PET imaging with the radiopharmaceutical florbetapir has revealed early evidence of Alzheimer's disease in patients with mild or no cognitive impairment, according to a study published online July 11 in Neurology.
Researchers at Duke University Medical Center discovered the presence of amyloid plaque during an 18-month follow-up, which may predict future decline in cognitive skills among this population. The findings could also help guide care and treatment decisions for patients with Alzheimer's disease.
Interestingly, the researchers also found that people with negative florbetapir-PET scans improved from minimally impaired indications to normal more often than people with positive florbetapir-PET results (Neurology, July 11, 2012).
Dr. P. Murali Doraiswamy, professor of psychiatry at Duke, co-led the study with the late Dr. R. Edward Coleman, professor of radiology at Duke.
Florbetapir's clearance
Florbetapir is marketed as Amyvid by Eli Lilly and its wholly owned subsidiary Avid Radiopharmaceuticals, which funded the study. The radiopharmaceutical was cleared in April 2012 by the U.S. Food and Drug Administration (FDA) for PET imaging of the brain to estimate beta-amyloid plaque density in patients being evaluated for cognitive impairment. Florbetapir is designed to bind to amyloid plaques, which have been associated with the onset of Alzheimer's disease in previous research.
Previous studies have shown that florbetapir uptake is higher in individuals who later were found to have high levels of beta amyloid in their brains at autopsy. But there's a lack of longitudinal data on whether florbetapir can predict cognitive decline in at-risk adults, a deficiency the current study was designed to address, the authors wrote.
For the current study, Doraiswamy and colleagues enrolled 51 subjects with mild cognitive impairment (MCI), 31 subjects with clinically diagnosed Alzheimer's dementia, and 69 cognitively normal controls. The 31 Alzheimer's dementia patients previously received a florbetapir-PET scan as part of a prospective, multicenter study (AV45-A11) sponsored by Avid and agreed to participate in this research.
The subjects with mild cognitive impairment had been diagnosed with the condition within the past year and were given an initial evaluation. They were 50 years of age or older, had memory or cognitive impairment issues, a Clinical Dementia Rating (CDR) scale global rating of 0.5, and Mini-Mental State Examination (MMSE) score greater than 24.
Members of the healthy control group were also 50 years or older, and they had a CDR rating of 0 and an MMSE score of 29 or 30. All subjects also underwent a detailed medical history, physical and neurologic examinations, clinical interview, and laboratory evaluations. An MRI was performed to rule out any central nervous system lesions.
The researchers excluded subjects with other neuropsychiatric diseases, those who had received antiamyloid investigational drugs, and those who were unable to complete testing or had contraindications to PET.
Imaging protocol
The amyloid scans were performed on commercially available PET scanners (ECAT HR+, Biograph PET/CT, Siemens Healthcare; Discovery LS PET/CT, Advance PET, GE Healthcare); scans were performed 50 minutes after injection of 10 mCi (370 MBq) of florbetapir. Three nuclear medicine physicians independently reviewed all PET images and rated them both on a scale of 0 to 4 and as either amyloid positive or negative, based on tracer uptake in gray-matter cortical areas of the brain.
Of the 151 study participants, 67 (97%) of 69 normal subjects completed 18 months of follow-up, as did 46 (90%) of 51 MCI individuals and 27 (87%) of 31 Alzheimer's dementia patients.
Cognitive decline
At the start of the study, 19 patients (37%) with mild cognitive impairment were beta amyloid-positive, as were 10 healthy subjects (14%) and 21 individuals (68%) with Alzheimer's dementia.
However, at the 18-month follow-up, individuals with mild cognitive impairment who had positive uptake of florbetapir exhibited worsening skills on almost all cognitive assessments, the researchers found. Patients with Alzheimer's dementia and florbetapir uptake also showed a greater decline in verbal skills and trended toward greater declines in mental acuity.
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| PET images using florbetapir to highlight beta-amyloid plaque show, above, a cognitively normal subject and an amyloid-negative patient with MCI. Below is an amyloid-positive patient with Alzheimer's disease, as well as an amyloid-positive patient with MCI. All images courtesy of Neurology. |
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Doraiswamy and colleagues also observed the following:
- Eight subjects with mild cognitive impairment progressed to Alzheimer's dementia at follow-up, while seven individuals with MCI reverted to normal status.
- Five (29%) of 17 MCI subjects who were beta amyloid-positive progressed to Alzheimer's dementia, compared with three (10%) of 29 individuals with mild cognitive impairment and beta amyloid-negative results.
- A greater proportion of beta amyloid-positive individuals with MCI and normal status worsened in terms of CDR score (23% and 30%, respectively), compared with beta amyloid-negative subjects with MCI and normal status (7% and 6%, respectively).
The researchers plan to conduct a final assessment of the study participants with a follow-up at 36 months.
"Our findings and other reports suggest that amyloid PET tracers may have promise for indicating risk of subsequent cognitive decline in patients with MCI and [normal] older adults," the authors concluded.
Additional PET and cognitive data could help determine florbetapir-PET's "prognostic role in the clinical setting, its ability to improve confidence in the recently proposed diagnoses of dementia and MCI due to [Alzheimer's disease], and for subject enrichment of therapeutic trials in the early clinical and preclinical stages of [Alzheimer's]," they added.
However, the authors did caution that florbetapir is not currently approved to predict the development of dementia or other neurologic conditions, and they emphasized that the radiopharmaceutical should not be used as a screening tool in otherwise normal or minimally impaired people. Similarly, a positive florbetapir-PET scan is not necessarily an indication of Alzheimer's.
Duke researchers plan to present the results of the study this week at the Alzheimer's Association International Conference in Vancouver, British Columbia.
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Study disclosures The study was funded by Avid Pharmaceuticals. Doraiswamy has received research grants and speaking/advisory fees in the past from pharmaceutical companies including Avid/Eli Lilly. Other co-authors on the study reported receiving funding and/or fees from companies including Avid and other sources. |
