Characterization of the central nervous system penetrant and selective purine P2X7 receptor antagonist JNJ-54175446 in patients with major depressive disorder.

JNJ-54175446 is a selective purine P2X7 receptor (P2X7R) antagonist that attenuates microglial IL-1ß/IL-18 release. In healthy volunteers, JNJ-54175446 suppressed peripheral interleukin (IL)-1ß release, and attenuated dexamphetamine-induced improvements of mood and (visuo)motor performance in a human dexamphetamine-challenge paradigm. In depression, P2X7R inhibition may dampen immune-related dysregulation of mood. These results suggest that the impact of P2X7R inhibition is most prominent in situations where mood regulation is disrupted. Total sleep deprivation (TSD) results in an acute emotional perturbation, which yields a transient antidepressant effect. In the current study, TSD was applied as a behavioral challenge to investigate whether such effects could be modulated by JNJ-54175446. This was a double-blind, placebo-controlled, randomized study to assess the safety and pharmacokinetics of JNJ-54175446 and explore its effects in patients with single episode and recurrent major depressive disorder (MDD) (N = 69) and baseline total Inventory of Depressive Symptomatology Clinician Rated (IDS-C) > 30. Patients were randomized to receive JNJ-54175446 throughout the 10-day treatment period, placebo for days 1-3 followed by JNJ-54175446 or placebo throughout. All patients underwent 36 h of TSD starting on day three until the evening of day four. The early start group was hypothesized to experience a reduced effect from TSD whilst the late starting group was hypothesized to experience prolonged effects from the TSD. JNJ-54175446 was well-tolerated and adverse events were mild to moderate. JNJ-54175446 reduced IL-1ß release by LPS-stimulated peripheral white blood cells in the presence of the P2X receptor agonist benzyl adenosine triphosphate (BzATP). JNJ-54175446 did not have a significant effect on mood as assessed using the Hamilton Depression Rating Scale, 17 items (HDRS17) and the Self-rated Quick Inventory of Depressive Symptoms (QIDS-SR). However, JNJ-54175446 blunted an acute reduction of anhedonia that occurred as a result of TSD, assessed by the Snaith-Hamilton Pleasure Scale (SHAPS) and the Probabilistic Instrumental Learning Task (PILT).

Profiling classical neuropsychiatric biomarkers across biological fluids and following continuous lumbar puncture: A guide to sample type and time.

Identification of putative biomarkers for neuropsychiatric disorders has produced a diverse list of analytes involved in inflammation, hypothalamic-pituitary-adrenal axis (HPA) regulation, growth factor and metabolic pathways. However, translation of these findings to accurate and robust assays has been stalled, affecting objective diagnoses, tracking relapse/remission, and prediction/monitoring of drug affect. Two important factors to control are the sample matrix (e.g. serum, plasma, saliva, or cerebrospinal fluid) and time of sample collection. Additionally, sample collection procedures may affect analyte level. In this study, a panel of 14 core neuropsychiatric biomarkers was measured in serum, plasma, saliva, and cerebrospinal fluid (CSF), all collected from 8 healthy volunteers at the same time. In a second cohort of 7 healthy volunteers, 6 analytes were measured in serum and CSF collected at 13 timepoints over a 24-h period after catheter placement. We found that many of the analytes were quantifiable in all sample types examined, but often at quite different concentrations and without correlation between the sample types. After catheter placement, a diurnal pattern was observed for cortisol and interleukin-6 in serum, and transient spikes were observed in interleukin-1ß. In CSF, a chronic elevation of several cytokines was observed instead, perhaps due to the continuous sampling procedure. These findings enable more informed decision-making around sample type and collection time, which can be implemented in future biomarker studies. Clinicaltrialgov identifiers: NCT02933762, NCT02475148.

No evidence for differential gene expression in major depressive disorder PBMCs, but robust evidence of elevated biological ageing.

