Autopsy, Biopsy Data Support Amyloid Imaging Agents

Results from new studies of the investigational imaging agents florbetaben and flutemetamol indicate that they may help to support a diagnosis of Alzheimer’s disease or rule it out, with the potential to improve both clinical management and research.

Comparisons of the radioactive imaging agents against the diagnostic standard of histopathology at autopsy in two studies, as well as against the results of brain biopsy in another, showed that the compounds have high sensitivity and specificity for detecting the presence of beta-amyloid plaques.

In a phase III trial, 204 patients from Japan, Australia, France, and the United States underwent PET imaging with florbetaben. The study group included 194 individuals with dementia and 10 healthy volunteers. All of the participants were near the end of life.

Patients underwent both MR and PET imaging 90-110 minutes after an intravenous infusion of florbetaben. The investigators coregistered the MRI and PET scans to more precisely track beta-amyloid deposits in each of the brain regions examined – the first time such a technique has been employed in amyloid imaging studies, said Dr. Marwan N. Sabbagh, lead author and the director of Banner Sun Health Research Institute in Sun City, Ariz.

The investigators then compared the imaging results with postmortem findings in 31 of the patients whose brains came to autopsy, for a total of 186 brain regions. They analyzed another 60 regions from the 10 participants without dementia whose brains also were autopsied. Three readers who analyzed the imaging data and three neuropathologists who scored the autopsy results were blinded to all clinical and autopsy data. They evaluated the presence of beta-amyloid plaques in six prespecified brain regions.

In the six brain regions, florbetaben detected beta-amyloid with an overall sensitivity of 77% and a specificity of 94%. Visual scoring of the entire brain for the presence of beta-amyloid plaques concurred with the autopsy results with 100% sensitivity and 92% specificity.

The inter-reader agreement for the presence of beta-amyloid plaques on imaging within each brain "was almost perfect, with a kappa value of 0.88," said one of the coauthors of the study, Dr. Cornelia Reininger, global clinical leader of the florbetaben development program at Bayer Pharma AG, in an interview. "This is important because a robust and reliable method for assessing the PET scans is also a prerequisite for approval of tracers of this type."

"These results confirm that florbetaben is able to detect beta-amyloid plaques in the brain during life with great accuracy and is a suitable biomarker," Dr. Sabbagh said in a written statement. "This is an easy, non-invasive way to assist an Alzheimer’s diagnosis at an early stage. Also exciting is the possibility of using florbetaben as tool in future therapeutic clinical research studies where therapy goals focus on reducing levels of beta-amyloid in the brain.

With a half-life of 10 hours, florbetaben could be much more clinically useful than the first amyloid imaging agent developed, Pittsburgh Compound B, which has a 20-minute half-life, making it much more difficult to obtain quality images in anything but a research setting.

(Bayer recently sold the rights to florbetaben and other in vivo imaging agents to Piramal Imaging SA, based in India. Piramal said it will seek Food and Drug Administration approval for florbetaben by the end of the year.)

Two separate studies of flutemetamol suggest that the drug not only binds strongly to beta-amyloid plaques, but that such binding also correlates with cognitive status.

Dr. David Wolk, assistant director of the Penn Memory Center at the University of Pennsylvania, Philadelphia, and his colleagues analyzed the results of flutemetamol PET imaging in 180 patients who were near the end of life and 49 patients who had a presumed diagnosis of normal pressure hydrocephalus (NPH).

NPH is a form of dementia characterized by enlarged cerebral ventricles, a specific gait imbalance, and urinary incontinence, Dr. Wolk said in an interview. "It also turns out that a significant proportion of these patients seem to have evidence of concomitant Alzheimer’s pathology. It’s thought that these are either coexistent diagnoses or that the NPH was an incorrect diagnosis and the patient actually has Alzheimer’s."

Placement of a cerebrospinal fluid shunt into a brain ventricle is the typical NPH treatment and, in true cases, can actually reverse some of the symptoms. Many neurosurgeons who perform the procedure take a biopsy of the tissue removed, and it was these samples that allowed Dr. Wolk and his associates to conduct their study.

In patients with suspected NPH, the investigators compared biopsy histopathology to PET scans of flutemetamol beta-amyloid binding. For the 69 end-of-life subjects who eventually came to autopsy, the investigators compared brain histopathology with the results of imaging.

Compared against autopsy results, five readers of the PET scans who were blinded to clinical data reported an overall sensitivity and specificity of 86% and 92%, respectively. In comparison against biopsy, the sensitivity and specificity of flutemetamol imaging by three separate readers who were blinded to clinical data were 93% and 100%.

The results not only confirm flutemetamol’s proclivity for beta-amyloid plaques, but also suggest the possibility that imaging could someday improve diagnostic accuracy and help pinpoint treatment decisions.

