17:17 Uhr
Strukturelle und funktionelle Konnektivität schizotyper Persönlichkeitszüge in gesunden Probanden
J. Hoffmann (Marburg, DE)
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Autor:innen:
J. Hoffmann (Marburg, DE)
T. Meller (DE)
U. Evermann (DE)
J. Pfarr (DE)
I. Nenadic (DE)
Einführung: Im angenommenen Kontinuum psychotischer Symptome, Erlebnisweisen und Störungen nehmen schizotype Persönlichkeitszüge als Ausdruck einer Psychose-Neigung eine wichtige Rolle für die Konzeptualisierung und Messung eines Risikophänotyps ein. Neuere Studien zeigen, dass Indikatoren der Integrität der Faserzüge der weißen Substanz, insbesondere die fraktionale Anisotropie (FA) in Abhängigkeit der Ausprägung von Schizotypie variiert, ebenso wie die funktionelle Interaktion verschiedener Hirnareale in Abhängigkeit von der inter-individuellen Variation schizotyper Persönlichkeitszüge. Wir untersuchten die Hypothese veränderter struktureller und funktioneller Konnektivität in Korrelation mit Schizotypie in gesunden Probanden.
Methode: Wir erfassten Schizotypie mit der deutschen Version des Oxford Liverpool Inventory of Feelings and Experiences. Unsere Studie umfasste 342 Probanden mit Diffusion Tensor Aufnahmen (DTI), welche mit der tract-based statistics pipeline in FSL analysiert wurden. Außerdem wurden mit 330 Probanden resting state Roi-to-Roi-Analysen in der CONN-Toolbox durchgeführt.
Ergebnisse: Der Gesamtscore, sowie die positive und desorganisierte Dimension der Schizotypie korrelierten negativ mit FA im Cingulum Bündel, während negative Schizotypie negativ mit FA im Fasciculus Uncinatus assoziiert war. Die Analyse der funktionellen resting state Konnektivität befindet sich aktuell in der finalen Phase.
Schlussfolgerung: Unsere Ergebnisse bestätigen vorherige Befunde veränderter struktureller Konnektivität in Korrelation mit schizotypen Persönlichkeitszügen. Da in vorherigen Studien allerdings hauptsächlich verringerte FA in Schizotypie, Schizotyper Persönlichkeitsstörung und Schizophrenie gefunden wurde, spricht die erhöhte FA in positiver, desorganisierter und Gesamt-Schizotypie gegen eine lineare Zunahme der Beeinträchtigung funktioneller Konnektivität über das Schizophrenie Spektrum und für einen nicht-linearen Zusammenhang innerhalb des Spektrums.
17:29 Uhr
Differential effect of comorbid posttraumatic stress disorder on white matter microstructure in major depressive disorder
S. Meinert (Münster, DE)
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Autor:innen:
S. Meinert (Münster, DE)
K. Schonhofen (Münster, DE)
A. Winter (Münster, DE)
K. Thiel (Münster, DE)
F. Stein (Marburg, DE)
I. Nenadic (Marburg, DE)
A. Krug (Marburg, DE)
A. Jansen (Marburg, DE)
T. Kircher (Marburg, DE)
U. Dannlowski (Münster, DE)
Exposure to environmental stressors can lead to psychiatric disorders like post-traumatic stress disorder (PTSD) or major depressive disorder (MDD). While white matter (WM) alterations are consistently reported in MDD compared with healthy controls (HC), effects in PTSD are more heterogeneous. The aim of this study was to show less distinct WM alterations in MDD with PTSD comorbidity.
MDD patients with (MDD_PTSD) and without comorbid PTSD (MDD_without), on top of HC were chosen from the FOR2107-cohort and carefully matched (N_total = 189). Fiber microstructure differences between the groups were analyzed with diffusion tensor imaging employing tract-based spatial statistics.
The F-Contrast revealed a significant main effect of diagnosis in MD and RD (p_tfce-FWE < .036) in the left corticospinal tract, the cingulum, the superior longitudinal fasciculus and the anterior thalamic radiation. Post-hoc t-contrasts revealed that MDD_PTSD and HC did not differ significantly in MD or RD (p_tfce-FWE > .066). Futher, MDD_without had significantly higher MD and RD values compared with HC (p_tfce-FWE < .021) and MDD_PTSD (p_tfce-FWE < .047). Reduced MD and RD values were specific for MDD_PTSD (MD: F(2,82) = 3.68, p = .029, η² = .082; RD: F(2,82) = 5.00, p = .009, η² = .109) when comparing MDD without any comorbidities, MDD patients with a comorbidity other then PTSD and MDD patients with only PTSD as its comorbidity.
WM alterations in MDD compared with HC differed from MDD_PTSD. Hence, future neurobiological studies should consider effects of psychiatric comorbidities. Divergent patterns of cortisol release in MDD compared with PTSD could explain these results, as previous studies linked higher cortisol levels to WM alterations. Whereas PTSD is associated with long-term reductions of cortisol levels compared with HC, higher levels are reported for MDD.
