Real-World Evidence to Support the Registration of a New Osteoporosis Medicinal Product in Europe.

Real-World Evidence (RWE), which has historically been used to support post-approval safety studies, has recently gained acceptance for new drug applications as supportive evidence or as new clinical evidence for medicinal products with orphan designation and/or in disease areas with high unmet need. Here, we present a case study for the use of RWE in the approval of abaloparatide in the European Union (EU) under the tradename Eladynos. In addition to data from the pivotal Phase 3 study, the marketing authorization application (MAA) included clinical data from additional interventional and observational studies, as well as post-marketing data obtained from the United States (US) market since approval of abaloparatide by the Food and Drug Administration (FDA) in 2017.

Markerless head motion tracking and event-by-event correction in brain PET.

Head motion correction (MC) is an essential process in brain positron emission tomography (PET) imaging. We have used the Polaris Vicra, an optical hardware-based motion tracking (HMT) device, for PET head MC. However, this requires attachment of a marker to the subject's head.

Dopamine D receptor availability in cocaine use disorder individuals with obesity as measured by [C]PHNO PET.

Background: Positron emission tomography (PET) work with the dopamine D3 receptor (DR) preferring ligand [C]PHNO in obese individuals has demonstrated higher binding and positive correlations with body mass index (BMI) in otherwise healthy individuals. These findings implicated brain reward areas including the substantia nigra/ventral tegmental area (SN/VTA) and pallidum. In cocaine use disorder (CUD), similar SN/VTA binding profiles have been found compared to healthy control subjects.

Effects of TOF Resolution Models on Edge Artifacts in PET Reconstruction from Limited-Angle Data.

Limited-angle data, such as data obtained from a dual-panel Breast-PET scanner, result in substantial image blur in directions coinciding with the missing cone of the image spectrum. On systems with time-of-flight (TOF) capabilities, this blur is reduced as given by the TOF uncertainty, with the image spectrum being correspondingly expanded into the missing spectral cone. Modeling of the TOF uncertainty in the reconstruction is expected to deconvolve this residual TOF blurring.

Dopaminergic Plasticity in the Bilateral Hippocampus Following Threat Reversal in Humans.

When a cue no longer predicts a threat, a diminished ability to extinguish or reverse this association is thought to increase risk for stress-related disorders. Despite the clear clinical relevance, the mediating neurochemical mechanisms of threat reversal have received relatively little study. One neurotransmitter implicated in rodent research of changing associations with threat is dopamine.

Spatially-variant image-based modeling of PSF deformations with application to a limited angle geometry from a dual-panel breast-PET imager.

Dual-panel PET system configuration can lead to spatially variable point-spread functions (PSF) of considerable deformations due to depth-of-interaction effects and limited angular coverage. If not modelled properly, these effects result in decreased and inconsistent recovery of lesion activity across the field-of-view (FOV), as well as mispositioning of lesions in the reconstructed image caused by strong PSF asymmetries. We implemented and evaluated models of such PSF deformations with spatially-variant image-based resolution modeling (IRM) within reconstruction (varRM) using the Direct Image REConstruction for Time-of-flight (DIRECT) method and within post-reconstruction deconvolution methods.

A novel patch-based procedure for estimating brain age across adulthood.

Aging is associated with structural alterations in many regions of the brain. Monitoring these changes contributes to increasing our understanding of the brain's morphological alterations across its lifespan, and could allow the identification of departures from canonical trajectories. Here, we introduce a novel and unique patch-based grading procedure for estimating a synthetic estimate of cortical aging in cognitively intact individuals.

Brain serotonin synthesis capacity in obsessive-compulsive disorder: effects of cognitive behavioral therapy and sertraline.

Cognitive behavioral therapy (CBT) and selective serotonin reuptake inhibitors (SSRIs) are both effective treatments for some patients with obsessive-compulsive disorder (OCD), yet little is known about the neurochemical changes related to these treatment modalities. Here, we used positron emission tomography and the α-[C]methyl-L-tryptophan tracer to examine the changes in brain regional serotonin synthesis capacity in OCD patients following treatment with CBT or SSRI treatment. Sixteen medication-free OCD patients were randomly assigned to 12 weeks of either CBT or sertraline treatment.

