TSPO PET brain inflammation imaging: A transdiagnostic systematic review and meta-analysis of 156 case-control studies.

INTRODUCTION: The 18-kDa translocator protein (TSPO) is increasingly recognized as a molecular target for PET imaging of inflammatory responses in various central nervous system (CNS) disorders. However, the reported sensitivity and specificity of TSPO PET to identify brain inflammatory processes appears to vary greatly across disorders, disease stages, and applied quantification methods. To advance TSPO PET as a potential biomarker to evaluate brain inflammation and anti-inflammatory therapies, a better understanding of its applicability across disorders is needed. We conducted a transdiagnostic systematic review and meta-analysis of all in vivo human TSPO PET imaging case-control studies in the CNS. Specifically, we investigated the direction, strength, and heterogeneity associated with the TSPO PET signal across disorders in pre-specified brain regions, and explored the demographic and methodological sources of heterogeneity. METHODS: We searched for English peer-reviewed articles that reported in vivo human case-control TSPO PET differences. We extracted the demographic details, TSPO PET outcomes, and technical variables of the PET procedure. A random-effects meta-analysis was applied to estimate case-control standardized mean differences (SMD) of the TSPO PET signal in the lobar/whole-brain cortical grey matter (cGM), thalamus, and cortico-limbic circuitry between different illness categories. Heterogeneity was evaluated with the I2 statistic and explored using subgroup and meta-regression analyses for radioligand generation, PET quantification method, age, sex, and publication year. Significance was set at the False Discovery Rate (FDR)-corrected P < 0.05. RESULTS: 156 individual case-control studies were included in the systematic review, incorporating data for 2381 healthy controls and 2626 patients. 139 studies documented meta-analysable data and were grouped into 11 illness categories. Across all the illness categories, we observed a significantly higher TSPO PET signal in cases compared to controls for the cGM (n = 121 studies, SMD = 0.358, PFDR < 0.001, I2 = 68%), with a significant difference between the illness categories (P = 0.004). cGM increases were only significant for Alzheimer's disease (SMD = 0.693, PFDR < 0.001, I2 = 64%) and other neurodegenerative disorders (SMD = 0.929, PFDR < 0.001, I2 = 73%). Cortico-limbic increases (n = 97 studies, SMD = 0.541, P < 0.001, I2 = 67%) were most prominent for Alzheimer's disease, mild cognitive impairment, other neurodegenerative disorders, mood disorders and multiple sclerosis. Thalamic involvement (n = 79 studies, SMD = 0.393, P < 0.001, I2 = 71%) was observed for Alzheimer's disease, other neurodegenerative disorders, multiple sclerosis, and chronic pain and functional disorders (all PFDR < 0.05). Main outcomes for systemic immunological disorders, viral infections, substance use disorders, schizophrenia and traumatic brain injury were not significant. We identified multiple sources of between-study variance to the TSPO PET signal including a strong transdiagnostic effect of the quantification method (explaining 25% of between-study variance; VT-based SMD = 0.000 versus reference tissue-based studies SMD = 0.630; F = 20.49, df = 1;103, P < 0.001), patient age (9% of variance), and radioligand generation (5% of variance). CONCLUSION: This study is the first overarching transdiagnostic meta-analysis of case-control TSPO PET findings in humans across several brain regions. We observed robust increases in the TSPO signal for specific types of disorders, which were widespread or focal depending on illness category. We also found a large and transdiagnostic horizontal (positive) shift of the effect estimates of reference tissue-based compared to VT-based studies. Our results can support future studies to optimize experimental design and power calculations, by taking into account the type of disorder, brain region-of-interest, radioligand, and quantification method.

Nephrotic Syndrome Gene TBC1D8B Is Required for Endosomal Maturation and Nephrin Endocytosis in Drosophila.

