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Prone position decreases acute lung macrophage inflammation quantified in vivo with [11C](R)-PK11195 positron emission tomography in an experimental acute respiratory distress syndrome. Regional macrophage inflammation is maximal in the most anterior and posterior lung section of supine animals, in relation with increased regional tidal strain and hyperinflation, and reduced regional lung compliance.

Purpose F13640 (a.k.a. befiradol, NLX-112) is a highly selective 5-HT1A receptor ligand that was selected as a PET radiopharmaceutical-candidate based on animal studies. Due to its high efficacy agonist properties, [18F]F13640 binds preferentially to functional 5-HT1A receptors, which are coupled to intracellular G-proteins. Here, we characterize brain labeling of 5-HT1A receptors by [18F]F13640 in humans and describe a simplified model for its quantification. Methods PET/CT and PET-MRI scans were conducted in a total of 13 healthy male volunteers (29 ± 9 years old), with arterial input functions (AIF) (n = 9) and test–retest protocol (n = 8). Several kinetic models were compared (one tissue compartment model, two-tissue compartment model, and Logan); two models with reference region were also evaluated: simplified reference tissue model (SRTM) and the logan reference model (LREF). Results [18F]F13640 showed high uptake values in raphe nuclei and cortical regions. SRTM and LREF models showed a very high correlation with kinetic models using AIF. As concerns test–retest parameters and the prolonged binding kinetics of [18F]F13640, better reproducibility, and reliability were found with the LREF method. Cerebellum white matter and frontal lobe white matter stand out as suitable reference regions. Conclusion The favorable brain labeling and kinetic profile of [18F]F13640, its high receptor specificity and its high efficacy agonist properties open new perspectives for studying functionally active 5-HT1A receptors, unlike previous radiopharmaceuticals that act as antagonists. [18F]F13640’s kinetic properties allow injection outside of the PET scanner with delayed acquisitions, facilitating the design of innovative longitudinal protocols in neurology and psychiatry. Trial Registration. Trial Registration EudraCT 2017–002,722-21.

Reperfusion therapies in acute ischemic stroke have demonstrated their efficacy in promoting clinical recovery. However, ischemia/reperfusion injury and related inflammation remain a major challenge in patient clinical management. We evaluated the spatio-temporal evolution of inflammation using sequential clinical [11C]PK11195 PET-MRI in a non-human primate (NHP) stroke model mimicking endovascular thrombectomy (EVT) with a neuroprotective cyclosporine A (CsA) treatment. The NHP underwent a 110-min transient endovascular middle cerebral artery occlusion. We acquired [11C]PK11195 dynamic PET-MR imaging at baseline, 7 and 30 days after intervention. Individual voxel-wise analysis was performed thanks to a baseline scan database. We quantified [11C]PK11195 in anatomical regions and in lesioned areas defined on per-occlusion MR diffusion-weighted imaging and perfusion [15O2]H2OPET imaging. [11C]PK11195 parametric maps showed a clear uptake overlapping the lesion core at D7, which further increased at D30. Voxel-wise analysis identified individuals with significant inflammation at D30, with voxels located within the most severe diffusion reduction area during occlusion, mainly in the putamen. The quantitative analysis revealed that thalamic inflammation lasted until D30 and was significantly reduced in the CsA-treated group compared to the placebo. In conclusion, we showed that chronic inflammation matched ADC decrease at occlusion time, a region exposed to an initial burst of damage-associated molecular patterns, in an NHP stroke model mimicking EVT. We described secondary thalamic inflammation and the protective effect of CsA in this region. We propose that major ADC drop in the putamen during occlusion may identify individuals who could benefit from early personalized treatment targeting inflammation.

We present a database of cerebral PET FDG and anatomical MRI for 37 normal adult human subjects (CERMEP-IDB-MRXFDG). Thirty-nine participants underwent static [18F]FDG PET/CT and MRI, resulting in [18F]FDG PET, T1 MPRAGE MRI, FLAIR MRI, and CT images. Two participants were excluded after visual quality control. We describe the acquisition parameters, the image processing pipeline and provide participants’ individual demographics (mean age 38 ± 11.5 years, range 23–65, 20 women). Volumetric analysis of the 37 T1 MRIs showed results in line with the literature. A leave-one-out assessment of the 37 FDG images using Statistical Parametric Mapping (SPM) yielded a low number of false positives after exclusion of artefacts. The database is stored in three different formats, following the BIDS common specification: (1) DICOM (data not processed), (2) NIFTI (multimodal images coregistered to PET subject space), (3) NIFTI normalized (images normalized to MNI space). Bona fide researchers can request access to the database via a short form. Supplementary Information The online version contains supplementary material available at 10.1186/s13550-021-00830-6.

International audience; Stroke is a devastating disease. Endovascular mechanical thrombectomy is dramatically changing the management of acute ischemic stroke, raising new challenges regarding brain outcome and opening up new avenues for brain protection. In this context, relevant experiment models are required for testing new therapies and addressing important questions about infarct progression despite successful recanalization, reversibility of ischemic lesions, blood-brain barrier disruption and reperfusion damage. Here, we developed a minimally invasive non-human primate model of cerebral ischemia (Macaca fascicularis) based on an endovascular transient occlusion and recanalization of the middle cerebral artery (MCA). We evaluated per-occlusion and post-recanalization impairment on PET-MRI, in addition to acute and chronic neuro-functional assessment. Voxel-based analyses between per-occlusion PET-MRI and day-7 MRI showed two different patterns of lesion evolution: "symptomatic salvaged tissue" (SST) and "asymptomatic infarcted tissue" (AIT). Extended SST was present in all cases. AIT, remote from the area at risk, represented 45% of the final lesion. This model also expresses both worsening of fine motor skills and dysexecutive behavior over the chronic post-stroke period, a result in agreement with cortical-subcortical lesions. We thus fully characterized an original translational model of ischemia-reperfusion damage after stroke, with consistent ischemia time, and thrombus retrieval for effective recanalization.

