Inflammasomes and autoimmune and rheumatic diseases: A comprehensive review.

Inflammasomes are a multi-protein platform forming a part of the innate immune system. Inflammasomes are at standby status and can be activated when needed. Inflammasome activation is an important mechanism for the production of active interleukin (IL)-1ß and IL-18, which have important roles to instruct adaptive immunity. Active forms of inflammasomes trigger a series of inflammatory cascades and lead to the differentiation and polarization of naïve T cells and secretion of various cytokines, which can induce various kinds of autoimmune and rheumatic diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), gout, Sjögren's syndrome, Behçet's disease, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis and IgA vasculitis (former Henoch-Schönlein purpura ). In this review, we summarize studies published on inflammasomes and review their roles in various autoimmune diseases. Understanding of the role of inflammasomes may facilitate the diagnosis of autoimmune diseases and the development of tailored therapies in the future.

Relationship of self-transcendence traits with in vivo dopamine D2/3 receptor availability and functional connectivity: An [18 F]fallypride PET and fMRI study.

Genetic research has implicated dopamine neurotransmission in the expression of the self-transcendence trait in humans. However, molecular imaging of dopaminergic markers is undocumented in relation to this personality trait. In this multimodal imaging study, we first investigated the relationship between the self-transcendence trait and in vivo dopamine D2/3 receptor availability using [18 F]fallypride positron emission tomography (PET). We next conducted seed-based functional connectivity analyses using resting-state functional magnetic resonance imaging (rs-fMRI) data with regions derived from the PET analysis as seeds to explore the functional significance of D2/3 receptor availability foci associated with the self-transcendence trait. Twenty-one healthy subjects underwent high-resolution PET with [18 F]fallypride and a subset of 18 subjects also completed 3-Tesla rs-fMRI. The Temperament and Character Inventory was used to measure the self-transcendence trait. A voxel-based whole brain analysis revealed that the [18 F]fallypride binding potential (BPND ) within the cluster of the left insula was significantly positively correlated with self-transcendence trait scores. A region-of-interest analysis also showed a significant positive correlation between self-transcendence and [18 F]fallypride BPND in the left insula. The exploratory [18 F]fallypride BPND seed-based rs-fMRI analysis showed that the functional connectivity from the left insula seed to the prefrontal cortices (including the inferior frontal region) was negatively associated with self-transcendence trait scores. The results of the present study suggest that D2/3 receptor-mediated neurotransmission in the left insula may constitute a significant neurobiological factor in the self-transcendence trait. The negative associations between BPND seed-based functional connectivity and self-transcendence trait scores may suggest reduced prefrontal control in this personality trait.

Altered connectivity between striatal and extrastriatal regions in patients with schizophrenia on maintenance antipsychotics: an [18 F]fallypride PET and functional MRI study.

In addition to probing regional differences in receptor availability, molecular positron emission tomography (PET) is proving useful for investigating perturbations in neurotransmitter networks using interregional correlation analyses. In a multi-modal imaging study, we examined interregional correlations of dopamine D2/3 receptor availability between striatal and extrastriatal regions using [18 F]fallypride high-resolution PET in 11 patients with schizophrenia receiving low-dose maintenance atypical antipsychotics and 14 healthy control subjects, and investigated resting-state functional connectivity in the same subjects using seed-based functional magnetic resonance imaging (fMRI) analysis. In the healthy control group, there were no significant correlations of [18 F]fallypride binding potential (BPND ) between striatal regions and any cortical areas, whereas the patient group showed significant and widespread inter-correlations. Correlations between BPND in striatum, amygdala and insula with cortex were significantly higher in patients than in controls. In seed-based resting-state fMRI analysis, the healthy controls revealed positive and negative functional connectivity patterns, while patients exhibited a pattern of exclusively positive connectivity. Functional connectivity was significantly higher between striatal regions and extrastriatal areas including cortical regions in patients compared to controls. In this first such report, molecular and functional connectivity between striatal and extrastriatal regions was primarily characterized by increased interregional relationships in treated patients with schizophrenia. The results suggest that the spatial organization of D2/3 receptor availability and related functional connectivity are significantly perturbed in stable outpatients on maintenance antipsychotics. Future studies should include antipsychotic-naïve patients to determine if these relationships are illness-related characteristics, or arising due to chronic antipsychotic treatment.

