Impact of meningeal uptake and partial volume correction techniques on [¹⁸F]MK-6240 binding in aMCI patients and healthy controls

Abstract

[18F]MK-6240 is a second-generation tau PET-tracer to quantify neurofibrillary tangles in-vivo. However, individually variable levels of meningeal uptake induce spill-in-effects into the cortex, complicating [18F]MK-6240 PET quantification. Group SUVR differences between age-matched HC subgroups with varying extracerebral uptake (EC-low/mixed/high), and between aMCI and each HC subgroup were assessed without and with partial volume correction (PVC). Both Müller-Gartner (MG-)PVC and region-based voxelwise (RBV-)PVC, with the latter also correcting for extracerebral spill-in-effects, were implemented. Between HC groups, where no differences are to be expected, HC EC-high showed spill-in differences compared to HC EC-low when no PVC was applied while for MG-PVC, differences were reduced and, for RBV-PVC, no statistically significant differences were observed. Between aMCI and HC, cortical SUVR differences were statistically significant, both without and with PVC, but modulated by the varying meningeal uptake in HC subgroups when no PVC was applied. After applying PVC, correlations to clinical parameters improved and effect sizes between HC and aMCI increased, independent of the HC-subgroup. Therefore, appropriate PVC with correction for extracerebral spill-in-effects is recommended to minimize the impact of varying meningeal uptake on cortical differences between HC and aMCI.

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

“…The diagnostic status of each participant was determined clinically by established criteria described by Albert et al 26 The Ab status of all subjects was determined using [ 11 C] Pittsburgh Compound B (PiB) PET with a threshold of 1.13 using gaussian mixture model 20 (see details in the Supplementary Materials). The tau status was determined using a SUVR 90-110 threshold of 1.35 in the temporal meta-ROI (comprised of entorhinal cortex, amygdala, inferior temporal, fusiform and parahippocampus) as described in a recent [ 18 F]MK-6240 study. 16 Twenty-five subjects completed follow-up [ 18 F] MK-6240 scans at six months (6.1 AE 0.5 months), and 16 subjects completed additional follow-up scans at one year (13.3 AE 0.9 months) after the baseline study.…”

“…Since this method entails technical and participant burden, semi-quantitative reference-tissue methods are often preferred, under the assumption that the reference region is: (1) devoid of specific binding, (2) representative of non-displaceable binding in the target regions, and (3) unaffected by disease or treatment. 6,8,10 The cerebellar gray matter (CerGM) has been shown to have kinetics consistent with nondisplaceable uptake across cognitively normal (CN) and AD/MCI subjects and thus, was suggested as a potential reference region for [ 18 F]MK-6240 quantification. 4,5 However, uptake in the CerGM may be contaminated by spill-in uptake signal from the extracerebral region and from the occipital and temporal cortices.…”

“…4,5 However, uptake in the CerGM may be contaminated by spill-in uptake signal from the extracerebral region and from the occipital and temporal cortices. To address these challenges, several studies utilized alternative reference regions, including the inferior cerebellar gray matter (InfCer) and CerGM with an erosion of the outer regional voxels 2,4,[6][7][8][11][12][13][14][15][16][17][18] (Supplementary Table.1). Studies with [ 18 F]Flortaucipir and amyloid-b (Ab) radioligands evaluated pons and cerebral white matter (WM) as reference regions, reporting increased sensitivity for detecting longitudinal changes in radiotracer uptake in target regions compared to CerGM-based reference regions.…”

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18 F]MK-6240 meningeal/extracerebral off-target binding may impact tau quantification. We examined the kinetics and longitudinal changes of extracerebral and reference regions.

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In Vivo Detection of Neurofibrillary Tangles by 18 F-MK-6240 PET/MR in Patients With Ischemic Stroke

“…For optimization of partial volume correction for this tracer, all cortical VOIs were merged per hemisphere (except for mesiotemporal region), and an extracerebral compartment was taken into account as well to correct for spill in from meningeal and/or extracerebral off-target binding. 30 Next, we calculated standardized uptake value ratio (SUVR) images using the cerebellum (as delineated with FreeSurfer) as the reference region 14 for both the images without and with correction for partial volume effects.…”