Integrated genetic, epigenetic, and gene set enrichment analyses identify NOTCH as a potential mediator for PTSD risk after trauma : Results from two independent African cohorts
2020-01, Conrad, Daniela, Wilker, Sarah, Schneider, Anna, Karabatsiakis, Alexander, Pfeiffer, Anett, Kolassa, Stephan, Freytag, Virginie, Vukojevic, Vanja, Elbert, Thomas, Kolassa, Iris-Tatjana
The risk of developing posttraumatic stress disorder (PTSD) increases with the number of traumatic event types experienced (trauma load) in interaction with other psychobiological risk factors. The NOTCH (neurogenic locus notch homolog proteins) signaling pathway, consisting of four different trans-membrane receptor proteins (NOTCH1-4), constitutes an evolutionarily well-conserved intercellular communication pathway (involved, e.g., in cell-cell interaction, inflammatory signaling, and learning processes). Its association with fear memory consolidation makes it an interesting candidate for PTSD research. We tested for significant associations of common genetic variants of NOTCH1-4 (investigated by microarray) and genomic methylation of saliva-derived DNA with lifetime PTSD risk in independent cohorts from Northern Uganda (N1 = 924) and Rwanda (N2 = 371), and investigated whether NOTCH-related gene sets were enriched for associations with lifetime PTSD risk. We found associations of lifetime PTSD risk with single nucleotide polymorphism (SNP) rs2074621 (NOTCH3) (puncorrected = 0.04) in both cohorts, and with methylation of CpG site cg17519949 (NOTCH3) (puncorrected = 0.05) in Rwandans. Yet, none of the (epi-)genetic associations survived multiple testing correction. Gene set enrichment analyses revealed enrichment for associations of two NOTCH pathways with lifetime PTSD risk in Ugandans: NOTCH binding (pcorrected = 0.003) and NOTCH receptor processing (pcorrected = 0.01). The environmental factor trauma load was significant in all analyses (all p < 0.001). Our integrated methodological approach suggests NOTCH as a possible mediator of PTSD risk after trauma. The results require replication, and the precise underlying pathophysiological mechanisms should be illuminated in future studies.
Does trauma event type matter in the assessment of traumatic load?
2017-07-06, Conrad, Daniela, Wilker, Sarah, Pfeiffer, Anett, Lingenfelder, Birke, Ebalu, Tracie, Lanzinger, Hartmut, Elbert, Thomas, Kolassa, Iris-Tatjana, Kolassa, Stephan
The likelihood of developing Posttraumatic Stress Disorder (PTSD) depends on the interaction of individual risk factors and cumulative traumatic experiences. Hence, the identification of individual susceptibility factors warrants precise quantification of trauma exposure. Previous research indicated that some traumatic events may have more severe influences on mental health than others; thus, the assessment of traumatic load may be improved by weighting event list items rather than calculating the simple sum score.
We compared two statistical methods, Random Forests using Conditional Interference (RF-CI) and Least Absolute Shrinkage and Selection Operator (LASSO), based on their ability to rank traumatic experiences according to their importance for predicting lifetime PTSD.
Statistical models were initially fitted in a sample of N1 = 441 survivors of the Northern Ugandan rebel war. The ability to correctly predict lifetime PTSD was then tested in an independent sample of N2 = 211, and subsequently compared with predictions by the simple sum score of different traumatic event types experienced.
Results indicate that RF-CI and LASSO allow for a ranking of traumatic events according to their predictive importance for lifetime PTSD. Moreover, RF-CI showed slightly better prediction accuracy than the simple sum score, followed by LASSO when comparing prediction results in the validation sample.
Given the expense in time and calculation effort by RF-CI and LASSO, and the relatively low increase in prediction accuracy by RF-CI, we recommend using the simple sum score to measure the environmental factor traumatic load, e.g., in analyses of gene × environment interactions.
Metabolite profiling in posttraumatic stress disorder
2015, Karabatsiakis, Alexander, Hamuni, Gilava, Wilker, Sarah, Kolassa, Stephan, Renu, Durairaj, Kadereit, Suzanne, Schauer, Maggie, Hennessy, Thomas, Kolassa, Iris-Tatjana
Traumatic stress does not only increase the risk for posttraumatic stress disorder (PTSD), but is also associated with adverse secondary physical health outcomes. Despite increasing efforts, we only begin to understand the underlying biomolecular processes. The hypothesis-free assessment of a wide range of metabolites (termed metabolite profiling) might contribute to the discovery of biological pathways underlying PTSD.