Imaging of acute lung inflammation is pivotal to evaluate innovative ventilation strategies. We aimed to develop and validate a three-tissue compartment kinetic model (3TCM) of [We analyzed the data of 38 positron emission tomography (PET) studies performed in 21 swine with or without experimental ARDS, receiving general anesthesia and mechanical ventilation. Model input function was a plasma, metabolite-corrected, image-derived input function measured in the main pulmonary artery. Regional lung analysis consisted in applying both the 3TCM and the two-tissue compartment model (2TCM); in each region, the best model was selected using a selection algorithm with a goodness-of-fit criterion. Regional best model binding potentials (BPThe 3TCM was preferred in 142 lung regions (62%, 95% confidence interval: 56 to 69%). BPTo assess the intensity and spatial distribution of acute macrophagic lung inflammation in the context of experimental ARDS with mechanical ventilation, PET quantification of [

Labeling of heterocycles with carbon-11 is generally performed through peripheral functionalizations and more scarcely inside heterocyclic core. Such less common approach usually requires preliminary multi-step synthesis of reactive species. Herein, a cyclization reaction by direct use of cyclotron-produced [ 11 C]CO2 is described to obtain various heterocycles intracyclically labeled in only 10 minutes.

BACKGROUND Parkinson's disease (PD) is characterized by heterogeneous motor and nonmotor manifestations related to alterations in monoaminergic neurotransmission systems. Nevertheless, the characterization of concomitant dopaminergic and serotonergic dysfunction after different durations of Parkinson's disease, as well as their respective involvement in the expression and severity of neuropsychiatric signs, has gained little attention so far. METHODS To fill this gap, we conducted a cross-sectional study combining clinical and dual-tracer positron emission tomography (PET) neuroimaging approaches, using radioligands of dopamine ([11 C]-N-(3-iodoprop-2E-enyl)-2-beta-carbomethoxy-3-beta-(4-methylphenyl)-nortropane) ([11 C]PE2I) and serotonin ([11 C]-N,N-dimethyl-2-(-2-amino-4-cyanophenylthio)-benzylamine) ([11 C]DASB) reuptake, after different durations of Parkinson's disease (ie, in short-disease duration drug-naive de novo (n = 27, 0-2 years-duration), suffering from apathy (n = 14) or not (n = 13); intermediate-disease duration (n = 15, 4-7 years-duration) and long-disease duration, non-demented (n = 15, 8-10 years-duration) patients). Fifteen age-matched healthy subjects were also enrolled. RESULTS The main findings are threefold: (1) both dopaminergic and serotonergic lesions worsen with the duration of Parkinson's disease, spreading from midbrain/subcortical to cortical regions; (2) the presence of apathy at PD onset is associated with more severe cortical and subcortical serotonergic and dopaminergic disruption, similar to the denervation pattern observed in intermediate-disease duration patients; and (3) the severity of parkinsonian apathy, depression, and trait-anxiety appears primarily related to serotonergic alteration within corticostriatal limbic areas. CONCLUSIONS Altogether, these findings highlight the prominent role of serotonergic degeneration in the expression of several neuropsychiatric symptoms occurring after different durations of Parkinson's disease. © 2021 International Parkinson and Movement Disorder Society.

We present a database of cerebral PET FDG and anatomical MRI for 37 normal adult human subjects (CERMEP-IDB-MRXFDG).Thirty-nine participants underwent [18F]FDG PET/CT and MRI, resulting in [18F]FDG PET, T1 MPRAGE MRI, FLAIR MRI, and CT images. Two participants were excluded after visual quality control. We describe the acquisition parameters, the image processing pipeline and provide participants’ individual demographics (mean age 38 ± 11.5 years, range 23-65, 20 women). Volumetric analysis of the 37 T1 MRIs showed results in line with the literature. A leave-one-out assessment of the 37 FDG images using Statistical Parametric Mapping (SPM) yielded a low number of false positives after exclusion of artefacts.The database is stored in three different formats, following the BIDS common specification: 1) DICOM (data not processed), 2) NIFTI (multimodal images coregistered to PET subject space), 3) NIFTI normalized (images normalized to MNI space).Bona fide researchers can request access to the database via a short form.

Previous studies have suggested the role of microcalcifications in plaque vulnerability. This exploratory study sought to assess the potential of hybrid positron-emission tomography (PET)/magnetic resonance imaging (MRI) usingWe included 12 patients with either recently symptomatic or asymptomatic carotid stenosis. All patients underwent

