The α-synuclein PET tracer [18F] ACI-12589 distinguishes multiple system atrophy from other neurodegenerative diseases.

A positron emission tomography (PET) tracer detecting α-synuclein pathology will improve the diagnosis, and ultimately the treatment of α-synuclein-related diseases. Here we show that the PET ligand, [F]ACI-12589, displays good in vitro affinity and specificity for pathological α-synuclein in tissues from patients with different α-synuclein-related disorders including Parkinson's disease (PD) and Multiple-System Atrophy (MSA) using autoradiography and radiobinding techniques. In the initial clinical evaluation we include 23 participants with α-synuclein related disorders, 11 with other neurodegenerative disorders and eight controls.

Kinetic models for estimating occupancy from single-scan PET displacement studies.

The traditional design of PET target engagement studies is based on a baseline scan and one or more scans after drug administration. We here evaluate an alternative design in which the drug is administered during an on-going scan (i.e.

Designing drug occupancy studies with PET neuroimaging: Sample size, occupancy ranges and analytical methods.

Molecular neuroimaging is today considered essential for evaluation of novel CNS drugs; it is used to quantify blood-brain barrier permeability, verify interaction with key target and determine the drug dose resulting in 50% occupancy, IC. In spite of this, there has been limited data available to inform on how to optimize study designs. Through simulations, we here evaluate how IC estimation is affected by the (i) range of drug doses administered, (ii) number of subjects included, and (iii) level of noise in the plasma drug concentration measurements.

In vivo correlation of serotonin transporter and 1B receptor availability in the human brain: a PET study.

Synaptic serotonin levels in the brain are regulated by active transport into the bouton by the serotonin transporter, and by autoreceptors, such as the inhibitory serotonin (5-HT) 1B receptor which, when activated, decreases serotonin release. Animal studies have shown a regulatory link between the two proteins. Evidence of such coupling could translate to an untapped therapeutic potential in augmenting the effect of selective serotonin reuptake inhibitors through pharmacological modulation of 5-HT receptors.

An Automated Quantification Tool for Angiogenic Sprouting From Endothelial Spheroids.

The process of sprouting angiogenesis can be measured using endothelial cells in sprouting assays such as the fibrin bead assay and the spheroid-based assay. While the technical aspects of these sprouting assays have been well-optimized, the analysis aspects have been limited to manual methods, which can be time-consuming and difficult to reproduce. Here, we developed an automated analysis tool called AQuTAS to quantify sprouting parameters from the spheroid-based sprouting assay.

Dorsal striatal dopamine induces fronto-cortical hypoactivity and attenuates anxiety and compulsive behaviors in rats.

Dorsal striatal dopamine transmission engages the cortico-striato-thalamo-cortical (CSTC) circuit, which is implicated in many neuropsychiatric diseases, including obsessive-compulsive disorder (OCD). Yet it is unknown if dorsal striatal dopamine hyperactivity is the cause or consequence of changes elsewhere in the CSTC circuit. Classical pharmacological and neurotoxic manipulations of the CSTC and other brain circuits suffer from various drawbacks related to off-target effects and adaptive changes.

Early stopping in clinical PET studies: How to reduce expense and exposure.

Clinical positron emission tomography (PET) research is costly and entails exposing participants to radioactivity. Researchers should therefore aim to include just the number of subjects needed to fulfill the purpose of the study. In this tutorial we show how to apply in order to stop the recruitment of subjects in a clinical PET study as soon as enough data have been collected to make a conclusion.

Serotonin transporter availability increases in patients recovering from a depressive episode.

Molecular imaging studies have shown low cerebral concentration of serotonin transporter in patients suffering from depression, compared to healthy control subjects. Whether or not this difference also is present before disease onset and after remission (i.e.

Nondisplaceable Binding Is a Potential Confounding Factor in C-PBR28 Translocator Protein PET Studies.

