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Abstract Introduction Endothelial dysfunction (ED) promotes the development of atherosclerosis, and studies suggest an association with age-related neurocognitive disorders. It is currently unclear whether ED is also associated with the risk of perioperative neurocognitive disorders. Method We included 788 participants aged ≥ 65 years of the BioCog study. Patients were scheduled to undergo elective surgery with expected duration > 60 min. Blood was collected before surgery for measurement of 5 biomarkers of ED: asymmetric and symmetric dimethylarginine (ADMA; SDMA), intercellular and vascular adhesion molecule (ICAM-1, VCAM-1), and von Willebrand factor (vWF). Patients were monitored for the occurrence of postoperative delirium (POD) daily until the 7th postoperative day. 537 (68.1%) patients returned for a 3-month follow-up. Post-operative cognitive dysfunction (POCD) was defined from the change in results on a battery of 6 neuropsychological tests between baseline and 3 months, compared to the change in results of a control group during the 3-month interval. The associations of each of the 5 ED biomarkers with POD and POCD respectively were determined using multiple logistic regression analyses with adjustment for age, sex, surgery type, pre-morbid IQ, body mass index, hypertension, diabetes, HbA1C, triglyceride, total and HDL cholesterol. Results 19.8% of 788 patients developed POD; 10.1% of 537 patients had POCD at 3 months. Concentrations of ED biomarkers were not significantly associated with a POD. A higher VCAM-1 concentration was associated with a reduced POCD risk (adjusted odds ratio 0.55; 95% CI: 0.35–0.86). No further statistically significant results were found. Conclusion Pre-operative concentrations of ED biomarkers were not associated with POD risk. We unexpectedly found higher VCAM-1 to be associated with a reduced POCD risk. Further studies are needed to evaluate these findings.

Abstract Background Beta-blocker (BB) therapy plays a central role in the treatment of cardiovascular diseases. An increasing number of patients with cardiovascular diseases undergoe noncardiac surgery, where opioids are an integral part of the anesthesiological management. There is evidence to suggest that short-term intravenous BB therapy may influence perioperative opioid requirements due to an assumed cross-talk between G-protein coupled beta-adrenergic and opioid receptors. Whether chronic BB therapy could also have an influence on perioperative opioid requirements is unclear. Methods A post hoc analysis of prospectively collected data from a multicenter observational (BioCog) study was performed. Inclusion criteria consisted of elderly patients (≥ 65 years) undergoing elective noncardiac surgery as well as total intravenous general anesthesia without the use of regional anesthesia and duration of anesthesia ≥ 60 min. Two groups were defined: patients with and without BB in their regular preopreative medication. The administered opioids were converted to their respective morphine equivalent doses. Multiple regression analysis was performed using the morphine-index to identify independent predictors. Results A total of 747 patients were included in the BioCog study in the study center Berlin. 106 patients fulfilled the inclusion criteria. Of these, 37 were on chronic BB. The latter were preoperatively significantly more likely to have arterial hypertension (94.6%), chronic renal failure (27%) and hyperlipoproteinemia (51.4%) compared to patients without BB. Both groups did not differ in terms of cumulative perioperative morphine equivalent dose (230.9 (BB group) vs. 214.8 mg (Non-BB group)). Predictive factors for increased morphine-index were older age, male sex, longer duration of anesthesia and surgery of the trunk. In a model with logarithmised morphine index, only gender (female) and duration of anesthesia remained predictive factors. Conclusions Chronic BB therapy was not associated with a reduced perioperative opioid consumption. Trial registration This study was registered at ClinicalTrials.gov ( NCT02265263 ) on the 15.10.2014 with the principal investigator being Univ.-Prof. Dr. med. Claudia Spies.