"In a prior study, we found that people with NPH and concomitant Alzheimer’s have a poor response to shunting," Dr. Wolk said. "If a patient gets a shunt and doesn’t get better, we typically do another shunt. But in someone who also has Alzheimer’s, we would be less inclined to do another procedure."

In a separate study of 11 community-dwelling older adults, Dustin Hammers, Ph.D., and his colleagues compared the relationship between flutemetamol uptake and cognitive status. All of the participants (eight women and three men with a mean age of 76 years) had a prior complaint of memory loss.

In these subjects, flutemetamol uptake was significantly related to several cognitive domains, including auditory delayed memory, processing speed, mental flexibility, and semantic fluency. Cognitive performance worsened with greater uptake of flutemetamol.

"Flutemetamol uptake was highly related to worse cognitive performance on tasks traditionally impaired in patients with Alzheimer’s disease, but not in others," said Dr. Hammers, a neuropsychologist at the University of Utah’s Center for Alzheimer’s Care, Imaging, and Research in Salt Lake City.

"What we found really interesting is that this was a population of normal, elderly adults who had no cognitive problems except for a prior complaint of some memory issue," he said in an interview. "The results clearly fall in the direction of what we would expect to see in Alzheimer’s, although clearly they were in a preclinical state."

The florbetaben study was sponsored by Bayer Pharma AG. Dr. Sabbagh said that he had no financial disclosures. Dr. Wolk’s study was sponsored by GE Healthcare. He has received personal compensation from the company for consulting activities. GE Healthcare partly sponsored Dr. Hammer’s study. Dr. Hammer had no financial disclosures.

Results from new studies of the investigational imaging agents florbetaben and flutemetamol indicate that they may help to support a diagnosis of Alzheimer’s disease or rule it out, with the potential to improve both clinical management and research.

Comparisons of the radioactive imaging agents against the diagnostic standard of histopathology at autopsy in two studies, as well as against the results of brain biopsy in another, showed that the compounds have high sensitivity and specificity for detecting the presence of beta-amyloid plaques.

In a phase III trial, 204 patients from Japan, Australia, France, and the United States underwent PET imaging with florbetaben. The study group included 194 individuals with dementia and 10 healthy volunteers. All of the participants were near the end of life.

Patients underwent both MR and PET imaging 90-110 minutes after an intravenous infusion of florbetaben. The investigators coregistered the MRI and PET scans to more precisely track beta-amyloid deposits in each of the brain regions examined – the first time such a technique has been employed in amyloid imaging studies, said Dr. Marwan N. Sabbagh, lead author and the director of Banner Sun Health Research Institute in Sun City, Ariz.

The investigators then compared the imaging results with postmortem findings in 31 of the patients whose brains came to autopsy, for a total of 186 brain regions. They analyzed another 60 regions from the 10 participants without dementia whose brains also were autopsied. Three readers who analyzed the imaging data and three neuropathologists who scored the autopsy results were blinded to all clinical and autopsy data. They evaluated the presence of beta-amyloid plaques in six prespecified brain regions.

In the six brain regions, florbetaben detected beta-amyloid with an overall sensitivity of 77% and a specificity of 94%. Visual scoring of the entire brain for the presence of beta-amyloid plaques concurred with the autopsy results with 100% sensitivity and 92% specificity.

The inter-reader agreement for the presence of beta-amyloid plaques on imaging within each brain "was almost perfect, with a kappa value of 0.88," said one of the coauthors of the study, Dr. Cornelia Reininger, global clinical leader of the florbetaben development program at Bayer Pharma AG, in an interview. "This is important because a robust and reliable method for assessing the PET scans is also a prerequisite for approval of tracers of this type."

"These results confirm that florbetaben is able to detect beta-amyloid plaques in the brain during life with great accuracy and is a suitable biomarker," Dr. Sabbagh said in a written statement. "This is an easy, non-invasive way to assist an Alzheimer’s diagnosis at an early stage. Also exciting is the possibility of using florbetaben as tool in future therapeutic clinical research studies where therapy goals focus on reducing levels of beta-amyloid in the brain.

With a half-life of 10 hours, florbetaben could be much more clinically useful than the first amyloid imaging agent developed, Pittsburgh Compound B, which has a 20-minute half-life, making it much more difficult to obtain quality images in anything but a research setting.

(Bayer recently sold the rights to florbetaben and other in vivo imaging agents to Piramal Imaging SA, based in India. Piramal said it will seek Food and Drug Administration approval for florbetaben by the end of the year.)

Two separate studies of flutemetamol suggest that the drug not only binds strongly to beta-amyloid plaques, but that such binding also correlates with cognitive status.