The PET ligand C-PBR28 (-((2-(methoxy-C)-phenyl)methyl)--(6-phenoxy-3-pyridinyl)acetamide) binds to the 18-kDa translocator protein (TSPO), a biomarker of glia. In clinical studies of TSPO, the ligand total distribution volume, V, is frequently the reported outcome measure. Since V is the sum of the ligand-specific distribution volume (V) and the nondisplaceable-binding distribution volume (V), differences in V across subjects and groups will have an impact on V Here, we used a recently developed method for simultaneous estimation of V (SIME) to disentangle contributions from V and V Data from 4 previously published C-PBR28 PET studies were included: before and after a lipopolysaccharide challenge (8 subjects), in alcohol use disorder (14 patients, 15 controls), in first-episode psychosis (16 patients, 16 controls), and in Parkinson disease (16 patients, 16 controls).

Quantification of [C]PBR28 data after systemic lipopolysaccharide challenge.

Background: Lipopolysaccharide (LPS) is a classic immune stimulus. LPS combined with positron emission tomography (PET) 18 kDa translocator protein (TSPO) brain imaging provides a robust human laboratory model to study neuroimmune signaling. To evaluate optimal analysis of these data, this work compared the sensitivity of six quantification approaches.

Guidelines for the content and format of PET brain data in publications and archives: A consensus paper.

It is a growing concern that outcomes of neuroimaging studies often cannot be replicated. To counteract this, the magnetic resonance (MR) neuroimaging community has promoted acquisition standards and created data sharing platforms, based on a consensus on how to organize and share MR neuroimaging data. Here, we take a similar approach to positron emission tomography (PET) data.

[ C]raclopride positron emission tomography study of dopamine-D receptor binding in patients with severe major depressive episodes before and after electroconvulsive therapy and compared to control subjects.

Aim: The aim of the study was to test: (i) if D /D binding in three functional subsections of striatum is different in patients with severe major depressive episodes than in controls; and (ii) if this difference is normalized after electroconvulsive therapy (ECT).

Methods: Nine inpatients were examined with positron emission tomography (PET) and the radioligand [ C]raclopride before and after an average of 8.4 ECT sessions.

Validity and reliability of extrastriatal [C]raclopride binding quantification in the living human brain.

[C]raclopride is a well established PET tracer for the quantification of dopamine 2/3 receptors (DR) in the striatum. Outside of the striatum the receptor density is up to two orders of magnitude lower. In contrast to striatal binding, the characteristics of extrastriatal [C]raclopride binding quantification has not been thoroughly described.

Association Between Sumatriptan Treatment During a Migraine Attack and Central 5-HT1B Receptor Binding.

Importance: Triptans, the most efficient acute treatment for migraine attacks, are 5-HT1B/1D receptor agonists, but their precise mechanism of action is not completely understood. The extent to which triptans enter the central nervous system and bind to 5-HT1B receptors in the brain is unknown.

Objectives: To determine the occupancy of sumatriptan to central 5-HT1B receptors, and to investigate changes in brain serotonin levels during migraine attacks.

Measuring endogenous changes in serotonergic neurotransmission with [C]Cimbi-36 positron emission tomography in humans.

Developing positron emission tomography (PET) radioligands for the detection of endogenous serotonin release will enable the investigation of serotonergic deficits in many neuropsychiatric disorders. The present study investigates how acute challenges that aim to increase or decrease cerebral serotonin levels affect binding of the serotonin 2A receptor (5-HTR) agonist radioligand [C]Cimbi-36. In a randomized, double-blind, placebo-controlled, three-arm design, 23 healthy volunteers were PET scanned twice with [C]Cimbi-36: at baseline and following double-blind assignment to one of three interventions (1) infusion of the selective serotonin reuptake inhibitor (SSRI) citalopram preceded by oral dosing of the 5-HTR antagonist pindolol, (n = 8) (2) acute tryptophan depletion (ATD) (n = 7) and (3) placebo (n = 8).

Resting regional brain activity correlates of verbal learning deficit in major depressive disorder.

Memory deficits are reported in major depressive disorder (MDD). Prefrontal cortical and mesiotemporal cortical (MTC)/subcortical regions are involved in the Buschke Selective Reminding Task (SRT), a verbal list-learning task. To determine whether depression-related changes in resting brain metabolism explain (in part) the deficits in SRT performance found in MDD, statistical correlation maps were calculated between SRT total recall score (TR) and relative regional cerebral metabolic rate for glucose (rCMRglu), measured by [F]-flourodeoxyglucose (FDG) positron emission tomography (PET), in unmedicated, depressed MDD patients (N = 29).

