Publications by authors named "Johannes Kornhuber"

604 Publications

The acid sphingomyelinase/ceramide system in COVID-19.

Mol Psychiatry 2021 Oct 4. Epub 2021 Oct 4.

Department of Molecular Biology, University of Duisburg-Essen, Essen, Germany.

Acid sphingomyelinase (ASM) cleaves sphingomyelin into the highly lipophilic ceramide, which forms large gel-like rafts/platforms in the plasma membrane. We showed that SARS-CoV-2 uses these platforms for cell entry. Lowering the amount of ceramide or ceramide blockade due to inhibitors of ASM, genetic downregulation of ASM, anti-ceramide antibodies or degradation by neutral ceramidase protected against infection with SARS-CoV-2. The addition of ceramide restored infection with SARS-CoV-2. Many clinically approved medications functionally inhibit ASM and are called FIASMAs (functional inhibitors of acid sphingomyelinase). The FIASMA fluvoxamine showed beneficial effects on COVID-19 in a randomized prospective study and a prospective open-label real-world study. Retrospective and observational studies showed favorable effects of FIASMA antidepressants including fluoxetine, and the FIASMA hydroxyzine on the course of COVID-19. The ASM/ceramide system provides a framework for a better understanding of the infection of cells by SARS-CoV-2 and the clinical, antiviral, and anti-inflammatory effects of functional inhibitors of ASM. This framework also supports the development of new drugs or the repurposing of "old" drugs against COVID-19.
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http://dx.doi.org/10.1038/s41380-021-01309-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8488928PMC
October 2021

Neutral sphingomyelinase mediates the co-morbidity trias of alcohol abuse, major depression and bone defects.

Mol Psychiatry 2021 Sep 28. Epub 2021 Sep 28.

Center for Behavioral Neuroscience, Institute of Experimental Psychology, University of Düsseldorf, Düsseldorf, Germany.

Mental disorders are highly comorbid and occur together with physical diseases, which are often considered to arise from separate pathogenic pathways. We observed in alcohol-dependent patients increased serum activity of neutral sphingomyelinase. A genetic association analysis in 456,693 volunteers found associations of haplotypes of SMPD3 coding for NSM-2 (NSM) with alcohol consumption, but also with affective state, and bone mineralisation. Functional analysis in mice showed that NSM controls alcohol consumption, affective behaviour, and their interaction by regulating hippocampal volume, cortical connectivity, and monoaminergic responses. Furthermore, NSM controlled bone-brain communication by enhancing osteocalcin signalling, which can independently supress alcohol consumption and reduce depressive behaviour. Altogether, we identified a single gene source for multiple pathways originating in the brain and bone, which interlink disorders of a mental-physical co-morbidity trias of alcohol abuse-depression/anxiety-bone disorder. Targeting NSM and osteocalcin signalling may, thus, provide a new systems approach in the treatment of a mental-physical co-morbidity trias.
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http://dx.doi.org/10.1038/s41380-021-01304-wDOI Listing
September 2021

Neutral sphingomyelinase mediates the co-morbidity trias of alcohol abuse, major depression and bone defects.

Mol Psychiatry 2021 Sep 28. Epub 2021 Sep 28.

Center for Behavioral Neuroscience, Institute of Experimental Psychology, University of Düsseldorf, Düsseldorf, Germany.

Mental disorders are highly comorbid and occur together with physical diseases, which are often considered to arise from separate pathogenic pathways. We observed in alcohol-dependent patients increased serum activity of neutral sphingomyelinase. A genetic association analysis in 456,693 volunteers found associations of haplotypes of SMPD3 coding for NSM-2 (NSM) with alcohol consumption, but also with affective state, and bone mineralisation. Functional analysis in mice showed that NSM controls alcohol consumption, affective behaviour, and their interaction by regulating hippocampal volume, cortical connectivity, and monoaminergic responses. Furthermore, NSM controlled bone-brain communication by enhancing osteocalcin signalling, which can independently supress alcohol consumption and reduce depressive behaviour. Altogether, we identified a single gene source for multiple pathways originating in the brain and bone, which interlink disorders of a mental-physical co-morbidity trias of alcohol abuse-depression/anxiety-bone disorder. Targeting NSM and osteocalcin signalling may, thus, provide a new systems approach in the treatment of a mental-physical co-morbidity trias.
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http://dx.doi.org/10.1038/s41380-021-01304-wDOI Listing
September 2021

Neuropeptide Y Reduces Social Fear in Male Mice: Involvement of Y1 and Y2 Receptors in the Dorsolateral Septum and Central Amygdala.

Int J Mol Sci 2021 Sep 20;22(18). Epub 2021 Sep 20.

Department of Psychiatry and Psychotherapy, Friedrich-Alexander University Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany.

Neuropeptide Y (NPY) has anxiolytic-like effects and facilitates the extinction of cued and contextual fear in rodents. We previously showed that intracerebroventricular administration of NPY reduces the expression of social fear in a mouse model of social fear conditioning (SFC) and localized these effects to the dorsolateral septum (DLS) and central amygdala (CeA). In the present study, we aimed to identify the receptor subtypes that mediate these local effects of NPY. We show that NPY (0.1 nmol/0.2 µL/side) reduced the expression of SFC-induced social fear in a brain region- and receptor-specific manner in male mice. In the DLS, NPY reduced the expression of social fear by acting on Y2 receptors but not on Y1 receptors. As such, prior administration of the Y2 receptor antagonist BIIE0246 (0.2 nmol/0.2 μL/side) but not the Y1 receptor antagonist BIBO3304 trifluoroacetate (0.2 nmol/0.2 μL/side) blocked the effects of NPY in the DLS. In the CeA, however, BIBO3304 trifluoroacetate but not BIIE0246 blocked the effects of NPY, suggesting that NPY reduced the expression of social fear by acting on Y1 receptors but not Y2 receptors within the CeA. This study suggests that at least two distinct receptor subtypes are differentially recruited in the DLS and CeA to mediate the effects of NPY on the expression of social fear.
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http://dx.doi.org/10.3390/ijms221810142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8472534PMC
September 2021

Clinico-genetic findings in 509 frontotemporal dementia patients.

Mol Psychiatry 2021 Sep 24. Epub 2021 Sep 24.

