Abstract
Importance: Tau positron emission tomography (PET) tracers have proven useful for the differential diagnosis of dementia, but their utility for predicting cognitive change is unclear. Objective: To examine the prognostic accuracy of baseline fluorine 18 ( 18F)-flortaucipir and [ 18F]RO948 (tau) PET in individuals across the Alzheimer disease (AD) clinical spectrum and to perform a head-to-head comparison against established magnetic resonance imaging (MRI) and amyloid PET markers. Design, Setting, and Participants: This prognostic study collected data from 8 cohorts in South Korea, Sweden, and the US from June 1, 2014, to February 28, 2021, with a mean (SD) follow-up of 1.9 (0.8) years. A total of 1431 participants were recruited from memory clinics, clinical trials, or cohort studies; 673 were cognitively unimpaired (CU group; 253 [37.6%] positive for amyloid-β [Aβ]), 443 had mild cognitive impairment (MCI group; 271 [61.2%] positive for Aβ), and 315 had a clinical diagnosis of AD dementia (315 [100%] positive for Aβ). Exposures: [ 18F]Flortaucipir PET in the discovery cohort (n = 1135) or [ 18F]RO948 PET in the replication cohort (n = 296), T1-weighted MRI (n = 1431), and amyloid PET (n = 1329) at baseline and repeated Mini-Mental State Examination (MMSE) evaluation. Main Outcomes and Measures: Baseline [ 18F]flortaucipir/[ 18F]RO948 PET retention within a temporal region of interest, MRI-based AD-signature cortical thickness, and amyloid PET Centiloids were used to predict changes in MMSE using linear mixed-effects models adjusted for age, sex, education, and cohort. Mediation/interaction analyses tested whether associations between baseline tau PET and cognitive change were mediated by baseline MRI measures and whether age, sex, and APOE genotype modified these associations. Results: Among 1431 participants, the mean (SD) age was 71.2 (8.8) years; 751 (52.5%) were male. Findings for [ 18F]flortaucipir PET predicted longitudinal changes in MMSE, and effect sizes were stronger than for AD-signature cortical thickness and amyloid PET across all participants (R 2, 0.35 [tau PET] vs 0.24 [MRI] vs 0.17 [amyloid PET]; P <.001, bootstrapped for difference) in the Aβ-positive MCI group (R 2, 0.25 [tau PET] vs 0.15 [MRI] vs 0.07 [amyloid PET]; P <.001, bootstrapped for difference) and in the Aβ-positive CU group (R 2, 0.16 [tau PET] vs 0.08 [MRI] vs 0.08 [amyloid PET]; P <.001, bootstrapped for difference). These findings were replicated in the [ 18F]RO948 PET cohort. MRI mediated the association between [ 18F]flortaucipir PET and MMSE in the groups with AD dementia (33.4% [95% CI, 15.5%-60.0%] of the total effect) and Aβ-positive MCI (13.6% [95% CI, 0.0%-28.0%] of the total effect), but not the Aβ-positive CU group (3.7% [95% CI, -17.5% to 39.0%]; P =.71). Age (t = -2.28; P =.02), but not sex (t = 0.92; P =.36) or APOE genotype (t = 1.06; P =.29) modified the association between baseline [ 18F]flortaucipir PET and cognitive change, such that older individuals showed faster cognitive decline at similar tau PET levels. Conclusions and Relevance: The findings of this prognostic study suggest that tau PET is a promising tool for predicting cognitive change that is superior to amyloid PET and MRI and may support the prognostic process in preclinical and prodromal stages of AD.
Original language | English |
---|---|
Pages (from-to) | 961-971 |
Number of pages | 11 |
Journal | JAMA Neurology |
Volume | 78 |
Issue number | 8 |
Early online date | 2021 |
DOIs | |
Publication status | Published - 1 Aug 2021 |
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In: JAMA Neurology, Vol. 78, No. 8, 01.08.2021, p. 961-971.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Accuracy of Tau Positron Emission Tomography as a Prognostic Marker in Preclinical and Prodromal Alzheimer Disease: A Head-to-Head Comparison against Amyloid Positron Emission Tomography and Magnetic Resonance Imaging
AU - Ossenkoppele, Rik
AU - Smith, Ruben
AU - Mattsson-Carlgren, Niklas
AU - Groot, Colin
AU - Leuzy, Antoine
AU - Strandberg, Olof
AU - Palmqvist, Sebastian
AU - Olsson, Tomas
AU - Jögi, Jonas
AU - Stormrud, Erik
AU - Cho, Hanna
AU - Ryu, Young Hoon
AU - Choi, Jae Yong
AU - Boxer, Adam L.
