18F-Florbetaben acquisition and image processing

Details on the PET image acquisition and reconstruction are provided in the respective original publication of the studies used (Table 1). In short, all subjects underwent a 20-min PET scan (4 × 5 min dynamic frames) starting at least 90 min after intravenous injection of 300 MBq ± 20% of ¹⁸F-florbetaben followed by a 10-mL saline flush. PET scans were reconstructed using Ordered Subsets Expectation Maximization (OSEM) algorithm using 4 iterations and 16 subsets (zoom = 2) or comparable reconstruction. Corrections were applied for attenuation, scatter, randoms, and dead time. Three-dimensional volumetric T1-weighted brain magnetic resonance imaging (MRI) data was also collected. Then, a Gaussian smoothing kernel was applied to all the scans to bring the ¹⁸F-florbetaben PET images from different scanner models to a uniform 8 × 8 × 8 mm spatial resolution. The Gaussian smoothing kernel for each scanner was determined using previously acquired Hoffman brain phantoms [27]. Image analysis of ¹⁸F-florbetaben PET scans was conducted using SPM8 (https://www.fil.ion.ucl.ac.uk/spm/software/spm8/). Motion correction was performed on each PET frame, and an average PET image was generated. Then, the average PET scan was co-registered to its associated T1-weighted MRI scan. Subsequently, the MRI image was segmented into gray matter, white matter, and cerebrospinal fluid, and spatially normalized to the standard MNI (Montreal Neurological Institute) space. The normalization transformation was applied to the co-registered PET scans and gray matter probability maps.

Regions of interest (ROIs) were defined as the intersection between the standard Automated Anatomic Labeling (AAL) atlas [28] and the normalized gray matter segmentation map thresholded at a probability level of 0.2. ROIs included the cerebellar gray matter and frontal (orbitofrontal and prefrontal), lateral temporal (inferior and superior), occipital, parietal, precuneus, anterior cingulate, posterior cingulate, striatum, amygdala, and thalamus. Mean radioactivity values were obtained from each ROI without correction for partial volume effects applied to the PET data. SUVR was calculated as the ratio of the activity in the target ROI to the activity in the reference region ROI (cerebellar gray matter). A composite SUVR was calculated by unweighted averaging the SUVR of the 6 cortical regions (frontal, lateral temporal, occipital, parietal, anterior, and posterior cingulate cortices) [29].

Given that SUVR values may depend on the tracer used and analytical methods, all the analysis of this paper were provided in CL scale to make the cutoffs useful to other groups or when using other amyloid tracers. Centiloid (CL) values were calculated for each ¹⁸F-florbetaben PET using the method described by Klunk et al. [30]. ROIs downloaded from the Global Alzheimer’s Association Interactive Network (GAAIN) website (http://www.gaain.org) for the cerebral cortex and the whole cerebellum were applied to the normalized ¹⁸F-florbetaben PET. Cortical SUVR was calculated as the ratio of the activity in the cortex to the activity in the reference region ROI (whole cerebellum). Finally, the CL values were calculated (CL = 153.4 ⋅ SUVR − 154.9) [31]. The in-house implementation of the standard CL analysis was validated using data freely accessible at the GAAIN website (http://www.gaain.org). SUVRs and CL values from the validation dataset were compared by means of linear correlation to those reported by Klunk et al. [30] (SUVR_Klunk, CL_Klunk). The in-house implementation of standard CL analysis passed all the validation criteria described by Klunk et al. [30] being SUVR = 1.01 SUVR_Klunk − 0.01 (R² = 0.998) and CL = 1.00 CL_Klunk + 0.00 (R² = 1.00) the regression lines when the whole cerebellum was used as the reference region.