Imaging Agents Florbetapir, Flutemetamol Quantify Brain Amyloid

With longer half-lives than previously used imaging agents, florbetapir and flutemetamol can be used in PET scanning to detect and quantify amyloid levels in the brain, according to two separate reports published online July 11 in Archives of Neurology.

Radiolabeled with fluorine-18, 18F-florbetapir and 18F-flutemetamol may eventually make the use of PET scanning to detect Alzheimer’s disease via brain imaging more accessible in clinical practice, concluded both teams of investigators.

In one study, data from four phase I and II clinical trials of florbetapir PET scanning were pooled to permit assessment of beta-amyloid burden in a large combined cohort of patients with probable AD (68 subjects) or mild cognitive impairment (60 subjects), and healthy age-matched controls (82 subjects). "To our knowledge, our study presents the largest analysis of multicenter [18F-florbetapir] amyloid PET data currently reported," said Dr. Adam S. Fleisher of Banner Alzheimer’s Institute, Phoenix, and his associates.

The extent of florbetapir activity on PET scanning reliably distinguished the three groups of subjects, with the highest activity seen in AD patients, an intermediate level seen in patients with mild cognitive impairment (MCI), and the least activity seen in control subjects. For both AD and MCI patients, there was preferential uptake of 18F-florbetapir in the posterior cingulate, the parietal lobe, and the temporal and frontal cortex – all areas that were found to be involved during previous PET studies of amyloid deposition that used a different imaging agent.

Dr. Fleisher and his colleagues used these data to devise two sets of criteria for classifying florbetapir activity.

The first set of criteria uses a conservative cutoff threshold associated with the extensive amyloid presence that characterizes AD, which "might be used in the clinical setting to determine whether or not a person has neuropathologically significant cerebral amyloidosis." The second set of criteria uses a more liberal threshold associated with any degree of amyloidosis, which "might identify those individuals in the earliest stages of amyloid accumulation." The latter group "might be especially responsive to presymptomatic amyloid-modifying treatments for AD," they speculated (Arch. Neurol. 2011 July 11 [doi:10.1001/archneurol.2011.150]).

Using the conservative criteria, the researchers found that 81% of the AD patients, 40% of the MCI patients, and 21% of the control subjects were correctly classified by florbetapir PET scanning. When the liberal criteria were used, the technology correctly classified 85%, 47%, and 28%, respectively.

Approximately 19% of the patients who had clinical AD showed florbetapir activity below the cutoff, and 15% showed no florbetapir activity at all. These percentages correspond with the results of autopsy studies showing that 10%-30% of patients with clinical AD lack amyloid deposits.

Similarly, 21%-28% of the control group showed slightly elevated florbetapir activity rather than no activity, which corresponds with previous reports from imaging studies showing that 20%-51% of healthy elderly adults have elevated (but not pathologic) amyloid levels.

Interestingly, florbetapir activity also increased with normal aging in the control group. The same finding has been reported in previous PET studies using a different imaging agent, Dr. Fleisher and his associates noted.

In the second report, investigators used 18F-flutemetamol PET scanning in seven patients who had normal pressure hydrocephalus (NPH), a progressive disorder characterized by a classic triad of dementia, gait abnormalities, and urinary incontinence. A large proportion of patients with normal pressure hydrocephalus – 68% in one study – also show AD pathology on cortical biopsy.

The seven patients in this study, all older than 50 years, had undergone placement of a ventriculoperitoneal shunt 3-45 months earlier, with concomitant cortical biopsy in the area of the shunt. The biopsy specimens allowed immunohistochemical detection and quantification of beta-amyloid pathology, said Dr. David A. Wolk of the Penn Memory Center and the department of neurology, University of Pennsylvania, Philadelphia, and his associates.

Investigators who were blind to the subjects’ biopsy status assessed their flutemetamol PET scans and classified three of them as normal (with no or minimal amyloid pathology) and the other four as abnormal (with amyloid pathology). These scan assessments corresponded 100% with the presence or absence of amlyoid plaques in the biopsy specimens.

"These findings provide support for the use of 18F-flutemetamol PET in the detection of AD-related amyloid pathology," Dr. Wolk and his colleagues said (Arch. Neurol. 2011 July 11 [doi:10/1001/archneurol.2011.153]).

In particular, this technology "may play an important prognostic role in patients with mild cognitive impairment and, perhaps, in preclinical populations," they added.