International audience; In neuropharmacology, the recent concept of 'biased agonism' denotes the capacity of certain agonists to target-specific intracellular pathways of a given receptor in specific brain areas. In the context of serotonin pharmacotherapy, 5-HT1A receptor-biased agonists could be of great interest in several neuropsychiatric disorders. The aim of this study was to determine whether biased agonists could be differentiated in terms of regional targeting by use of simultaneous functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) brain imaging. We compared two 5-HT1A-biased agonists, NLX-112 and NLX-101, injected at three different doses in anaesthetised cats (n = 4). PET imaging was acquired for 90 min after bolus administration followed by constant infusion of the 5-HT1A radiotracer, [18F]MPPF. Drug occupancy was evaluated after injection at 50 min and BOLD fMRI was simultaneously acquired to evaluate subsequent brain activation patterns. 5-HT1A receptor occupancy was found to be dose-dependent for both agonists, but differed in magnitude and spatial distribution at equal doses with distinct BOLD patterns. Functional connectivity, as measured by BOLD signal temporal correlations between regions, was also differently modified by NLX-112 or NLX-101. Voxel-based correlation analyses between PET and fMRI suggested that NLX-112 stimulates both 5-HT1A autoreceptors and post-synaptic receptors, whereas NLX-101 preferentially stimulates post-synaptic cortical receptors. In cingulate cortex, the agonists induced opposite BOLD signal changes in response to receptor occupancy. These data constitute the first simultaneous exploration of 5-HT1A occupancy and its consequences in terms of brain activation, and demonstrates differential signalling by two 5-HT1A-biased agonists. Combined PET/fMRI represents a powerful tool in neuropharmacology, and opens new ways to address the concept of biased agonism by translational approaches.

Oxytocin (OT), a neuropeptide involved in affiliation has been shown to enhance social skills in patients with autism spectrum disorders (ASD). Nevertheless, OT improvements seem ephemeral. Animal research has demonstrated OT action on serotonin (5-HT), an interaction that we also found in the healthy human brain. Whether such synaptic interplay also occurs in ASD patients is unknown. To address this issue, we mapped the effects of intranasal OT on 5-HT in 18 patients with ASD and 24 healthy controls (HC) in a double blind, placebo controlled, within subject PET-scan experiment. Each participant underwent two scans: baseline and spray (OT or placebo). Using the radiotracer [18 F]MPPF, marking the 5-HT 1A receptor (5-HT1AR), we measured MPPF-Binding Potential (BP) as an index of OT-induced serotonin functional modulation. At baseline ASD patients did not differ from controls for 5-HT1AR concentration and distribution. However, while OT significantly increased MPPF BP in several brain regions of HC, no changes were observed in the ASD group. Serotonin serum concentration analysis corroborated these results. Our findings suggest a disturbed OT-serotonin interaction in autism. This may limit the potential benefits of OT in these patients and open the ways to investigate combined OT-serotonin treatments.

International audience; The vast majority of PET radiopharmaceuticals used for receptor neuroimaging are antagonists. This is particularly true for 5-HT1A receptor radiopharmaceuticals such as 18F-MPPF or 11C-WAY100635. These radiolabeled antagonists allow PET neuroimaging of the total pool of receptors, regardless of their functional state. In contrast, agonists bind preferentially to the functionally active state of receptors, a pharmacological property that has not yet been exploited for PET imaging of functional 5-HT1A receptors [1]. To this end, we have developed a highly selective 5-HT1A receptor agonist, 18FF13640, and validated it in animal models [2]. A postmortem study in Alzheimer subjects showed that the in vitro binding of 18F-F13640 differs from that of 18F-MPPF, the prototypical radiopharmaceutical [3]. Here we show the first human brain image obtained in vivo with 18F-F13640 (study registration, EudraCT2017-002722-21). A summed brain PET image was obtained in a 32-year-old healthy man after IV injection of the radiopharmaceutical (90-min scan). 18F-F13640 brain distribution, expressed by the standardized uptake value with the body weight (SUV bw), showed a binding pattern different from that seen with conventional antagonist 5-HT1A radiopharmaceuticals. Although the binding regions are well correlated to the density of 5-HT1A receptors, the ROIs are mainly cortical, indicating that these brain regions are enriched in functionally active receptors. 18F-F13640 is the first radiopharmaceutical that enables in vivo investigation of functional 5-HT1A receptors that are likely to be altered in pathological conditions such as neurodegenerative diseases or psychiatric disorders. The development of this agonist PET radiopharmaceutical opens new opportunities for nuclear medicine.

Previous studies have suggested the role of microcalcifications in plaque vulnerability. This exploratory study sought to assess the potential of hybrid positron-emission tomography (PET)/magnetic resonance imaging (MRI) using 18F-sodium fluoride (18F-NaF) to check simultaneously 18F-NaF uptake, a marker of microcalcifications, and morphological criteria of vulnerability. We included 12 patients with either recently symptomatic or asymptomatic carotid stenosis. All patients underwent 18F-NaF PET/MRI. 18F-NaF target-to-background ratio (TBR) was measured in culprit and nonculprit (including contralateral plaques of symptomatic patients) plaques as well as in other arterial walls. Morphological criteria of vulnerability were assessed on MRI. Mineral metabolism markers were also collected. 18F-NaF uptake was higher in culprit compared to nonculprit plaques (median TBR 2.6 [2.2-2.8] vs 1.7 [1.3-2.2]; P = 0.03) but was not associated with morphological criteria of vulnerability on MRI. We found a positive correlation between 18F-NaF uptake and calcium plaque volume and ratio but not with circulating tissue-nonspecific alkaline phosphatase (TNAP) activity and inorganic pyrophosphate (PPi) levels. 18F-NaF uptake in the other arterial walls did not differ between symptomatic and asymptomatic patients. 18F-NaF PET/MRI may be a promising tool for providing additional insights into the plaque vulnerability.

