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Purpose: The in vivo binding parameters of the novel imidazopyridine TSPO ligand [F]PBR102 were assessed and compared with those of [F]PBR111 in a rodent model of neuroinflammation. The validity of the key assumptions of the simplified reference tissue model (SRTM) for estimation of binding potential (BP) was determined, with validation against a two-tissue compartment model (2TC). Methods: Acute neuroinflammation was assessed 7 days after unilateral stereotaxic administration of ( R, S)-α-amino-3-hydroxy-5-methyl-4-isoxazolopropionique (AMPA) in anaesthetized adult Wistar rats. Anaesthetized rats were implanted with a femoral arterial cannula then injected with a low mass of [F]PBR102 or [F]PBR111 and dynamic images were acquired over 60 min using an INVEON PET/CT camera. Another population of rats underwent the same PET protocol after pretreatment with a presaturating mass of the same unlabelled tracer (1 mg/kg) to assess the validity of the reference region for SRTM analysis. Arterial blood was sampled during imaging, allowing pharmacokinetic determination of radiotracer concentrations. Plasma activity concentration-time curves were corrected for unchanged tracer based on metabolic characterization experiments in a separate cohort of Wistar rats. The stability of neuroinflammation in both imaging cohorts was assessed by [I] CLINDE TSPO quantitative autoradiography, OX42/GFAP immunohistochemistry, Fluoro-Jade C histology, and elemental mapping using microparticle-induced x-ray emission spectroscopy. The BP of each ligand were assessed in the two cohorts of lesioned animals using both SRTM and a 2TC with arterial parent compound concentration, coupled with the results from the presaturation cohort for comparison and validation of the SRTM. Results: The BPs of [F]PBR102 [F]PBR111 were equivalent, with improved signal-to-noise ratio and sensitivity compared with [C]PK11195. The presaturation study showed differences in the volume of distribution between the ipsilateral striatum and the striatum contralateral to the injury (0.7) indicating that an assumption of the SRTM was not met. The modelling indicated that the BPs were consistent for both ligands. Between the SRTM and 2TC model, the BPs were highly correlated, but there was a bias in BP. Conclusion: [F]PBR102 and [F]PBR111 have equivalent binding properties in vivo, displaying significantly greater BPs with lower signal-to-noise ratio than [C]PK11195. While an assumption of the SRTM was not met, this modelling approach was validated against 2TC modelling for both ligands, facilitating future use in longitudinal PET imaging of neuroinflammation. [ABSTRACT FROM AUTHOR]

The 18 kDa translocator protein is a well-known biomarker of neuroinflammation, but also plays a role in homeostasis. PET with 18 kDa translocator protein radiotracers [ 11 C]PBR28 in humans and [ 18 F]GE180 in mice has demonstrated sex-dependent uptake patterns in the healthy brain, suggesting sex-dependent 18 kDa translocator protein expression, although humans and mice had differing results. This study aimed to assess whether the 18 kDa translocator protein PET radiotracer [ 18 F]LW223 exhibited sexually dimorphic uptake in healthy murine brain and peripheral organs. Male and female C57Bl6/J mice (13.6 ± 5.4 weeks, 26.8 ± 5.4 g, mean ± SD) underwent 2 h PET scanning post-administration of [ 18 F]LW223 (6.7 ± 3.6 MBq). Volume of interest and parametric analyses were performed using standard uptake values (90-120 min). Statistical differences were assessed by unpaired t -test or two-way ANOVA with Šidak's test (alpha = 0.05). The uptake of [ 18 F]LW223 was significantly higher across multiple regions of the male mouse brain, with the most pronounced difference detected in hypothalamus ( P < 0.0001). Males also exhibited significantly higher [ 18 F]LW223 uptake in the heart when compared to females ( P = 0.0107). Data support previous findings on sexually dimorphic 18 kDa translocator protein radiotracer uptake patterns in mice and highlight the need to conduct sex-controlled comparisons in 18 kDa translocator protein PET imaging studies., Competing Interests: A patent for TSPO binders has been submitted (application GB1810312.7, PCT/EP2019/066546 and WO2019243616). No other potential conflicts of interest relevant to this article exist., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Autoimmune limbic encephalitis (ALE) presents with new-onset mesial temporal lobe seizures, progressive memory disturbance, and other behavioral and cognitive changes. CD8 T cells are considered to play a key role in those cases where autoantibodies (ABs) target intracellular antigens or no ABs were found. Assessment of such patients presents a clinical challenge, and novel noninvasive imaging biomarkers are urgently needed. Here, we demonstrate that visualization of the translocator protein (TSPO) with [ 18 F]DPA-714-PET-MRI reveals pronounced microglia activation and reactive gliosis in the hippocampus and amygdala of patients suspected with CD8 T cell ALE, which correlates with FLAIR-MRI and EEG alterations. Back-translation into a preclinical mouse model of neuronal antigen-specific CD8 T cell-mediated ALE allowed us to corroborate our preliminary clinical findings. These translational data underline the potential of [ 18 F]DPA-714-PET-MRI as a clinical molecular imaging method for the direct assessment of innate immunity in CD8 T cell-mediated ALE.

