Impact of meningeal and age‐related off‐target binding on longitudinal [ ¹⁸ F]MK6240 quantification.

Background [ 18 F]MK6240 tau‐PET can detect changes in the early and late stages of tau tangles accumulation. However, off‐target binding, often observed in the meninges and neuromelanin‐containing cells, can interfere with longitudinal tracer quantification. Here, we investigated the association of longitudinal changes in off‐target and target signals using [ 18 F]MK6240. Method We assessed individuals from the TRIAD cohort with [ 18 F]MK6240 tau‐PET and clinical evaluation. Longitudinal analyses included 83 cognitively unimpaired (CU) and 37 cognitively impaired (CI) individuals. Age‐related off‐target binding was estimated comparing 36 CU young individuals (<25 y.o) and 28 CU elderly amyloid/tau negative (40‐65 y.o). A t‐test was used to compare both groups. The ratio between baseline and follow‐up SUVR measured changes in off‐target and target regions. Pearson correlations tested the associations between regions, and Bonferroni analysis corrected for multiple comparisons. Result Although averaged images did not present a striking visual difference in [ 18 F]MK6240 uptake between CU young and elderlies, t‐test revealed significant differences between groups in the cerebellar white matter and subcortical regions (Figure 1). Table 1 depicts the percentage of area of selected regions overlapping with the age‐related off‐target binding. Notably, we did not observe a significant association between longitudinal changes in age‐related or meningeal off‐target binding with longitudinal change in target regions (Braak‐II, BraakIII‐IV, BraakV‐VI), whereas changes in target regions were highly correlated (Figure 2). Conclusion Despite not being visually perceptible, [ 18 F]MK6240 presents age‐related off‐target binding in subcortical regions, similar to regions reported using [ 18 F]Flortaupicir. The overlap between age‐related off‐target and Braak IV region (∼3%) may lead to the confounding results in quantifying this region. The lack of correlation between off‐target and target [ 18 F]MK6240 changes suggests little influence of the off‐target binding on longitudinal tracer quantification. Our results suggest that although off‐target uptake appears to have a modest influence on longitudinal quantification, it is necessary to consider both age‐related and meningeal off‐target signals for an accurate tracer assessment.