Renal positron emission tomography (PET) functional imaging allows non-invasive and dynamic measurements of functional and metabolic parameters. [In 10 healthy subjects, dynamic PET acquisitions were performed after [Renal time activity curves of [In healthy subjects, over a wide range of renal perfusion, direct estimates of renal oxygen consumption as well as tissue perfusion can be obtained by PET with a single tracer [

Purpose The opioid system role in anorexia nervosa (AN) pathophysiology is still unclear since conflicting results were reported on peripheral and cerebrospinal fluid opioids levels. The study main aim was to evaluate cerebral AN opiate receptor availability by using [11C] diprenorphine, a ligand with non-selective binding. Methods In vivo [11C]diprenorphine cerebral non-displaceable binding potential (BPND) evaluated by PET imaging was compared between three groups : 17 undernourished restrictive-type AN patients (LeanAN), 15 AN patients having regained normal weight (RecAN) and 15 controls. A lower BPND may account for an increased opioid tone and vice versa. Serum hormones and endogenous opioids levels, eating-related and unspecific psychological traits were also evaluated. Results Compared to controls, LeanAN and RecAN patients had decreased [11C]diprenorphine BPND in middle frontal gyrus, temporo-parietal cortices, anterior cingulate cortex and in left accumbens nucleus. Hypothalamo-pituitary (H-P), left amygdala and insula BPND was found decreased only in LeanAN and that of putamen only in RecAN. LeanAN presented higher dynorphin A and enkephalin serum levels than in controls or RecAN. Inverse correlations were found in total group between : 24 h mean serum cortisol levels and anterior cingulate gyrus or insula BPND; eating concern score and left amygdala BPND. Positive correlation were found between leptin and hypothamus BPND; LH and pituitary BPND. Conclusions Low opiate receptor availability may be interpreted as an increased opioid tone in areas associated with both reward/aversive system in both AN groups. The relationship between the opioid receptors activity and hypercorticism or specific psychometric scores in some of these regions suggests adaptive mechanisms facing anxiety but also may play a role in the disease perpetuation.

International audience; Rationale: Renal positron emission tomography (PET) functional imaging allows non-invasive and dynamic measurements of functional and metabolic parameters. [O-15]H2O is used as a perfusion tracer, and [C-11]acetate as an oxidative metabolism in this purpose, requiring two injections to assess those fundamental parameters. Yet, in cardiac physiology study, the high first-pass myocardial extraction fraction of [C-11]acetate allowed to use its influx rate as a blood flow marker too. Since [C-11]acetate has been characterized by a 20-25% single pass renal extraction in dogs, it could be used as a potential tracer for renal perfusion. The aim of this study was to determine whether [C-11]acetate influx rate can be used as quantitative in vivo marker of kidney perfusion in human. Methods: In 10 healthy subjects, dynamic PET acquisitions were performed after [O-15]H2O and [C-11]acetate injections spaced by a 15-minute interval. As previously validated, with compartmental modeling of kinetics, renal perfusion and oxidative metabolism were estimated respectively with influx rate of [O-15]H2O and efflux rate of [C-11]acetate. Additionally, influx rate of [C-11]acetate was regressed to influx rate of [O-15]H2O. Results: Renal time activity curves of [C-11]-acetate was best fitted with a mono compartmental model compared to a bi-compartmental model (p \textless 0.0001). [C-11]acetate influx rate was significantly correlated with perfusion quantified with [O-15]H2O (r(2) = 0.37, p \textless 0.001) at baseline. This regression allowed the computation of a renal [C-11]acetate extraction fraction (EF), and further the computation of renal blood flow from its influx rate. Conclusion: In healthy subjects, over a wide range of renal perfusion, direct estimates of renal oxygen consumption as well as tissue perfusion can be obtained by PET with a single tracer [C-11]acetate. This approach needs to be validated in CKD patients, and would be of great interest to design clinical protocol aiming at evaluating ischemic nephropathies candidate to revascularization. (C) 2019 Elsevier Inc. All rights reserved.

Although structural and functional neuroimaging techniques have recently been used to investigate the mechanisms of sexual attraction to children, a hallmark of pedophilic disorder, the differences in the processing of child sexual stimuli between men attracted to children and those attracted to adults remain unclear. Here, our purpose was to identify through positron emission tomography the brain responses of 15 male outpatients with pedophilic disorder to validated visual sexual stimuli depicting children (VSSc) and to compare them with 15 male healthy controls matched for sexual orientation (to female or male adults), age, and handedness. The patients' sample comprised both offenders and non-offenders. In response to VSSc, the between-groups analysis showed that activation in the right inferior temporal cortex [Brodmann area (BA) 20] was lower in patients than in controls. Moreover, in patients but not in controls, the presentation of VSSc induced an activation in a more caudal region of the right inferior temporal gyrus (BA 37) and in the left middle occipital gyrus (BA 19). In addition, in patients the level of activation in the caudal right inferior temporal gyrus was positively correlated with ratings of sexual arousal elicited by VSSc, whereas this correlation was negative in BA 20. These results implicate the right inferior temporal gyrus as a possible candidate area mediating sexual arousal in patients with pedophilic disorder and suggest that two of its areas play opposite, i.e., activating and inhibitory, roles., Highlights • Images of children activate the pedophilic patients' right Brodmann area (BA) 37. • Images of children (IC) activate the pedophilic patients' left BA 19. • Right BA37 activation correlates with pedophilic patients' rating of sexual arousal. • IC induce lower right BA 20 activation in pedophilic patients than in controls.

