Translational studies on bipolar disorder and anorexia nervosa

Translational medicine aims at closing the gap between basic and clinical sciences in an integrative way. Psychiatry is one of the few medical specialties in which diagnosis is primarily based on clinical observation and all mental disorders are defined by abnormal behaviors and cognitions. The lack of biomarkers supporting diagnostic and therapeutic procedures has been a challenge in psychiatry. A better biological understanding is needed to move the field forward, it will enhance diagnostics and treatment, while reducing the stigma that surrounds mental disorders that are so poorly understood. Over the last years, advances in fundamental sciences like genetics and neuroscience have made it clear that there is shared biology between many psychiatric disorders and that integration of methods might lead to new understandings. The studies presented in this thesis focus on bipolar disorder (BD) and anorexia nervosa (AN), both severe mental disorders with high suicide rates, high heritability, and both lacking in biological understanding. BD, formerly known as manic-depressive disorder, is a mood disorder, characterized by manic or hypomanic episodes, often in combination with depressive episodes. AN is an eating disorder characterized by severe weight loss together with pathological behaviors. This thesis includes five main studies on the biology underlying these disorders, based on large, well characterized cohorts, covering several methods, including genetic, imaging and protein markers, as well as preliminary data on the establishment of in vitro models. Specifically, in study I, we attempted to replicate previously published findings on the association between subphenotypes of bipolar disorder and genetic variations in the AKT1 gene. Using frequentist and Bayesian approaches, as well as publicly available results from genome-wide association studies (GWAS), we were able to reject previously proposed associations. In study II, we explored the effects of genetic variations in genes involved in glutamate regulation on glutamate levels in two brain regions and their associations with other phenotypes. We found that the minor allele of rs3812778/rs3829280 in the 5’-untranslated region of SLC1A2, coding for a glutamate transporter, is associated (1) with increased glutamate levels in the anterior cingulate cortex, (2) with increased expression levels, in several brain regions, of the transmembrane receptor gene CD44, which is implicated in inflammation and brain development, as well as (3) with an increased risk for rapid-cycling in bipolar disorder, potentially linking CD44/SLC1A2 to a more severe phenotype of BD. In study III, we investigated the effects of clinical and genetic parameters on lithium pharmacokinetics in order to better understand lithium biology and improve lithium dose prediction models for bipolar patients, using the ratio between serum lithium and daily lithium intake, as outcome. We were able to confirm the association of several clinical predictors. Although no genome-wide significant locus was found, we report that genetic variation is important and might influence the outcome. Finally, based on the results obtained in the study, we developed a prediction algorithm that can be tested in the clinic. In study IV, we investigated the involvement of neuronal degeneration in AN by studying neurofilament light chain (NfL), a known marker of neurodegeneration, in a case-control setting and found increased levels of NfL in patients with active AN in two different cohorts. In study V, we studied the involvement of inflammation in AN, using a panel of 92 inflammatory markers in a case-control setting and report an aberrant inflammatory profile in patients with active AN, but not in patients that have recovered from AN. These studies exemplify possible approaches that can be taken in translational psychiatry. The integration of clinical, technical and analytical approaches illustrates important learning outcomes for an aspiring clinical scientist in psychiatr

Les espaces de l'halieutique

Les tactiques de pêches développées par les pêcheurs peuvent être interprétées comme des adaptations à l'hétérogénéité spatiale de la distribution d'une ressource. Elles visent en effet à réduire l'incertitude relative aux probabilités de captures que peut attendre le pêcheur, incertitude induite par la répartition spatiale de la ressource. Les facteurs intervenants dans la constitution d'une tactique donnée sont a priori nombreux, mais surtout difficiles à quantifier car issus pour une grande part de choix subjectifs et qualitatifs. On se propose ici de les aborder de manière théorique à partir d'un travail de simulations. Les comportements individuels des pêcheurs sont ainsi modélisés en fonction de trois types de facteurs : facteurs informatifs, concernant les échanges d'informations entre pêcheurs au sein d'une flotille ; facteurs "cognitifs", liés à la connaissance partielle du milieu et la faculté d'apprentissage des pêcheurs ; facteurs directifs, liés au comportement du pêcheurs ; facteurs directifs, liés au comportement du pêcheur : interactions pêcheur-pêcheur, pêcheur-ressource, pêcheur-structure d'autorité. Plus précisément, la présente étude se concentre sur les déterminants des tactiques de pêche relevant des deux premières composantes. On définit ainsi un modèle d'échange d'informations individuelles entre navires d'une part, et de savoir-faire individuel d'autre part. Ces modèles définissent des tactiques de recherche de la ressource. Ils sont mis en oeuvre au sein d'un simulateur de type système multi-agent, où sont représentées explicitement l'activité de pêche des navires d'une flotille et la ressource sur laquelle elle se développe... (D'après résumé d'auteur

