, especially the ACG and the PRC/PCG cortex

"These folks can tolerate the pathology, so there's time to do something about it," said Dr. Klunk. "They have amyloid, but the brain isn't malfunctioning yet."

Unexpectedly, the amyloid-positive group performed better on 1 of the cognitive tests — the delayed word-recall test — perhaps because they have particularly high cognitive reserves in areas such as the medial temporal lobe that are relatively unaffected by amyloid deposition. But Dr. Klunk does not want to place too much emphasis on this finding. "We did a lot of tests, so I don't think the fact that 1 of them was a little better in the people who had amyloid than those who didn't is the message," he said. "What's more important is that in all these tests, there's really nothing to shake a stick at as far as picking the amyloid-positive people out from the amyloid-negative people."

Will the 9 seniors with amyloid go on to develop AD, and are the other 34 subjects protected from developing this disease? "That's what the research will tell us as we follow these people," said Dr. Klunk. "But the working hypothesis for now is that the Alzheimer's patients will come from this cohort who already has the pathology. We'll find out if this is correct."

"We're Not There Yet"

Meanwhile, it would be ideal if these 9 patients could be treated to decrease the risk of developing AD. "We're not there yet, although that's obviously what we would love to do," said Dr. Klunk, adding that he and his colleagues have some ideas of potential preventive approaches. One such approach could be to use 1 of the promising immunotherapies now being tested. "But we first need to show that the latest iteration of these immunotherapies is safe in AD patients and that they effectively remove amyloid from these patients," he said.

Although he recognizes the value of autopsy studies, Dr. Klunk pointed out the advantages of PiB in detecting amyloid in the brain of cognitively normal people. For one thing, in the case of postmortem examinations in people with normal cognitive test results, the assessment may have taken place months or even years before death, raising the possibility that such individuals were not cognitively normal when they died.

"Also, if they were tested very close to death [and did not test normal], you can't be sure if something related to their death affected their cognitive function, and, most important, you can't follow them to then find out if this really was a precursor to AD or whether it was just an irrelevant finding in their brain."

This research adds another element to the ongoing discussion of the relationship between amyloid and cognition. While some studies have found that the amyloid burden is related to the degree of cognitive impairment in AD, others have failed to uncover a correlation. This current study points to the complicated nature of this relationship, said Dr. Klunk. "It's not a one-to-one thing," he said. "Just as a certain mass of cholesterol in our arteries does not equal a certain number of heart attacks, a given mass of amyloid does not equal a given deficit on a cognitive test."

GE Healthcare holds a license agreement with the University of Pittsburgh based on the technology described in this paper. Drs. Klunk and Mathis are coinventors of PiB and, as such, have a financial interest in this license agreement. GE Healthcare provided no grant support for this study and had no role in the design or interpretation of results or preparation of the manuscript. All other authors have no conflict of interest.

Arch Neurol. 2008;65:1509-1517. Abstract