Current PET datasets are becoming larger, thereby increasing the demand for fast and reproducible processing pipelines. This paper presents a freely available, open source, Python-based software package called NiftyPAD, for versatile analyses of static, full or dual-time window dynamic brain PET data. The key novelties of NiftyPAD are the analyses of dual-time window scans with reference input processing, pharmacokinetic modelling with shortened PET acquisitions through the incorporation of arterial spin labelling (ASL)-derived relative perfusion measures, as well as optional PET data-based motion correction. Results obtained with NiftyPAD were compared with the well-established software packages PPET and QModeling for a range of kinetic models. Clinical data from eight subjects scanned with four different amyloid tracers were used to validate the computational performance. NiftyPAD achieved [Formula: see text] correlation with PPET, with absolute difference [Formula: see text] for linearised Logan and MRTM2 methods, and [Formula: see text] correlation with QModeling, with absolute difference [Formula: see text] for basis function based SRTM and SRTM2 models. For the recently published SRTM ASL method, which is unavailable in existing software packages, high correlations with negligible bias were observed with the full scan SRTM in terms of non-displaceable binding potential ([Formula: see text]), indicating reliable model implementation in NiftyPAD. Together, these findings illustrate that NiftyPAD is versatile, flexible, and produces comparable results with established software packages for quantification of dynamic PET data. It is freely available ( https://github.com/AMYPAD/NiftyPAD ), and allows for multi-platform usage. The modular setup makes adding new functionalities easy, and the package is lightweight with minimal dependencies, making it easy to use and integrate into existing processing pipelines., (© 2023. The Author(s).)

Background: Despite its widespread use, the semi-quantitative standardized uptake value ratio (SUVR) may be biased compared with the distribution volume ratio (DVR). This bias may be partially explained by changes in cerebral blood flow (CBF) and is likely to be also dependent on the extent of the underlying amyloid-β (Aβ) burden. This study aimed to compare SUVR with DVR and to evaluate the effects of underlying Aβ burden and CBF on bias in SUVR in mainly cognitively unimpaired participants. Participants were scanned according to a dual-time window protocol, with either [ 18 F]flutemetamol (N = 90) or [ 18 F]florbetaben (N = 31). The validated basisfunction-based implementation of the two-step simplified reference tissue model was used to derive DVR and R 1 parametric images, and SUVR was calculated from 90 to 110 min post-injection, all with the cerebellar grey matter as reference tissue. First, linear regression and Bland-Altman analyses were used to compare (regional) SUVR with DVR. Then, generalized linear models were applied to evaluate whether (bias in) SUVR relative to DVR could be explained by R 1 for the global cortical average (GCA), precuneus, posterior cingulate, and orbitofrontal region., Results: Despite high correlations (GCA: R 2  ≥ 0.85), large overestimation and proportional bias of SUVR relative to DVR was observed. Negative associations were observed between both SUVR or SUVR bias and R 1, albeit non-significant., Conclusion: The present findings demonstrate that bias in SUVR relative to DVR is strongly related to underlying Aβ burden. Furthermore, in a cohort consisting mainly of cognitively unimpaired individuals, the effect of relative CBF on bias in SUVR appears limited. EudraCT Number: 2018-002277-22, registered on: 25-06-2018., (© 2022. The Author(s).)

Purpose: Translocator protein 18-kDa (TSPO) imaging with positron emission tomography (PET) is widely used in research studies of brain diseases that have a neuro-immune component. Quantification of TSPO PET images, however, is associated with several challenges, such as the lack of a reference region, a genetic polymorphism affecting the affinity of the ligand for TSPO, and a strong TSPO signal in the endothelium of the brain vessels. These challenges have created an ongoing debate in the field about which type of quantification is most useful and whether there is an appropriate simplified model., Methods: This review focuses on the quantification of TSPO radioligands in the human brain. The various methods of quantification are summarized, including the gold standard of compartmental modeling with metabolite-corrected input function as well as various alternative models and non-invasive approaches. Their advantages and drawbacks are critically assessed., Results and Conclusions: Researchers employing quantification methods for TSPO should understand the advantages and limitations associated with each method. Suggestions are given to help researchers choose between these viable alternative methods., (© 2021. The Author(s).)

Purpose: To provide a comprehensive assessment of the novel 18 kDa translocator protein (TSPO) radiotracer, [ 18 F]LW223, kinetics in the heart and brain when using a simplified imaging approach., Methods: Naive adult rats and rats with surgically induced permanent coronary artery ligation received a bolus intravenous injection of [ 18 F]LW223 followed by 120 min PET scanning with arterial blood sampling throughout. Kinetic modelling of PET data was applied to estimated rate constants, total volume of distribution (V T ) and binding potential transfer corrected (BP TC ) using arterial or image-derived input function (IDIF). Quantitative bias of simplified protocols using IDIF versus arterial input function (AIF) and stability of kinetic parameters for PET imaging data of different length (40-120 min) were estimated., Results: PET outcome measures estimated using IDIF significantly correlated with those derived with invasive AIF, albeit with an inherent systematic bias. Truncation of the dynamic PET scan duration to less than 100 min reduced the stability of the kinetic modelling outputs. Quantification of [ 18 F]LW223 uptake kinetics in the brain and heart required the use of different outcome measures, with BP TC more stable in the heart and V T more stable in the brain., Conclusion: Modelling of [ 18 F]LW223 PET showed the use of simplified IDIF is acceptable in the rat and the minimum scan duration for quantification of TSPO expression in rats using kinetic modelling with this radiotracer is 100 min. Carefully assessing kinetic outcome measures when conducting a systems level as oppose to single-organ centric analyses is crucial. This should be taken into account when assessing the emerging role of the TSPO heart-brain axis in the field of PET imaging., (© 2021. The Author(s).)

