Effects of placebo administration on immune mechanisms and relationships with central endogenous opioid neurotransmission

Behavioral conditioning and expectation can have profound impact on animal and human physiology. Placebo, administered under positive expectation in clinical trials, can have potent effects on disease pathology, obscuring active medications. Emerging evidence suggests placebo-responsive neurotransmitter systems (e.g., endogenous opioid) regulate immune function by manipulating inflammatory proteins including IL-18, a potent pro-inflammatory, nociceptive cytokine implicated in pathophysiology of various diseases. Validation that neuroimmune interactions involving brain μ-opioid receptor (MOR) activity and plasma IL-18 underlie placebo analgesic expectation could have widespread clinical applications. Unfortunately, current lack of mechanistic clarity obfuscates clinical translation. To elucidate neuroimmune interactions underlying placebo analgesia, we exposed 37 healthy human volunteers to a standardized pain challenge on each of 2 days within a Positron Emission Tomography (PET) neuroimaging paradigm using the MOR selective radiotracer, 11C-Carfentanil (CFN). Each day volunteers received an intervention (placebo under analgesic expectation or no treatment), completed PET scanning, and rated their pain experience. MOR BPND parametric maps were generated from PET scans using standard methods. Results showed placebo reduced plasma IL-18 during pain (W74 = −3.7, p < 0.001), the extent correlating with reduction in pain scores. Placebo reduction in IL-18 covaried with placebo-induced endogenous opioid release in the left nucleus accumbens (T148 = 3.33; puncorr < 0.001) and left amygdala (T148 = 3.30; puncorr < 0.001). These findings are consistent with a modulating effect of placebo (under analgesic expectation in humans) on a potent nociceptive, pro-inflammatory cytokine (IL-18) and underlying relationships with endogenous opioid activity, a neurotransmitter system critically involved in pain, stress, and mood regulation.

PET-guided treatment for personalised therapy of Hodgkin lymphoma and aggressive non-Hodgkin lymphoma

FDG-PET scanning has a central role in lymphoma staging and response assessment. There is a growing body of evidence that PET response assessment during and after initial systemic therapy can provide useful prognostic information, and PET response has an evolving role in guiding patient care. This review provides a perspective on the role of PET response assessment for individualised management of patients with the most common aggressive lymphomas, Hodgkin lymphoma and diffuse large B-cell lymphoma.

Identification of Genes Related to 68Ga-DOTATATE Organ Distribution in Homo Sapiens

Purpose 68Ga-DOTATATE is a somatostatin analogue that has been used for imaging neuroendocrine tumours. However, there is nonspecific uptake in some organs, and the reasons for that are not clear. The aim of the study is to outline the dynamic distribution pattern of 68Ga-DOTATATE in human body, and identify the genes responsible for 68Ga-DOTATATE uptake by bioinformatics analysis.Methods 68Ga-DOTATATE PET/CT was performed in 32 patients, and dynamic total-body PET scanning was performed with uEXPLORER. The gene expression datasets of human organs were downloaded from the Human Protein Atlas. WGCNA analysis was performed to screen the potential genes related to 68Ga-DOTATATE. BindingDB, SEA and SwissTargetPrediction databases were used to predict the potential binding proteins of DOTATATE based on molecular structure. Results Dynamic total-body PET scanning showed that 68Ga-DOTATATE uptake was not consistent with expression of SSTR2 in human organs. WGCNA analysis revealed 800 genes whose expression level was positively correlated to 68Ga-DOTATATE uptake. According to the molecular structure of DOTATATE, 135 proteins with potential binding ability to DOTATATE were screened by analysis based on drug database. Based on the results of the above two parts, 8 proteins were finally obtained, respectively AVPR1A, EPHA8, EPHB4, OPRL1, SSTR2, SSTR5, ST3GAL1 and NPY1R, which had potential binding possibility with DOTATATE, and their expression was positively correlated with 68Ga-DOTATATE uptake.Conclusion WGCNA analysis was combined with the drug database to obtain new potential binding targets of DOTATATE. The bioinformatics approach developed in this study could potentially be used to discover new potential binding targets for molecular imaging agents.

