Untersuchung des Zusammenspiels metabolischer und autoimmuner Oligodendrogliopathie im kombinatorischen Mausmodell der Multiplen Sklerose

Hintergrund: Oligodendrozyten-Degeneration und die daraus resultierende Demyelinisierung sind zentrale Merkmale der MS-Pathologie. Behandlungsansätze, welche die Oligodendrozyten und das Myelin schützen und die endogenen Regenerationsmechanismen fördern, stehen bisher noch nicht zur Verfügung. Oligodendrogliopathie und Demyelinisierung werden üblicherweise als direkte Folgen einer immun-vermittelten entzündlichen Reaktion gesehen. Intrinsische metabolische Störungen sind aber wahrscheinlich von ähnlicher Bedeutung. Obwohl wir über gute präklinische Modelle für die isolierte Untersuchung immun-vermittelter und metabolischer Oligodendrogliopathie verfügen, fehlen uns Modelle zur Untersuchung des Zusammenspiels zwischen beiden Prozessen. Fragestellung: Wir vermuten, dass die kontinuierliche Cuprizone-Intoxikation und die aktive Induktion der experimentellen autoimmunen Enzephalomyelitis (EAE) bei Mäusen uns erlauben würde, Interaktionen zwischen metabolischer und inflammatorischer Schädigung von Oligodendrozyten im ZNS zu untersuchen. Methoden: Weibliche C57BL/6 Mäuse wurden zur Induktion einer metabolischen Oligodendrozyten-Degeneration mit 0,25% Cuprizone für 18 Tage intoxikiert. Am 3. Tag der Cuprizone-Intoxikation wurden die Tiere mit MOG35-55 („myelin oligodendrocyte glycoprotein peptide“) immunisiert. Diese bewirkte die Formierung Myelin-autoreaktiver T-Zellen in den peripheren lymphatischen Organen. Die Mäuse wurden mithilfe eines strukturierten klinischen Score-Systems täglich beurteilt und am Höhepunkt der EAE finalisiert. Die ZNS-Präparate wurden (immun-) histochemisch hinsichtlich inflammatorischer Infiltrate, Demyelinisierung, Oligodendrozyten-Degeneration, Mikrogliose und Neurodegeneration untersucht. Ergebnisse: Trotz der immunsuppressiven Wirkung von Cuprizone kam es bei kontinuierlicher Intoxikation zur Formierung Myelin-autoreaktiver T-Zellen und zur Entwicklung motorischer Defizite. Obwohl die Cuprizone-Intoxikation zu einem milderen klinischen EAE-Verlauf und geringerem Ausmaß an Inflammation im Rückenmark führte, sorgte die Cuprizone-induzierte Oligodendrogliopathie im Vorderhirn zur verstärkten Lymphozyteninvasion am Ort der Läsion. Diese Vorderhirnläsionen ähnelten stark den Typ III MS-Läsionen und waren u.a. durch Oligodendrozyten-Apoptose, Demyelinisierung, Mikrogliose und Infiltration von Lymphozyten gekennzeichnet. Ausblick: Zusammenfassend haben wir im Rahmen dieser Studie ein präklinisches Mausmodell entwickelt, welches es uns erlaubt, das direkte Zusammenspiel zwischen immun-vermittelter und metabolischer Oligodendrogliopathie zu untersuchen. Das bessere Verständnis der genauen Mechanismen, die zur Demyelinisierung und folglich klinischen Progression führen, würde zur Entwicklung neuer Behandlungsansätze und Verbesserung der Prognose der Patienten mit MS führen

Signature of altered retinal microstructures and electrophysiology in schizophrenia spectrum disorders is associated with disease severity and polygenic risk

BACKGROUND Optical coherence tomography (OCT) and electroretinography (ERG) studies have revealed structural and functional retinal alterations in individuals with schizophrenia spectrum disorders (SSD). However, it remains unclear which specific retinal layers are affected, how the retina, brain, and clinical symptomatology are connected, and how alterations of the visual system are related to genetic disease risk. METHODS OCT, ERG, and brain magnetic resonance imaging (MRI) were applied to comprehensively investigate the visual system in a cohort of 103 patients with SSD and 130 healthy control individuals. The sparse partial least squares (SPLS) algorithm was used to identify multivariate associations between clinical disease phenotype and biological alterations of the visual system. The association of the revealed patterns with the individual polygenetic disease risk for schizophrenia was explored in a post hoc analysis. In addition, covariate-adjusted case-control comparisons were performed for each individual OCT and ERG parameter. RESULTS The SPLS analysis yielded a phenotype-eye-brain signature of SSD in which greater disease severity, longer duration of illness, and impaired cognition were associated with electrophysiological alterations and microstructural thinning of most retinal layers. Higher individual loading onto this disease-relevant signature of the visual system was significantly associated with elevated polygenic risk for schizophrenia. In case-control comparisons, patients with SSD had lower macular thickness, thinner retinal nerve fiber and inner plexiform layers, less negative a-wave amplitude, and lower b-wave amplitude. CONCLUSIONS This study demonstrates multimodal microstructural and electrophysiological retinal alterations in individuals with SSD that are associated with disease severity and individual polygenetic burden

Association of symptom severity and cerebrospinal fluid alterations in recent onset psychosis in schizophrenia-spectrum disorders – an individual patient data meta-analysis

