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Childhood maltreatment is an important risk factor for adult depression and has been associated with changes in the hypothalamic pituitary adrenal (HPA) axis, including cortisol secretion and methylation of the FKBP5 gene. Furthermore, associations between depression and HPA changes have been reported. This study investigated the associations of whole-blood FKBP5 mRNA levels, serum cortisol levels, childhood maltreatment, and depressive symptoms with the whole-blood methylation status (assessed via target bisulfite sequencing) of 105 CpGs at the FKBP5 locus using data from the general population-based Study of Health in Pomerania (SHIP) (N = 203). Both direct and interaction effects with the rs1360780 single-nucleotide polymorphism were investigated. Nominally significant associations of main effects on methylation of a single CpG site were observed at intron 3, intron 7, and the 3′-end of the gene. Additionally, methylation at two clusters at the 3′-end and intron 7 were nominally associated with childhood maltreatment × rs1360780 and depressive symptoms × rs1360780, respectively. The results add to the understanding of molecular mechanisms underlying the emergence of depression and could aid the development of personalised depression therapy and drug development.
Previous studies provided evidence for the importance of cardiac structure abnormalities, in particular greater left ventricular (LV) mass, for brain aging, but longitudinal studies are lacking to date. We included 926 individuals (median age 48 years; 53% women) from the TREND cohort of the Study of Health in Pomerania (SHIP) without reduced ejection fraction or a history of myocardial infarction. LV mass index (LVMI) was determined by echocardiography at baseline. Brain morphometric measurements were derived from magnetic resonance images at baseline and 7‐year follow‐up. Direct effects of baseline LVMI on brain morphometry at follow‐up were estimated using linear regression models with adjustment for baseline brain morphometry. At baseline, median LVMI was 40 g/m2.7 and 241 individuals (26%) met the criterion of LV hypertrophy. After correction for multiple testing, baseline LVMI was directly associated with reduced global cortical thickness and increased cortical brain age at follow‐up independent from hypertension and blood pressure. Exposure‐outcome relations were nonlinear and significantly stronger in the upper half of the exposure distribution. Specifically, an increase in baseline LVMI from the 50% quantile to the 95% quantile was associated additional 2.7 years (95% confidence interval = [1.5 years, 3.8 years]) of cortical brain age at follow‐up. Additional regional analyses yielded bilateral effects on multiple frontal cortical regions. Our findings highlight the role of cardiac structure in brain aging. LVMI constitutes an easily measurable marker that might help to identify persons at risk for cognitive impairment and dementia.
COVID-19, a systemic multi-organ disease resulting from infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is known to result in a wide array of disease outcomes, ranging from asymptomatic to fatal. Despite persistent progress, there is a continued need for more accurate determinants of disease outcomes, including post-acute symptoms after COVID-19. In this study, we characterised the serum metabolomic changes due to hospitalisation and COVID-19 disease progression by mapping the serum metabolomic trajectories of 71 newly hospitalised moderate and severe patients in their first week after hospitalisation. These 71 patients were spread out over three hospitals in Switzerland, enabling us to meta-analyse the metabolomic trajectories and filter consistently changing metabolites. Additionally, we investigated differential metabolite–metabolite trajectories between fatal, severe, and moderate disease outcomes to find prognostic markers of disease severity. We found drastic changes in serum metabolite concentrations for 448 out of the 901 metabolites. These results included markers of hospitalisation, such as environmental exposures, dietary changes, and altered drug administration, but also possible markers of physiological functioning, including carboxyethyl-GABA and fibrinopeptides, which might be prognostic for worsening lung injury. Possible markers of disease progression included altered urea cycle metabolites and metabolites of the tricarboxylic acid (TCA) cycle, indicating a SARS-CoV-2-induced reprogramming of the host metabolism. Glycerophosphorylcholine was identified as a potential marker of disease severity. Taken together, this study describes the metabolome-wide changes due to hospitalisation and COVID-19 disease progression. Moreover, we propose a wide range of novel potential biomarkers for monitoring COVID-19 disease course, both dependent and independent of the severity.