Parametric Estimation of Reference Signal Intensity for Semi-Quantification of Tau Deposition: A Flortaucipir and [18F]-APN-1607 Study

BackgroundTau positron emission tomography (PET) imaging can reveal the pathophysiology and neurodegeneration that occurs in Alzheimer’s disease (AD) in vivo. The standardized uptake value ratio (SUVR) is widely used for semi-quantification of tau deposition but is susceptible to disturbance from the reference region and the partial volume effect (PVE). To overcome this problem, we applied the parametric estimation of reference signal intensity (PERSI) method—which was previously evaluated for flortaucipir imaging—to two tau tracers, flortaucipir and [18F]-APN-1607.MethodsTwo cohorts underwent tau PET scanning. Flortaucipir PET imaging data for cohort I (65 healthy controls [HCs], 60 patients with mild cognitive impairment [MCI], and 12 AD patients) were from the AD Neuroimaging Initiative database. [18F]-APN-1607 ([18F]-PM-PBB3) PET imaging data were for Cohort II, which included 21 patients with a clinical diagnosis of amyloid PET-positive AD and 15 HCs recruited at Huashan Hospital. We used white matter (WM) postprocessed by PERSI (PERSI-WM) as the reference region and compared this with the traditional semi-quantification method that uses the whole cerebellum as the reference. SUVRs were calculated for regions of interest including the frontal, parietal, temporal, and occipital lobes; anterior and posterior cingulate; precuneus; and Braak I/II (entorhinal cortex and hippocampus). Receiver operating characteristic (ROC) curve analysis and effect sizes were used to compare the two methods in terms of ability to discriminate between different clinical groups.ResultsIn both cohorts, regional SUVR determined using the PERSI-WM method was superior to using the cerebellum as reference region for measuring tau retention in AD patients (e.g., SUVR of the temporal lobe: flortaucipir, 1.08 ± 0.17 and [18F]-APN-1607, 1.57 ± 0.34); and estimates of the effect size and areas under the ROC curve (AUC) indicated that it also increased between-group differences (e.g., AUC of the temporal lobe for HC vs AD: flortaucipir, 0.893 and [18F]-APN-1607: 0.949).ConclusionThe PERSI-WM method significantly improves diagnostic discrimination compared to conventional approach of using the cerebellum as a reference region and can mitigate the PVE; it can thus enhance the efficacy of semi-quantification of multiple tau tracers in PET scanning, making it suitable for large-scale clinical application.

EXPRESS: Application of [18F]FLT-PET in Pulmonary Arterial Hypertension (PAH): A clinical study in PAH patients and unaffected BMPR2 mutation carriers

Background: Pulmonary arterial hypertension (PAH) is a heterogeneous group of diseases characterized by vascular cell proliferation leading to pulmonary vascular remodelling and ultimately right heart failure. Previous data indicated that 3'-deoxy-3'-[18F]-fluorothymidine (18FLT) positron emission tomography (PET) scanning was increased in PAH patients, hence providing a possible biomarker for PAH as it reflects vascular cell hyperproliferation in the lung. This study sought to validate 18FLT-PET in an expanded cohort of PAH patients in comparison to matched healthy controls and unaffected bone morphogenetic protein receptor type 2 (BMPR2) mutation carriers. Methods and Results: 18FLT-PET scanning was performed in 21 PAH patients (15 hereditary PAH and 6 idiopathic PAH), 11 unaffected mutation carriers and 9 healthy control subjects. In-depth kinetic analysis indicated that there were no differences in lung 18FLT k3 phosphorylation among PAH patients, unaffected BMPR2 mutation carriers and healthy controls. Lung 18FLT uptake did not correlate with hemodynamic or clinical parameters in PAH patients. Sequential 18FLT-PET scanning in three patients demonstrated uneven regional distribution in 18FLT uptake by 3D parametric mapping of the lung, although this did not follow the clinical course of the patient. Conclusion: We did not detect significantly increased lung 18FLT uptake in PAH patients, nor in the unaffected BMPR2 mutation carriers, as compared to healthy subjects. The conflicting results with our preliminary human 18FLT report may be explained by a small sample size previously and we observed large variation of lung 18FLT signals between patients, challenging the application of 18FLT-PET as a biomarker in the PAH clinic.

Neuroimaging Studies

This short chapter first describes studies using PET scanning and fMRI imaging carried out by the author in collaboration with colleagues over the past 25 years. The main purpose of the chapter is to assess the extent to which current work on neuroimaging is compatible with the findings and ideas derived from the cognitive experiments described in previous chapters. The questions asked include: What are the neural correlates of deeper processing, and does the neuroimaging evidence illuminate the reasons for the strong relation between semantic processing and good memory? Is there evidence to support the proposal that retrieval processes recapitulate encoding processes? Is the similarity between perception and memory borne out at the neural level? How does novelty affect memory, and is there a conflict between the claims that both novel and familiar experiences are associated with good levels of recollection? What exactly are processing resources at the neural level? And, finally, how does the author’s emphasis on remembering as an activity square with the evidence from neuroimaging studies?

