Validating novel tau positron emission tomography tracer [F-18]-AV-1451 (T807) on postmortem brain tissue.
OBJECTIVE
To examine region- and substrate-specific autoradiographic and in vitro binding patterns of positron emission tomography tracer [F-18]-AV-1451 (previously known as T807), tailored to allow in vivo detection of paired helical filament-tau-containing lesions, and to determine whether there is off-target binding to other amyloid/non-amyloid proteins.


METHODS
We applied [F-18]-AV-1451 phosphor screen autoradiography, [F-18]-AV-1451 nuclear emulsion autoradiography, and [H-3]-AV-1451 in vitro binding assays to the study of postmortem samples from patients with a definite pathological diagnosis of Alzheimer disease, frontotemporal lobar degeneration-tau, frontotemporal lobar degeneration-transactive response DNA binding protein 43 (TDP-43), progressive supranuclear palsy, corticobasal degeneration, dementia with Lewy bodies, multiple system atrophy, cerebral amyloid angiopathy and elderly controls free of pathology.


RESULTS
Our data suggest that [F-18]-AV-1451 strongly binds to tau lesions primarily made of paired helical filaments in Alzheimer brains (eg, intraneuronal and extraneuronal tangles and dystrophic neurites), but does not seem to bind to a significant extent to neuronal and glial inclusions mainly composed of straight tau filaments in non-Alzheimer tauopathy brains or to lesions containing β-amyloid, α-synuclein, or TDP-43. [F-18]-AV-1451 off-target binding to neuromelanin- and melanin-containing cells and, to a lesser extent, to brain hemorrhagic lesions was identified.


CONCLUSIONS
Our data suggest that [F-18]-AV-1451 holds promise as a surrogate marker for the detection of brain tau pathology in the form of tangles and paired helical filament-tau-containing neurites in Alzheimer brains but also point to its relatively lower affinity for lesions primarily made of straight tau filaments in non-Alzheimer tauopathy cases and to the existence of some [F-18]-AV-1451 off-target binding. These findings provide important insights for interpreting in vivo patterns of [F-18]-AV-1451 retention.
MassGeneral Institute for Neurodegenerative Disease, Charlestown, MA.|Department of Neurology, Massachusetts General Hospital, Boston, MA.|Autonomous University of Barcelona, Medicine Doctoral Studies, Barcelona, Spain.
Marta
M
Marquié
Center for Advanced Medical Imaging Sciences, Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
Marc D
MD
Normandin
MassGeneral Institute for Neurodegenerative Disease, Charlestown, MA.|Department of Neurology, Massachusetts General Hospital, Boston, MA.|Harvard NeuroDiscovery Center, Harvard Medical School, Boston, MA.
Charles R
CR
Vanderburg
MassGeneral Institute for Neurodegenerative Disease, Charlestown, MA.|Department of Neurology, Massachusetts General Hospital, Boston, MA.
Isabel M
IM
Costantino
MassGeneral Institute for Neurodegenerative Disease, Charlestown, MA.|Department of Neurology, Massachusetts General Hospital, Boston, MA.|Harvard NeuroDiscovery Center, Harvard Medical School, Boston, MA.
Elizabeth A
EA
Bien
MassGeneral Institute for Neurodegenerative Disease, Charlestown, MA.|Department of Neurology, Massachusetts General Hospital, Boston, MA.|Harvard NeuroDiscovery Center, Harvard Medical School, Boston, MA.
Lisa G
LG
Rycyna
Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA.
William E
WE
Klunk
Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA.
Chester A
CA
Mathis
Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA.|Geriatric Research Education and Clinical Center, Veterans Administration Pittsburgh Clinical System, Pittsburgh, PA.
Milos D
MD
Ikonomovic
Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA.
Manik L
ML
Debnath
Center for Advanced Medical Imaging Sciences, Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
Neil
N
Vasdev
Department of Neurology, Massachusetts General Hospital, Boston, MA.
Bradford C
BC
Dickerson
MassGeneral Institute for Neurodegenerative Disease, Charlestown, MA.|Department of Neurology, Massachusetts General Hospital, Boston, MA.
Stephen N
SN
Gomperts
Department of Neurology, Massachusetts General Hospital, Boston, MA.
John H
JH
Growdon
Department of Neurology, Massachusetts General Hospital, Boston, MA.
Keith A
KA
Johnson
MassGeneral Institute for Neurodegenerative Disease, Charlestown, MA.|Department of Neurology, Massachusetts General Hospital, Boston, MA.|C. S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital, Boston, MA.
Matthew P
MP
Frosch
MassGeneral Institute for Neurodegenerative Disease, Charlestown, MA.|Department of Neurology, Massachusetts General Hospital, Boston, MA.|Harvard NeuroDiscovery Center, Harvard Medical School, Boston, MA.
Bradley T
BT
Hyman
MassGeneral Institute for Neurodegenerative Disease, Charlestown, MA.|Department of Neurology, Massachusetts General Hospital, Boston, MA.
Teresa
T
Gómez-Isla
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000000981:diagnostic imaging; D000682:Amyloid / Q000378:metabolism; D001345:Autoradiography; D001921:Brain / Q000000981:diagnostic imaging*; D002102:Cadaver; D002243:Carbolines; D003704:Dementia / Q000000981:diagnostic imaging; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000000981:diagnostic imaging; D006801:Humans; D002479:Inclusion Bodies / Q000000981:diagnostic imaging; D020300:Intracranial Hemorrhages / Q000000981:diagnostic imaging; D008297:Male; D008875:Middle Aged; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D057177:TDP-43 Proteinopathies / Q000000981:diagnostic imaging; D024801:Tauopathies / Q000000981:diagnostic imaging*; D016875:tau Proteins / Q000378:metabolism*
D000682:Amyloid; D002243:Carbolines; D019275:Radiopharmaceuticals; D016875:tau Proteins; C000591008:7-(6-fluoropyridin-3-yl)-5H-pyrido(4,3-b)indole