A wide range of buprenorphine doses are used for either pain management or maintenance therapy in opioid addiction. The complex in vitro profile of buprenorphine, with affinity for µ-, δ-, and κ-opioid receptors (OR), makes it difficult to predict its dose-related neuropharmacology in vivo. In rats, microPET imaging and pretreatment by OR antagonists were performed to assess the binding of radiolabeled buprenorphine (microdose 11 C-buprenorphine) to OR subtypes in vivo (n = 4 per condition). The µ-selective antagonist naloxonazine (10 mg/kg) and the non-selective OR antagonist naloxone (1 mg/kg) blocked the binding of 11 C-buprenorphine, while pretreatment by the δ-selective (naltrindole, 3 mg/kg) or the κ-selective antagonist (norbinaltorphimine, 10 mg/kg) did not. In four macaques, PET imaging and kinetic modeling enabled description of the regional brain kinetics of 11 C-buprenorphine, co-injected with increasing doses of unlabeled buprenorphine. No saturation of the brain penetration of buprenorphine was observed for doses up to 0.11 mg/kg. Regional differences in buprenorphine-associated receptor occupancy were observed. Analgesic doses of buprenorphine (0.003 and 0.006 mg/kg), respectively, occupied 20% and 49% of receptors in the thalamus while saturating the low but significant binding observed in cerebellum and occipital cortex. Occupancy >90% was achieved in most brain regions with plasma concentrations >7 µg/L. PET data obtained after co-injection of an analgesic dose of buprenorphine (0.003 mg/kg) predicted the binding potential of microdose 11 C-buprenorphine. This strategy could be further combined with pharmacodynamic exploration or pharmacological MRI to investigate the neuropharmacokinetics and neuroreceptor correlate, at least at µ-OR, of the acute effects of buprenorphine in humans.

Myocardial infarction (MI) is one of the leading causes of death worldwide, and inflammation is central to tissue response and patient outcomes. The 18-kDa translocator protein (TSPO) has been used in PET as an inflammatory biomarker. The aims of this study were to screen novel, fluorinated, TSPO radiotracers for susceptibility to the rs6971 genetic polymorphism using in vitro competition binding assays in human brain and heart; assess whether the in vivo characteristics of our lead radiotracer, 18 F-LW223, are suitable for clinical translation; and validate whether 18 F-LW223 can detect macrophage-driven inflammation in a rat MI model. Methods: Fifty-one human brain and 29 human heart tissue samples were screened for the rs6971 polymorphism. Competition binding assays were conducted with 3 H-PK11195 and the following ligands: PK11195, PBR28, and our novel compounds (AB5186 and LW223). Naïve rats and mice were used for in vivo PET kinetic studies, radiometabolite studies, and dosimetry experiments. Rats underwent permanent coronary artery ligation and were scanned using PET/CT with an invasive input function at 7 d after MI. For quantification of PET signal in the hypoperfused myocardium, K 1 (rate constant for transfer from arterial plasma to tissues) was used as a surrogate marker of perfusion to correct the binding potential for impaired radiotracer transfer from plasma to tissue (BP TC ). Results: LW223 binding to TSPO was not susceptible to the rs6971 genetic polymorphism in human brain and heart samples. In rodents, 18 F-LW223 displayed a specific uptake consistent with TSPO expression, a slow metabolism in blood (69% of parent at 120 min), a high plasma free fraction of 38.5%, and a suitable dosimetry profile (effective dose of 20.5-24.5 μSv/MBq). 18 F-LW223 BP TC was significantly higher in the MI cohort within the infarct territory of the anterior wall relative to the anterior wall of naïve animals (32.7 ± 5.0 vs. 10.0 ± 2.4 cm 3 /mL/min, P ≤ 0.001). Ex vivo immunofluorescent staining for TSPO and CD68 (macrophage marker) resulted in the same pattern seen with in vivo BP TC analysis. Conclusion: 18 F-LW223 is not susceptible to the rs6971 genetic polymorphism in in vitro assays, has favorable in vivo characteristics, and is able to accurately map macrophage-driven inflammation after MI., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

