Tau PET Imaging With [18F]MK-6240: Limited Affinity for Primary Tauopathies and High Specificity for Alzheimer's Disease

Abstract

Introduction: Second-generation tau-PET tracers like [¹⁸F]MK-6240 are increasingly used both for diagnosing and quantifying Alzheimer's Disease (AD) tauopathy. However, while [¹⁸F]MK-6240 tau-PET has demonstrated excellent sensitivity for AD tauopathy, data assessing its specificity and binding in non-AD tauopathies are still scarce.

Methods: Participants were assigned to exclusive categorical diagnoses based on their amyloid (Aβ) and cognitive status. We quantified mesiotemporal (MTL) and neocortical [¹⁸F]MK-6240 tau-PET signal in 28 Aβ- cognitively impaired (CI) patients presenting various non-AD neurodegenerative disorders. Tau-PET quantifications were compared with Aβ- cognitively unimpaired (CU) subjects (n = 51) and Aβ+ CI patients (n = 77).

Results: Among the 28 Aβ- impaired subjects, only five presented significant and isolated mesiotemporal signal, most of them being suspected of primary age-related tauopathy (PART). Only two Aβ- impaired patients (7%) presented positive neocortical signal, both being diagnosed with fronto-temporal degeneration (FTD). The Tau-PET results of all the remaining Aβ- patients were comparable to the CU population, including eight other FTD patients. Importantly, 4R-only tauopathies (CBD and PSP) and sv-PPA were negative.

Conclusion: [¹⁸F]MK-6240 tau-PET has a special affinity for tauopathies involving 3R/4R paired helical filaments: AD, PART (Aβ- subjects with MTL-restricted tau-PET signal) and some forms of FTD while most primary tauopathies do not exhibit significant cortical signal. Positive neocortical scans are therefore highly specific for AD tauopathy. Based on those and previous results, we propose a diagnostic flowchart for MCI subjects suspected of AD or another tauopathy which may significantly reduce the need for amyloid PET or CSF measurement.

Keywords: Alzheimer's disease; MK‐6240; Tau PET; neurodegenerative diseases; tauopathy.

FIGURE 1

Distribution of the participants in the different bioclinical categorical groups.

FIGURE 2

Graphic of EOT values in regions Braak ≤ 2 and Braak ≤ 6 for the different diagnostic groups (and subgroups for the Aβ− impaired subjects). Positivity cutoff is displayed as a dotted line. Demented subjects are displayed as ★. Groups are compared with Kruskal–Wallis test and Dunn's multiple comparison. Significant results are displayed. EOT, extent of tauopathy (in %). Braak ≤ 2: region corresponding to the mesiotemporal lobe. Braak ≤ 6: region corresponding to the whole neocortex and some gray nuclei. Aβ− uMCI, amyloid negative undefined MCI; Aβ, amyloid; CBD, corticobasal degeneration; CN, cognitively normal; FTLD, frontotemporal lobar degeneration; PSP, progressive supranuclear palsy.

FIGURE 3

ROC curves calculating the diagnostic performances of [¹⁸F]MK‐6240 to distinguish amyloid positive from amyloid negative subjects among a cognitively impaired population. EOT, extent of tauopathy (in %). Braak ≤ 2: region corresponding to the mesiotemporal lobe. Braak ≤ 6: region corresponding to the whole neocortex and some gray nuclei. Aβ, amyloid; AUC, area under the curve; Sn, sensitivity; Sp, specificity.

FIGURE 4

Graph presenting the relation between the global cognitive Z‐score and extent of tauopathy (EOT) in the regions Braak ≤ 2 and Braak ≤ 6 in the amyloid negative (Aβ−) population (Cognitively normal and cognitively impaired). Simple linear regression and Spearman's correlation results are displayed. Braak ≤ 2: region corresponding to the mesiotemporal lobe. Braak ≤ 6: region corresponding to the whole neocortex and some gray nuclei.

FIGURE 5

[¹⁸F]MK‐6240 PET‐MR fused images of five etiologically undefined mild cognitively impaired amyloid negative subjects (Aβ− uMCI). Aβ− uMCI 13 is suspected of early Alzheimer's disease and the remaining four are suspected of Primary age‐related tauopathy (PART). Quantitative [¹⁸F]MK‐6240 PET data, cognitive tests results, Amyloid PET, and CSF results are displayed. Braak ≤ 2: Region corresponding to the mesiotemporal lobe. Braak ≤ 6: Region corresponding to the whole neocortex and some gray nuclei. CSF, cerebrospinal fluid; MMSE, mini‐mental score examination.

FIGURE 6

[¹⁸F]MK‐6240 PET‐MR fused images of the two (out of nine) subjects diagnosed with frontotemporal dementia (FTD) and presenting significant neocortical signal. Quantitative [¹⁸F]MK‐6240 PET data, cognitive tests results, Amyloid PET, and CSF results are displayed. Braak ≤ 2: Region corresponding to the mesiotemporal lobe. Braak ≤ 6: Region corresponding to the whole neocortex and some gray nuclei. CSF, cerebrospinal fluid; MMSE, mini‐mental score examination.

FIGURE 7

Diagnostic flowchart for MCI patient suspected of Alzheimer's disease (AD). EOT, extent of tauopathy (in %). Braak ≤ 2: Region corresponding to the mesiotemporal lobe. Braak ≤ 6: Region corresponding to the whole neocortex and some gray nuclei. PART, primary age‐related tauopathy.