2. Academic Validation
  3. Validating novel tau positron emission tomography tracer [F-18]-AV-1451 (T807) on postmortem brain tissue

Validating novel tau positron emission tomography tracer [F-18]-AV-1451 (T807) on postmortem brain tissue

  • Ann Neurol. 2015 Nov;78(5):787-800. doi: 10.1002/ana.24517.
Marta Marquié 1 2 3,  Marc D Normandin 4,  Charles R Vanderburg 1 2 5,  Isabel M Costantino 1 2,  Elizabeth A Bien 1 2 5,  Lisa G Rycyna 1 2 5,  William E Klunk 6,  Chester A Mathis 7,  Milos D Ikonomovic 8 9,  Manik L Debnath 6,  Neil Vasdev 4,  Bradford C Dickerson 2,  Stephen N Gomperts 1 2,  John H Growdon 2,  Keith A Johnson 2,  Matthew P Frosch 1 2 10,  Bradley T Hyman 1 2 5,  Teresa Gómez-Isla 1 2
Affiliations

Affiliations

  • 1 MassGeneral Institute for Neurodegenerative Disease, Charlestown, MA.
  • 2 Department of Neurology, Massachusetts General Hospital, Boston, MA.
  • 3 Autonomous University of Barcelona, Medicine Doctoral Studies, Barcelona, Spain.
  • 4 Center for Advanced Medical Imaging Sciences, Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
  • 5 Harvard NeuroDiscovery Center, Harvard Medical School, Boston, MA.
  • 6 Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA.
  • 7 Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA.
  • 8 Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA.
  • 9 Geriatric Research Education and Clinical Center, Veterans Administration Pittsburgh Clinical System, Pittsburgh, PA.
  • 10 C. S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital, Boston, MA.
PMID: 26344059 DOI: 10.1002/ana.24517
Abstract

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.

Interpretation: 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.

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