Alzheimer’s disease (AD) is a progressive neurodegenerative disease representing the most common type of dementia in older adults. The major risk factors include increased age, genetic predisposition and socioeconomic factors. Among the genetic factors, the apolipoprotein E (ApoE) ε4 allele poses the greatest risk. Growing evidence suggests that cerebrovascular dysfunctions, including blood–brain barrier (BBB) leakage, are also linked to AD pathology. Within the scope of this paper, we, therefore, look upon the relationship between ApoE, BBB integrity and AD. In doing so, both brain-derived and peripheral ApoE will be considered. Despite the considerable evidence for the involvement of brain-derived ApoE ε4 in AD, information about the effect of peripheral ApoE ε4 on the central nervous system is scarce. However, a recent study demonstrated that peripheral ApoE ε4 might be sufficient to impair brain functions and aggravate amyloid-beta pathogenesis independent from brain-based ApoE ε4 expression. Building upon recent literature, we provide an insight into the latest research that has enhanced the understanding of how ApoE ε4, secreted either in the brain or the periphery, influences BBB integrity and consequently affects AD pathogenesis. Subsequently, we propose a pathway model based on current literature and discuss future research perspectives.
The aim of this study was to disentangle the effects of various genetic factors on hippocampal subfield volumes using three different approaches: a biologically driven candidate gene approach, a hypothesis-free GWAS approach, and a polygenic approach, where AD risk alleles are combined with a polygenic risk score (PRS). The impact of these genetic factors was investigated in a large dementia-free general population cohort from the Study of Health in Pomerania (SHIP, n = 1806). Analyses were performed using linear regression models adjusted for biological and environmental risk factors. Hippocampus subfield volume alterations were found for APOE ε4, BDNF Val, and 5-HTTLPR L allele carriers. In addition, we were able to replicate GWAS findings, especially for rs17178139 (MSRB3), rs1861979 (DPP4), rs7873551 (ASTN2), and rs572246240 (MAST4). Interaction analyses between the significant SNPs as well as the PRS for AD revealed no significant results. Our results confirm that hippocampal volume reductions are influenced by genetic variation, and that different variants reveal different association patterns that can be linked to biological processes in neurodegeneration. Thus, this study underlines the importance of specific genetic analyses in the quest for acquiring deeper insights into the biology of hippocampal volume loss, memory impairment, depression, and neurodegenerative diseases.
The FKBP5 gene is part of an ultra-short feedback loop of the hypothalamic-pituitary-adrenal (HPA) axis and was linked to HPA axis alterations due to genetic variations, expression patterns, cortisol concentrations, and stressors. The thesis investigated the interplay of multi-omics factors, focusing on sex-specific responses and environmental stressors such as childhood maltreatment (CM), depression, and oral contraceptive (OC) use. Three studies were conducted using data from a large population-based study: The first study investigated HPA axis alterations in premenopausal OC users versus non-users through multi-omics analyses. OC users exhibited stress-like HPA axis alterations, particularly higher cortisol and FKBP5 mRNA concentrations. Associations with FKBP5 methylation levels were largely dependent on FKBP5 genotype and stress-exposure. The second study focused on FKBP5 SNPs, notably rs1360780, and explored their relationship with FKBP5 methylation levels in the context of CM and depression. Reduced FKBP5 methylation in rs1360780 TT carriers and those with more severe depressive symptoms were observed. No association was found with CM. The third study integrated neuronal changes via sex-specific associations between cortisol concentrations and cortical thickness. Higher cortisol concentrations were associated with reduced cortical thickness in men, but not in women, independent of CM and depression. Additionally, men had higher cortisol concentrations than women. Our results indicate stress-like HPA axis alterations in OC users, FKBP5-genotype-dependent methylation changes, and neurotoxic effects of elevated cortisol concentrations. By integrating multi-omics data, we offer a comprehensive view of HPA axis dynamics, pointing to the potential for personalized approaches in managing stress-related disorders. Additionally, future HPA axis research should consider sex- differences more frequently.
Zusammenfassung
43,6 % der Schwangeren in Deutschland leiden unter mindestens einer psychischen Erkrankung, am häufigsten sind Depressionen und Ängste. Das Risiko für eine verlängerte Geburtsdauer, einen pathologischen Geburtsverlauf und Geburtsmodus ist erhöht. Durch eine individualisierte psychotherapeutische Intervention soll ein positiver Einfluss auf den Verlauf der Geburt erreicht werden.