Introduction: Increasing evidence suggests that neuroinflammation is active in Parkinson disease (PD) and contributes to neurodegeneration. This process can be studied in vivo with PET and radioligands targeting TSPO, upregulated in activated microglia. Initial PET studies investigating microglial activation in PD with the [ 11 C]-PK11195 have provided inconclusive results. Here we assess the presence and distribution of neuroinflammatory response in PD patients using [ 18 F]-DPA714 and to correlate imaging biomarkers to dopamine transporter imaging and clinical status., Methods: PD patients (n = 24, Hoehn and Yahr I-III) and 28 healthy controls were scanned with [ 18 F]-DPA714 and [ 11 C]-PE2I and analyzed. They were all genotyped for TSPO polymorphism. Regional binding parameters were estimated (reference Logan graphical approach with supervised cluster analysis). Impact of TSPO genotype was analyzed using Wilcoxon signed-rank test. Differences between groups were investigated using a two-way ANOVA and Tukey post hoc tests., Results: PD patients showed significantly higher [ 18 F]-DPA714 binding compared to healthy controls bilaterally in the midbrain (p < 0.001), the frontal cortex (p = 0.001), and the putamen contralateral to the more clinically affected hemibody (p = 0.038). Microglial activation in these regions did not correlate with the severity of motor symptoms, disease duration nor putaminal [ 11 C]-PE2I uptake. However, there was a trend toward a correlation between cortical TSPO binding and disease duration (p = 0.015 uncorrected, p = 0.07 after Bonferroni correction)., Conclusion: [ 18 F]-DPA714 binding confirmed that there is a specific topographic pattern of microglial activation in the nigro-striatal pathway and the frontal cortex of PD patients., Trial Registration: Trial registration: INFLAPARK, NCT02319382. Registered 18 December 2014- Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02319382., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Longitudinal mouse PET imaging is becoming increasingly popular due to the large number of transgenic and disease models available but faces challenges. These challenges are related to the small size of the mouse brain and the limited spatial resolution of microPET scanners, along with the small blood volume making arterial blood sampling challenging and impossible for longitudinal studies. The ability to extract an input function directly from the image would be useful for quantification in longitudinal small animal studies where there is no true reference region available such as TSPO imaging., Methods: Using dynamic, whole-body 18 F-DPA-714 PET scans (60 min) in a mouse model of hippocampal sclerosis, we applied a factor analysis (FA) approach to extract an image-derived input function (IDIF). This mouse-specific IDIF was then used for 4D-resolution recovery and denoising (4D-RRD) that outputs a dynamic image with better spatial resolution and noise properties, and a map of the total volume of distribution (V T ) was obtained using a basis function approach in a total of 9 mice with 4 longitudinal PET scans each. We also calculated percent injected dose (%ID) with and without 4D-RRD. The V T and %ID parameters were compared to quantified ex vivo autoradiography using regional correlations of the specific binding from autoradiography against V T and %ID parameters., Results: The peaks of the IDIFs were strongly correlated with the injected dose (Pearson R = 0.79). The regional correlations between the %ID estimates and autoradiography were R = 0.53 without 4D-RRD and 0.72 with 4D-RRD over all mice and scans. The regional correlations between the V T estimates and autoradiography were R = 0.66 without 4D-RRD and 0.79 with application of 4D-RRD over all mice and scans., Conclusion: We present a FA approach for IDIF extraction which is robust, reproducible and can be used in quantification methods for resolution recovery, denoising and parameter estimation. We demonstrated that the proposed quantification method yields parameter estimates closer to ex vivo measurements than semi-quantitative methods such as %ID and is immune to tracer binding in tissue unlike reference tissue methods. This approach allows for accurate quantification in longitudinal PET studies in mice while avoiding repeated blood sampling.

The 18 kDa translocator protein (TSPO) is the main molecular target to image neuroinflammation by positron emission tomography (PET). However, TSPO-PET quantification is complex and none of the kinetic modelling approaches has been validated using a voxel-by-voxel comparison of TSPO-PET data with the actual TSPO levels of expression. Here, we present a single case study of binary classification of in vivo PET data to evaluate the statistical performance of different TSPO-PET quantification methods. To that end, we induced a localized and adjustable increase of TSPO levels in a non-human primate brain through a viral-vector strategy. We then performed a voxel-wise comparison of the different TSPO-PET quantification approaches providing parametric [ 18 F]-DPA-714 PET images, with co-registered in vitro three-dimensional TSPO immunohistochemistry (3D-IHC) data. A data matrix was extracted from each brain hemisphere, containing the TSPO-IHC and TSPO-PET data for each voxel position. Each voxel was then classified as false or true, positive or negative after comparison of the TSPO-PET measure to the reference 3D-IHC method. Finally, receiver operating characteristic curves (ROC) were calculated for each TSPO-PET quantification method. Our results show that standard uptake value ratios using cerebellum as a reference region (SUV CBL ) has the most optimal ROC score amongst all non-invasive approaches.

