PET Tracer Picks Up Alzheimer's Plaques in Live Patient

PITTSBURGH, March 28 -- Beta-amyloid plaques were successfully visualized with a PET scan in a living Alzheimer's disease patient, researchers here said. With a fluorescent tracer called Pittsburgh Compound-B used to highlight beta-amyloid plaques, a 64-year-old woman with clinically diagnosed Alzheimer's disease underwent a PET scan 10 months before her death, with plaques then conclusively identified at autopsy, reported Steven T. DeKosky, M.D., and colleagues at the University of Pittsburgh, online in Brain. The autopsy findings showed that the regions visualized in the PET scans were the same as the beta-amyloid plaques. Furthermore, the autopsy-confirmed plaques all showed up on the scans, except for a few in the cerebellum.
"This is final confirmation of what we have believed all along, that Pittsburgh Compound-B allows us to accurately assess the amount of beta-amyloid plaques in brains of people afflicted with Alzheimer's," Dr. DeKosky said.
The researchers said the findings could be useful for clinical diagnosis and monitoring, and also as a surrogate marker of treatment response in clinical trials of new Alzheimer's drugs.
Pittsburgh researchers had reported a similar finding in a 76-year-old man a year ago, but said it needed to be confirmed in additional patients (See: Imaging Exposes Alzheimer's-Like Plaque in the Human Brain)
In the new study, Dr. DeKosky and colleagues also reported that Pittsburgh Compound-B bound almost exclusively to beta-amyloid plaques and large amyloid-laden blood vessels when it was applied to brain tissue taken post-mortem from 27 patients with clinical Alzheimer's disease.
Pittsburgh Compound-B is a thioflavin derivative first identified in 2001 as a potent and selective binding agent for amyloid protein in the insoluble beta-sheet configuration.
It penetrates the blood-brain barrier, and hence can be administered intravenously before PET scanning.
The PET scan gives quantitative readings of the amount of the tracer retained in brain tissue. The Pitt researchers believe that it therefore indicates the amount of insoluble beta-amyloid protein present.
Dr. DeKosky and colleagues determined in the new study that the agent does not allow good visualization of diffuse plaques, such as those found in the caudate nucleus and presubiculum.
It also did not highlight amorphous amyloid plaques in the cerebellum at all, they reported.
The researchers also said a small subset of tau protein-based neurofibrillary tangles were labeled by Pittsburgh Compound-B. "These resembled extracellular 'ghost' neurofibrillary tangles," Dr. DeKosky and colleagues wrote.
In a further test of the tracer's specificity, they treated plaque-heavy tissue sections with formic acid, which disrupts the beta-sheet conformation. The treatments abolished binding by Pittsburgh Compound-B.
But they said their most important findings were in the woman who underwent PET scanning with Pittsburgh Compound-B before her death.
The autopsy revealed that beta-amyloid plaques had infested much of her brain, confirming the clinical diagnosis of Alzheimer's disease.
More to the point, the researchers found that the amount of insoluble beta-amyloid protein closely matched the levels of Pittsburgh Compound-B at the same locations as measured with the PET scan 10 months earlier.
"These results demonstrate, in a typical Alzheimer's disease brain, that Pittsburgh Compound-B binding is highly selective for insoluble (fibrillar) beta-amyloid deposits," the researchers wrote.
Moreover, the tracer had not highlighted neurofibrillary tangles in the woman's brain, showing that it is specific for beta-amyloid and not other aspects of Alzheimer's pathology.
However, as in the studies with brain tissue from the 27 patients post-mortem, the researchers found that the tracer did not bind well to plaques in the cerebellum.
Pittsburgh Compound-B did bind strongly to areas of cerebral amyloid angiopathy, potentially a problem in clinical situations. But such structures, which are distinct from plaques, are uncommon in Alzheimer's patients, they said.
"This work is an important step forward in the development of new tools for both research and clinical care," said Neil Buckholtz, Ph.D., chief of the Dementias of Aging Branch of the National Institute on Aging, which helped fund the study.
He added that it further supports the tracer's validity in detecting beta-amyloid deposits in live patients.
If confirmed once and for all, Pittsburgh Compound-B could also be useful "as an outcome measure in clinical trials of anti-beta-amyloid therapeutics," Dr. Buckholtz said.
The study was funded by the National Institutes of Health, the Department of Energy, the Alzheimer's Association, and the Dana Foundation.
No potential conflicts of interest were disclosed.
Additional source: BrainSource reference: Ikonomovic M, et al "Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer's disease" Brain 2008; DOI: 10.1093/brain/awn016.