Further evaluation of 18F-MK-6240 reference region kinetics

1058 Introduction: 18F-MK-6240 is a second-generation positron emission tomography (PET) tau imaging agent that has demonstrated higher signal-to-noise, lower off-target binding, and in-vivo kinetics that are more favourable than previous tau PET radioligands. Reference tissue methods have been used to quantify 18F-MK-6240 binding, using cerebellar gray matter (CerGM) based reference regions1-4. However, contamination of CerGM, by extra-axial signal, remains a challenge for the detection of emergent specific tau signal. In this work, we further explored alternative reference regions less prone to extra-axial contamination: eroded CerGM and pons1,2,3. Methods: Dynamic 120 min 18F-MK-6240 (180±10 MBq, GE Discovery-MI PET/CT) PET imaging was performed in 19 cognitively unimpaired control participants (CN, age 70±10 years) and 5 individuals diagnosed with mild cognitive impairment (4 MCI) and Alzheimer’s disease (age 64±6 years). Dynamic PET data were reconstructed with the ordered-subset expectation-maximization algorithm (5 iterations, 16 subsets) including time-of-flight information and point spread function modeling. Reconstructed PET data were motion corrected and coregistered to the corresponding T1-weighted magnetic resonance images with FSL Flirt. Time activity curves were generated using Freesurfer segmentations in 4 reference regions (CerGM, CerGM with 2mm and 3mm erosion from the outer edge to reduce contamination from adjacent high uptake areas, and pons) and 7 target regions (entorhinal, parahippocampal, amygdala, hippocampus, precuneus, inferior temporal and lateral occipital). Standardized uptake value tissue ratios (SUVR) were computed using 90-110 min of dynamic data. Distribution volume ratios (DVR) were computed by multilinear reference tissue modeling (MRTM2, t*=30min, k2’=0.04). Analysis of variance (ANOVA, p<0.05) and coefficients-of-variation were used to compare the mean and variability of SUVR and DVR values computed using different reference regions. Correlations between SUVR and DVR values were evaluated using linear regression models. Bonferroni correction for multiple comparisons was applied. Results: SUVRCerGM and SUVRerodedCerGM curves exhibited most consistent plateaus across target regions after 90 min. SUVRPons curves were still increasing at 120 min in the target tau-binding regions-of-interest. The SUVRPons and DVRPons values were approximately 2-fold greater than SUVRCerGM and DVRCerGM (p 0.96, p < 10-4), with positive bias of 1.34±0.13 in SUVRCerGM and 1.34±0.18 in SUVRPons values. Conclusions: Eroded CerCM reference regions performed similarly to CerGM, while potentially reducing contamination from extra-axial and cortical signal. Using pons as the reference region in 18F-MK-6240 MRTM2 analyses resulted in greater dynamic range (magnitudes) and variability similar to that for CerGM for both SUVR and DVR measures. Using reference regions that generate larger dynamic ranges of outcome measures (e.g. pons) may improve the sensitivity for longitudinal tracking of tau accumulation in subjects with low tau accumulation; however, further studies are needed to better characterize factors that impact the specific and non-specific 18F-MK-6240 kinetics and the bias in outcome measures in target regions.