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

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DNA-Binding Proteins
Tauopathies
Neurofibrillary Tangles
Dementia
Alzheimer Disease
Synucleins
Pathology
Autoradiography
Neurodegenerative Diseases
Pick Disease of the Brain
Multiple System Atrophy
Lewy Body Disease
Frontotemporal Dementia
Choroid Plexus
Melanins
Parkinsonian Disorders
Substantia Nigra
Neuroimaging
Autopsy
Protein Isoforms

Keywords

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

ASJC Scopus subject areas

  • Medicine(all)

Cite this

@article{00007f2c636e4bfe8ba02a1ef186da99,
title = "An autoradiographic evaluation of AV-1451 Tau PET in dementia",
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.",
keywords = "Alzheimer's disease, Atypical alzheimer's disease, AV-1451, Corticobasal degeneration, Frontotemporal dementia, Pick disease, Pick's disease, Progressive supranuclear palsy, Tau, Tauopathy, TDP-43",
author = "Val Lowe and Geoffry Curran and Ping Fang and Liesinger, {Amanda M.} and Josephs, {Keith Anthony} and Parisi, {Joseph E} and Kantarci, {Kejal M} and Boeve, {Bradley F} and Mukesh Pandey and Tyler Bruinsma and Knopman, {David S} and Jones, {David T} and Leonard Petrucelli and Casey Cook and {Graff Radford}, {Neill R} and Dickson, {Dennis W} and Petersen, {Ronald Carl} and Jack, {Clifford R Jr.} and Murray, {Melissa E}",
year = "2016",
doi = "10.1186/s40478-016-0315-6",
language = "English (US)",
volume = "4",
journal = "Acta neuropathologica communications",
issn = "2051-5960",
publisher = "BioMed Central",
number = "1",

}

TY - JOUR

T1 - An autoradiographic evaluation of AV-1451 Tau PET in dementia

AU - Lowe, Val

AU - Curran, Geoffry

AU - Fang, Ping

AU - Liesinger, Amanda M.

AU - Josephs, Keith Anthony

AU - Parisi, Joseph E

AU - Kantarci, Kejal M

AU - Boeve, Bradley F

AU - Pandey, Mukesh

AU - Bruinsma, Tyler

AU - Knopman, David S

AU - Jones, David T

AU - Petrucelli, Leonard

AU - Cook, Casey

AU - Graff Radford, Neill R

AU - Dickson, Dennis W

AU - Petersen, Ronald Carl

AU - Jack, Clifford R Jr.

AU - Murray, Melissa E

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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.

KW - Alzheimer's disease

KW - Atypical alzheimer's disease

KW - AV-1451

KW - Corticobasal degeneration

KW - Frontotemporal dementia

KW - Pick disease

KW - Pick's disease

KW - Progressive supranuclear palsy

KW - Tau

KW - Tauopathy

KW - TDP-43

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U2 - 10.1186/s40478-016-0315-6

DO - 10.1186/s40478-016-0315-6

M3 - Article

C2 - 27296779

AN - SCOPUS:85007591207

VL - 4

JO - Acta neuropathologica communications

JF - Acta neuropathologica communications

SN - 2051-5960

IS - 1

M1 - 58

ER -