期刊
ACTA NEUROPATHOLOGICA COMMUNICATIONS
卷 4, 期 -, 页码 -出版社
BMC
DOI: 10.1186/s40478-016-0315-6
关键词
AV-1451; Tau; Alzheimer's disease; TDP-43; Pick Disease; Corticobasal degeneration; Progressive supranuclear palsy; Tauopathy; Pick's disease; Atypical Alzheimer's disease; Frontotemporal dementia
资金
- NIH [P50 AG016574, P50-NS072187, R01 NS89757, R01 NS089544, R01 DC10367, U01 AG006786, R21 NS094489]
- Robert Wood Johnson Foundation
- Elsie and Marvin Dekelboum Family Foundation
- Liston Family Foundation
- Robert H. and Clarice Smith and Abigail van Buren Alzheimer's Disease Research Program
- CurePSP
- Mangurian Foundation Lewy Body Dementia Program
- Bright Focus Foundation
- GHR Foundation
- Gerstner Family Career Development Award
- Donors Cure Foundation New Visions Award
- Mayo Foundation
Background: It is essential to determine the specificity of AV-1451 PET for tau in brain imaging by using pathological comparisons. We performed autoradiography in autopsy-confirmed Alzheimer disease and other neurodegenerative disorders to evaluate the specificity of AV-1451 binding for tau aggregates. Methods: Tissue samples were selected that had a variety of dementia-related neuropathologies including Alzheimer disease, primary age-related tauopathy, tangle predominant dementia, non-Alzheimer disease tauopathies, frontotemporal dementia, parkinsonism, Lewy body disease and multiple system atrophy (n = 38). Brain tissue sections were stained for tau, TAR DNA-binding protein-43, and alpha-synuclein and compared to AV-1451 autoradiography on adjacent sections. Results: AV-1451 preferentially localized to neurofibrillary tangles, with less binding to areas enriched in neuritic pathology and less mature tau. The strength of AV-1451 binding with respect to tau isoforms in various neurodegenerative disorders was: 3R + 4R tau (e.g., AD) > 3R tau (e.g., Pick disease) or 4R tau. Only minimal binding of AV-1451 to TAR DNA-binding protein-43 positive regions was detected. No binding of AV-1451 to a-synuclein was detected. Off-target binding was seen in vessels, iron-associated regions, substantia nigra, calcifications in the choroid plexus, and leptomeningeal melanin. Conclusions: Reduced AV-1451 binding in neuritic pathology compared to neurofibrillary tangles suggests that the maturity of tau pathology may affect AV-1451 binding and suggests complexity in AV-1451 binding. Poor association of AV-1451 with tauopathies that have preferential accumulation of either 4R tau or 3R tau suggests limited clinical utility in detecting these pathologies. In contrast, for disorders associated with 3R + 4R tau, such as Alzheimer disease, AV-1451 binds tau avidly but does not completely reflect the early stage tau progression suggested by Braak neurofibrillary tangle staging. AV-1451 binding to TAR DNA-binding protein-43 or TAR DNA-binding protein-43 positive regions can be weakly positive. Clinical use of AV-1451 will require a familiarity with distinct types of off-target binding.
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