The relationship between excitement symptom severity and extrastriatal dopamine D2/3 receptor availability in patients with schizophrenia: a high-resolution PET study with [18F]fallypride.

The purpose of this study was to investigate the relationship between specific symptom severity and D2/3 receptor availability in extrastriatal regions in outpatients with schizophrenia to shed light on the role of extrastriatal dopaminergic neurotransmission in the pathophysiology of symptoms of schizophrenia. Sixteen schizophrenia patients receiving relatively low-dose maintenance atypical antipsychotics and seventeen healthy controls underwent 3-Tesla magnetic resonance imaging and high-resolution positron emission tomography with [18F]fallypride. For D2/3 receptor availability, the binding potential with respect to non-displaceable compartment (BPND) was derived using the simplified reference tissue model. The BPND values were lower in patients on antipsychotic treatment than in controls across all regions with large effect sizes (1.03-1.42). The regions with the largest effect size were the substantia nigra, amygdala, and insula. Symptoms of schizophrenia were assessed using a five-factor model of the Positive and Negative Syndrome Scale (PANSS). The region of interest-based analysis showed that PANSS excitement factor score had a significant positive correlation with the [18F]fallypride BPND in the insula. The equivalent dose of antipsychotics was not significantly correlated with PANSS factor scores or regional BPND values. The voxel-based analysis also revealed a significant positive association between the PANSS excitement factor and the [18F]fallypride BPND in the insula. The present study revealed a significant association between excitement symptom severity and D2/3 receptor availability in the insula in schizophrenia, suggesting a possible important role of D2/3 receptor-mediated neurotransmission in the insula and related limbic system in the pathophysiology of this specific symptom cluster.

Differences in mGluR5 Availability Depending on the Level of Social Avoidance in Drug-Naïve Young Patients with Major Depressive Disorder.

Background: Previous research has shown that metabotropic glutamate receptor-5 (mGluR5) signaling is significantly involved in social avoidance. We investigated the relationship between levels of social avoidance and mGluR5 availability in drug-naïve young patients with major depressive disorder (MDD). Methods: Twenty non-smoking patients and eighteen matched non-smoking healthy controls underwent [11C]ABP688 positron emission tomography (PET) and magnetic resonance imaging scans. The binding potential (BPND) of [11C]ABP688 was obtained using the simplified reference tissue model. Patients' level of social avoidance was assessed using the Social Avoidance and Distress Scale (SADS). For [11C]ABP688 BPND, the region-of-interest (ROI)-based between-group comparisons and correlations with SADS scores were investigated. The frontal cortices were chosen as a priori ROIs based on previous PET investigations in MDD, and on literature underscoring the importance of the frontal cortex in social avoidance. Results: Independent samples t-tests revealed no significant differences in [11C]ABP688 BPND in the frontal cortices between the MDD patient group as a whole and healthy controls. One-way analysis of variance with post-hoc tests revealed significantly lower BPND in the bilateral superior frontal cortex (SFC) and left middle frontal cortex (MFC) in MDD patients with low levels of social avoidance (L-SADS) than in healthy controls. The L-SADS patients also had significantly lower BPND in the medial part of the right SFC than both MDD patients with high levels of social avoidance (H-SADS) and healthy controls. The L-SADS patients also showed significantly lower BPND in the orbital parts of the SFC, MFC, and inferior frontal cortex than H-SADS patients. No significant group differences were found between H-SADS patients and healthy controls. The ROI-based correlation analysis revealed significant positive correlations between social avoidance levels and frontal [11C]ABP688 BPND in the entire patients. Conclusion: Our exploratory study shows significant differences in frontal mGluR5 availability depending on the level of social avoidance in drug-naïve non-smoking MDD patients, suggesting that social avoidance should be considered as one of the clinical factors involved in mGluR5 signaling changes in depression.

Functional Analysis of Brain Imaging Suggests Changes in the Availability of mGluR5 and Altered Connectivity in the Cerebral Cortex of Long-Term Abstaining Males with Alcohol Dependence: A Preliminary Study.

