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



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.



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.



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.
Department of Radiology, Mayo Clinic, Rochester, MN, USA. vlowe@mayo.edu.
Val J
VJ
Lowe
Department of Radiology, Mayo Clinic, Rochester, MN, USA.
Geoffry
G
Curran
Department of Radiology, Mayo Clinic, Rochester, MN, USA.
Ping
P
Fang
Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
Amanda M
AM
Liesinger
Department of Neurology, Mayo Clinic, Rochester, MN, USA.
Keith A
KA
Josephs
Department of Neurology, Mayo Clinic, Rochester, MN, USA.|Department of Anatomic Pathology, Mayo Clinic, Rochester, MN, USA.
Joseph E
JE
Parisi
Department of Radiology, Mayo Clinic, Rochester, MN, USA.
Kejal
K
Kantarci
Department of Neurology, Mayo Clinic, Rochester, MN, USA.
Bradley F
BF
Boeve
Department of Radiology, Mayo Clinic, Rochester, MN, USA.
Mukesh K
MK
Pandey
Department of Radiology, Mayo Clinic, Rochester, MN, USA.
Tyler
T
Bruinsma
Department of Neurology, Mayo Clinic, Rochester, MN, USA.
David S
DS
Knopman
Department of Neurology, Mayo Clinic, Rochester, MN, USA.
David T
DT
Jones
Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
Leonard
L
Petrucelli
Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
Casey N
CN
Cook
Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA.
Neill R
NR
Graff-Radford
Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
Dennis W
DW
Dickson
Department of Neurology, Mayo Clinic, Rochester, MN, USA.
Ronald C
RC
Petersen
Department of Radiology, Mayo Clinic, Rochester, MN, USA.
Clifford R
CR
Jack
Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
Melissa E
ME
Murray
D000368:Aged; D000369:Aged, 80 and over; D001345:Autoradiography; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D002243:Carbolines / Q000138:chemical synthesis; D004268:DNA-Binding Proteins / Q000378:metabolism; D003704:Dementia / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D019636:Neurodegenerative Diseases / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D049268:Positron-Emission Tomography; D020033:Protein Isoforms; D019275:Radiopharmaceuticals / Q000138:chemical synthesis; D016875:tau Proteins / Q000378:metabolism*
D002243:Carbolines; D004268:DNA-Binding Proteins; C054369:MAPT protein, human; D020033:Protein Isoforms; D019275:Radiopharmaceuticals; C000598624:TARDBP protein, human; D016875:tau Proteins; C000591008:7-(6-fluoropyridin-3-yl)-5H-pyrido(4,3-b)indole
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