MAO-B Inhibitors Do Not Block In Vivo Flortaucipir([18F]-AV-1451) Binding

Hansen, Allan K; Brooks, David J.; Borghammer, Per

doi:10.1007/s11307-017-1143-1

Cited by 45 publications

(35 citation statements)

References 35 publications

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“…While the lack of significance when using standard uptake value ratios likely reflects a decline in MAO-B availability in the reference region as a result of the pharmacological challenge, an alternative explanation may involve altered brain perfusion, and thus delivery of the tracer, possibly via changes in blood pressure [13] . While a recent retrospective study involving Parkinson's disease patients treated chronically with MAO-B inhibitors showed no effect on [ 18 F]flortaucipir uptake [14] , due to the between-study differences, it cannot be ruled out that the pretreatment could affect the availability of the binding site for [ 18 F]THK5351.…”

Section: In Vivo Tau Pet and Off-target Bindingmentioning

confidence: 99%

Tau positron emission tomography imaging in tauopathies: The added hurdle of off‐target binding

Lemoine

Leuzy

Chiotis

et al. 2018

Alz & Dem Diag Ass & Dis Mo

113

103

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Ligands targeting tau for use with positron emission tomography have rapidly been developed during the past several years, enabling the in vivo study of tau pathology in patients with Alzheimer's disease and related non-Alzheimer's disease tauopathies. Several candidate compounds have been developed, showing good in vitro characteristics with respect to their ability to bind tau deposits; off-target binding, however, has also been observed. In this short commentary, we briefly summarize the available in vivo and in vitro evidence pertaining to their off-target binding and discuss the different approaches that are needed for the future development of tau positron emission tomography tracers.

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Section: In Vivo Tau Pet and Off-target Bindingmentioning

confidence: 99%

Tau positron emission tomography imaging in tauopathies: The added hurdle of off‐target binding

Lemoine

Leuzy

Chiotis

et al. 2018

Alz & Dem Diag Ass & Dis Mo

113

103

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“…Both exist in lower concentrations in the cerebellum than the cortex (23). 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).…”

mentioning

confidence: 91%

“…Neuromelanin plays a role in the sequestration of iron and is found in lower concentrations in the cerebellum than in cortical regions (20). Although 3 H-flortaucipir binds to monoamine oxidase A (MAO-A) and B (MAO-B) in vitro (21), in vivo studies have yet to replicate 18 F-flortaucipir binding to MAO-A or MAO-B (22). Both exist in lower concentrations in the cerebellum than the cortex (23).…”

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confidence: 99%

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

et al. 2019

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Measuring early tau accumulation is important in studying aging and Alzheimer disease and is only as accurate as the signal-to-noise ratio of the tracer. Along with aggregated tau in the form of neurofibrillary tangles, 18 F-flortaucipir has been reported to bind to neuromelanin, monoamine oxidase, calcifications, iron, leptomeningeal melanocytes, and microhemorrages. Although 18 F-flortaucipir successfully differentiates healthy controls (HCs) from subjects with Alzheimer disease, variability exists in the cortical signal in amyloid-negative HCs. We aimed to explore the relationship between off-target binding signal and variability in the cortical signal in HCs. Methods: Subjects (n 5 139) received 11 C-Pittsburgh compound B (PIB) and 18 F-flortaucipir PET scans and a magnetizationprepared rapid gradient echo MRI scan. PET frames were realigned and coregistered to the MR images, which were segmented using FreeSurfer. In amyloid-negative HCs (n 5 90; age range, 21-94 y), 7 nonspecific or off-target binding regions were considered: caudate, pallidum, putamen, thalamus, cerebellar white matter, hemispheric white matter, and choroid plexus. These regions of interest were assigned to 3 similarly behaving groups using principle components analysis, exploratory factor analysis, and Pearson correlations for caudate, putamen, and pallidum (also correlated with age); thalamus and white matter; and choroid plexus. In amyloid-negative HCs with 11 C-PIB and 18 F-flortaucipir scans, correlations were calculated between white and gray matter before and after partial-volume correction. Results: The correlation between white and gray matter disappeared after partial-volume correction in 11 C-PIB (r 2 5 0) but persisted for 18 F-flortaucipir (r 2 5 0.27), demonstrating that the correlation between white and gray matter signal in 18 F-flortaucipir is not solely due to partial-volume effects. A linear regression showed that off-target signal from putamen and thalamus together explained 64% of the variability in the cortical signal in amyloid-negative HCs (not seen in amyloid-positive HCs). Variability in amyloid-negative HCs but not amyloid-positive HCs correlated with white matter signal (unrelated to partial-volume effects) and age-related off-target signal (possibly related to iron load). Conclusion: The noise in the 18 Fflortaucipir measurement could pose challenges when studying early tau accumulation. Across the Life SpanF-Flortaucipir Variability in Healthy Controls 18 Effect of Off-Target Binding on http://jnm.snmjournals.org/content/60/10/1444 This article and updated information are available at: http://jnm.snmjournals.org/site/subscriptions/online.xhtml Information about subscriptions to JNM can be found at: http://jnm.snmjournals.org/site/misc/permission.xhtml

