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

Journal Article · Mon Jun 28 00:00:00 EDT 2021 · JAMA Neurology

DOI:https://doi.org/10.1001/jamaneurol.2021.1858· OSTI ID:1815926

Ossenkoppele, Rik ^[1]; Smith, Ruben ^[2]; Mattsson-Carlgren, Niklas ^[3]; Groot, Colin ^[4]; Leuzy, Antoine ^[2]; Strandberg, Olof ^[2]; Palmqvist, Sebastian ^[2]; Olsson, Tomas ^[5]; Jögi, Jonas ^[6]; Stormrud, Erik ^[7]; Cho, Hanna ^[8]; Ryu, Young Hoon ^[9]; Choi, Jae Yong ^[10]; Boxer, Adam L. ^[11]; Gorno-Tempini, Maria L. ^[11]; Miller, Bruce L. ^[11]; Soleimani-Meigooni, David ^[11]; Iaccarino, Leonardo ^[11]; La Joie, Renaud ^[11]; Baker, Suzanne ^[12] ; Borroni, Edilio ^[13]; Klein, Gregory ^[13]; Pontecorvo, Michael J. ^[14]; Devous, Michael D. ^[14]; Jagust, William J. ^[15]; Lyoo, Chul Hyoung ^[16]; Rabinovici, Gil D. ^[17]; Hansson, Oskar ^[7]

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1. Lund Univ. (Sweden). Clinical Memory Research Unit; Vrije Univ., Amsterdam (Netherlands). Amsterdam University Medical Center. Dept. of Neurology. Alzheimer Center Amsterdam
2. Lund Univ. (Sweden). Clinical Memory Research Unit
3. Lund Univ. (Sweden). Clinical Memory Research Unit; Skåne Univ. Hospital, Lund (Sweden). Dept. of Neurology; Lund Univ. (Sweden). Wallenberg Centre for Molecular Medicine
4. Vrije Univ., Amsterdam (Netherlands). Amsterdam University Medical Center. Dept. of Neurology. Alzheimer Center Amsterdam
5. Skåne Univ. Hospital, Lund (Sweden). Dept. of Radiation Physics
6. Skåne Univ. Hospital, Lund (Sweden). Dept. of Clinical Physiology and Nuclear Medicine
7. Lund Univ. (Sweden). Clinical Memory Research Unit; Skåne University Hospital, Malmö (Sweden). Memory Clinic
8. Yonsei Univ., Seoul (Korea, Republic of). College of Medicine. Gangnam Severance Hospital. Dept. of Neurology
9. Yonsei Univ., Seoul (Korea, Republic of). College of Medicine. Gangnam Severance Hospital. Dept. of Nuclear Medicine
10. Yonsei Univ., Seoul (Korea, Republic of). College of Medicine. Gangnam Severance Hospital. Dept. of Nuclear Medicine; Korea Inst. Radiological and Medical Sciences, Seoul (Korea, Republic of). Division of Applied Radiological Imaging
11. Univ. of California, San Francisco, CA (United States). Dept. of Neurology, Memory and Aging Center
12. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
13. F. Hoffmann–La Roche Ltd, Basel (Switzerland)
14. Avid Radiopharmaceuticals, Philadelphia, PA (United States)
15. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Univ. of California, Berkeley, CA (United States). Helen Wills Neuroscience Inst.
16. Yonsei Univ., Seoul (Korea, Republic of). College of Medicine. Gangnam Severance Hospital. Dept. of Neurology
17. Univ. of California, San Francisco, CA (United States). Dept. of Neurology, Memory and Aging Center; Univ. of California, San Francisco, CA (United States). Dept. of Radiology and Biomedical Imaging; Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Molecular Biophysics and Integrated Bioimaging Division; Associate Editor, JAMA Neurology

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.

• Sponsoring Organization: USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division
• Grant/Contract Number: AC02-05CH11231
• OSTI ID: 1815926
• Journal Information: JAMA Neurology, Vol. 78, Issue 8; ISSN 2168-6149
• Publisher: American Medical Association
• Country of Publication: United States
• Language: English

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