The increasingly compelling data supporting the involvement of immunobiological mechanisms in Major Depressive Disorder (MDD) might provide some explanation forthe variance in this heterogeneous condition. Peripheral blood measures of cytokines and chemokines constitute the bulk of evidence, with consistent meta-analytic data implicating raised proinflammatory cytokines such as IL6, IL1ß and TNF. Among the potential mechanisms linking immunobiological changes to affective neurobiology is the accelerated biological ageing seen in MDD, particularly via the senescence associated secretory phenotype (SASP). However, the cellular source of immunobiological markers remains unclear. Pre-clinical evidence suggests a role for peripheral blood mononuclear cells (PBMC), thus here we aimed to explore the transcriptomic profile using RNA sequencing in PBMCs in a clinical sample of people with various levels of depression and treatment response comparing it with that in healthy controls (HCs). There were three groups with major depressive disorder (MDD): treatment-resistant (n = 94), treatment-responsive (n = 47) and untreated (n = 46). Healthy controls numbered 44. Using PBMCs gene expression analysis was conducted using RNAseq to a depth of 54.5 million reads. Differential gene expression analysis was performed using DESeq2. The data showed no robust signal differentiating MDD and HCs. There was, however, significant evidence of elevated biological ageing in MDD vs HC. Biological ageing was evident in these data as a transcriptional signature of 888 age-associated genes (adjusted p < 0.05, absolute log2fold > 0.6) that also correlated strongly with chronological age (spearman correlation coefficient of 0.72). Future work should expand clinical sample sizes and reduce clinical heterogeneity. Exploration of RNA-seq signatures in other leukocyte populations and single cell RNA sequencing may help uncover more subtle differences. However, currently the subtlety of any PBMC signature mitigates against its convincing use as a diagnostic or predictive biomarker.

Correction: Whole-blood expression of inflammasome- and glucocorticoid-related mRNAs correctly separates treatment-resistant depressed patients from drug-free and responsive patients in the BIODEP study.

We have corrected this Article post-publication, because Dr. Cattaneo's affiliation details were originally incorrect (she was affiliated with three institutions but is in fact only linked to one: Biological Psychiatry Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia). These changes reflect in both the PDF and HTML versions of this Article.

Whole-blood expression of inflammasome- and glucocorticoid-related mRNAs correctly separates treatment-resistant depressed patients from drug-free and responsive patients in the BIODEP study.

The mRNA expression signatures associated with the 'pro-inflammatory' phenotype of depression, and the differential signatures associated with depression subtypes and the effects of antidepressants, are still unknown. We examined 130 depressed patients (58 treatment-resistant, 36 antidepressant-responsive and 36 currently untreated) and 40 healthy controls from the BIODEP study, and used whole-blood mRNA qPCR to measure the expression of 16 candidate mRNAs, some never measured before: interleukin (IL)-1-beta, IL-6, TNF-alpha, macrophage inhibiting factor (MIF), glucocorticoid receptor (GR), SGK1, FKBP5, the purinergic receptor P2RX7, CCL2, CXCL12, c-reactive protein (CRP), alpha-2-macroglobulin (A2M), acquaporin-4 (AQP4), ISG15, STAT1 and USP-18. All genes but AQP4, ISG15 and USP-18 were differentially regulated. Treatment-resistant and drug-free depressed patients had both increased inflammasome activation (higher P2RX7 and proinflammatory cytokines/chemokines mRNAs expression) and glucocorticoid resistance (lower GR and higher FKBP5 mRNAs expression), while responsive patients had an intermediate phenotype with, additionally, lower CXCL12. Most interestingly, using binomial logistics models we found that a signature of six mRNAs (P2RX7, IL-1-beta, IL-6, TNF-alpha, CXCL12 and GR) distinguished treatment-resistant from responsive patients, even after adjusting for other variables that were different between groups, such as a trait- and state-anxiety, history of childhood maltreatment and serum CRP. Future studies should replicate these findings in larger, longitudinal cohorts, and test whether this mRNA signature can identify patients that are more likely to respond to adjuvant strategies for treatment-resistant depression, including combinations with anti-inflammatory medications.

Deep learning-based reconstruction of in vivo pelvis conductivity with a 3D patch-based convolutional neural network trained on simulated MR data.

