Kinetic evaluation and assessment of longitudinal changes in reference region and extracerebral [¹⁸F]MK-6240 PET uptake

Abstract

[18F]MK-6240 meningeal/extracerebral off-target binding may impact tau quantification. We examined the kinetics and longitudinal changes of extracerebral and reference regions. [18F]MK-6240 PET was performed in 24 cognitively-normal and eight cognitively-impaired subjects, with arterial samples in 13 subjects. Follow-up scans at 6.1 ± 0.5 (n = 25) and 13.3 ± 0.9 (n = 16) months were acquired. Extracerebral and reference region (cerebellar gray matter (CerGM)-based, cerebral white matter (WM), pons) uptake were evaluated using standardized uptake values (SUV90-110), spectral analysis, and distribution volume. Longitudinal changes in SUV90-110 were examined. The impact of reference region on target region outcomes, partial volume correction (PVC) and regional erosion were evaluated. Eroded WM and pons showed lower variability, lower extracerebral contamination, and lower longitudinal changes than CerGM-based regions. CerGM-based regions resulted larger cross-sectional effect sizes for group differentiation. Extracerebral signal was high in 50% of subjects and exhibited irreversible kinetics and nonsignificant longitudinal changes over one-year but was highly variable at subject-level. PVC resulted in higher variability in reference region uptake and longitudinal changes. Our results suggest that eroded CerGM may be preferred for cross-sectional, whilst eroded WM or pons may be preferred for longitudinal [18F]MK-6240 studies. For CerGM, erosion was necessary (preferred over PVC) to address the heterogenous nature of extracerebral signal.

Test-Retest performance of [18F]MK-6240 tau burden and relative delivery indices in cognitively normal older subjects using PET/MRI

“…The pattern of [ 18 F]MK-6240 uptake distribution was consistent with previous studies 17,23,69,70 and with the expected localization of tau across the AD spectrum 20,71,72 , and was similar in the Test and Retest scans. Some degree of meningeal or extracerebral signal was observed in all subjects, with 7 of them presenting visually high extracerebral signal.…”

“…Currently, there is no consensus on the optimal reference region for [ 18 F]MK-6240, and various studies have chosen different regions for normalization 17,19,23,[27][28][29][30][31][32] . In a recent study, Fu et al 23 evaluated longitudinal changes in reference region SUV 90 − 110 , as well as the impact of the reference region on target region outcomes. The authors suggested that, for cross-sectional studies, eroded CerGM may be preferred for differentiation between CN and AD groups, whilst eroded WM or pons may be preferred for detecting longitudinal [ 18 F]MK-6240 changes.…”

“…Numerous [ 18 F]MK-6240 PET studies have reported strong signal-to-noise in tau-bearing areas, showing utility for the detection of early and late accumulation of tau, as well as for disease staging in individuals ranging from preclinical to symptomatic AD [19][20][21][22] . However, a substantial off-target binding signal is evident in the extracerebral space [23][24][25] in about 50% of subjects 23 . Neuropathological evaluations of human tissue have veri ed [ 18 F]MK-6240 binding to melanin-containing cells, such as those found in the meninges within the extracerebral space 26 .…”

Development, initial validation, and application of a visual read method for [18F]MK‐6240 tau PET

“…that different off‐target binding adjustment methods, including PVC and erosion, 38 did not significantly impact relationships between measured uptake and other endpoints. It can be noted that different compensation methods have various advantages and disadvantages when applied to longitudinal evaluation (such as increased variability with PVC), 39 but this was not the focus or scope of the present work. The finding of general concordance between visual detection of uptake and quantitative values for [ 18 F]MK‐6250 was consistent with results reported by others 34,40 …”

Tau positron emission tomography in tauopathies: A narrative review

“…Interestingly, eroded WM may be more sensitive for longitudinal analyses. An eroded subcortical WM or eroded subcortical WM cerebellar composite RR may be more suitable for longitudinal analyses examining regional patterns of change [157][158][159][160]. The eroded WM RR more consistently detected significant change over time [157].…”