In an editorial accompanying these two reports, Dr. William J. Jagust said that with their longer half-lives, these two radioimaging agents labeled with fluorine-18 may make PET imaging of brain amyloid levels more accessible and commercially viable.

But it is likely that clinical use of the technology will depend on highly trained readers to visually interpret scans and to convert quantitative scores into diagnoses. Even with reliance on such experts, "there will always be results that can be described as ‘borderline’ with visual reads or as ‘intermediate’ between liberal and conservative [numerical] thresholds," and clinicians won’t know how to classify such patients, said Dr. Jagust of the Helen Wills Neuroscience Institute and School of Public Health at the University of California, Berkeley.

As more patients are scanned, there will be more such "intermediate" cases. "How these radiotracers fare with larger samples along the full spectrum of both imaging and pathology will be very important for clinical applications to patients who express a wide range of dementia syndromes," he noted (Arch. Neurol. 2011 July 11 [doi:10.1001/archneurol.2011.152]).

Dr. Jagust reported serving as a consultant to GE Healthcare, which manufactures flutemetamol, and collaborating with Avid Radiopharmaceuticals, which manufactures florbetapir, through the Alzheimer’s Disease Neuroimaging Initiative. Dr. Fleisher’s study was supported by Avid Radiopharmaceuticals, which manufactures florbetapir and is owned by Eli Lilly. Dr. Fleisher and his associates reported numerous ties to industry sources. Dr. Wolk’s study was sponsored by GE Healthcare, which manufactures flutemetamol.

With longer half-lives than previously used imaging agents, florbetapir and flutemetamol can be used in PET scanning to detect and quantify amyloid levels in the brain, according to two separate reports published online July 11 in Archives of Neurology.

Radiolabeled with fluorine-18, 18F-florbetapir and 18F-flutemetamol may eventually make the use of PET scanning to detect Alzheimer’s disease via brain imaging more accessible in clinical practice, concluded both teams of investigators.

In one study, data from four phase I and II clinical trials of florbetapir PET scanning were pooled to permit assessment of beta-amyloid burden in a large combined cohort of patients with probable AD (68 subjects) or mild cognitive impairment (60 subjects), and healthy age-matched controls (82 subjects). "To our knowledge, our study presents the largest analysis of multicenter [18F-florbetapir] amyloid PET data currently reported," said Dr. Adam S. Fleisher of Banner Alzheimer’s Institute, Phoenix, and his associates.

The extent of florbetapir activity on PET scanning reliably distinguished the three groups of subjects, with the highest activity seen in AD patients, an intermediate level seen in patients with mild cognitive impairment (MCI), and the least activity seen in control subjects. For both AD and MCI patients, there was preferential uptake of 18F-florbetapir in the posterior cingulate, the parietal lobe, and the temporal and frontal cortex – all areas that were found to be involved during previous PET studies of amyloid deposition that used a different imaging agent.

Dr. Fleisher and his colleagues used these data to devise two sets of criteria for classifying florbetapir activity.

The first set of criteria uses a conservative cutoff threshold associated with the extensive amyloid presence that characterizes AD, which "might be used in the clinical setting to determine whether or not a person has neuropathologically significant cerebral amyloidosis." The second set of criteria uses a more liberal threshold associated with any degree of amyloidosis, which "might identify those individuals in the earliest stages of amyloid accumulation." The latter group "might be especially responsive to presymptomatic amyloid-modifying treatments for AD," they speculated (Arch. Neurol. 2011 July 11 [doi:10.1001/archneurol.2011.150]).

Using the conservative criteria, the researchers found that 81% of the AD patients, 40% of the MCI patients, and 21% of the control subjects were correctly classified by florbetapir PET scanning. When the liberal criteria were used, the technology correctly classified 85%, 47%, and 28%, respectively.

Approximately 19% of the patients who had clinical AD showed florbetapir activity below the cutoff, and 15% showed no florbetapir activity at all. These percentages correspond with the results of autopsy studies showing that 10%-30% of patients with clinical AD lack amyloid deposits.

Similarly, 21%-28% of the control group showed slightly elevated florbetapir activity rather than no activity, which corresponds with previous reports from imaging studies showing that 20%-51% of healthy elderly adults have elevated (but not pathologic) amyloid levels.

Interestingly, florbetapir activity also increased with normal aging in the control group. The same finding has been reported in previous PET studies using a different imaging agent, Dr. Fleisher and his associates noted.

