Patterns of tau pathology identified with <sup>18</sup>F‐MK‐6240 PET imaging

Kreisl, William Charles; Lao, Patrick J.; Johnson, Aubrey S.; Tomljanovic, Zeljko; Klein, Julia; Polly, Krista; Maas, Benjamin; Laing, Krystal K; Chesebro, Anthony G.; Igwe, Kay C.; Razlighi, Qolamreza R.; Honig, Lawrence S.; Yan, Xinyu; Lee, Seonjoo; Mintz, Akiva; Luchsinger, José A.; Stern, Yaakov; Devanand, Davangere P.; Brickman, Adam M.

doi:10.1002/alz.12384

Cited by 14 publications

(30 citation statements)

References 43 publications

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“…This finding was in concordance with the expected spatiotemporal patterns of tau deposition in the brain reflected in the Braak and Delacourte staging [ 32 , 33 ]. In addition, high 18 F-PI-2620 retention was associated with higher CSF p-tau and t-tau and lower hippocampal volume, as previously reported for other tau tracers [ 4 , 6 , 7 , 34 ]. 18 F-PI-2620 is not yet validated using histopathological confirmation of tau load in the brain.…”

Section: Discussionsupporting

confidence: 83%

Evaluation of tau deposition using 18F-PI-2620 PET in MCI and early AD subjects—a MissionAD tau sub-study

Bullich¹,

Mueller²,

Santi

et al. 2022

Alz Res Therapy

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Background The ability of 18F-PI-2620 PET to measure the spatial distribution of tau pathology in Alzheimer’s disease (AD) has been demonstrated in previous studies. The objective of this work was to evaluate tau deposition using 18F-PI-2620 PET in beta-amyloid positive subjects with a diagnosis of mild cognitive impairment (MCI) or mild AD dementia and characterize it with respect to amyloid deposition, cerebrospinal fluid (CSF) assessment, hippocampal volume, and cognition. Methods Subjects with a diagnosis of MCI due to AD or mild AD dementia and a visually amyloid-positive 18F-florbetaben PET scan (n=74, 76 ± 7 years, 38 females) underwent a baseline 18F-PI-2620 PET, T1-weighted magnetic resonance imaging (MRI), CSF assessment (Aβ42/Aβ40 ratio, p-tau, t-tau) (n=22) and several cognitive tests. A 1-year follow-up 18F-PI-2620 PET scans and cognitive assessments were done in 15 subjects. Results Percentage of visually tau-positive scans increased with amyloid-beta deposition measured in 18F-florbetaben Centiloids (CL) (7.7% (<36 CL), 80% (>83 CL)). 18F-PI-2620 standardized uptake value ratio (SUVR) was correlated with increased 18F-florbetaben CL in several regions of interest. Elevated 18F-PI-2620 SUVR (fusiform gyrus) was associated to high CSF p-tau and t-tau (p=0.0006 and p=0.01, respectively). Low hippocampal volume was associated with increased tau load at baseline (p=0.006 (mesial temporal); p=0.01 (fusiform gyrus)). Significant increases in tau SUVR were observed after 12 months, particularly in the mesial temporal cortex, fusiform gyrus, and inferior temporal cortex (p=0.04, p=0.047, p=0.02, respectively). However, no statistically significant increase in amyloid-beta load was measured over the observation time. The MMSE (Recall score), ADAS-Cog14 (Word recognition score), and CBB (One-card learning score) showed the strongest association with tau deposition at baseline. Conclusions The findings support the hypothesis that 18F-PI-2620 PET imaging of neuropathologic tau deposits may reflect underlying neurodegeneration in AD with significant correlations with hippocampal volume, CSF biomarkers, and amyloid-beta load. Furthermore, quantifiable increases in 18F-PI-2620 SUVR over a 12-month period in regions with early tau deposition are consistent with the hypothesis that cortical tau is associated with cognitive impairment. This study supports the utility of 18F-PI-2620 PET to assess tau deposits in an early AD population. Quantifiable tau load and its corresponding increase in early AD cases could be a relevant target engagement marker in clinical trials of anti-amyloid and anti-tau agents. Trial registration Data used in this manuscript belong to a tau PET imaging sub-study of the elenbecestat MissionAD Phase 3 program registered in ClinicalTrials.gov (NCT02956486; NCT03036280).

