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

Educational Objective
To determine the accuracy of antemorten [18F]flortaucipir PET images for predicting the presence of Alzheimer disease–type tau pathology at autopsy.
1 Credit CME
Key Points

Question  Do the findings of visual reads of [18F]flortaucipir positron emission tomography (PET) images correspond with postmortem assessment of Alzheimer disease tau and amyloid pathologies?

Findings  In this diagnostic study of 82 individuals with or without dementia, visual reads of [18F]flortaucipir PET scans corresponded with postmortem Braak stages V and VI levels of cortical neurofibrillary tangles and high levels of Alzheimer disease neuropathological change.

Meaning  Findings from this study suggest that visual reads of [18F]flortaucipir PET scans may accurately support a pathological diagnosis of Alzheimer disease.

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.

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Article Information

Accepted for Publication: January 10, 2020.

Published Online: April 27, 2020. doi:10.1001/jamaneurol.2020.0528

Open Access: This is an open access article distributed under the terms of the CC-BY-NC-ND License. © 2020 Fleisher AS et al. JAMA Neurology.

Corresponding Author: Adam S. Fleisher, MD, MAS, Avid Radiopharmaceuticals, 3711 Market St, Philadelphia, PA 19104 (afleisher@avidRP.com).

Author Contributions: Dr Fleisher had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Fleisher, Pontecorvo, Devous, Lu, Truocchio, Flitter, Siderowf, Beach, Seeley, Masdeu, Mintun.

Acquisition, analysis, or interpretation of data: Fleisher, Devous, Lu, Arora, Truocchio, Aldea, Flitter, Locascio, Devine, Siderowf, Beach, Montine, Serrano, Curtis, Perrin, Salloway, Daniel, Wellman, Joshi, Irwin, Lowe, Seeley, Ikonomovic, Masdeu, Kennedy, Harris, Navitsky, Southekal, Mintun.

Drafting of the manuscript: Fleisher, Pontecorvo, Devous, Lu, Aldea, Flitter, Salloway, Southekal.

Critical revision of the manuscript for important intellectual content: Fleisher, Pontecorvo, Devous, Lu, Arora, Truocchio, Aldea, Locascio, Devine, Siderowf, Beach, Montine, Serrano, Curtis, Perrin, Daniel, Wellman, Joshi, Irwin, Lowe, Seeley, Ikonomovic, Masdeu, Kennedy, Harris, Navitsky, Southekal, Mintun.

Statistical analysis: Lu.

Obtained funding: Lowe, Seeley, Ikonomovic, Mintun.

Administrative, technical, or material support: Fleisher, Pontecorvo, Arora, Truocchio, Aldea, Flitter, Locascio, Devine, Beach, Curtis, Perrin, Salloway, Daniel, Lowe, Ikonomovic, Masdeu, Harris, Navitsky, Southekal, Mintun.

Supervision: Fleisher, Pontecorvo, Devous, Aldea, Flitter, Devine, Siderowf, Beach, Montine, Seeley, Mintun.

Other—image analysis, data analysis: Joshi.

Other—Flortuacipir processing and analysis: Kennedy.

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.

Funding/Support: This study and the confirmatory reader study were funded by Avid Radiopharmaceuticals, a wholly owned subsidiary of Eli Lilly and Company, which owns a license to the patent of [18F]flortaucipir. The supplemental autopsy cases data were provided by the following academic collaborators with independently funded preexisting autopsy and imaging data: Drs Irwin and (Murray) Grossman (funded by NIH grants AG017586 and NIH AG054519); Dr Lowe (funded by NIH grants P50 AG016574, R01 NS89757, R01 NS089544, R01 DC10367, R01 AG011378, R01 AG041851, R01 AG034676, R01 AG054449, R01 NS097495, U01 AG006786, and R21 NS094489, as well as by the Robert Wood Johnson Foundation, The Elsie and Marvin Dekelboum Family Foundation, the Liston Family Foundation, the Robert H. and Clarice Smith and Abigail van Buren Alzheimer’s Disease Research Program, the Alexander Family Foundation, the GHR Foundation, Dr Corinne Schuler, and the Mayo Foundation for Medical Education and Research); Dr Seeley (funded by NIH grants P01AG019724 and P50AG023501 as well as by the Consortium for Frontotemporal Dementia Research and the Tau Consortium); Dr Ikonomovic (funded by NIH grants AG05133 and AG025204); and Dr Masdeu (funded by the Chao, Harrison, and Nantz Funds of the Houston Methodist Foundation).

Role of the Funder/Sponsor: The main funder, Avid Radiopharmaceuticals, had a role in the design and conduct of this study and the confirmatory reader study; collection, management, analysis, and interpretation of the data; preparation, review, and approval of the manuscript; and decision to submit the manuscript for publication. Avid Radiopharmaceuticals had no role in the original acquisition of the supplemental autopsy cases data, which were acquired, managed, and funded through independent collaborator protocols before transfer to Avid Radiopharmaceuticals.

Group Information: A16 Study Investigators: Murray Grossman, MD, EdD, University of Pennsylvania; Marc E. Agronin, MD, Miami Jewish Health; Alireza Atri, MD, PhD, Banner Sun Health Research Institute; Donald M. Brandon, MD, California Research Foundation; Richard S. Cherlin, MD, private practice; Robert C. Cupelo, MD, Clarity Clinical Research; Dagoberto de la Vega, MD, D de la Vega MD Research Group; Jamehl Demons Shegog, MD, Wake Forest School of Medicine; Kimiko Domoto-Reilly, MD, Memory and Brain Wellness Center, University of Washington; P. Murali Doraiswamy, MD, MBBS, Duke University School of Medicine; John G. Duffy, MD, MS, Syrentis Clinical Research; Jose E. Gamez, MD, BS, Galiz Research; Andrew W. Garner MD, Adirondack Medical Research Center; Allen J. Geltzer, MD, Radiant Clinical Research; William T. Hu, MD, PhD, Emory University School of Medicine; Cathy A. Hurley, MD, Sante Clinical Research; Gregory A. Kirk, MD, Merritt Island Medical Research, LLC; Colin L. Masters, MD, MBBS, The Florey Institute of Neuroscience and Mental Health; Anil K. Nair, MD, Alzheimer's Disease Center; Esteban Olivera, MD, MS, Bioclinica Research (formerly Compass Research); Jorg J. Pahl, MD, American Clinical Trials; Meenakshi C. Patel, MD, Valley Medical Research; Marvin L. Peyton, MD, Rivus Wellness and Research Institute; Frederick W. Schaerf, MD, PhD, Neuropsychiatric Research Center of Southwest Florida; William R. Shankle, MD, MS, The Shankle Clinic; Jiong Shi, MD, PhD, St Joseph's Hospital and Medical Center; Upinder Singh, MD, MBBS, Geriatric Solutions, LLC; Kaycee M. Sink, MD, MAS, Wake Forest School of Medicine; Stephen G. Thein; PhD, MA, Pacific Research Network, Inc.

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