08:30 Uhr
Brain-inflammation signatures in recent onset mental health disorders – a high dimensional data driven approach
D. Popovic (München, DE)
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Autor:innen:
D. Popovic (München, DE)
C. Weyer (DE)
A. Ruef (DE)
D. Dwyer (AU)
S. Griffiths (GB)
P. Lalousis (GB)
J. Steiner (DE)
P. Falkai (DE)
S. Wood (AU)
N. Koutsouleris (DE)
R. Upthegrove (GB)
Background: An early and comprehensive neurobiological characterization of severe mental disorders could elucidate mechanistic pathways, aid the development of novel therapeutics, and therefore enable timely and targeted intervention in at-risk youth and young adults. Therefore, we present an unsupervised transdiagnostic machine learning approach to investigate patterns of early-stage depressive and psychotic disorders on multiple clinical and neurobiological levels.
Methods: From the multicenter European PRONIA cohort, we acquired data from 678 individuals (51% female) comprising young, minimally medicated individuals with clinical high-risk (CHR) states for psychosis, recent-onset depression (ROD) or psychosis (ROP), and healthy control (HC) individuals. We employed Sparse Partial Least Squares Analysis to detect associations between peripheral inflammation markers and grey matter volume (GMV). We investigated these signatures on biographical, clinical, neurocognitive, proteomic, and functional levels.
Results: First, a psychosis staging signature separated ROP from CHR via GMV in the cortico-thalamo-cerebellar circuitry and an immune marker set of elevated IL-6, TNF-α and decreased CRP. Second, a depression signature separated ROD from HC via altered GMV in the limbic system with an immune marker set of elevated IL-1ß, IL-2, IL-4, S100B and BDNF. The psychosis staging signature showed a proteomic enrichment regarding innate immune response, abnormal neutrophil function, cellular senescence, and anti-inflammatory drug targets. Childhood trauma differentially loaded onto both psychosis and depression signatures, while both signatures impacted level of functioning, personality and quality of life in similar fashion.
Conclusions: Psychosis and depression exhibit distinct multi-level signatures evident in early disease stages. Enhanced insight into these signatures could help delineate individual trajectories and new mechanisms for pharmacological treatment.
08:42 Uhr
Investigating the role of CCL11 in shaping microglial age and long-COVID related inflammatory activation
D. Helbing (Jena, DE)
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Autor:innen:
N. Oraha (DE)
M. Reuter (DE)
A. Stockdale (DE)
A. Stockdale (DE)
E. Cirri (DE)
T. Dau (DE)
M. Groth (DE)
F. Haas (DE)
R. Bauer (DE)
H. Morrison (DE)
D. Helbing (Jena, DE)
Microglia are the innate immune cells of the brain and are at the centre of neuroinflammatory cascades initiated during ageing and in several neuropsychiatric disorders. In recent years, a specific systemically circulating cytokine, CCL11, has been identified that is elevated in both blood and CSF during ageing in mice and humans, and is one of the major inflammatory cytokines that is elevated in blood and CSF during acute COVID-19 infection and in patients with neuropsychiatric long COVID (LC) syndrome up to several weeks after infection. However, a systematic and unbiased analysis of the effects of CCL11 on the molecular architecture of the CNS and specifically on microglial phenotypes and responses has not yet been performed. In this study, we used mouse models and primary microglial cell culture as well as proteomics and RNAseq to investigate the effects of CCL11 on microglia across the lifespan. In particular, we found that systemic administration of CCL11 for several weeks leads to a profound remodelling of the CNS proteome in different brain regions profiled, with several age-related molecular pathways being induced by CCL11. This was accompanied by morphological changes towards a more activated microglial phenotype and induction of a DNA damage response. RNAseq of CCL11-stimulated cultured primary microglia revealed the induction of a microglial phenotype transcriptionally similar to inflammatory and disease-associated microglia as seen in Alzheimer's mouse models. Therefore, we used global CCL11 knockout mice to investigate microglial changes during ageing in the absence of CCL11. Interestingly, we identified a partial rescue of specific age-related molecular subdomains in isolated microglia from old knockout mice. Taken together, our data suggest that CCL11 may be of high importance in inducing age- and LC-associated microglial dysfunction, which may subsequently contribute to age-associated neuropsychiatric diseases as well as neuropsychiatric longCOVID.
08:54 Uhr
Influence of the angiotensin converting enzyme polymorphism on ventricular volume in patients with recurrent depression – interaction with childhood trauma?
