Apelin controls emotional behavior in age- and metabolic state-dependent manner.

Apelin is a small peptide secreted by the adipose tissue notably in conditions of obesity-induced hyper-insulinemia. Apelin exerts a range of physiological functions at the periphery including the improvement of insulin sensitivity and the increase of muscle strength or cardiac contractibility. Interestingly, the brain is endowed with a high density of APJ, the single target of apelin, and growing evidence suggests various central actions of this adipokine. Recent studies reported that the intracerebroventricular infusion of apelin modulates emotional states in middle age stressed animals. However, results are so far been mixed and have not allowed for definitive conclusions about the impact of apelin on anxio-depressive-like phenotype. This study aims 1) to evaluate whether serum apelin levels are associated with mood in older adults and 2) to determine the impact of the genetic apelin inactivation in 12-month old mice fed a standard diet (STD) or in 6-month old mice fed a high fat diet (HFD). A higher plasma apelin level was associated with higher depressive symptoms in older adults. In line with these clinical findings, 12-month old apelin knock-out (Ap-/-) mice displayed a spontaneous antidepressant-like phenotype. In a marked contrast, 6-month old Ap-/- mice harbored a higher degree of peripheral insulin resistance than wild-types in response to HFD and were more prone to develop anxiety while the depressive-like state was not modified. We also provided evidence that such anxious behavior was associated with an impairment of central serotonergic and dopaminergic neuronal activities. Finally, although the insulin sensitizing drug metformin failed to reverse HFD-induced insulin resistance in 6-month old Ap-/- mice, it reversed their anxious phenotype. These results emphasize a complex contribution of apelin in the regulation of emotional state that might depend on the age and the metabolic status of the animals. Further investigations are warranted to highlight the therapeutic potential of manipulating the apelinergic system in mood-related disorders.

Impact of scatter correction on D2 receptor occupancy measurements using 123I-IBZM SPECT: comparison to 11C-Raclopride PET.

Reported values of D(2) receptor occupancy (RO) achieved by antipsychotic drugs tend to be lower when measured with (123)I-IBZM SPECT than with (11)C-Raclopride PET. Image degrading factors such as attenuation, distance-dependent collimator response and scatter could account for this difference. While attenuation correction is routinely applied to SPECT images, the other degradations are not usually accounted for. The aim of this work was to assess the impact of scatter correction on D(2) RO quantification with (123)I-IBZM SPECT, and to compare the results of both corrected and un-corrected SPECT values with (11)C-Raclopride PET measurements. Phantom experiments as well as within-subject human data from a previous study were used for this purpose. SPECT images were reconstructed using filtered back-projection including attenuation correction (FBP(A)), ordered subsets expectation maximization including attenuation and point spread function corrections (OSEM(A+PSF)) and ordered subsets expectation maximization including attenuation, point spread function and scatter corrections (OSEM(A+PSF+SCT)). PET images were reconstructed using the FBP algorithm and corrected for attenuation, scatter, random coincidences and dead time. Quantification of receptor availability was performed using the tissue ratio at pseudoequilibrium for SPECT, and the simplified reference tissue model (SRTM) for PET. Analysis was performed using both occipital cortex (occ) and cerebellum (cer) as reference regions for both modalities. When images were reconstructed using FBP(A), SPECT D(2) RO values were significantly lower as compared with PET leading to a D(2) RO difference of -20% (CI(95%): -13, -27%) (occ) and -23% (CI(95%): -14, -31%) (cer). When images were reconstructed using OSEM(A+PSF), SPECT D(2) RO values were also lower as compared with PET leading to a D(2) RO difference of -21% (CI(95%): -14, -27%) (occ) and -24% (CI(95%): -18, -30%) (cer). When images were reconstructed using OSEM(A+PSF+SCT), the D(2) RO bias was reduced to -6% (CI(95%): 0, -13%) (occ) and -11% (CI(95%): -4, -18%) (cer). These data suggest that the scatter correction plays a major role in explaining the differences between D(2) RO measurements using (123)I-IBZM SPECT and (11)C-Raclopride PET.

Neurotransmission SPECT and MR registration combining mutual and gradient information.