BACKGROUND: Variants in TBC1D8B cause nephrotic syndrome. TBC1D8B is a GTPase-activating protein for Rab11 (RAB11-GAP) that interacts with nephrin, but how it controls nephrin trafficking or other podocyte functions remains unclear. METHODS: We generated a stable deletion in Tbc1d8b and used microhomology-mediated end-joining for genome editing. Ex vivo functional assays utilized slit diaphragms in podocyte-like Drosophila nephrocytes. Manipulation of endocytic regulators and transgenesis of murine Tbc1d8b provided a comprehensive functional analysis of Tbc1d8b. RESULTS: A null allele of Drosophila TBC1D8B exhibited a nephrocyte-restricted phenotype of nephrin mislocalization, similar to patients with isolated nephrotic syndrome who have variants in the gene. The protein was required for rapid nephrin turnover in nephrocytes and for endocytosis of nephrin induced by excessive Rab5 activity. The protein expressed from the Tbc1d8b locus bearing the edited tag predominantly localized to mature early and late endosomes. Tbc1d8b was required for endocytic cargo processing and degradation. Silencing Hrs, a regulator of endosomal maturation, phenocopied loss of Tbc1d8b. Low-level expression of murine TBC1D8B rescued loss of the Drosophila gene, indicating evolutionary conservation. Excessive murine TBC1D8B selectively disturbed nephrin dynamics. Finally, we discovered four novel TBC1D8B variants within a cohort of 363 patients with FSGS and validated a functional effect of two variants in Drosophila, suggesting a personalized platform for TBC1D8B-associated FSGS. CONCLUSIONS: Variants in TBC1D8B are not infrequent among patients with FSGS. TBC1D8B, functioning in endosomal maturation and degradation, is essential for nephrin trafficking.

Multivariate semi-blind deconvolution of fMRI time series.

Whole brain estimation of the haemodynamic response function (HRF) in functional magnetic resonance imaging (fMRI) is critical to get insight on the global status of the neurovascular coupling of an individual in healthy or pathological condition. Most of existing approaches in the literature works on task-fMRI data and relies on the experimental paradigm as a surrogate of neural activity, hence remaining inoperative on resting-stage fMRI (rs-fMRI) data. To cope with this issue, recent works have performed either a two-step analysis to detect large neural events and then characterize the HRF shape or a joint estimation of both the neural and haemodynamic components in an univariate fashion. In this work, we express the neural activity signals as a combination of piece-wise constant temporal atoms associated with sparse spatial maps and introduce an haemodynamic parcellation of the brain featuring a temporally dilated version of a given HRF model in each parcel with unknown dilation parameters. We formulate the joint estimation of the HRF shapes and spatio-temporal neural representations as a multivariate semi-blind deconvolution problem in a paradigm-free setting and introduce constraints inspired from the dictionary learning literature to ease its identifiability. A fast alternating minimization algorithm, along with its efficient implementation, is proposed and validated on both synthetic and real rs-fMRI data at the subject level. To demonstrate its significance at the population level, we apply this new framework to the UK Biobank data set, first for the discrimination of haemodynamic territories between balanced groups (n=24 individuals in each) patients with an history of stroke and healthy controls and second, for the analysis of normal aging on the neurovascular coupling. Overall, we statistically demonstrate that a pathology like stroke or a condition like normal brain aging induce longer haemodynamic delays in certain brain areas (e.g. Willis polygon, occipital, temporal and frontal cortices) and that this haemodynamic feature may be predictive with an accuracy of 74 % of the individual's age in a supervised classification task performed on n=459 subjects.

Contribution of TSPO imaging in the understanding of the state of gliosis in substance use disorders.