Abstract A growing body of literature suggests the important role of the thalamus in cognition and neurodegenerative diseases. This study aims to elucidate whether the preoperative thalamic volume is associated with preoperative cognitive impairment (preCI) and whether it is predictive for postoperative cognitive dysfunction at 3 months (POCD). We enrolled 301 patients aged 65 or older and without signs of dementia who were undergoing elective surgery. Magnetic resonance imaging was conducted prior to surgery. Freesurfer (version 5.3.) was used to automatically segment the thalamus volume. A neuropsychological test battery was administered before surgery and at a 3 month follow-up. It included the computerized tests Paired Associate Learning (PAL), Verbal Recognition Memory (VRM), Spatial Span Length (SSP), Simple Reaction Time (SRT), the pen-and-paper Trail-Making-Test (TMT) and the manual Grooved Pegboard Test (GPT). Using a reliable change index, preCI and POCD were defined as total Z-score > 1.96 (sum score over all tests) and/or Z-scores > 1.96 in ≥ 2 individual cognitive test parameters. For statistical analyses, multivariable logistic regression models were applied. Age, sex and intracranial volume were covariates in the models. Of 301 patients who received a presurgical neuropsychological testing and MRI, 34 (11.3%) had preCI. 89 patients (29.5%) were lost to follow-up. The remaining 212 patients received a follow-up cognitive test after 3 months, of whom 25 (8.3%) presented with POCD. Independently of age, sex and intracranial volume, neither preCI (OR per cm3 increment 0.81 [95% CI 0.60–1.07] p = 0.14) nor POCD (OR 1.02 per cm3 increment [95% CI 0.75–1.40] p = 0.87) were statistically significantly associated with patients’ preoperative thalamus volume. In this cohort we could not show an association of presurgical thalamus volume with preCI or POCD. Clinical Trial Number: NCT02265263 ( https://clinicaltrials.gov/ct2/show/results/NCT02265263 ).

BackgroundPostoperative delirium (POD) and postoperative cognitive dysfunction (POCD) are postoperative neurocognitive disorders (PNDs) that frequently occur in the aftermath of a surgical intervention. Cognitive reserve (CR) is a concept posited to explain why cognitive health varies between individuals. On this qualitative understanding of cognitive health, factors like IQ, education level, and occupational complexity can affect the impact of neuropathological processes on cognitive outcomes.MethodsWe investigated the association between CR and POD and CR and POCD on data from 713 patients aged≥65 years with elective surgery. Peak pre-morbid IQ was estimated from vocabulary. Occupational complexity was coded according to the Dictionary of Occupational Titles (DOT). Education level was classed according to the International Standard Classification of Education (ISCED). These three factors were used as proxies of CR. In a series of regression models, age, sex, depression, site of surgery, and several lifestyle and vascular factors were controlled for.ResultsPatients with a higher IQ had lower odds of developing POD. We found no significant association between the other two CR markers with POD. None of the CR markers was associated with POCD.ConclusionThe significant association of a higher IQ with lower POD risk allows for the stratification of elderly surgical patients by risk. This knowledge can aid the prevention and/or early detection of POD. Further research should attempt to determine the lack of associations of CR markers with POCD in our study.

Background: The Trail Making Test B (TMT-B) is indicative of cognitive flexibility and several other cognitive domains. Previous studies suggest that it might be associated with the risk of developing postoperative delirium, but evidence is limited and conflicting. We therefore aimed to replicate the association of preoperative TMT-B results with postoperative delirium. Methods: We included older adults (≥65 yr) scheduled for major surgery and without signs of dementia to participate in this binational two-centre longitudinal observational cohort study. Presurgical TMT-B scores were obtained. Delirium was assessed twice daily using validated instruments. Logistic regression was applied and the area under the receiver operating characteristic curve calculated to determine the predictive performance of TMT-B. We subsequently included covariates used in previous studies for consecutive sensitivity analyses. We further analysed the impact of outliers, missing or impaired data. Results: Data from 841 patients were included and of those, 151 (18%) developed postoperative delirium. TMT-B scores were statistically significantly associated with the incidence of postoperative delirium {odds ratio per 10-s increment 1.06 (95% confidence interval [CI] 1.02–1.09), P=0.001}. The area under the receiver operating characteristic curve was 0.60 ([95% CI 0.55–0.64], P