Opioid receptors are localized throughout peripheral and central nervous system and interact with endogenous opioid peptides and drugs including heroin, synthetic opioids, and pain relievers (codeine, morphine). If several opioid PET tracers exist for preclinical studies, only a few have been used in human. Some tracers are selective for one subtype of opioid receptors (e.g., [

OBJECTIVE Chronic kidney disease is associated with higher morbidity and mortality in patients with diabetes. A low-protein diet is recommended to slow diabetic nephropathy progression because each protein load leads to renal hemodynamic variations. The aim of our study was to evaluate whether the advanced glycation end products (AGE) content of a protein load is responsible for the protein-induced renal hemodynamic variations in humans. RESEARCH DESIGN AND METHODS Ten healthy subjects were assigned to a high-protein (1 g/kg) low-AGE (3,000 kU AGE) versus high-AGE (30,000 kU AGE) meal. Renal perfusion, oxygen consumption, and oxygen content were measured before and 120 min after each meal. RESULTS Renal perfusion (3.2 ± 0.5 vs. 3.8 ± 0.4 mL/min/g; P = 0.0002) and oxygen consumption (0.3 ± 0.04 vs. 0.4 ± 0.08 min−1; P = 0.005) increased significantly after the high-AGE meal compared with the low-AGE meal. CONCLUSIONS Our results suggest that the AGE content of a protein load is responsible for renal hemodynamic modifications. Therefore, prevention of diabetic nephropathy progression could aim predominantly at reducing food AGE content.

A single transcranial direct current stimulation (tDCS) session applied over the dorsolateral prefrontal cortex (DLFPC) can be associated with procognitive effects. Furthermore, repeated DLPFC tDCS sessions are under investigation as a new therapeutic tool for a range of neuropsychiatric conditions. A possible mechanism explaining such beneficial effects is a modulation of meso-cortico-limbic dopamine transmission. We explored the spatial and temporal neurobiological effects of bifrontal tDCS on subcortical dopamine transmission during and immediately after the stimulation. In a double blind sham-controlled study, 32 healthy subjects randomly received a single session of either active (20 min, 2 mA; n = 14) or sham (n = 18) tDCS during a dynamic positron emission tomography scan using [11C]raclopride binding. During the stimulation period, no significant effect of tDCS was observed. After the stimulation period, compared with sham tDCS, active tDCS induced a significant decrease in [11C]raclopride binding potential ratio in the striatum, suggesting an increase in extracellular dopamine in a part of the striatum involved in the reward-motivation network. The present study provides the first evidence that bifrontal tDCS induces neurotransmitter release in polysynaptic connected subcortical areas. Therefore, levels of dopamine activity and reactivity should be a new element to consider for a general hypothesis of brain modulation by bifrontal tDCS.

[11C]Methylation (t1/2 = 20.4 min) is a main labeling strategy for the development of PET (positron emission tomography) radiotracers. A straight radiomethylation of amines with cyclotron-produced 11CO2 has been developed to obtain various radiolabeled compounds with good radiochemical yields. This strategy is a new approach to simplifying radiolabeling processes and transpositions onto automatic synthesizers and has been applied to the synthesis of radiolabeled drugs and a PET radiotracer used in the study of Alzheimer's disease.

The α-trifluoromethylthiolation of carbonyl compounds in soft acidic conditions has been developed. With this method only mono-trifluoromethylthiolation was selectively observed. Base-sensitive ketones can then be trifluoromethylthiolated. More sensitive aldehydes are also trifluoromethylthiolated under these conditions with good yields. This work provides a new route towards the synthesis of various valuable trifluoromethylthiolated molecules.

Opioid receptors are localized throughout peripheral and central nervous system and interact with endogenous opioid peptides and drugs including heroin, synthetic opioids, and pain relievers (codeine, morphine). If several opioid PET tracers exist for preclinical studies, only a few have been used in human. Some tracers are selective for one subtype of opioid receptors (e.g., [11C]CAF (carfentanil) for μ receptor) while others are not ([11C]DPN (diprenorphine)). As shown by imaging studies, the opioid system is involved in pain processing, but also in addiction, neuropsychiatric manifestations (harm avoidance, sadness, novelty seeking behavior), feeding and food disorders and, finally, movement disorders and levodopa-induced dyskinesias. However, no imaging study has analyzed the potential dysfunction of opioid system in pain manifestations in Parkinson's disease. In addition, the involvement of opioid system in impulse control disorders and neuropsychiatric manifestations has never been studied in Parkinson's disease. Thus, there is an urgent need to understand the impact of opioid system dysfunctions in Parkinson's disease.

Gait disturbances, including freezing of gait, are frequent and disabling symptoms of Parkinson's disease. They often respond poorly to dopaminergic treatments. Although recent studies have shed some light on their neural correlates, their modulation by dopaminergic treatment remains quite unknown. Specifically, the influence of levodopa on the networks involved in motor imagery (MI) of parkinsonian gait has not been directly studied, comparing the off and on medication states in the same patients. We therefore conducted an [H2 (15) 0] Positron emission tomography study in eight advanced parkinsonian patients (mean disease duration: 12.3 ± 3.8 years) presenting with levodopa-responsive gait disorders and FoG, and eight age-matched healthy subjects. All participants performed three tasks (MI of gait, visual imagery and a control task). Patients were tested off, after an overnight withdrawal of all antiparkinsonian treatment, and on medication, during consecutive mornings. The order of conditions was counterbalanced between subjects and sessions. Results showed that imagined gait elicited activations within motor and frontal associative areas, thalamus, basal ganglia and cerebellum in controls. Off medication, patients mainly activated premotor-parietal and pontomesencephalic regions. Levodopa increased activation in motor regions, putamen, thalamus, and cerebellum, and reduced premotor-parietal and brainstem involvement. Areas activated when patients are off medication may represent compensatory mechanisms. The recruitment of these accessory circuits has also been reported for upper-limb movements in Parkinson's disease, suggesting a partly overlapping pathophysiology between imagined levodopa-responsive gait disorders and appendicular signs. Our results also highlight a possible cerebellar contribution in the pathophysiology of parkinsonian gait disorders through kinesthetic imagery.