PURPOSE: To demonstrate that mapping pelvis conductivity at 3T with deep learning (DL) is feasible. METHODS: 210 dielectric pelvic models were generated based on CT scans of 42 cervical cancer patients. For all dielectric models, electromagnetic and MR simulations with realistic accuracy and precision were performed to obtain B1+ and transceive phase (ϕ± ). Simulated B1+ and ϕ± served as input to a 3D patch-based convolutional neural network, which was trained in a supervised fashion to retrieve the conductivity. The same network architecture was retrained using only ϕ± in input. Both network configurations were tested on simulated MR data and their conductivity reconstruction accuracy and precision were assessed. Furthermore, both network configurations were used to reconstruct conductivity maps from a healthy volunteer and two cervical cancer patients. DL-based conductivity was compared in vivo and in silico to Helmholtz-based (H-EPT) conductivity. RESULTS: Conductivity maps obtained from both network configurations were comparable. Accuracy was assessed by mean error (ME) with respect to ground truth conductivity. On average, ME < 0.1 Sm-1 for all tissues. Maximum MEs were 0.2 Sm-1 for muscle and tumour, and 0.4 Sm-1 for bladder. Precision was indicated with the difference between 90th and 10th conductivity percentiles, and was below 0.1 Sm-1 for fat, bone and muscle, 0.2 Sm-1 for tumour and 0.3 Sm-1 for bladder. In vivo, DL-based conductivity had median values in agreement with H-EPT values, but a higher precision. CONCLUSION: Anatomically detailed, noise-robust 3D conductivity maps with good sensitivity to tissue conductivity variations were reconstructed in the pelvis with DL.

Characterisation of the pharmacodynamic effects of the P2X7 receptor antagonist JNJ-54175446 using an oral dexamphetamine challenge model in healthy males in a randomised, double-blind, placebo-controlled, multiple ascending dose trial.

BACKGROUND: This is the first report of the pharmacodynamic (PD) effects of the selective, potent and brain-penetrant P2X7 receptor (P2X7R) antagonist JNJ-54175446. Activation of the P2X7R, an adenosine triphosphate-gated ion channel, leads to the production of pro-inflammatory cytokines, which have been linked to neuroinflammation and play a role in the pathogenesis of mood disorders. Previous clinical studies with JNJ-54175446 demonstrated peripheral target engagement of JNJ-54175446 by assessing ex vivo lipopolysaccharide (LPS)-stimulated cytokine production. Blood-brain barrier penetration and a clear dose-receptor occupancy relationship was demonstrated using positron emission tomography. AIMS: The objectives of this double-blind, placebo-controlled, translational study were to assess the safety and tolerability of administering multiple doses of JNJ-54175446 and to explore its PD effects using a dexamphetamine challenge. METHODS: Subjects (N = 64) were randomised to either JNJ-54175446 (50-450 mg; n = 48) or placebo (n = 16) and underwent a baseline oral 20 mg dexamphetamine challenge followed by 11 consecutive days q.d. dosing with JNJ-54175446/placebo and a randomised crossover dexamphetamine/placebo challenge. RESULTS: At all doses tested, JNJ-54175446 was well tolerated and suppressed the ex vivo LPS-induced release of cytokines. At doses ⩾100 mg, JNJ-54175446 attenuated dexamphetamine-induced increases in locomotion and enhanced the mood-elevating effects of dexamphetamine, suggesting that a dose that is approximately twice as high is needed to obtain a central PD response compared to the dose needed for maximum peripheral occupancy. CONCLUSION: Overall, the observed pharmacological profile of JNJ-54175446 in the dexamphetamine challenge paradigm is compatible with a potential mood-modulating effect.

Peripheral Blood Cell-Stratified Subgroups of Inflamed Depression.

BACKGROUND: Depression has been associated with increased inflammatory proteins, but changes in circulating immune cells are less well defined. METHODS: We used multiparametric flow cytometry to count 14 subsets of peripheral blood cells in 206 depression cases and 77 age- and sex-matched controls (N = 283). We used univariate and multivariate analyses to investigate the immunophenotypes associated with depression and depression severity. RESULTS: Depression cases, compared with controls, had significantly increased immune cell counts, especially neutrophils, CD4+ T cells, and monocytes, and increased inflammatory proteins (C-reactive protein and interleukin-6). Within-group analysis of cases demonstrated significant associations between the severity of depressive symptoms and increased myeloid and CD4+ T-cell counts. Depression cases were partitioned into 2 subgroups by forced binary clustering of cell counts: the inflamed depression subgroup (n = 81 out of 206; 39%) had increased monocyte, CD4+, and neutrophil counts; increased C-reactive protein and interleukin-6; and more severe depression than the uninflamed majority of cases. Relaxing the presumption of a binary classification, data-driven analysis identified 4 subgroups of depression cases, 2 of which (n = 38 and n = 100; 67% collectively) were associated with increased inflammatory proteins and more severe depression but differed in terms of myeloid and lymphoid cell counts. Results were robust to potentially confounding effects of age, sex, body mass index, recent infection, and tobacco use. CONCLUSIONS: Peripheral immune cell counts were used to distinguish inflamed and uninflamed subgroups of depression and to indicate that there may be mechanistically distinct subgroups of inflamed depression.