PURPOSE: Recent research in last years in substance use disorders (SUD) synthesized a proinflammatory hypothesis of SUD based on reported pieces of evidence of non-neuronal central immune signalling pathways modulated by drug of abuse and that contribute to their pharmacodynamic actions. Positron emission tomography has been shown to be a precious imaging technique to study in vivo neurochemical processes involved in SUD and to highlight the central immune signalling actions of drugs of abuse. METHODS: In this review, we investigate the contribution of the central immune system, with a particular focus on translocator protein 18 kDa (TSPO) imaging, associated with a series of drugs involved in substance use disorders (SUD) specifically alcohol, opioids, tobacco, methamphetamine, cocaine, and cannabis. RESULTS: The large majority of preclinical and clinical studies presented in this review converges towards SUD modulation of the neuroimmune responses and TSPO expression and speculated a pivotal positioning in the pathogenesis of SUD. However, some contradictions concerning the same drug or between preclinical and clinical studies make it difficult to draw a clear picture about the significance of glial state in SUD. DISCUSSION: Significant disparities in clinical and biological characteristics are present between investigated populations among studies. Heterogeneity in genetic factors and other clinical co-morbidities, difficult to be reproduced in animal models, may affect findings. On the other hand, technical aspects including study designs, radioligand limitations, or PET imaging quantification methods could impact the study results and should be considered to explain discrepancies in outcomes. CONCLUSION: The supposed neuroimmune component of SUD provides new therapeutic approaches in the prediction and treatment of SUD pointing to the central immune signalling.

Nalmefene alleviates the neuroimmune response to repeated binge-like ethanol exposure: A TSPO PET imaging study in adolescent rats.

A large body of preclinical research has shown that neuroimmunity plays a key role in the deleterious effects of alcohol (ethanol) to the brain. Translational imaging techniques are needed to monitor the efficacy of strategies to prevent or mitigate neuroinflammation and alleviate ethanol-induced neurotoxicity. Opioid receptor antagonists such as nalmefene are antagonists of the toll-like receptor 4, which may block the proinflammatory signaling cascade induced by ethanol at this specific target. Male adolescent rats received a validated protocol of ethanol injection (i.p, 3 g/kg daily for two consecutive days followed by two resting days) during 14 days. Positron emission tomography (PET) imaging with the translocator protein 18 kDa (TSPO) radioligand [18 F]DPA-714 was performed at day-15. Toxicity induced by repeated binge-like ethanol exposure (71% mortality) was drastically reduced by nalmefene pretreatment (0.4 mg/kg, 14% mortality). No mortality was observed in animals that received vehicle (control) or nalmefene alone. Compared with control animals (n = 10), a significant 2.8-fold to 4.6-fold increase in the volume of distribution (VT ) of [18 F]DPA-714 was observed among brain regions in animals exposed to ethanol only (n = 9). Pretreatment with nalmefene significantly alleviated the neuroimmune response to ethanol exposure in all brain regions (1.2-fold to 2.5-fold increase in VT ; n = 5). Nalmefene alone (n = 6) did not impact [18 F]DPA-714 VT compared with the control group. Nalmefene may protect against the neuroinflammatory response and overall toxicity associated with binge drinking. [18 F]DPA-714 PET imaging can be used to noninvasively address the neuroimmune impact of ethanol exposure and its modulation by pharmacological strategies in vivo, with translational perspectives.

[Nursing management of patients with intrathecal pumps in oncology]. / Prise en charge infirmière de patients porteurs de pompe intrathécale en oncologie.

Some pains, especially in oncology, are refractory to standard analgesics. Epidural analgesia is an efficient way to manage them. It allows the patient to be relieved, to improve his quality of life and the conditions of his return home or in an institution. The nurse has a very important role in the therapeutic education of the patient, the follow-up of the management, the accompaniment of the family and the anticipation of these needs.

Cortico-Amygdala-Striatal Activation by Modafinil/Flecainide Combination.

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.

Imaging the neuroimmune response to alcohol exposure in adolescent baboons: a TSPO PET study using 18 F-DPA-714.

