Pauline Anderson

April 27, 2012

April 27, 2012 (New Orleans, Louisiana) — Yet another amyloid tracing agent is showing promise as a diagnostic tool in the field of Alzheimer's disease (AD).

New biopsy and autopsy studies show that the investigational imaging agent [18F]flutemetamol has a high specificity and sensitivity in the detection of beta-amyloid plaque in the brain. Other research shows that the uptake of this biomarker in older nondemented adults correlates well with their cognitive function.

Results of these investigations were released here during an Emerging Science Session at the American Academy of Neurology's 64th Annual Meeting.

[18F]flutemetamol (GE Healthcare) is the next-generation 11C Pittsburgh Compound-B (11C-PIB). It's the same agent except it has an F18-radiolabel instead of carbon 11. PIB's short half-life of 20 minutes limits its use in clinical practice and is generally restricted to the research setting.

Two other amyloid tracers — florbetapir (Amyvid, Eli Lilly), and florbetaben (Bayer Healthcare) — also have the longer half-life. Florbetapir is the only such agent approved by the US Food and Drug Administration, having received approval earlier this month.

Biopsy Study

The 4-site biopsy study using flutemetamol was somewhat unique, said lead investigator David Wolk, MD, assistant professor, neurology, Cognitive Neurology Division, University of Pennsylvania, Philadelphia. Researchers used 49 living patients with normal-pressure hydrocephalus, a third to a half of whom might have underlying AD pathology. Treatment for this condition includes draining fluid from ventricles that requires inserting a shunt. During this procedure, researchers took cortical tissue for biopsy.

Dr. David Wolk

"When you place the shunt, you damage tissue, so you can actually take a piece of that tissue out and look at it under the microscope," said Dr. Wolk. "What makes this study different was that unlike getting people at end of life, we got them in an early stage when they have less disease in their brain, theoretically.

"It's a very rare population in a sense that we almost never have brain tissue in people who are alive and well and have a high risk for having AD pathology," he added. "It was a group of people who served as a good potential cohort to test the validity of this amyloid imaging scan."

The autopsy study was carried out in a fashion similar to that for florbetapir, said Dr. Wolk. Researchers recruited and scanned 180 patients who had a life expectancy of less than a year and who agreed to a brain autopsy. During the course of the study, 68 of these patients died. The average time between their scan and their death was about 3 months. The images were assessed by blinded readers.

The data showed that both biopsy and autopsy study images had high sensitivity and specificity and that there was strong concordance between flutemetamol images and beta-amyloid brain pathology. For the brain biopsy tissue samples, the biomarker detected beta-amyloid with a pooled sensitivity of 93% and a pooled specificity of 100%. In autopsied patients, the biomarker showed the ability to detect beta-amyloid with a sensitivity of 86% and a specificity of 92%.

"Both data sets looked very, very similar with regard to the visual reads of the flutemetamol scans in relation to finding levels of evidence of AD pathology, either based on biopsy tissue or based on the autopsy," commented Dr. Wolk. "There was also a pretty high correlation between the amount of signal on the scan and the amyloid plaque burden in the brain, suggesting or supporting the notion that this agent does provide you with information about the amyloid plaque burden in the brain."

The results confirm the potential of this imaging agent to detect beta-amyloid plaque in living patients, he added.

The specificity and sensitivity of flutemetamol are similar to those of the other amyloid imaging agents, but there have been no head-to-head comparisons that might separate out 1 as being superior, said Dr. Wolk. He theorizes that in time, though, 1 of the agents may distinguish itself as being more sensitive to different levels of amyloid. "This might be particularly useful in following the disease course or to see how someone responds to treatment," said Dr. Wolk.

According to a press release, GE Healthcare intends to file an application for regulatory approval of [18F]flutemetamol later this year.

Cognitive Study

Another 18F flutemetamol–related study discussed at the meeting concluded that uptake of the biomarker was significantly related to worse cognitive performance on tasks that are usually impaired in patients with AD.

The study included 11 nondemented community-dwelling older adults, with an average age of 75 years, who underwent positron emission tomography with flutemetamol and completed a battery of neuropsychological tests.

To analyze flutemetamol uptake, researchers used a composite of standardized value ratios normalized to the cerebellar cortex, using the cerebellum as a reference. The analysis used age- and education-corrected scaled scores.

The study, which is ongoing, found significant correlations between the tracer uptake and performances on auditory delayed memory, processing speed/mental flexibility and semantic fluency variables (r = -0.62 to 0.70; P < .05). The biomarker was not correlated with age, education, mental status, symptoms of depression, or premorbid intellectual functioning of the participants.

"The study showed negative correlations," noted lead investigator Dustin Hammers, PhD, Center for Alzheimer's Care, Imaging and Research, Department of Neurology, University of Utah, Salt Lake City. "The greater uptake was related to worse cognitive performance."

Dr. Dustin Hammers

Asked to comment on this research, Dr. Wolk said it illustrates a possible main use for amyloid biomarkers. A "potential role" for these agents, especially when AD treatments become available, is to separate out those who would benefit from an early intervention.

"This is where the field wants to go," said Dr. Wolk "The question is, how do we distinguish those with normal aging who say their memory is not quite as sharp as it used to be, but it's not enough for them to qualify for any clinical diagnosis, from those who have early signs of Alzheimer's disease."

Dr. Wolk and Dr. Hammers have disclosed no relevant financial relationships.

American Academy of Neurology 64th Annual Meeting. Emerging Science Abstracts #006, 007. Presented April 25, 2012.

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