Abstract Background Postoperative delirium (POD) is a frequent complication after surgery. Older adult patients undergoing abdominal surgery are at higher risk for developing POD. Studies on the association of cholinesterase activities and POD are rare, but leading hypotheses implicate that the cholinergic pathway might play an important role in neuroinflammation and development of POD. The objective of this study was to figure out if there is an association between the development of POD and acetyl- and butyrylcholinesterase (AChE and BuChE) activities in older adult patients undergoing abdominal surgery. Methods The investigation was performed with a subpopulation of BioCog study patients. The BioCog project ( http://www.biocog.eu ) is a prospective multicenter observational study in older adult surgical patients. Patients ≥ 65 years undergoing elective surgery of at least 60 minutes who scored more than 23 points in the Mini-Mental-State-Examination were included. POD was assessed twice a day on seven consecutive days after the surgery, using the test instruments Nursing Delirium Screening Scale (Nu-Desc) and Confusion Assessment Method (CAM and CAM-ICU) and a patient chart review. Pre- and postoperative blood cholinesterase activities were measured with a photometric rapid-point-of-care-testing. The association between cholinesterase activities and POD was analyzed in a subpopulation of abdominal surgical patients using multivariable logistic regression analysis adjusting for confounders. Results One hundred twenty-seven patients were included for analysis (mean age 73 years, 59% female). Fifty-two patients (41%) fulfilled the criteria of POD. These patients were significantly older, had a longer time of surgery and anesthesia and achieved higher comorbidity scores compared to patients without POD. After adjusting for age, duration of surgery and charlson comorbity index, we found an association between pre- and postoperative AChE activity (U/gHb) and the development of POD (Odds ratio (OR), [95% confidence interval (CI)], preoperative 0.95 [0.89–1.00], postoperative 0.94 [0.89–1.00]). Conclusions We found an association between POD and AChE activity and provided new information considering patients with abdominal surgery. Future analyses should examine course dynamics of postoperative cholinesterase activities in order to clarify interactions between the cholinergic system and pathophysiological mechanisms leading to POD. Trial registration ClinicalTrials.gov: NCT02265263.

Abstract Background Postoperative delirium (POD) and postoperative cognitive dysfunction (POCD) are frequent and serious complications after surgery. We aim to investigate the association between genetic variants in cholinergic candidate genes according to the Kyoto encyclopedia of genes and genomes - pathway: cholinergic neurotransmission with the development of POD or POCD in elderly patients. Methods This analysis is part of the European BioCog project ( www.biocog.eu ), a prospective multicenter observational study with elderly surgical patients. Patients with a Mini-Mental-State-Examination score ≤ 23 points were excluded. POD was assessed up to seven days after surgery using the Nursing Delirium Screening Scale, Confusion Assessment Method and a patient chart review. POCD was assessed three months after surgery with a neuropsychological test battery. Genotyping was performed on the Illumina Infinium Global Screening Array. Associations with POD and POCD were analyzed using logistic regression analysis, adjusted for age, comorbidities and duration of anesthesia (for POCD analysis additionally for education). Odds ratios (OR) refer to minor allele counts (0, 1, 2). Results 745 patients could be included in the POD analysis, and 452 in the POCD analysis. The rate of POD within this group was 20.8% (155 patients), and the rate of POCD was 10.2% (46 patients). In a candidate gene approach three genetic variants of the cholinergic genes CHRM2 and CHRM4 were associated with POD (OR [95% confidence interval], rs8191992: 0.61[0.46; 0.80]; rs8191992: 1.60[1.22; 2.09]; rs2067482: 1.64[1.10; 2.44]). No associations were found for POCD. Conclusions We found an association between genetic variants of CHRM2 and CHRM4 and POD. Further studies are needed to investigate whether disturbances in acetylcholine release and synaptic plasticity are involved in the development of POD. Trial registration: ClinicalTrials.gov: NCT02265263.

Abstract Postoperative delirium (POD) and postoperative (neuro‐)cognitive disorder (POCD) are frequent and serious complications after operations. We aim to investigate the association between pre‐operative polypharmacy and potentially inappropriate medications and the development of POD/POCD in elderly patients. This investigation is part of the European BioCog project (www.biocog.eu), a prospective multicenter observational study with elderly surgical patients. Patients with a Mini‐Mental State Examination score less than or equal to 23 points were excluded. POD was assessed up to 7 days after surgery using the Nursing Delirium Screening Scale, Confusion Assessment Method (for the intensive care unit [ICU]), and a patient chart review. POCD was assessed 3 months after surgery with a neuropsychological test battery. Pre‐operative long‐term medication was evaluated in terms of polypharmacy (≥5 agents) and potentially inappropriate medication (defined by the PRISCUS and European list of potentially inappropriate medications [EU(7)‐PIM] lists), and associations with POD and POCD were analyzed using logistic regression analysis. Eight hundred thirty‐seven participants were included for analysis of POD and 562 participants for POCD. Of these, 165 patients (19.7%) fulfilled the criteria of POD and 60 (10.7%) for POCD. After adjusting for confounders, pre‐operative polypharmacy and intake of potentially inappropriate medications could not be shown to be associated with the development of POD nor POCD. We found no associations between pre‐operative polypharmacy and potentially inappropriate medications and development of POD and POCD. Future studies should focus on the evaluation of drug interactions to determine whether patients benefit from a pre‐operative adjustment.