The 18 kDa translocator protein (TSPO) is a marker of microglia activation and the main target of positron emission tomography (PET) ligands for neuroinflammation. Previous works showed that accounting for TSPO endothelial binding improves PET quantification for [ 11 C]PBR28, [ 18 F]DPA714 and [ 11 C]-R-PK11195. It is still unclear, however, whether the vascular signal is tracer-dependent. This work aims to explore the relationship between the TSPO vascular and tissue components for PET tracers with varying affinity, also assessing the impact of affinity towards the differentiability amongst kinetics and the ensuing ligand amenability to cluster analysis for the extraction of a reference region. First, we applied the compartmental model accounting for vascular binding to [ 11 C]-R-PK11195 data from six healthy subjects. Then, we compared the [ 11 C]-R-PK11195 vascular binding estimates with previously published values for [ 18 F]DPA714 and [ 11 C]PBR28. Finally, we determined the suitability for reference region extraction by calculating the angle between grey and white matter kinetics. Our results showed that endothelial binding is common to all TSPO tracers and proportional to their affinity. By consequence, grey and white matter kinetics were most similar for the radioligand with the highest affinity (i.e. [ 11 C]PBR28), hence poorly suited for the extraction of a reference region using supervised clustering.

PET imaging using radiolabeled avid substrates of the ATP-binding cassette (ABC) transporter P-glycoprotein (ABCB1) has convincingly revealed the role of this major efflux transporter in limiting the influx of its substrates from blood into the brain across the blood-brain barrier (BBB). Many drugs, such as metoclopramide, are weak ABCB1 substrates and distribute into the brain even when ABCB1 is fully functional. In this study, we used kinetic modeling and validated simplified methods to highlight and quantify the impact of ABCB1 on the BBB influx and efflux of 11 C-metoclopramide, as a model of a weak ABCB1 substrate, in nonhuman primates. Methods: The regional brain kinetics of a tracer dose of 11 C-metoclopramide (298 ± 44 MBq) were assessed in baboons using PET without ( n = 4) or with ( n = 4) intravenous coinfusion of the ABCB1 inhibitor tariquidar (4 mg/kg/h). Metabolite-corrected arterial input functions were generated to estimate the regional volume of distribution ( V T ), as well as the influx ( K 1 ) and efflux ( k 2 ) rate constants, using a 1-tissue-compartment model. Modeling outcome parameters were correlated with image-derived parameters, that is, areas under the regional time-activity curves (AUCs) from 0 to 30 min and from 30 to 60 min (SUV⋅min) and the elimination slope ( k C-metoclopramide ( E ; min -1 ) from 30 to 60 min. Results: Tariquidar significantly increased the brain distribution of 11 C-metoclopramide ( V T = 4.3 ± 0.5 mL/cm 3 and 8.7 ± 0.5 mL/cm 3 for baseline and ABCB1 inhibition conditions, respectively, P < 0.001), with a 1.28-fold increase in K 1 ( P < 0.05) and a 1.64-fold decrease in k 2 ( P < 0.001). The effect of tariquidar was homogeneous across different brain regions. The parameters most sensitive to ABCB1 inhibition were V C-metoclopramide PET imaging revealed the relative importance of both the influx hindrance and the efflux enhancement components of ABCB1 in a relevant model of the human BBB. The overall impact of ABCB1 on drug delivery to the brain can be noninvasively estimated from image-derived outcome parameters without the need for an arterial input function.T (2.02-fold increase) and AUC from 30 to 60 min (2.02-fold increase). V T correlated significantly ( P < 0.0001) with AUC from 30 to 60 min ( r 2 = 0.95), with AUC from 0 to 30 min ( r 2 = 0.87), and with k E ( r 2 = 0.62). Conclusion: 11 C-metoclopramide PET imaging revealed the relative importance of both the influx hindrance and the efflux enhancement components of ABCB1 in a relevant model of the human BBB. The overall impact of ABCB1 on drug delivery to the brain can be noninvasively estimated from image-derived outcome parameters without the need for an arterial input function., (© 2018 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: Modafinil, a nonamphetaminic wake-promoting compound, is prescribed as first line therapy in narcolepsy, an invalidating disorder characterized by excessive daytime sleepiness and cataplexy. Although its mode of action remains incompletely known, recent studies indicated that modafinil modulates astroglial connexin-based gap junctional communication as administration of a low dose of flecainide, an astroglial connexin inhibitor, enhanced the wake-promoting and procognitive activity of modafinil in rodents and healthy volunteers. The aim of this study is to investigate changes in glucose cerebral metabolism in rodents, induced by the combination of modafinil+flecainide low dose (called THN102)., Methods: The impact of THN102 on brain glucose metabolism was noninvasively investigated using 18F-2-fluoro-2-deoxy-D-glucose Positron Emission Tomography imaging in Sprague-Dawley male rats. Animals were injected with vehicle, flecainide, modafinil, or THN102 and further injected with 18F-2-fluoro-2-deoxy-D-glucose followed by 60-minute Positron Emission Tomography acquisition. 18F-2-fluoro-2-deoxy-D-glucose Positron Emission Tomography images were coregistered to a rat brain template and normalized from the total brain Positron Emission Tomography signal. Voxel-to-voxel analysis was performed using SPM8 software. Comparison of brain glucose metabolism between groups was then performed., Results: THN102 significantly increased regional brain glucose metabolism as it resulted in large clusters of 18F-2-fluoro-2-deoxy-D-glucose uptake localized in the cortex, striatum, and amygdala compared with control or drugs administered alone. These regions, highly involved in the regulation of sleep-wake cycle, emotions, and cognitive functions were hence quantitatively modulated by THN102., Conclusion: Data presented here provide the first evidence of a regional brain activation induced by THN102, currently being tested in a phase II clinical trial in narcoleptic patients.

