Long-term test-retest of cerebral [${}^{18}$F]MK-6240 binding and longitudinal evaluation of extracerebral tracer uptake in healthy controls and amnestic MCI patients

Neurofibrillary tangles (NFTs) in Alzheimer's disease can be accurately quantified in vivo using [${}^{18}$F]MK-6240 PET. Short-term [${}^{18}$F]MK-6240 test-retest (TRT) is about 6%, but also long-term stability of cerebral uptake is of importance for longitudinal studies. Furthermore, although there is very little cerebral off-target binding, [${}^{18}$F]MK-6240 shows variable extracerebral uptake (ECU) assumed to represent off-target binding to leptomeningeal melanocytes. Here, we examined 6-month TRT of [${}^{18}$F]MK-6240 in healthy controls (HC) and investigated ECU in HC and patients with amnestic mild cognitive impairment (aMCI) with up to 2 years of follow-up. We also explored demographic factors that may be associated to ECU, including age, sex, education, smoking, and disease status. A total cohort of 40 HC (57 ± 19 years, 21F/19 M) and 24 aMCI (72 ± 8 years, 14F/10 M) underwent baseline [${}^{18}$F]MK-6240 PET-MR (GE Signa), 90-120 min post injection. [${}^{18}$F]MK-6240 was quantified by standardized uptake value ratios (SUVR) in predefined volumes-of-interest relative to the cerebellar cortex. Ten HC (56 ± 12 years, 8F/2 M) underwent a 6-month follow-up [${}^{18}$F]MK-6240 to assess TRT. Also, 10 aMCI (72 ± 6 years, 5F/5 M) underwent a 2-year follow-up [${}^{18}$F]MK-6240 PET-MR. Longitudinal changes in ECU were assessed in both cohorts. ECU was quantified as the mean SUVR of the skull parcel (FreeSurfer 6.0) that includes the meninges. The mean gray matter [${}^{18}$F]MK-6240 SUVR TRT and absolute TRT in HC were 1.6 ± 3.4% and 2.4 ± 2.8%, respectively. We found no significant 6-month or 2-year differences in ECU in HC (4.4 ± 20%) and aMCI (7.9 ± 19%), respectively. In the total cohort, ECU was significantly correlated to age (r${}_s$ = - 0.48; p < 0.0001), and a multivariate analysis also showed sex differences (higher ECU in women). [${}^{18}$F]MK-6240 shows excellent 6-month TRT, which confirms its suitability for quantification of longitudinal NFT changes. The ECU of [${}^{18}$F]MK-6240 is variable between subjects, influenced by age and sex, but remains stable within subjects over a 2-year time period.