Serotonin (5-HT) and oxytocin (OXT) are two neuromodulators involved in human affect and sociality and in disorders like depression and autism. We asked whether these chemical messengers interact in the regulation of emotion-based behavior by administering OXT or placebo to 24 healthy subjects and mapping cerebral 5-HT system by using 2'-methoxyphenyl-(N-2'-pyridinyl)-p-[(18)F]fluoro-benzamidoethylpiperazine ([(18)F]MPPF), an antagonist of 5-HT1A receptors. OXT increased [(18)F]MPPF nondisplaceable binding potential (BPND) in the dorsal raphe nucleus (DRN), the core area of 5-HT synthesis, and in the amygdala/hippocampal complex, insula, and orbitofrontal cortex. Importantly, the amygdala appears central in the regulation of 5-HT by OXT: [(18)F]MPPF BPND changes in the DRN correlated with changes in right amygdala, which were in turn correlated with changes in hippocampus, insula, subgenual, and orbitofrontal cortex, a circuit implicated in the control of stress, mood, and social behaviors. OXT administration is known to inhibit amygdala activity and results in a decrease of anxiety, whereas high amygdala activity and 5-HT dysregulation have been associated with increased anxiety. The present study reveals a previously unidentified form of interaction between these two systems in the human brain, i.e., the role of OXT in the inhibitory regulation of 5-HT signaling, which could lead to novel therapeutic strategies for mental disorders.

Summary Objective Tuberous sclerosis complex (TSC) is often associated with cerebral tubers and medically intractable epilepsy. We reevaluated whether increased uptake of α-[11C]methyl-l-tryptophan (AMT) in cerebral tubers is associated with tuber epileptogenicity. Methods We included 12 patients (six male, 4–53 years old) with TSC and refractory seizures who were evaluated for epilepsy surgery in our center, including video-electroencephalographic (EEG) monitoring, fluid-attenuated inversion recovery magnetic resonance imaging (FLAIR MRI), and positron emission tomography (PET) with α-[11C]methyl-l-tryptophan (AMT-PET). Nine of these 12 patients also underwent intracerebral EEG recording. AMT uptake in each tuber was visually evaluated on PET coregistered with MRI. An AMT uptake index based on lesional/healthy cortex ratio was also calculated. Sensitivity and specificity values of AMT-PET in the detection of epileptogenic lesions were obtained, using the available electroclinical and neuroimaging evidence as the gold standard for epileptogenicity. Results A total of 126 tubers were identified. Two of 12 patients demonstrated a tuber with clearly increased AMT uptake, one of whom also showed a subtle increased AMT uptake in another contralateral tuber. Four other patients showed only subtle increased AMT uptake. The only two tubers with clearly increased AMT uptake proved to be epileptogenic based on intracerebral EEG data, whereas none of the tubers associated with subtle increased AMT uptake were involved at ictal onset. In a per-patient approach, this yielded a sensitivity of clearly increased AMT uptake in detecting tuber epileptogenicity of 17% (2/12 patients), whereas the per-lesion sensitivity and specificity were 12% (95% confidence interval [CI]: 3–34%) and 100% (95% CI: 97–100%), respectively. Significance AMT-PET is a specific neuroimaging technique in the identification of epileptogenic tubers in TSC. Despite its low sensitivity, the clinical usefulness of AMT-PET still deserves to be considered according to the challenging complexity of epilepsy surgery in tuberous sclerosis.

Pulmonary blood flow (PBF) is a critical determinant of oxygenation during acute lung injury (ALI). PET/CT with 18F-FDG allows the assessment of both lung aeration and neutrophil inflammation as well as an estimation of the regional fraction of blood (FB) if compartmental modeling is used to quantify 18F-FDG pulmonary uptake. The aim of this study was to validate the use of FB to assess PBF, with PET and compartmental modeling of 15O-H2O kinetics as a reference method, in both control animals and animals with ALI. For the purpose of studying a wide range of PBF values, supine and prone positions and various positive end-expiratory pressures (PEEPs) and tidal volumes (VTs) were selected. Methods: Pigs were randomized into 3 groups in which ALI was induced by HCl inhalation: pigs studied in the supine position with a low PEEP (5 ± 3 [mean ± SD] cm of H2O; n = 9) or a high PEEP (12 ± 1 cm of H2O; n = 8) and pigs studied in the prone position with a low PEEP (6 ± 3 cm of H2O; n = 9). Also included were a control group that did not have ALI (n = 6) and 2 additional groups (n = 6 each) that had a high VT to maintain a transpulmonary pressure of greater than or equal to 35 cm of H2O and that either received HCl inhalation or did not receive HCl inhalation. PBF and FB were measured with PET and compartmental modeling of 15O-H2O and 18F-FDG kinetics in 10 lung regions along the anterior-to-posterior lung dimension, and both were expressed in each region as a fraction of their values in the whole lung. Results: PBF and FB were strongly correlated (R2 = 0.9), with a slope of the regression line close to unity and a negligible intercept. The mean difference between PBF and FB was 0, and the 95% limits of agreement were −0.035 to 0.035. This good agreement between methods was obtained in both normal and injured lungs and under a wide range of VT, PEEP, and regional PBF values (7–71 mL/kg, 0–15 cm of H2O, and 24–603 mL⋅ min−1⋅100 mL of lung−1, respectively). Conclusion: FB assessed with 18F-FDG is a good surrogate for PBF in both normal animals and animals with ALI. PET/CT has the potential to be used to study ventilation, perfusion, and lung inflammation with a single tracer.

