Comparison of Visual and Quantitative Florbetapir F 18 Positron Emission Tomography Analysis in Predicting Mild Cognitive Impairment Outcomes

Abstract

The applicability of β-amyloid peptide (Aβ) positron emission tomography (PET) as a biomarker in clinical settings to aid in selection of individuals at preclinical and prodromal Alzheimer disease (AD) will depend on the practicality of PET image analysis. In this context, visual-based Aβ PET assessment seems to be the most feasible approach.OBJECTIVES To determine the agreement between visual and quantitative Aβ PET analysis and to assess the ability of both techniques to predict conversion from mild cognitive impairment (MCI) to AD. DESIGN, SETTING, AND PARTICIPANTS A longitudinal study was conducted among the Alzheimer's Disease Neuroimaging Initiative (ADNI) sites in the United States and Canada during a 1.6-year mean follow-up period. The study was performed from September 21, 2010, to August 11, 2014; data analysis was conducted from September 21, 2014, to May 26, 2015. Participants included 401 individuals with MCI receiving care at a specialty clinic (219 [54.6%] men; mean [SD] age, 71.6 [7.5] years; 16.2 [2.7] years of education). All participants were studied with florbetapir F 18 [ 18 F] PET. The standardized uptake value ratio (SUVR) positivity threshold was 1.11, and one reader rated all images, with a subset of 125 scans rated by a second reader. MAIN OUTCOMES AND MEASURESSensitivity and specificity of positive and negative [ 18 F] florbetapir PET categorization, which was estimated with cerebrospinal fluid Aβ1-42 as the reference standard. Risk for conversion to AD was assessed using Cox proportional hazards regression models. RESULTSThe frequency of Aβ positivity was 48.9% (196 patients; visual analysis), 55.1% (221 patients; SUVR), and 64.8% (166 patients; cerebrospinal fluid), yielding substantial agreement between visual and SUVR data (κ = 0.74) and between all methods (Fleiss κ = 0.71). For approximately 10% of the 401 participants in whom visual and SUVR data disagreed, interrater reliability was moderate (κ = 0.44), but it was very high if visual and quantitative results agreed (κ = 0.92). Visual analysis had a lower sensitivity (79% vs 85%) but higher specificity (96% vs 90%), respectively, compared with SUVR. The conversion rate was 15.2% within a mean of 1.6 years, and a positive [ 18 F] florbetapir baseline scan was associated with a 6.91-fold (SUVR) or 11.38-fold (visual) greater hazard for AD conversion, which changed only modestly after covariate adjustment for apolipoprotein ε4, concurrent fludeoxyglucose F 18 PET scan, and baseline cognitive status. CONCLUSIONS AND RELEVANCEVisual and SUVR Aβ PET analysis may be equivalently used to determine Aβ status for individuals with MCI participating in clinical trials, and both approaches add significant value for clinical course prognostication.

Kinetic Modeling of the Tau PET Tracer 18F-AV-1451 in Human Healthy Volunteers and Alzheimer Disease Subjects

“…18 F-AV-1451 ( 18 F-T807, flortaucipir) (2) is a PET radiotracer with high affinity and specificity for tau aggregates, while lacking affinity for concomitant amyloid-b plaques in human AD (3,4). Several additional PET agents have been proposed for the imaging of tau in the brain, in particular 11 C-PBB3 (5,6), 18 F-THK-5117 (7), 18 F-T808 (8), 18 F-PI-2014 (9), and more recently 11 C-RO6924963, 11 C-RO6931643, 18 F-RO6958948 (10), 18 F-THK-5351 (11), 18 F-GTP1 (12), and 18 F-MK6240 (13), and have been or are being characterized and evaluated in humans. Currently, 18 F-AV-1451 has been the most widely used and characterized PET tracer (2)(3)(4)14,15) in clinical studies.…”

“…Several additional PET agents have been proposed for the imaging of tau in the brain, in particular 11 C-PBB3 (5,6), 18 F-THK-5117 (7), 18 F-T808 (8), 18 F-PI-2014 (9), and more recently 11 C-RO6924963, 11 C-RO6931643, 18 F-RO6958948 (10), 18 F-THK-5351 (11), 18 F-GTP1 (12), and 18 F-MK6240 (13), and have been or are being characterized and evaluated in humans. Currently, 18 F-AV-1451 has been the most widely used and characterized PET tracer (2)(3)(4)14,15) in clinical studies. Early clinical evaluation has demonstrated heterogeneous and asymmetric brain uptake of the radiotracer (2) consistent with the earlier reports by Braak and Braak (1) showing distribution of tau that follows discrete patterns in cross-sectional postmortem analyses generally correlating with AD severity.…”

“…Validation of a quantitative PET outcome measure for 18 F-AV-1451 is necessary to address questions relevant to drug development and the primary pathophysiology of AD. SUV ratio (SUVR) has been widely used as a semiquantitative outcome measure, because it can be obtained using simplified methods of acquisition and analysis.…”

“…SUV ratio (SUVR) has been widely used as a semiquantitative outcome measure, because it can be obtained using simplified methods of acquisition and analysis. Quantification using this method may be influenced by confounding factors such that assessment of 18 F-AV-1451 signal or longitudinal changes of signal may not solely reflect the actual tau density in brain tissue.…”

“…Recently, SUVR was compared with a tissuebased method (15). In this study, an arterial input function corrected for metabolites was obtained in both healthy volunteers (HV) and subjects with AD, and classic pharmacokinetic modeling of the 18 F-AV-1451 PET data using plasma-based or tissue-based methods was performed.…”