Direct in vivo evidence of altered metabotropic glutamate receptor-5 (mGluR5) availability in alcohol-related disorders is lacking. We performed [11C]ABP688 positron emission tomography (PET) and resting-state functional magnetic resonance imaging (rs-fMRI) in prolonged abstinent subjects with alcohol dependence to examine alterations of mGluR5 availability, and to investigate their functional significance relating to neural systems-level changes. Twelve prolonged abstinent male subjects with alcohol dependence (median abstinence duration: six months) and ten healthy male controls underwent [11C]ABP688 PET imaging and 3-Tesla MRI. For mGluR5 availability, binding potential (BPND) was calculated using the simplified reference tissue model with cerebellar gray matter as the reference region. The initial region-of-interest (ROI)-based analysis yielded no significant group differences in mGluR5 availability. The voxel-based analysis revealed significantly lower [11C]ABP688 BPND in the middle temporal and inferior parietal cortices, and higher BPND in the superior temporal cortex in the alcohol dependence group compared with controls. Functional connectivity analysis of the rs-fMRI data employed seed regions identified from the quantitative [11C]ABP688 PET analysis, which revealed significantly altered functional connectivity from the inferior parietal cortex seed to the occipital pole and dorsal visual cortex in the alcohol dependence group compared with the control group. To our knowledge, this is the first report on the combined analysis of mGluR5 PET imaging and rs-fMRI in subjects with alcohol dependence. These preliminary results suggest the possibility of region-specific alterations of mGluR5 availability in vivo and related functional connectivity perturbations in prolonged abstinent subjects.

In Vivo Cerebral Translocator Protein (TSPO) Binding and Its Relationship with Blood Adiponectin Levels in Treatment-Naïve Young Adults with Major Depression: A [11C]PK11195 PET Study.

Adiponectin is an adipokine that mediates cellular cholesterol efflux and plays important roles in neuroinflammatory processes. In this study, we undertook positron emission tomography (PET) with the translocator protein (TSPO) ligand [11C]PK11195 and measured serum adiponectin levels in groups of treatment-naïve young adult patients with major depressive disorder (MDD) and matched healthy controls. Thirty treatment-naïve MDD patients (median age: 24 years) and twenty-three healthy controls underwent [11C]PK11195 PET. We quantified TSPO availability in brain as the [11C]PK11195 binding potential (BPND) using a reference tissue model in conjunction with the supervised cluster analysis (SVCA4) algorithm. Age, sex distribution, body mass index, and serum adiponectin levels did not differ between the groups. Between-group analysis using a region-of-interest approach showed significantly higher [11C]PK11195 BPND in the left anterior and right posterior cingulate cortices in MDD patients than in controls. Serum adiponectin levels had significant negative correlations with [11C]PK11195 BPND in the bilateral hippocampus in MDD patients, but significant positive correlations in the bilateral hippocampus in the control group. Our results indicate significantly higher TSPO binding in the anterior and posterior cingulate cortices in treatment-naïve young MDD patients, suggesting microglial activation in these limbic regions, which are involved in cognitive and emotional processing. The opposite correlations between [11C]PK11195 BPND in the hippocampus with serum adiponectin levels in MDD and control groups suggest that microglial activation in the hippocampus may respond differentially to adiponectin signaling in MDD and healthy subjects, possibly with respect to microglial phenotype.

In vivo glucose metabolism and glutamate levels in mGluR5 knockout mice: a multimodal neuroimaging study using [18F]FDG microPET and MRS.

