Participants
In the present study, 20 younger controls (YCs), 27 older controls (OCs), 27 mild cognitive impairment (MCI), 29 Alzheimer’s dementia (AD), and 4 subcortical vascular dementia (SVAD) patients were recruited. All participants underwent Aβ PET with both FBB and FMM as well as magnetic resonance imaging (MRI). AD was diagnosed based on the National Institute on Aging-Alzheimer’s Association (NIA-AA) research criteria for probable AD [9]. Participants diagnosed with MCI had to meet Petersen’s criteria [10] and show objective memory impairment one standard deviation (SD) below the norm in at least one memory test. OCs were over 65 years of age with normal cognitive function determined using neuropsychological tests and no history of neurological or psychiatric disorders. Healthy YCs were under 40 years of age with normal cognitive function and no history of neurological or psychiatric disorders.
All participants underwent clinical interviews, neurological and neuropsychological examinations, and laboratory tests including complete blood count, blood chemistry, thyroid function tests, syphilis serology, and vitamin B12/folate levels. The absence of structural lesions including cerebral infarctions, brain tumours, vascular malformations, and hippocampal sclerosis was confirmed based on brain MRI.
The Institutional Review Board of Samsung Medical Centre (SMC) approved the study protocol, and all methods were performed according to the approved guidelines. Written consent was obtained from each participant.
Mri Data Acquisition
Standardised three-dimensional (3D) T1turbo field echo images were acquired from all participants at SMC using the same scanner (Achieva 3.0-Tesla MRI 164 scanner, Philips, Best, the Netherlands) and the following parameters: sagittal slice thickness, 1.0 mm with 50% overlap; no gap; repetition time, 9.9 msec; echo time, 4.6 msec; flip angle, 8°, and matrix size, 240 × 240 pixels reconstructed to 480 × 480 over a field of view of 240 mm.
Aβ Pet Data Acquisition
Participants underwent FBB PET and FMM PET at SMC using a Discovery STe PET/ computed tomography (CT) scanner (GE Medical Systems, Milwaukee, WI, USA) in 3D scanning mode that examined 47 slices of 3.3-mm thickness spanning the entire brain [11]. Paired FBB and FMM PET images were acquired on two separate days; mean interval times (4.0 ± 3.4 months across all groups) among the groups were not different (P = 0.92). FBB PET was performed first in half of the participants (total 46; 7 AD, 10 MCI, 16 OCs, 9 YCs, and 4 SVaD) and FMM PET first in the other half (total 61; 22 AD, 17 MCI, 11 OCs and 11 YCs). CT images were acquired using a 16-slice helical CT system (140 KeV, 80 mA; 3.75-mm section width) for attenuation correction. A 20-min emission PET scan in dynamic mode (consisting of 4 × 5 min frames) was performed 90 min after injection of a mean dose of 311.5 MBq FBB or 185 MBq FMM. 3D PET images were reconstructed in a 128 × 128 × 48 matrix with 2 mm × 2 mm × 3.27 mm voxel size using the ordered-subsets expectation maximization (OSEM) algorithm (FBB iterations = 4 and subset = 20; FMM iterations = 4 and subsets = 20).
Aβ Pet Imaging Analysis
PET images were co-registered to individual MR images normalized to a T1-weighted MNI-152 template using SPM8 in Matlab 2014b (Mathworks, Natick, MA, USA). After standard space registration, the grey matter was divided into 116 regions using the Automated Anatomical Labeling atlas and white matter [12]. The whole cerebellum (WC) was used as an ROI to reference uptake ratio (which is identical to SUVR) and quantify FBB and FMM retention. Global cerebral cortex amyloid retention ratio was assessed from the volume-weighted average SUVR of 28 bilateral cerebral cortical volumes of interest (VOI) [11, 13]. The cerebral cortical VOI chosen for this study consisted of the following areas: bilateral frontal (superior and middle frontal gyri; medial part of the superior frontal gyrus; opercular part of the inferior frontal gyrus; triangular part of the inferior frontal gyrus; supplementary motor area; orbital part of the superior, middle, and inferior orbital frontal gyri; rectus; and olfactory cortex), posterior cingulate gyri, parietal (superior and inferior parietal, supramarginal and angular gyri, and precuneus), lateral temporal (superior, middle, and inferior temporal gyri and Heschl’s gyri), and occipital (superior, middle, and inferior occipital gyri; cuneus; calcarine fissure; and lingual and fusiform gyri).
Aβ Pet Positivity Based On Visual Assessment
Three experienced doctors (two nuclear medicine doctors and one neurologist) visually quantified FBB and FMM. For FBB, tracer uptake was assessed according to the regional cortical tracer uptake (RCTU) system in four brain regions (frontal cortex, posterior cingulate cortex/precuneus, parietal cortex, and lateral temporal cortex). The global uptake in the brain was assessed according to the brain amyloid plaque load (BAPL) system [14]. For FMM, each doctor scored the frontal, temporoparietal/insula, posterior cingulate/precuneus, lateral temporal, and striatum as positive or negative and recorded the overall amyloid status. A scan was categorized as positive if there was uptake in any region. A scan was categorized as negative if there was no uptake in all five regions [15].
Inter-rater agreement was excellent for FBB (Fleiss k = 0.86) and FMM (Fleiss k = 0.78). After individual ratings were performed, the final visual positivity was determined based on the majority of agreement regarding visual reading results.
Aβ Pet Positivity Based On Suvr Assessment
SUVR positivity was classified based on SUVR cut-off value calculated using the iterative outlier approach in different samples consisting of cognitively normal participants over 55 years of age [16]. To calculate the SUVR cut-off value of Aβ positivity, 171 FMM PET and 202 FBB PET scans were evaluated. Consequently, when WC was used as a reference region, the cortical SUVR cut-off value was 1.1 for FBB and 1.03 for FMM.
For direct comparison of the FBB-FMM conversion method, SUVR values of the FBB-FMM cortical target volume of interest (CTX VOI) were directly converted into Centiloid (CL) units using the direct comparison of FBB-FMM CL (dcCL) method based on the CL conversion equation [17, 18]:
where SUVRind represents the individual SUVR values of all YC-0 and ADCI-100 participants, and SUVRYC−0 and SUVRADCI−100 represent each group’s mean SUVR values. The CL equation was derived for FBB and FMM PET separately and applied to the FBB and FMM SUVR, respectively, from the FBB-FMM CTX VOI. The SUVR from the FBB-FMM CTX VOI used to determine dcCL was termed dcSUVR. When WC was used as a reference region, the dcCL cut-off value was 24.9 dcCL units for FBB and 15.1 dcCL units for FMM.
Statistical analysis
Analysis of variance (ANOVA) was performed for continuous demographic variables, and chi-square test was performed for such categorical variables. The Fleiss kappa value was calculated for inter-rater reliability. The McNemar test was used to compare the false-positive and false-negative rates between FBB and FMM. The MedCalc Statistical Software version 19.1 (MedCalc Software, Ostend, Belgium; https://www.medcalc.org; 2019) was used for the for the chi-square test, ANOVA, and McNemar test and R v3.4.1 (Institute for Statistics and Mathematics, Vienna, Austria; www.R-project.org) was used for Fleiss kappa.