A mood state-specific interaction between kynurenine metabolism and inflammation is present in bipolar disorder.

OBJECTIVES: Cytokines are thought to contribute to the pathogenesis of psychiatric symptoms by kynurenine pathway activation. Kynurenine metabolites affect neurotransmission and can cause neurotoxicity. We measured inflammatory markers in patients with bipolar disorder (BD) and studied their relation to kynurenine metabolites and mood. METHODS: Patients with BD suffering from an acute mood episode were assigned to the depressive (n = 35) or (hypo)manic (n = 32) subgroup. Plasma levels of inflammatory markers [cytokines, C-reactive protein] and kynurenine metabolites [tryptophan (TRP), kynurenine (KYN), 3-hydroxykynurenine (3-HK), quinolinic acid (QA), kynurenic acid (KYNA)] were measured on 6 time points during 8 months follow-up. Biological marker levels in patients were compared to controls (n = 35) and correlated to scores on mood scales. Spearman correlations and linear mixed models were used for statistical analysis. RESULTS: Twenty patients of the manic subgroup, 29 of the depressive subgroup, and 30 controls completed the study. The manic subgroup had a rapid remission of mood symptoms, but in the depressive subgroup subsyndromal symptoms persisted. No differences in inflammation were found between groups. A strong correlation between tumor necrosis factor-α and KYN, KYN/TRP, 3-HK and QA (ρ > 0.60) was specific for the manic group, but only at baseline (during mania). The depressive subgroup had a lower neuroprotective ratio (KYNA/3-HK, P = .0004) and a strong association between interferon-y and kynurenine pathway activation (P < .0001). KYNA was low in both patient groups versus controls throughout the whole follow-up (P = .0008). CONCLUSIONS: Mania and chronic depressive symptoms in BD are accompanied by a strong interaction between inflammation and a potentially neurotoxic kynurenine metabolism.

Ketamine effects on default mode network activity and vigilance: A randomized, placebo-controlled crossover simultaneous fMRI/EEG study.

In resting-state functional connectivity experiments, a steady state (of consciousness) is commonly supposed. However, recent research has shown that the resting state is a rather dynamic than a steady state. In particular, changes of vigilance appear to play a prominent role. Accordingly, it is critical to assess the state of vigilance when conducting pharmacodynamic studies with resting-state functional magnetic resonance imaging (fMRI) using drugs that are known to affect vigilance such as (subanesthetic) ketamine. In this study, we sought to clarify whether the previously described ketamine-induced prefrontal decrease of functional connectivity is related to diminished vigilance as assessed by electroencephalography (EEG). We conducted a randomized, double-blind, placebo-controlled crossover study with subanesthetic S-Ketamine in N = 24 healthy, young subjects by simultaneous acquisition of resting-state fMRI and EEG data. We conducted seed-based default mode network functional connectivity and EEG power spectrum analyses. After ketamine administration, decreased functional connectivity was found in medial prefrontal cortex whereas increased connectivities were observed in intraparietal cortices. In EEG, a shift of energy to slow (delta, theta) and fast (gamma) wave frequencies was seen in the ketamine condition. Frontal connectivity is negatively related to EEG gamma and theta activity while a positive relationship is found for parietal connectivity and EEG delta power. Our results suggest a direct relationship between ketamine-induced functional connectivity changes and the concomitant decrease of vigilance in EEG. The observed functional changes after ketamine administration may serve as surrogate end points and provide a neurophysiological framework, for example, for the antidepressant action of ketamine (trial name: 29JN1556, EudraCT Number: 2009-012399-28).

