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Maternal infection during pregnancy and childhood social trauma have been associated with neurodevelopmental and affective disorders, such as schizophrenia, autism spectrum disorders, bipolar disorder and depression. These disorders are characterized by changes in microglial cells, which play a notable role in synaptic pruning, and synaptic deficits. Here, we investigated the effect of prenatal infection and social adversity during adolescence – either alone or in combination – on behavior, microglia, and synaptic density. Male offspring of pregnant rats injected with poly I:C, mimicking prenatal infection, were exposed to repeated social defeat during adolescence. We found that maternal infection during pregnancy prevented the reduction in social behavior and increase in anxiety induced by social adversity during adolescence. Furthermore, maternal infection and social adversity, alone or in combination, induced hyperlocomotion in adulthood. Longitudinal in vivo imaging with [11C]PBR28 positron emission tomography revealed that prenatal infection alone and social adversity during adolescence alone induced a transient increase in translocator protein TSPO density, an indicator of glial reactivity, whereas their combination induced a long-lasting increase that remained until adulthood. Furthermore, only the combination of prenatal infection and social adversity during adolescence induced an increase in microglial cell density in the frontal cortex. Prenatal infection increased proinflammatory cytokine IL-1β protein levels in hippocampus and social adversity reduced anti-inflammatory cytokine IL-10 protein levels in hippocampus during adulthood. This reduction in IL-10 was prevented if rats were previously exposed to prenatal infection. Adult offspring exposed to prenatal infection or adolescent social adversity had a higher synaptic density in the frontal cortex, but not hippocampus, as evaluated by synaptophysin density. Interestingly, such an increase in synaptic density was not observed in rats exposed to the combination of prenatal infection and social adversity, perhaps due to the long-lasting increase in microglial density, which may lead to an increase in microglial synaptic pruning. These findings suggest that changes in microglia activity and cytokine release induced by prenatal infection and social adversity during adolescence may be related to a reduced synaptic pruning, resulting in a higher synaptic density and behavioral changes in adulthood.

Adverse experiences in early life can increase mental vulnerability to immune challenges experienced later in life, which may induce the development of stress-related psychopathologies. Here, we investigated whether the combined effect of both events is higher if the first adverse experience occurs when the brain is still in development. Therefore, male Wistar rats were exposed to repeated social defeat (RSD, first hit) during juvenile age or adulthood and to an immune challenge consisting of a single injection of lipopolysaccharide (LPS, second hit) in adulthood. Control animals were not exposed to RSD, but only to the LPS challenge. Translocator protein density, a marker for reactive microglia, microglia cell density and plasma corticosterone levels were measured using in vivo [11C]PBR28 positron emission tomography, iba1 immunostaining, and corticosterone ELISA, respectively. Anhedonia, social behavior and anxiety were measured with the sucrose preference, social interaction, and open field tests, respectively. Rats exposed to RSD during juvenile age exhibited enhanced anhedonia and social interaction dysfunction after an immune challenge in adulthood. This enhanced susceptibility was not observed in rats exposed to RSD during adulthood. In addition, exposure to RSD synergistically increased microglia cell density and glial reactivity to the LPS challenge. This increase in microglia cell density and reactivity to the LPS challenge was more pronounced in rats exposed to RSD during juvenile age than in adulthood. Exposure to RSD alone in juvenile age or adulthood induced similar short-term anhedonia, a long-lasting increase in plasma corticosterone and microglial activity, but no change in anxiety and social behavior. Our findings indicate that exposure to social stress during juvenile age, but not adulthood, primes the immune system and increases the sensitivity to an immune challenge experienced later in life. This suggests that juvenile social stress can have more deleterious effects in the long term than similar stress in adulthood.