Department of Neurology, University of Ulm, Ulm, Germany.

Frontotemporal dementia (FTD) is a clinically and genetically heterogeneous disorder. To which extent genetic aberrations dictate clinical presentation remains elusive. We investigated the spectrum of genetic causes and assessed the genotype-driven differences in biomarker profiles, disease severity and clinical manifestation by recruiting 509 FTD patients from different centers of the German FTLD consortium where individuals were clinically assessed including biomarker analysis. Exome sequencing as well as C9orf72 repeat analysis were performed in all patients. These genetic analyses resulted in a diagnostic yield of 18.1%. Pathogenic variants in C9orf72 (n = 47), GRN (n = 26), MAPT (n = 11), TBK1 (n = 5), FUS (n = 1), TARDBP (n = 1), and CTSF (n = 1) were identified across all clinical subtypes of FTD. TBK1-associated FTD was frequent accounting for 5.4% of solved cases. Detection of a homozygous missense variant verified CTSF as an FTD gene. ABCA7 was identified as a candidate gene for monogenic FTD. The distribution of APOE alleles did not differ significantly between FTD patients and the average population. Male sex was weakly associated with clinical manifestation of the behavioral variant of FTD. Age of onset was lowest in MAPT patients. Further, high CSF neurofilament light chain levels were found to be related to GRN-associated FTD. Our study provides large-scale retrospective clinico-genetic data such as on disease manifestation and progression of FTD. These data will be relevant for counseling patients and their families.
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http://dx.doi.org/10.1038/s41380-021-01271-2DOI Listing
September 2021

Cognitive profiles of patients with mild cognitive impairment due to Alzheimer's versus Parkinson's disease defined using a base rate approach: Implications for neuropsychological assessments.

Alzheimers Dement (Amst) 2021 14;13(1):e12223. Epub 2021 Sep 14.

Department of Neurodegenerative Diseases and Gerontopsychiatry University Hospital of Bonn University of Bonn Bonn Germany.

Introduction: Large studies on cognitive profiles of patients with mild cognitive impairment (MCI) due to Alzheimer's disease (AD-MCI) compared to Parkinson's disease (PD-MCI) are rare.

Methods: Data from two multicenter cohort studies in AD and PD were merged using a unified base rate approach for the MCI diagnosis. Cognitive profiles were compared using scores derived from the Consortium to Establish a Registry for Alzheimer's Disease battery.

Results: Patients with AD-MCI showed lower standardized scores on all memory test scores and a language test. Patients with PD-MCI showed lower standardized scores in a set-shifting measure as an executive task. A cross-validated logistic regression with test scores as predictors was able to classify 72% of patients correctly to AD-MCI versus PD-MCI.

Discussion: The applied test battery successfully discriminated between AD-MCI and PD-MCI. Neuropsychological test batteries in clinical practice should always include a broad spectrum of cognitive domains to capture any cognitive changes.
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http://dx.doi.org/10.1002/dad2.12223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8438680PMC
September 2021

Repurposing antidepressants inhibiting the sphingomyelinase acid/ceramide system against COVID-19: current evidence and potential mechanisms.

Mol Psychiatry 2021 Aug 12. Epub 2021 Aug 12.

DMU Psychiatrie et Addictologie, Département de Psychiatrie, Assistance Publique-Hôpitaux de Paris, Hôpital Corentin-Celton,INSERM, Institut de Psychiatrie et Neurosciences de Paris (IPNP), UMR_S1266, Université de Paris, Paris, France.

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http://dx.doi.org/10.1038/s41380-021-01254-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8359627PMC
August 2021

Association of Prenatal Alcohol Exposure and Prenatal Maternal Depression with Offspring Low-Grade Inflammation in Early Adolescence.

Int J Environ Res Public Health 2021 07 27;18(15). Epub 2021 Jul 27.

Department of Child and Adolescent Mental Health, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany.

(1) This longitudinal study aimed to investigate the link between prenatal alcohol exposure and prenatal maternal depression with the offspring's low-grade inflammatory status. (2) Prenatal alcohol exposure was determined via maternal self-report during the 3rd trimester of pregnancy (self-report+: = 29) and the meconium alcohol metabolite Ethyl Glucuronide (EtG), collected at birth (≥30 ng/g: = 23). The Edinburgh Postnatal Depression Scale (EPDS) was used to screen for prenatal maternal depressive symptoms during the 3rd trimester (≥10: = 35). Fifteen years later, 122 adolescents ( = 13.32 years; 48.4% female) provided blood samples for the analysis of high sensitivity C-reactive protein (hsCRP; = 0.91; = 1.28). (3) Higher hsCRP levels were found in EtG positive adolescents ( = 0.036, ηp = 0.04) and an inverse non-significant dose-response relation with hsCRP ( = -0.35, = 0.113). For maternal self-reported prenatal alcohol consumption ( = 0.780, ηp = 0.00) and prenatal depressive symptoms ( = 0.360, ηp = 0.01) no differences for hsCRP levels between the affected and unaffected groups were found. (4) Adolescents with prenatal alcohol exposure are at risk for low-grade systemic inflammation. The EtG biomarker may be more accurate compared to self-reports. The findings suggest that prenatal maternal depression does not evoke low-grade systemic inflammation.
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http://dx.doi.org/10.3390/ijerph18157920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8345560PMC
July 2021

[Gustav Nikolaus Specht (1860-1940) : His impact on Kraepelin's nosology and approaches to his position in National Socialism].

Nervenarzt 2021 Jul 23. Epub 2021 Jul 23.

Psychiatrische und Psychotherapeutische Klinik, Friedrich-Alexander-Universität Erlangen-Nürnberg, Schwabachanlage 6, 91054, Erlangen, Deutschland.

Introduction: Gustav Specht (1860-1940) represents the beginning of the university psychiatry in Erlangen. 80 years after his death, this article focuses on Specht's role in the psychopathologic nosological discussion initiated by Kraepelin. Despite the sparse data situation, the authors approach for the first time Specht's position within psychiatry under National Socialism.

Methods: The relevant primary and secondary literature as well as archival sources were evaluated.

