Use of florbetapir-PET for imaging beta-amyloid pathology

Abstract

Context: The ability to identify and quantify brain β-amyloid could increase the accuracy of a clinical diagnosis of Alzheimer disease.

Objective: To determine if florbetapir F 18 positron emission tomographic (PET) imaging performed during life accurately predicts the presence of β-amyloid in the brain at autopsy.

Design, setting, and participants: Prospective clinical evaluation conducted February 2009 through March 2010 of florbetapir-PET imaging performed on 35 patients from hospice, long-term care, and community health care facilities near the end of their lives (6 patients to establish the protocol and 29 to validate) compared with immunohistochemistry and silver stain measures of brain β-amyloid after their death used as the reference standard. PET images were also obtained in 74 young individuals (18-50 years) presumed free of brain amyloid to better understand the frequency of a false-positive interpretation of a florbetapir-PET image.

Main outcome measures: Correlation of florbetapir-PET image interpretation (based on the median of 3 nuclear medicine physicians' ratings) and semiautomated quantification of cortical retention with postmortem β-amyloid burden, neuritic amyloid plaque density, and neuropathological diagnosis of Alzheimer disease in the first 35 participants autopsied (out of 152 individuals enrolled in the PET pathological correlation study).

Results: Florbetapir-PET imaging was performed a mean of 99 days (range, 1-377 days) before death for the 29 individuals in the primary analysis cohort. Fifteen of the 29 individuals (51.7%) met pathological criteria for Alzheimer disease. Both visual interpretation of the florbetapir-PET images and mean quantitative estimates of cortical uptake were correlated with presence and quantity of β-amyloid pathology at autopsy as measured by immunohistochemistry (Bonferroni ρ, 0.78 [95% confidence interval, 0.58-0.89]; P <.001]) and silver stain neuritic plaque score (Bonferroni ρ, 0.71 [95% confidence interval, 0.47-0.86]; P <.001). Florbetapir-PET images and postmortem results rated as positive or negative for β-amyloid agreed in 96% of the 29 individuals in the primary analysis cohort. The florbetapir-PET image was rated as amyloid negative in the 74 younger individuals in the nonautopsy cohort.

Conclusions: Florbetapir-PET imaging was correlated with the presence and density of β-amyloid. These data provide evidence that a molecular imaging procedure can identify β-amyloid pathology in the brains of individuals during life. Additional studies are required to understand the appropriate use of florbetapir-PET imaging in the clinical diagnosis of Alzheimer disease and for the prediction of progression to dementia.

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Drs Clark, Mintun, Pontecorvo, Hefti, Carpenter, and Skovronsky and Messrs Flitter and Krautkramer reported owning Avid stock and/or stock options and being employed by Avid Radiopharmaceuticals Inc. Dr Schneider reported being a consultant for Avid Radiopharmaceuticals and receiving compensation for services. Drs Bedell and Zehntner reported receiving compensation and shares from Biospective Inc. Dr Beach reported receiving funding related to the topic of this article from the National Institute on Aging (grant P30 AG19610), the Arizona Department of Health Services (contract 211002 awarded to the Arizona Alzheimer’s Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05–901 and 1001), Avid Radiopharmaceuticals, Bayer Healthcare Inc, and GE Healthcare. Dr Bilker reported working as consultant for Avid Radiopharmaceuticals on issues related to this study. Dr Kung reported receiving financial support from National Institutes of Health grant AG-0222559; serving on the Avid Scientific Advisory board; participating in the formation of Avid; and being an Avid stockholder. Dr Coleman reported being on the medical advisory board for General Electric Healthcare from 2003–2008; being a consultant for General Electric Healthcare from 2003–2008; receiving a research grant from General Electric Healthcare in 2010; receiving funding for a clinical trial from Molecular Insights Pharmaceuticals in 2010; serving on a medical advisory board for Molecular Insights Pharmaceuticals from 2004–2009; and receiving a grant from Avid to support his participation in this study. Dr Doraiswamy reported receiving research grants (awarded to Duke University); currently or previously serving as an advisor to Forest, Bristol-Myers Squibb, Avid Radiopharmaceuticals, Lundbeck, Medivation, Pfizer, Elan, Eli Lilly, Bayer, Neuroptix, Neuronetrix, Sonexa, Accera, TauRx, Myriad, National Institute on Aging, AstraZeneca, Labopharm, Clarimedix, National Institute of Mental Health, National Institute of Neurological Disorders and Stroke, Alzheimer’s Association, Alzheimer’s Foundation, Rutgers University, and the University of California; owning stock in Sonexa; and receiving a grant from Avid (awarded to Duke University) for his participation in this study. Dr Fleisher reported receiving research contracts from Avid Radiopharmaceuticals to the Banner Alzheimer’s Institute, from which he receives no personal compensation; being a consultant on a scientific advisory board for Eli Lilly; serving on an advisory board for Elan Pharmaceuticals; and having a pending investigator-initiated grant from Avid Radiopharmaceuticals. Dr Sabbagh reported working as a consultant for Eisai, Pfizer, Amerisciences, Takeda, and GlaxoSmithKline; receiving royalties from Wiley, FT Pearson Press, and Amerisciences; and having grants and contracts with Eli Lilly, Baxter, Bayer, General Electric Healthcare, Bristol-Myers Squibb, Eisai, Janssen, Wyeth/Elan, Avid, and Medivation. Dr Sadowsky reported being on the speaker’s bureau and receiving honoraria from Novartis, Forrest, Accera, and Pamlab; and serving on the advisory board for Novartis. Dr Reiman reported serving as a scientific advisor to Amnestix/Sygnis, AstraZeneca, Elan, Eli Lilly, GlaxoSmithKline, Intellect, Siemens, Bayer, Takeda, and Eisai; having research contracts with the National Institute on Aging, Arizona Department of Health Services, AstraZeneca, Avid Radiopharmaceuticals, and Kronos Life Sciences; receiving research grants from the National Institute on Aging, National Institute for Mental Health, the Anonymous Foundation, Nomis Foundation, Banner Alzheimer’s Foundation, and the State of Arizona; holding patents for imaging strategy for the screening of AD treatments in laboratory animals (active), biomarker strategy for the evaluation of presymptomatic AD treatments (pending, through Banner Health), statistical strategy for the analysis of complementary complex data sets (pending, through Banner Health), and GAB2 testing in clinical assessment of AD (pending, through Translational Genomics Research Institute); and serving as the executive director for the Banner Alzheimer’s Institute and the director of the Arizona Alzheimer’s Consortium.

Figures

Figure.. Paired Representative Florabetapir-PET Scans and β-amyloid Antibody 4G8 Immunohistochemistry Photo Micrographs

Sagittal and axial views of positron emission tomographic (PET) scans of representative patients. The vertical bars indicate the range of semiautomated quantitative analysis of the ratio of cortical to cerebellar signal (SUVr) scores. The maximum color (red) corresponds to an SUVr of approximately 2.2. The 4G8 immunohistochemistry shows precuneus gray matter with aggregated β-amyloid (red) using a 3-amino-9-ethyl-carbazol chromogen stain and counterstained with acid blue 129 (original magnification ×5).