H. Murck (Marburg, DE)
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Autor:innen:
S. Zesakes (Marburg, DE)
K. Brosch (DE)
F. Stein (DE)
H. Murck (Marburg, DE)
The renin-angiotensin- aldosterone system (RAAS) is involved in stress regulation and treatment outcome in patients with major depression. A documented genetic marker related to the RAAS, which appears to be associated with treatment outcome is the polymorphism of the angiotensin-converting enzyme (ACE) SNP rs4291 of the ACE gene, which determines ACE activity and therefore high aldosterone levels. High aldosterone in patients with depression is related to treatment resistance enlarged ventricle volumes (Buttner et al., 2015; Murck et al., 2020), which may be determined by changes in cerebrospinal fluid secretion. Furthermore, childhood trauma was associated with increased aldosterone plasma concentration (Terock et al., 2022) in a study in the general population and with treatment resistance in depressed subjects. We are exploring the mechanistic role of an ACE-polymorphism rs4291, and its interaction with childhood trauma (CHT+ vs. CHT-) in patients with recurrent depression. Duration of disease and intracerebral volume had the expected high correlation with combined volume of the lateral ventricles. Separate models testing for the effect of the polymorphism AT vs. AA and the presence of childhood trauma found an unexpected enlargement of CHT- subjects, but no effect of genotype. An extended model checking for interactions found in addition a positive interaction between genotype and the duration of disease in a way that the AT genotype shows a significantly steeper increase in ventricular volume with the duration of disease than the AA genotype. This is in particular the case for CHT- subjects. In conclusion, provided that ventricular volume is a risk marker of depression, we could confirm the risk increase by the AT genotype. Unexpectedly, patients with a history of depression and childhood trauma have smaller ventricular volumes, potentially as a sign of resiliency.
09:06 Uhr
Reduzierte Pregnenolon-Konzentration im Urin nach klinischer Response bei Patienten mit Depression: eine prospektive Open-Label-Studie
B. Pedraz (Mannheim, DE)
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Autor:innen:
B. Pedraz (Mannheim, DE)
E. Lamadé (Mannheim, DE)
J. Vítků (Prag, CZ)
M. Hill (Prag, CZ)
M. Gilles (Mannheim, DE)
M. Deuschle (Mannheim, DE)
Einführung: Die Identifizierung biologischer Veränderungen in Depression, insbesondere solche, die sich zwischen Responders und Non-Responders unterscheiden, ist von klinischem Interesse. Biomarker-Kandidaten umfassen neuroaktive Steroide, wie Pregnenolon (PREG) und Allopregnanolon (ALLO). Der Zusammenhang zwischen Veränderungen von PREG und ALLO und der therapeutischen Response ist jedoch unzureichend untersucht. Das Hauptziel dieser Forschungsarbeit ist es daher, die Effekte der antidepressiven Therapie, des klinischen Ansprechens und der Therapiedauer auf PREG und ALLO bei Patienten mit Depression zu untersuchen.
Methode: In einer 4-wöchigen Open-label-Studie wurden Patienten mit Depression randomisiert der Venlafaxin- (n = 27) oder der Mirtazapin-Gruppe (n = 30) zugeteilt. Nächtliche Konzentrationen i.U. von PREG und ALLO wurden mittels Gaschromatographie mit Massenspektrometrie-Kopplung bewertet. Zwei primäre Endpunkte wurden umfasst: (1) die Untersuchung der Effekte der antidepressiven Therapie (Mirtazapin und Venlafaxin), der klinischen Response (HDRS) und der Therapiedauer (Baseline und nach 28 Tagen Therapie) auf die Konzentrationen von PREG oder ALLO und (2) die Untersuchung der Effekte der klinischen Response und der Therapiedauer auf die Konzentrationen von PREG oder ALLO i.U., unabhängig von diesen Antidepressiva. Ein lineares gemischtes Model wurde durchgeführt.
Ergebnisse: Es gab keine signifikanten Unterschiede in den PREG- und ALLO-Konzentrationen zwischen der Baseline und den 28 Tagen Therapie bei Respondern und Non-Respondern in der Venlafaxin- und Mirtazapin-Gruppe. Es wurde jedoch eine signifikante Reduktion der PREG-Konzentration nach Behandlung bei den Respondern, unabhängig von den in dieser Studie verabreichten Antidepressiva.
Schlussfolgerungen: Responders bei Depression weisen nach 4 Wochen eine reduzierte PREG-Konzentration i.U. auf, unabhängig von der verwendeten medikamentösen Therapie. Mehrere Studien sind jedoch erforderlich.