18F-MK-6240 tau-PET in genetic frontotemporal dementia

Abstract

Tau is one of several proteins associated with frontotemporal dementia. While knowing which protein is causing a patient's disease is crucial, no biomarker currently exists for identifying tau in vivo in frontotemporal dementia. The objective of this study was to investigate the potential for the promising 18F-MK-6240 PET tracer to bind to tau in vivo in genetic frontotemporal dementia. We enrolled subjects with genetic frontotemporal dementia, who constitute an ideal population for testing because their pathology is already known based on their mutation. Ten participants (three with symptomatic P301L and R406W MAPT mutations expected to show tau binding, three with presymptomatic MAPT mutations and four with non-tau mutations who acted as disease controls) underwent clinical characterization, tau-PET scanning with 18F-MK-6240, amyloid-PET imaging with 18F-NAV-4694 to rule out confounding Alzheimer's pathology, and high-resolution structural MRI. Tau-PET scans of all three symptomatic MAPT carriers demonstrated at least mild 18F-MK-6240 binding in expected regions, with particularly strong binding in a subject with an R406W MAPT mutation (known to be associated with Alzheimer's like neurofibrillary tangles). Two asymptomatic MAPT carriers estimated to be 5 years from disease onset both showed modest 18F-MK-6240 binding, while one ∼30 years from disease onset did not exhibit any binding. Additionally, four individuals with symptomatic frontotemporal dementia caused by a non-tau mutation were scanned (two C9orf72; one GRN; one VCP): 18F-MK-6240 scans were negative for three subjects, while one advanced C9orf72 case showed minimal regionally non-specific binding. All 10 amyloid-PET scans were negative. Furthermore, a general linear model contrasting genetic frontotemporal dementia subjects to a set of 83 age-matched controls showed significant binding only in the MAPT carriers in selected frontal, temporal and subcortical regions. In summary, our findings demonstrate mild but significant binding of MK-6240 in amyloid-negative P301L and R406W MAPT mutation subjects, with higher standardized uptake value ratio in the R406W mutation associated with the presence of NFTs, and little non-specific binding. These results highlight that a positive 18F-MK-6240 tau-PET does not necessarily imply a diagnosis of Alzheimer's disease and point towards a potential use for 18F-MK-6240 as a biomarker in certain tauopathies beyond Alzheimer's, although further patient recruitment and autopsy studies will be necessary to determine clinical applicability.

Keywords: PET imaging; biomarkers; frontotemporal dementia.

Figure 1

18F-MK-6240 tau-PET scans in symptomatic MAPT mutation subjects. A higher SUVR represents stronger binding. Binding to meninges, including the tentorium cerebelli, is considered to be off-target. Scans are masked to minimize off-target binding to meninges. (A) A 71-year-old male with bvFTD due to P301L MAPT mutation, FTLD-CDR 2, MMSE 6/30. (B) A 67-year-old male with bvFTD due to P301L MAPT mutation, FTLD-CDR 2, MMSE 8/30. (C) A 60-year-old female with bvFTD due to R406W MAPT mutation, FTLD-CDR 1, MMSE 29/30.

Figure 2

¹⁸F-MK-6240 tau-PET scans in presymptomatic MAPT mutation subjects. A higher SUVR represents stronger binding. Binding to meninges, including the tentorium cerebelli, is considered to be off-target. Scans are masked to minimize off-target binding to meninges. (A) A 30-year-old male with asymptomatic P301L MAPT mutation, estimated years to onset (EYO) 30, MMSE 29/30. (B) A 57-year-old male with asymptomatic P301L MAPT mutation, EYO 1, MMSE 29/30. (C) A 52-year-old male with asymptomatic P301L MAPT mutation, EYO 5, MMSE 28/30.

Figure 3

¹⁸F-MK-6240 tau-PET scans in symptomatic non-tau mutation subjects. A higher SUVR represents stronger binding. Binding to meninges, including the tentorium cerebelli, is considered to be off-target. Scans are masked to minimize off-target binding to meninges. (A) A 51-year-old male with bvFTD/svPPA due to VCP mutation, FTLD-CDR 0.5, MMSE 23/25. (B) A 41-year-old male with bvFTD due to C9orf72 mutation, FTLD-CDR 0.5, MMSE 27/30. (C) A 44-year-old male with bvFTD due to C9orf72 mutation, FTLD-CDR 2, MMSE 12/30. (D) A 61-year-old male with bvFTD due to GRN mutation, FTLD-CDR 1, MMSE 19/30.

Figure 4

FTD versus cognitively normal model. Results of the general linear model. Left: RFT-corrected maps showing voxels with the greatest difference between FTD and cognitively normal (CN), focusing on the slices showing salient voxels for inferior temporal cortex (top), basal ganglia (middle) and medial orbitofrontal cortex (bottom). Right: Comparisons of SUVR distributions for the salient regions of interest (ROI) including right inferior temporal cortex (top), left putamen (middle) and left medial orbitofrontal cortex (bottom). The significance is shown as: *P < 0.05, **P < 0.01 (two-sample t-test).

Figure 5

Hippocampal Atrophy versus ¹⁸F-MK-6240 temporal meta-ROI SUVR. Hippocampal atrophy and its association with MK-6240 SUVR in the temporal meta-ROI for the studied FTD cases. The T₁-weighted MRI maps are shown both alone (top) and with MK-6240 SUVR overlaid (bottom) for (A) symptomatic MAPT, (B) non-tau mutation FTD and (C) asymptomatic MAPT cases. (D) Adjusted hippocampal volume plotted versus MK-6240 SUVR in the temporal meta-ROI for each FTD case in this study. Note the three symptomatic MAPT cases having the lowest hippocampal volume and the highest MK-6240 SUVR among all cases.