Regional profiles of the candidate tau PET ligand¹⁸F-AV-1451 recapitulate key features of Braak histopathological stages

Abstract

SEE THAL AND VANDENBERGHE DOI101093/BRAIN/AWW057 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Post-mortem Braak staging of neurofibrillary tau tangle topographical distribution is one of the core neuropathological criteria for the diagnosis of Alzheimer's disease. The recent development of positron emission tomography tracers targeting neurofibrillary tangles has enabled the distribution of tau pathology to be imaged in living subjects. Methods for extraction of classic Braak staging from in vivo imaging of neurofibrillary tau tangles have not yet been explored. Standardized uptake value ratio images were calculated from 80-100 minute (18)F-AV-1451 (also known as T807) positron emission tomography scans obtained from n = 14 young reference subjects (age 21-39 years, Mini-Mental State Examination 29-30) and n = 173 older test subjects (age 50-95 years) comprising amyloid negative cognitively normal (n = 42), clinically-diagnosed mild cognitive impairment (amyloid positive, n = 47, and amyloid negative, n = 40) and Alzheimer's disease (amyloid positive, n = 28, and amyloid negative, n = 16). We defined seven regions of interest in anterior temporal lobe and occipital lobe sections corresponding closely to those used as decision points in Braak staging. An algorithm based on the Braak histological staging procedure was applied to estimate Braak stages directly from the region of interest profiles in each subject. Quantitative region-based analysis of (18)F-AV-1451 images yielded region of interest and voxel level profiles that mirrored key features of neuropathological tau progression including profiles consistent with Braak stages 0 through VI. A simple set of decision rules enabled plausible Braak stages corresponding to stereotypical progression patterns to be objectively estimated in 149 (86%) of test subjects. An additional 12 (7%) subjects presented with predefined variant profiles (relative sparing of the hippocampus and/or occipital lobe). The estimated Braak stage was significantly associated with amyloid status, diagnostic category and measures of global cognition. In vivo (18)F-AV-1451 positron emission tomography images across the Alzheimer's disease spectrum could be classified into patterns similar to those prescribed by Braak neuropathological staging of tau pathology.

[18F]AV‐1451 binding is increased in frontotemporal dementia due to C9orf72 expansion

“…In vivo studies have confirmed elevated and distributed binding in keeping with typical and atypical presentations of Alzheimer's disease,2, 3 consistent with Braak staging 4. Binding characteristics in neurodegenerative diseases other than Alzheimer's disease are controversial.…”

Longitudinal changes of tau PET imaging in relation to hypometabolism in prodromal and Alzheimer’s disease dementia

“…[28][29][30] In this study, we used [ 18 F] THK5317 PET imaging in a longitudinal, multimodal design to investigate in vivo the propagation of tau pathology in a cohort of patients with AD and cases with CBS, in relation to markers of glucose metabolism and cognitive performance.…”

[18F]AV‐1451 PET in behavioral variant frontotemporal dementia due to MAPT mutation

“…The distribution and magnitude of in vivo tau binding correlates with AD staging,5 and recapitulates the anatomical distribution of focal onset forms including logopenic aphasia 6 and posterior cortical atrophy 7. Binding to tau in primary, non‐AD tauopathies is less well established, with inconsistency between in vivo PET findings and post‐mortem analysis in progressive supranuclear palsy 3, 8, 9…”