RT Journal Article SR Electronic T1 The association of age-related and off-target retention with longitudinal quantification of [18F]MK6240 tau-PET in target regions. JF Journal of Nuclear Medicine JO J Nucl Med FD Society of Nuclear Medicine SP jnumed.122.264434 DO 10.2967/jnumed.122.264434 A1 Cécile Tissot A1 Stijn Servaes A1 Firoza Z. Lussier A1 João Pedro Ferrari-Souza A1 Joseph Therriault A1 Pâmela C. L. Ferreira A1 Gleb Bezgin A1 Bruna Bellaver A1 Douglas Teixeira Leffa A1 Sulantha S. Mathotaarachchi A1 Mira Chamoun A1 Jenna Stevenson A1 Nesrine Rahmouni A1 Min Su Kang A1 Vanessa Pallen A1 Nina Margherita Poltronetti A1 Yi-Ting Wang A1 Jaime Fernandez-Arias A1 Andrea L. Benedet A1 Eduardo R. Zimmer A1 Jean-Paul Soucy A1 Dana L. Tudorascu A1 Ann D. Cohen A1 Madeleine Sharp A1 Serge Gauthier A1 Gassan Massarweh A1 Brian J. Lopresti A1 William E. Klunk A1 Suzanne L. Baker A1 Victor L. Villemagne A1 Pedro Rosa-Neto A1 Tharick A. Pascoal YR 2022 UL http://jnm.snmjournals.org/content/early/2022/11/17/jnumed.122.264434.abstract AB [18F]MK6240 tau-PET tracer quantifies brain tau neurofibrillary tangles (NFT) load in Alzheimer’s disease (AD). The aims of our study are to test the stability of common reference region estimates in the cerebellum over time and across diagnoses and evaluate the effects of age-related and off-target retention on the longitudinal quantification of [18F]MK6240 in target regions. Methods: We assessed reference, target, age-related and off-target regions in 125 individuals across the aging and AD spectrum with longitudinal [18F]MK6240 standardized uptake values (SUV) and ratios (SUVR) (2.25±0.40 years of follow-up duration). We obtained SUVR from meninges, exhibiting frequent off-target retention with [18F]MK6240. Additionally, we compared tracer uptake between 37 cognitively unimpaired (CU) young (CUY, mean age: 23.41±3.33 years) and 27 CU older adults (CU, amyloid-β and tau negative, mean age: 58.50±9.01 years) to identify possible, non-visually apparent, age-related signal. Two-tailed t-test and Pearson correlations tested the difference between groups and associations between changes in region uptake, respectively. Results: Inferior cerebellar grey (CG) SUV did not differ based on diagnosis and Aβ status, cross-sectionally and over time. [18F]MK6240 uptake was significantly different between CUY and CU older adults in putamen/pallidum (affecting ~75% of the region) and in Braak II region (affecting ~35%). Changes in meningeal and putamen/pallidum SUVRs were not significantly different from zero, nor varied across diagnostic groups. We did not observe significant correlations between longitudinal changes in age-related or meningeal off-target retention and changes in target regions, whereas changes in all target regions were highly correlated. Conclusion: Inferior CG was similar across diagnostic groups cross-sectionally and stable over time, thus deemed a suitable reference region for quantification. Despite not being visually perceptible, [18F]MK6240 has age-related retention in subcortical regions, in much lower magnitude but topographically co-localized with significant off-target signal of the first-generation tau tracers. The lack of correlation between changes in age-related/meningeal and target retention suggests little influence of possible off-target signals on longitudinal tracer quantification. Nevertheless, the age-related retention in Braak II needs to be further investigated. Future post-mortem studies should elucidate the source of the newly reported age-related [18F]MK6240 signal, and in vivo studies further explore its impact on tracer quantification.