BACKGROUND: Perturbed functional coupling between the metabotropic glutamate receptor-5 (mGluR5) and N-methyl-D-aspartate (NMDA) receptor-mediated excitatory glutamatergic neurotransmission may contribute to the pathophysiology of psychiatric disorders such as schizophrenia. We aimed to establish the functional interaction between mGluR5 and NMDA receptors in brain of mice with genetic ablation of the mGluR5. METHODS: We first measured the brain glutamate levels with magnetic resonance spectroscopy (MRS) in mGluR5 knockout (KO) and wild-type (WT) mice. Then, we assessed brain glucose metabolism with [18F]fluorodeoxyglucose ([18F]FDG) positron emission tomography before and after the acute administration of an NMDA antagonist, MK-801 (0.5 mg/kg), in the same mGluR5 KO and WT mice. RESULTS: Between-group comparisons showed no significant differences in [18F]FDG standardized uptake values (SUVs) in brain of mGluR5 KO and WT mice at baseline, but widespread reductions in mGluR5 KO mice compared to WT mice after MK-801 administration (p < 0.05). The baseline glutamate levels did not differ significantly between the two groups. However, there were significant negative correlations between baseline prefrontal glutamate levels and regional [18F]FDG SUVs in mGluR5 KO mice (p < 0.05), but no such correlations in WT mice. Fisher's Z-transformation analysis revealed significant between-group differences in these correlations (p < 0.05). CONCLUSIONS: This is the first multimodal neuroimaging study in mGluR5 KO mice and the first report on the association between cerebral glucose metabolism and glutamate levels in living rodents. The results indicate that mGluR5 KO mice respond to NMDA antagonism with reduced cerebral glucose metabolism, suggesting that mGluR5 transmission normally moderates the net effects of NMDA receptor antagonism on neuronal activity. The negative correlation between glutamate levels and glucose metabolism in mGluR5 KO mice at baseline may suggest an unmasking of an inhibitory component of the glutamatergic regulation of neuronal energy metabolism.

Association between human gray matter metabotropic glutamate receptor-5 availability in vivo and white matter properties: a [11C]ABP688 PET and diffusion tensor imaging study.

Excitatory corticofugal projections in the subcortical white matter (WM) convey signals arising from local neuronal activity in the gray matter (GM). We hypothesized that metabotropic glutamate receptor-5 (mGluR5) availability in GM, as a surrogate marker for local glutamatergic neuronal activity, correlates with WM properties in healthy brain. We examined the relationship in healthy individuals between GM mGluR5 availability measured in vivo using [11C]ABP688 positron emission tomography (PET) and WM properties measured as fractional anisotropy (FA) using diffusion tensor imaging (DTI). Twenty-three healthy volunteers underwent this multimodal imaging. We calculated mGluR5 availability, [11C]ABP688 binding potential (BPND), using the simplified reference tissue model, and generated DTI FA maps using FMRIB's Diffusion Toolbox (FDT) along with Tract-Based Spatial Statistics (TBSS). To investigate the relationship between mGluR5 availability and FA, we performed voxel-wise and region of interest (ROI)-based analyses. The voxel-wise analysis showed significant positive correlations between the whole cerebral GM [11C]ABP688 BPND and the FA in widespread WM regions including the corpus callosum body, internal capsule, and corona radiata (FWE corrected p < 0.05). The ROI-based analysis also revealed significant positive correlations (Bonferroni-corrected threshold p < 0.00021) between [11C]ABP688 BPND in the frontal and parietal cortical GM and FA in the internal capsule (anterior limb and retrolenticular part). Using a novel multimodal imaging interrogation, we provide the first evidence that GM mGluR5 availability is significantly positively associated with WM properties in healthy subjects. Future comparison studies could determine whether this relationship is perturbed in neuropsychiatric disorders with dysregulated mGluR5 signaling.

Development of Positron Emission Tomography With Wobbling and Zooming for High Sensitivity and High-Resolution Molecular Imaging.

Demands for in-vivo human molecular imaging with high resolution and high sensitivity in positron emission tomography (PET) require several new design formulae. A classical problem of the PET design, however, was the trade-off between sensitivity and resolution. To satisfy both requirements, the brain-body convertible PET with wobbling and zooming is proposed. The features of this new proposed system are wobble sampling for high-resolution imaging and zooming mode for high sensitivity, especially for the brain dedicated imaging. For the high resolution, wobbling with a linear interpolation and line spread function (LSF) deconvolution reconstruction algorithm was introduced. The result of the proposed system provided resolution up to 1.56 mm full width at half maximum (FWHM) in the brain mode and resulting in the detector-to-resolution ratio (DRR) was 2.47. For both brain phantom and in-vivo rat brain imaging, the proposed system demonstrated superior image quality compared with the commercial PET systems. The newly designed PET with wobbling and zooming also demonstrated the possibility of developing practically usable high-resolution human brain PET-MRI fusion system, especially for the neuroscience research.

In vivo metabotropic glutamate receptor 5 availability-associated functional connectivity alterations in drug-naïve young adults with major depression.

