Amyloid burden was imaged with PET using (11 C)-Pittsburgh Compound B (PIB; Klunk et al., 2004 (link)) or (18 F)-Florbetapir (AV45; Wong et al., 2010 (link)). Regional standard uptake ratios (SUVRs) were modeled from 30 to 60 min after injection for PIB and from 50 to 70 min for AV45, using cerebellar gray as the reference region (Su et al., 2013 (link)). Regions of interest were segmented automatically using FreeSurfer 5.3 (Fischl, 2012 (link)). Global amyloid burden was defined as the mean of partial-volume-corrected (PVC) SUVRs from bilateral precuneus, superior and rostral middle frontal, lateral and medial orbitofrontal, and superior and middle temporal regions (Su et al., 2013 (link)). Amyloid summary SUVRs were harmonized across tracers using a centiloid conversion (Su et al., 2018 (link)).
Tau deposition was imaged with PET using (18 F)-Flortaucipir (AV-1451; Chien et al., 2013 (link)). Regional SUVRs were modeled from 80 to 100 min after injection, using cerebellar gray as the reference region. A tau summary measure was defined in the mean PVC SUVRs from bilateral amygdala, entorhinal, inferior temporal, and lateral occipital regions (Mishra et al., 2017 (link)).
CSF was collected via lumbar puncture using methods described previously (Fagan et al., 2006 (link)). After overnight fasting, 20–30 mL samples of CSF were collected, centrifuged, then aliquoted (500 µL) in polypropylene tubes, and stored at –80°C. CSF amyloid β peptide 42 (Aβ42), Aβ40, and phosphorylated tau-181 (pTau) were measured with automated Lumipulse immunoassays (Fujirebio, Malvern, PA, USA) using a single lot of assays for each analyte. Aβ42 and pTau estimates were each normalized for individual differences in CSF production rates by forming a ratio with Aβ40 as the denominator (Hansson et al., 2019 (link); Guo et al., 2020 (link)). As pTau/Aβ40 was highly skewed, we applied a log transformation to these estimates before statistical analysis.
Amyloid positivity was defined using previously published cutoffs for PIB (SUVR > 1.42; Vlassenko et al., 2016 (link)) or AV45 (SUVR > 1.19; Su et al., 2019 (link)). Additionally, the CSF Aβ42/Aβ40 ratio has been shown to be highly concordant with amyloid PET (positivity cutoff < 0.0673; Schindler et al., 2018 (link); Volluz et al., 2021 (link)). Thus, participants were defined as amyloid-positive (for CN/A+ and CI groups) if they had either a PIB, AV45, or CSF Aβ42/Aβ40 ratio measure in the positive range. Participants with discordant positivity between PET and CSF estimates were defined as amyloid-positive.
Tau deposition was imaged with PET using (18 F)-Flortaucipir (AV-1451; Chien et al., 2013 (link)). Regional SUVRs were modeled from 80 to 100 min after injection, using cerebellar gray as the reference region. A tau summary measure was defined in the mean PVC SUVRs from bilateral amygdala, entorhinal, inferior temporal, and lateral occipital regions (Mishra et al., 2017 (link)).
CSF was collected via lumbar puncture using methods described previously (Fagan et al., 2006 (link)). After overnight fasting, 20–30 mL samples of CSF were collected, centrifuged, then aliquoted (500 µL) in polypropylene tubes, and stored at –80°C. CSF amyloid β peptide 42 (Aβ42), Aβ40, and phosphorylated tau-181 (pTau) were measured with automated Lumipulse immunoassays (Fujirebio, Malvern, PA, USA) using a single lot of assays for each analyte. Aβ42 and pTau estimates were each normalized for individual differences in CSF production rates by forming a ratio with Aβ40 as the denominator (Hansson et al., 2019 (link); Guo et al., 2020 (link)). As pTau/Aβ40 was highly skewed, we applied a log transformation to these estimates before statistical analysis.
Amyloid positivity was defined using previously published cutoffs for PIB (SUVR > 1.42; Vlassenko et al., 2016 (link)) or AV45 (SUVR > 1.19; Su et al., 2019 (link)). Additionally, the CSF Aβ42/Aβ40 ratio has been shown to be highly concordant with amyloid PET (positivity cutoff < 0.0673; Schindler et al., 2018 (link); Volluz et al., 2021 (link)). Thus, participants were defined as amyloid-positive (for CN/A+ and CI groups) if they had either a PIB, AV45, or CSF Aβ42/Aβ40 ratio measure in the positive range. Participants with discordant positivity between PET and CSF estimates were defined as amyloid-positive.
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