Objective To examine region and substrate-specific autoradiographic and in vitro binding patterns of PET 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’s disease, frontotemporal lobar degeneration-tau, frontotemporal lobar degeneration-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 AV-1451 strongly binds to tau lesions primarily made of paired helical filaments in Alzheimer’s brains e.g. intra 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 β-amyloid, α-synuclein or TDP-43-containing lesions. 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 AV-1451 holds promise as surrogate marker for the detection of brain tau pathology in the form of tangles and paired helical filament-tau-containing neurites in Alzheimer’s 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 AV-1451 off-target binding. These findings provide important insights for interpreting in vivo patterns of [F-18]-AV-1451 retention.

Tau pathology is known to spread in a hierarchical pattern in Alzheimer’s disease (AD) brain during disease progression, likely by trans-synaptic tau transfer between neurons. However, the tau species involved in inter-neuron propagation remains unclear. To identify tau species responsible for propagation, we examined uptake and propagation properties of different tau species derived from postmortem cortical extracts and brain interstitial fluid of tau-transgenic mice, as well as human AD cortices. Here we show that PBS-soluble phosphorylated high-molecular-weight (HMW) tau, though very low in abundance, is taken up, axonally transported, and passed on to synaptically connected neurons. Our findings suggest that a rare species of soluble phosphorylated HMW tau is the endogenous form of tau involved in propagation and could be a target for therapeutic intervention and biomarker development.

Objective Recent studies have shown that PET tracer AV-1451 exhibits high binding affinity for paired helical filament (PHF)-tau pathology in Alzheimer’s brains. However, the ability of this ligand to bind to tau lesions in other tauopathies remains controversial. Our goal was to examine the correlation of in vivo and postmortem AV-1451 binding patterns in three autopsy-confirmed non-Alzheimer tauopathy cases. Methods We quantified in vivo retention of [F-18]-AV-1451 and performed autoradiography, [H-3]-AV-1451 binding assays and quantitative tau measurements in postmortem brain samples from two Progressive Supranuclear Palsy (PSP) cases and a MAPT P301L mutation carrier. They all underwent [F-18]-AV-1451 PET imaging prior to death. Results The three subjects exhibited [F-18]-AV-1451 in vivo retention predominantly in basal ganglia and midbrain. Neuropathologic examination confirmed the PSP diagnosis in the first two subjects; the MAPT P301L mutation carrier had an atypical tauopathy characterized by grain-like tau-containing neurites in grey and white matter with heaviest burden in basal ganglia. In all three cases, autoradiography failed to show detectable [F-18]-AV-1451 binding in multiple brain regions examined with the exception of entorhinal cortex (reflecting incidental age-related neurofibrillary tangles) and neuromelanin-containing neurons in the substantia nigra (off-target binding). The lack of a consistent significant correlation between in vivo [F-18]-AV-1541 retention and postmortem in vitro binding and tau measures in these cases suggests that this ligand has low affinity for tau lesions primarily made of straight tau filaments. Interpretation AV-1451 may have limited utility for in vivo selective and reliable detection of tau aggregates in these non-Alzheimer tauopathies.