Results: In 1897 Specht was appointed supernumerary professor and in 1903 the first full professor for psychiatry in Erlangen. Specht elaborated the role of the manic element in paranoia. Specht added the depressive reaction to Bonhoeffers "exogenic reaction type" in 1913; Specht himself was in the view of some colleagues suspected of having a cyclothyme temperament and twice suffered from exogenous depressive reaction.

Discussion: Specht's research studies on the pathological affect in chronic paranoia influenced the contemporary psychopathological discussion in a sustainable manner. Specht's change of attitude towards eugenic measures can be interpreted as an adaptation to the National Socialist regime.

Conclusion: The work of Gustav Specht can stimulate the cultivation of an interdisciplinary psychopathological discourse.
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http://dx.doi.org/10.1007/s00115-021-01153-6DOI Listing
July 2021

Cerebrospinal Fluid of Patients With Alzheimer's Disease Contains Increased Percentages of Synaptophysin-Bearing Microvesicles.

Front Aging Neurosci 2021 6;13:682115. Epub 2021 Jul 6.

Department of Psychiatry and Psychotherapy, Friedrich-Alexander-University of Erlangen-Nuremberg (FAU), Erlangen, Germany.

Introduction: In Alzheimer's disease, the severity of symptoms is linked to a loss of synaptic density and the spread of pathologically hyperphosphorylated tau. The established cerebrospinal fluid markers Aβ, tau and phospho-tau reflect the histopathological hallmarks of Alzheimer's disease but do not indicate disease progression. Such markers are of special interest, especially for trials of disease modifying drugs. Microvesicles are produced by stressed cells and reflect part of the metabolism of their cells of origin. Therefore, we investigated microvesicles of neuronal origin in cerebrospinal fluid.

Materials And Methods: We used flow cytometry to analyze microvesicles carrying tau, phospho-tau-Thr181, phospho-tau-Ser202Thr205, synaptophysin, and SNAP-25 in the cerebrospinal fluid of 19 patients with Alzheimer's disease and 15 non-inflammatory neurological disease controls.

Results: The percentages of synaptophysin-bearing microvesicles were significantly higher in the cerebrospinal fluid of patients with Alzheimer's disease than in the CSF of non-inflammatory neurological disease controls. Tau, phospho-tau-Thr181, phospho-tau-Ser202Thr205, and SNAP-25 did not differ between the groups. The percentages of synaptophysin-bearing vesicles distinguished patients with Alzheimer's disease from the controls (AUC = 0.81).

Conclusion: The loss of synapses in Alzheimer's disease may be reflected by synaptophysin-bearing microvesicles in the cerebrospinal fluid. Future studies are needed to investigate the possibility of using these MVs as a marker to determine the activity of Alzheimer's disease.
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http://dx.doi.org/10.3389/fnagi.2021.682115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8290128PMC
July 2021

Beyond Functional Impairment: Redefining Favorable Outcome in Patients with Subarachnoid Hemorrhage.

Cerebrovasc Dis 2021 Jul 20:1-9. Epub 2021 Jul 20.

Department of Neurology, University of Erlangen-Nuremberg, Erlangen, Germany.

Background: For outcome assessment in patients surviving subarachnoid hemorrhage (SAH), the modified Rankin scale (mRS) represents the mostly established outcome tool, whereas other dimensions of outcome such as mood disorders and impairments in social life remain unattended so far.

Objective: The aim of our study was to correlate 12-month functional and subjective health outcomes in SAH survivors.

Methods: All SAH patients treated over a 5-year period received outcome assessment at 12 months, including functional scores (mRS and Barthel Index [BI]), subjective health measurement (EQ-5D), and whether they returned to work. Analyses - including utility-weighted mRS - were conducted to detect associations and correlations among different outcome measures, especially in patients achieving good functional outcome (i.e., mRS 0-2) at 12 months.

Results: Of 351 SAH survivors, 287 (81.2%) achieved favorable functional outcome at 12 months. Contrary to the BI, the EQ-5D visual analog scale (VAS) showed a strong association with different mRS grades, accentuated in patients with favorable functional outcome. Despite favorable functional outcome, patients reported a high rate of impairments in activities (24.0%), pain (33.4%), and anxiety/depression (42.5%). Further, multivariable analysis revealed (i) impairments in activities (odds ratio [OR] [95% confidence interval {CI}]: 0.872 [0.817-0.930]), (ii) presence of depression or anxiety (OR [95% CI]: 0.836 [0.760-0.920]), and (iii) return to work (OR [95% CI]: 1.102 [0.1.013-1.198]) to be independently associated with self-reported subjective health.

Conclusion: Established stroke scores mainly focusing on functional outcomes do poorly reflect the high rate of subjective impairments reported in SAH survivors, specifically in those achieving good functional outcome. Further studies are needed to investigate whether psychoeducational approaches aiming at improving coping mechanisms and perceived self-efficacy may result in higher subjective health in these patients.
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http://dx.doi.org/10.1159/000517242DOI Listing
July 2021

Synthesis and characterization of a new two photon excitable acid sphingomyelinase FRET probe.

Bioorg Med Chem 2021 Aug 13;44:116303. Epub 2021 Jul 13.

Institute for Chemistry, Humboldt Universität zu Berlin, Brook-Taylor-Str. 2, 12489 Berlin, Germany. Electronic address:

Recently, FRET probes for acid sphingomyelinase (ASM) have enabled the observation of enzyme activity in intact cells for the first time. Here we present an ASM FRET probe specifically optimized for 2-photon excitation. To facilitate probe characterization and comparison to the previous probe, we mixed the two intact probes with defined amounts of the probes' ceramide cleavage products and mounted them on lipid beads. Directly excited NBD FRET acceptor fluorescene proved to be a useful means of reference and showed that the new probe is brighter, albeit only moderately, than the previous one. The new probe was then used to detect inhibition by various ASM inhibitors microscopically for the first time. Also in cells, directly excited acceptor fluorescence proved to be a useful parameter in addition to FRET to visualize inhibition of ASM.
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http://dx.doi.org/10.1016/j.bmc.2021.116303DOI Listing
August 2021

Male depression syndrome is characterized by pronounced Cluster B personality traits.

J Affect Disord 2021 09 4;292:725-732. Epub 2021 Jun 4.