Objective: Mesiotemporal lobe epilepsy is the most common type of drug-resistant partial epilepsy, with a specific history that often begins with status epilepticus due to various neurological insults followed by a silent period. During this period, before the first seizure occurs, a specific lesion develops, described as unilateral hippocampal sclerosis (HS). It is still challenging to determine which drugs, administered at which time point, will be most effective during the formation of this epileptic process. Neuroinflammation plays an important role in pathophysiological mechanisms in epilepsy, and therefore brain inflammation biomarkers such as translocator protein 18 kDa (TSPO) can be potent epilepsy biomarkers. TSPO is associated with reactive astrocytes and microglia. A unilateral intrahippocampal kainate injection mouse model can reproduce the defining features of human temporal lobe epilepsy with unilateral HS and the pattern of chronic pharmacoresistant temporal seizures. We hypothesized that longitudinal imaging using TSPO positron emission tomography (PET) with 18 F-DPA-714 could identify optimal treatment windows in a mouse model during the formation of HS., Methods: The model was induced into the right dorsal hippocampus of male C57/Bl6 mice. Micro-PET/computed tomographic scanning was performed before model induction and along the development of the HS at 7 days, 14 days, 1 month, and 6 months. In vitro autoradiography and immunohistofluorescence were performed on additional mice at each time point., Results: TSPO PET uptake reached peak at 7 days and mostly related to microglial activation, whereas after 14 days, reactive astrocytes were shown to be the main cells expressing TSPO, reflected by a continuing increased PET uptake., Significance: TSPO-targeted PET is a highly potent longitudinal biomarker of epilepsy and could be of interest to determine the therapeutic windows in epilepsy and to monitor response to treatment., (Wiley Periodicals, Inc. © 2018 International League Against Epilepsy.)

18 F-DPA-714 is a second-generation tracer for PET imaging of the 18-kDa translocator protein (TSPO), a marker of neuroinflammation. Analysis and interpretation of TSPO PET are challenging, especially because of the basal expression of TSPO. The aim of this study was to evaluate a compartmental model that accounts for the effect of endothelial TSPO binding on the quantification of 18 F-DPA-714 PET scans from a cohort of healthy subjects. Methods: Fifteen healthy subjects (9 high-affinity binders and 6 mixed-affinity binders) underwent 18 F-DPA-714 PET scans with arterial blood sampling and metabolite analysis. The kinetic parameters were quantified using a 2-tissue compartmental model (2TC) as well as a 2TC with an extra, irreversible, compartment for endothelial binding (2TC-1K). These regional parameters and messenger RNA (mRNA) expression specific to endothelial cells were correlated with regional TSPO mRNA expression. Results: The 2TC-1K model was more appropriate than the 2TC for 81% of fits. The total volume of distribution was significantly reduced by 21% ± 12% across all regions with the 2TC-1K, compared with the 2TC. The endothelial binding parameter K b varied highly across brain regions. K b strongly and significantly correlated with all 3 probes extracted for TSPO mRNA expression ( r = 0.80, r = 0.79, and r = 0.90), but no correlation was seen with the other binding parameters from the 2TC-1K. For the 2TC, there was a lower but significant correlation between the volume of distribution and one of the TSPO mRNA probes ( r = 0.65). A strong, significant correlation was seen between mRNA for TSPO and genes specific to endothelial cells. Conclusion: Accounting for endothelial TSPO in the kinetic model improved the fit of PET data. The high correlation between K b and TSPO mRNA suggests that the 2TC-1K model reveals more biologic information about the regional density of TSPO than the 2TC. The correlation between TSPO and endothelial cell mRNA supports the relationship between the regional variation of K b and endothelial TSPO. These results can improve the estimation of binding parameter estimates from 18 F-DPA-714 PET, especially in diseases that induce vascular change., (© 2018 by the Society of Nuclear Medicine and Molecular Imaging.)

There is a great need for a non-invasive methodology enabling the quantification of translocator protein overexpression in PET clinical imaging. [ 18 F]DPA-714 has emerged as a promising translocator protein radiotracer as it is fluorinated, highly specific and returned reliable quantification using arterial input function. Cerebellum gray matter was proposed as reference region for simplified quantification; however, this method cannot be used when inflammation involves cerebellum. Here we adapted and validated a supervised clustering (supervised clustering algorithm (SCA)) for [ 18 F]DPA-714 analysis. Fourteen healthy subjects genotyped for translocator protein underwent an [ 18 F]DPA-714 PET, including 10 with metabolite-corrected arterial input function and three for a test-retest assessment. Two-tissue compartmental modelling provided [Formula: see text] estimates that were compared to either [Formula: see text] or [Formula: see text] generated by Logan analysis (using supervised clustering algorithm extracted reference region or cerebellum gray matter). The supervised clustering algorithm successfully extracted a pseudo-reference region with similar reliability using classes that were defined using either all subjects, or separated into HAB and MAB subjects. [Formula: see text], [Formula: see text] and [Formula: see text] were highly correlated (ICC of 0.91 ± 0.05) but [Formula: see text] were ∼26% higher and less variable than [Formula: see text]. Reproducibility was good with 5% variability in the test-retest study. The clustering technique for [ 18 F]DPA-714 provides a simple, robust and reproducible technique that can be used for all neurological diseases.