There has been increasing interest in glutamatergic neurotransmission as a putative underlying mechanism of depressive disorders. We performed [11C]ABP688 positron emission tomography (PET) and resting-state functional magnetic resonance imaging (rs-fMRI) in drug-naïve young adult patients with major depression to examine alterations in metabotropic glutamate receptor-5 (mGluR5) availability, and to investigate their functional significance relating to neural systems-level changes in major depression. Sixteen psychotropic drug-naïve patients with major depression without comorbidity (median age: 22.8 years) and fifteen matched healthy controls underwent [11C]ABP688 PET imaging and 3-T MRI. For mGluR5 availability, we quantified [11C]ABP688 binding potential (BPND) using the simplified reference tissue model. Seed-based functional connectivity analysis was performed using rs-fMRI data with regions derived from quantitative [11C]ABP688 PET analysis as seeds. In region-of-interest (ROI)-based and voxel-based analyses, the [11C]ABP688 BPND was significantly lower in patients than in controls in the prefrontal cortex ROI and in voxel clusters within the prefrontal, temporal, and parietal cortices, and supramarginal gyrus. The [11C]ABP688 BPND seed-based functional connectivity analysis showed significantly less negative connectivity from the inferior parietal cortex seed to the fusiform gyrus and inferior occipital cortex in patients than in controls. The correlation patterns between [11C]ABP688 BPND and functional connectivity strength (ß) for the superior prefrontal cortex seed were opposite in the depression and control groups. In conclusion, using a novel approach combining [11C]ABP688 PET and rs-fMRI analyses, our study provides a first evidence of lower mGluR5 availability and related functional connectivity alterations in drug-naïve young adults with major depression without comorbidity.

Altered interregional correlations between serotonin transporter availability and cerebral glucose metabolism in schizophrenia: A high-resolution PET study using [11C]DASB and [18F]FDG.

The purpose of the present study was to investigate the patterns of interregional correlations of serotonin transporter (SERT) availability with glucose metabolism using 7-Tesla magnetic resonance imaging (MRI) and high-resolution positron emission tomography (PET) with 11C-3-amino-4-(2-dimethylaminomethylphenylthio)benzonitrile ([11C]DASB) and [18F]fluorodeoxyglucose ([18F]FDG) in antipsychotic-free patients with schizophrenia in order to shed new light on the disrupted functional connectivity in schizophrenia. Nineteen patients with schizophrenia and 18 healthy controls underwent high-resolution PET and MRI. The binding potential (BPND) of [11C]DASB and standardized uptake value ratio (SUVR) of [18F]FDG were obtained. In SERT availability, the region of interest (ROI)-based analyses showed no significant group differences in any region, except for the anterior hippocampus where the SERT availability was lower in patients with schizophrenia than in controls. The ROI- and voxel-based analyses revealed that the [18F]FDG SUVR values were significantly lower in patients than in controls in the right superior frontal gyrus and medial part of the left superior frontal gyrus. Regarding the interregional correlations of [11C]DASB BPND with [18F]FDG SUVR, more widespread positive correlations across the brain regions were observed in control subjects than in patients with schizophrenia. Notably, the patients and control subjects showed statistically significant differences in correlations between the SERT availability in the parietal and temporal cortices and the glucose metabolism in the posterior cingulate cortex. These results suggest abnormal functional connectivity between the higher-order cortical regions in schizophrenia and a possible important role of the posterior cingulate gyrus and its related circuitry in the pathophysiology of schizophrenia.

Self-perceived cognitive deficits and their relationship with internalized stigma and quality of life in patients with schizophrenia.