Association of Catechol-Omethyltransferase (COMT Val158Met) with future risk of cardiovascular disease in depressed individuals - a Swedish population-based cohort study

Background: Catechol-O-methyltransferase (COMT Val158Met) has been implicated in both depression and cardiovascular disease. The purpose of this study was to assess if COMT Val158Met, which influences the COMT enzyme activity, has an effect on the risk of cardiovascular disease (CVD) in individuals with a history of depression and also to determine if the risk differs depending on gender. Methods: Data from a longitudinal cohort study of mental health among Swedish adults was used. Depression was assessed twice 3 years apart for each participant, in 1998-2001 and 2001-2003. Saliva DNA was contributed by 4349 (41.7%) of the participants and 3525 was successfully genotyped for COMT Val158Met. Participants were followed up until December 2014 from the National Patient register with regard to cardiovascular outcomes (hypertensive or ischemic heart disease, and stroke). Results: Those with depression and the high COMT enzyme activity genotype (Val/Val) had almost a three-fold increased risk of later CVD (OR 3.6; 95% CI: 2.0-6.6) compared to those non-depressed carrying the Val/Val allele. This effect on risk for CVD was higher in women compared to men (OR 7.0; 95% CI: 3.0-14.0 versus OR 2.1; 95% CI: 1.0-6.8). Both additive interaction (attributable proportion (AP) = 0.56; 95% CI: 0.24-0.90 and synergy index (SI) = 4.39; 1.0-18.7) and multiplicative interaction (log likelihood test p = 0.1) was present between depression and COMT Val158Met in predicting risk of later CVD. Conclusion: High COMT activity genotype Val158Met increased the risk of CVD in depressed persons. The risk was higher in women compared to men

Prenatal diagnosis and outcome of fetuses with isolated agenesis of septum pellucidum: cohort study and meta-analysis

Objective: To evaluate the postnatal outcome of children with a prenatal diagnosis of apparently isolated agenesis of the septum pellucidum (ASP). Methods: A retrospective cohort study of cases of prenatally diagnosed ASP followed in two tertiary centers and a meta-analysis combining data from the cohort study with data from published studies identified in a systematic review were carried out. Only cases with apparently isolated ASP on antenatal ultrasound and/or magnetic resonance imaging and with available postnatal follow-up data were considered eligible for inclusion. The following outcomes were analyzed: incidence of chromosomal anomalies, agreement between antenatal and postnatal findings, overall incidence of septo-optic dysplasia (SOD) and incidence of major neurological disability (motor, language, coordination or behavioral disorder or epilepsy) in non-SOD children. The incidence of SOD in infants with apparently normal optic pathways on antenatal imaging was also evaluated. Results: Fifteen cases of isolated ASP, with median postnatal follow-up of 36 months (range, 12-60 months), were selected from the two centers. Six previously published studies met the inclusion criteria for the systematic review and a total of 78 cases were eligible for the analysis, including the 15 cases from our series. Genetic tests were carried out antenatally in 30 fetuses, of which two had an abnormal result (pooled proportion, 9.0% (95% CI, 1.8-20.7%); I2  = 0%). Additional or discordant imaging findings were noted postnatally in 9/70 (pooled proportion, 13.7% (95% CI, 3.5-29.0%); I2  = 63.9%) cases. Of all 78 neonates with available follow-up, SOD was diagnosed postnatally in 14 (pooled proportion, 19.4% (95% CI, 8.6-33.2%); I2  = 51.2%). In 60 cases, the optic pathways were considered to be normal on antenatal imaging, and six of these (pooled proportion, 9.1% (95% CI, 1.1-24.0%); I2  = 62.0%) were diagnosed postnatally with SOD. Of the 46 infants with available neurological follow-up who were not affected by SOD, a major neurological disability was diagnosed in three (pooled proportion, 6.5% (95% CI, 0.5-18.6%); I2  = 40.1%). Conclusions: In the vast majority of cases with a prenatal diagnosis of apparently isolated ASP, the prognosis is favorable. However, an additional anomaly is detected after birth in about 14% of cases and has a negative impact on clinical outcome. Detailed antenatal assessment of the brain and optic pathways is strongly recommended in order to identify the presence of associated anomalies. Antenatal visualization of apparently normal optic pathways does not rule out SOD. © 2021 International Society of Ultrasound in Obstetrics and Gynecology

