Development, initial validation, and application of a visual read method for [18F]MK-6240 tau PET

Abstract

Background: The positron emission tomography (PET) radiotracer [¹⁸F]MK-6240 exhibits high specificity for neurofibrillary tangles (NFTs) of tau protein in Alzheimer's disease (AD), high sensitivity to medial temporal and neocortical NFTs, and low within-brain background. Objectives were to develop and validate a reproducible, clinically relevant visual read method supporting [¹⁸F]MK-6240 use to identify and stage AD subjects versus non-AD and controls.

Methods: Five expert readers used their own methods to assess 30 scans of mixed diagnosis (47% cognitively normal, 23% mild cognitive impairment, 20% AD, 10% traumatic brain injury) and provided input regarding regional and global positivity, features influencing assessment, confidence, practicality, and clinical relevance. Inter-reader agreement and concordance with quantitative values were evaluated to confirm that regions could be read reliably. Guided by input regarding clinical applicability and practicality, read classifications were defined. The readers read the scans using the new classifications, establishing by majority agreement a gold standard read for those scans. Two naïve readers were trained and read the 30-scan set, providing initial validation. Inter-rater agreement was further tested by two trained independent readers in 131 scans. One of these readers used the same method to read a full, diverse database of 1842 scans; relationships between read classification, clinical diagnosis, and amyloid status as available were assessed.

Results: Four visual read classifications were determined: no uptake, medial temporal lobe (MTL) only, MTL and neocortical uptake, and uptake outside MTL. Inter-rater kappas were 1.0 for the naïve readers gold standard scans read and 0.98 for the independent readers 131-scan read. All scans in the full database could be classified; classification frequencies were concordant with NFT histopathology literature.

Discussion: This four-class [¹⁸F]MK-6240 visual read method captures the presence of medial temporal signal, neocortical expansion associated with disease progression, and atypical distributions that may reflect different phenotypes. The method demonstrates excellent trainability, reproducibility, and clinical relevance supporting clinical use.

Highlights: A visual read method has been developed for [¹⁸F]MK-6240 tau positron emission tomography.The method is readily trainable and reproducible, with inter-rater kappas of 0.98.The read method has been applied to a diverse set of 1842 [¹⁸F]MK-6240 scans.All scans from a spectrum of disease states and acquisitions could be classified.Read classifications are consistent with histopathological neurofibrillary tangle staging literature.

Keywords: Alzheimer's disease; MK‐6240; [18F]MK‐6240; florquinitau; neurofibrillary tangles; positron emission tomography; tau; tracer; visual read.

FIGURE 1

Process overview of visual read method development with expert reader input, development of a gold standard read set, initial validation based upon read of the gold standard set by two naïve readers, selection of 131 scans for reading by two independent trained readers to provide further testing, and application of the visual read method to the full database of 1842 [¹⁸F]MK‐6240 PET scans. MRI, magnetic resonance imaging; PET, positron emission tomography; SUVR, standardized uptake value ratio

FIGURE 2

Examples of the four read classifications of the [¹⁸F]MK‐6240 read method: (A) no uptake, (B) MTL only, (C) MTL And, and (D) outside MTL. Images are displayed as PET only at left, and superimposed and display‐thresholded on co‐registered, spatially normalized MRI scans at right. It can be seen that elevated uptake is apparent in both the displays of PET‐only and PET thresholded and superimposed on MRI underlay. Images were contrast adjusted to display the range of intensities from just above cerebellar cortex signal to high intensity. While these are not SUVR images, the approximate voxel range of elevated uptake values referenced to cerebellar cortex is from 1.35 to 5 in these images although higher values are observed depending on subject and scanner. MRI, magnetic resonance imaging; PET, positron emission tomography; SUVR, standardized uptake value ratio

FIGURE 3

(A,B) “MTL only” with (A) emerging perirhinal/entorhinal signal and (B) spread producing a sagittal “hook” appearance associated with Braak Stage III involvement of entorhinal cortex, hippocampus, and amygdala; (C–E) “MTL AND” with (C) right hemisphere spread into right lateral temporal cortex, (D) asymmetric right hemispheric widespread cortical deposition, and (E) bilateral widespread cortical accumulation. Images also show various display states of smoothed (A,B), unsmoothed (inverted gray C, D, E), inverted gray and color tables, PET‐only and thresholded and superimposed on MRI. Images are from five different participants. Images were contrast adjusted to display range from cerebellar cortex signal to high intensity; the overlay PET images were display thresholded to exclude cerebellar cortex signal levels. MRI, magnetic resonance imaging; PET, positron emission tomography

FIGURE 4

(A) Read classification distribution for full database; (B–D) read classifications for scans of participants with (B) reported amyloid negative (A–) or (C) amyloid positive (A+) status and clinical diagnoses of cognitively unimpaired (CU), mild cognitive impairment (MCI), and Alzheimer's dementia (AD), (D) clinical diagnosis of traumatic brain injury (TBI), amyloid negative and positive. *It is noted that six of eight participants with a clinical diagnosis of AD, negative amyloid status, and “MTL and” classification are from a single site