Department of Psychiatry and Psychotherapy, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Germany; Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health (CIMH), Medical Faculty Mannheim, Heidelberg University, Germany. Electronic address:

Background: Male depression syndrome (Male-DS) refers to alternative depression symptoms related to the male sex, such as externalizing behaviors, emotional suppression, substance misuse, and risk-seeking. Although these symptoms contribute to gender bias in the diagnosis of depression, Male-DS can be found in both sexes. In this cross-sectional study, we analyzed associations between Male-DS and clinical personality accentuations.

Methods: We compared clinical personality accentuations between 78 depressed patients with high Male-DS scores (46% women; mean age ± standard error of the mean: 36.5 ± 1.6 years) and 76 depressed patients with low Male-DS scores (43% women; age 44.8 ± 1.7 years). We also explored differences between the two patient groups and 176 healthy controls (51% women; age 37.2 ± 1.0 years).

Results: Depressed patients with high Male-DS scores showed stronger borderline (partial η 0.121), impulsive (0.112), and antisocial (0.078) personality accentuations than those with low Male-DS scores after Bonferroni adjustment and controlling for sex, depression severity, and age. Relative to healthy controls, patients with high Male-DS values scored higher in all personality dimensions except for the narcissistic dimension. Patients with low Male-DS values scored higher in all Cluster A and C dimensions and the impulsive and borderline dimensions, but their scores were lower in the narcissistic dimension.

Limitations: Cross-sectional design and focus on in-patients.

Conclusions: We found pronounced Cluster B personality in patients with high Male-DS scores versus patients with low scores. Further prospective research is needed to verify that Cluster B personality traits represent a pre-morbid risk factor for Male-DS.
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http://dx.doi.org/10.1016/j.jad.2021.05.114DOI Listing
September 2021

Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.

Nat Commun 2021 06 7;12(1):3417. Epub 2021 Jun 7.

Servei de Neurologia, Hospital Universitari i Politècnic La Fe, Valencia, Spain.

Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease.
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http://dx.doi.org/10.1038/s41467-021-22491-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184987PMC
June 2021

Oxytocin blood concentrations in alcohol use disorder: A cross-sectional, longitudinal, and sex-separated study.

Eur Neuropsychopharmacol 2021 Oct 30;51:55-67. Epub 2021 May 30.

Department of Psychiatry and Psychotherapy, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Germany.

Alcohol use disorder (AUD) is a severe illness, for which we lack sufficient mechanistic understanding. Preliminary evidence associates AUD with the oxytocin (OXT) system. Here we investigated alterations in endogenous OXT blood concentrations in patients with AUD and their association with alcohol drinking and prospective course. In sex-separated analyses, OXT serum concentrations of 200 in-patients with AUD (56.5% male; baseline, 24-72 h of abstinence) were compared with those of 240 age-matched healthy controls (55.4% male), investigated longitudinally (follow-up, 5 days later), and tested for associations with alcohol drinking behavior and prospective 24-month alcohol-related hospital readmissions. At baseline, the patients showed increased OXT concentrations relative to controls (men, 156%, P < 0.001; women, 124%, P = 0.002). The elevations normalized at follow-up. In male patients, baseline OXT concentrations correlated positively with alcohol concentration at admission, the amount of alcohol consumption per drinking year, and the number of previous withdrawal treatments (Rho > 0.195, P < 0.044). In beverage type-specific analysis, baseline OXT concentrations correlated with liquor consumption positively in male and negatively in female patients (|Rho| > 0.277, P < 0.017). Higher baseline OXT concentrations predicted more readmissions and fewer days to the first readmission (|Rho| > 0.185, P < 0.050) in male patients. This study provides novel and sex-separated insights into the role of the OXT system in AUD. We identified a mechanism that might underlie the sex-separated choice of beverage type and established that increased OXT concentrations during early abstinence predict a worse outcome in male patients with AUD.
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http://dx.doi.org/10.1016/j.euroneuro.2021.04.015DOI Listing
October 2021

mRNA Expression of Encoding Acid Sphingomyelinase Decreases upon Antidepressant Treatment.

Int J Mol Sci 2021 May 27;22(11). Epub 2021 May 27.

Department of Psychiatry and Psychotherapy, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Schwabachanlage 6, D-91054 Erlangen, Germany.

Major depressive disorder (MDD) is a severe psychiatric condition with key symptoms of low mood and lack of motivation, joy, and pleasure. Recently, the acid sphingomyelinase (ASM)/ceramide system has been implicated in the pathogenesis of MDD. ASM is a lysosomal glycoprotein that catalyzes the hydrolysis of sphingomyelin, an abundant component of membranes, into the bioactive sphingolipid ceramide, which impacts signaling pathways. ASM activity is inhibited by several common antidepressant drugs. Human and murine studies have confirmed that increased ASM activity and ceramide levels are correlated with MDD. To define a molecular marker for treatment monitoring, we investigated the mRNA expression of , which encodes ASM, in primary cell culture models, a mouse study, and a human study with untreated MDD patients before and after antidepressive treatment. Our cell culture study showed that a common antidepressant inhibited ASM activity at the enzymatic level and also at the transcriptional level. In a genetically modified mouse line with depressive-like behavior, mRNA expression in dorsal hippocampal tissue was significantly decreased after treatment with a common antidepressant. The large human study showed that mRNA expression in untreated MDD patients decreased significantly after antidepressive treatment. This translational study shows that mRNA expression could serve as a molecular marker for treatment and adherence monitoring of MDD.
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http://dx.doi.org/10.3390/ijms22115700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8198802PMC
May 2021

Association Between FIASMAs and Reduced Risk of Intubation or Death in Individuals Hospitalized for Severe COVID-19: An Observational Multicenter Study.

Clin Pharmacol Ther 2021 May 29. Epub 2021 May 29.

Assistance Publique-Hopitaux de Paris, DMU Psychiatrie et Addictologie, Hôpital Corentin-Celton, Institut de Psychiatrie et Neurosciences de Paris (IPNP), INSERM, UMR_S1266, Université de Paris, Paris, France.