Here, we present the results of the first metabolite profiling study in PTSD, which investigated peripheral blood serum samples of 20 PTSD patients and 18 controls. We performed liquid chromatography (LC) coupled to Quadrupole/Time-Of-Flight (QTOF) mass spectrometry. Two complementary statistical approaches were used to identify metabolites associated with PTSD status including univariate analyses and Partial Least Squares Discriminant Analysis (PLS-DA).
Thirteen metabolites displayed significant changes in PTSD, including four glycerophospholipids, and one metabolite involved in endocannabinoid signaling. A biomarker panel of 19 metabolites classifies PTSD with 85% accuracy, while classification accuracy from the glycerophospholipid with the highest differentiating ability already reached 82%.
This study illustrates the feasibility and utility of metabolite profiling for PTSD and suggests lipid-derived and endocannabinoid signaling as potential biological pathways involved in trauma-associated pathophysiology.
The role of FKBP5 genotype in moderating long-term effectiveness of exposure-based psychotherapy for posttraumatic stress disorder
2014, Wilker, Sarah, Pfeiffer, Anett, Kolassa, Stephan, Elbert, Thomas, Lingenfelder, Birke, Ovuga, Emilio, Papassotiropoulos, Andreas, de Quervain, Dominique, Kolassa, Iris-Tatjana
Exposure-based therapies are considered the state-of-the-art treatment for Posttraumatic Stress Disorder (PTSD). Yet, a substantial number of PTSD patients do not recover after therapy. In the light of the well-known gene × environment interactions on the risk for PTSD, research on individual genetic factors that influence treatment success is warranted. The gene encoding FK506-binding protein 51 (FKBP5), a co-chaperone of the glucocorticoid receptor (GR), has been associated with stress reactivity and PTSD risk. As FKBP5 single-nucleotide polymorphism rs1360780 has a putative functional role in the regulation of FKBP5 expression and GR sensitivity, we hypothesized that this polymorphism influences PTSD treatment success. We investigated the effects of FKBP5 rs1360780 genotype on Narrative Exposure Therapy (NET) outcome, an exposure-based short-term therapy, in a sample of 43 survivors of the rebel war in Northern Uganda. PTSD symptom severity was assessed before and 4 and 10 months after treatment completion. At the 4-month follow-up, there were no genotype-dependent differences in therapy outcome. However, the FKBP5 genotype significantly moderated the long-term effectiveness of exposure-based psychotherapy. At the 10-month follow-up, carriers of the rs1360780 risk (T) allele were at increased risk of symptom relapse, whereas non-carriers showed continuous symptom reduction. This effect was reflected in a weaker treatment effect size (Cohen's D=1.23) in risk allele carriers compared with non-carriers (Cohen's D=3.72). Genetic factors involved in stress response regulation seem to not only influence PTSD risk but also responsiveness to psychotherapy and could hence represent valuable targets for accompanying medication.
Auditory Memory Decay as Reflected by a New Mismatch Negativity Score Is Associated with Episodic Memory in Older Adults at Risk of Dementia
2018, Laptinskaya, Daria, Thurm, Franka, Küster, Olivia C., Fissler, Patrick, Schlee, Winfried, Kolassa, Stephan, von Arnim, Christine A. F., Kolassa, Iris-Tatjana
The auditory mismatch negativity (MMN) is an event-related potential (ERP) peaking about 100-250 ms after the onset of a deviant tone in a sequence of identical (standard) tones. Depending on the interstimulus interval (ISI) between standard and deviant tones, the MMN is suitable to investigate the pre-attentive auditory discrimination ability (short ISIs, ≤ 2 s) as well as the pre-attentive auditory memory trace (long ISIs, >2 s). However, current results regarding the MMN as an index for mild cognitive impairment (MCI) and dementia are mixed, especially after short ISIs: while the majority of studies report positive associations between the MMN and cognition, others fail to find such relationships. To elucidate these so far inconsistent results, we investigated the validity of the MMN as an index for cognitive impairment exploring the associations between different MMN indices and cognitive performance, more specifically with episodic memory performance which is among the most affected cognitive domains in the course of Alzheimer's dementia (AD), at baseline and at a 5-year-follow-up. We assessed the amplitude of the MMN for short ISI (stimulus onset asynchrony, SOA = 0.05 s) and for long ISI (3 s) in a neuropsychologically well-characterized cohort of older adults at risk of dementia (subjective memory impairment, amnestic and non-amnestic MCI;n= 57). Furthermore, we created a novel difference score (ΔMMN), defined as the difference between MMNs to short and to long ISI, as a measure to assess the decay of the auditory memory trace, higher values indicating less decay. ΔMMN and MMN amplitude after long ISI, but not the MMN amplitude after short ISI, was associated with episodic memory at baseline (β= 0.38,p= 0.003;β= -0.27,p= 0.047, respectively). ΔMMN, but not the MMN for long ISIs, was positively associated with episodic memory performance at the 5-year-follow-up (β= 0.57,p= 0.013). The results suggest that the MMN after long ISI might be suitable as an indicator for the decline in episodic memory and indicate ΔMMN as a potential biomarker for memory impairment in older adults at risk of dementia.