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Section: Discussionsupporting

confidence: 83%

Evaluation of tau deposition using 18F-PI-2620 PET in MCI and early AD subjects—a MissionAD tau sub-study

Bullich¹,

Mueller²,

Santi

et al. 2022

Alz Res Therapy

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“… 29 Sample collected was tinged pink, with a red blood cell count of 1600/μL. b = AIBL composite value from a combined immunoprecipitation and mass spectrometry method previously described, 30 a measure validated in the AIBL cohort. c = plasma p217+tau assay was performed on a SIMOA platform, using a method previously described, 31 and has been evaluated in the AIBL cohort.…”

Section: Resultsmentioning

confidence: 99%

“… b = AIBL composite value from a combined immunoprecipitation and mass spectrometry method previously described, 30 a measure validated in the AIBL cohort. …”

Section: Resultsmentioning

confidence: 99%

Exploring discordant low amyloid beta and high neocortical tau positron emission tomography cases

Krishnadas

Doré

Laws

et al. 2022

Alz & Dem Diag Ass & Dis Mo

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Introduction Neocortical 3R4R (3‐repeat/4‐repeat) tau aggregates are rarely observed in the absence of amyloid beta (Aβ). 18 F‐MK6240 binds specifically to the 3R4R form of tau that is characteristic of Alzheimer's disease (AD). We report four cases with negative Aβ, but positive tau positron emission tomography (PET) findings. Methods All Australian Imaging, Biomarkers and Lifestyle study of aging (AIBL) study participants with Aβ ( 18 F‐NAV4694) and tau ( 18 F‐MK6240) PET scans were included. Centiloid <25 defined negative Aβ PET (Aβ–). The presence of neocortical tau was defined quantitatively and visually. Results Aβ– PET was observed in 276 participants. Four of these participants (one cognitively unimpaired [CU], two mild cognitive impairment [MCI], one AD) had tau tracer retention in a pattern consistent with Braak tau stages V to VI. Fluid biomarkers supported a diagnosis of AD. In silico analysis of APP, PSEN1, PSEN2 , and MAPT genes did not identify relevant functional mutations. Discussion Discordant cases were infrequent (1.4% of all Aβ– participants). In these cases, the Aβ PET ligand may not be detecting the Aβ that is present.

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“…7 Several landmark studies have used [ 18 F]MK-6240 to quantify NFTs in patients with amnestic mild cognitive impairment (aMCI) and AD [8][9][10][11][12][13] and have shown its correspondence to pathological stages. 14 Although [ 18 F]MK-6240 displays very low offtarget signal in brain parenchyma, 15 varying levels of meningeal tracer uptake have been noticed, confirmed by postmortem autoradiography studies. [16][17][18] Even though the exact nature of the uptake is still under debate, this varying extracerebral (EC) tracer uptake causes partial volume effects (PVE) due to spill-over of this activity to nearby cortical regions which may hamper accurate quantification and hinder optimal interpretation of [ 18 F]MK-6240 PET scans.…”

Section: Introductionmentioning

confidence: 85%

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

Mertens

Michiels

Vanderlinden

et al. 2022

J Cereb Blood Flow Metab

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[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.

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Patterns of tau pathology identified with ¹⁸F‐MK‐6240 PET imaging

Cited by 14 publications

References 43 publications

Evaluation of tau deposition using 18F-PI-2620 PET in MCI and early AD subjects—a MissionAD tau sub-study

Evaluation of tau deposition using 18F-PI-2620 PET in MCI and early AD subjects—a MissionAD tau sub-study

Exploring discordant low amyloid beta and high neocortical tau positron emission tomography cases

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

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Patterns of tau pathology identified with 18F‐MK‐6240 PET imaging

Cited by 14 publications

References 43 publications

Evaluation of tau deposition using 18F-PI-2620 PET in MCI and early AD subjects—a MissionAD tau sub-study

Evaluation of tau deposition using 18F-PI-2620 PET in MCI and early AD subjects—a MissionAD tau sub-study

Exploring discordant low amyloid beta and high neocortical tau positron emission tomography cases

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

Contact Info

Product

Resources

About

Patterns of tau pathology identified with ¹⁸F‐MK‐6240 PET imaging

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