In the second report, investigators used 18F-flutemetamol PET scanning in seven patients who had normal pressure hydrocephalus (NPH), a progressive disorder characterized by a classic triad of dementia, gait abnormalities, and urinary incontinence. A large proportion of patients with normal pressure hydrocephalus – 68% in one study – also show AD pathology on cortical biopsy.

The seven patients in this study, all older than 50 years, had undergone placement of a ventriculoperitoneal shunt 3-45 months earlier, with concomitant cortical biopsy in the area of the shunt. The biopsy specimens allowed immunohistochemical detection and quantification of beta-amyloid pathology, said Dr. David A. Wolk of the Penn Memory Center and the department of neurology, University of Pennsylvania, Philadelphia, and his associates.

Investigators who were blind to the subjects’ biopsy status assessed their flutemetamol PET scans and classified three of them as normal (with no or minimal amyloid pathology) and the other four as abnormal (with amyloid pathology). These scan assessments corresponded 100% with the presence or absence of amlyoid plaques in the biopsy specimens.

"These findings provide support for the use of 18F-flutemetamol PET in the detection of AD-related amyloid pathology," Dr. Wolk and his colleagues said (Arch. Neurol. 2011 July 11 [doi:10/1001/archneurol.2011.153]).

In particular, this technology "may play an important prognostic role in patients with mild cognitive impairment and, perhaps, in preclinical populations," they added.

In an editorial accompanying these two reports, Dr. William J. Jagust said that with their longer half-lives, these two radioimaging agents labeled with fluorine-18 may make PET imaging of brain amyloid levels more accessible and commercially viable.

But it is likely that clinical use of the technology will depend on highly trained readers to visually interpret scans and to convert quantitative scores into diagnoses. Even with reliance on such experts, "there will always be results that can be described as ‘borderline’ with visual reads or as ‘intermediate’ between liberal and conservative [numerical] thresholds," and clinicians won’t know how to classify such patients, said Dr. Jagust of the Helen Wills Neuroscience Institute and School of Public Health at the University of California, Berkeley.

As more patients are scanned, there will be more such "intermediate" cases. "How these radiotracers fare with larger samples along the full spectrum of both imaging and pathology will be very important for clinical applications to patients who express a wide range of dementia syndromes," he noted (Arch. Neurol. 2011 July 11 [doi:10.1001/archneurol.2011.152]).

Dr. Jagust reported serving as a consultant to GE Healthcare, which manufactures flutemetamol, and collaborating with Avid Radiopharmaceuticals, which manufactures florbetapir, through the Alzheimer’s Disease Neuroimaging Initiative. Dr. Fleisher’s study was supported by Avid Radiopharmaceuticals, which manufactures florbetapir and is owned by Eli Lilly. Dr. Fleisher and his associates reported numerous ties to industry sources. Dr. Wolk’s study was sponsored by GE Healthcare, which manufactures flutemetamol.

With longer half-lives than previously used imaging agents, florbetapir and flutemetamol can be used in PET scanning to detect and quantify amyloid levels in the brain, according to two separate reports published online July 11 in Archives of Neurology.

Radiolabeled with fluorine-18, 18F-florbetapir and 18F-flutemetamol may eventually make the use of PET scanning to detect Alzheimer’s disease via brain imaging more accessible in clinical practice, concluded both teams of investigators.

In one study, data from four phase I and II clinical trials of florbetapir PET scanning were pooled to permit assessment of beta-amyloid burden in a large combined cohort of patients with probable AD (68 subjects) or mild cognitive impairment (60 subjects), and healthy age-matched controls (82 subjects). "To our knowledge, our study presents the largest analysis of multicenter [18F-florbetapir] amyloid PET data currently reported," said Dr. Adam S. Fleisher of Banner Alzheimer’s Institute, Phoenix, and his associates.

The extent of florbetapir activity on PET scanning reliably distinguished the three groups of subjects, with the highest activity seen in AD patients, an intermediate level seen in patients with mild cognitive impairment (MCI), and the least activity seen in control subjects. For both AD and MCI patients, there was preferential uptake of 18F-florbetapir in the posterior cingulate, the parietal lobe, and the temporal and frontal cortex – all areas that were found to be involved during previous PET studies of amyloid deposition that used a different imaging agent.

Dr. Fleisher and his colleagues used these data to devise two sets of criteria for classifying florbetapir activity.