BACKGROUND: We investigated self-perceived cognitive deficits and their relationship with internalized stigma and quality of life in patients with schizophrenia in order to shed light on the clinical correlates of subjective cognitive deficits in schizophrenia. METHODS: Seventy outpatients with schizophrenia were evaluated. Patients' self-perceived cognitive deficits, internalized stigma, and subjective quality of life were assessed using the Scale to Investigate Cognition in Schizophrenia (SSTICS), the Internalized Stigma of Mental Illness Scale (ISMI), and the Schizophrenia Quality of Life Scale Revision 4 (SQLS-R4), respectively. Correlation and regression analyses controlling for the severity of symptoms of schizophrenia were performed, and a mediation analysis was conducted to examine the hypothesis that internalized stigma mediates the relationship between self-perceived cognitive deficits and subjective quality of life. RESULTS: Pearson's partial correlation analysis showed significant correlations among the SSTICS, ISMI, and SQLS-R4 scores (P<0.01). Multiple regression analysis showed that the SSTICS and ISMI scores significantly predicted the SQLS-R4 score (P<0.01). Mediation analysis revealed that the strength of the association between the SSTICS and SQLS-R4 scores decreased from ß=0.74 (P<0.01) to ß=0.56 (P<0.01), when the ISMI score was statistically controlled. The Sobel test revealed that this difference was significant (P<0.01), indicating that internalized stigma partially mediated the relationship between self-perceived cognitive deficits and quality of life. CONCLUSION: The present study indicates that self-perceived cognitive deficits are significantly associated with internalized stigma and quality of life. Furthermore, internalized stigma was identified as a partial mediator of the relationship between self-perceived cognitive deficits and quality of life. These findings suggest that clinicians should be aware that patients with schizophrenia experience significantly greater self-stigma when they suffer subjective cognitive deficits, and that this may further compromise their quality of life.

Gallstone ileus inducing obstructive jaundice at the afferent loop of Roux-en-Y hepaticojejunostomy after bile duct cancer surgery: a case report.

The diagnosis of gallstone ileus is occasionally challenging due to the variability of its presentation. We herein present a very rare case of gallstone ileus inducing obstructive jaundice at the afferent loop of Roux-en-Y hepaticojejunostomy after 10 years of bile duct cancer surgery. We describe the case of a 74-year-old Korean woman with obstructive jaundice, treated conservatively. She showed severely impaired liver function test and obstructive jaundice. The computed tomography (CT) scan led to a diagnosis of very rare type of gallstones ileus at the afferent jejunal loop. Since the clinical manifestation was improved, we decided to observe her closely. On the next follow-up CT scan, the gallstone disappeared with mild distension of the afferent bowel loop, implicating spontaneous passage of the gallstone. She recovered and returned to normal life after 10 days of initiation of clinical manifestations. We presume that the gallstone may enter the afferent jejunal loop through the hepaticojejunostomy and later increase in size. The presence of narrow tract of intestine may facilitate the incidence of gallstone ileus. It appears to be the first report on this rare type of gallstone ileus inducing obstructive jaundice.

Self-transcendence trait and its relationship with in vivo serotonin transporter availability in brainstem raphe nuclei: An ultra-high resolution PET-MRI study.

Self-transcendence is an inherent human personality trait relating to the experience of spiritual aspects of the self. We examined the relationship between self-transcendence and serotonin transporter (SERT) availability in brainstem raphe nuclei, which are collections of five different serotonergic nuclei with rostro-caudal extension, using ultra-high resolution magnetic resonance imaging (MRI) and positron emission tomography (PET) with (11)C-3-amino-4-(2-dimethylaminomethylphenylthio)benzonitrile ([(11)C]DASB) to elucidate potential roles of serotonergic neuronal activities in this personality trait. Sixteen healthy subjects completed 7.0T MRI and High Resolution Research Tomograph (HRRT) PET. The regions of interest (ROIs) included the dorsal raphe nucleus (R1), median raphe nucleus (R2), raphe pontis (R3), and the caudal raphe nuclei (R4 and R5). For the estimation of SERT availability, the binding potential (BPND) was derived using the simplified reference tissue model (SRTM2). The Temperament and Character Inventory was used to measure self-transcendence. The analysis revealed that the self-transcendence total score had a significant negative correlation with the [(11)C]DASB BPND in the caudal raphe (R5). The subscale score for spiritual acceptance was significantly negatively correlated with the [(11)C]DASB BPND in the median raphe nucleus (R2). The results indicate that the self-transcendence trait is associated with SERT availability in specific raphe subnuclei, suggesting that the serotonin system may serve as an important biological basis for human self-transcendence. Based on the connections of these nuclei with cortico-limbic and visceral autonomic structures, the functional activity of these nuclei and their related neural circuitry may play a crucial role in the manifestation of self-transcendence.