Identifizierung von neuroimmunologischen Korrelaten stress-bedingter Symptome bei Multipler Sklerose

Major depressive disorder (MDD) is one of the most common mental disorders affecting people worldwide. With the risk to develop depression 2-5 times higher than the general population and a lifetime prevalence of 50% it is the most common comorbidity in multiple sclerosis (MS), a chronic autoimmune and neurodegenerative CNS disease. Over the last decades, evidence has been highlighting the role of inflammation in developing depressive symptoms. It is also plausible that different inflammatory profiles are associated with different subtypes of depression. Therefore, studying depressed patients with a comorbid inflammatory condition could provide a good example to investigate the inflammatory subtype of depression. Besides its well-established role in the pathophysiology of MDD, the stress in MS has also been discussed since the disease was described and there has been growing evidence that disease activity in MS is associated with stress. This PhD thesis investigated the immune correlates of depression in the context of background inflammation in MS patients with depression and the association between the cellular measure of immune system responsivity to stress hormones and neural stress processing in MS. We conducted a cross-sectional case-control study that enrolled MS patients with and without depression (N=45) as well as healthy controls (N=30). The study design combined clinical assessments, immunophenotyping, cell-specific quantification of stress hormone signalling in the immune system as well as brain imaging, which included an fMRI stress task to quantify central stress processing. Using clustering analysis of immunophenotyping data our results identified decreased CD4+CCR7low TCM cell frequencies as an immune correlate of MS-associated depression. These cell frequencies correlated with clinical measures of depression severity, specifically with affective symptoms of depression such as sadness, but not with MS severity, measured as disability or cognitive impairment. We also found that lower pe-ripheral CD4+CCR7low TCM cell frequencies were associated with lesion load, a measure of increased neuroinflammation. CD4+CCR7low TCM cell frequencies, however, were not associated with HPA axis activity, suggesting that identified immune correlate of depression is not secondary to stress system alterations. Further examination of cellular and CNS stress processing revealed that the activity of a network comprising the right anterior insula, right fusiform gyrus, left midcingulate and lingual gyrus was differentially associated with T cell glucocorticoid signalling across groups of MS patients and healthy controls and linked to disease severity indicating the importance of CNS-immune system crosstalk in MS.Depressionen (Major Depression = MDD) gehören zu den weltweit häufigsten psychischen Störungen. Mit einem 2- bis 5-mal höheren Risiko, an einer Depression zu erkranken und einer Lebenszeitprävalenz von 50 % ist die Depression die häufigste Komorbidität bei Multipler Sklerose (MS), einer chronischen Autoimmun- und neurodegenerativen ZNS-Erkrankung. In den letzten Jahrzehnten wurde deutlich, dass Entzündungen bei der Entwicklung depressiver Symptome eine Rolle spielen könnten. Es wurde auch gezeigt, dass unterschiedliche Entzündungsprofile mit unterschiedlichen Subtypen von Depressionen assoziiert sind. Daher könnte die Untersuchung depressiver Patienten mit einer komorbiden entzündlichen Erkrankung wertvolle Erkenntnisse zum entzündlichen Subtyp der Depression liefern. Darüber hinaus wird Stress, neben seiner etablierten Rolle in der Pathophysiologie von MDD, auch als Einflussfaktor bei MS diskutiert und es gibt zunehmend Hinweise, dass die Krankheitsaktivität bei MS mit Stress assoziiert ist. Diese Doktorarbeit untersuchte die Immunkorrelate von Depressionen vor dem Hintergrund des Entzündungsgeschehens bei MS-Patienten mit Depressionen sowie den Zusammenhang zwischen der zellulären Stressreaktion des Immunsystems und der neuronalen Stressverarbeitung bei MS. Wir führten eine Fall-Kontroll-Querschnittsstudie durch, in die MS-Patienten mit und ohne Depression (N=45) sowie gesunde Kontrollpersonen (N=30) eingeschlossen wurden. Das Studiendesign kombinierte klinische Bewertungen mit Immunphänotypisierung, zellspezifischer Quantifizierung der Stressreaktion im Immunsystem sowie mit einem bildgebenden Verfahren, welches eine fMRI-basierte Stressaufgabe zur Quantifizierung der zentralen Stressverarbeitung im Gehirn beinhaltete. Clustering-Analysen der Immunphänotypisierungsdaten konnten eine verringerte CD4+CCR7low-TCM-Zellfrequenz als Immunkorrelat von MS-assoziierter Depression identifizieren. Diese Zellfrequenz korrelierte mit der Depressionsschwere, insbesondere mit affektiven Symptomen wie Traurigkeit, aber nicht mit dem Schweregrad der MS-Erkrankung oder der kognitiven Beeinträchtigung. Niedrigere periphere CD4+CCR7low-TCM-Zellfrequenzen waren mit der Läsionslast assoziiert, ein Maß für eine erhöhte Neuroinflammation. CD4+CCR7low-TCM-Zellfrequenzen waren jedoch nicht mit der Aktivität der HPA-Achse assoziiert, was darauf hindeutet, dass dieses Immunkorrelat der Depression nicht sekundär zu Veränderungen im Stresssystem auftritt. Eine weitere Untersuchung der zellulären und der ZNS-Stressverarbeitung ergab, dass die Aktivität eines Gehirn-Netzwerks, das die rechte vordere Insula, den rechten Gyrus fusiformis, den linken mittleren cingulären Kortex sowie den lingualen Gyrus umfasst, bei MS-Patienten und gesunden Kontrollpersonen unterschiedlich mit der T-Zell-Glukokortikoid-Signalübertragung assoziiert und zudem mit der Schwere der Erkrankung verknüpft ist, was die Bedeutung der ZNS-Immunsystem-Interaktion bei MS unterstreicht