Serotonin (5-HT) neurotransmission plays a key modulatory role in the brain. This system is critical for pathophysiological processes and many drug treatments for brain disorders interact with its 14 subtypes of receptors. Positron emission tomography (PET) is a unique tool for the study of the living brain in translational studies from animal models to patients in neurology or psychiatry. This short review is intended to cover the current status of PET radioligands used for imaging human brain 5-HT receptors. Here, we describe the available PET radioligands for the 5-HT1A, 5-HT1B, 5-HT2A, 5-HT4 and 5-HT6 receptors. Finally, we highlight the future challenges for a functional PET imaging of serotonin receptors, including the research towards specific PET radiotracers for yet unexplored serotonin receptors, the need of radiotracers for endogenous serotonin level measurement and the contribution of agonist radiotracers for functional imaging of 5-HT neurotransmission.

The (benzenesulfonyl)difluoromethylsulfanyl (PhSO2CF2S) group is a valuable substituent with specific properties which can provide access to new applications of fluoroalkylthiolated compounds. Direct introduction of this moiety can be performed by in an electrophilic manner by using a new shelf-stable reagent, namely a (benzenesulfonyl)difluoromethanesulfenamide. Furthermore, mild magnesium-mediated reduction of the PhSO2CF2S group leads to a facile synthesis of difluoromethylthiolated molecules and their deuterated analogs.

See Schrag and Politis (doi:[10.1093/aww190][1]) for a scientific commentary on this article . Apathy, which can occur separately or in combination with depression and anxiety, is one of the most frequently encountered neuropsychiatric symptoms in Parkinson’s disease. Pathophysiological evidence suggests that parkinsonian apathy is primarily due to a mesolimbic dopaminergic denervation, but the role of the serotonergic alteration has never been examined, despite its well-known involvement in the pathogenesis of depression and anxiety. To fill this gap, we address here the pure model of de novo Parkinson’s disease, without the confounding effects of antiparkinsonian treatment. Fifteen apathetic (Lille Apathy Rating Scale scores ≥ −21) and 15 non-apathetic (−36 ≤ Lille Apathy Rating Scale scores ≤ −22) drug-naive de novo parkinsonian patients were enrolled in the present study and underwent detailed clinical assessment and positron emission tomography imaging, using both dopaminergic [11C- N -(3-iodoprop-2E-enyl)-2-beta-carbomethoxy-3-beta-(4-methylphenyl)-nortropane (PE2I)] ( n = 29) and serotonergic [11C- N , N -dimethyl-2-(-2-amino-4-cyanophenylthio)-benzylamine (DASB)] ( n = 27) presynaptic transporter radioligands. Apathetic parkinsonian patients presented higher depression ( P = 0.0004) and anxiety ( P = 0.004) scores – as assessed using the Beck Depression Inventory and the part B of the State-Trait Anxiety Inventory, respectively – compared to the non-apathetic ones – who were not different from the age-matched healthy subjects ( n = 15). Relative to the controls, the non-apathetic parkinsonian patients mainly showed dopaminergic denervation ( n = 14) within the right caudate nucleus, bilateral putamen, thalamus and pallidum, while serotonergic innervation ( n = 15) was fairly preserved. Apathetic parkinsonian patients exhibited, compared to controls, combined and widespread dopaminergic ( n = 15) and serotonergic ( n = 12) degeneration within the bilateral caudate nuclei, putamen, ventral striatum, pallidum and thalamus, but also a specific bilateral dopaminergic disruption within the substantia nigra–ventral tegmental area complex, as well as a specific serotonergic alteration within the insula, the orbitofrontal and the subgenual anterior cingulate cortices. When comparing the two parkinsonian groups, the apathetic patients mainly displayed greater serotonergic alteration in the ventral striatum, the dorsal and the subgenual parts of the anterior cingulate cortices, bilaterally, as well as in the right-sided caudate nucleus and the right-sided orbitofrontal cortex. Regression analyses also revealed that the severity of apathy was moreover mainly related to specific serotonergic lesions within the right-sided anterior caudate nucleus and the orbitofrontal cortex, while the degree of both depression and anxiety was primarily linked to serotonergic disruption within the bilateral subgenual parts and/or the right dorsal part of the anterior cingulate cortex, without prominent role of the dopaminergic degeneration in the pathogenesis of these three non-motor signs. Altogether, these findings highlight a prominent role of the serotonergic degeneration in the expression of the neuropsychiatric symptoms occurring at the onset of Parkinson’s disease. * Abbreviations : ACC : anterior cingulate cortex BDI : Beck Depression Inventory BPND : non-displaceable binding potential DASB : N , N -dimethyl-2-(-2-amino-4-cyanophenylthio)-benzylamine DAT : dopaminergic transporter GPe : globus pallidus pars externa or external pallidum LARS : Lille Apathy Rating Scale MDS-UPDRS : Movement Disorders Society Unified Parkinson’s Disease Rating Scale OFC : orbitofrontal cortex PE2I : N -(3-iodoprop-2E-enyl)-2-beta-carbomethoxy-3-beta-(4-methylphenyl)-nortropane SERT : serotonergic transporter SN-VTA : substantia nigra–ventral tegmental area STAI-YB : State-Trait Anxiety Inventory part B [1]: /lookup/doi/10.1093/brain/aww190

The (benzenesulfonyl)difluoromethylsulfanyl (PhSO2CF2S) group is a valuable substituent with specific properties which can provide access to new applications of fluoroalkylthiolated compounds. Direct introduction of this moiety can be performed by in an electrophilic manner by using a new shelf-stable reagent, namely a (benzenesulfonyl)difluoromethanesulfenamide. Furthermore, mild magnesium-mediated reduction of the PhSO2CF2S group leads to a facile synthesis of difluoromethylthiolated molecules and their deuterated analogs.

