Pathological correlations of [F‐18]‐AV‐1451 imaging in non‐alzheimer tauopathies

Abstract

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.

18F‐flortaucipir tau positron emission tomography distinguishes established progressive supranuclear palsy from controls and Parkinson disease: A multicenter study

“…A study of two patients with PSP pathology (including one patient from our cohort) found co-localization of tau aggregates with in vivo PET signal, but no correlation between regional 18 F-flortaucipir uptake and the degree of tau pathology as measured by immunohistochemistry. 16,20 Additionally, two case reports in autopsy-confirmed CBD patients (including one clinical PSP patient from our cohort) found significant correlations between 18 F-flortaucipir uptake and tau pathological burden. 21,42 The CBD case that we presented here is consistent with these earlier reports, showing co-localization between in vivo 18 F-flortaucipir and postmortem tau pathology.…”

“…16–20 Across postmortem binding studies, 18 F-flortaucipir has been found to have high affinity for AD-type PHF tau. Results in PSP and CBD have differed in subtle but important ways: some studies reported no binding on autoradiography to 4-repeat, straight filamentous tau in PSP and CBD, 17,18 while others found low level binding in both conditions.…”

“…11–15 However, discrepancies have been noted between these positive in vivo results and in vitro autoradiography studies that showed high affinity binding of 18 F-flortaucipir to PHF tau but low affinity or no targeted binding to straight filamentous tau in PSP and CBD. 16–20 …”

“…Prior studies assessed PET-to-autopsy relations for two additional clinical PSP patients in our cohort. 20,21 …”

18F-Flortaucipir Binding in Choroid Plexus: Related to Race and Hippocampus Signal

“…In vivo and autoradiography studies suggest that FTP PET may be useful for detection of PHF-tau aggregates in AD; however, both have also identified other tracer binding substrates that appear not to be tau-related, so called “off-target” binding [7, 8, 10]. FTP PET signal is particularly prominent within the choroid plexus (CP) among a subset of individuals [5], but the substrate of this binding has not been established.…”