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

Tau is one of several proteins associated with frontotemporal dementia (FTD). While knowing which protein is causing a patient's disease is crucial, no biomarker currently exists for identifying tau in vivo in FTD. The objective of this study was to investigate the potential for the promising [18F]MK-6240 positron emission tomography (PET) tracer to bind to tau in vivo in genetic FTD. We enrolled subjects with genetic FTD, 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 magnetic resonance imaging (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-NFTs). Two asymptomatic MAPT carriers estimated to be five years from disease onset both showed modest [18F]MK-6240 binding, while one approximately thirty years from disease onset did not exhibit any binding. Additionally, four individuals with symptomatic FTD 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 ten amyloid-PET scans were negative. Furthermore, a general linear model contrasting genetic FTD 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 SUVR 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.