On neuroinflammation in psychotic disorders

Neuroinflammation has been implicated in several psychiatric conditions. Based on experimental studies, the glia-derived tryptophan metabolite kynurenic acid (KYNA) may be especially relevant for positive psychotic symptoms and impaired executive functioning. The first two studies (I and II) of this thesis translate these experimental findings to bipolar disorder patients. Rooted in a genome-wide association study against cerebrospinal fluid (CSF) concentrations of KYNA, we used a multi-pronged approach and linked the identified genetic risk marker not only with other CSF biomarkers in bipolar patients, but also with specific symptoms such as delusions, hallucinations, and impaired executive functioning. We conducted cell studies, postmortem analyses, and clinical association studies that together suggested a sorting nexin 7 driven activation of caspase-8/IL-1ß as a mechanism underlying increased CSF concentration of KYNA in psychotic bipolar patients. Caspase-1 is activated by the purinergic ionotropic receptor P2X7R. This receptor is suggested to be internalized by a G-protein coupled receptor kinase 3 (GRK-3)-dependent mechanism. Decreased protein levels of GRK-3 have been observed in postmortem studies of schizophrenia and psychotic bipolar patients. In study III, we used a mouse with a targeted deletion for GRK3. These mice displayed impaired P2X7R internalization, increased brain levels of IL-1ß, increased immunoreactivity for the astrocytic marker glial fibrillary acidic protein (GFAP), a more pronounced accumulation of hippocampal KYNA, as well as an accentuated dopaminergic response to amphetamine. In behavior models, these animals displayed disrupted pre-pulse inhibition, as well as impaired contextual fear conditioning with spared cue-specific fear conditioning. Taken together, these findings suggest that the GRK3-/-mouse is a novel genetic animal model of schizophrenia that may prove useful in exploring the actions of the emerging immunomodulatory drugs in psychotic disorders. Study IV was a validation study aiming at defining an algorithm that identifies bipolar disorder patients in Swedish national registries as accurate as possible, a pre-requisite for study V. In the last study V of this thesis, we studied the association between psychotic disorders and rheumatoid arthritis (RA). We found that the previously reported inverse association is likely to have been confounded by underreporting and/or underdiagnosis of RA. However, an inverse association between schizophrenia and seronegative RA may be real, tentatively due to shared genetic underpinnings involving glia functioning. In conclusion, this thesis suggests an important role of glial mechanisms in the pathophysiology of the two main psychiatric disorders, schizophrenia and bipolar disorder. Our results add to growing evidence that cytokine and kynurenine metabolite signaling is tied to psychotic and cognitive symptoms. These findings open up for novel drug targets and imply that contemporary glia research can provide a rewarding foundation for investigations into pathology of psychiatric disorders

The association between schizophrenia and rheumatoid arthritis : a nationwide population-based Swedish study on intra-individual and familial risks

Numerous studies have reported a reduced risk of rheumatoid arthritis (RA) in schizophrenia. The mechanisms are unknown, but recent genome-wide association studies of schizophrenia have shown strong associations with markers spanning the major histocompatibility complex region, indicating a possible role for adaptive immunity also in schizophrenia. In this population-based cohort study, we assess the associations between RA and schizophrenia and the extent to which any observed associations are specific to RA/schizophrenia. We then extend the assessments per RA subtype and to risks in first-degree relatives. The study population included every individual identified in the Swedish Population Register born in Sweden between 1932 and 1989. The risk for RA in schizophrenia was significantly decreased (hazard ratio [HR] = 0.69, 95% CI = 0.59-0.80), but similar reductions were noted for osteoarthritis (a noninflammatory joint disorder) and ankylosing spondylitis (a non-RA inflammatory disorder). Comparable associations were seen in schizoaffective subjects while no significant associations were observed in bipolar disorder. Overall, first-degree relatives of schizophrenia patients were not at reduced risk of RA, but the risk for seronegative RA was significantly decreased in children and siblings of schizophrenia probands (HR = 0.13, 95% CI = 0.02-0.95 and HR = 0.67, 95% CI = 049-0.92, respectively). In conclusion, our intraindividual analyses suggest that differential misclassification bias is an important factor for the observed inverse association and emphasize the need of optimized care-provision for nonpsychiatric symptoms in schizophrenia patients. Our familial analyses indicted the possibility of an inverse coinheritance of schizophrenia and seronegative RA.The Swedish Medical Research CouncilThe Swedish Foundation for Strategic ResearchThe COMBINE research consortiumAccepte

