Florbetapir

PiB and florbetapir image data were analyzed using 2 processing streams. The PET-template analysis method was described in a separate study (10 (link)). This method was applied to the raw and unsmoothed datasets. Briefly, image data were spatially normalized to standard atlas coordinates in Talairach space using statistical parametric mapping software (11 ). Mean tracer retention was calculated for 6 predefined target cortical regions of interest (medial orbital frontal, temporal, parietal, anterior cingulate, posterior cingulate, and precuneus) that resulted from a statistical contrast of AD patients and cognitively normal subjects (1 (link)).
The Freesurfer method for quantifying cortical Aβ was applied to the unsmoothed and smoothed datasets. This method was described in detail elsewhere (2 (link),12 (link)) and online (13 ). Structural 1.5-T or 3-T MRI scans (T1-weighted images) were used to define cortical regions of interest and the cerebellar reference region. In general, 2 structural MRI scans were acquired at each visit across several years of follow-up, with the result that several MR images were available for each subject. For processing the PiB images, we chose the T1 scans acquired concurrently with (or closest in time to) the first PiB scan; and for the florbetapir processing, we chose the T1 scans acquired concurrently with (or closest in time to) the florbetapir scan. Structural MR images were segmented and parceled into individual cortical regions with Freesurfer (version 4.5.0; surfer.nmr.mgh.harvard.edu/) and subsequently used to extract mean PiB and florbetapir cortical retention ratios from gray matter within lateral and medial frontal, anterior and posterior cingulate, lateral parietal, and lateral temporal regions.
To examine several reference regions, the unscaled cortical means for each analysis method were divided by mean retention in the following 3 reference regions: brain stem–pons, whole cerebellum (white and gray matter), and cerebellar gray matter, yielding 3 cortical retention ratios for each preprocessing method. Because Freesurfer creates a brain stem, but not pons, region as part of its automated processing stream, the brain stem was used for the Free-surfer processing analysis method and the pons was used for the PET-template processing method.
To summarize, for each of 3 PET sessions (2 PiB scans and 1 florbetapir scan), every subject had cortical retention ratios for 2 levels of processing and 2 analysis methods (raw and unsmoothed for the PET-template method and unsmoothed and smoothed for the Freesurfer method), using 3 reference regions (brain stem–pons, whole cerebellum, cerebellar gray matter), resulting in 36 mean cortical retention ratios per subject that were compared in subsequent statistical analyses.

ADNI PET image data were acquired as described online (adni.loni.ucla.edu/about-data-samples/image-data/), and processed by our laboratory as described online (adni.loni.ucla.edu/research/pet-post-processing/) and summarized briefly below.
Florbetapir image data were acquired 50 to 70 minutes postinjection, and images were averaged, spatially aligned, interpolated to a standard voxel size, and smoothed to a common resolution of 8mm full width at half maximum.
For quantification of florbetapir, we used 1 or, in most cases, 2 structural 1.5T or 3T MRI scans (magnetization-prepared rapid acquisition gradient echo [MPRAGE]) acquired concurrently with the florbetapir scan to define cortical regions of interest and the cerebellar reference region. MPRAGE scans within 1 year of the florbetapir scan were available for approximately 80% of subjects. For the remaining subjects, we used the MPRAGE that was closest in time to the florbetapir scan (average MRI–florbetapir interval = 1.9 ± 0.8 years). MPRAGE images were segmented and parcellated into individual cortical regions with Freesurfer version 4.5.0 (surfer.nmr.mgh.harvard.edu/), which was used to extract mean florbetapir uptake from gray matter within lateral and medial frontal, anterior, and posterior cingulate, lateral parietal, and lateral temporal regions relative to uptake in the whole cerebellum (white and gray matter). This summary measure was used as the florbetapir cortical mean for each subject.

Participants were imaged at 23 sites using clinical PET and PET/computed tomographic scanners. Each participant underwent a 10-minute PET scan, which began 50 minutes after receiving an intravenous bolus of 370 MBq (10 mCi) florbetapir F 18. Images were acquired with a 128 × 128 matrix (zoom × 2) and were reconstructed using iterative or row action maximization likelihood algorithms.
Florbetapir-PET images were assessed visually using a semiquantitative score ranging from 0 (no amyloid) to 4 (high levels of cortical amyloid) by 3 board-certified nuclear medicine physicians who were not involved in any other aspects of the study. The only experience these physicians had with florbetapir-PET imaging occurred during a half-day training session. The median rating of the readers served as a primary outcome variable. Readers were blinded to clinical, demographic, and neuropathological information and viewed and rated images under the supervision and at the facility of the imaging core laboratory (ImageMetrix, a division of the American College of Radiology, Philadelphia, Pennsylvania). The initial 6 postmortem evaluations were rated by 4 readers and the median rating of the 4 raters served as the primary outcome variable for these 6 participants.
For the younger control cohort, the PET images were mixed in random order with 40 images from the autopsy cohort that had a median visual read score between 2 and 4 (inclusive). To remove image recognition bias, these images were rated as amyloid positive or negative at ImageMetrix by a different group of 3 external readers. The majority rating was used as the primary outcome variable for this analysis.
A semiautomated quantitative analysis of the ratio of cortical to cerebellar signal (SUVr) also was performed for florbetapir-PET images from all study participants. The images were first normalized to a standard template in the Talairach space and then the SUVrs were calculated for the 6 predefined cortical regions of interest (frontal, temporal, parietal, anterior cingulate, posterior cingulate, and precuneus). The whole cerebellum was used as the reference region.