Altered Regional Cerebral Blood Flow in Idiopathic Hypersomnia.

Study Objectives: Idiopathic hypersomnia is characterized by excessive daytime sleepiness, despite normal or long sleep time. Its pathophysiological mechanisms remain unclear. This pilot study aims at characterizing the neural correlates of idiopathic hypersomnia using single photon emission computed tomography.

Quantification of brain cholinergic denervation in Alzheimer's disease using PET imaging with [F]-FEOBV.

F-fluoroethoxybenzovesamicol (FEOBV) is a new PET radiotracer that binds to the vesicular acetylcholine transporter. In both animals and healthy humans, FEOBV was found sensitive and reliable to characterize presynaptic cholinergic nerve terminals in the brain. It has been used here for we believe the first time in patients with Alzheimer's disease (AD) to quantify brain cholinergic losses.

Posterior dopamine D2/3 receptors and brain network functional connectivity.

Recent studies suggest that dopaminergic tone influences resting state activity in multiple brain networks. Although dopamine receptors and transporters have been identified in the posteromedial and parietal cortices, which are linked to functional networks such as the default mode network (DMN), the relationship between dopamine receptor distribution in these posterior regions and resting-state connectivity has yet to be explored. Here, we used a multi-modal neuroimaging strategy, combining resting-state functional magnetic resonance imaging (rsfMRI) and [18 F]-fallypride high-resolution positron emission tomography (PET), to examine the association between within-network functional connectivity and the dopamine D2/3 receptor distribution in the posterior portion of the brain in 13 healthy adults.

When the Wedding March becomes sad: Semantic memory impairment for music in the semantic variant of primary progressive aphasia.

Music can induce particular emotions and activate semantic knowledge. In the semantic variant of primary progressive aphasia (svPPA), semantic memory is impaired as a result of anterior temporal lobe (ATL) atrophy. Semantics is responsible for the encoding and retrieval of factual knowledge about music, including associative and emotional attributes.

Cocaine cue-induced dopamine release in the human prefrontal cortex.

Background: Accumulating evidence indicates that drug-related cues can induce dopamine (DA) release in the striatum of substance abusers. Whether these same cues provoke DA release in the human prefrontal cortex remains unknown.

Methods: We used high-resolution positron emission tomography with [18F]fallypride to measure cortical and striatal DA D2/3 receptor availability in the presence versus absence of drug-related cues in volunteers with current cocaine dependence.

Direct 4D PET MLEM reconstruction of parametric images using the simplified reference tissue model with the basis function method for [¹¹C]raclopride.

This work assesses the one-step late maximum likelihood expectation maximization (OSL-MLEM) 4D PET reconstruction algorithm for direct estimation of parametric images from raw PET data when using the simplified reference tissue model with the basis function method (SRTM-BFM) for the kinetic analysis. To date, the OSL-MLEM method has been evaluated using kinetic models based on two-tissue compartments with an irreversible component. We extend the evaluation of this method for two-tissue compartments with a reversible component, using SRTM-BFM on simulated 3D + time data sets (with use of [(11)C]raclopride time-activity curves from real data) and on real data sets acquired with the high resolution research tomograph.

Maintaining polarization in polarimetric multiphoton microscopy.

Polarimetric measurements in multiphoton microscopy can reveal information about the local molecular order of a sample. However, the presence of a dichroic through which the excitation beam propagates will generally scramble its polarization. We propose a simple scheme whereby a second properly-oriented compensation dichroic is used to negate any alteration regardless of the wavelength and the initial polarization.

Brain serotonin synthesis in MDMA (ecstasy) polydrug users: an alpha-[(11) C]methyl-l-tryptophan study.