Mesolimbic opioid-dopamine interaction is disrupted in obesity but recovered by weight loss following bariatric surgery

Obesity is a growing burden to health and the economy worldwide. Obesity is associated with central µ-opioid receptor (MOR) downregulation and disruption of the interaction between MOR and dopamine D2 receptor (D2R) system in the ventral striatum. Weight loss recovers MOR function, but it remains unknown whether it also recovers aberrant opioid-dopamine interaction. Here we addressed this issue by studying 20 healthy non-obese and 25 morbidly obese women (mean BMI 41) eligible for bariatric surgery. Brain MOR and D2R availability were measured using positron emission tomography (PET) with [11C]carfentanil and [11C]raclopride, respectively. Either Roux-en-Y gastric bypass or sleeve gastrectomy was performed on obese subjects according to standard clinical treatment. 21 obese subjects participated in the postoperative PET scanning six months after bariatric surgery. In the control subjects, MOR and D2R availabilities were associated in the ventral striatum (r = .62) and dorsal caudate (r = .61). Preoperatively, the obese subjects had disrupted association in the ventral striatum (r = .12) but the unaltered association in dorsal caudate (r = .43). The association between MOR and D2R availabilities in the ventral striatum was recovered (r = .62) among obese subjects following the surgery-induced weight loss. Bariatric surgery and concomitant weight loss recover the interaction between MOR and D2R in the ventral striatum in the morbidly obese. Consequently, the dysfunctional opioid-dopamine interaction in the ventral striatum is likely associated with an obese phenotype and may mediate excessive energy uptake. Striatal opioid-dopamine interaction provides a feasible target for pharmacological and behavioral interventions for treating obesity.

Prostate cancer GTV delineation with biparametric MRI and 68Ga-PSMA-PET: comparison of expert contours and semi-automated methods

Objective: The optimal method for delineation of dominant intraprostatic lesions (DIL) for targeted radiotherapy dose escalation is unclear. This study evaluated interobserver and intermodality variability of delineations on biparametric MRI (bpMRI), consisting of T2 weighted (T2W) and diffusion-weighted (DWI) sequences, and 68Ga-PSMA-PET/CT; and compared manually delineated GTV contours with semi-automated segmentations based on quantitative thresholding of intraprostatic apparent diffusion coefficient (ADC) and standardised uptake values (SUV). Methods: 16 patients who had bpMRI and PSMA-PET scanning performed prior to any treatment were eligible for inclusion. Four observers (two radiation oncologists, two radiologists) manually delineated the DIL on: (1) bpMRI (GTVMRI), (2) PSMA-PET (GTVPSMA) and (3) co-registered bpMRI/PSMA-PET (GTVFused) in separate sittings. Interobserver, intermodality and semi-automated comparisons were evaluated against consensus Simultaneous Truth and Performance Level Estimation (STAPLE) volumes, created from the relevant manual delineations of all observers with equal weighting. Comparisons included the Dice Similarity Coefficient (DSC), mean distance to agreement (MDA) and other metrics. Results: Interobserver agreement was significantly higher (p < 0.05) for GTVPSMA (DSC: 0.822, MDA: 1.12 mm) and GTVFused (DSC: 0.787, MDA: 1.34 mm) than for GTVMRI (DSC: 0.705, MDA 2.44 mm). Intermodality agreement between GTVMRI and GTVPSMA was low (DSC: 0.440, MDA: 4.64 mm). Agreement between semi-automated volumes and consensus GTV was low for MRI (DSC: 0.370, MDA: 8.16 mm) and significantly higher for PSMA-PET (0.571, MDA: 4.45 mm, p < 0.05). Conclusion: 68Ga-PSMA-PET appears to improve interobserver consistency of DIL localisation vs bpMRI and may be more viable for simple quantitative delineation approaches; however, more sophisticated approaches to semi-automatic delineation factoring for patient- and disease-related heterogeneity are likely required. Advances in knowledge: This is the first study to evaluate the interobserver variability of prostate GTV delineations with co-registered bpMRI and 68Ga-PSMA-PET.