Effects of a Synbiotic on Plasma Immune Activity Markers and Short-Chain Fatty Acids in Children and Adults with ADHD—A Randomized Controlled Trial

Synbiotic 2000, a pre + probiotic, reduced comorbid autistic traits and emotion dysregulation in attention deficit hyperactivity disorder (ADHD) patients. Immune activity and bacteria-derived short-chain fatty acids (SCFAs) are microbiota–gut–brain axis mediators. The aim was to investigate Synbiotic 2000 effects on plasma levels of immune activity markers and SCFAs in children and adults with ADHD. ADHD patients (n = 182) completed the 9-week intervention with Synbiotic 2000 or placebo and 156 provided blood samples. Healthy adult controls (n = 57) provided baseline samples. At baseline, adults with ADHD had higher pro-inflammatory sICAM-1 and sVCAM-1 and lower SCFA levels than controls. Children with ADHD had higher baseline sICAM-1, sVCAM-1, IL-12/IL-23p40, IL-2Rα, and lower formic, acetic, and propionic acid levels than adults with ADHD. sICAM-1, sVCAM-1, and propionic acid levels were more abnormal in children on medication. Synbiotic 2000, compared to placebo, reduced IL-12/IL-23p40 and sICAM-1 and increased propionic acid levels in children on medication. SCFAs correlated negatively with sICAM-1 and sVCAM-1. Preliminary human aortic smooth-muscle-cell experiments indicated that SCFAs protected against IL-1β-induced ICAM-1 expression. These findings suggest that treatment with Synbiotic 2000 reduces IL12/IL-23p40 and sICAM-1 and increases propionic acid levels in children with ADHD. Propionic acid, together with formic and acetic acid, may contribute to the lowering of the higher-than-normal sICAM-1 levels

Aberrant inflammatory profile in acute but not recovered anorexia nervosa

Anorexia nervosa (AN) is a severe psychiatric disorder with high mortality and relapse rates. Even though changes in inflammatory markers and cytokines are known to accompany cachexia associated with somatic disorders such as cancer and chronic kidney disorder, studies on inflammatory markers in AN are rare and typically include few individuals. Here, we utilize an Olink Proteomics inflammatory panel to explore the concentrations of 92 preselected inflammation-related proteins in plasma samples from women with active AN (N = 113), recovered from AN (AN-REC, N = 113), and normal weight healthy controls (N = 114). After correction for multiple testing, twenty-five proteins differed significantly between the AN group and controls (lower levels: ADA, CCL19, CD40, CD5, CD8A, CSF1, CXCL1, CXCL5, HGF, IL10RB, IL12B, 1L18R1, LAP TGFß1, MCP3, OSM, TGFα, TNFRSF9, TNFS14 and TRANCE; higher levels: CCL11, CCL25, CST5, DNER, LIFR and OPG). Although more than half of these differences (N = 15) were present in the comparison between AN and AN-REC, no significant differences were seen between AN-REC and controls. Furthermore, twenty-five proteins correlated positively with BMI (ADA, AXIN1, CASP8, CD5, CD40, CSF1, CXCL1, CXCL5, EN-RAGE, HGF, IL6, IL10RB, IL12B, IL18, IL18R1, LAP TGFß1, OSM, SIRT2, STAMBP, TGFα, TNFRSF9, TNFS14, TRANCE, TRAIL and VEGFA) and four proteins correlated negatively with BMI (CCL11, CCL25, CCL28 and DNER). These results suggest that a dysregulated inflammatory status is associated with AN, but, importantly, seem to be confined to the acute illness state

An integrative proteomics method identifies a regulator of translation during stem cell maintenance and differentiation

To characterize molecular changes during cell type transitions, the authors develop a method to simultaneously measure protein expression and thermal stability changes. They apply this approach to study differences between human pluripotent stem cells, their progenies, parental and allogeneic cells. Detailed characterization of cell type transitions is essential for cell biology in general and particularly for the development of stem cell-based therapies in regenerative medicine. To systematically study such transitions, we introduce a method that simultaneously measures protein expression and thermal stability changes in cells and provide the web-based visualization tool ProteoTracker. We apply our method to study differences between human pluripotent stem cells and several cell types including their parental cell line and differentiated progeny. We detect alterations of protein properties in numerous cellular pathways and components including ribosome biogenesis and demonstrate that modulation of ribosome maturation through SBDS protein can be helpful for manipulating cell stemness in vitro. Using our integrative proteomics approach and the web-based tool, we uncover a molecular basis for the uncoupling of robust transcription from parsimonious translation in stem cells and propose a method for maintaining pluripotency in vitro