The effects of acute alcohol exposure to the central nervous system are hypothesized to involve the innate immune system. The neuroimmune response to an initial and acute alcohol exposure was investigated using translocator protein 18 kDa (TSPO) PET imaging, a non-invasive marker of glial activation, in adolescent baboons. Three different alcohol-naive adolescent baboons (3-4 years old, 9 to 14 kg) underwent 18 F-DPA-714 PET experiments before, during and 7-12 months after this initial alcohol exposure (0.7-1.0 g/l). The brain distribution of 18 F-DPA-714 (VT ; in ml/cm3 ) was estimated in several brain regions using the Logan plot analysis and the metabolite-corrected arterial input function. Compared with alcohol-naive animals (VTbrain  = 3.7 ± 0.7 ml/cm3 ), the regional VT s of 18 F-DPA-714 were significantly increased during alcohol exposure (VTbrain  = 7.2 ± 0.4 ml/cm3 ; p < 0.001). Regional VT s estimated several months after alcohol exposure (VTbrain  = 5.7 ± 1.4 ml/cm3 ) were lower (p < 0.001) than those measured during alcohol exposure, but remained significantly higher (p < 0.001) than in alcohol-naive animals. The acute and long-term effects of ethanol exposure were observed globally across all brain regions. Acute alcohol exposure increased the binding of 18 F-DPA-714 to the brain in a non-human primate model of alcohol exposure that reflects the 'binge drinking' situation in adolescent individuals. The effect persisted for several months, suggesting a 'priming' of glial cell function after initial alcohol exposure.

Acute Morphine Exposure Increases the Brain Distribution of [18F]DPA-714, a PET Biomarker of Glial Activation in Nonhuman Primates.

Background: The neuroinflammatory response to morphine exposure modulates its antinociceptive effects, tolerance, and dependence. Positron emission tomography radioligands for translocator protein-18kDa such as [18F]DPA-714 are noninvasive biomarkers of glial activation, a hallmark of neuroinflammation. Methods: [18F]DPA-714 positron emission tomography imaging was performed in 5 baboons at baseline and 2 hours after i.m. morphine injection (1 mg/kg). Brain kinetics and metabolite-corrected input function were measured to estimate [18F]DPA-714 brain distribution. Results: Morphine significantly increased [18F]DPA-714 brain distribution by a 1.3 factor (P<.05; paired t test). The effect was not restricted to opioid receptor-rich regions. Differences in baseline [18F]DPA-714 binding were observed among baboons. The response to morphine predominated in animals with the highest baseline uptake. Conclusions: [18F]DPA-714 positron emission tomography imaging may be useful to noninvasively investigate the brain immune component of morphine pharmacology. Correlation between baseline brain distribution and subsequent response to morphine exposure suggest a role for priming parameters in controlling the neuroinflammatory properties of opioids.

Early and protective microglial activation in Alzheimer's disease: a prospective study using 18F-DPA-714 PET imaging.

While emerging evidence suggests that neuroinflammation plays a crucial role in Alzheimer's disease, the impact of the microglia response in Alzheimer's disease remains a matter of debate. We aimed to study microglial activation in early Alzheimer's disease and its impact on clinical progression using a second-generation 18-kDa translocator protein positron emission tomography radiotracer together with amyloid imaging using Pittsburgh compound B positron emission tomography. We enrolled 96 subjects, 64 patients with Alzheimer's disease and 32 controls, from the IMABio3 study, who had both (11)C-Pittsburgh compound B and (18)F-DPA-714 positron emission tomography imaging. Patients with Alzheimer's disease were classified as prodromal Alzheimer's disease (n = 38) and Alzheimer's disease dementia (n = 26). Translocator protein-binding was measured using a simple ratio method with cerebellar grey matter as reference tissue, taking into account regional atrophy. Images were analysed at the regional (volume of interest) and at the voxel level. Translocator protein genotyping allowed the classification of all subjects in high, mixed and low affinity binders. Thirty high+mixed affinity binders patients with Alzheimer's disease were dichotomized into slow decliners (n = 10) or fast decliners (n = 20) after 2 years of follow-up. All patients with Alzheimer's disease had an amyloid positive Pittsburgh compound B positron emission tomography. Among controls, eight had positive amyloid scans (n = 6 high+mixed affinity binders), defined as amyloidosis controls, and were analysed separately. By both volumes of interest and voxel-wise comparison, 18-kDa translocator protein-binding was higher in high affinity binders, mixed affinity binders and high+mixed affinity binders Alzheimer's disease groups compared to controls, especially at the prodromal stage, involving the temporo-parietal cortex. Translocator protein-binding was positively correlated with Mini-Mental State Examination scores and grey matter volume, as well as with Pittsburgh compound B binding. Amyloidosis controls displayed higher translocator protein-binding than controls, especially in the frontal cortex. We found higher translocator protein-binding in slow decliners than fast decliners, with no difference in Pittsburgh compound B binding. Microglial activation appears at the prodromal and possibly at the preclinical stage of Alzheimer's disease, and seems to play a protective role in the clinical progression of the disease at these early stages. The extent of microglial activation appears to differ between patients, and could explain the overlap in translocator protein binding values between patients with Alzheimer's disease and amyloidosis controls.