AU - Gorno-Tempini, Maria L.
AU - Miller, Bruce L.
AU - Soleimani-Meigooni, David
AU - Iaccarino, Leonardo
AU - la Joie, Renaud
AU - Baker, Suzanne
AU - Borroni, Edilio
AU - Klein, Gregory
AU - Pontecorvo, Michael J.
AU - Devous, Michael D.
AU - Jagust, William J.
AU - Lyoo, Chul Hyoung
AU - Rabinovici, Gil D.
AU - Hansson, Oskar
N1 - Funding Information: receiving research support from the National Institutes of Health (NIH), the Tau Research Consortium, the Association for Frontotemporal Degeneration, the Bluefield Project to Cure Frontotemporal Dementia, Avid Radiopharmaceuticals, Eisai Inc, Biogen Inc, and Roche and serving as a consultant for Applied Genetic Technologies Corporation, Alector, Inc, Arkuda Therapeutics, Arvinas, Inc, Bioage, Ionis Pharmaceuticals, Inc, H Lundbeck A/S, Passage Bio, Inc, Samumed, Ono Pharmaceutical Co, Ltd, Sangamo Therapeutics, Inc, Stealth BioTherapeutics Inc, Third Rock Ventures, Transposon Therapeutics, Inc, UCB, and Wave Life Sciences. Dr Pontecorvo reported being a minor stockholder in Eli Lilly and Company. Dr Devous reported being a minor stockholder in Eli Lilly and Company. Dr Rabinovici reported receiving research support from the NIH, Alzheimer’s Association, American College of Radiology, Avid Radiopharmaceuticals, GE Healthcare, and Life Molecular Imaging and receiving consulting fees from AXON Neuroscience, Eisai Inc, GE Healthcare, Johnson & Johnson, and Merck & Co, Inc, in the past 2 years. Dr Hansson reported acquiring research support (for the institution) from Avid Radiopharmaceuticals, Biogen Inc, Eli Lilly and Company, Eisai Inc, GE Healthcare, Pfizer Inc, and Roche and receiving consultancy/speaker fees from AC Immune, ALZpath, Biogen Inc, Cerveau Technologies, and Roche in the past 2 years. No other disclosures were reported. Funding/Support: This project was supported by grant agreement 949570 from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (principal investigator, Dr Ossenkoppele). Work at Lund University was supported by grant 2016-00906 from the Swedish Research Council, grant 2017-0383 from the Knut and Alice Wallenberg Foundation, grant 2015.0125 from the Marianne and Marcus Wallenberg Foundation, the Strategic Research Area MultiPark (Multidisciplinary Research in Parkinson’s Disease) at Lund University, grant AF-939932 from the Swedish Alzheimer Foundation, grant FO2019-0326 from the Swedish Brain Foundation, grant 1280/20 from the Parkinson Foundation of Sweden, grant 2020-O000028 from the Skåne University Hospital Foundation, grant 2020-0314 from Regionalt Forskningsstöd, and Medical Training and Research agreement 2018-Projekt0279 from the Swedish federal government. Work at University of California, San Francisco, was supported by grants P30-AG062422 (Drs Miller and Rabinovici), P01-AG019724 (Drs Miller and Rabinovici), R01-AG038791 (Dr Rabinovici), R01-NS050915 (Dr Gorno-Tempini), K99 AG065501 (Dr La Joie), and R01 AG045611 (Dr Rabinovici) from the NIH; grant AACSF-19-617663 from the Alzheimer’s Association (Dr Soleimani-Meigooni); and the Rainwater Charitable Foundation (Dr Rabinovici). The Tau PET study in Gangnam Severance Hospital was supported by a grant from Basic Science Research Program through the National Research Foundation of Korea funded by grants NRF2018R1D1A1B07049386 and NRF2020R1F1A1076154 from the Ministry of Education and a grant of the Korea Health Technology Research and Development Project through the Korea Health Industry Development Institute funded by grant HI18C1159 by the Ministry of Health and Welfare, Republic of Korea. Doses of [18F]flutemetamol injection were sponsored by GE Healthcare in the BioFINDER-1 study. The precursor of [18F]flutemetamol was sponsored by GE Healthcare in the BioFINDER-2 study. The precursor of [18F]flortaucipir was provided by Avid Radiopharmaceuticals. The precursor of [18F]RO948 was provided by Roche. Data collection and sharing for this project was funded by grant U01 AG024904 from the ADNI, NIH, and award W81XWH-12-2-0012 from the Department of Defense, ADNI. The ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from AbbVie, Alzheimer’s Association, Alzheimer’s Drug Discovery Foundation, Araclon Biotech, BioClinica, Biogen Inc, Bristol Myers Squibb Company, CereSpir, Inc, Cogstate, Eisai Inc, Elan