A review on multiple sclerosis prognostic findings from imaging, inflammation, and mental health studies

Magnetic resonance imaging (MRI) of the brain is commonly used to detect where chronic and active lesions are in multiple sclerosis (MS). MRI is also extensively used as a tool to calculate and extrapolate brain health by way of volumetric analysis or advanced imaging techniques. In MS patients, psychiatric symptoms are common comorbidities, with depression being the main one. Even though these symptoms are a major determinant of quality of life in MS, they are often overlooked and undertreated. There has been evidence of bidirectional interactions between the course of MS and comorbid psychiatric symptoms. In order to mitigate disability progression in MS, treating psychiatric comorbidities should be investigated and optimized. New research for the prediction of disease states or phenotypes of disability have advanced, primarily due to new technologies and a better understanding of the aging brain

Immunological substrates of depressive symptoms in patients with severe obesity: An exploratory study

In this pilot study, we explored the immune phenotype of patients with severe obesity and comorbid depressive symptoms compared to non-depressed patients with obesity and normal-weight controls. Immune cell subsets were analysed by flow cytometry and depressive symptoms assessed using the Patient Health Questionnaire (PHQ-9). Cell frequencies were correlated with depressive symptom scores and waist-to-hip ratio (WHR). Patients with obesity and comorbid depression showed significantly lower numbers of circulating cytotoxic natural killer cells, dendritic cells and CD8(+) effector memory T cells, compared to normal-weight controls. Regulatory T cells and CD4(+) central memory T cells were increased compared to non-depressed patients with obesity and compared to normal-weight controls, respectively. Frequencies of cytotoxic natural killer cells and CD4(+) central memory T cells significantly correlated with PHQ-9 scores, but not with WHR. Reduced numbers of dendritic cells were observed in both patient groups with obesity and correlated with PHQ-9 scores and WHR. These findings provide evidence for an altered immune composition in comorbid obesity and depression, supporting a pathobiological overlap between the two disorders

Supplementary data for the article: Brasanac-Vukanovic, S.; Mutic, J.; Stankovic, D. M.; Arsic, I.; Blagojevic, N.; Vukasinovic-Pesic, V.; Tadic, V. M. Wild Bilberry (Vaccinium Myrtillus l., Ericaceae) from Montenegro as a Source of Antioxidants for Use in the Production of Nutraceuticals. Molecules 2018, 23 (8). https://doi.org/10.3390/molecules23081864