The neuronal component of gray matter damage in multiple sclerosis: A [(11) C]flumazenil positron emission tomography study.

OBJECTIVE: Using positron emission tomography (PET) with [(11) C]flumazenil ([(11) C]FMZ), an antagonist of the central benzodiazepine site located within the GABAA receptor, we quantified and mapped neuronal damage in the gray matter (GM) of patients with multiple sclerosis (MS) at distinct disease stages. We investigated the relationship between neuronal damage and white matter (WM) lesions and evaluated the clinical relevance of this neuronal PET metric. METHODS: A cohort of 18 MS patients (9 progressive and 9 relapsing-remitting) was compared to healthy controls and underwent neurological and cognitive evaluations, high-resolution dynamic [(11) C]FMZ PET imaging and brain magnetic resonance imaging. [(11) C]FMZ binding was estimated using the partial saturation protocol providing voxel-wise absolute quantification of GABAA receptor concentration. PET data were evaluated using a region of interest (ROI) approach as well as on a vertex-by-vertex basis. RESULTS: [(11) C]FMZ binding was significantly decreased in the cortical GM of MS patients, compared to controls (-10%). Cortical mapping of benzodiazepine receptor concentration ([(11) C]FMZ Bmax) revealed significant intergroup differences in the bilateral parietal cortices and right frontal areas. ROI analyses taking into account GM volume changes showed extensive decrease in [(11) C]FMZ binding in bilateral parietal, cingulate, and insular cortices as well as in the thalami, amygdalae, and hippocampi. These changes were significant in both progressive and relapsing-remitting forms of the disease and correlated with WM T2-weighted lesion load. [(11) C]FMZ cortical binding correlated with cognitive performance. INTERPRETATION: This pilot study showed that PET with [(11) C]FMZ could be a promising and sensitive quantitative marker to assess and map the neuronal substrate of GM pathology in MS.

Brain Glucose Metabolism as a Readout of the Central Nervous System Impact of Cigarette Smoke Exposure and Withdrawal and the Effects of NFL-101, as an Immune-Based Drug Candidate for Smoking Cessation Therapy.

Neuroimaging biomarkers are needed to investigate the impact of smoking withdrawal on brain function. NFL-101 is a denicotinized aqueous extract of tobacco leaves currently investigated as an immune-based smoking cessation therapy in humans. However, the immune response to NFL-101 and its ability to induce significant changes in brain function remain to be demonstrated. Brain glucose metabolism was investigated using [18F]fluoro-deoxy-glucose ([18F]FDG) PET imaging in a mouse model of cigarette smoke exposure (CSE, 4-week whole-body inhalation, twice daily). Compared with control animals, the relative uptake of [18F]FDG in CSE mice was decreased in the thalamus and brain stem (p < 0.001, n = 14 per group) and increased in the hippocampus, cortex, cerebellum, and olfactory bulb (p < 0.001). NFL-101 induced a humoral immune response (specific IgGs) in mice and activated human natural-killer lymphocytes in vitro. In CSE mice, but not in control mice, single-dose NFL-101 significantly increased [18F]FDG uptake in the thalamus (p < 0.01), thus restoring normal brain glucose metabolism after 2-day withdrawal in this nicotinic receptor-rich region. In tobacco research, [18F]FDG PET imaging provides a quantitative method to evaluate changes in the brain function associated with the withdrawal phase. This method also showed the CNS effects of NFL-101, with translational perspectives for future clinical evaluation in smokers.