Cognitive change is more positively associated with an active lifestyle than with training interventions in older adults at risk of dementia : a controlled interventional clinical trial
2016, Küster, Olivia C., Fissler, Patrick, Laptinskaya, Daria, Thurm, Franka, Scharpf, Andrea, Woll, Alexander, Kolassa, Stephan, Kramer, Arthur F., Elbert, Thomas, Kolassa, Iris-Tatjana
While observational studies show that an active lifestyle including cognitive, physical, and social activities is associated with a reduced risk of cognitive decline and dementia, experimental evidence from corresponding training interventions is more inconsistent with less pronounced effects. The aim of this study was to evaluate and compare training- and lifestyle-related changes in cognition. This is the first study investigating these associations within the same time period and sample.
The effect of trauma-focused therapy on the altered T cell distribution in individuals with PTSD : evidence from a randomized controlled trial
2014-07, Morath, Julia, Gola, Hannah, Sommershof, Annette, Hamuni, Gilava, Kolassa, Stephan, Catani, Claudia, Adenauer, Hannah, Ruf-Leuschner, Martina, Schauer, Maggie, Elbert, Thomas, Gröttrup, Marcus, Kolassa, Iris-Tatjana
Posttraumatic stress disorder (PTSD) is associated with a reduced ratio of naïve cytotoxic T lymphocytes, an increased ratio of memory cytotoxic T lymphocytes, and a reduced proportion of FoxP3+ regulatory T lymphocytes. This study investigated whether these immunological alterations are reversible through an evidence-based psychotherapeutic treatment. Therefore, 34 individuals with PTSD were randomly assigned to either a treatment condition of 12 sessions narrative exposure therapy (NET) or a waitlist control (WLC) group. PTSD symptoms were significantly reduced in the NET group, but not in the WLC group, four months post-therapy (effect size: Hedges' g = −1.61). One year after therapy, PTSD symptoms were improved even further in the NET group compared to baseline (Hedges' g = −1.96). This symptom improvement was mirrored in an increase in the originally reduced proportion of regulatory T cells (Tregs) in the NET group at the one-year follow-up, when comparing subgroups matched for baseline Treg numbers. However, no changes were found for the initially reduced proportion of CD45RA+CCR7+ naïve T lymphocytes. In conclusion, NET was effective in reducing trauma-related PTSD symptoms and had a positive effect on the proportion of Tregs cells, thus demonstrating an effect of psychotherapy on an immunological level. Yet, the shift in the proportion of naïve and memory T lymphocytes in individuals with PTSD, discussed in the literature as a correlate of premature immunosenescence, was not reversible and thus might render these patients permanently more susceptible to infectious diseases.
Alterations of hair cortisol and dehydroepiandrosterone in mother-infant-dyads with maternal childhood maltreatment
2017-12, Schury, Katharina, Koenig, Alexandra M., Isele, Dorothea, Hulbert, A. L., Krause, Sabrina, Umlauft, Maria, Kolassa, Stephan, Ziegenhain, Ute, Karabatsiakis, Alexander, Kolassa, Iris-Tatjana
Child maltreatment (CM) has severe effects on psychological and physical health. The hypothalamic-pituitary-adrenal (HPA) axis, the major stress system of the body, is dysregulated after CM. The analysis of cortisol and dehydroepiandrosterone (DHEA) in scalp hair presents a new and promising methodological approach to assess chronic HPA axis activity. This study investigated the effects of CM on HPA axis activity in the last trimester of pregnancy by measuring the two important signaling molecules, cortisol and DHEA in hair, shortly after parturition. In addition, we explored potential effects of maternal CM on her offspring’s endocrine milieu during pregnancy by measuring cortisol and DHEA in newborns’ hair.