Abstract Background Studies suggest that a higher education and occupation are each associated with a higher late-life cognitive ability, but their inter-relationships in their association with cognitive ability and the contribution of peak IQ in young adulthood (‘pre-morbid IQ’) often remain unclear. Methods Cross-sectional analysis of 623 participants aged ≥65 years of the BioCog study. Education was coded according to the International Standard Classification of Education (ISCED; range 1 to 6). Occupation was coded as ‘semi/unskilled’, ‘skilled manual’, ‘skilled non-manual’, ‘managerial’, ‘professional’. A summary score of global ability (‘g’) was constructed from six cognitive tests. Pre-morbid IQ was estimated from vocabulary. The Geriatric Depression Scale assessed symptoms of depression. Age- and sex-adjusted analyses of covariance were performed. Results Education (partial eta2 0.076; p

Abstract Postoperative delirium (POD) represents a confusional state during days/weeks after surgery and is particularly frequent in elderly patients. Hardly any fMRI studies were conducted to understand the underlying pathophysiology of POD patients. This prospective observational cohort study aims to examine changes of specific resting-state functional connectivity networks across different time points (pre- and 3–5 months postoperatively) in delirious patients compared to no-POD patients. Two-hundred eighty-three elderly surgical patients underwent preoperative resting-state fMRI (46 POD). One-hundred seventy-eight patients completed postoperative scans (19 POD). For functional connectivity analyses, three functional connectivity networks with seeds located in the orbitofrontal cortex (OFC), nucleus accumbens (NAcc), and hippocampus were investigated. The relationship of POD and connectivity changes between both time points (course connectivity) were examined (ANOVA). Preoperatively, delirious patients displayed hyperconnectivities across the examined functional connectivity networks. In POD patients, connectivities within NAcc and OFC networks demonstrated a decrease in course connectivity [max. F = 9.03, p = 0.003; F = 4.47, p = 0.036, resp.]. The preoperative hyperconnectivity in the three networks in the patients at risk for developing POD could possibly indicate existing compensation mechanisms for subtle brain dysfunction. The observed pathophysiology of network function in POD patients at least partially involves dopaminergic pathways.

There is strong genetic evidence for cigarette smoking behaviors, yet little is known on nicotine dependence (ND). Here, the authors perform a genome-wide association study on ND in 58,000 smokers, identifying five genome-wide significant loci.

Abstract Objective Studies of postoperative cognitive dysfunction (POCD) rely on repeat neuropsychological testing. The stability of the applied instruments, which are affected by natural variability in performance and measurement imprecision, is often unclear. We determined the stability of a neuropsychological test battery using a sample of older adults from the general population. Forty-five participants aged 65 to 89 years performed six computerized and non-computerized neuropsychological tests at baseline and again at 7 day and 3 months follow-up sessions. Mean scores on each test were compared across time points using repeated measures analyses of variance (ANOVA) with pairwise comparison. Two-way mixed effects, absolute agreement analyses of variance intra-class correlation coefficients (ICC) determined test–retest reliability. Results All tests had moderate to excellent test–retest reliability during 7-day (ICC range 0.63 to 0.94; all p

Objective: Studies have suggested that inflammation contributes to the pathogenesis of postoperative delirium, but previous results on the proinflammatory cytokine IL-8 in plasma are contradictory. Additionally, a significant fraction of IL-8 is bound to erythrocytes, but the relevance of whole blood IL-8 in delirium has not been studied. In this work, we analyzed the association of postoperative delirium with levels of unbound IL-8 in plasma and levels of IL-8 in whole blood in patients from two studies which were conducted in our department and have not been presented previously. We assessed the prognostic value of whole blood IL-8. Methods: Plasma/whole blood IL-8 was measured at least once in N ​= ​504 patients preoperatively, on day one (d1) and/or three months after surgery in the BioCog observational study. Whole blood IL-8 was measured in N ​= ​64 patients from the PHYDELIO trial preoperatively, on d1 and d7 after surgery. For the determination of whole blood IL-8, EDTA-preserved blood samples underwent lysis by adding Triton-X100 surfactant. Plasma and whole blood IL-8 levels were assessed with two different immunoassay kits. Delirium was appraised systematically for seven postoperative days according to DSM criteria using two comparable protocols consisting of validated screening tools. Results: Delirium occurred in 25% of BioCog and 14% of PHYDELIO patients. In BioCog, IL-8 was elevated on d1 and in delirious patients. A steeper postoperative increase in delirium was confounded by surgery-related factors. A crescendo-decrescendo pattern of whole blood IL-8 levels was observed in non-delirious patients with a peak on d1. This pattern was more distinct in delirious BioCog patients, but inverted in delirious PHYDELIO patients. Preoperative whole blood IL-8>318.4 ​pg/mL (reference