The first set of criteria uses a conservative cutoff threshold associated with the extensive amyloid presence that characterizes AD, which "might be used in the clinical setting to determine whether or not a person has neuropathologically significant cerebral amyloidosis." The second set of criteria uses a more liberal threshold associated with any degree of amyloidosis, which "might identify those individuals in the earliest stages of amyloid accumulation." The latter group "might be especially responsive to presymptomatic amyloid-modifying treatments for AD," they speculated (Arch. Neurol. 2011 July 11 [doi:10.1001/archneurol.2011.150]).

Using the conservative criteria, the researchers found that 81% of the AD patients, 40% of the MCI patients, and 21% of the control subjects were correctly classified by florbetapir PET scanning. When the liberal criteria were used, the technology correctly classified 85%, 47%, and 28%, respectively.

Approximately 19% of the patients who had clinical AD showed florbetapir activity below the cutoff, and 15% showed no florbetapir activity at all. These percentages correspond with the results of autopsy studies showing that 10%-30% of patients with clinical AD lack amyloid deposits.

Similarly, 21%-28% of the control group showed slightly elevated florbetapir activity rather than no activity, which corresponds with previous reports from imaging studies showing that 20%-51% of healthy elderly adults have elevated (but not pathologic) amyloid levels.

Interestingly, florbetapir activity also increased with normal aging in the control group. The same finding has been reported in previous PET studies using a different imaging agent, Dr. Fleisher and his associates noted.

In the second report, investigators used 18F-flutemetamol PET scanning in seven patients who had normal pressure hydrocephalus (NPH), a progressive disorder characterized by a classic triad of dementia, gait abnormalities, and urinary incontinence. A large proportion of patients with normal pressure hydrocephalus – 68% in one study – also show AD pathology on cortical biopsy.

The seven patients in this study, all older than 50 years, had undergone placement of a ventriculoperitoneal shunt 3-45 months earlier, with concomitant cortical biopsy in the area of the shunt. The biopsy specimens allowed immunohistochemical detection and quantification of beta-amyloid pathology, said Dr. David A. Wolk of the Penn Memory Center and the department of neurology, University of Pennsylvania, Philadelphia, and his associates.

Investigators who were blind to the subjects’ biopsy status assessed their flutemetamol PET scans and classified three of them as normal (with no or minimal amyloid pathology) and the other four as abnormal (with amyloid pathology). These scan assessments corresponded 100% with the presence or absence of amlyoid plaques in the biopsy specimens.

"These findings provide support for the use of 18F-flutemetamol PET in the detection of AD-related amyloid pathology," Dr. Wolk and his colleagues said (Arch. Neurol. 2011 July 11 [doi:10/1001/archneurol.2011.153]).

In particular, this technology "may play an important prognostic role in patients with mild cognitive impairment and, perhaps, in preclinical populations," they added.

In an editorial accompanying these two reports, Dr. William J. Jagust said that with their longer half-lives, these two radioimaging agents labeled with fluorine-18 may make PET imaging of brain amyloid levels more accessible and commercially viable.

But it is likely that clinical use of the technology will depend on highly trained readers to visually interpret scans and to convert quantitative scores into diagnoses. Even with reliance on such experts, "there will always be results that can be described as ‘borderline’ with visual reads or as ‘intermediate’ between liberal and conservative [numerical] thresholds," and clinicians won’t know how to classify such patients, said Dr. Jagust of the Helen Wills Neuroscience Institute and School of Public Health at the University of California, Berkeley.

As more patients are scanned, there will be more such "intermediate" cases. "How these radiotracers fare with larger samples along the full spectrum of both imaging and pathology will be very important for clinical applications to patients who express a wide range of dementia syndromes," he noted (Arch. Neurol. 2011 July 11 [doi:10.1001/archneurol.2011.152]).

Dr. Jagust reported serving as a consultant to GE Healthcare, which manufactures flutemetamol, and collaborating with Avid Radiopharmaceuticals, which manufactures florbetapir, through the Alzheimer’s Disease Neuroimaging Initiative. Dr. Fleisher’s study was supported by Avid Radiopharmaceuticals, which manufactures florbetapir and is owned by Eli Lilly. Dr. Fleisher and his associates reported numerous ties to industry sources. Dr. Wolk’s study was sponsored by GE Healthcare, which manufactures flutemetamol.