Pharmaceuticals, Inc, Eli Lilly and Company, EUROIMMUN Medizinische Labordiagnostika AG, F. Hoffmann–La Roche Ltd and its affiliated company Genentech, Inc, Fujirebio, Inc, GE Healthcare, IXICO plc, Janssen Alzheimer Immunotherapy Research & Development, LLC, Johnson & Johnson Pharmaceutical Research & Development LLC, Lumosity, H Lundbeck A/S, Merck & Co, Inc, Meso Scale Diagnostics, LLC, NeuroRx Research Inc, Neurotrack Technologies, Inc, Novartis International AG, Pfizer Inc, Piramal Imaging, Servier Laboratories, Takeda Pharmaceutical Company Limited, and Transition Therapeutics, Inc. The Canadian Institutes of Health Research provided funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health. The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California. The ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. Publisher Copyright: © 2021 American Medical Association. All rights reserved. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/8/1
Y1 - 2021/8/1
N2 - Importance: Tau positron emission tomography (PET) tracers have proven useful for the differential diagnosis of dementia, but their utility for predicting cognitive change is unclear. Objective: To examine the prognostic accuracy of baseline fluorine 18 ( 18F)-flortaucipir and [ 18F]RO948 (tau) PET in individuals across the Alzheimer disease (AD) clinical spectrum and to perform a head-to-head comparison against established magnetic resonance imaging (MRI) and amyloid PET markers. Design, Setting, and Participants: This prognostic study collected data from 8 cohorts in South Korea, Sweden, and the US from June 1, 2014, to February 28, 2021, with a mean (SD) follow-up of 1.9 (0.8) years. A total of 1431 participants were recruited from memory clinics, clinical trials, or cohort studies; 673 were cognitively unimpaired (CU group; 253 [37.6%] positive for amyloid-β [Aβ]), 443 had mild cognitive impairment (MCI group; 271 [61.2%] positive for Aβ), and 315 had a clinical diagnosis of AD dementia (315 [100%] positive for Aβ). Exposures: [ 18F]Flortaucipir PET in the discovery cohort (n = 1135) or [ 18F]RO948 PET in the replication cohort (n = 296), T1-weighted MRI (n = 1431), and amyloid PET (n = 1329) at baseline and repeated Mini-Mental State Examination (MMSE) evaluation. Main Outcomes and Measures: Baseline [ 18F]flortaucipir/[ 18F]RO948 PET retention within a temporal region of interest, MRI-based AD-signature cortical thickness, and amyloid PET Centiloids were used to predict changes in MMSE using linear mixed-effects models adjusted for age, sex, education, and cohort. Mediation/interaction analyses tested whether associations between baseline tau PET and cognitive change were mediated by baseline MRI measures and whether age, sex, and APOE genotype modified these associations. Results: Among 1431 participants, the mean (SD) age was 71.2 (8.8) years; 751 (52.5%) were male. Findings for [ 18F]flortaucipir PET predicted longitudinal changes in MMSE, and effect sizes were stronger than for AD-signature cortical thickness and amyloid PET across all participants (R 2, 0.35 [tau PET] vs 0.24 [MRI] vs 0.17 [amyloid PET]; P <.001, bootstrapped for difference) in the Aβ-positive MCI group (R 2, 0.25 [tau PET] vs 0.15 [MRI] vs 0.07 [amyloid PET]; P <.001, bootstrapped for difference) and in the Aβ-positive CU group (R 2, 0.16 [tau PET] vs 0.08 [MRI] vs 0.08 [amyloid PET]; P <.001, bootstrapped for difference). These findings were replicated in the [ 18F]RO948 PET cohort. MRI mediated the association between [ 18F]flortaucipir PET and MMSE in the groups with AD dementia (33.4% [95% CI, 15.5%-60.0%] of the total effect) and Aβ-positive MCI (13.6% [95% CI, 0.0%-28.0%] of the total effect), but not the Aβ-positive CU group (3.7% [95% CI, -17.5% to 39.0%]; P =.71). Age (t = -2.28; P =.02), but not sex (t = 0.92; P =.36) or APOE genotype (t = 1.06; P =.29) modified the association between baseline [ 18F]flortaucipir PET and cognitive change, such that older individuals showed faster cognitive decline at similar tau PET levels. Conclusions and Relevance: The findings of this prognostic study suggest that tau PET is a promising tool for predicting cognitive change that is superior to amyloid PET and MRI and may support the prognostic process in preclinical and prodromal stages of AD.