Accuracy and reliability of [C]PBR28 specific binding estimated without the use of a reference region.

[C]PBR28 is a positron emission tomography radioligand used to examine the expression of the 18 kDa translocator protein (TSPO). TSPO is located in glial cells and can function as a marker for immune activation. Since TSPO is expressed throughout the brain, no true reference region exists.

Regional times to equilibria and their impact on semi-quantification of [F]AV-1451 uptake.

The semi-quantitative estimate standardised uptake value ratios (SUVR) correlate well with specific binding of the tracer expressed as distribution volume ratios (DVR) for the tau positron emission tomography tracer [F]AV-1451 uptake and are therefore widely used as proxy for tracer binding. With regard to tracer kinetic modelling, there exists a time point when SUVR deviates minimally from DVR, occurring when the specific binding reaches a transient equilibrium Here, we have investigated whether the time to equilibrium affects the agreement between SUVR and DVR across different brain regions. We show that the time required to reach equilibrium differs across brain regions, resulting in region-specific biases.

Likelihood estimation of drug occupancy for brain PET studies.

Neuroimaging with PET is unique in its capability to measure in vivo the occupancy of a drug. The occupancy is typically obtained by conducting PET measurements before and after administration of the drug. For radioligands for which no reference region exists, however, the only established procedure to estimate the occupancy from these data is via linear regression analysis, forming the basis for the so-called Lassen plot.

[C]Harmine Binding to Brain Monoamine Oxidase A: Test-Retest Properties and Noninvasive Quantification.

Purpose: Inhibition of the isoform A of monoamine oxidase (MAO-A), a mitochondrial enzyme catalyzing deamination of monoamine neurotransmitters, is useful in treatment of depression and anxiety disorders. [C]harmine, a MAO-A PET radioligand, has been used to study mood disorders and antidepressant treatment. However, [C]harmine binding test-retest characteristics have to date only been partially investigated.

Non-invasive estimation of [C]PBR28 binding potential.

[C]PBR28 is a PET radioligand used to estimate densities of the 18 kDa translocator protein (TSPO) in vivo. Since there is no suitable reference region, arterial blood samples are required for full quantification. Here, we evaluate a methodology for full quantification of [C]PBR28 PET data that does not require either a reference region or blood samples.

Revisiting the Logan plot to account for non-negligible blood volume in brain tissue.

Background: Reference tissue-based quantification of brain PET data does not typically include correction for signal originating from blood vessels, which is known to result in biased outcome measures. The bias extent depends on the amount of radioactivity in the blood vessels. In this study, we seek to revisit the well-established Logan plot and derive alternative formulations that provide estimation of distribution volume ratios (DVRs) that are corrected for the signal originating from the vasculature.

Neuroinflammation in Neurodegenerative Disorders-a Review.

The potential for positron emission tomography (PET) to detect neuroinflammation in vivo has sparked a remarkable interest in various disciplines of neuroscience. Early PET radioligands, such as [C]PK(R)-11195 for the 18-kDa translocator protein (TSPO) and [C]L-deprenyl for monoamine oxidase B, have been used in studies designed to clarify the role of neuroinflammation in a variety of psychiatric and neurological disorders. Recent years have witnessed the development of several second-generation PET radioligands for TSPO and radioligands to measure endogenous targets that are active in various stages of the inflammatory cascade, such as cyclooxygenase and arachidonic acid.

Patterns of age related changes for phosphodiesterase type-10A in comparison with dopamine D receptors and sub-cortical volumes in the human basal ganglia: A PET study with F-MNI-659 and C-raclopride with correction for partial volume effect.

Phosphodiesterase 10A enzyme (PDE10A) is an important striatal target that has been shown to be affected in patients with neurodegenerative disorders, particularly Huntington´s disease (HD). PDE10A is expressed on striatal neurones in basal ganglia where other known molecular targets are enriched such as dopamine D receptors (D R). The aim of this study was to examine the availability of PDE10A enzyme in relation with age and gender and to compare those changes with those related to D R and volumes in different regions of the basal ganglia.