Lessons learned about [F-18]-AV-1451 off-target binding from an autopsy-confirmed Parkinson’s case

Abstract

[F-18]-AV-1451 is a novel positron emission tomography (PET) tracer with high affinity to neurofibrillary tau pathology in Alzheimer’s disease (AD). PET studies have shown increased tracer retention in patients clinically diagnosed with dementia of AD type and mild cognitive impairment in regions that are known to contain tau lesions. In vivo uptake has also consistently been observed in midbrain, basal ganglia and choroid plexus in elderly individuals regardless of their clinical diagnosis, including clinically normal whose brains are not expected to harbor tau pathology in those areas. We and others have shown that [F-18]-AV-1451 exhibits off-target binding to neuromelanin, melanin and blood products on postmortem material; and this is important for the correct interpretation of PET images. In the present study, we further investigated [F-18]-AV-1451 off-target binding in the first autopsy-confirmed Parkinson’s disease (PD) subject who underwent antemortem PET imaging. The PET scan showed elevated [F-18]-AV-1451 retention predominantly in inferior temporal cortex, basal ganglia, midbrain and choroid plexus. Neuropathologic examination confirmed the PD diagnosis. Phosphor screen and high resolution autoradiography failed to show detectable [F-18]-AV-1451 binding in multiple brain regions examined with the exception of neuromelanin-containing neurons in the substantia nigra, leptomeningeal melanocytes adjacent to ventricles and midbrain, and microhemorrhages in the occipital cortex (all reflecting off-target binding), in addition to incidental age-related neurofibrillary tangles in the entorhinal cortex. Additional legacy postmortem brain samples containing basal ganglia, choroid plexus, and parenchymal hemorrhages from 20 subjects with various neuropathologic diagnoses were also included in the autoradiography experiments to better understand what [F-18]-AV-1451 in vivo positivity in those regions means. No detectable [F-18]-AV-1451 autoradiographic binding was present in the basal ganglia of the PD case or any of the other subjects. Off-target binding in postmortem choroid plexus samples was only observed in subjects harboring leptomeningeal melanocytes within the choroidal stroma. Off-target binding to parenchymal hemorrhages was noticed in postmortem material from subjects with cerebral amyloid angiopathy. The imaging-postmortem correlation analysis in this PD case reinforces the notion that [F-18]-AV-1451 has strong affinity for neurofibrillary tau pathology but also exhibits off-target binding to neuromelanin, melanin and blood components. The robust off-target in vivo retention in basal ganglia and choroid plexus, in the absence of tau deposits, meningeal melanocytes or any other identifiable binding substrate by autoradiography in the PD case reported here, also suggests that the PET signal in those regions may be influenced, at least in part, by biological or technical factors that occur in vivo and are not captured by autoradiography.

Tau‐positron emission tomography correlates with neuropathology findings

“…They concluded that FTP‐PET has limited utility for in vivo selective and reliable detection of tau aggregates in these non‐Alzheimer tauopathies. The imaging‐postmortem correlation analysis in a Parkinson's disease case demonstrated strong FTP‐PET affinity for neurofibrillary tau pathology but also for off‐target binding to neuromelanin and blood components . A sporadic Creutzfeldt‐Jakob disease case showed no unique pattern of FTP‐PET by visual inspection or SUVR (1.17, 1.08–1.36) again suggesting that FTP‐PET has better specificity for the paired helical tau filaments associated with AD dementia .…”

“…PET imaging with flortaucipir (FTP) has shown highly sensitive binding affinity to tau in AD patients . FTP “off‐target” binding has been reported in entities not considered to be associated with tau accumulation such as neuromelanin and the choroid plexus . To date, only single‐case studies of in vivo tau‐PET compared to autopsy in various tauopathies have been reported .…”

“…FTP “off‐target” binding has been reported in entities not considered to be associated with tau accumulation such as neuromelanin and the choroid plexus . To date, only single‐case studies of in vivo tau‐PET compared to autopsy in various tauopathies have been reported . Of these, one postmortem AD case with correlation with FTP‐PET has been published .…”

Neuromelanin, aging, and neuronal vulnerability in Parkinson's disease

“…This could also be envisaged with the use of [ 18 F]-AV-1451 (Flortaucipir), a novel Positron Emission Tomography (PET) tracer that was initially developed for its high affinity to neurofibrillary tau in Alzheimer's disease but was subsequently found to bind strongly and specifically to neuromelanin and melanin. 89,90 Alternatively, it could be also interesting to determine whether brain neuromelanin levels might correlate with, and thus be inferred from, the production and/or type of pigmentation in the skin or hair. Supporting this concept: (1) PD patients have an increased risk of developing cutaneous melanoma and, reciprocally, patients with cutaneous melanoma have an increased risk of developing PD 91 ; (2) similar to neurons, cutaneous melanocytes derive from pluripotent neural crest cells and their maturation is influenced by the same signaling molecules that play a role in central and peripheral nervous tissue 92 ; (3) loss-of-function variants of the melanocortin 1 receptor gene, which are associated with red hair and fair skin, are linked to an increased risk of both cutaneous melanoma and PD 93,94 ; (4) genetically modified mice carrying an inactivating mutation of melanocortin 1 receptor mimicking the human redhead phenotype have compromised nigrostriatal dopaminergic neuronal integrity and are more susceptible to dopaminergic parkinsonian neurotoxins.…”

Effect of Off-Target Binding on 18F-Flortaucipir Variability in Healthy Controls Across the Life Span

“…Also, there was no significant difference in the 18 F-flortaucipir OFF in the basal ganglia between Parkinson disease patients receiving MAO-B inhibitors and those who were not (22). Many targets have been postulated to explain the binding of 18 F-flortaucipir in the choroid plexus (ChPlex) (19,24), although a difference in 18 F-flortaucipir-ChPlex between African American and Caucasian subjects suggests 18 F-flortaucipir could be binding to neuromelanin (25). Lastly, variability in hemispheric white matter (HemiW) signal was reported in HCs as minor displaceable binding (19), leading us to classify white matter (WM) as an OFF region.…”