Several medications commonly used for a number of medical conditions share a property of functional inhibition of acid sphingomyelinase (ASM), or FIASMA. Preclinical and clinical evidence suggest that the ASM/ceramide system may be central to severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection. We examined the potential usefulness of FIASMA use among patients hospitalized for severe coronavirus disease 2019 (COVID-19) in an observational multicenter study conducted at Greater Paris University hospitals. Of 2,846 adult patients hospitalized for severe COVID-19, 277 (9.7%) were taking an FIASMA medication at the time of their hospital admission. The primary end point was a composite of intubation and/or death. We compared this end point between patients taking vs. not taking an FIASMA medication in time-to-event analyses adjusted for sociodemographic characteristics and medical comorbidities. The primary analysis was a Cox regression model with inverse probability weighting (IPW). Over a mean follow-up of 9.2 days (SD = 12.5), the primary end point occurred in 104 patients (37.5%) receiving an FIASMA medication, and 1,060 patients (41.4%) who did not. Despite being significantly and substantially associated with older age and greater medical severity, FIASMA medication use was significantly associated with reduced likelihood of intubation or death in both crude (hazard ratio (HR) = 0.71, 95% confidence interval (CI) = 0.58-0.87, P < 0.001) and primary IPW (HR = 0.58, 95%CI = 0.46-0.72, P < 0.001) analyses. This association remained significant in multiple sensitivity analyses and was not specific to one particular FIASMA class or medication. These results show the potential importance of the ASM/ceramide system in COVID-19 and support the continuation of FIASMA medications in these patients. Double-blind controlled randomized clinical trials of these medications for COVID-19 are needed.
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http://dx.doi.org/10.1002/cpt.2317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8239599PMC
May 2021

Cerebrospinal fluid α synuclein concentrations in patients with positive AD biomarkers and extrapyramidal symptoms.

J Neural Transm (Vienna) 2021 Jun 25;128(6):817-825. Epub 2021 May 25.

Department of Psychiatry and Psychotherapy, Universitätsklinikum Erlangen, and Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany.

Extrapyramidal symptoms (EP) are not uncommon in Alzheimer's Disease (AD); when present, they negatively influence the course of the disorder. A large proportion of AD patients shows concomitant Lewy bodies' pathology post mortem. Total α Synuclein (αSyn) concentrations are frequently increased in the cerebrospinal fluid (CSF) of AD patients, but are decreased in Parkinson's Disease (PD) and Dementia with Lewy Bodies (DLB). αSyn CSF concentrations in AD patients with EP (EP+) have not been reported so far. αSyn and the four Neurochemical Dementia Diagnostics (NDD) CSF biomarkers, (Aβ1-42, Aβ42/40, Tau, and pTau181), interpreted according to the Erlangen Score algorithm, were measured in patients with positive NDD results and presence of extrapyramidal symptoms (NDD + / EP+; n = 26), in patients with positive NDD results and absence of extrapyramidal symptoms (NDD+ / EP-; n = 54), and in subjects with negative NDD results (NDD-; n = 34). Compared to the NDD- controls (379.8 ± 125.2 pg/mL), NDD+ patients showed, on average, highly significantly increased CSF αSyn (519 ± 141.3 pg/mL, p < 0.01), but without differences between NDD+ / EP+ and NDD+ / EP- subgroups (p = 0. 38). Moderate but highly significant association was observed between concentrations of αSyn and Tau (r = 0.47, p < 0.01) and pTau181 (r = 0.65, p < 0.01). Adjusted for diagnoses, age, and sex, subjects with more advanced neurodegeneration on neuroimaging showed significantly lower αSyn concentrations (p < 0.02). In the setting AD versus controls, the area under the receiver operating characteristic (ROC) curve was 0.804 [0.712; 0.896] with the sensitivity and the specificity of 0.863 and 0.618, respectively. αSyn in AD patients does not differentiate between subjects with- and without EP. Its increased average concentration reflects probably neurodegenerative process, and is not specific for any pathophysiologic mechanisms. Further studies are necessary to explain the role of CSF αSyn as a potential biomarker.
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http://dx.doi.org/10.1007/s00702-021-02351-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205875PMC
June 2021

Motor speech disorders in the nonfluent, semantic and logopenic variants of primary progressive aphasia.

Cortex 2021 07 2;140:66-79. Epub 2021 Apr 2.

Center for Cognitive Disorders, Department of Psychiatry and Psychotherapy, Technische Universität München, München, Germany; Munich Cluster for Systems Neurology (SyNergy), München, Germany.

Objective: Motor speech disorders (MSDs) are characteristic for nonfluent primary progressive aphasia (nfvPPA). In primary progressive aphasia (PPA) of the semantic (svPPA) and of the logopenic type (lvPPA), speech motor function is considered typically intact. However, knowledge on the prevalence of MSDs in svPPA and lvPPA is mainly based on studies with a priori knowledge of PPA syndrome diagnosis. This fully blinded retrospective study aims to provide data on the prevalence of all types of MSDs in a large sample of German-speaking patients with different subtypes of PPA.

Method: Two raters, blinded for PPA subtype, independently evaluated connected speech samples for MSD syndrome and severity from 161 patients diagnosed with nfvPPA, svPPA or lvPPA in the database of the German Consortium of Frontotemporal Lobar Degeneration (FTLDc). In case of disagreement, a third experienced rater re-evaluated the speech samples, followed by a consensus procedure. Consensus was reached for 160 patients (74 nfvPPA, 49 svPPA, 37 lvPPA).

Main Results: Across all PPA syndromes, 43.8% of the patients showed MSDs. Patients with nfvPPA demonstrated the highest proportion of MSDs (62.2%), but MSDs were also identified in svPPA (26.5%) and lvPPA (29.7%), respectively. Overall, dysarthria was the most common class of MSDs, followed by apraxia of speech. In addition, we identified speech abnormalities presenting as "syllabic speech", "dysfluent speech", and "adynamic speech".

Discussion: Our study confirmed MSDs as frequently occurring in PPA. The study also confirmed MSDs to be most common in patients with nfvPPA. However, MSDs were also found in substantial proportions of patients with svPPA and lvPPA. Furthermore, our study identified speech motor deficits that have not received attention in previous studies on PPA. The results are discussed against the background of the existing literature on MSDs in PPA, including theoretical considerations of the neuroanatomical conditions described for each of the different subtypes of PPA.
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http://dx.doi.org/10.1016/j.cortex.2021.03.017DOI Listing
July 2021

E-Learning Is Not Inferior to On-Site Teaching in a Psychiatric Examination Course.

