Dataset Information

The cortical origin and initial spread of medial temporal tauopathy in Alzheimer's disease assessed with positron emission tomography.

ABSTRACT: Advances in molecular positron emission tomography (PET) have enabled anatomic tracking of brain pathology in longitudinal studies of normal aging and dementia, including assessment of the central model of Alzheimer's disease (AD) pathogenesis, according to which TAU pathology begins focally but expands catastrophically under the influence of amyloid-β (Aβ) pathology to mediate neurodegeneration and cognitive decline. Initial TAU deposition occurs many years before Aβ in a specific area of the medial temporal lobe. Building on recent work that enabled focus of molecular PET measurements on specific TAU-vulnerable convolutional temporal lobe anatomy, we applied an automated anatomic sampling method to quantify TAU PET signal in 443 adult participants from several observational studies of aging and AD, spanning a wide range of ages, Aβ burdens, and degrees of clinical impairment. We detected initial cortical emergence of tauopathy near the rhinal sulcus in clinically normal people and, in a subset with longitudinal 2-year follow-up data (n = 104), tracked Aβ-associated spread of TAU from this site first to nearby neocortex of the temporal lobe and then to extratemporal regions. Greater rate of TAU spread was associated with baseline measures of both global Aβ burden and medial temporal lobe TAU. These findings are consistent with clinicopathological correlation studies of Alzheimer's tauopathy and enable precise tracking of AD-related TAU progression for natural history studies and prevention therapeutic trials.

SUBMITTER: Sanchez JS

PROVIDER: S-EPMC7978042 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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The cortical origin and initial spread of medial temporal tauopathy in Alzheimer's disease assessed with positron emission tomography.

Sanchez Justin S JS Becker J Alex JA Jacobs Heidi I L HIL Hanseeuw Bernard J BJ Jiang Shu S Schultz Aaron P AP Properzi Michael J MJ Katz Samantha R SR Beiser Alexa A Satizabal Claudia L CL O'Donnell Adrienne A DeCarli Charles C Killiany Ron R El Fakhri Georges G Normandin Marc D MD Gómez-Isla Teresa T Quiroz Yakeel T YT Rentz Dorene M DM Sperling Reisa A RA Seshadri Sudha S Augustinack Jean J Price Julie C JC Johnson Keith A KA

Science translational medicine 20210101 577

Advances in molecular positron emission tomography (PET) have enabled anatomic tracking of brain pathology in longitudinal studies of normal aging and dementia, including assessment of the central model of Alzheimer's disease (AD) pathogenesis, according to which TAU pathology begins focally but expands catastrophically under the influence of amyloid-β (Aβ) pathology to mediate neurodegeneration and cognitive decline. Initial TAU deposition occurs many years before Aβ in a specific area of the m ...[more]

PMID: 33472953

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Project description:ImportanceCharacterization of early tau deposition in individuals with preclinical Alzheimer disease (AD) is critical for prevention trials that aim to select individuals at risk for AD and halt the progression of disease.ObjectiveTo evaluate the prevalence of cortical tau positron emission tomography (PET) heterogeneity in a large cohort of clinically unimpaired older adults with elevated β-amyloid (A+).Design, setting, and participantsThis cross-sectional study examined prerandomized tau PET, amyloid PET, structural magnetic resonance imaging, demographic, and cognitive data from the Anti-Amyloid Treatment in Asymptomatic AD (A4) Study from April 2014 to December 2017. Follow-up analyses used observational tau PET data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), the Harvard Aging Brain Study (HABS), and the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center (together hereinafter referred to as Wisconsin) to evaluate consistency. Participants were clinically unimpaired at the study visit closest to the tau PET scan and had available amyloid and tau PET data (A4 Study, n = 447; ADNI, n = 433; HABS, n = 190; and Wisconsin, n = 328). No participants who met eligibility criteria were excluded. Data were analyzed from May 11, 2021, to January 25, 2022.Main outcomes and measuresIndividuals with preclinical AD with heterogeneous cortical tau PET patterns (A+T cortical+) were identified by examining asymmetrical cortical tau signal and disproportionate cortical tau signal relative to medial temporal lobe (MTL) tau. Voxelwise tau patterns, amyloid, neurodegeneration, cognition, and demographic characteristics were examined.ResultsThe 447 A4 participants (A+ group, 392; and normal β-amyloid group, 55), with a mean (SD) age of 71.8 (4.8) years, included 239 women (54%). A total of 36 individuals in the A+ group (9% of the A+ group) exhibited heterogeneous cortical tau patterns and were further categorized into 3 subtypes: asymmetrical left, precuneus dominant, and asymmetrical right. A total of 116 individuals in the A+ group (30% of the A+ group) showed elevated MTL tau (A+T MTL+). Individuals in the A+T cortical+ group were younger than those in the A+T MTL+ group (t61.867 = -2.597; P = .03). Across the A+T cortical+ and A+T MTL+ groups, increased regional tau was associated with reduced hippocampal volume and MTL thickness but not with cortical thickness. Memory scores were comparable between the A+T cortical+ and A+T MTL+ groups, whereas executive functioning scores were lower for the A+T cortical+ group than for the A+T MTL+ group. The prevalence of the A+T cortical+ group and tau patterns within the A+T cortical+ group were consistent in ADNI, HABS, and Wisconsin.Conclusions and relevanceThis study suggests that early tau deposition may follow multiple trajectories during preclinical AD and may involve several cortical regions. Staging procedures, especially those based on neuropathology, that assume a uniform trajectory across individuals are insufficient for disease monitoring with tau imaging.

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Dataset Information

The cortical origin and initial spread of medial temporal tauopathy in Alzheimer's disease assessed with positron emission tomography.

Publications

The cortical origin and initial spread of medial temporal tauopathy in Alzheimer's disease assessed with positron emission tomography.

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