The emergence of bacterial pathogens resistant to all known antibiotics is a global health crisis. Adding to this problem is that major pharmaceutical companies have shifted away from antibiotic discovery due to low profitability. As a result, the pipeline of new antibiotics is essentially dry and many bacteria now resist the effects of most commonly used drugs. To address this global health concern, citizen science through the Small World Initiative (SWI) was formed in 2012. As part of SWI, students isolate bacteria from their local environments, characterize the strains, and assay for antibiotic production. During the 2015 fall semester at Bowling Green State University, students isolated 77 soil-derived bacteria and genetically characterized strains using the 16S rRNA gene, identified strains exhibiting antagonistic activity, and performed an expanded SWI workflow using transposon mutagenesis to identify a biosynthetic gene cluster involved in toxigenic compound production. We identified one mutant with loss of antagonistic activity and through subsequent whole-genome sequencing and linker-mediated PCR identified a 24.9 kb biosynthetic gene locus likely involved in inhibitory activity in that mutant. Further assessment against human pathogens demonstrated the inhibition of Bacillus cereus, Listeria monocytogenes, and methicillin-resistant Staphylococcus aureus in the presence of this compound, thus supporting our molecular strategy as an effective research pipeline for SWI antibiotic discovery and genetic characterization., (© 2017 The Authors. MicrobiologyOpen published by John Wiley & Sons Ltd.)

A wide range of medical imaging applications benefits from the availability of realistic ground truth data. In the case of positron emission tomography (PET), ground truth data is crucial to validate processing algorithms and assessing their performances. The design of such ground truth data often relies on Monte-Carlo simulation techniques. Since the creation of a large dataset is not trivial both in terms of computing time and realism, we propose the OSSI-PET database containing 350 simulated [(11)C]Raclopride dynamic scans for rats, created specifically for the Inveon pre-clinical PET scanner. The originality of this database lies on the availability of several groups of scans with controlled biological variations in the striata. Besides, each group consists of a large number of realizations (i.e., noise replicates). We present the construction methodology of this database using rat pharmacokinetic and anatomical models. A first application using the OSSI-PET database is presented. Several commonly used reconstruction techniques were compared in terms of image quality, accuracy and variability of the activity estimates and of the computed kinetic parameters. The results showed that OP-OSEM3D iterative reconstruction method outperformed the other tested methods. Analytical methods such as FBP2D and 3DRP also produced satisfactory results. However, FORE followed by OSEM2D reconstructions should be avoided. Beyond the illustration of the potential of the database, this application will help scientists to understand the different sources of noise and bias that can occur at the different steps in the processing and will be very useful for choosing appropriate reconstruction methods and parameters.

In PET imaging, research groups have recently proposed different experimental set ups allowing multiple animals to be simultaneously imaged in a scanner in order to reduce the costs and increase the throughput. In those studies, the technical feasibility was demonstrated and the signal degradation caused by additional mice in the FOV characterized, however, the impact of the signal degradation on the outcome of a PET study has not yet been studied. Here we thoroughly investigated, using Monte Carlo simulated [18F]FDG and [11C]Raclopride PET studies, different experimental designs for whole-body and brain acquisitions of two mice and assessed the actual impact on the detection of biological variations as compared to a single-mouse setting. First, we extended the validation of the PET-SORTEO Monte Carlo simulation platform for the simultaneous simulation of two animals. Then, we designed [18F]FDG and [11C]Raclopride input mouse models for the simulation of realistic whole-body and brain PET studies. Simulated studies allowed us to accurately estimate the differences in detection between single- and dual-mode acquisition settings that are purely the result of having two animals in the FOV. Validation results showed that PET-SORTEO accurately reproduced the spatial resolution and noise degradations that were observed with actual dual phantom experiments. The simulated [18F]FDG whole-body study showed that the resolution loss due to the off-center positioning of the mice was the biggest contributing factor in signal degradation at the pixel level and a minimal inter-animal distance as well as the use of reconstruction methods with resolution modeling should be preferred. Dual mode acquisition did not have a major impact on ROI-based analysis except in situations where uptake values in organs from the same subject were compared. The simulated [11C]Raclopride study however showed that dual-mice imaging strongly reduced the sensitivity to variations when mice were positioned side-by-side while no sensitivity reduction was observed when they were facing each other. This is the first study showing the impact of different experimental designs for whole-body and brain acquisitions of two mice on the quality of the results using Monte Carlo simulated [18F]FDG and [11C]Raclopride PET studies.