PURPOSE: Image registration is important in functional image analysis. In neurotransmission single photon emission tomography (nSPECT), specific uptake sites can be accurately localized by superimposing the SPECT study onto a high-resolution structural image such as a magnetic resonance (MR) of the subject. Mutual-information (MI)-based algorithms are usually employed for this purpose. Nevertheless, nSPECT/MR registration using MI is often limited by the low count rates present in nSPECT. Several works have proposed extensions of the MI measures to include gradient information (GI) from the images but their performance has not been evaluated in SPECT studies. METHODS: In this work, the accuracy of the MI including gradient information (MIG) was compared with the standard MI using data from healthy volunteers and data simulating a specific uptake reduction using three different radioligands: 123I-IBZM, 123I-ADAM, 123I-R91150. RESULTS: The results showed that MIG-based registration yielded better accuracy than MI. The MIG-based similarity measures were less sensitive to sparse sampling and diminished computational time without a substantial decrease in registration accuracy. CONCLUSIONS: Accuracy of nSPECT/MR registration is improved when gradient information is included in the MI-based algorithm, which makes MIG-based registration potentially useful for clinical applications.

Pharmacokinetics and time-course of D(2) receptor occupancy induced by atypical antipsychotics in stabilized schizophrenic patients.

The (123)I-IBZM SPECT measured D(2) receptor occupancy (D(2)RO) in chronically dosed, stabilized schizophrenic patients and its relationship with antipsychotic (AP) pharmacokinetics (PK) over time is still unclear. The aims of this study were: 1) To define the relationship between striatal D(2) receptor occupancy (D( 2)RO) and plasma concentration (C(P)) in stabilized schizophrenic patients on clinically relevant doses using (123)I-IBZM SPECT; 2) To investigate the time course of AP-induced D(2)RO and corresponding C(P). Forty-six schizophrenic patients on their clinically required doses of risperidone, olanzapine, clozapine or quetiapine were included. D( 2)RO and C(P) were measured over time following a sparse-sampling experimental design, and individual PK and D(2)RO-time profiles were estimated using a population approach. Observed striatal D(2)RO and C(P) ranges were 28-75% and 9.4-60.5 ng/mL for risperidone, 22-84% and 8.6-89.5 ng/mL for olanzapine, 5-53% and 41.6-818.2 ng/mL for clozapine and 0-64% and 37.9-719.6 ng/mL for quetiapine. A PK-D(2)RO relationship was found for the four APs. D(2)RO pattern over time was stable for risperidone, olanzapine and clozapine but fluctuating for quetiapine. Stabilized schizophrenic patients show a wide range of both D(2)RO and C(P) at clinically effective doses of the four AP, suggesting that clinical response to these AP may be maintained with D(2)RO below 65%. D(2)RO patterns over time differ between AP. These results should be considered for accurate interpretation of D(2)RO measurements, proper design of studies and optimization of drug regimens for patients on AP treatment.

Impact of Region-of-Interest Delineation Methods, Reconstruction Algorithms, and Intra- and Inter-Operator Variability on Internal Dosimetry Estimates Using PET.

PURPOSE: Human dosimetry studies play a central role in radioligand development for positron emission tomography (PET). Drawing regions of interest (ROIs) on the PET images is used to measure the dose in each organ. In the study aspects related to ROI delineation methods were evaluated for two radioligands of different biodistribution (intestinal vs urinary). PROCEDURES: PET images were simulated from a human voxel-based phantom. Several ROI delineation methods were tested: antero-posterior projections (AP), 3D sub-samples of the organs (S), and a 3D volume covering the whole-organ (W). Inter- and intra-operator variability ROI drawing was evaluated by using human data. RESULTS: The effective dose estimates using S and W methods were comparable to the true values. AP methods overestimated (49 %) the dose for the radioligand with intestinal biodistribution. Moreover, the AP method showed the highest inter-operator variability: 11 ± 1 %. CONCLUSIONS: The sub-sampled organ method showed the best balance between quantitative accuracy and inter- and intra-operator variability.

Dynamic model of the left ventricle for use in simulation of myocardial perfusion SPECT and gated SPECT.

