An autoradiographic evaluation of AV-1451 Tau PET in dementia

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Abstract

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 α-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 α-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.

Original languageEnglish (US)
Article number58
JournalActa Neuropathologica Communications
Volume4
Issue number1
DOIs
StatePublished - 2016

Keywords

  • AV-1451
  • Alzheimer's disease
  • Atypical alzheimer's disease
  • Corticobasal degeneration
  • Frontotemporal dementia
  • Pick disease
  • Pick's disease
  • Progressive supranuclear palsy
  • TDP-43
  • Tau
  • Tauopathy

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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