CM was assessed with the Childhood Trauma Questionnaire (CTQ). Cortisol and DHEA were measured in hair samples of 94 mothers and 30 newborns, collected within six days after delivery. Associations of maternal CM on her own and her newborn’s cortisol as well as DHEA concentrations in hair were analyzed with heteroscedastic regression models.
Higher CM was associated with significantly higher DHEA levels, but not cortisol concentrations in maternal hair. Moreover, maternal CM was positively, but only as a non-significant trend, associated with higher DHEA levels in the newborns’ hair.
Results suggest that the steroid milieu of the mother, at least on the level of DHEA, is altered after CM, possibly leading to non-genomic transgenerational effects on the developing fetus in utero. Indeed, we observed on an explorative level first hints that the endocrine milieu for the developing child might be altered in CM mothers. These results need extension and replication in future studies. The measurement of hair steroids in mothers and their newborns is promising, but more research is needed to better understand the effects of a maternal history of CM on the developing fetus.
How to quantify exposure to traumatic stress? : Reliability and predictive validity of measures for cumulative trauma exposure in a post-conflict population
2015, Wilker, Sarah, Pfeiffer, Anett, Kolassa, Stephan, Koslowski, Daniela, Elbert, Thomas, Kolassa, Iris-Tatjana
Background: While studies with survivors of single traumatic experiences highlight individual response variation following trauma, research from conflict regions shows that almost everyone develops posttraumatic stress disorder (PTSD) if trauma exposure reaches extreme levels. Therefore, evaluating the effects of cumulative trauma exposure is of utmost importance in studies investigating risk factors for PTSD. Yet, little research has been devoted to evaluate how this important environmental risk factor can be best quantified.
Methods: We investigated the retest reliability and predictive validity of different trauma measures in a sample of 227 Ugandan rebel war survivors. Trauma exposure was modeled as the number of traumatic event types experienced or as a score considering traumatic event frequencies. In addition, we investigated whether age at trauma exposure can be reliably measured and improves PTSD risk prediction.
Results: All trauma measures showed good reliability. While prediction of lifetime PTSD was most accurate from the number of different traumatic event types experienced, inclusion of event frequencies slightly improved the prediction of current PTSD.
Conclusions: As assessing the number of traumatic events experienced is the least stressful and time-consuming assessment and leads to the best prediction of lifetime PTSD, we recommend this measure for research on PTSD etiology.
Mitochondrial respiration in peripheral blood mononuclear cells correlates with depressive subsymptoms and severity of major depression
2014, Karabatsiakis, Alexander, Böck, Christina, Salinas-Manrique, Juan, Kolassa, Stephan, Calzia, Enrico, Dietrich, Detlef E., Kolassa, Iris-Tatjana
Mitochondrial dysfunction might have a central role in the pathophysiology of depression. Phenotypically, depression is characterized by lack of energy, concentration problems and fatigue. These symptoms might be partially explained by reduced availability of adenosine triphosphate (ATP) as a consequence of impaired mitochondrial functioning. This study investigated mitochondrial respiration in peripheral blood mononuclear cells (PBMCs), an established model to investigate the pathophysiology of depression. Mitochondrial respiration was assessed in intact PBMCs in 22 individuals with a diagnosis of major depression (MD) compared with 22 healthy age-matched controls using high-resolution respirometry. Individuals with MD showed significantly impaired mitochondrial functioning: routine and uncoupled respiration as well as spare respiratory capacity, coupling efficiency and ATP turnover-related respiration were significantly lower in the MD compared with the control group. Furthermore, mitochondrial respiration was significantly negatively correlated with the severity of depressive symptoms, in particular, with loss of energy, difficulties concentrating and fatigue. The results suggest that mitochondrial dysfunction contributes to the biomolecular pathophysiology of depressive symptoms. The decreased immune capability observed in MD leading to a higher risk of comorbidities could be attributable to impaired energy supply due to mitochondrial dysfunction. Thus mitochondrial respiration in PBMCs and its functional consequences might be an interesting target for new therapeutical approaches in the treatment of MD and immune-related comorbidities.