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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

Ossenkoppele, Rik ; Smith, Ruben ; Mattsson-Carlgren, Niklas LU orcid ; Groot, Colin ; Leuzy, Antoine ; Strandberg, Olof ; Palmqvist, Sebastian ; Olsson, Tomas LU ; Jögi, Jonas LU orcid and Stormrud, Erik , et al. (2021) In JAMA Neurology 78(8). p.961-971
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... (More)

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 (R2, 0.35 [tau PET] vs 0.24 [MRI] vs 0.17 [amyloid PET]; P <.001, bootstrapped for difference) in the Aβ-positive MCI group (R2, 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 (R2, 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.

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Contribution to journal
publication status
published
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JAMA Neurology
volume
78
issue
8
pages
11 pages
publisher
American Medical Association
external identifiers
  • scopus:85107270562
  • pmid:34180956
ISSN
2168-6149
DOI
10.1001/jamaneurol.2021.1858
language
English
LU publication?
yes
id
8e2b153c-6b47-4828-849f-4f0ca3d53ef8
date added to LUP
2021-12-08 14:45:04
date last changed
2024-04-20 18:15:40
@article{8e2b153c-6b47-4828-849f-4f0ca3d53ef8,
  abstract     = {{<p>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 (<sup>18</sup>F)-flortaucipir and [<sup>18</sup>F]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: [<sup>18</sup>F]Flortaucipir PET in the discovery cohort (n = 1135) or [<sup>18</sup>F]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 [<sup>18</sup>F]flortaucipir/[<sup>18</sup>F]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 [<sup>18</sup>F]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<sup>2</sup>, 0.35 [tau PET] vs 0.24 [MRI] vs 0.17 [amyloid PET]; P &lt;.001, bootstrapped for difference) in the Aβ-positive MCI group (R<sup>2</sup>, 0.25 [tau PET] vs 0.15 [MRI] vs 0.07 [amyloid PET]; P &lt;.001, bootstrapped for difference) and in the Aβ-positive CU group (R<sup>2</sup>, 0.16 [tau PET] vs 0.08 [MRI] vs 0.08 [amyloid PET]; P &lt;.001, bootstrapped for difference). These findings were replicated in the [<sup>18</sup>F]RO948 PET cohort. MRI mediated the association between [<sup>18</sup>F]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 [<sup>18</sup>F]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.</p>}},
  author       = {{Ossenkoppele, Rik and Smith, Ruben and Mattsson-Carlgren, Niklas and Groot, Colin and Leuzy, Antoine and Strandberg, Olof and Palmqvist, Sebastian and Olsson, Tomas and Jögi, Jonas and Stormrud, Erik and Cho, Hanna and Ryu, Young Hoon and Choi, Jae Yong and Boxer, Adam L. and Gorno-Tempini, Maria L. and Miller, Bruce L. and Soleimani-Meigooni, David and Iaccarino, Leonardo and La Joie, Renaud and Baker, Suzanne and Borroni, Edilio and Klein, Gregory and Pontecorvo, Michael J. and Devous, Michael D. and Jagust, William J. and Lyoo, Chul Hyoung and Rabinovici, Gil D. and Hansson, Oskar}},
  issn         = {{2168-6149}},
  language     = {{eng}},
  number       = {{8}},
  pages        = {{961--971}},
  publisher    = {{American Medical Association}},
  series       = {{JAMA Neurology}},
  title        = {{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}},
  url          = {{http://dx.doi.org/10.1001/jamaneurol.2021.1858}},
  doi          = {{10.1001/jamaneurol.2021.1858}},
  volume       = {{78}},
  year         = {{2021}},
}