Quantitative measurements in dynamic PET imaging are usually limited by the poor counting statistics particularly in short dynamic frames and by the low spatial resolution of the detection system, resulting in partial volume effects (PVEs). In this work, we present a fast and easy to implement method for the restoration of dynamic PET images that have suffered from both PVE and noise degradation. It is based on a weighted least squares iterative deconvolution approach of the dynamic PET image with spatial and temporal regularization. Using simulated dynamic [(11)C] Raclopride PET data with controlled biological variations in the striata between scans, we showed that the restoration method provides images which exhibit less noise and better contrast between emitting structures than the original images. In addition, the method is able to recover the true time activity curve in the striata region with an error below 3% while it was underestimated by more than 20% without correction. As a result, the method improves the accuracy and reduces the variability of the kinetic parameter estimates calculated from the corrected images. More importantly it increases the accuracy (from less than 66% to more than 95%) of measured biological variations as well as their statistical detectivity., (Crown Copyright © 2015. Published by Elsevier Inc. All rights reserved.)

Positron emission tomography (PET) with [(11)C]Raclopride is an important tool for studying dopamine D2 receptor expression in vivo. [(11)C]Raclopride PET binding experiments conducted using the Partial Saturation Approach (PSA) allow the estimation of receptor density (B(avail)) and the in vivo affinity appK(D). The PSA is a simple, single injection, single scan experimental protocol that does not require blood sampling, making it ideal for use in longitudinal studies. In this work, we generated a complete Monte Carlo simulated PET study involving two groups of scans, in between which a biological phenomenon was inferred (a 30% decrease of B(avail)), and used it in order to design an optimal data processing chain for the parameter estimation from PSA data. The impact of spatial smoothing, noise removal and image resolution recovery technique on the statistical detection was investigated in depth. We found that image resolution recovery using iterative deconvolution of the image with the system point spread function associated with temporal data denoising greatly improves the accuracy and the statistical reliability of detecting the imposed phenomenon. Before optimisation, the inferred B(avail) variation between the two groups was underestimated by 42% and detected in 66% of cases, while a false decrease of appK(D) by 13% was detected in more than 11% of cases. After optimisation, the calculated B(avail) variation was underestimated by only 3.7% and detected in 89% of cases, while a false slight increase of appK(D) by 3.7% was detected in only 2% of cases. We found during this investigation that it was essential to adjust a factor that accounts for difference in magnitude between the non-displaceable ligand concentrations measured in the target and in the reference regions, for different data processing pathways as this ratio was affected by different image resolutions., (Crown Copyright © 2014. Published by Elsevier Inc. All rights reserved.)

Purpose: Imbalance of inhibitory GABAergic neurotransmission has been proposed to play a role in the pathogenesis of temporal lobe epilepsy (TLE). This study aimed to investigate whether [(18)F]-flumazenil ([(18)F]-FMZ) PET could be used to non-invasively characterise GABAA/central benzodiazepine receptor (GABAA/cBZR) density and affinity in vivo in the post-kainic acid status epilepticus (SE) model of TLE., Methods: Dynamic [(18)F]-FMZ -PET scans using a multi-injection protocol were acquired in four male wistar rats for validation of the partial saturation model (PSM). SE was induced in eight male Wistar rats (10 weeks of age) by i.p. injection of kainic acid (7.5-25 mg/kg), while control rats (n = 7) received saline injections. Five weeks post-SE, an anatomic MRI scan was acquired and the following week an [(18)F]-FMZ PET scan (3.6-4.6 nmol). The PET data was co-registered to the MRI and regions of interest drawn on the MRI for selected structures. A PSM was used to derive receptor density and apparent affinity from the [(18)F]-FMZ PET data., Key Findings: The PSM was found to adequately model [(18)F]-FMZ binding in vivo. There was a significant decrease in hippocampal receptor density in the SE group (p<0.01), accompanied by an increase in apparent affinity (p<0.05) compared to controls. No change in cortical receptor binding was observed. Hippocampal volume reduction and cell loss was only seen in a subset of animals. Histological assessment of hippocampal cell loss was significantly correlated with hippocampal volume measured by MRI (p<0.05), but did not correlate with [(18)F]-FMZ binding., Significance: Alterations to hippocampal GABAA/cBZR density and affinity in the post-kainic acid SE model of TLE are detectable in vivo with [(18)F]-FMZ PET and a PSM. These changes are independent from hippocampal cell and volume loss. [(18)F]-FMZ PET is useful for investigating the role that changes GABAA/cBZR density and binding affinity play in the pathogenesis of TLE.

3D shape context is a method to define matching points between similar shapes. It can be used as a pre-processing step in a non-rigid registration. The main limitation of the method is point mismatching, which includes long geodesic distance mismatch causing wrong topological structure, and neighbors crossing mismatch between two adjacent points. In this paper, we propose a topological structure verification method to correct the long geodesic distance mismatch and a correspondence field smoothing method to correct the neighbors crossing mismatch. A robust 3D shape context model is generated and further combined with thin-plate spline model for non-rigid registration. The method was tested on phantoms and applied to rat hind limb and mouse hind limb skeletons registration from micro-CT images. Errors between the registered surfaces were reduced by using the proposed method. The robustness of the method is demonstrated., (Crown Copyright 2009. Published by Elsevier Ltd. All rights reserved.)