In dem Präventionsnetzwerk Vorpommern: Psychosoziale und neurobiologische Gesundheit von Schwangeren und jungen Müttern (PriVileG-M), einer randomisierten kontrollierten Studie wurden die gesunden Schwangeren der gesunden Gruppe (GG) und die psychisch belasteten Schwangeren einer Interventions- (PBI) oder einer Kontrollgruppe (PBK) zugeteilt. Die Interventionsgruppe erhielt eine individualisierte Psychotherapie, die pränatal, ab ca. der 25. Schwangerschaftswoche begann. Bis zum Zeitpunkt der Geburt erfolgten ca. 7-10 Interventionen mit einer Frequenz von ein bis zwei Wochen zwischen jeder psychotherapeutischen Intervention. Im Geburtsfollow-up wurden die Geburtsparameter dokumentiert.
Die Ergebnisse zeigten hypothesenkonform, dass die gestressten bzw. psychisch belasteten Frauen eine längere Geburtsdauer und mehr pathologische Geburtsausgänge (Sectio, Forceps, Vakuumextraktion) haben. Insbesondere wurde der Verlauf der Geburt durch Angstsymptome und erlebte Kindheitstraumata, sogar unabhängig von der Gruppenzuteilung beeinflusst. Die individualisierte psychotherapeutische Intervention mit ihren 7- 10 Sitzungen bewirkte keine messbaren, signifikanten Veränderungen in der Geburtsdauer und Geburtsmodus in der Interventionsgruppe gegenüber der psychisch belasten Kontrollgruppe oder der gesunden Gruppe (GG).
Die möglichen Effekte der Psychotherapie könnten aufgrund der noch zu kleinen Gruppengröße statistisch nicht deutlich geworden sein. Denkbar ist auch, dass der Beginn in der 25. Schwangerschaftswoche zu spät gewählt war oder die Anzahl der Interventionen in der Schwangerschaft. So bleibt weiterhin eine interdisziplinäre Forschung notwendig, welche Art der Behandlung, wie oft und in welcher Schwangerschaftswoche beginnend eine psychische Stabilisierung erreichen könnte, um eine signifikante Verringerung der pathologischen Geburtsverläufe, insbesondere der Kaiserschnittrate, eine durchschnittliche Geburtsdauer und eine positive Geburtserfahrung zu erreichen.
Dies erfordert ein frühzeitiges standardisiertes Screening psychischer Belastungen, Kindheitstraumata und vorausgegangene schwierige Geburten in der gynäkologischen oder hebammengeleiteten Schwangerenvorsorge, wie es in einigen Ländern bereits zur Routine gehört.
Schlüsselwörter: präpartale psychische Belastung, Geburt, psychotherapeutische Intervention, Schwangere, Geburtsmodus, Geburtsdauer
Belastende Lebensereignisse sind seit jeher ein fester Bestandteil der menschlichen Existenz. Außerordentlich belastende Erlebnisse werden auf unterschiedliche Weise verarbeitet. Eine mögliche Folge ist eine posttraumatische Belastungsstörung (PTBS). Für die Betroffenen ist es nicht selbstverständlich, über ihre Erlebnisse zu sprechen, und für die Behandelnden kann es zu einer Herausforderung werden, eine PTBS zu erkennen. Obwohl die PTBS in den letzten Jahrzehnten an Bedeutung gewonnen hat, fehlen noch immer Studien sowohl über die Anzahl der Patienten, die an einer unerkannten PTBS leiden, als auch über den Vergleich von Patienten mit unerkannter PTBS mit anderen Patientengruppen. Daher befasst sich diese Dissertation mit den Schwierigkeiten bei der Identifizierung von PTBS-Fällen in der Psychiatrie. Darüber hinaus werden mithilfe von diagnostischen Testverfahren und demografischen Daten Unterschiede zwischen den Gruppen der Patienten mit bekannter PTBS, den Patienten ohne PTBS und der interessierenden Gruppe der Patienten mit einer zum Zeitpunkt der Studie nicht identifizierten PTBS ermittelt. Mit den gewonnenen Informationen sollen eine differenziertere Betrachtung und bessere Behandlungsmöglichkeiten der PTBS ermöglicht werden. Die Erscheinungsformen der PTBS werden anhand der Posttraumatic Stress Diagnostic Scale (PDS) und der Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) untersucht. Eine differenziertere Untersuchung der Stichprobe wird mit dem Beck Depression Inventory (BDI-II), der Symptom Checklist-90 Standard (SCL-90) und dem Childhood Trauma Screener (CTQ) durchgeführt. Beschrieben wird die Untersuchung von 102 Probanden, die schließlich ihre Fragebögen einreichten, von 114 Probanden, die dazu grundsätzlich bereit waren, aus einem Pool von 637 ursprünglich in Betracht kommenden Patienten. Bei 17 der 102 auswertbaren Probanden wurde eine zuvor nicht erkannte PTBS-Diagnose festgestellt, was einem Anteil von 17,89 % der Patienten im klinisch-psychiatrischen Bereich mit unerkannter und damit unbehandelter