Simulation is a useful tool in cardiac SPECT to assess quantification algorithms. However, simple equation-based models are limited in their ability to simulate realistic heart motion and perfusion. We present a numerical dynamic model of the left ventricle, which allows us to simulate normal and anomalous cardiac cycles, as well as perfusion defects. Bicubic splines were fitted to a number of control points to represent endocardial and epicardial surfaces of the left ventricle. A transformation from each point on the surface to a template of activity was made to represent the myocardial perfusion. Geometry-based and patient-based simulations were performed to illustrate this model. Geometry-based simulations modeled (1) a normal patient, (2) a well-perfused patient with abnormal regional function, (3) an ischaemic patient with abnormal regional function, and (4) a patient study including tracer kinetics. Patient-based simulation consisted of a left ventricle including a realistic shape and motion obtained from a magnetic resonance study. We conclude that this model has the potential to study the influence of several physical parameters and the left ventricle contraction in myocardial perfusion SPECT and gated-SPECT studies.

Study of the point spread function (PSF) for 123I SPECT imaging using Monte Carlo simulation.

The iterative reconstruction algorithms employed in brain single-photon emission computed tomography (SPECT) allow some quantitative parameters of the image to be improved. These algorithms require accurate modelling of the so-called point spread function (PSF). Nowadays, most in vivo neurotransmitter SPECT studies employ pharmaceuticals radiolabelled with 123I. In addition to an intense line at 159 keV, the decay scheme of this radioisotope includes some higher energy gammas which may have a non-negligible contribution to the PSF. The aim of this work is to study this contribution for two low-energy high-resolution collimator configurations, namely, the parallel and the fan beam. The transport of radiation through the material system is simulated with the Monte Carlo code PENELOPE. We have developed a main program that deals with the intricacies associated with tracking photon trajectories through the geometry of the collimator and detection systems. The simulated PSFs are partly validated with a set of experimental measurements that use the 511 keV annihilation photons emitted by a 18F source. Sensitivity and spatial resolution have been studied, showing that a significant fraction of the detection events in the energy window centred at 159 keV (up to approximately 49% for the parallel collimator) are originated by higher energy gamma rays, which contribute to the spatial profile of the PSF mostly outside the 'geometrical' region dominated by the low-energy photons. Therefore, these high-energy counts are to be considered as noise, a fact that should be taken into account when modelling PSFs for reconstruction algorithms. We also show that the fan beam collimator gives higher signal-to-noise ratios than the parallel collimator for all the source positions analysed.

Blood cyclosporine C0 and C2 concentrations and cytomegalovirus infections following lung transplantation.

The aim of this study was to determine whether cyclosporine levels predose (C0) and at two hours postdose (C2) were higher among patients presenting with cytomegalovirus (CMV) infection or disease. Between days 40 and 365 posttransplantation serial C0 and C2 levels were measured in 15 lung transplant recipients. Nine developed 13 episodes of CMV infection or disease. Both C0 and C2 levels were higher during CMV infection or disease episodes. Eleven of the 13 CMV episodes (84%) displayed C0 >220 ng/mL and none had C0 <200 ng/mL. For C2, 11 of 13 CMV episodes (84%) showed C2 >1200 ng/mL and none had C2 <1000 ng/mL. Among determinations that did not coincide with a CMV episode, 7 of 21 (33%) showed C0 >220 and 9 of 21 (42%) showed C2 >1200, respectively (P<.05). In conclusion, cyclosporine blood levels are higher among patients presenting with CMV infection or disease.

Molecular imaging PET and SPECT approaches for improving productivity of antipsychotic drug discovery and development.

The need for innovation in research is leading to an increased use of imaging biomarkers, which have shown to reduce timings and increase productivity, thus saving costs. PET and SPECT neurotransmission imaging has shown usefulness in the discovery and development of drugs for the central nervous system, providing unique information on drug-target interactions in the living human brain. Among the different therapeutic areas, antipsychotic drugs pioneered the application of these technologies in early phases of development. PET and SPECT radioligands for the most commonly targeted neurotransmission systems in the development of these drugs, such as the dopaminergic and serotoninergic systems are available, thus fostering the inclusion of PET and SPECT studies in the antipsychotic drug development plans. Radioligands for other neurotransmission systems more recently implicated in the pathophysiology of schizophrenia, such as the glutamatergic system, are being currently investigated. This review focuses on neurotransmission PET and SPECT aiming to serve as guidance for procedure requirements and methodology choices to be applied in antipsychotic drug development, through specific examples. Cutting-edge study designs and quantification approaches will be reviewed. Finally, some clues to get the most out of the PET and SPECT studies in the development of antipsychotic drugs will be provided.