18F-flortaucipir PET to autopsy comparisons in Alzheimer's disease and other neurodegenerative diseases

Abstract

Few studies have evaluated the relationship between in vivo18F-flortaucipir PET and post-mortem pathology. We sought to compare antemortem 18F-flortaucipir PET to neuropathology in a consecutive series of patients with a broad spectrum of neurodegenerative conditions. Twenty patients were included [mean age at PET 61 years (range 34-76); eight female; median PET-to-autopsy interval of 30 months (range 4-59 months)]. Eight patients had primary Alzheimer's disease pathology, nine had non-Alzheimer tauopathies (progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, and frontotemporal lobar degeneration with MAPT mutations), and three had non-tau frontotemporal lobar degeneration. Using an inferior cerebellar grey matter reference, 80-100-min 18F-flortaucipir PET standardized uptake value ratio (SUVR) images were created. Mean SUVRs were calculated for progressive supranuclear palsy, corticobasal degeneration, and neurofibrillary tangle Braak stage regions of interest, and these values were compared to SUVRs derived from young, non-autopsy, cognitively normal controls used as a standard for tau negativity. W-score maps were generated to highlight areas of increased tracer retention compared to cognitively normal controls, adjusting for age as a covariate. Autopsies were performed blinded to PET results. There was excellent correspondence between areas of 18F-flortaucipir retention, on both SUVR images and W-score maps, and neurofibrillary tangle distribution in patients with primary Alzheimer's disease neuropathology. Patients with non-Alzheimer tauopathies and non-tau frontotemporal lobar degeneration showed a range of tracer retention that was less than Alzheimer's disease, though higher than age-matched, cognitively normal controls. Overall, binding across both tau-positive and tau-negative non-Alzheimer disorders did not reliably correspond with post-mortem tau pathology. 18F-flortaucipir SUVRs in subcortical regions were higher in autopsy-confirmed progressive supranuclear palsy and corticobasal degeneration than in controls, but were similar to values measured in Alzheimer's disease and tau-negative neurodegenerative pathologies. Quantification of 18F-flortaucipir SUVR images at Braak stage regions of interest reliably detected advanced Alzheimer's (Braak VI) pathology. However, patients with earlier Braak stages (Braak I-IV) did not show elevated tracer uptake in these regions compared to young, tau-negative controls. In summary, PET-to-autopsy comparisons confirm that 18F-flortaucipir PET is a reliable biomarker of advanced Braak tau pathology in Alzheimer's disease. The tracer cannot reliably differentiate non-Alzheimer tauopathies and may not detect early Braak stages of neurofibrillary tangle pathology.

Trial registration: ClinicalTrials.gov NCT03040713.

Keywords: Alzheimer’s disease; neurofibrillary tangle; neuropathology; positron emission tomography; tau.

© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Figures

Figure 1

FTP-PET SUVR and W-score map images. (A) Example SUVR and W-map images are shown for patients with primary Alzheimer’s disease (AD) neuropathological diagnosis. One patient had a typical amnestic clinical phenotype and the other patient had an atypical posterior cortical atrophy (PCA) phenotype. Patients with primary Alzheimer’s disease pathology had marked FTP uptake, and high SUVR and W-map thresholds were chosen to highlight the full range of tracer retention in these patients. Images for all Alzheimer’s disease patients are shown in Supplementary Fig. 1. (B) Example SUVR and W-map images are shown for patients with primary autopsy diagnoses of non-Alzheimer tauopathies, FTLD-TDP, and FTLD-FUS. These patients had lower FTP uptake than patients with primary Alzheimer’s disease autopsy diagnosis, and lower SUVR and W-map thresholds needed to be used to highlight the areas of tracer retention in these patients. To allow for comparison with the Alzheimer’s disease cases, the W-map upper threshold (W > 3.10) is the same as the lower threshold used in patients with primary Alzheimer’s disease pathology. Images for all patients with non-Alzheimer’s autopsy diagnoses are shown in Supplementary Fig. 2.

Figure 2

Comparison of FTP-PET SUVR images to tau immunohistochemistry in Alzheimer’s disease. SUVR images are shown for two patients with autopsy diagnoses of Alzheimer’s disease. Both patients were assigned antemortem clinical diagnoses of Alzheimer’s disease, but one patient had a typical amnestic phenotype and the other patient had an atypical posterior cortical atrophy (PCA) phenotype. CA1, calcarine cortex, and middle frontal gyrus are indicated on each patient’s SUVR images (arrows), and the corresponding tau (CP-13 antibody) immunohistochemistry is shown. Scale bars = 250 µm in the CA1 micrographs and 25 µm in the other micrographs.

Figure 3

Comparison of FTP-PET SUVR images with tau immunohistochemistry in PSP. SUVR images are shown for two patients with autopsy diagnoses of PSP. The cerebellar dentate nucleus, globus pallidus, and motor cortex are indicated on each patient’s SUVR images (arrows), and the corresponding tau (CP-13 antibody) immunohistochemistry is shown. Superior frontal gyrus is also shown for one of the patients. Scale bars = 25 µm.

Figure 4

Comparison of FTP-PET SUVR images with tau immunohistochemistry in patient with FTLD-tau due to MAPT S305I mutation. The cerebellar dentate nucleus, entorhinal cortex, globus pallidus, inferior frontal gyrus, middle frontal gyrus (cortex and white matter), and motor cortex are indicated on the patient’s SUVR images (arrows), and the corresponding tau (CP-13 antibody) immunohistochemistry is shown. Scale bars = 10 µm.

Figure 5

Comparison of FTP-PET SUVR images with tau and TDP-43 immunohistochemistry in a patient with FTLD TDP-43 type A due to GRN (NM_002087: c.708 + 6_708 + 9del) mutation. The left middle frontal gyrus is indicated on the patient’s SUVR image (arrow). Left middle frontal gyrus tau immunohistochemistry (CP-13 antibody, haematoxylin counterstain, left) was negative, whereas TDP-43 immunohistochemistry (pan-TDP-43 antibody, right) showed short, thin neurites, crescentic neuronal cytoplasmic inclusions, and other typical features of FTLD-TDP type A, consistent with the patient’s known mutation in GRN. Scale bars = 500 µm and 100 µm for the tau and TDP-43 immunohistochemistry micrographs, respectively.

Figure 6

FTP-PET SUVR quantification at precentral gryus, postcentral gyrus, and subcortical regions of interest. SUVR quantification, not corrected for partial volume effects, was performed at precentral gyrus, postcentral gyrus, putamen, globus pallidus, subthalamic nucleus, substantia nigra, and dentate nucleus regions of interest. Each patient is represented by a single point and coded by time from PET-to-autopsy (shape) and primary neuropathological diagnosis (x-axis). The dotted line represents the threshold for significance, which is calculated from the mean SUVR plus two standard deviations for the young, cognitively normal (CN), non-autopsy controls. Points crossing the significance threshold are highlighted with a black outline. AD = Alzheimer’s disease; AGD = argyrophilic grain disease.

Figure 7

FTP-PET SUVR quantification of Braak stage regions of interest. SUVR quantification, not corrected for partial volume effects, was performed at entorhinal cortex (Braak I), Braak III/IV, and Braak V/VI regions of interest. Each patient is represented by a single point and coded by their primary autopsy diagnosis (colour), time from PET-to-autopsy (shape), and Braak neurofibrillary tangle stage (x-axis). The dotted line represents the threshold for significance, which is calculated from the mean SUVR plus two standard deviations for the young, cognitively normal (CN), non-autopsy controls. Points crossing the significance threshold are highlighted with a black outline.