New Advances in Brain Amyloid Imaging for Alzheimer's
July 13, 2011 — Two new studies provide more evidence that fluorine-18-labeled radiotracers used with positron emission tomography (PET) can help detect and quantify β-amyloid in the brain associated with Alzheimer's disease.
One study focuses on the PET imaging agent florbetapir, the other study on the PET tracer flutemetamol. Both were published online July 11 in the Archives of Neurology.
In a linked commentary, William Jagust, MD, from the Helen Wills Neuroscience Institute and School of Public Health, University of California, Berkeley, says these studies "continue to advance the field" of amyloid imaging.
In their paper, Adam S. Fleisher, MD, from Banner Alzheimer's Institute in Phoenix, Arizona, and a multicenter team report evidence that florbetapir PET can characterize brain amyloid burden in patients with clinically probably Alzheimer's disease, mild cognitive impairment, and older cognitively normal adults.
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| Transaxial slice of the brain of a 56-year-old man obtained with positron emission tomography |
The researchers also introduce criteria to determine whether a florbetapir PET image is associated with "an intermediate-to-high likelihood of pathologic Alzheimer's disease or with having an identifiable cortical amyloid level above that seen in low-risk controls," they report.
The study builds on earlier work by the same investigators published in January 2011 and reported by Medscape Medical News at that time (JAMA. 2011;305:275-283).
The earlier study "focused on the association of florbetapir F18 PET activity with pathology in patients at the end of life, with and without dementia," Dr. Fleisher noted in an email.
This latest study "emphasizes its ability to distinguish clinical syndromes of Alzheimer's disease, as well as identify the degree of abnormality seen in normal aging populations — potential pre-clinical AD [Alzheimer's disease]," he explained.
Defining Thresholds
"The study also introduces thresholds of florbetapir PET levels associated with having 'any amyloid' in the brain, or levels associated with pathologically proven dementia of the Alzheimer’s type," Dr. Fleisher said.
Included in the study were 68 individuals with probable Alzheimer's disease, 60 with mild cognitive impairment, and 82 healthy controls who were at least 55 years of age.
The researchers computed cerebral-to-whole-cerebellar florbetapir mean standardized uptake value ratios and compared mean cortical ratios between the 3 groups.
They used a threshold of 1.17 or greater to signify pathologic levels of amyloid associated with Alzheimer's disease based on separate antemortem PET and postmortem neuropathology data from 19 end-of-life patients in the earlier study.
They used a threshold of ratios greater than 1.08 to reflect the presence of any identifiable β-amyloid because this was the upper limit from a separate set of 46 individuals aged 18 to 40 years who did not carry the apolipoprotein E4 allele.
The researchers observed that mean cortical florbetapir ratios were highest in individuals with probable Alzheimer's disease (1.39), intermediate in those with mild cognitive impairment (1.17), and lowest in healthy controls (1.05).
The percentages of individuals classified as having amyloid levels associated with Alzheimer's disease were 81% in those with probable Alzheimer's disease, 40% in those with mild cognitive impairment, and 12% in healthy controls. The percentages classified as having any identifiable β-amyloid were 85%, 47%, and 28%, respectively.
Florbetapir uptake increased with age in healthy individuals and was higher in those who carried the APOE-4 allele, the researchers note.
This study, Dr. Fleisher told Medscape Medical News, shows that "florbetapir PET can distinguish clinical stages of Alzheimer’s disease, and can identify amyloid pathology in a percentage of cognitively normal individuals over the age of 55."
"It presents compiled data for several registered trials documenting its ability to distinguish between diagnostic groups, and establishes clinically relevant thresholds of PET activity," he added.
In his commentary, Dr. Jagust says this latest study with florbetapir "continues to put its use on stronger scientific footing."
Flutemetamol PET Also Amyloid-Sensitive
The other study focused on a different amyloid PET imaging agent, F18 flutemetamol, and is the first, the authors say, to compare this tracer with in vivo histopathologic evidence of Alzheimer's disease–related amyloid pathologic abnormality.
David Wolk, MD, from the Penn Memory Center in Philadelphia, Pennsylvania, and colleagues performed biopsies in 7 patients during an evaluation for normal-pressure hydrocephalus; 4 had evidence of β-amyloid pathologic abnormality on histopathologic examination.
According to the investigators, there was complete agreement by 3 blinded readers between visual ratings of scans as positive or negative and histologic findings. "Despite variability in the delay from biopsy to PET scanning, there was remarkable correspondence of F18-flutemetamol uptake and quantitative measures of amyloid pathology based on immunohistochemical and histological estimates," Dr. Wolk and colleagues point out.
In his commentary, Dr. Jagust says an "interesting point" is how exceptionally well these tracers perform in comparison to pathologic findings. This could be due to the still relatively small sample sizes they've been tested in, he notes.
"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," Dr. Jagust writes.
The florbetapir study was funded by Avid Radiopharmaceuticals, a wholly owned subsidiary of Eli Lilly, which manufactures the agent. Dr. Adam Fleisher has received research support from Avid Radiopharmaceuticals and is a consultant for Eli Lilly. The flutemetamol study was paid for by GE Healthcare, which manufactures the agent. Dr. David Wolk has received consulting fees from GE Healthcare. Dr. William Jagust has served as a consultant to GE Healthcare and collaborates with Avid Radiopharmaceuticals.
Arch Neurol. Published online July 11, 2011. Fleisher abstractWolk abstract
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