Our objective was to evaluate amyloid deposition in posterior cortical atrophy (PCA), using both cerebrospinal fluid (CSF) biomarker analysis and amyloid imaging. Five PCA patients, selected based on their neuropsychological profile and atrophic changes in posterior regions on MRI, underwent CSF analysis. CSF amyloid-beta 1-42, total tau, and phosphorylated tau at threonine 181 levels were determined. They also had positron emission tomography (PET) with Pittsburgh Compound B ([(11)C]PIB). [(11)C]PIB ratio images were assessed with visual, regional and voxel-based analyses and compared to eight typical Alzheimer's disease (AD) patients and eight controls. The biological profile in the five PCA patients, resulting from CSF and [(11)C]PIB images analysis, was consistent with AD. Individual comparisons of PCA patients' [(11)C]PIB images with the AD group with Statistical Parametric Mapping (SPM) revealed a distinctive posterior uptake in four out of the five patients showing increased amyloid deposition in occipital, temporal, and/or parietal regions. ROI group analysis showed a tendency for higher amyloid deposition in occipital and temporal regions. However, this pattern was not found with SPM group analysis when the global level of [(11)C]PIB uptake was used as a covariate. Our results indicate that amyloid burden can be demonstrated in vivo in PCA suggesting a diagnosis of AD. PCA patients may present a higher global amyloid load than AD that was not related to age at onset, disease severity, disease duration, or educational level in our study. Combined CSF and PET biomarkers seem helpful for in vivo diagnosis of this focal syndrome with underlying AD pathology.

International audience; PURPOSE: Gastro-entero-pancreatic (GEP) endocrine tumours are a heterogenous group of tumours of variable localization and prognosis. It has been suggested that positron emission tomography (PET) using 2-[18F]fluoro-2-deoxy-D-glucose (18F-FDG) may have a prognostic value and help to identify patients at risk of progression. [18F]fluoro-3'-deoxy-3'-L-fluorothymidine (18F-FLT) has been recently developed as a PET proliferation tracer. At present, there are no studies investigating its role in GEP. The aim of this prospective study was to assess the value of 18F-FLT-PET for the evaluation of GEP. MATERIALS AND METHODS: Ten patients with biopsy-proven locally advanced or metastasized, well-differentiated GEP neuroendocrine tumours were prospectively enrolled and scheduled for 18F-FDG and 18F-FLT-PET. Images were compared with other conventional diagnostic procedures, namely computed tomography, ultrasound, somatostatin receptor scintigraphy and with clinical and diagnostic follow-up. RESULTS: Evaluation criteria were interpreted in terms of assumed presence of tumoral tissue. According to the patient's status, FDG was positive in five out of the seven patients with stable disease and in two out of the three patients with progressive disease. No positive case was identified by 18F-FLT in either the primary or the metastatic tumour site, whatever the status of patients, and this was probably a reflection of the slow proliferation rate of tumours. CONCLUSION: These preliminary data suggest that 18F-FLT-PET is not a suitable tracer for the evaluation of advanced well-differentiated GEP tumours. FDG showed good diagnostic performance but does not help to identify patients at risk of progression.

This study aimed to characterize the neural networks involved in patients with chronic low-back pain during hypnoanalgesia. PET was performed in 2 states of consciousness, normal alertness and hypnosis. Two groups of patients received direct or indirect analgesic suggestion. The normal alertness state showed activations in a cognitive-sensory pain modulation network, including frontotemporal cortex, insula, somatosensory cortex, and cerebellum. The hypnotic state activated an emotional pain modulation network, including frontotemporal cortex, insula, caudate, accumbens, lenticular nuclei, and anterior cingulate cortex (ACC). Direct suggestion activated cognitive processes via frontal, prefrontal, and orbitofrontal cortices, while indirect suggestion activated a widespread and more emotional network including frontal cortex, anterior insula, inferior parietal lobule, lenticular nucleus, and ACC. Confirmed by visual analog scale data, these results suggest that chronic pain modulation is greater with hypnosis, which enhances both activated networks.

Background— Despite the major role attributed to myocardial vagal activity in left ventricular arrhythmogenesis in chronic myocardial infarction, the impact of infarction on left ventricular muscarinic receptor density remains unknown. Methods and Results— Left ventricular muscarinic receptor density was measured in vivo by positron emission tomography using the specific antagonist [ 11 C]methylquinuclidinyl benzilate ([ 11 C]MQNB) in 11 patients 43�20 days after myocardial infarction and 9 healthy volunteers. The extent of myocardial damage was quantified by delayed contrast-enhanced MRI. Three short-axis slices from each subject were analyzed in matched positron emission tomography and MRI images. A 2-injection positron emission tomography protocol was used; [ 11 C]MQNB time-activity curves were obtained in 6 regions per slice and fitted to a 3-compartment ligand-receptor model. Four classes of myocardial regions were considered: normal (in volunteers); remote, supplied by healthy or 70% diameter reduction arteries and without signs of damage; and damaged, with damage. The muscarinic receptor density in remote (67�30 pmol/mL tissue; n=86) and potentially damaged (71�30 pmol/mL tissue; n=42) regions of patients was higher than in normal regions of volunteers (32�17 pmol/mL tissue; n=156; P P P =0.093). Conclusions— Vagal control in patients with chronic myocardial infarction involves muscarinic receptor upregulation in remote nondamaged left ventricular regions. Our results suggest that the receptor density remains within normal values in myocardial regions containing damaged tissue.