Neuroendocrine and Inflammatory Effects of Childhood Trauma Following Psychosocial and Inflammatory Stress in Women with Remitted Major Depressive Disorder.

The dysregulation of the inflammatory and neuroendocrine systems seen in major depressive disorder (MDD) may persist after remission and this is associated with a higher risk of relapse. This vulnerable subgroup may be characterized by a history of childhood trauma. In a single-blind randomized placebo-controlled crossover study, 21 women with remitted recurrent MDD and 18 healthy controls were exposed to psychosocial stress (Trier social stress test) or inflammatory stress (typhoid vaccine), or both, to investigate the effects of childhood trauma on the neuroendocrine and inflammatory responses. Childhood trauma was assessed using the Childhood Trauma Questionnaire and participants were dichotomized into a traumatized and non-traumatized group. Serum adrenocorticotropic hormone (ACTH), cortisol, interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and interleukin (IL)-6 were measured at regular intervals after each intervention. The effects of trauma, time, and intervention on these parameters were modeled by fitting linear mixed models. Childhood trauma in itself did not have a main effect on the outcome measurements. However, an interactional effect of trauma with stressor type was found in the remitted MDD group: trauma was associated with higher cortisol levels only after adding immunological to psychosocial stress, and with lower TNF-α levels in response to vaccination. This suggests the existence of a vulnerable trauma-associated MDD endophenotype.

Correction to: The selective orexin-2 antagonist seltorexant (JNJ-42847922/MIN-202) shows antidepressant and sleep-promoting effects in patients with major depressive disorder.

In the original Article, Tables two and three had formatting issues which affected their clarity. This has been corrected in the PDF and HTML versions of this Article.

The selective orexin-2 antagonist seltorexant (JNJ-42847922/MIN-202) shows antidepressant and sleep-promoting effects in patients with major depressive disorder.

Excessive arousal has a role in the pathophysiology of major depressive disorder (MDD). Seltorexant (JNJ-42847922/MIN-202) is a selective antagonist of the human orexin-2 receptor (OX2R) that may normalize excessive arousal and thereby attenuate depressive symptoms. In this study, the effects of night-time arousal suppression on depressive symptoms were investigated. 47 MDD patients with a total Inventory of Depressive Symptomatology (IDS) score of ≥30 at screening were included in a randomized, double-blind, diphenhydramine-, and placebo-controlled multicentre study. Symptoms of depression were rated using the 17-item Hamilton Depression Rating Scale (HDRS17). Effects on sleep were evaluated by polysomnography and by the Leeds Sleep Evaluation Questionnaire (LSEQ). To investigate the safety and tolerability of seltorexant, vital signs, suicidal ideation and adverse events were monitored. At baseline the severity of depressive symptoms correlated with sleep efficiency (SE), wake after sleep onset (WASO), duration of stage 2 sleep, and ruminations. Ten days of treatment with seltorexant (and not diphenhydramine) resulted in a significant improvement of core depressive symptoms compared to placebo; the antidepressant efficacy of seltorexant was maintained with continued treatment up to 28 days. Compared to placebo, the antidepressant efficacy of seltorexant coincided with an overall increase in (left posterior) EEG power and a relative increase in delta- and decrease in theta-, alpha- and beta power during stage 2 sleep. Treatment with seltorexant was associated with mild, self-limiting adverse drug reactions. Seltorexant affected core symptoms of depression in the absence of overt changes in the hypnogram; in contrast, diphenhydramine was not efficacious.

Prospective validation of craniocaudal tumour size on MR imaging compared to histoPAthology in patients with uterine cervical cancer: The MPAC study.