Front Psychiatry 2021 13;12:624005. Epub 2021 Apr 13.

Department of Psychiatry and Psychotherapy, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen, Germany.

Implementing e-learning into medical education is a growing field of research. Researchers have had positive experiences so far, and evidence suggests it to be no less effective than offline teaching. However, there are a few findings concerning psychiatric education and the use of simulated patients online. We developed an online workshop for medical students at our psychiatric clinic, including group work exercises, lectures, and interviews with simulated patients. To compare the learning outcome, a cohort of students learning online was compared with a previous cohort that learned on-site. The same objective structured clinical examination (OSCE) was used in both cases. Evaluation questionnaires were gathered from students and lecturers and were compared with the former semesters along with the exam results. The exam grades did not significantly differ between on-site and online teaching, even though students rated their own communication skills better with online teaching. We also found that the connection experienced between students and teachers was impaired without on-site contact. We conclude that an online course may be an effective alternative to on-site teaching but requires further improvement to maintain a dependable student-teacher relationship.
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http://dx.doi.org/10.3389/fpsyt.2021.624005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076569PMC
April 2021

Brain Region-Dependent Effects of Neuropeptide Y on Conditioned Social Fear and Anxiety-Like Behavior in Male Mice.

Int J Mol Sci 2021 Apr 2;22(7). Epub 2021 Apr 2.

Department of Psychiatry and Psychotherapy, Friedrich-Alexander University Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany.

Neuropeptide Y (NPY) has anxiolytic-like effects and facilitates the extinction of cued and contextual fear in rodents. We have previously shown that the intracerebroventricular administration of NPY reduces the expression of social fear in a mouse model of social fear conditioning (SFC). In the present study, we aimed to identify the brain regions that mediate these effects of NPY. We show that NPY (0.1 nmol/0.2 µL/side) reduces the expression of SFC-induced social fear in a brain-region-dependent manner. In more detail, NPY reduced the expression of social fear when administered into the dorsolateral septum (DLS) and central amygdala (CeA), but not when administered into the dorsal hippocampus (DH), medial amygdala (MeA) and basolateral amygdala (BLA). We also investigated whether the reduced expression of social fear might partly be due to a reduced anxiety-like behavior, and showed that NPY exerted anxiolytic-like effects when administered into the DH, DLS, CeA and BLA, but not when administered into the MeA. This study identifies the DLS and the CeA as brain regions mediating the effects of NPY on the expression of social fear and suggests that partly distinct neural circuitries mediate the effects of NPY on the expression of social fear and on anxiety-like behavior.
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http://dx.doi.org/10.3390/ijms22073695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037261PMC
April 2021

Tonic Control of Secretory Acid Sphingomyelinase Over Ventral Hippocampal Synaptic Transmission and Neuron Excitability.

Front Cell Neurosci 2021 9;15:660561. Epub 2021 Apr 9.

Institute of Physiology and Pathophysiology, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.

The acid sphingomyelinase (ASM) converts sphingomyelin into ceramide. Recent work has advanced the ASM/ceramide system as a major player in the pathogenesis of major depressive disorder (MDD). Indeed, ASM activity is enhanced in MDD patients and antidepressant drugs like fluoxetine act as functional inhibitors of ASM. Here, we employed the specific ASM inhibitor ARC39 to explore the acute effects of the enzyme on hippocampal synaptic transmission and cell excitability in adult mouse brain slice preparations. In both field potential and whole-cell recordings, ARC39 (1-3 μM) enhanced excitatory synaptic input onto ventral hippocampal CA1 pyramidal cells. The specificity of drug action was demonstrated by its lacking effect in slices from ASM knockout mice. In control condition, ARC39 strongly reduced firing in most CA1 pyramidal cells, together with membrane hyperpolarization. Such pronounced inhibitory action of ARC39 on soma excitability was largely reversed when GABA receptors were blocked. The idea that ARC39 recruits GABAergic inhibition to dampen cell excitability was further reinforced by the drug's ability to enhance the inhibitory synaptic drive onto pyramidal cells. In pyramidal cells that were pharmacologically isolated from synaptic input, the overall effect of ARC39 on cell firing was inhibitory, but some neurons displayed a biphasic response with a transient increase in firing, suggesting that ARC39 might alter intrinsic firing properties in a cell-specific fashion. Because ARC39 is charged at physiological pH and exerted all its effects within minutes of application, we propose that the neurophysiological actions reported here are due to the inhibition of secretory rather than lysosomal ASM. In summary, the ASM inhibitor ARC39 reveals a tonic control of the enzyme over ventral hippocampal excitability, which involves the intrinsic excitability of CA1 pyramidal cells as well as their excitatory and inhibitory synaptic inputs.
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http://dx.doi.org/10.3389/fncel.2021.660561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062921PMC
April 2021

Inhibition of acid sphingomyelinase by ambroxol prevents SARS-CoV-2 entry into epithelial cells.

J Biol Chem 2021 Jan-Jun;296:100701. Epub 2021 Apr 23.

Institute of Molecular Biology, University of Duisburg-Essen, Essen, Germany; Department of Surgery, Medical School, University of Cincinnati, Cincinnati, Ohio, USA. Electronic address:

The acid sphingomyelinase/ceramide system has been shown to be important for cellular infection with at least some viruses, for instance, rhinovirus or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Functional inhibition of the acid sphingomyelinase using tricyclic antidepressants prevented infection of epithelial cells, for instance with SARS-CoV-2. The structure of ambroxol, that is, trans-4-[(2,4-dibromanilin-6-yl)-methyamino]-cyclohexanol, a mucolytic drug applied by inhalation, suggests that the drug might inhibit the acid sphingomyelinase and thereby infection with SARS-CoV-2. To test this, we used vesicular stomatitis virus pseudoviral particles presenting SARS-CoV-2 spike protein on their surface (pp-VSV-SARS-CoV-2 spike), a bona fide system for mimicking SARS-CoV-2 entry into cells. Viral uptake and formation of ceramide localization were determined by fluorescence microscopy, activity of the acid sphingomyelinase by consumption of [C]sphingomyelin and ceramide was quantified by a kinase method. We found that entry of pp-VSV-SARS-CoV-2 spike required activation of acid sphingomyelinase and release of ceramide, events that were all prevented by pretreatment with ambroxol. We also obtained nasal epithelial cells from human volunteers prior to and after inhalation of ambroxol. Inhalation of ambroxol reduced acid sphingomyelinase activity in nasal epithelial cells and prevented pp-VSV-SARS-CoV-2 spike-induced acid sphingomyelinase activation, ceramide release, and entry of pp-VSV-SARS-CoV-2 spike ex vivo. The addition of purified acid sphingomyelinase or C16 ceramide restored entry of pp-VSV-SARS-CoV-2 spike into ambroxol-treated epithelial cells. We propose that ambroxol might be suitable for clinical studies to prevent coronavirus disease 2019.
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http://dx.doi.org/10.1016/j.jbc.2021.100701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062550PMC
July 2021

