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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 [

Ribonucleoprotein (RNP) granules are dynamic condensates enriched in regulatory RNA binding proteins (RBPs) and RNAs under tight spatiotemporal control. Extensive recent work has investigated the molecular principles underlying RNP granule assembly, unraveling that they form through the self-association of RNP components into dynamic networks of interactions. How endogenous RNP granules respond to external stimuli to regulate RNA fate is still largely unknown. Here, we demonstrate through high-resolution imaging of intact

AIMS: Alpha‐synuclein (α‐syn) aggregation is a neuropathological hallmark of neurodegenerative synucleinopathies. This in vivo study explored glucose metabolism and dopaminergic and serotoninergic neurotransmission in KO α‐syn, wild‐type mice and an accelerated murine model of synucleinopathy (M83). METHODS: MicroPET acquisitions were performed in all animals aged 5‐6 months using five radiotracers exploring brain glucose metabolism ([(18)F]FDG), dopamine neurotransmission ([(11)C]raclopride, [(11)C]PE2I) and serotonin neurotransmission ([(18)F]MPPF, [(11)C]DASB). For all radiotracers, except [(18)F]FDG, PET data were analyzed with a MRI‐based VOI method and a voxel‐based analysis. RESULTS: MicroPET data showed a decrease in [(11)C]raclopride uptake in the caudate putamen of KO α‐syn mice, in comparison with M83 and WT mice, reflecting a lower concentration of D(2) receptors. The increase in [(18)F]MPPF uptake in M83 vs WT and KO mice indicates overexpression of 5‐HT (1A) receptors. The lack of change in dopamine and serotonin transporters in all groups suggests unchanged neuronal density. CONCLUSIONS: This PET study highlights an effect of α‐syn modulation on the expression of the D(2) receptor, whereas aggregated α‐syn leads to overexpression of 5‐HT (1A) receptor, as a pathophysiological signature.

The aim of this study was to perform in-vitro and in-vivo radiopharmacological characterizations of [In-vitro autoradiography and saturation binding assays were performed in postmortem brain tissues from rat, pig, non-human primate and human caudate nucleus, completed by serum stability assessment in all species and cerebral radiometabolite and biodistribution studies in rat.In all species, autoradiography data revealed high binding levels of [These radiopharmacological data confirm that [

International audience; Accumulation of α-synuclein (α-syn) is a neuropathological hallmark of synucleinopathies. To date, no selective α-syn positron emission tomography (PET) radiotracer has been identified. Our objective was to develop the first original, selective, and specific α-syn PET radiotracer. Chemical design inspired from three structural families that demonstrated interesting α-syn binding characteristics was used as a starting point. Bioinformatics modeling of α-syn fibrils was then employed to select the best molecular candidates before their syntheses. An in vitro binding assay was performed to evaluate the affinity of the compounds. Radiotracer specificity and selectivity were assessed by in vitro autoradiography and in vivo PET studies in animal (rodents) models. Finally, gold standard in vitro autoradiography with patients’ postmortem tissues was performed to confirm/infirm the α-syn binding characteristics. Two compounds exhibited a good brain availability and bound to α-syn and Aβ fibrils in a rat model. In contrast, no signal was observed in a mouse model of synucleinopathy. Experiments in human tissues confirmed these negative results.

Alpha-synuclein (α-syn) aggregation is a neuropathological hallmark of many neurodegenerative diseases, collectively termed synucleinopathies. There is currently no pre-mortem diagnosis tool for these diseases. Although some compounds have been described as potential ligands for α-syn aggregates, no specific PET radiotracer of aggregated α-syn is currently available. Recently, [(18)F]BF227 has been proposed as an α-syn PET radiotracer in the absence of other specific candidates. We proposed here, for the first time, to use this radiotracer in an accelerated mouse model of synucleinopathy presenting α-syn depositions in brainstem and thalamus. Our in vivo and in vitro studies showed that [(18)F]BF227 does not bind to α-syn aggregates. These results highlight the fact that [(18)F]BF227 PET has no suitable characteristics for monitoring this experimental synucleinopathy, justifying the need to develop alternative α-syn PET radiotracers.