Dr. David Wolk, assistant director of the Penn Memory Center at the University of Pennsylvania, Philadelphia, and his colleagues analyzed the results of flutemetamol PET imaging in 180 patients who were near the end of life and 49 patients who had a presumed diagnosis of normal pressure hydrocephalus (NPH).

NPH is a form of dementia characterized by enlarged cerebral ventricles, a specific gait imbalance, and urinary incontinence, Dr. Wolk said in an interview. "It also turns out that a significant proportion of these patients seem to have evidence of concomitant Alzheimer’s pathology. It’s thought that these are either coexistent diagnoses or that the NPH was an incorrect diagnosis and the patient actually has Alzheimer’s."

Placement of a cerebrospinal fluid shunt into a brain ventricle is the typical NPH treatment and, in true cases, can actually reverse some of the symptoms. Many neurosurgeons who perform the procedure take a biopsy of the tissue removed, and it was these samples that allowed Dr. Wolk and his associates to conduct their study.

In patients with suspected NPH, the investigators compared biopsy histopathology to PET scans of flutemetamol beta-amyloid binding. For the 69 end-of-life subjects who eventually came to autopsy, the investigators compared brain histopathology with the results of imaging.

Compared against autopsy results, five readers of the PET scans who were blinded to clinical data reported an overall sensitivity and specificity of 86% and 92%, respectively. In comparison against biopsy, the sensitivity and specificity of flutemetamol imaging by three separate readers who were blinded to clinical data were 93% and 100%.

The results not only confirm flutemetamol’s proclivity for beta-amyloid plaques, but also suggest the possibility that imaging could someday improve diagnostic accuracy and help pinpoint treatment decisions.

"In a prior study, we found that people with NPH and concomitant Alzheimer’s have a poor response to shunting," Dr. Wolk said. "If a patient gets a shunt and doesn’t get better, we typically do another shunt. But in someone who also has Alzheimer’s, we would be less inclined to do another procedure."

In a separate study of 11 community-dwelling older adults, Dustin Hammers, Ph.D., and his colleagues compared the relationship between flutemetamol uptake and cognitive status. All of the participants (eight women and three men with a mean age of 76 years) had a prior complaint of memory loss.

In these subjects, flutemetamol uptake was significantly related to several cognitive domains, including auditory delayed memory, processing speed, mental flexibility, and semantic fluency. Cognitive performance worsened with greater uptake of flutemetamol.

"Flutemetamol uptake was highly related to worse cognitive performance on tasks traditionally impaired in patients with Alzheimer’s disease, but not in others," said Dr. Hammers, a neuropsychologist at the University of Utah’s Center for Alzheimer’s Care, Imaging, and Research in Salt Lake City.

"What we found really interesting is that this was a population of normal, elderly adults who had no cognitive problems except for a prior complaint of some memory issue," he said in an interview. "The results clearly fall in the direction of what we would expect to see in Alzheimer’s, although clearly they were in a preclinical state."

The florbetaben study was sponsored by Bayer Pharma AG. Dr. Sabbagh said that he had no financial disclosures. Dr. Wolk’s study was sponsored by GE Healthcare. He has received personal compensation from the company for consulting activities. GE Healthcare partly sponsored Dr. Hammer’s study. Dr. Hammer had no financial disclosures.

Results from new studies of the investigational imaging agents florbetaben and flutemetamol indicate that they may help to support a diagnosis of Alzheimer’s disease or rule it out, with the potential to improve both clinical management and research.

Comparisons of the radioactive imaging agents against the diagnostic standard of histopathology at autopsy in two studies, as well as against the results of brain biopsy in another, showed that the compounds have high sensitivity and specificity for detecting the presence of beta-amyloid plaques.

In a phase III trial, 204 patients from Japan, Australia, France, and the United States underwent PET imaging with florbetaben. The study group included 194 individuals with dementia and 10 healthy volunteers. All of the participants were near the end of life.

Patients underwent both MR and PET imaging 90-110 minutes after an intravenous infusion of florbetaben. The investigators coregistered the MRI and PET scans to more precisely track beta-amyloid deposits in each of the brain regions examined – the first time such a technique has been employed in amyloid imaging studies, said Dr. Marwan N. Sabbagh, lead author and the director of Banner Sun Health Research Institute in Sun City, Ariz.

The investigators then compared the imaging results with postmortem findings in 31 of the patients whose brains came to autopsy, for a total of 186 brain regions. They analyzed another 60 regions from the 10 participants without dementia whose brains also were autopsied. Three readers who analyzed the imaging data and three neuropathologists who scored the autopsy results were blinded to all clinical and autopsy data. They evaluated the presence of beta-amyloid plaques in six prespecified brain regions.

In the six brain regions, florbetaben detected beta-amyloid with an overall sensitivity of 77% and a specificity of 94%. Visual scoring of the entire brain for the presence of beta-amyloid plaques concurred with the autopsy results with 100% sensitivity and 92% specificity.

