Imaging Exposes Alzheimer's-Like Plaque in the Human Brain

BOSTON, March 12 -- Beta-amyloid plaques in the brains of people with Alzheimer's type dementia can be spotted with the aid of the imaging agent Pittsburgh Compound B, researchers here determined.

The distribution of amyloid plaques seen on positron emission tomography imaging with the tracer compound closely correlated with that discovered post-mortem in a 76-year-old man with Lewy body dementia, reported Brian J. Bacskai, Ph.D., of Massachusetts General Hospital and the University of Pittsburgh, and colleagues.

The findings provide confirmation that when investigators thought they were seeing amyloid deposition and distribution on PET scan images, they really were, the authors wrote in the March issue of the Archives of Neurology.

"What it says is that if you see positive Pittsburgh Compound B, you're going to find that that person has amyloid pathology in their brain, and that's a valuable first step," said co-author Steven T. DeKosky, M.D., director of the Alzheimer's Disease Research Center at the University of Pittsburgh, in an interview.

Commenting in an accompanying editorial, David M. Holtzman, M.D., of Washington University in St. Louis, agreed.

"This is an important case report, as for the first time it documents correspondence between cortical Pittsburgh Compound B retention and amyloid deposition in a human," Dr Holtzman wrote.

"The advent of in vivo amyloid imaging has led to great hope that this type of technique will aid in the differential diagnosis of dementia, serve as an antecedent biomarker for Alzheimer's disease, and be useful in determining whether agents designed to clear amyloid are effective. This article provides strong validation that Pittsburgh Compound B retention is very likely reflective of beta-amyloid that is deposited as amyloid."

John H. Growdon, M.D., a study co-author and neurologist at Massachusetts General, agreed with Dr. Holzman that imaging of beta-amyloid with the compound, if confirmed in further human studies, may ultimately be most useful for monitoring the success or failure of anti-amyloid therapies, rather than as a definitive diagnostic tool.

"The lesson we're trying to convey in this report is that Pittsburgh Compound B uptake does not necessarily equal Alzheimer's disease as a diagnostic entity," Dr. Growdon said in an interview.

"What it does reflect, however," he continued "is amyloid deposit in the brain from whatever reason, whether it be mild cognitive impairment, Alzheimer's disease, Lewy body disease, or cerebral angiopathy. So its clinical utility down the line may turn out to be more in following anti-amyloid treatments -- are you clearing the brain of this stuff? -- than in, strictly speaking, accurate diagnosis."

Pittsburgh Compound B, developed by co-authors William E. Klunk, M.D, Ph.D. and Chester A. Mathis, Ph.D., of the University of Pittsburgh, is a thioflavin derivative that binds to amyloid protein.

In previous human studies, Dr. Klunk and Dr. Mathis, with colleagues at Pittsburgh and Uppsala University in Sweden, found that in PET images from 16 patients diagnosed with mild Alzheimer's and nine controls, there was evidence that the compound was taken up in significantly greater amounts in the brains of the patients with dementia compared with controls. The Pittsburgh Compound B signal was particularly strong in cortical areas, notably frontal cortex and striatum. In contrast, the compound was quickly cleared from the brains of healthy young controls, with no evidence of binding.

In the current study, the authors evaluated the association between uptake of the compound in life as seen on PET scans with measures of beta-amyloid from tissues collected on autopsy.

The patient was a 76-year-old man who had a clinical diagnosis of dementia with Lewy bodies. Three months before his death (from complications of surgical trauma during evacuation of a traumatic subdural hematoma) he underwent PET scanning enhanced with fluorodeoxyglucose 18F (FDG-PET) Pittsburgh Compound B.

The Pittsburgh Compound B -PET scan showed marked uptake of the compound in neocortical regions, including the posterior cingulate, precuneus, posterior parietal, middle and inferior temporal, insular, and lateral and orbital frontal cortices. Cognitive tests performed after the scan showed global cognitive and function impairments.

"Autopsy confirmed the clinical diagnosis, the authors wrote, "In addition, there was severe cerebral amyloid angiopathy and only moderate numbers of parenchymal beta-amyloid plaques. Biochemical measures revealed a positive correlation between beta-amyloid levels and regional Pittsburgh Compound B binding."

The authors also saw features of Alzheimer's pathology -- amyloid plaques and neurofibrillary tangles -- these features were not present at sufficiently high levels to support a separate diagnosis of Alzheimer's, the authors said.

The study strongly supports the idea that in vivo imaging alone can be used to confirm the presence of amyloid deposition, Dr. Holtzman said in his editorial.