Background: The thalamus seems to be important in the development of postoperative delirium (POD) as previously revealed by volumetric and diffusion magnetic resonance imaging. In this observational cohort study, we aimed to further investigate the impact of the microstructural integrity of the thalamus and thalamic nuclei on the incidence of POD by applying diffusion kurtosis imaging (DKI). Methods: Older patients without dementia (≥65 years) who were scheduled for major elective surgery received preoperative DKI at two study centres. The DKI metrics fractional anisotropy (FA), mean diffusivity (MD), mean kurtosis (MK) and free water (FW) were calculated for the thalamus and – as secondary outcome – for eight predefined thalamic nuclei and regions. Low FA and MK and, conversely, high MD and FW, indicate aspects of microstructural abnormality. To assess patients’ POD status, the Nursing Delirium Screening Scale (Nu-DESC), Richmond Agitation Sedation Scale (RASS), Confusion Assessment Method (CAM) and Confusion Assessment Method for the Intensive Care Unit score (CAM-ICU) and chart review were applied twice a day after surgery for the duration of seven days or until discharge. For each metric and each nucleus, logistic regression was performed to assess the risk of POD. Results: This analysis included the diffusion scans of 325 patients, of whom 53 (16.3 %) developed POD. Independently of age, sex and study centre, thalamic MD was statistically significantly associated with POD [OR 1.65 per SD increment (95 %CI 1.17 – 2.34) p = 0.004]. FA (p = 0.84), MK (p = 0.41) and FW (p = 0.06) were not significantly associated with POD in the examined sample. Exploration of thalamic nuclei also indicated that only the MD in certain areas of the thalamus was associated with POD. MD was increased in bilateral hemispheres, pulvinar nuclei, mediodorsal nuclei and the left anterior nucleus. Conclusions: Microstructural abnormalities of the thalamus and thalamic nuclei, as reflected by increased MD, appear to predispose to POD. These findings affirm the thalamus as a region of interest in POD research.

Abstract Background The metabolic syndrome (MetS) is an established cardiovascular risk factor. Here, we investigated its role in cognitive impairment. Methods Baseline data from 202 participants (aged 65 to 87 years) of the BioCog study were used. All were free of clinical dementia (MMSE≥24/30). Cognitive impairment was defined as the lowest tertile of a cognitive summary score. Multiple logistic regression analyses examined associations of body mass index (BMI), triglycerides (TG), high-density lipoprotein (HDL-C), glucose and glycated hemoglobin A1c (HbA1c) levels with the odds of cognitive impairment. MetS was defined as ≥3 of its 5 components obesity (BMI ≥ 30 kg/m2), elevated TG (TG ≥1.7 mmol/L), reduced HDL-C (males: 0.05). Results for HDL-C were similar when HDL-C, glucose, BMI and TG were entered into a single model (OR 2.56 per 1 mmol/L reduction, 95% CI 1.09, 5.88, p = 0.031) and when cerebrovascular disease and coronary heart disease were additionally controlled for (OR 2.56 per 1 mmol/L reduction, 95% CI 1.06, 6.25, p = 0.036). Among the 5 MetS components, participants with elevated TG were at 2-fold increased odds of impairment (OR 2.09, 95% CI 1.08, 4.05, p = 0.028) including when the remaining 4 MetS components were entered (OR 2.23, 95% CI 1.07, 4.65, p = 0.033), but the finding was no longer statistically significant when cerebrovascular disease and coronary heart disease were additionally controlled for (p = 0.11). Presence of MetS and of obesity, reduced HDL-C, elevated glucose or elevated blood pressure were not significantly associated with impairment (all p > 0.05). Conclusion Our findings support low HDL-C as an independent risk marker of cognitive impairment in older age. The need for research into mediatory and confounding factors, and re-evaluation of traditional cut-off points is highlighted. Trial registration The study was registered on 15th October 2014 at clinicaltrials.gov (NCT02265263).

