Beta-amyloid plaques predict cognitive disease advance

Results from a preliminary PET imaging study suggest that 80% of elderly people with mild cognitive impairment and evidence of beta-amyloid plaque in their brains will develop Alzheimer's disease.

Dr. Victor Villemagne, a dementia researcher from the Center for PET at Austin Hospital in Melbourne, Australia, drew this conclusion from a two-year study of 85 MCI subjects, Alzheimer's patients, and normal volunteers. His results were presented in June at the 2008 Society of Nuclear Medicine meeting.

Using carbon-11 Pittsburgh Compound B (PIB) PET imaging, Villemagne and colleagues affiliated with the University of Melbourne discovered that the disposition of intercortical beta-amyloid protein-a key indicator for the presence of Alzheimer's disease-changed only slightly after 21 months, but the changes were large enough to accurately show that 80% (12 of 15) of MCI subjects classified as PIB-positive would progress to Alzheimer's disease within two years. C-11 PIB PET was deemed 86% accurate for predicting the conversion to Alzheimer's disease, and it had a negative predictive value of 92% for ruling out its development among MCI subjects, Villemagne said. Apo-E genetic status, another possible indicator, was 78% accurate and had an NPV of 90%.

These results were among several important imaging findings pertinent to Alzheimer's disease diagnosis and characterization reported at the SNM meeting. Also related to MCI-to-Alzheimer's conversion was a study by Dr. Kai Kendziorra of the University of Zurich in Switzerland suggesting that a reduced prevalence of cerebral nicotinic acetylcholine receptors (nAChRs) in the brain can also single out which individuals with MCI will go on to develop Alzheimer's disease.

PET imaging was performed with fluorine-18-2-FA-85340, a radioligand with an affinity for nAChRs, Kendziorra said. Follow-up PET with the same investigational probe was performed 10 months later. A region-of-interest analysis identified significant reductions in the presence of receptors in the thalamus and frontal, parietal, temporal, and cingulate cortex of MCI patients who would convert to Alzheimer's disease. A loss of receptors was not observed in patients with stable MCI.

Another C-11 PIB study from Melbourne's Center for PET established a correlation between beta-amyloid deposition in the brain and the natural aging process. Working with center director Dr. Christopher Rowe, Villemagne and colleagues found amyloid deposits in the brains of 23% of cognitively normal volunteers between the ages of 60 and 69. The percentage rose to 37% for individuals aged 70 to 79 and was detected in 52% of the subjects over age 80.

Progress was also reported in the effort to develop a more clinically acceptable version of PIB. Because of its 20-minute half-life, C-11, the cyclotron-generated isotope used in early PIB trials, is considered unrealistic for nonacademic use, so researchers have searched for a compound that performs as well as PIB but uses F-18, which has a half-life of 110 minutes.

Five potential candidates were discussed at the SNM meeting. Using F-18 BAY 94-9172, Dr. Henry Barthel and colleagues at the University of Leipzig in Germany imaged 10 patients (mean age 69) with probable Alzheimer's disease and 10 healthy age-matched controls. Based on a visual analysis, all 10 healthy controls were amyloid-negative on PET imaging performed with the fluorine-based agent. Nine of 10 suspected AD patients were amyloid-positive.

Dr. Daniel M. Skovronsky, chief executive officer of Avid Pharmaceuticals, described how his company screened more than 200 fluorinated compounds to identify five F-18 agents that could potentially perform as well as C-11 PIB. One was F-18 BAY 94-9172. It was turned over to Avid's collaborator Bayer Schering Pharma in Berlin for further evaluation.

Four other candidate compounds were tested on 94 Alzheimer's patients and cognitively normal adults. All were well tolerated, easily metabolized, and shared acceptable dosimetry, Skovronsky said. AV-45 was singled out for further development. Phase I clinical trials involving 31 subjects were performed at Johns Hopkins University Hospital and elsewhere. Phase II clinical trials involving 35 facilities were announced in June.

-By James Brice