High density of nicotinic receptors in the cingulo-insular network.

The nicotinic system plays an important role in ordinary cognition, particularly in attention. The main nicotinic receptor in the human brain is the heteromeric α4ß2 neuronal nicotinic acetylcholine receptor (nAChR), which is distributed throughout the brain, with an especially high density in the thalamus and brainstem. Despite the important role of α4ß2 nAChRs in various physiological functions and pathological conditions, their distribution in the human cortex remains poorly characterized. We assessed the in vivo distribution of α4ß2 nAChRs in the human cortex in a group of seven non-smoking healthy subjects, using 2-[(18)F]F-A-85380 PET and a volume-of-interest-based analysis. We showed that cortical nAChR density was highest in the insular and anterior cingulate cortices. In functional magnetic resonance imaging studies, these two cortical regions and the thalamus have been shown to be highly correlated during the resting state and various tasks. Here, we also directly assessed nAChR density in this cingulo-insular network as defined in an independent dataset using resting-state functional connectivity, and compared it to other control-related networks, to the default mode network as well as to sensory and motor networks. Receptor density was significantly higher in the cingulo-insular network. This network has been suggested to maintain a variety of foundational capacities fundamental to cognitive function. The demonstration of a high nAChR density in the insular and anterior cingulate cortices reflects a particular neurochemical organization of the cingulo-insular network, and suggests an important role of the nicotinic receptors in its functions.

[18F]DPA-714 PET Imaging in the Presurgical Evaluation of Patients With Drug-Resistant Focal Epilepsy.

BACKGROUND AND OBJECTIVES: Translocator protein 18 kDa (TSPO) PET imaging is used to monitor glial activation. Recent studies have proposed TSPO PET as a marker of the epileptogenic zone (EZ) in drug-resistant focal epilepsy (DRFE). This study aims to assess the contributions of TSPO imaging using [18F]DPA-714 PET and [18F]FDG PET for localizing the EZ during presurgical assessment of DRFE, when phase 1 presurgical assessment does not provide enough information. METHODS: We compared [18F]FDG and [18F]DPA-714 PET images of 23 patients who had undergone a phase 1 presurgical assessment, using qualitative visual analysis and quantitative analysis, at both the voxel and the regional levels. PET abnormalities (increase in binding for [18F]DPA-714 vs decrease in binding for [18F]FDG) were compared with clinical hypotheses concerning the localization of the EZ based on phase 1 presurgical assessment. The additional value of [18F]DPA-714 PET imaging to [18F]FDG for refining the localization of the EZ was assessed. To strengthen the visual analysis, [18F]DPA-714 PET imaging was also reviewed by 2 experienced clinicians blind to the EZ location. RESULTS: The study included 23 patients. Visual analysis of [18F]DPA-714 PET was significantly more accurate than [18F]FDG PET to both, show anomalies (95.7% vs 56.5%, p = 0.022), and provide additional information to refine the EZ localization (65.2% vs 17.4%, p = 0.019). All 10 patients with normal [18F]FDG PET had anomalies when using [18F]DPA-714 PET. The additional value of [18F]DPA-714 PET seemed to be greater in patients with normal brain MRI or with neocortical EZ (especially if insula is involved). Regional analysis of [18F]DPA-714 and [18F]FDG PET provided similar results. However, using voxel-wise analysis, [18F]DPA-714 was more effective than [18F]FDG for unveiling clusters whose localization was more often consistent with the EZ hypothesis (87.0% vs 39.1%, p = 0.019). Nonrelevant bindings were seen in 14 of 23 patients in visual analysis and 9 patients of 23 patients in voxel-wise analysis. DISCUSSION: [18F]DPA-714 PET imaging provides valuable information for presurgical assessments of patients with DRFE. TSPO PET could become an additional tool to help to the localization of the EZ, especially in patients with negative [18F]FDG PET. TRIAL REGISTRATION INFORMATION: Eudract 2017-003381-27. Inclusion of the first patient: September 24, 2018. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence on the utility of [18F]DPA-714 PET compared with [18F]FDG PET in identifying the epileptic zone in patients undergoing phase 1 presurgical evaluation for intractable epilepsy.

