Accuracy of Tau Positron Emission Tomography as a Prognostic Marker in Preclinical and Prodromal Alzheimer Disease

Rik Ossenkoppele,Jae Yong Choi,Sebastian Palmqvist,Bruce L Miller,Tomas Olsson,Colin Groot,Gregory Klein,Michael D Devous,David N Soleimani‐Meigooni ,Leonardo Iaccarino,Chul Hyoung Lyoo,William J Jagust,Renaud La Joie,Niklas Mattsson‐Carlgren ,Adam L Boxer,Olof Strandberg,Ruben Smith,Gil D Rabinovici,Maria Luisa Gorno‐Tempini ,Edilio Borroni,Jonas Jögi,Antoine Leuzy,Erik Stormrud,Hanna Cho,Michael J Pontecorvo,Young Hoon Ryu,Suzanne L Baker ,Oskar Hansson

doi:10.1001/jamaneurol.2021.1858

Abstract

Tau positron emission tomography (PET) tracers have proven useful for the differential diagnosis of dementia, but their utility for predicting cognitive change is unclear. 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. 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). [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. 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. 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. 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.

Highlights

magnetic resonance imaging (MRI) mediated the association between [18F]flortaucipir positron emission tomography (PET) and Mini-Mental State Examination (MMSE) in the groups with Alzheimer disease (AD) dementia (33.4% [95% CI, 15.5%-60.0%] of the total effect) and Aβ-positive mild cognitive impairment (MCI) (13.6% [95% CI, 0.0%-28.0%] of the total effect), but not the Aβ-positive cognitively unimpaired (CU) group (3.7% [95% CI, −17.5% to 39.0%]; P = .71)
A n accurate prognosis for individuals with Alzheimer disease (AD) is essential for patients and families to plan for the future, reduce uncertainty, increase safety, and optimize medical decision-making.[1]
Given the strong links between tau pathology and key correlates of cognition observed in vitro and at autopsy,[4,5] in vivo information about the magnitude of cerebral tau pathology might improve the prediction of future cognitive decline

Summary

Methods

Participants From an ongoing multicenter study,[18,28,29,30] we included 1431 participants from the Memory Disorder Clinic of Gangnam Severance Hospital, Seoul, South Korea (n = 161); the Swedish BioFINDER-1 (n = 136) and BioFINDER-2 (n = 296) studies at Lund University, Lund, Sweden; University of California, San Francisco (UCSF [n = 44]); the Alzheimer Disease Neuroimaging Initiative (ADNI [n = 445]) Avid Radiopharmaceuticals studies (A05 [n = 160]) and the placebo arm of the Eli Lilly solanezumab Expedition-3 study [n = 79]); and the Berkeley Aging Cohort Study (BACS [n = 110]). Data were collected from June 1, 2014, to February 28, 2021. Tau PET was performed using [18F]flortaucipir-PET in the discovery cohort (1135 [79.3%] of the total sample) and [18F]RO948-PET in the replication cohort (296 [20.7%] of the total sample from BioFINDER-2).

Results

Discussion

Conclusion