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.

In vivo rate-determining steps of tau seed accumulation in Alzheimer’s disease

“…We used the TAU PET 18 F-flortaucipir (FTP) signal, given as standardized uptake value ratio (SUVr) and normalized to cerebral white matter, from 80 to 100 min (38). The data used are partial volume-corrected SUVr values of 101 individuals [4 diagnosed AD, 7 with mild cognitive impairment, 27 A-positive cognitively normal, and 63 A-negative cognitively normal; for definitions of these classes, see Sanchez et al (24)]. Further experimental details and information on how the region-specific SUVr values were determined can be found in the study of Sanchez et al (24).…”

Local Functional MR Change Pattern and Its Association With Cognitive Function in Objectively-Defined Subtle Cognitive Decline

“…Recent studies have shown that the temporal lobe is one of the critical areas of pathological changes in multiple types of dementia (Mak et al, 2020;Sanchez et al, 2021). In preclinical AD, tau protein deposition and Aβ burden in the inferior temporal gyrus is related to cognitive performance, mainly memory function (Schultz et al, 2018;Norton et al, 2020;Scott et al, 2020;Vila-Castelar et al, 2020).…”

MicroRNAs as Potential Orchestrators of Alzheimer's Disease-Related Pathologies: Insights on Current Status and Future Possibilities

“…Tau pathology begins focally but expands catastrophically under the influence of Aβ pathology to mediate neurodegeneration and cognitive decline. Subsequent Tau elevation in the temporal neocortex is associated with age, Aβ, and APOE status (Sanchez et al, 2021 ). This indicates a loss of connection between the nerve cells, or neurons, in the brain.…”