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“…18 F-AV-1451 uptake correlated well with quantitatively measured 4-repeat tau burden, as determined post-mortem in the brain of a patient presenting with nfvPPA (43). Furthermore, unlike other tau PET tracers, 18 F-AV-1451 is not appreciably blocked by monoamine oxidase B inhibitors (44), ruling out the possibility that the increased 18 F-AV-1451 signal may simply correspond to an increase in monoamine oxidase B induced by the pathologic process (45). In FTD, small but detectable and accurate 18 F-AV-1451 binding has been found in most studies (39,43), and its regional distribution corresponds well to the clinical syndromes (46).…”

Section: Discussionmentioning

confidence: 56%

Multimodal ¹⁸F-AV-1451 and MRI Findings in Nonfluent Variant of Primary Progressive Aphasia: Possible Insights on Nodal Propagation of Tau Protein Across the Syntactic Network

Pascual¹,

Funk²,

Zanotti‐Fregonara³

et al. 2019

J Nucl Med

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Although abnormally folded tau protein has been found to selfpropagate from neuron to connected neuron, similar propagation through human brain networks has not been fully documented. We studied tau propagation in the left hemispheric syntactic network, which comprises an anterior frontal node and a posterior temporal node connected by the white matter of the left arcuate fasciculus. This network is affected in the nonfluent variant of primary progressive aphasia, a neurodegenerative disorder with tau accumulation. Methods: Eight patients with the nonfluent variant of primary progressive aphasia (age, 67.0 ± 7.4 y; 4 women) and 8 healthy controls (age, 69.6 ± 7.0 y; 4 women) were scanned with 18 F-AV-1451 tau PET to determine tau deposition in the brain and with MRI to determine the fractional anisotropy of the arcuate fasciculus. Normal syntactic network characteristics were confirmed with structural MRI diffusion imaging in our healthy controls and with blood oxygenation level-dependent functional imaging in 35 healthy participants from the Alzheimer Disease Neuroimaging Initiative database. Results: Language scores in patients indicated dysfunction of the anterior node. 18 F-AV-1451 deposition was greatest in the 2 nodes of the syntactic network. The left arcuate fasciculus had decreased fractional anisotropy, particularly near the anterior node. Normal MRI structural connectivity from an area similar to the one containing tau in the anterior frontal node projected to an area similar to the one containing tau in the patients in the posterior temporal node. Conclusion: Tau accumulation likely started in the more affected anterior node and, at the disease stage at which we studied these patients, appeared as well in the brain region (in the temporal lobe) spatially separate from but most connected with it. The arcuate fasciculus, connecting both of them, was most severely affected anteriorly, as would correspond to a loss of axons from the anterior node. These findings are suggestive of tau propagation from node to connected node in a natural human brain network and support the idea that neurons that wire together die together. This article and updated information are available at: http://jnm.snmjournals.org/site/subscriptions/online.xhtml Information about subscriptions to JNM can be found at: http://jnm.snmjournals.org/site/misc/permission.xhtml

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MAO-B Inhibitors Do Not Block In Vivo Flortaucipir([18F]-AV-1451) Binding

Abstract: Use of MAO-B inhibitors at pharmaceutical levels did not significantly affect flortaucipir binding. Thus, MAO-B does not appear to be a significant binding target of flortaucipir.

Cited by 45 publications

References 35 publications

Tau positron emission tomography imaging in tauopathies: The added hurdle of off‐target binding

Tau positron emission tomography imaging in tauopathies: The added hurdle of off‐target binding

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

Multimodal ¹⁸F-AV-1451 and MRI Findings in Nonfluent Variant of Primary Progressive Aphasia: Possible Insights on Nodal Propagation of Tau Protein Across the Syntactic Network

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MAO-B Inhibitors Do Not Block In Vivo Flortaucipir([18F]-AV-1451) Binding

Abstract: Use of MAO-B inhibitors at pharmaceutical levels did not significantly affect flortaucipir binding. Thus, MAO-B does not appear to be a significant binding target of flortaucipir.

Cited by 45 publications

References 35 publications

Tau positron emission tomography imaging in tauopathies: The added hurdle of off‐target binding

Tau positron emission tomography imaging in tauopathies: The added hurdle of off‐target binding

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

Multimodal 18F-AV-1451 and MRI Findings in Nonfluent Variant of Primary Progressive Aphasia: Possible Insights on Nodal Propagation of Tau Protein Across the Syntactic Network

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Resources

About

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

Multimodal ¹⁸F-AV-1451 and MRI Findings in Nonfluent Variant of Primary Progressive Aphasia: Possible Insights on Nodal Propagation of Tau Protein Across the Syntactic Network