AB - Importance: Tau positron emission tomography (PET) tracers have proven useful for the differential diagnosis of dementia, but their utility for predicting cognitive change is unclear. Objective: To examine the prognostic accuracy of baseline fluorine 18 ( 18F)-flortaucipir and [ 18F]RO948 (tau) PET in individuals across the Alzheimer disease (AD) clinical spectrum and to perform a head-to-head comparison against established magnetic resonance imaging (MRI) and amyloid PET markers. Design, Setting, and Participants: This prognostic study collected data from 8 cohorts in South Korea, Sweden, and the US from June 1, 2014, to February 28, 2021, with a mean (SD) follow-up of 1.9 (0.8) years. A total of 1431 participants were recruited from memory clinics, clinical trials, or cohort studies; 673 were cognitively unimpaired (CU group; 253 [37.6%] positive for amyloid-β [Aβ]), 443 had mild cognitive impairment (MCI group; 271 [61.2%] positive for Aβ), and 315 had a clinical diagnosis of AD dementia (315 [100%] positive for Aβ). Exposures: [ 18F]Flortaucipir PET in the discovery cohort (n = 1135) or [ 18F]RO948 PET in the replication cohort (n = 296), T1-weighted MRI (n = 1431), and amyloid PET (n = 1329) at baseline and repeated Mini-Mental State Examination (MMSE) evaluation. Main Outcomes and Measures: Baseline [ 18F]flortaucipir/[ 18F]RO948 PET retention within a temporal region of interest, MRI-based AD-signature cortical thickness, and amyloid PET Centiloids were used to predict changes in MMSE using linear mixed-effects models adjusted for age, sex, education, and cohort. Mediation/interaction analyses tested whether associations between baseline tau PET and cognitive change were mediated by baseline MRI measures and whether age, sex, and APOE genotype modified these associations. Results: Among 1431 participants, the mean (SD) age was 71.2 (8.8) years; 751 (52.5%) were male. Findings for [ 18F]flortaucipir PET predicted longitudinal changes in MMSE, and effect sizes were stronger than for AD-signature cortical thickness and amyloid PET across all participants (R 2, 0.35 [tau PET] vs 0.24 [MRI] vs 0.17 [amyloid PET]; P <.001, bootstrapped for difference) in the Aβ-positive MCI group (R 2, 0.25 [tau PET] vs 0.15 [MRI] vs 0.07 [amyloid PET]; P <.001, bootstrapped for difference) and in the Aβ-positive CU group (R 2, 0.16 [tau PET] vs 0.08 [MRI] vs 0.08 [amyloid PET]; P <.001, bootstrapped for difference). These findings were replicated in the [ 18F]RO948 PET cohort. MRI mediated the association between [ 18F]flortaucipir PET and MMSE in the groups with AD dementia (33.4% [95% CI, 15.5%-60.0%] of the total effect) and Aβ-positive MCI (13.6% [95% CI, 0.0%-28.0%] of the total effect), but not the Aβ-positive CU group (3.7% [95% CI, -17.5% to 39.0%]; P =.71). Age (t = -2.28; P =.02), but not sex (t = 0.92; P =.36) or APOE genotype (t = 1.06; P =.29) modified the association between baseline [ 18F]flortaucipir PET and cognitive change, such that older individuals showed faster cognitive decline at similar tau PET levels. Conclusions and Relevance: The findings of this prognostic study suggest that tau PET is a promising tool for predicting cognitive change that is superior to amyloid PET and MRI and may support the prognostic process in preclinical and prodromal stages of AD.
UR - http://www.scopus.com/inward/record.url?scp=85107270562&partnerID=8YFLogxK
U2 - https://doi.org/10.1001/jamaneurol.2021.1858
DO - https://doi.org/10.1001/jamaneurol.2021.1858
M3 - Article
C2 - 34180956
SN - 2168-6149
VL - 78
SP - 961
EP - 971
JO - JAMA Neurology
JF - JAMA Neurology
IS - 8
ER -