3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) use may have long-term neurotoxic effects. In this study, positron emission tomography with the tracer alpha-[(11) C]methyl-l-tryptophan ((11) C-AMT) was used to compare human brain serotonin (5-HT) synthesis capacity in 17 currently drug-free MDMA polydrug users with that in 18 healthy matched controls. Gender differences and associations between regional (11) C-AMT trapping and characteristics of MDMA use were also examined.

Coxofemoral joint kinematics using video fluoroscopic images of treadmill-walking cats: development of a technique to assess osteoarthritis-associated disability.

The objectives of this pilot study were to develop a video fluoroscopy kinematics method for the assessment of the coxofemoral joint in cats with and without osteoarthritis (OA)-associated disability. Two non-OA cats and four cats affected by coxofemoral OA were evaluated by video fluoroscopy. Video fluoroscopic images of the coxofemoral joints were captured at 120 frames/s using a customized C-arm X-ray system while cats walked freely on a treadmill at 0.

Stress-induced dopamine release in human medial prefrontal cortex--18F-fallypride/PET study in healthy volunteers.

Background: In laboratory animals, environmental stressors markedly activate the mesocortical dopamine system. The present study tested whether this occurs in humans.

Methods: The effects of a laboratory psychological stressor (Montreal Imaging Stress Task, MIST) on mesocortical dopamine release in healthy young adults (11 males, mean age ± SD, 20.

Cocaine cue-induced dopamine release in amygdala and hippocampus: a high-resolution PET [¹⁸F]fallypride study in cocaine dependent participants.

Drug-related cues are potent triggers for relapse in people with cocaine dependence. Dopamine (DA) release within a limbic network of striatum, amygdala and hippocampus has been implicated in animal studies, but in humans it has only been possible to measure effects in the striatum. The objective here was to measure drug cue-induced DA release in the amygdala and hippocampus using high-resolution PET with [(18)F]fallypride.

Two innovative pharmaceutical forms of leuprorelin: results from 818 patients with advanced prostate cancer.

Objectives: This study set out to examine the efficacy and tolerability of two innovative implant forms of leuprorelin acetate in men with advanced hormone-dependent prostate cancer in everyday clinical practice.

Methods: Data were collected from 818 patients (from 273 centers across Germany) who were pretreated with slow-release luteinizing hormone-releasing hormone (LHRH) agonist formulations and who were about to be switched to the leuprorelin implants. Patients received three injections of 1- or 3-month leuprorelin implant and physicians were asked to complete a case report form specific to each of the three clinic visits.

Grey matter density and GABAA binding potential show a positive linear relationship across cortical regions.

Voxel based morphometry (VBM) is a widely used technique for studying the structure of the brain. Direct comparisons between the results obtained using VBM and the underlying histology are limited, however. To circumvent the problems inherent in comparing VBM data in vivo with tissue samples that must generally be obtained post-mortem, we chose to consider GABAA receptors, measured using (18)F-flumazenil PET (18F-FMZ-PET), as non-invasive neural markers to be compared with VBM data.

Clinical development of two innovative pharmaceutical forms of leuprorelin acetate.

Objectives: Two innovative pharmaceutical forms of leuprorelin acetate have been developed as 1-month and 3-month implants for the treatment of advanced hormone-dependent prostate cancer. These products contain active substance dispersed homogeneously in a biodegradable polymer. Here we present the key results from the clinical development of these slow-release implant formulations of leuprorelin.

GABA(A) receptors in visual and auditory cortex and neural activity changes during basic visual stimulation.

Recent imaging studies have demonstrated that levels of resting γ-aminobutyric acid (GABA) in the visual cortex predict the degree of stimulus-induced activity in the same region. These studies have used the presentation of discrete visual stimulus; the change from closed eyes to open also represents a simple visual stimulus, however, and has been shown to induce changes in local brain activity and in functional connectivity between regions. We thus aimed to investigate the role of the GABA system, specifically GABA(A) receptors, in the changes in brain activity between the eyes closed (EC) and eyes open (EO) state in order to provide detail at the receptor level to complement previous studies of GABA concentrations.