Performance of CMS muon reconstruction in pp collision events at sqrt(s) = 7 TeV

The performance of muon reconstruction, identification, and triggering in CMS has been studied using 40 inverse picobarns of data collected in pp collisions at sqrt(s) = 7 TeV at the LHC in 2010. A few benchmark sets of selection criteria covering a wide range of physics analysis needs have been examined. For all considered selections, the efficiency to reconstruct and identify a muon with a transverse momentum pT larger than a few GeV is above 95% over the whole region of pseudorapidity covered by the CMS muon system, abs(eta) < 2.4, while the probability to misidentify a hadron as a muon is well below 1%. The efficiency to trigger on single muons with pT above a few GeV is higher than 90% over the full eta range, and typically substantially better. The overall momentum scale is measured to a precision of 0.2% with muons from Z decays. The transverse momentum resolution varies from 1% to 6% depending on pseudorapidity for muons with pT below 100 GeV and, using cosmic rays, it is shown to be better than 10% in the central region up to pT = 1 TeV. Observed distributions of all quantities are well reproduced by the Monte Carlo simulation.Comment: Replaced with published version. Added journal reference and DO

Performance of CMS muon reconstruction in pp collision events at sqrt(s) = 7 TeV

The performance of muon reconstruction, identification, and triggering in CMS has been studied using 40 inverse picobarns of data collected in pp collisions at sqrt(s) = 7 TeV at the LHC in 2010. A few benchmark sets of selection criteria covering a wide range of physics analysis needs have been examined. For all considered selections, the efficiency to reconstruct and identify a muon with a transverse momentum pT larger than a few GeV is above 95% over the whole region of pseudorapidity covered by the CMS muon system, abs(eta) < 2.4, while the probability to misidentify a hadron as a muon is well below 1%. The efficiency to trigger on single muons with pT above a few GeV is higher than 90% over the full eta range, and typically substantially better. The overall momentum scale is measured to a precision of 0.2% with muons from Z decays. The transverse momentum resolution varies from 1% to 6% depending on pseudorapidity for muons with pT below 100 GeV and, using cosmic rays, it is shown to be better than 10% in the central region up to pT = 1 TeV. Observed distributions of all quantities are well reproduced by the Monte Carlo simulation.Comment: Replaced with published version. Added journal reference and DO

X-ray emission from the Sombrero galaxy: discrete sources

We present a study of discrete X-ray sources in and around the bulge-dominated, massive Sa galaxy, Sombrero (M104), based on new and archival Chandra observations with a total exposure of ~200 ks. With a detection limit of L_X = 1E37 erg/s and a field of view covering a galactocentric radius of ~30 kpc (11.5 arcminute), 383 sources are detected. Cross-correlation with Spitler et al.'s catalogue of Sombrero globular clusters (GCs) identified from HST/ACS observations reveals 41 X-rays sources in GCs, presumably low-mass X-ray binaries (LMXBs). We quantify the differential luminosity functions (LFs) for both the detected GC and field LMXBs, whose power-low indices (~1.1 for the GC-LF and ~1.6 for field-LF) are consistent with previous studies for elliptical galaxies. With precise sky positions of the GCs without a detected X-ray source, we further quantify, through a fluctuation analysis, the GC LF at fainter luminosities down to 1E35 erg/s. The derived index rules out a faint-end slope flatter than 1.1 at a 2 sigma significance, contrary to recent findings in several elliptical galaxies and the bulge of M31. On the other hand, the 2-6 keV unresolved emission places a tight constraint on the field LF, implying a flattened index of ~1.0 below 1E37 erg/s. We also detect 101 sources in the halo of Sombrero. The presence of these sources cannot be interpreted as galactic LMXBs whose spatial distribution empirically follows the starlight. Their number is also higher than the expected number of cosmic AGNs (52+/-11 [1 sigma]) whose surface density is constrained by deep X-ray surveys. We suggest that either the cosmic X-ray background is unusually high in the direction of Sombrero, or a distinct population of X-ray sources is present in the halo of Sombrero.Comment: 11 figures, 5 tables, ApJ in pres