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

Abstract

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.

Increased basal ganglia binding of 18F‐AV‐1451 in patients with progressive supranuclear palsy

“…The ultrastructure of the inclusions in PSP are straight filaments in tufted astrocytes, coiled bodies, and globose tangle inclusions, mainly consisting of 4R tau, in contrast to the paired helical filament structure of aggregates in neurofibrillary tangles of 3R and 4R tau in AD 22, 23. The autoradiographic findings of the present study are in line with recently published results showing an absence of19, 20 or minimal24 specific binding of the tracer AV‐1451 to tau aggregates in cortical postmortem samples from PSP cases. The authors suggested that AV‐1451 binds stronger to the paired helical filaments of tau seen in AD compared to the predominantly straight tau filaments typical of PSP 19, 20, 24.…”

“…One study has shown increased retention of 18 F‐AV‐1451 in the basal ganglia in healthy controls18 despite the fact that there is no in vitro binding of the ligand in the same structures when using autoradiography 19, 20. Interestingly, in the present study some of the healthy controls, in addition to all of the PSP patients, exhibited increased retention of 18 F‐AV‐1451 in the basal ganglia.…”

[18F]AV‐1451 PET in behavioral variant frontotemporal dementia due to MAPT mutation

“…The distribution and magnitude of in vivo tau binding correlates with AD staging,5 and recapitulates the anatomical distribution of focal onset forms including logopenic aphasia 6 and posterior cortical atrophy 7. Binding to tau in primary, non‐AD tauopathies is less well established, with inconsistency between in vivo PET findings and post‐mortem analysis in progressive supranuclear palsy 3, 8, 9…”

“…There is strong evidence in vivo and post‐mortem that [ 18 F]AV‐1451 binds paired helical filaments of tau in Alzheimer's disease (AD) 3, 4. The distribution and magnitude of in vivo tau binding correlates with AD staging,5 and recapitulates the anatomical distribution of focal onset forms including logopenic aphasia 6 and posterior cortical atrophy 7.…”

Impact of tau and amyloid burden on glucose metabolism in Alzheimer's disease

“…With the advent of a novel PET tracer ([ 18 F]AV‐1451 aka T807) that shows high affinity to intracellular tau tangle pathology,5 it has now become possible to examine the potential interactive relationship between protein aggregation and neurodegeneration in vivo. Understanding the contribution of tau and A β pathology to neurodegeneration in AD will greatly advance our knowledge of disease mechanisms and could become paramount in identifying or evaluating therapeutic approaches.…”