Supplementary material: [https://doi.org/10.3390/molecules23081864]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/2221

Wild Bilberry (Vaccinium myrtillus L., Ericaceae) from Montenegro as a Source of Antioxidants for Use in the Production of Nutraceuticals

The aim of this study was to establish correlation of chemical composition and antioxidant activity of bilberry plants from Montenegro. Total phenolic, tannin, flavonoid, procyanidin and anthocyanin contents were determined in fruits and leaves extracts using spectrophotometric methods, while the measurements of metal content was carried out in an Inductively Coupled Atomic Emission Spectrometer. Qualitative and quantitative analyses of major phenolics were achieved by HPLC. In the investigated extracts, the most abundant phenolic was chlorogenic acid, followed by protocatechuic acid, while resveratrol, isoquercetin, quecetin and hyperoside were also present in significant quantities. Antioxidant potential was evaluated using two in vitro assays-FRAP and DPPH-being in the accordance with the cyclic voltammetry tests, performed as well. The results revealed that all the investigated extracts were rich in phenolic and essential mineral constituents, with significant antioxidant activity, depending on the polyphenolic and mineral contents, which was confirmed by principal component analysis.Supplementary material: [http://cherry.chem.bg.ac.rs/handle/123456789/3314

(In)credible Research 2020 - online-conference for Credibility, Integrity and Reproducibility of Research

This is the online repository of the Berlin University Aliance's online-conference “(In)credible Research - for Credibility, Integrity and Reproducibility of Research" that took place on 29th and 30th of October 2020. Here you will find slides, recordings and other materials and resources from the online event. (We will upload those gradually.) For further information take a look at our website: https://promotion.charite.de/en/early_career_researchers_conference_2020

Negative Associations of Stress and Anxiety Levels With Cytotoxic and Regulatory Natural Killer Cell Frequency in Chronic Tinnitus

BackgroundDepression and anxiety are known to be associated with stress-induced changes in the immune system. Bothersome tinnitus can be related to stress and often co-occurs with depression and anxiety. This study investigates associations of psychological and audiological tinnitus-related factors with inflammatory parameters and immune cell subsets in chronic tinnitus patients as well as treatment-related effects. MethodsThis longitudinal study of inpatients treated with compact multimodal tinnitus-specific cognitive behavioral therapy included four repeated measurement sessions: baseline (N = 41), treatment end, 7.8-week (N = 35), and 13.8-week follow-up (N = 34). Data collection included audiometric testing, blood sampling, and psychometric questionnaires: Tinnitus Handicap Inventory (THI), Perceived Stress Questionnaire (PSQ-20), and Hospital Anxiety Depression Scale (HADS). Flow cytometry was used to analyze immune cell subsets. Statistical analyses comprised correlation and network analysis (cross-sectional), and linear mixed effect models (longitudinal). ResultsBootstrapped network analysis showed negative averaged cross-sectional associations of cytotoxic natural killer (NKc) cell frequency (CD56 + CD16+) and PSQ-20 (-0.21 [-0.48, 0]) and of regulatory natural killer (NKreg) cell frequency (CD56 + CD16dim/-) and HADS anxiety (-0.14 [-0.38, 0]). No significant treatment effects were found. A negative predictive effect of baseline PSQ-20 scores (beta = -6.22 [-12.18, -0.26], p = 0.041) and a positive predictive effect of baseline ferritin levels (beta = 8.90 [2.76, 15.03], p = 0.004) on NKc cell frequency across the repeated measurement sessions were observed. ConclusionWe observed negative relationships between perceived stress levels and NKc cell frequency and between anxiety levels and NKreg cell frequency in chronic tinnitus patients. These exploratory results suggest stress-/anxiety-related immune alterations in bothersome tinnitus but need to be tested in further confirmatory studies with larger sample sizes. The potential of NK cells as biomarkers of emotional distress in chronic tinnitus should be further investigated