TY - JOUR
T1 - Positron Emission Tomography Imaging with [18F]flortaucipir and Postmortem Assessment of Alzheimer Disease Neuropathologic Changes
AU - Fleisher, Adam S.
AU - Pontecorvo, Michael J.
AU - Devous, Michael D.
AU - Lu, Ming
AU - Arora, Anupa K.
AU - Truocchio, Stephen P.
AU - Aldea, Patricia
AU - Flitter, Matthew
AU - Locascio, Tricia
AU - Devine, Marybeth
AU - Siderowf, Andrew
AU - Beach, Thomas G.
AU - Montine, Thomas J.
AU - Serrano, Geidy E.
AU - Curtis, Craig
AU - Perrin, Allison
AU - Salloway, Stephen
AU - Daniel, Misty
AU - Wellman, Charles
AU - Joshi, Abhinay D.
AU - Irwin, David J.
AU - Lowe, Val J.
AU - Seeley, William W.
AU - Ikonomovic, Milos D.
AU - Masdeu, Joseph C.
AU - Kennedy, Ian
AU - Harris, Thomas
AU - Navitsky, Michael
AU - Southekal, Sudeepti
AU - Mintun, Mark A.
N1 - Funding Information:
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).
Funding Information:
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
Publisher Copyright:
© 2020 American Medical Association. All rights reserved.
PY - 2020/7/1
Y1 - 2020/7/1
N2 - 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.
AB - 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.
KW - Aged
KW - Aged, 80 and over
KW - Alzheimer Disease/diagnostic imaging
KW - Amyloid beta-Peptides/metabolism
KW - Autopsy
KW - Brain/diagnostic imaging
KW - Carbolines
KW - Contrast Media
KW - Female
KW - Humans
KW - Male
KW - Neurofibrillary Tangles/pathology
KW - Neuroimaging/methods
KW - Plaque, Amyloid/diagnostic imaging
KW - Positron-Emission Tomography/methods
KW - Radiopharmaceuticals
KW - Sensitivity and Specificity
KW - tau Proteins/metabolism
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U2 - 10.1001/jamaneurol.2020.0528
DO - 10.1001/jamaneurol.2020.0528
M3 - Article
C2 - 32338734
AN - SCOPUS:85084128805
SN - 2168-6149
VL - 77
SP - 829
EP - 839
JO - JAMA Neurology
JF - JAMA Neurology
IS - 7
ER -