Cerebrospinal fluid proteomic study of two bipolar disorder cohorts

The pathophysiology of bipolar disorder remains to be elucidated and there are no diagnostic or prognostic biomarkers for the condition. In this explorative proteomic study, we analyzed 201 proteins in cerebrospinal fluid (CSF) from mood stable bipolar disorder patients and control subjects sampled from two independent cohorts, amounting to a total of 204 patients and 144 controls. We used three Olink Multiplex panels, whereof one specifically targets immune biomarkers, to assess a broad set of CSF protein concentrations. After quality control and removal of proteins with a low detection rate, 105 proteins remained for analyses in relation to case-control status and clinical variables. Only case-control differences that replicated across cohorts were considered. Results adjusted for potential confounders showed that CSF concentrations of growth hormone were lower in bipolar disorder compared with controls in both cohorts. The effect size was larger when the analysis was restricted to bipolar disorder type 1 and controls. We found no indications of immune activation or other aberrations. Growth hormone exerts many effects in the central nervous system and our findings suggest that growth hormone might be implicated in the pathophysiology of bipolar disorder

AHAA- Agile, Hybrid Assessment Method for Automotive, Safety Critical SMEs

The need for software is increasingly growing in the automotive industry. Software development projects are, however, often troubled by time and budget overruns, resulting in systems that do not fulfill customer requirements. Both research and industry lack strategies to combine reducing the long software development lifecycles (as required by time-to-market demands) with increasing the quality of the software developed. Software process improvement (SPI) provides the first step in the move towards software quality, and assessments are a vital part of this process. Unfortunately, software process assessments are often expensive and time consuming. Additionally, they often provide companies with a long list of issues without providing realistic suggestions. The goal of this paper is to describe a new low-overhead assessment method that has been designed specifically for small-to-medium-sized (SMEs) organisations wishing to be automotive software suppliers. This assessment method integrates the structured-ness of the plan-driven SPI models of Capability Maturity Model Integration (CMMI) and Automotive SPICETM with the flexibleness of agile practices

Elevated endogenous GDNF induces altered dopamine signalling in mice and correlates with clinical severity in schizophrenia

Presynaptic increase in striatal dopamine is the primary dopaminergic abnormality in schizophrenia, but the underlying mechanisms are not understood. Here, we hypothesized that increased expression of endogenous GDNF could induce dopaminergic abnormalities that resemble those seen in schizophrenia. To test the impact of GDNF elevation, without inducing adverse effects caused by ectopic overexpression, we developed a novel in vivo approach to conditionally increase endogenous GDNF expression. We found that a 2-3-fold increase in endogenous GDNF in the brain was sufficient to induce molecular, cellular, and functional changes in dopamine signalling in the striatum and prefrontal cortex, including increased striatal presynaptic dopamine levels and reduction of dopamine in prefrontal cortex. Mechanistically, we identified adenosine A2a receptor (A(2A)R), a G-protein coupled receptor that modulates dopaminergic signalling, as a possible mediator of GDNF-driven dopaminergic abnormalities. We further showed that pharmacological inhibition of A(2A)R with istradefylline partially normalised striatal GDNF and striatal and cortical dopamine levels in mice. Lastly, we found that GDNF levels are increased in the cerebrospinal fluid of first episode psychosis patients, and in post-mortem striatum of schizophrenia patients. Our results reveal a possible contributor for increased striatal dopamine signalling in a subgroup of schizophrenia patients and suggest that GDNF-A(2A)R crosstalk may regulate dopamine function in a therapeutically targetable manner.</p

PDRs4All II: JWST's NIR and MIR imaging view of the Orion Nebula

The JWST has captured the most detailed and sharpest infrared images ever taken of the inner region of the Orion Nebula, the nearest massive star formation region, and a prototypical highly irradiated dense photo-dissociation region (PDR). We investigate the fundamental interaction of far-ultraviolet photons with molecular clouds. The transitions across the ionization front (IF), dissociation front (DF), and the molecular cloud are studied at high-angular resolution. These transitions are relevant to understanding the effects of radiative feedback from massive stars and the dominant physical and chemical processes that lead to the IR emission that JWST will detect in many Galactic and extragalactic environments. Due to the proximity of the Orion Nebula and the unprecedented angular resolution of JWST, these data reveal that the molecular cloud borders are hyper structured at small angular scales of 0.1-1" (0.0002-0.002 pc or 40-400 au at 414 pc). A diverse set of features are observed such as ridges, waves, globules and photoevaporated protoplanetary disks. At the PDR atomic to molecular transition, several bright features are detected that are associated with the highly irradiated surroundings of the dense molecular condensations and embedded young star. Toward the Orion Bar PDR, a highly sculpted interface is detected with sharp edges and density increases near the IF and DF. This was predicted by previous modeling studies, but the fronts were unresolved in most tracers. A complex, structured, and folded DF surface was traced by the H2 lines. This dataset was used to revisit the commonly adopted 2D PDR structure of the Orion Bar. JWST provides us with a complete view of the PDR, all the way from the PDR edge to the substructured dense region, and this allowed us to determine, in detail, where the emission of the atomic and molecular lines, aromatic bands, and dust originate