Neuroinflammation and blood-cerebrospinal fluid barrier (BCB) disruption could be key elements in schizophrenia-spectrum disorderś(SSDs) etiology and symptom modulation. We present the largest two-stage individual patient data (IPD) meta-analysis, investigating the association of BCB disruption and cerebrospinal fluid (CSF) alterations with symptom severity in first-episode psychosis (FEP) and recent onset psychotic disorder (ROP) individuals, with a focus on sex-related differences. Data was collected from PubMed and EMBASE databases. FEP, ROP and high-risk syndromes for psychosis IPD were included if routine basic CSF-diagnostics were reported. Risk of bias of the included studies was evaluated. Random-effects meta-analyses and mixed-effects linear regression models were employed to assess the impact of BCB alterations on symptom severity. Published (6 studies) and unpublished IPD from n = 531 individuals was included in the analyses. CSF was altered in 38.8 % of individuals. No significant differences in symptom severity were found between individuals with and without CSF alterations (SMD = -0.17, 95 %CI −0.55–0.22, p = 0.341). However, males with elevated CSF/serum albumin ratios or any CSF alteration had significantly higher positive symptom scores than those without alterations (SMD = 0.34, 95 %CI 0.05–0.64, p = 0.037 and SMD = 0.29, 95 %CI 0.17–0.41p = 0.005, respectively). Mixed-effects and simple regression models showed no association (p > 0.1) between CSF parameters and symptomatic outcomes. No interaction between sex and CSF parameters was found (p > 0.1). BCB disruption appears highly prevalent in early psychosis and could be involved in positive symptomś severity in males, indicating potential difficult-to-treat states. This work highlights the need for considering BCB breakdown and sex-related differences in SSDs clinical trials and treatment strategies

The multimodal Munich Clinical Deep Phenotyping study to bridge the translational gap in severe mental illness treatment research

Introduction: Treatment of severe mental illness (SMI) symptoms, especially negative symptoms and cognitive dysfunction in schizophrenia, remains a major unmet need. There is good evidence that SMIs have a strong genetic background and are characterized by multiple biological alterations, including disturbed brain circuits and connectivity, dysregulated neuronal excitation-inhibition, disturbed dopaminergic and glutamatergic pathways, and partially dysregulated inflammatory processes. The ways in which the dysregulated signaling pathways are interconnected remains largely unknown, in part because well-characterized clinical studies on comprehensive biomaterial are lacking. Furthermore, the development of drugs to treat SMIs such as schizophrenia is limited by the use of operationalized symptom-based clusters for diagnosis. Methods: In line with the Research Domain Criteria initiative, the Clinical Deep Phenotyping (CDP) study is using a multimodal approach to reveal the neurobiological underpinnings of clinically relevant schizophrenia subgroups by performing broad transdiagnostic clinical characterization with standardized neurocognitive assessments, multimodal neuroimaging, electrophysiological assessments, retinal investigations, and omics-based analyzes of blood and cerebrospinal fluid. Moreover, to bridge the translational gap in biological psychiatry the study includes in vitro investigations on human-induced pluripotent stem cells, which are available from a subset of participants. Results: Here, we report on the feasibility of this multimodal approach, which has been successfully initiated in the first participants in the CDP cohort; to date, the cohort comprises over 194 individuals with SMI and 187 age and gender matched healthy controls. In addition, we describe the applied research modalities and study objectives. Discussion: The identification of cross-diagnostic and diagnosis-specific biotype-informed subgroups of patients and the translational dissection of those subgroups may help to pave the way toward precision medicine with artificial intelligence-supported tailored interventions and treatment. This aim is particularly important in psychiatry, a field where innovation is urgently needed because specific symptom domains, such as negative symptoms and cognitive dysfunction, and treatment-resistant symptoms in general are still difficult to treat

Label-free characterization of white blood cells using fluorescence lifetime imaging and flow-cytometry: molecular heterogeneity and erythrophagocytosis [Invited]

Article reporting the results of blood cell characterization using label-free fluorescence imaging techniques and flow-cytometry. Autofluorescence parameters of different cell types – white blood cells, red blood cells, erythrophagocytic cells – are assessed and analyzed in terms of molecular heterogeneity and possibilities of differentiation between different cell types in vitro and in vivo

Target tracking with composite linear filters on noisy scenes

A tracking system using a bank of adaptive linear filters is proposed. Tracking is carried out by means of multiple target detections. The linear filters are designed from multiple views of a target using synthetic discriminant functions. For each view an optimum filter is derived from noisy reference image and disjoint background model. An iterative algorithm is used to improve the performance of the synthesized filters. The number of filters in the bank can be controlled to guarantee a prescribed tracking accuracy. Computer simulation results show that the proposed algorithm is able to precisely track a target.This work was supported the Russian Science Foundation grant №15-19-10010

Heat Flux Measurement in Shock Heated Combustible Gases and Clarification of Ignition Delay Time

Correct understanding of the ignition and combustion processes in the combustion chambers are critical for modeling advanced schemes of engines of high-speed aircraft and promising spacecraft. Moreover, experimental data on the ignition delay time are a universal basis for the development and testing of combustion kinetic models. Moreover, the higher the temperature of the fuel mixture, the smaller this time value and the more important its correct determination. The use of a thermoelectric detector allows to measure ignition delay times and record heat fluxes with a high time resolution (to tenths of μs) during ignition in propane–air mixtures. Due to the faster response time, the use of it allows refining the ignition delay time of the combustible mixture, and the detector itself can serve as a useful device that allows a more detailed study of the ignition processes