Positron Emission Tomography Imaging With [18F]flortaucipir and Postmortem Assessment of Alzheimer Disease Neuropathologic Changes

Abstract

Importance: Positron emission tomography (PET) may increase the diagnostic accuracy and confirm the underlying neuropathologic changes of Alzheimer disease (AD).

Objective: To determine the accuracy of antemortem [18F]flortaucipir PET images for predicting the presence of AD-type tau pathology at autopsy.

Design, setting, and participants: This diagnostic study (A16 primary cohort) was conducted from October 2015 to June 2018 at 28 study sites (27 in US sites and 1 in Australia). Individuals with a terminal illness who were older than 50 years and had a projected life expectancy of less than 6 months were enrolled. All participants underwent [18F]flortaucipir PET imaging, and scans were interpreted by 5 independent nuclear medicine physicians or radiologists. Supplemental autopsy [18F]flortaucipir images and pathological samples were also collected from 16 historically collected cases. A second study (FR01 validation study) was conducted from March 26 to April 26, 2019, in which 5 new readers assessed the original PET images for comparison to autopsy.

Main outcomes and measures: [18F]flortaucipir PET images were visually assessed and compared with immunohistochemical tau pathology. An AD tau pattern of flortaucipir retention was assessed for correspondence with a postmortem B3-level (Braak stage V or VI) pathological pattern of tau accumulation and to the presence of amyloid-β plaques sufficient to meet the criteria for high levels of AD neuropathological change. Success was defined as having at least 3 of the 5 readers above the lower bounds of the 95% CI for both sensitivity and specificity of 50% or greater.

Results: A total of 156 patients were enrolled in the A16 study and underwent [18F]flortaucipir PET imaging. Of these, 73 died during the study, and valid autopsies were performed for 67 of these patients. Three autopsies were evaluated as test cases and removed from the primary cohort (n = 64). Of the 64 primary cohort patients, 34 (53%) were women and 62 (97%) were white; mean (SD) age was 82.5 (9.6) years; and 49 (77%) had dementia, 1 (2%) had mild cognitive impairment, and 14 (22%) had normal cognition. Prespecified success criteria were met for the A16 primary cohort. The flortaucipir PET scans predicted a B3 level of tau pathology, with sensitivity ranging from 92.3% (95% CI, 79.7%-97.3%) to 100.0% (95% CI, 91.0%-100.0%) and specificity ranging from 52.0% (95% CI, 33.5%-70.0%) to 92.0% (95% CI, 75.0%-97.8%). A high level of AD neuropathological change was predicted with sensitivity of 94.7% (95% CI, 82.7%-98.5%) to 100.0% (95% CI, 90.8%-100.0%) and specificity of 50.0% (95% CI, 32.1%-67.9%) to 92.3% (95% CI, 75.9%-97.9%). The FR01 validation study also met prespecified success criteria. Addition of the supplemental autopsy data set and 3 test cases, which comprised a total of 82 patients and autopsies for both the A16 and FR01 studies, resulted in improved specificity and comparable overall accuracy. Among the 156 enrolled participants, 14 (9%) experienced at least 1 treatment-emergent adverse event.