PDRs4All IV. An embarrassment of riches: Aromatic infrared bands in the Orion Bar

(Abridged) Mid-infrared observations of photodissociation regions (PDRs) are dominated by strong emission features called aromatic infrared bands (AIBs). The most prominent AIBs are found at 3.3, 6.2, 7.7, 8.6, and 11.2 $\mu$m. The most sensitive, highest-resolution infrared spectral imaging data ever taken of the prototypical PDR, the Orion Bar, have been captured by JWST. We provide an inventory of the AIBs found in the Orion Bar, along with mid-IR template spectra from five distinct regions in the Bar: the molecular PDR, the atomic PDR, and the HII region. We use JWST NIRSpec IFU and MIRI MRS observations of the Orion Bar from the JWST Early Release Science Program, PDRs4All (ID: 1288). We extract five template spectra to represent the morphology and environment of the Orion Bar PDR. The superb sensitivity and the spectral and spatial resolution of these JWST observations reveal many details of the AIB emission and enable an improved characterization of their detailed profile shapes and sub-components. While the spectra are dominated by the well-known AIBs at 3.3, 6.2, 7.7, 8.6, 11.2, and 12.7 $\mu$m, a wealth of weaker features and sub-components are present. We report trends in the widths and relative strengths of AIBs across the five template spectra. These trends yield valuable insight into the photochemical evolution of PAHs, such as the evolution responsible for the shift of 11.2 $\mu$m AIB emission from class B$_{11.2}$ in the molecular PDR to class A$_{11.2}$ in the PDR surface layers. This photochemical evolution is driven by the increased importance of FUV processing in the PDR surface layers, resulting in a "weeding out" of the weakest links of the PAH family in these layers. For now, these JWST observations are consistent with a model in which the underlying PAH family is composed of a few species: the so-called 'grandPAHs'.Comment: 25 pages, 10 figures, to appear in A&

PDRs4All III: JWST's NIR spectroscopic view of the Orion Bar

(Abridged) We investigate the impact of radiative feedback from massive stars on their natal cloud and focus on the transition from the HII region to the atomic PDR (crossing the ionisation front (IF)), and the subsequent transition to the molecular PDR (crossing the dissociation front (DF)). We use high-resolution near-IR integral field spectroscopic data from NIRSpec on JWST to observe the Orion Bar PDR as part of the PDRs4All JWST Early Release Science Program. The NIRSpec data reveal a forest of lines including, but not limited to, HeI, HI, and CI recombination lines, ionic lines, OI and NI fluorescence lines, Aromatic Infrared Bands (AIBs including aromatic CH, aliphatic CH, and their CD counterparts), CO2 ice, pure rotational and ro-vibrational lines from H2, and ro-vibrational lines HD, CO, and CH+, most of them detected for the first time towards a PDR. Their spatial distribution resolves the H and He ionisation structure in the Huygens region, gives insight into the geometry of the Bar, and confirms the large-scale stratification of PDRs. We observe numerous smaller scale structures whose typical size decreases with distance from Ori C and IR lines from CI, if solely arising from radiative recombination and cascade, reveal very high gas temperatures consistent with the hot irradiated surface of small-scale dense clumps deep inside the PDR. The H2 lines reveal multiple, prominent filaments which exhibit different characteristics. This leaves the impression of a "terraced" transition from the predominantly atomic surface region to the CO-rich molecular zone deeper in. This study showcases the discovery space created by JWST to further our understanding of the impact radiation from young stars has on their natal molecular cloud and proto-planetary disk, which touches on star- and planet formation as well as galaxy evolution.Comment: 52 pages, 30 figures, submitted to A&

Large-scale analysis of structural brain asymmetries in schizophrenia via the ENIGMA consortium

Left-right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small samples and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case-control study of structural brain asymmetries in schizophrenia, using MRI data from 5,080 affected individuals and 6,015 controls across 46 datasets in the ENIGMA consortium, using a single image analysis protocol. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected individuals and controls per dataset, and effect sizes were meta-analyzed across datasets. Small average case-control differences were observed for thickness asymmetries of the rostral anterior cingulate and the middle temporal gyrus, both driven by thinner left-hemispheric cortices in schizophrenia. Analyses of these asymmetries with respect to the use of antipsychotic medication and other clinical variables did not show any significant associations. Assessment of age- and sex-specific effects revealed a stronger average leftward asymmetry of pallidum volume between older cases and controls. Case-control differences in a multivariate context were assessed in a subset of the data (N = 2,029), which revealed that 7% of the variance across all structural asymmetries was explained by case-control status. Subtle case-control differences of brain macro-structural asymmetry may reflect differences at the molecular, cytoarchitectonic or circuit levels that have functional relevance for the disorder. Reduced left middle temporal cortical thickness is consistent with altered left-hemisphere language network organization in schizophrenia