17:41 Uhr
Regulation of cerebellar gene expression and its role for the risk of neuropsychiatric disorders
N. Müller (Jülich, DE)
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Autor:innen:
N. Müller (Jülich, DE)
T. Mühleisen (Jülich, DE)
D. Hilger (Jülich, DE)
S. Bludau (Jülich, DE)
P. Pieperhoff (Jülich, DE)
S. Cichon (Jülich, DE)
K. Amunts (Jülich, DE)
M. Minnerop (Jülich, DE)
Most neuropsychiatric diseases (NPD) like depression and Alzheimer’s dementia underly a multifactorial pathogenesis. An interesting, but in relation to NPD rarely studied brain region is the cerebellum. In particular, its posterior lobe and vermis are known to play a role in cognitive and affective functions and could therefore contribute to the etiology of NPD. Relevant genetic risk factors for NPD are single-nucleotide polymorphisms (SNPs). However, even strongly associated SNPs are often difficult to interpret, e. g. being intronic/intergenic. Analyzing SNP-dependent and tissue-specific expression regulation of genes (called expression quantitative trait locus, eQTL) in the cerebellum could therefore be a promising strategy to search for NPD-associated SNPs and genes.
We performed a database analysis of eQTLs using a discovery-replication approach with GTEx, Braineac and the software JuGEx. The findings were then evaluated for association with disease and pathways using the GWAS Catalog and gene-set enrichment analysis.
We analyzed the 200 most significant cerebellar eQTLs of which 118 were replicated. These were grouped by tissue specificity and analyzed for associations with biological pathways or diseases. Amongst others, we identified an eQTL-SNP with a strong effect in the cerebellum known to be both a risk factor for depression as well as having an eQTL-effect by lowering the expression of the MICB gene, which produces a protein activating immunologic cells. The expression of MICB was in turn particularly low in the posterior cerebellar lobe.
Our most striking finding concerning the highlighted SNP implies that the lower expression of MICB following the eQTL effect of the SNP plays a role in the genesis of depression. Since the expression of MICB is particularly low in the posterior lobe, we hypothesize that this expression regulation could be of relevance for the pathogenesis of depression. Our findings support the relevance of the cerebellum for NPD.
17:53 Uhr
Blood biomarker discovery of neuropsychiatric symptoms in older people: a proteomic approach
M. Rabl (Zürich, CH)
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Autor:innen:
M. Rabl (Zürich, CH)
C. Clark (CH)
L. Dayon (Lausanne, CH)
G. Bowman (Lausanne, CH)
J. Popp (CH)
Neuropsychiatric symptoms (NPS) severely affect patients and their caregivers, and are associated with worse long-term outcomes. This study tested the hypothesis that altered protein levels in blood plasma could serve as biomarkers of NPS; and that altered protein levels are associated with persisting NPS and cognitive decline over time.
We performed a cross-sectional and longitudinal study in older subjects with normal cognition or with cognitive impairment in a memory clinic setting. NPS were recorded through the Neuropsychiatric Inventory Questionnaire (NPI-Q) while cognitive and functional impairment was assessed using the clinical dementia rating sum of boxes (CDR-SoB) score at baseline and follow-up visits. Shotgun proteomic analysis based on liquid chromatography-mass spectrometry was conducted in blood plasma samples, identifying 420 proteins. The presence of Alzheimer’s Disease (AD) pathology was determined by cerebrospinal fluid biomarkers.
85 subjects with a mean age of 70 (± 7.4) years, 62% female and 54% with mild cognitive impairment or mild dementia were included. We found 15 plasma proteins with altered baseline levels in participants with NPS (NPI-Q score > 0). Adding those 15 proteins to a reference model based on clinical data (age, CDR-SoB) significantly improved the prediction of NPS (from receiver operating characteristic area under the curve (AUC) 0.75 to AUC 0.91, p = 0.004) with a specificity of 89% and a sensitivity of 74%. The identified proteins additionally predicted both persisting NPS and cognitive decline at follow-up visits. The observed associations were independent of the presence of AD pathology.
Using proteomics, we identified a panel of specific blood proteins associated with current and future NPS, and related cognitive decline in older people. These findings show the potential of untargeted proteomics to identify blood-based biomarkers of pathological alterations relevant for NPS and related clinical disease progression.
18:05 Uhr
(2R,6R)-Hydroxynorketamine injections alter chromatin accessibility in activated neurons using targeted recombination in female, but not male transgenic mice
D. Herzog (Mainz, DE)
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Autor:innen:
D. Herzog (Mainz, DE)
G. Treccani (Mainz, DE)
J. Klüpfel (Mainz, DE)
S. Möckel (Mainz, DE)
M. Müller (Mainz, DE)
Ketamine acts as a rapid-acting antidepressant in both clinical and preclinical conditions. The molecular mechanisms of action of ketamine and its major metabolite (2R,6R)-hydroxynorketamine (HNK) are only partly understood. We analyzed these mechanisms using a transgenic mouse line capable of a targeted recombination in active populations (TRAP), the Arc-CreERT2 × CAG-Sun1/sfGFP.
An increase of Arc-expression induces the permanent labeling of activated neurons by combining a GFP and a tamoxifen-dependent Cre-line. We injected male and female mice with tamoxifen and either ketamine, HNK, or saline. After three days, we performed the Forced Swim Test (FST) to analyze the antidepressant-like effects. We extracted activated neurons of hippocampus (HC) and prefrontal cortex (PFC) samples by flow cytometry. We applied RNA-sequencing and ATAC-sequencing to analyze the molecular processes.
Ketamine (p < 0.1) and HNK injection (p < 0.001) led to an antidepressant-like effect in female, but not in male TRAP mice. After ketamine injections, we found more GFP-positive neurons in HC and PFC of female mice compared to male mice (p < 0.05). We found differentially upregulated ATAC binding sites in HC samples of HNK-injected female mice (padj < 0.05, |log2fc| > 1). We validated these binding cites using qPCR of neighboring genes. These validation experiments remain ongoing and will be reported at the congress.
We showed that HNK effects seem to be more pronounced in female TRAP mice. The TRAP mouse model is suitable to further analyze molecular processes specifically in activated neurons.