Conclusions and relevance: This study's findings suggest that PET imaging with [18F]flortaucipir could be used to identify the density and distribution of AD-type tau pathology and the presence of high levels of AD neuropathological change, supporting a neuropathological diagnosis of AD.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Fleisher reported being a full-time employee of Avid Radiopharmaceuticals and being a minor shareholder in Eli Lilly and Company. Dr Pontecorvo reported receiving other from Eli Lilly and Company and being a full-time employee of Avid Radiopharmaceuticals during the conduct of the study. Dr Devous reported being a full-time employee of Avid Radiopharmaceuticals during the conduct of the study. Dr Lu reported being a full-time employee of Avid Radiopharmaceuticals during the conduct of the study. Dr Arora reported being a full-time employee of Avid Radiopharmaceuticals during the conduct of the study. Mr Truocchio reported being a full-time employee of Avid Radiopharmaceuticals during the conduct of the study. Ms Aldea reported receiving other from Eli Lilly and Company during the conduct of the study. Mr Flitter reported receiving other from Eli Lilly and Company during the conduct of the study and being a full-time employee of Avid Radiopharmaceuticals. Ms Devine reported being a full-time employee of Avid Radiopharmaceuticals during the conduct of the study. Dr Siderowf reported receiving personal fees from Avid Radiopharmaceuticals during the conduct of the study and being a former employee of Avid Radiopharmaceuticals. Dr Beach reported receiving grants from Avid Radiopharmaceuticals during the conduct of the study and personal fees from Vivid Genomics and Prothena Biosciences, and holding stock options with Vivid Genomics. Dr Montine reported receiving personal fees and consulting fees from Avid Radiopharmaceuticals during the conduct of the study. Dr Serrano reported being a full-time employee of Avid Radiopharmaceuticals during the conduct of the study. Dr Perrin reported receiving other from Banner Alzheimer's Institute during the conduct of the study. Mr Joshi reported being a former employee of Avid Radiopharmaceuticals. Dr Irwin reported receiving grants from the National Institutes of Health (NIH) and from Avid Radiopharmaceuticals during the conduct of the study. Dr Lowe reported receiving nonfinancial support from Avid Radiopharmaceuticals, grants from GE Healthcare, and grants from Seimens Molecular Imaging outside the submitted work. Dr Ikonomovic reported receiving grants from the NIH during the conduct of the study. Dr Masdeu reported receiving grants from Eli Lilly and Company during the conduct of the study as well as grants and personal fees from GE Healthcare outside the submitted work. Mr Kennedy reported being a full-time employee of Avid Radiopharmaceuticals during the conduct of the study. Mr Harris reported being a full-time employee of Avid Radiopharmaceuticals during the conduct of the study. Dr Southekal reported being a full-time employee of Avid Radiopharmaceuticals during the conduct of the study and being an employee of and minor stockholder in Eli Lilly and Company. Dr Mintun reported being an employee of Eli Lilly and Company. No other disclosures were reported.

Figures

Figure 1.. Positron Emission Tomography With [18F]flortaucipir Visual Read Categories and Comparative Histologic Structure

Three cases representing the 3 levels of visual reads and corresponding histologic sections from the superior or middle temporal (sup/middle temp) gyrus (Braak region of interest [ROI] 7) and middle frontal gyrus (Braak ROI 6) stained for neurofibrillary tangles (NFTs) with AT8 antibodies and for amyloid plaque with 6E10 antibodies. Images presented in a blue-green-red-yellow color scale, with cortical counts scaled to 1.65 × the mean cerebellar counts (eAppendix in the Supplement). A indicates anterior; AD, Alzheimer disease; L, left; P, posterior; R, right.

Figure 2.. Braak Neurofibrillary Tangle (NFT) Scores vs Majority Read Interpretations for the A16 Primary Cohort (n = 64)

AD, Alzheimer disease; Advanced AD, consistent with advanced AD tau pattern; Moderate AD, consistent with moderate AD tau pattern; and Negative AD, not consistent with AD tau pattern.

Figure 3.. Consortium to Establish a Registry for Alzheimer Disease (CERAD) Amyloid Plaque Scores vs Braak Neurofibrillary Tangle (NFT) Scores

A16 primary cohort. CERAD amyloid plaque scores vs Braak NFT stages (highest score from both hemispheres), categorized by clinical diagnosis and flortaucipir majority visual read category. Data points were randomly scattered within each grid square to minimize overlap for presentation purposes. AD, Alzheimer disease; Adv, consistent with advanced AD tau pattern; CN, cognitively normal; MCI, mild cognitive impairment; Mod, consistent with moderate AD tau pattern; Negative, not consistent with AD tau pattern; and ODD, other non-AD dementia diagnoses. All PET image reads represent the majority read interpretation for each image.