PURPOSE: To determine the accuracy of MRI in detecting craniocaudal tumour extension, compared to histopathology, of the hysterectomy specimen in patients with early-stage uterine cervical cancer. Three complementary methods were investigated. MATERIALS AND METHODS: Thirty-four patients with early-stage cervical cancer had pre-operative MRI, followed by radical hysterectomy or trachelectomy. 1) craniocaudal tumour extension was measured on MRI by two radiologists and compared to microscopy by a pathologist, 2) to compensate for changes in uterine shape between pre-operative MRI and the surgical specimen, craniocaudal tumour extensions were directly compared and appreciated as being a part of a 3-dimensional tumour by a radiation oncologist and resident, and 3) tumour size on MRI was compared macroscopically after digital non-rigid registration of the uterus, uterine cavity and tumour of both modalities. RESULTS: The craniocaudal tumour extension measured on histopathology minus MRI gives: 1) on average +3 mm difference when measured by a radiologist compared to the microscopic extension (range -13 to +15 mm), 2) -0.2 mm (range -11 to +6.0 mm) when evaluated on MRI by a radiation oncologist compared to the macroscopic tumour; 3) after non-rigid organ registration, a margin of 10 mm around the tumour on MRI would be needed to cover 95% of the tumour in 90% of the patients. CONCLUSIONS: Results indicate that microscopic tumour extension towards the uterine fundus is within a margin of 10 mm around the visible tumour on MRI. The major source of measurement uncertainty is post-surgical change of organ shape and form.

The selective orexin-2 receptor antagonist seltorexant improves sleep: An exploratory double-blind, placebo controlled, crossover study in antidepressant-treated major depressive disorder patients with persistent insomnia.

BACKGROUND: Insomnia is common in patients with major depressive disorder. Although antidepressants improve mood, insomnia often persists as a result of physiological hyperarousal. The orexin-2 receptor is increasingly being recognized as a new target for the treatment of persistent insomnia in major depressive disorder . AIM: This exploratory study investigated the effects of seltorexant on objective sleep parameters and subjective depressive symptoms in antidepressant treated major depressive disorder patients with persistent insomnia. METHODS: Twenty male and female patients received a single dose of 10, 20, 40 mg seltorexant and placebo with a washout period of seven days in a double-blind four-way crossover study. Effects on latency to persistent sleep, total sleep time and sleep efficiency were assessed with polysomnography. Subjective changes in mood were explored by the Quick Inventory of Depressive Symptomatology Self-Report. Safety was recorded and suicidal ideation and behavior were assessed with the Columbia Suicide Severity Rating Scale. RESULTS: Latency to persistent sleep was significantly shorter for all doses of seltorexant compared to placebo. Placebo least square mean was 61.05 min with least square mean ratios treatment/placebo (80% confidence interval) of 0.32 (0.24-0.44), 0.15 (0.11-0.2) and 0.17 (0.12-0.23) 19.69, 9.2, 10.15 for 10, 20 and 40 mg seltorexant respectively, (all p<0.001). Total sleep time was significantly longer for all doses of seltorexant compared to placebo. Sleep efficiency was significantly improved. The Quick Inventory of Depressive Symptomatology Self-Report demonstrated a trend to mood-improvement for the 40 mg group. CONCLUSIONS: Seltorexant showed a statistically significant, dose-dependent decrease in latency to persistent sleep, and increase in total sleep time and sleep efficiency combined with a tendency toward subjectively improved mood.

Treatment-resistant depression and peripheral C-reactive protein.

BACKGROUND: C-reactive protein (CRP) is a candidate biomarker for major depressive disorder (MDD), but it is unclear how peripheral CRP levels relate to the heterogeneous clinical phenotypes of the disorder.AimTo explore CRP in MDD and its phenotypic associations. METHOD: We recruited 102 treatment-resistant patients with MDD currently experiencing depression, 48 treatment-responsive patients with MDD not currently experiencing depression, 48 patients with depression who were not receiving medication and 54 healthy volunteers. High-sensitivity CRP in peripheral venous blood, body mass index (BMI) and questionnaire assessments of depression, anxiety and childhood trauma were measured. Group differences in CRP were estimated, and partial least squares (PLS) analysis explored the relationships between CRP and specific clinical phenotypes. RESULTS: Compared with healthy volunteers, BMI-corrected CRP was significantly elevated in the treatment-resistant group (P = 0.007; Cohen's d = 0.47); but not significantly so in the treatment-responsive (d = 0.29) and untreated (d = 0.18) groups. PLS yielded an optimal two-factor solution that accounted for 34.7% of variation in clinical measures and for 36.0% of variation in CRP. Clinical phenotypes most strongly associated with CRP and heavily weighted on the first PLS component were vegetative depressive symptoms, BMI, state anxiety and feeling unloved as a child or wishing for a different childhood. CONCLUSIONS: CRP was elevated in patients with MDD, and more so in treatment-resistant patients. Other phenotypes associated with elevated CRP included childhood adversity and specific depressive and anxious symptoms. We suggest that patients with MDD stratified for proinflammatory biomarkers, like CRP, have a distinctive clinical profile that might be responsive to second-line treatment with anti-inflammatory drugs.Declaration of interestS.R.C. consults for Cambridge Cognition and Shire; and his input in this project was funded by a Wellcome Trust Clinical Fellowship (110049/Z/15/Z). E.T.B. is employed half time by the University of Cambridge and half time by GlaxoSmithKline; he holds stock in GlaxoSmithKline. In the past 3 years, P.J.C. has served on an advisory board for Lundbeck. N.A.H. consults for GlaxoSmithKline. P.d.B., D.N.C.J. and W.C.D. are employees of Janssen Research & Development, LLC., of Johnson & Johnson, and hold stock in Johnson & Johnson. The other authors report no financial disclosures or potential conflicts of interest.