PET brain imaging of the serotonin 1A (5-hydroxytryptamine 1A [5-HT(1A)]) receptor has been widely used in clinical studies. Currently, only a few well-validated radiolabeled antagonist tracers are available for in vivo imaging of this central receptor. 5-HT(1A) receptors exist in high- and low-affinity states, depending on their coupling to G proteins. Agonists bind preferentially to receptors in the high-affinity state and thereby could provide a measure of functional 5-HT(1A) receptors. Therefore, it is of great interest to develop an (18)F-labeled full agonist 5-HT(1A) receptor radiotracer. In this study, we radiolabeled the high-affinity 5-HT(1A) receptor agonist (18)F-F13714 and investigated its potential as a PET tracer.F13714 nitro precursor was synthesized and radiolabeled via a fluoronucleophilic substitution. In vitro binding assays were performed using established protocols. Radiopharmacologic evaluations included in vitro autoradiography in rat brain and PET scans on anesthetized cats.The chemical and radiochemical purities of (18)F-F13714 were greater than 98%. F13714 has a high affinity (0.1 nM) and selectivity for 5-HT(1A) receptors. In vitro (18)F-F13714 binding in rats was consistent with the known 5-HT(1A) receptors distribution (hippocampus and cortical areas) and was particularly high in the dorsal raphe. In vitro binding of (18)F-F13714 was blocked in a dose-dependent fashion by WAY100635, the prototypical 5-HT(1A) antagonist, and by the endogenous agonist, serotonin (5-HT). Addition of Gpp(NH)p also inhibited in vitro (18)F-F13714 binding, consistent with a preferential binding of the compound to G-protein-coupled receptors. Ex vivo tissue measurements in rat revealed an absence of brain radioactive metabolites. In vivo studies showed that the radiotracer entered the cat brain readily and displayed a preferential labeling of 5-HT(1A) receptors located in cingulate cortex. In vivo labeling was prevented by preinjection of WAY100635.(18)F-F13714 is a radiofluorinated agonist that presents suitable characteristics for probing the high-affinity states of the 5-HT(1A) receptors in vitro and in vivo. Thus, it is a promising tool for investigation of 5-HT(1A) agonist binding in the living human brain.

Background Extra-cellular roles of Tat might be the main cause of maintenance of HIV-1 infected CD4 T cells or reservoir cells. We developed a synthetic vaccine based on a Tat variant of 101 residues called Tat Oyi, which was identified in HIV infected patients in Africa who did not progress to AIDS. We compared, using rabbits, different adjuvants authorized for human use to test on ELISA the recognition of Tat variants from the five main HIV-1 subtypes. A formulation was tested on macaques followed by a SHIV challenge with a European strain. Results Tat Oyi with Montanide or Calcium Phosphate gave rabbit sera able to recognize all Tat variants. Five on seven Tat Oyi vaccinated macaques showed a better control of viremia compared to control macaques and an increase of CD8 T cells was observed only on Tat Oyi vaccinated macaques. Reservoir cells were not detectable at 56 days post-challenge in all Tat Oyi vaccinated macaques but not in the controls. Conclusion The Tat Oyi vaccine should be efficient worldwide. No toxicity was observed on rabbits and macaques. We show in vivo that antibodies against Tat could restore the cellular immunity and make it possible the elimination of reservoir cells.

IntroductionPreclinical in vivo imaging requires precise and reproducible delineation of brain structures. Manual segmentation is time consuming and operator dependent. Automated segmentation as usually performed via single atlas registration fails to account for anatomo-physiological variability. We present, evaluate, and make available a multi-atlas approach for automatically segmenting rat brain MRI and extracting PET activies.MethodsHigh-resolution 7T 2DT2 MR images of 12 Sprague-Dawley rat brains were manually segmented into 27-VOI label volumes using detailed protocols. Automated methods were developed with 7/12 atlas datasets, i.e. the MRIs and their associated label volumes. MRIs were registered to a common space, where an MRI template and a maximum probability atlas were created. Three automated methods were tested: 1/registering individual MRIs to the template, and using a single atlas (SA), 2/using the maximum probability atlas (MP), and 3/registering the MRIs from the multi-atlas dataset to an individual MRI, propagating the label volumes and fusing them in individual MRI space (propagation & fusion, PF). Evaluation was performed on the five remaining rats which additionally underwent [18F]FDG PET. Automated and manual segmentations were compared for morphometric performance (assessed by comparing volume bias and Dice overlap index) and functional performance (evaluated by comparing extracted PET measures).ResultsOnly the SA method showed volume bias. Dice indices were significantly different between methods (PF>MP>SA). PET regional measures were more accurate with multi-atlas methods than with SA method.ConclusionsMulti-atlas methods outperform SA for automated anatomical brain segmentation and PET measure's extraction. They perform comparably to manual segmentation for FDG-PET quantification. Multi-atlas methods are suitable for rapid reproducible VOI analyses.