Validation of a pharmacological imaging challenge using 11C-buprenorphine and 18F-2-fluoro-2-deoxy-D-glucose positron emission tomography to study the effects of buprenorphine to the rat brain.

Aim: Buprenorphine mainly acts as an agonist of mu-opioid receptors (mu-OR). High dose buprenorphine does not cause respiratory depression and can be safely administered to elicit typical opioid effects and explore pharmacodynamics. Acute buprenorphine, associated with functional and quantitative neuroimaging, may therefore provide a fully translational pharmacological challenge to explore the variability of response to opioids in vivo. We hypothesized that the CNS effects of acute buprenorphine could be monitored through changes in regional brain glucose metabolism, assessed using 18F-FDG microPET in rats. Materials and methods: First, level of receptor occupancy associated with a single dose of buprenorphine (0.1 mg/kg, s.c) was investigated through blocking experiments using 11C-buprenorphine PET imaging. Behavioral study using the elevated plus-maze test (EPM) was performed to assess the impact of the selected dose on anxiety and also locomotor activity. Then, brain PET imaging using 18F-FDG was performed 30 min after injection of unlabeled buprenorphine (0.1 mg/kg, s.c) vs. saline. Two different 18F-FDG PET acquisition paradigms were compared: (i) 18F-FDG injected i.v. under anesthesia and (ii) 18F-FDG injected i.p. in awake animals to limit the impact of anesthesia. Results: The selected dose of buprenorphine fully blocked the binding of 11C-buprenorphine in brain regions, suggesting complete receptor occupancy. This dose had no significant impact on behavioral tests used, regardless of the anesthetized/awake handling paradigm. In anesthetized rats, injection of unlabeled buprenorphine decreased the brain uptake of 18F-FDG in most brain regions except in the cerebellum which could be used as a normalization region. Buprenorphine treatment significantly decreased the normalized brain uptake of 18F-FDG in the thalamus, striatum and midbrain (p < 0.05), where binding of 11C-buprenorphine was the highest. The awake paradigm did not improve sensitivity and impact of buprenorphine on brain glucose metabolism could not be reliably estimated. Conclusion: Buprenorphine (0.1 mg/kg, s.c) combined with 18F-FDG brain PET in isoflurane anesthetized rats provides a simple pharmacological imaging challenge to investigate the CNS effects of full receptor occupancy by this partial mu-OR agonist. Sensitivity of the method was not improved in awake animals. This strategy may be useful to investigate de desensitization of mu-OR associated with opioid tolerance in vivo.

Striatal and extrastriatal dopamine transporter in cannabis and tobacco addiction: a high-resolution PET study.