The inter-reader agreement for the presence of beta-amyloid plaques on imaging within each brain "was almost perfect, with a kappa value of 0.88," said one of the coauthors of the study, Dr. Cornelia Reininger, global clinical leader of the florbetaben development program at Bayer Pharma AG, in an interview. "This is important because a robust and reliable method for assessing the PET scans is also a prerequisite for approval of tracers of this type."

"These results confirm that florbetaben is able to detect beta-amyloid plaques in the brain during life with great accuracy and is a suitable biomarker," Dr. Sabbagh said in a written statement. "This is an easy, non-invasive way to assist an Alzheimer’s diagnosis at an early stage. Also exciting is the possibility of using florbetaben as tool in future therapeutic clinical research studies where therapy goals focus on reducing levels of beta-amyloid in the brain.

With a half-life of 10 hours, florbetaben could be much more clinically useful than the first amyloid imaging agent developed, Pittsburgh Compound B, which has a 20-minute half-life, making it much more difficult to obtain quality images in anything but a research setting.

(Bayer recently sold the rights to florbetaben and other in vivo imaging agents to Piramal Imaging SA, based in India. Piramal said it will seek Food and Drug Administration approval for florbetaben by the end of the year.)

Two separate studies of flutemetamol suggest that the drug not only binds strongly to beta-amyloid plaques, but that such binding also correlates with cognitive status.

Dr. David Wolk, assistant director of the Penn Memory Center at the University of Pennsylvania, Philadelphia, and his colleagues analyzed the results of flutemetamol PET imaging in 180 patients who were near the end of life and 49 patients who had a presumed diagnosis of normal pressure hydrocephalus (NPH).

NPH is a form of dementia characterized by enlarged cerebral ventricles, a specific gait imbalance, and urinary incontinence, Dr. Wolk said in an interview. "It also turns out that a significant proportion of these patients seem to have evidence of concomitant Alzheimer’s pathology. It’s thought that these are either coexistent diagnoses or that the NPH was an incorrect diagnosis and the patient actually has Alzheimer’s."

Placement of a cerebrospinal fluid shunt into a brain ventricle is the typical NPH treatment and, in true cases, can actually reverse some of the symptoms. Many neurosurgeons who perform the procedure take a biopsy of the tissue removed, and it was these samples that allowed Dr. Wolk and his associates to conduct their study.

In patients with suspected NPH, the investigators compared biopsy histopathology to PET scans of flutemetamol beta-amyloid binding. For the 69 end-of-life subjects who eventually came to autopsy, the investigators compared brain histopathology with the results of imaging.

Compared against autopsy results, five readers of the PET scans who were blinded to clinical data reported an overall sensitivity and specificity of 86% and 92%, respectively. In comparison against biopsy, the sensitivity and specificity of flutemetamol imaging by three separate readers who were blinded to clinical data were 93% and 100%.

The results not only confirm flutemetamol’s proclivity for beta-amyloid plaques, but also suggest the possibility that imaging could someday improve diagnostic accuracy and help pinpoint treatment decisions.

"In a prior study, we found that people with NPH and concomitant Alzheimer’s have a poor response to shunting," Dr. Wolk said. "If a patient gets a shunt and doesn’t get better, we typically do another shunt. But in someone who also has Alzheimer’s, we would be less inclined to do another procedure."

In a separate study of 11 community-dwelling older adults, Dustin Hammers, Ph.D., and his colleagues compared the relationship between flutemetamol uptake and cognitive status. All of the participants (eight women and three men with a mean age of 76 years) had a prior complaint of memory loss.

In these subjects, flutemetamol uptake was significantly related to several cognitive domains, including auditory delayed memory, processing speed, mental flexibility, and semantic fluency. Cognitive performance worsened with greater uptake of flutemetamol.

"Flutemetamol uptake was highly related to worse cognitive performance on tasks traditionally impaired in patients with Alzheimer’s disease, but not in others," said Dr. Hammers, a neuropsychologist at the University of Utah’s Center for Alzheimer’s Care, Imaging, and Research in Salt Lake City.

"What we found really interesting is that this was a population of normal, elderly adults who had no cognitive problems except for a prior complaint of some memory issue," he said in an interview. "The results clearly fall in the direction of what we would expect to see in Alzheimer’s, although clearly they were in a preclinical state."

The florbetaben study was sponsored by Bayer Pharma AG. Dr. Sabbagh said that he had no financial disclosures. Dr. Wolk’s study was sponsored by GE Healthcare. He has received personal compensation from the company for consulting activities. GE Healthcare partly sponsored Dr. Hammer’s study. Dr. Hammer had no financial disclosures.