Background: Subanesthetic dosages of the NMDAR antagonist, S-Ketamine, can cause changes in behavior in healthy subjects, which are similar to the state acute psychosis and are relevant in translational schizophrenia research. Functional magnetic resonance imaging (fMRI) can be used for non-hypothesis-driven analysis of brain connectivity. The correlation between clinical behavioral scores and neuroimaging can help to characterize ketamine effects on healthy brains in resting state. Method: seventeen healthy, male subjects (mean: 27.42 years, SD: 4.42) were administered an infusion with S-Ketamine (initial bolus 1 mg/kg and continuous infusion of 0.015625 mg/kg/min with dosage reduction −10%/10 min) or saline in a randomized, double-blind, cross-over study. During infusion, resting state connectivity was measured and analyzed with a seed-to-voxel fMRI analysis approach. The seed regions were located in the posterior cingulate cortex, intraparietal sulcus, dorsolateral prefrontal cortex and fronto-insular cortex. Receiver operating characteristics (ROC) were calculated to assess the accuracy of the ketamine-induced functional connectivity changes. Bivariate Pearson correlation was used for correlation testing of functional connectivity changes with changes of clinical scores (PANSS, 5D-ASC). Results: In the executive network (ECN), ketamine significantly increases the functional connectivity with parts of the anterior cingulum and superior frontal gyrus, but no significant correlations with clinical symptoms were found. Decreased connectivity between the salience network (SN) and the calcarine fissure was found, which is significantly correlated with negative symptoms (PANSS) (R2 > 0.4). Conclusion: Decreased ketamine-induced functional connectivity in the salience network may qualify as accurate and highly predictive biomarkers for ketamine induced negative symptoms. Keywords: Subanesthetic ketamine effects, Cross-over fMRI study, Resting-state fMRI, Seed-to-voxel fMRI analysis, Correlation testing

BackgroundCerebral microbleeds (CMB) occur in the context of cerebral small vessel disease. Other brain MRI markers of cerebral small vessel disease are associated with the occurrence of postoperative delirium (POD) and postoperative cognitive dysfunction (POCD), but for CMB this is unknown. We aimed to study the association between CMB and the occurrence of POD and POCD in older individuals.MethodsThe current study consists of 65 patients (72±5 years) from the BIOCOG study, which is a prospective, observational study of patients who underwent an elective surgery of at least 60 minutes. Patients in the current study received a preoperative cerebral MRI scan including a 3D susceptibility-weighted imaging sequence to detect CMB. The occurrence of POD was screened for twice a day until postoperative day 7 by using the DSM-5, NuDesc, CAM, and CAM-ICU. The occurrence of POCD was determined by the reliable change index model at 7 days after surgery or discharge, respectively, and 3 months after surgery. Statistical analyses consisted of logistic regression adjusted for age and gender.ResultsA total of 39 CMB were detected in 17 patients (26%) prior to surgery. POD occurred in 14 out of 65 patients (22%). POCD at 7 days after surgery occurred in 11 out of 54 patients (20%) and in 3 out of 40 patients at the 3 month follow-up (8%). Preoperative CMB were not associated with the occurrence of POD (OR (95%-CI): 0.28 (0.05, 1.57); p = 0.147) or POCD at 7 days after surgery (0.76 (0.16, 3.54); p = 0.727) or at 3 months follow-up (0.61 (0.03, 11.64); p = 0.740).ConclusionWe did not find an association between preoperative CMB and the occurrence of POD or POCD.Trial registrationclinicaltrials.gov (NCT02265263) on 23 September 2014.

Abstract Loss of plasticity‐related gene 1 (PRG‐1), which regulates synaptic phospholipid signaling, leads to hyperexcitability via increased glutamate release altering excitation/inhibition (E/I) balance in cortical networks. A recently reported SNP in prg‐1 (R345T/mutPRG‐1) affects ~5 million European and US citizens in a monoallelic variant. Our studies show that this mutation leads to a loss‐of‐PRG‐1 function at the synapse due to its inability to control lysophosphatidic acid (LPA) levels via a cellular uptake mechanism which appears to depend on proper glycosylation altered by this SNP. PRG‐1+/− mice, which are animal correlates of human PRG‐1+/mut carriers, showed an altered cortical network function and stress‐related behavioral changes indicating altered resilience against psychiatric disorders. These could be reversed by modulation of phospholipid signaling via pharmacological inhibition of the LPA‐synthesizing molecule autotaxin. In line, EEG recordings in a human population‐based cohort revealed an E/I balance shift in monoallelic mutPRG‐1 carriers and an impaired sensory gating, which is regarded as an endophenotype of stress‐related mental disorders. Intervention into bioactive lipid signaling is thus a promising strategy to interfere with glutamate‐dependent symptoms in psychiatric diseases.