PTBS entspricht. Darüber hinaus weisen die Probanden mit unerkannter PTBS signifikant höhere Werte auf den Skalen „Emotionaler Missbrauch“, „Körperlicher Missbrauch“ und „Bagatellisierung“ des CTQ-Fragebogens auf. Diese Gruppe ist um einiges jünger als ihre Vergleichsgruppen, jedoch ohne signifikanten Unterschied. Darüber hinaus sind die Punktwerte im BDI-II für die Probanden mit nicht identifizierter PTBS höher mit einer gleichzeitig ausgeprägteren Gesamtbelastung ihrer Symptome (GSI) nach der SCL-90. Es ist jedoch kein signifikanter Unterschied zwischen den Gruppen hinsichtlich des Geschlechts festzustellen. Diese Ergebnisse verdeutlichen die Bedeutung einer umfassenden Erstdiagnose einschließlich einer sorgfältigen Traumaexploration durch gründlich geschultes Personal im psychiatrischen Alltag.
Although the common pathology of Alzheimer’s disease (AD) and white matter hyperintensities (WMH) is disputed, the gene TREML2 has been implicated in both conditions: its whole-blood gene expression was associated with WMH volume and its missense variant rs3747742 with AD risk. We re-examined those associations within one comprehensive dataset of the general population, additionally searched for cross-relations and illuminated the role of the apolipoprotein E (APOE) ε4 status in the associations. For our linear regression and linear mixed effect models, we used 1949 participants from the Study of Health in Pomerania (Germany). AD was assessed using a continuous pre-symptomatic MRI-based score evaluating a participant’s AD-related brain atrophy. In our study, increased whole-blood TREML2 gene expression was significantly associated with reduced WMH volume but not with the AD score. Conversely, rs3747742-C was significantly associated with a reduced AD score but not with WMH volume. The APOE status did not influence the associations. In sum, TREML2 robustly associated with WMH volume and AD-related brain atrophy on different molecular levels. Our results thus underpin TREML2’s role in neurodegeneration, might point to its involvement in AD and WMH via different biological mechanisms, and highlight TREML2 as a worthwhile target for disentangling the two pathologies.
Background
Lower cortisol concentrations in adulthood were repeatedly associated with more severe childhood maltreatment. Additionally, childhood maltreatment was reported to promote health risk behavior, such as smoking or alcohol consumption, and to increase the risk of mental and somatic diseases during adulthood, such as major depressive disorders or obesity. The present study investigated if health risk behavior and disease symptoms in adults mediate the associations between past childhood maltreatment and present basal serum cortisol concentrations.
Methods
Data from two independent adult cohorts of the general population-based Study of Health in Pomerania (SHIP-TREND-0: N = 3,517; SHIP-START-2: N = 1,640) was used. Childhood maltreatment was assessed via the Childhood Trauma Questionnaire (CTQ). Cortisol concentrations were measured in single-point serum samples. Health risk behavior and mental and physical symptoms were used as mediators. Mediation analyses were calculated separately for both cohorts; results were integrated via meta-analyses.
Results
In mediator-separated analyses, associations between childhood maltreatment and basal serum cortisol concentrations were partly mediated by depressive symptoms (BDI-II: βindirect effect = -.011, pFDR = .017, 21.0% mediated) and subjective somatic health complaints (somatic complaints: βindirect effect = -.010, pFDR = .005, 19.4% mediated). In the second step, both mediators were simultaneously integrated into one mediation model. The model replicated the mediation effects of the subjective somatic health complaints (whole model: βindirect effect = -.014, p = .001, 27.6% mediated; BDI-II: βindirect effect = -.006, p = .163, 11.4% mediated, somatic complaints: βindirect effect = -.020, p = .020, 15.5% mediated).
Conclusion
The results support the hypothesis that the long-lasting effects of childhood maltreatment on the stress response system are partly mediated through self-perceived disease symptoms. However, no mediation was found for health risk behavior or physically measured mediators. Mediation models with multiple simultaneous mediators pointed to a relevant overlap between the potential mediators. This overlap should be focused on in future studies.