Amyloid Imaging May Identify Preclinical Alzheimer's Disease

Janis C. Kelly

December 16, 2009

December 16, 2009 — Brain imaging using the using the Pittsburgh compound B (PiB) shows that the presence of amyloid plaques in the brains of apparently cognitively normal individuals is associated with an increased risk for Alzheimer's disease (AD) in the near future, new research suggests.

Two studies published in the December issue of Archives of Neurology show that apparently healthy individuals with brain plaques on imaging at baseline were more likely to have declining scores on annual cognitive tests, experience volume loss in the parahippocampal gyrus, and eventually be diagnosed as having AD.

"PiB imaging enables us to evaluate 1 aspect of AD pathology — amyloid plaques — in living people. This study is the first to demonstrate that just carrying these plaques puts you at high risk of becoming demented within a very few years,” principal investigator John C. Morris, MD, director of Washington University's Alzheimer's Disease Research Center and the Friedman Center for Aging, St. Louis, Missouri, told Medscape Neurology.

"We don't have enough data yet to definitively say that people who scan positive for these brain plaques have presymptomatic Alzheimer's disease, but something is clearly going on that does not bode well for the health of their aging brains," Dr. Morris said.

The researchers tracked a group of 159 volunteers, ages 51 to 88 years, who were scanned using positron emission tomography (PET) PiB between 2004 and 2008. None showed signs of mental impairment at study entry.

At 5-year follow-up, 23 subjects developed mild cognitive impairment, and 9 these subjects were ultimately diagnosed as having AD.

Amyloid Imaging a Game Changer

The factors that predicted progression to mild impairment were higher concentrations of PiB and age. Mild impairment primarily affected episodic memory, semantic memory, and visuospatial performance, and these subjects also had shrinkage of the parahippocampal gyrus, including the entorhinal cortex.

Amyloid imaging with PiB is a game changer, the researchers say. "We had been looking at the idea of presynaptic AD for about 20 years. Autopsy data showed that many apparently normal people had AD neuropathology, but we had no way to determine if the person would have become symptomatic after living longer or whether some people with AD-type plaques had a protective factor against dementia," Dr. Morris said.

Martha Storandt, PhD, professor of psychology and neurology, Washington University, who led the second study, said that one of the main goals of the research was to determine whether individuals who scanned positive for brain plaques had abnormally low cognitive test scores.

"They didn't, but when we looked at their annual testing records over a period of years, we saw that the scores of the plaque-positive group were declining, while those of the plaque-negative group were not."

The 2 amyloid imaging studies are part of a conceptual change in thinking about Alzheimer's prevention and treatment.

"The paradigm is shifting from looking for drugs to treat people who already have the dementia of AD (which has not been very successful) to intervening early enough in the disease process to prevent dementia from developing," Dr. Morris said.

The amyloid imaging studies suggest that this will be very early, indeed, and will likely involve treating patients who are at risk but cognitively healthy at the time of treatment.

Support for the Amyloid Hypothesis

Niklas Mattsson, MD, of the Institute of Neuroscience and Physiology at Sahlgren’s University Hospital in Mölndal, Sweden, told Medscape Neurology that this research "further strengthen the case for preclinical AD as a condition with deleterious consequences."

"Using PiB-PET, these studies focus on the amyloid brain pathology, and they help establish the fact that amyloid pathology is present in preclinical AD. Having verified this, crucial questions regarding the role of amyloid in AD still remain. The Holy Grail within AD research is now to push the limit of knowledge beyond this point, to reveal such mysteries as why amyloid pathology starts in the first place," Dr. Mattsson said.

Joseph Quinn, MD, from Oregon Health and Sciences University in Portland, who was not involved in either study, told Medscape Neurology that by showing that asymptomatic cerebral amyloid has subtle effects on cognition and brain structure and increases the odds of developing AD over time, the findings strengthen the amyloid hypothesis.

"For a long time we've known that patients can die with lots of amyloid in the brain without dementia. Skeptics said this proved that amyloid was not neurotoxic, while others argued that these people were simply 'presymptomatic.' This argument could not be resolved until we had the means to identify living nondemented subjects with cerebral amyloid, so we could see whether they developed symptoms over time."

Opportunity for Early Intervention

Dr. Morris predicted that amyloid imaging will become a major tool in research, clinical trials, and routine clinical practice — but it will not be imaging with PiB, which has a 20-minute half-life and costs about $3000 per scan. He said that several PiB-like compounds with longer half-lives are under development.

The researchers' next task is to validate their approach to identifying high-risk individuals. This is being done by the Dominantly Inherited Alzheimer's Network (DINA).

“Assuming that we can use PiB imaging to identify the high-risk subgroup, we are considering following the DINA trial with an early intervention, and we hope to report initial plans for that study at the 2010 International Conference on Alzheimer's Disease meeting in Honolulu,” Dr. Morris said.

Dr. Morris found the failure of antiamyloid agents in patients with full-blown AD dementia unsurprising. He predicted that some of these agents will be more effective if used before brain damage is so advanced.

"I don't think we have really tested the amyloid hypothesis. It is possible that the failures were not of the drugs but of when the interventions were administered." If so, he added, several drugs approved for study in humans, including secretase and immunotherapy agents, are already waiting in the wings.

Funding from the National Institute on Aging and the Charles and Joanne Knight Alzheimer's Research Initiative supported this research. The authors have disclosed no relevant financial relationships.

Arch Neurol. 2009;66:1469-1475.