Multiple sclerosis (MS) is an inflammatory demyelinating disease. Current treatments are focussed on immune suppression to modulate pathogenic activity that causes myelin damage. New treatment strategies are needed to prevent demyelination and promote remyelination. Development of such myelin repair therapies require a sensitive and specific biomarker for efficacy evaluation. Recently, it has been shown that quantification of myelin density is possible using [11C]MeDAS PET. This method, however, requires arterial blood sampling to generate an arterial input function (AIF). As the invasive nature of arterial sampling will reduce clinical applicability, the purpose of this study was to assess whether an image-derived input function (IDIF) can be used as an alternative way to facilitate its routine clinical use.Six healthy controls and 11 MS patients underwent MRI and [11C]MeDAS PET with arterial blood sampling. The application of both population-based whole blood-to-plasma conversion and metabolite corrections were assessed for the AIF. Next, summed images of the early time frames (0–70 s) and the frame with the highest blood-brain contrast were used to generate IDIFs. IDIFs were created using either the hottest 2, 4, 6 or 12 voxels, or an isocontour of the hottest 10% voxels of the carotid artery. This was followed by blood-to-plasma conversion and metabolite correction of the IDIF.The application of a population-based metabolite correction of the AIF resulted in high correlations of tracer binding (Ki) within subjects, but variable bias across subjects. All IDIFs had a sharper and higher peak in the blood curves than the AIF, most likely due to dispersion during blood sampling. All IDIF methods resulted in similar high correlations within subjects (r = 0.95–0.98), but highly variable bias across subjects (mean slope=0.90–1.09).Therefore, both the use of population based blood-plasma and metabolite corrections and the generation of the image-derived whole-blood curve resulted in substantial bias in [11C]MeDAS PET quantification, due to high inter-subject variability. Consequently, when unbiased quantification of [11C]MeDAS PET data is required, individual AIF needs to be used.

Objectives: Currently, multiple sclerosis is treated with anti-inflammatory therapies, but these treatments lack efficacy in progressive disease. New treatment strategies aim to repair myelin damage and efficacy evaluation of such new therapies would benefit from validated myelin imaging techniques. Several MRI methods for quantification of myelin density are available now. This systematic review aims to analyse the performance of these MRI methods. Methods: Studies comparing myelin quantification by MRI with histology, the current gold standard, or assessing reproducibility were retrieved from PubMed/MEDLINE and Embase (until December 2019). Included studies assessed both myelin histology and MRI quantitatively. Correlation or variance measurements were extracted from the studies. Non-parametric tests were used to analyse differences in study methodologies. Results: The search yielded 1348 unique articles. Twenty-two animal studies and 13 human studies correlated myelin MRI with histology. Eighteen clinical studies analysed the reproducibility. Overall bias risk was low or unclear. All MRI methods performed comparably, with a mean correlation between MRI and histology of R2=0.54 (SD=0.30) for animal studies, and R2=0.54 (SD=0.18) for human studies. Reproducibility for the MRI methods was good (ICC=0.75–0.93, R2=0.90–0.98, COV=1.3–27%), except for MTR (ICC=0.05–0.51). Conclusions: Overall, MRI-based myelin imaging methods show a fairly good correlation with histology and a good reproducibility. However, the amount of validation data is too limited and the variability in performance between studies is too large to select the optimal MRI method for myelin quantification yet.

Background: High physiological 16α-[18F]-fluoro-17β-estradiol ([18F]-FES) uptake in the abdomen is a limitation of this positron emission tomography (PET) tracer. Therefore, we investigated the effect of food intake prior to PET acquisition on abdominal background activity in [18F]-FES-PET scans. Methods: Breast cancer patients referred for [18F]-FES-PET were included. Three groups were designed: (1) patients who consumed a chocolate bar (fatty meal) between tracer injection and imaging (n = 20), (2) patients who fasted before imaging (n = 20), and (3) patients without diet restrictions (control group, n = 20). We compared the physiological [18F]-FES uptake, expressed as mean standardized uptake value (SUVmean), in the abdomen between groups. Results: A significant difference in [18F]-FES uptake in the gall bladder and stomach lumen was observed between groups, with the lowest values for the chocolate group and highest for the fasting group (p = 0.015 and p = 0.011, respectively). Post hoc analysis showed significant differences in the SUVmean of these organs between the chocolate and fasting groups, but not between the chocolate and control groups. Conclusion: This exploratory study showed that, compared to fasting, eating chocolate decreases physiological gall bladder and stomach [18F]-FES uptake; further reduction through a normal diet was not seen. A prospective study is warranted to confirm this finding.