Evaluation of T2-W MR imaging and diffusion-weighted imaging for the early post-treatment local response assessment of patients treated conservatively for cervical cancer: a multicentre study.

OBJECTIVES: To compare MR imaging with or without DWI and clinical response evaluation (CRE) in the local control evaluation of cervical carcinoma after radiotherapy. METHODS: In a multicentre university setting, we prospectively included 107 patients with primary cervical cancer treated with radiotherapy. Sensitivity and specificity for CRE and MR imaging (with pre-therapy MR imaging as reference) (2 readers) were evaluated using cautious and strict criteria for identifying residual tumour. Nested logistic regression models were constructed for CRE, subsequently adding MR imaging with and without DWI as independent variables, as well as the pre- to post-treatment change in apparent diffusion coefficient (delta ADC). RESULTS: Using cautious criteria, CRE and MR imaging with DWI (reader 1/reader 2) have comparable high specificity (83% and 89%/95%, respectively), whereas MR imaging without DWI showed significantly lower specificity (63%/53%) than CRE. Using strict criteria, CRE and MR imaging with DWI both showed very high specificity (99% and 92%/95%, respectively), whereas MR imaging without DWI showed significantly lower specificity (89%/77%) than CRE. All sensitivities were not significantly different. Addition of MR imaging with DWI to CRE has statistically significant incremental value in identifying residual tumour (reader 1: estimate, 1.06; p = 0.001) (reader 2: estimate, 0.62; p = 0.02). Adding the delta ADC did not have significant incremental value in detecting residual tumour. CONCLUSIONS: DWI significantly increases the specificity of MR imaging in the detection of local residual tumour. Furthermore, MR imaging with DWI has significant incremental diagnostic value over CRE, whereas adding the delta ADC has no incremental diagnostic value. KEY POINTS: • If MR imaging is used for response evaluation, DWI should be incorporated • MR imaging with DWI has diagnostic value comparable/complementary to clinical response evaluation • Inter-reader agreement is moderate to fair for two experienced radiologist readers • Quantitative measurements of ADC early post-therapy have limited diagnostic value.

Digging deeper in the differential effects of inflammatory and psychosocial stressors in remitted depression: Effects on cognitive functioning.

BACKGROUND: Major Depressive Disorder (MDD) covers a wide spectrum of symptoms, including cognitive dysfunction, which can persist during remission. Both inflammatory states and psychosocial stress play a role in MDD pathogenesis. METHODS: The effects of inflammatory (i.e., Salmonella typhi vaccine) and psychosocial stressor (i.e., Trier Social Stress Test), as well as their combination were investigated on cognition in women (aged 25-45 years, n = 21) with (partially) remitted MDD and healthy controls (n = 18) in a single-blind placebo-controlled study. In a crossover design, patients received on the first day one of the aforementioned interventions and on the other day a placebo, or vice versa, with a washout period of 7-14 days. Short-term and verbal memory, working memory, attention, verbal fluency, information processing speed, psychomotor function, and measures of attentional bias to emotions were measured. Exploratory analyses were performed to assess the correlation between biomarkers of inflammation and the Hypothalamic-Pituitary-Adrenal axis and cognitive functioning. RESULTS: In patients, inflammatory stress decreased information processing speed and verbal memory, and increased working memory; after psychosocial stress, there was an increase in attention. There was also an increased negative attentional bias in patients after inflammatory stress. Neither stressor had any effect in controls. LIMITIATIONS: Limitations are the relatively small sample size and antidepressant use by a part of the participants. The effects of the stressors were also measured a relatively short period after administration. CONCULSION: Patients were sensitive to the cognitive effects of inflammation and psychosocial stress on cognition, while controls were not.