Inhibition of acid sphingomyelinase by ambroxol prevents SARS-CoV-2 entry into epithelial cells.

J Biol Chem 2021 Jan-Jun;296:100701. Epub 2021 Apr 23.

Institute of Molecular Biology, University of Duisburg-Essen, Essen, Germany; Department of Surgery, Medical School, University of Cincinnati, Cincinnati, Ohio, USA. Electronic address:

The acid sphingomyelinase/ceramide system has been shown to be important for cellular infection with at least some viruses, for instance, rhinovirus or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Functional inhibition of the acid sphingomyelinase using tricyclic antidepressants prevented infection of epithelial cells, for instance with SARS-CoV-2. The structure of ambroxol, that is, trans-4-[(2,4-dibromanilin-6-yl)-methyamino]-cyclohexanol, a mucolytic drug applied by inhalation, suggests that the drug might inhibit the acid sphingomyelinase and thereby infection with SARS-CoV-2. To test this, we used vesicular stomatitis virus pseudoviral particles presenting SARS-CoV-2 spike protein on their surface (pp-VSV-SARS-CoV-2 spike), a bona fide system for mimicking SARS-CoV-2 entry into cells. Viral uptake and formation of ceramide localization were determined by fluorescence microscopy, activity of the acid sphingomyelinase by consumption of [C]sphingomyelin and ceramide was quantified by a kinase method. We found that entry of pp-VSV-SARS-CoV-2 spike required activation of acid sphingomyelinase and release of ceramide, events that were all prevented by pretreatment with ambroxol. We also obtained nasal epithelial cells from human volunteers prior to and after inhalation of ambroxol. Inhalation of ambroxol reduced acid sphingomyelinase activity in nasal epithelial cells and prevented pp-VSV-SARS-CoV-2 spike-induced acid sphingomyelinase activation, ceramide release, and entry of pp-VSV-SARS-CoV-2 spike ex vivo. The addition of purified acid sphingomyelinase or C16 ceramide restored entry of pp-VSV-SARS-CoV-2 spike into ambroxol-treated epithelial cells. We propose that ambroxol might be suitable for clinical studies to prevent coronavirus disease 2019.
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http://dx.doi.org/10.1016/j.jbc.2021.100701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062550PMC
July 2021

Quantifying progression in primary progressive aphasia with structural neuroimaging.

Alzheimers Dement 2021 Mar 30. Epub 2021 Mar 30.

Department of Neurology, University Hospital Ulm, Ulm, Germany.

Introduction: The term primary progressive aphasia (PPA) sums up the non-fluent (nfv), the semantic (sv), and the logopenic (lv) variant. Up to now, there is only limited data available concerning magnetic resonance imaging volumetry to monitor disease progression.

Methods: Structural brain imaging and an extensive assessment were applied at baseline and up to 4-year(s) follow-up in 269 participants. With automated atlas-based volumetry 56 brain regions were assessed. Atrophy progression served to calculate sample sizes for therapeutic trials.

Results: At baseline highest atrophy appeared in parts of the left frontal lobe for nfvPPA (-17%) and of the left temporal lobe for svPPA (-34%) and lvPPA (-24%). Severest progression within 1-year follow-up occurred in the basal ganglia in nfvPPA (-7%), in the hippocampus/amygdala in svPPA (-9%), and in (medial) temporal regions in lvPPA (-6%).

Conclusion: PPA presents as a left-dominant, mostly gray matter sensitive disease with considerable atrophy at baseline that proceeds variant-specific.
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http://dx.doi.org/10.1002/alz.12323DOI Listing
March 2021

Body mass index and serum levels of soluble leptin receptor are sex-specifically related to alcohol binge drinking behavior.

Psychoneuroendocrinology 2021 05 25;127:105179. Epub 2021 Feb 25.

Department of Psychiatry and Psychotherapy, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Germany; Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health (CIMH), Medical Faculty Mannheim, Heidelberg University, Germany.

Objective: Binge drinking is a highly prevalent behavior in adolescents and young adults and a risk factor to develop alcohol use disorder. Body mass index (BMI) and blood levels of leptin peptide and its soluble receptor have been implicated in alcohol use disorder; however, their role in binge drinking remains to be investigated.

Method: We studied associations of BMI, serum levels of soluble leptin receptor (ObRe) and leptin as well as the free leptin index with binge drinking in 93 male and 99 female young adults.

Results: In men, binge drinkers showed significantly higher BMI (kg/m) than non-binge drinkers (23.67 vs. 22.08) and higher BMI correlated significantly with more severe binge drinking episodes (ρ = 0.251). In women, we found significantly higher ObRe (ng/ml) / BMI (kg/m) values in binge drinkers than in non-binge drinkers (0.52 vs. 0.44) and ObRe/BMI values correlated significantly with more severe binge drinking episodes (ρ = 0.210).

Conclusion: This study confirms that higher BMI associates with binge drinking in men and shows for the first time a role of ObRe/BMI in binge drinking in women. Our data emphasize the importance of further research in the field of metabolic markers and implications in neurobiological processes of binge drinking.
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http://dx.doi.org/10.1016/j.psyneuen.2021.105179DOI Listing
May 2021

Plasma neurofilament light and phosphorylated tau 181 as biomarkers of Alzheimer's disease pathology and clinical disease progression.

Alzheimers Res Ther 2021 03 25;13(1):65. Epub 2021 Mar 25.