In the last few decades, a number of radiopharmaceuticals for imaging inflammation have been proposed that differ in their specificity and mechanism of uptake in inflamed foci as compared to the traditional inflammation imaging agents. Radiolabelled cytokines represent a reliable tool for the preclinical diagnosis of chronic inflammatory processes, even before anatomical and functional changes occur in affected tissues. Moreover, the introduction of radiolabelled monoclonal antibodies and sophisticated technique like PET/CT now make the field of inflammation imaging highly specific and accurate. In this review, different approaches of the established and experimental radiopharmaceuticals for imaging of chronic inflammation are discussed.Nas últimas décadas, foram propostos vários radiofármacos para obtenção de imagens de sítios de inflamação, diferindo em suas especificidades e mecanismos de captação quando comparados aos tradicionais agentes utilizados para essa finalidade. Citocinas radiomarcadas representam uma ferramenta confiável para o diagnóstico pré-clinico precoce de processos inflamatórios crônicos, anterior às alterações anatômicas e funcionais, em tecidos afetados. Além disso, a introdução de anticorpos monoclonais radiomarcados e técnicas sofisticadas, como PET/CT, tornaram a obtenção de imagens de focos de inflamação altamente específica e apurada. Nesta revisão, diferentes abordagens com radiofármacos já bem estabelecidos e com outros em nível experimental para a obtenção de imagens de sítios de inflamação crônica são discutidas.

β-Glucuronidase (β-GUS) plays an important role in inflammation and degenerative processes. The enzyme has also been investigated as a target in prodrug therapy for cancer. To investigate the role of β-GUS in pathologies and to optimize β-GUS-based prodrug therapies, we recently developed a positron emission tomographic (PET) tracer, 1-O-(4-(2-fluoroethyl-carbamoyloxymethyl)-2-nitrophenyl)-O-β-D>-glucopyronuronate ([ 18 F]FEAnGA), which proved to be selectively cleaved by β-GUS. Here we present the in vivo evaluation of [ 18 F]FEAnGA for imaging of β-GUS in a tumor/inflammation model. Ex vivo biodistribution of [ 18 F]FEAnGA was conducted in healthy rats. PET imaging and pharmacokinetic modeling were performed in Wistar rats bearing C6 tumors of different sizes and sterile inflammation. The biodistribution studies of [ 18 F]FEAnGA indicated low uptake in major organs and rapid excretion through the renal pathway. MicroPET studies revealed three times higher uptake in the viable part of larger C6 gliomas than in smaller C6 gliomas. Uptake in inflamed muscle was significantly higher than in control muscle. The distribution volume of [ 18 F]FEAnGA in the viable part of the tumor correlated well with the cleavage of the tracer to [ 18 F]fluoroethylamine and the spacer 4-hydroxy-3-nitrobenzyl alcohol. [ 18 F]FEAnGA is a PET tracer able to detect increased activity of β-GUS in large solid tumors and in inflamed tissues.

The introduction of neural stem cells into the brain has promising therapeutic potential for the treatment of neurodegenerative diseases. To monitor the cellular replacement therapy, that is, to determine stem cell migration, survival, and differentiation, in vivo tracking methods are needed. Ideally, these tracking methods are noninvasive. Noninvasive tracking methods that have been successfully used for the visualization of blood-derived progenitor cells include magnetic resonance imaging and radionuclide imaging using single-photon emission computed tomography (SPECT) and positron emission tomography (PET). The SPECT tracer In-111-oxine is suitable for stem cell labeling, but for studies in small animals, the higher sensitivity and facile quantification that can be obtained with PET are preferred. Here the potential of 2′-[ 18 F]fluoro-2′-deoxy-D-glucose ([ 18 F]-FDG), a PET tracer, for tracking of neural stem cell (NSCs) trafficking toward an inflammation site was investigated. [ 18 F]-FDG turns out to be a poor radiopharmaceutical to label NSCs owing to the low labeling efficiency and substantial release of radioactivity from these cells. Efflux of [ 18 F]-FDG from NSCs can be effectively reduced by phloretin in vitro, but inhibition of tracer release is insufficient in vivo for accurate monitoring of stem cell trafficking.