Abstract
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Introduction: [18F]MK-6240 PET is used for detecting tau deposition in Alzheimer's disease (AD). Off-target binding of [18F]MK-62401 in the meningeal/extracerebral area can impact the quantification of reference and target region uptake2. A previous study suggested an annual increase of 0.01-0.15 in target region standardized uptake value (SUV) ratios (SUVR90-110) in cognitively normal (CN) and AD subjects3. However, reports on longitudinal stability of reference region and extracerebral uptake have been limited. In a cross-sectional dataset, we previously showed that lower uptake in white-matter (WM)-rich reference regions allows for larger dynamic range of target uptake in low-binders. Here, we extended the previous study by evaluating the longitudinal change of reference region and extracerebral uptake across the AD spectrum.
Methods: Baseline [18F]MK-6240 PET imaging (0-120 min, 180±10 MBq, GE Discovery-MI) was performed in 24 CN (age 68±12), 6 mild cognitive impairment (MCI) and 2 AD subjects (age 70±11)4. Follow-up scans at 6.1±0.5 months and 13.3±0.9 months (1-year) were performed in 25 (20 CN, 5 AD/MCI) and 16 (11 CN, 5 AD/MCI) subjects, respectively. Candidate reference regions included cerebellar gray matter (CerGM), CerGM eroded by 3mm (CerGM3mm), inferior CerGM, cerebral WM and pons. Uptake kinetics were evaluated using SUV90-110 for reference regions, and using SUV90-110 and SUVR90-110 (reference region: CerGM3mm) for extracerebral uptake. Longitudinal change (?SUV) was calculated as (SUV90-110,follow-up-SUV90-110,baseline) and was compared between reference regions and diagnostic groups. The proportion of subjects with high extracerebral SUVR90-110 was examined with histogram analysis. Baseline amyloid-b burden was estimated in frontal, lateral temporo-parietal and retrosplenial (FLR) regions using 11C-PiB distribution volume ratio (DVR >1.2, PiB-positive). Partial volume correction (PVC) was not performed.
Results: Baseline SUV90-110 (0.16–1.01 g/mL) was higher in CerGM-based regions than WM-rich regions. WM SUV90-110 was ~1.5-fold higher in AD/MCI than CN subjects. At group-level, no reference region showed significant ?SUV at either follow-up (Table.1, Fig.1A). ?SUV was similar between diagnostic groups and was lowest in pons (6-month:0.02±0.05, 1-year: -0.002±0.07) and highest in CerGM-based regions (6-month: 0.04±0.07, 1-year: 0.04±0.13, Table.1), although no significant difference was observed across reference regions. ?SUV in reference regions indicated high inter-subject (standard deviation: 0.05–0.13) and intra-subject (range: -0.24–0.26) variability at both follow-ups. Baseline extracerebral SUV90-110 (0.54–1.12 g/mL) was similar across groups. At group-level, extracerebral ?SUV (6-month: 0.01±0.12, 1-year: 0.0002±0.16) was similar across diagnostic groups with similar magnitude but larger variability than the reference regions. Histogram analysis yielded a baseline extracerebral SUVR90-110 threshold of 1.39 that assigned 50% of subjects to a high extracerebral uptake group (Fig.1B-C). At follow-ups, the group assignments remained for all subjects except for 1 MCI subject.
Conclusions: Based on these analyses, the WM reference region showed higher SUV90-110 in AD/MCI than CN subjects possibly due to spill-in signal, and is not optimal for cross-sectional nor longitudinal studies involving high-binders without PVC. The reference region ?SUV was similar in magnitude and variability as annual increases reported for target uptake in CN subjects3, although ?SUV90-110 was not significant over 1-year. The pons may be preferred for longitudinal studies due to its lower magnitude and variability of ?SUV. The extracerebral uptake was stable over 1 year at group-level, but exhibited high variability independent of the diagnostic groups. This work is our first step to evaluate factors that impact the sensitivity for detecting robust biological changes in target uptake. Our next efforts will examine how these factors propagate to target region uptake.
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