State-associated changes in longitudinal [18F]-PBR111 TSPO PET imaging of psychosis patients: Evidence for the accelerated ageing hypothesis?

OBJECTIVE: To determine whether state-associated changes in microglial activity, measured with translocator-protein positron emission tomography (TSPO PET), can be identified in psychosis patients through longitudinal evaluation of their regional tracer uptake over the clinical course from acute psychosis to post-treatment follow-up, and comparison to healthy controls. We also evaluated the relation between tracer uptake, clinical symptoms and peripheral immunological markers. METHOD: Second-generation radioligand [18F]-PBR111 TSPO PET-CT was used for longitudinal dynamic imaging in 14 male psychosis patients and 17 male age-matched healthy control subjects. Patients were first scanned during an acute psychotic episode followed by a second scan after treatment. Prior genotyping of subjects for the rs6917 polymorphism distinguished high- and mixed-affinity binders. The main outcome was regional volume of distribution (VT), representing TSPO binding. Plasma concentrations of CRP, cytokines and kynurenines were measured at each timepoint. RESULTS: We found a significant three-way interaction between time of scan, age and cohort (cortical grey matter F6.50, p.020). Age-dependent differences in VT existed between cohorts during the psychotic state, but not at follow-up. Patients' relative change in VT over time correlated with age (cortical grey matter Pearson's r.574). PANSS positive subscale scores correlated with regional VT during psychosis (cortical grey matter r.767). Plasma CRP and quinolinic acid were independently associated with lower VT. CONCLUSIONS: We identified a differential age-dependent pattern of TSPO binding from psychosis to follow-up in our cohort of male psychosis patients. We recommend future TSPO PET studies in psychosis patients to differentiate between clinical states and consider potential age-related effects.

Cervical cancer apparent diffusion coefficient values during external beam radiotherapy.

BACKGROUND AND PURPOSE: Apparent diffusion coefficient (ADC) reflects micro-enviromental changes and therefore might be useful in predicting recurrence prior to brachytherapy. The purpose of this study is to evaluate change in ADC of the primary tumour and pathologic lymph nodes during treatment and to correlate this with clinical outcome. MATERIAL AND METHODS: Twenty patients were included who received chemoradiation for locally advanced cervical cancer between July 2016 and November 2017. All patients underwent magnetic resonance imaging (MRI) prior to treatment, and three MRIs in weeks 1/2, 3 and 4 of treatment, including T2 and diffusion weighted imaging (b-values 0, 200, 800 s/mm2) for determining an ADC-map. Primary tumour was delineated on T2 and ADC-map and pathologic lymph nodes were delineated only on ADC-map. RESULTS: At time of analysis median follow-up was 15 (range 7-22) months. From MRI one to four, primary tumour on ADC-map showed a significant signal increase of 0.94 (range 0.74-1.46) × 10-3 mm2/s to 1.13 (0.98-1.49) × 10-3 mm2/s (p < 0.001). When tumour was delineated on T2, ADC-value signal increase (in tumour according to T2) was similar. All 46 delineated pathologic lymph nodes showed an ADC-value increase on average from 0.79 (range 0.33-1.12) × 10-3 mm2/s to 1.14 (0.59-1.75) × 10-3 mm2/s (p < 0.001). The mean tumour/suspected lymph node volumes decreased respectively 51/40%. Four patients developed relapse (one local and three nodal), without clear relation with ΔADC. However, the median volume decrease of the primary tumour was substantially lower in the failing patients compared to the group without relapse (19 vs. 57%). CONCLUSIONS: ADC values can be acquired using T2-based tumour delineations unless there are substantial shifts between ADC-mapping and T2 acquisition. It remains plausible that ΔADC is a predictor for response to EBRT. However, the correlation in this study was not statistically significant.