Old age Psychiatry, Department of Psychiatry, University Hospital of Lausanne, Lausanne, Switzerland.

Background: To assess the performance of plasma neurofilament light (NfL) and phosphorylated tau 181 (p-tau181) to inform about cerebral Alzheimer's disease (AD) pathology and predict clinical progression in a memory clinic setting.

Methods: Plasma NfL and p-tau181, along with established cerebrospinal fluid (CSF) biomarkers of AD pathology, were measured in participants with normal cognition (CN) and memory clinic patients with cognitive impairment (mild cognitive impairment and dementia, CI). Clinical and neuropsychological assessments were performed at inclusion and follow-up visits at 18 and 36 months. Multivariate analysis assessed associations of plasma NfL and p-tau181 levels with AD, single CSF biomarkers, hippocampal volume, and clinical measures of disease progression.

Results: Plasma NfL levels were higher in CN participants with an AD CSF profile (defined by a CSF p-tau181/Aβ > 0.0779) as compared with CN non-AD, while p-tau181 plasma levels were higher in CI patients with AD. Plasma NfL levels correlated with CSF tau and p-tau181 in CN, and with CSF tau in CI patients. Plasma p-tau181 correlated with CSF p-tau181 in CN and with CSF tau, p-tau181, Aβ, and Aβ/Aβ in CI participants. Compared with a reference model, adding plasma p-tau181 improved the prediction of AD in CI patients while adding NfL did not. Adding p-tau181, but not NfL levels, to a reference model improved prediction of cognitive decline in CI participants.

Conclusion: Plasma NfL indicates neurodegeneration while plasma p-tau181 levels can serve as a biomarker of cerebral AD pathology and cognitive decline. Their predictive performance depends on the presence of cognitive impairment.
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http://dx.doi.org/10.1186/s13195-021-00805-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7995778PMC
March 2021

Evaluation of the German biographic screening interview for fetal alcohol spectrum disorder (BSI-FASD).

Sci Rep 2021 Mar 4;11(1):5233. Epub 2021 Mar 4.

Department of Psychiatry and Psychotherapy, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Schwabachanlage 6, 91054, Erlangen, Germany.

Alcohol consumption during pregnancy may lead to permanent damage in the offspring, including fetal alcohol spectrum disorders (FASD), which have an estimated prevalence of 1-8% worldwide. In adulthood, diagnosing FASD is time-consuming and costly. This study aimed to evaluate the discriminatory power of a German screening instrument for FASD in adults-the biographic screening interview (BSI-FASD). In an open-label comparative cohort study wherein a one-time survey was administered per participant, we compared 22 subjects with confirmed FASD with control groups of 15 subjects diagnosed with attention deficit hyperactivity disorder (ADHD), 20 subjects with alcohol or opiate dependence, 18 subjects with depression, and 31 controls without prenatal alcohol exposure. The BSI-FASD was found to be resource-efficient, user-friendly, comprehensible, and easily applicable. It provided an overall good convergent and discriminant validity with a sensitivity of 0.77 (adapted 0.86) and specificities between 0.70 and 1.00. The BSI-FASD subdomains differed in their power to differentiate FASD from the groups. This study established that the BSI-FASD is an efficient instrument to screen adults with suspected FASD. The BSI-FASD may facilitate future diagnostic evaluation and thereby contribute to improved treatment of affected individuals.
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http://dx.doi.org/10.1038/s41598-021-83942-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933170PMC
March 2021

Progesterone serum levels correlate negatively with craving in female postmenopausal in-patients with alcohol use disorder: A sex- and menopausal status-separated study.

Prog Neuropsychopharmacol Biol Psychiatry 2021 Aug 9;110:110278. Epub 2021 Feb 9.

Department of Psychiatry and Psychotherapy, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Germany; Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health (CIMH), Medical Faculty Mannheim, Heidelberg University, Germany.

Objective: Alcohol use disorder (AUD) shows a high prevalence and often takes a severe and chronic course. However, the underlying mechanisms still need to be better understood. There is increasing evidence for a role of sex hormones in AUD and for the importance of sex-separated concepts in addiction research. Nevertheless, only few data give insight into how progesterone is involved in AUD.

Method: Serum progesterone levels were measured at baseline (during early abstinence) in 186 in-patients with AUD (19% premenopausal females, 20% postmenopausal females, 61% males) and at median 5 days later. They were compared with those of 233 healthy control subjects (24% premenopausal females, 19% postmenopausal females, 57% males). We quantified craving with the Obsessive Compulsive Drinking Scale (OCDS) and visual analogue scales (VAS). Alcohol-related hospital readmissions within a 24-month period following initial in-patient treatment were recorded. We conducted analyses separately for sex and for menopausal status in female participants.

Results: Postmenopausal females with AUD reported higher craving than premenopausal females. In postmenopausal females, higher baseline progesterone levels correlated with lower OCDS total craving and VAS craving, i.e., lower state craving and lower average, maximum, and less frequent craving during withdrawal. In males with AUD, progesterone levels at baseline tended to be higher than in controls and declined to follow-up. Alcohol-related readmissions were not significantly associated with serum progesterone levels.

Conclusion: We provide first evidence that progesterone levels correlate with craving in females with AUD.
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http://dx.doi.org/10.1016/j.pnpbp.2021.110278DOI Listing
August 2021

assay to evaluate the efficacy of drugs targeting sphingolipids in preventing SARS-CoV-2 infection of nasal epithelial cells.

STAR Protoc 2021 Mar 3;2(1):100356. Epub 2021 Feb 3.

Institute of Molecular Biology, University of Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany.

This protocol enables the testing of drugs against infection of epithelial cells with SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2), using pseudo-typed replication deficient vesicular stomatitis virus particles (pp-VSV) presenting the SARS-CoV-2 spike protein. After treating human volunteers with amitriptyline, an approved antidepressant and inhibitor of the acid sphingomyelinase, freshly isolated nasal epithelial cells were infected and infection levels were quantified. This protocol offers the possibility to rapidly test the efficacy of potential drugs in the fight against COVID-19. For complete details on the use and execution of this protocol, please refer to Carpinteiro et al. (2020).
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http://dx.doi.org/10.1016/j.xpro.2021.100356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857112PMC
March 2021
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