The association of age-related and off-target retention with longitudinal quantification of [¹⁸F]MK6240 tau-PET in target regions

Abstract

Introduction: [18F]MK6240 is a tau-PET tracer that 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 regions estimates in the cerebellum over time and across diagnoses and evaluate the effects of age-related and off-target retention in 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±0.4 years of follow-up duration). We obtained SUVR values from meninges, a region exhibiting frequent off-target retention of [18F]MK6240, as well as compared tracer uptake between cognitively unimpaired young (CUY, mean age: 23.41±3.3 years) and cognitively unimpaired older adults (CU, amyloid-β and tau negative, mean age: 58.50±9.0 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) and full CG presented stable SUV cross-sectionally and over time, across diagnosis and Aβ status. [18F]MK6240 uptake was significantly different between CU young and adults mostly in putamen/pallidum (affecting ~75% of the region) but also in Braak II region (affecting ~35%), comprised of the entorhinal cortex and hippocampus. 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 and full CG were similar across diagnostic groups cross-sectionally and stable over time, and thus were deemed suitable reference regions for quantification. Despite this not being visually perceptible, [18F]MK6240 has age-related retention in subcortical regions, in much lower magnitude but topographically co-localized with the most 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. On the other hand, the age-related tracer 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 should further explore its impact on tracer quantification.

Revealing the combined roles of Aβ and tau in Alzheimer’s disease via a pathophysiological activity decoder

“…We chose baseline assessments in all cases. Only participants with “cognitively unimpaired” (N=81), “mild cognitive impairment” (N=35), or “probable Alzheimer’s disease” (N=16) clinical and pathophysiological diagnoses were considered 55 .…”