The dopamine (DA) system is known to be involved in the reward and dependence mechanisms of addiction. However, modifications in dopaminergic neurotransmission associated with long-term tobacco and cannabis use have been poorly documented in vivo. In order to assess striatal and extrastriatal dopamine transporter (DAT) availability in tobacco and cannabis addiction, three groups of male age-matched subjects were compared: 11 healthy non-smoker subjects, 14 tobacco-dependent smokers (17.6 ± 5.3 cigarettes/day for 12.1 ± 8.5 years) and 13 cannabis and tobacco smokers (CTS) (4.8 ± 5.3 cannabis joints/day for 8.7 ± 3.9 years). DAT availability was examined in positron emission tomography (HRRT) with a high resolution research tomograph after injection of [11C]PE2I, a selective DAT radioligand. Region of interest and voxel-by-voxel approaches using a simplified reference tissue model were performed for the between-group comparison of DAT availability. Measurements in the dorsal striatum from both analyses were concordant and showed a mean 20% lower DAT availability in drug users compared with controls. Whole-brain analysis also revealed lower DAT availability in the ventral striatum, the midbrain, the middle cingulate and the thalamus (ranging from -15 to -30%). The DAT availability was slightly lower in all regions in CTS than in subjects who smoke tobacco only, but the difference does not reach a significant level. These results support the existence of a decrease in DAT availability associated with tobacco and cannabis addictions involving all dopaminergic brain circuits. These findings are consistent with the idea of a global decrease in cerebral DA activity in dependent subjects.

Reduced exposure evaluation of an Electrically Heated Cigarette Smoking System. Part 7: A one-month, randomized, ambulatory, controlled clinical study in Poland.

This randomized, open-label, ambulatory, controlled clinical study investigated biomarkers associated with cardiovascular risk and biomarkers of exposure to 10 selected harmful and potentially harmful constituents (HPHC) in cigarette smoke in 316 male and female Polish smokers. Subjects were randomized to continue smoking conventional cigarettes (CC; N=79) or switch to smoking the Electrically Heated Cigarette Smoking System series-K cigarette (EHCSS-K6; N=237). Biomarker assessments were performed at several time points during the study at baseline and during the 1-month investigational period. The primary biomarkers were high-sensitivity C-reactive protein and white blood cell counts. No statistically significant differences in the two primary biomarkers were found between the study groups at the end of the study. End-of-study comparisons of secondary biomarkers between study groups indicated an increase in high-density lipoprotein cholesterol, and reductions in red blood cell count, hemoglobin, and hematocrit levels in the EHCSS-K6 group. All biomarkers of exposure to cigarette smoke HPHC were decreased in the EHCSS-K6 group, despite an increase in cigarette consumption, compared to the CC group. There were no apparent differences in any of the safety assessment parameters between the groups, and the overall incidence of study-related adverse events was low.

Reduced exposure evaluation of an Electrically Heated Cigarette Smoking System. Part 4: Eight-day randomized clinical trial in Korea.

A randomized, controlled, open-label parallel-group, single-center study to determine biomarkers of exposure to 12 selected harmful and potentially harmful constituents (HPHC) in cigarette smoke and urinary excretion of mutagenic material in 72 male and female Korean subjects smoking Lark One cigarettes (1.0mg tar, 0.1mg nicotine, and 1.5mg CO) at baseline. Subjects were randomized to continue smoking Lark One cigarettes, or switch to an Electrically Heated Cigarette Smoking System (EHCSS) and EHCSS-K3 cigarette (3mg tar, 0.2mg nicotine, and 0.6 mg CO), or to no-smoking. The mean decreases from baseline to Day 8 were statistically significant (all p<0.05) for 10 of 12 HPHC in mainstream cigarette smoke including CO (the primary objective) in the EHCSS-K3 group (range: -1.5% to -74.2%). Exposure to the other determined HPHC was not significantly different. In the Lark One group, the mean exposure to 6 of 12 HPHC in cigarette smoke was significantly (all p<0.05) decreased; however, exposure to CO was significantly increased. The largest mean reductions in biomarkers of exposure to HPHC occurred in smokers who switched to no-smoking (-3.4% to -98.9%). The mean excretion of mutagenic material was significantly decreased (p<0.05) in the EHCSS-K3 and no-smoking groups (-31.8% and -45.3%, respectively), and increased in the Lark One group (+31.5%).