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Aims To examine the association between benzodiazepine receptor agonist (BZRA) use and mortality in patients hospitalised for coronavirus disease 2019 (COVID-19). Methods A multicentre observational study was performed at Greater Paris University hospitals. The sample involved 14 381 patients hospitalised for COVID-19. A total of 686 (4.8%) inpatients received a BZRA at hospital admission at a mean daily diazepam-equivalent dose of 19.7 mg (standard deviation (s.d.) = 25.4). The study baseline was the date of admission, and the primary endpoint was death. We compared this endpoint between patients who received BZRAs and those who did not in time-to-event analyses adjusted for sociodemographic characteristics, medical comorbidities and other medications. The primary analysis was a Cox regression model with inverse probability weighting (IPW). Results Over a mean follow-up of 14.5 days (s.d. = 18.1), the primary endpoint occurred in 186 patients (27.1%) who received BZRAs and in 1134 patients (8.3%) who did not. There was a significant association between BZRA use and increased mortality both in the crude analysis (hazard ratio (HR) = 3.20; 95% confidence interval (CI) = 2.74–3.74; p < 0.01) and in the IPW analysis (HR = 1.61; 95% CI = 1.31–1.98, p < 0.01), with a significant dose-dependent relationship (HR = 1.55; 95% CI = 1.08–2.22; p = 0.02). This association remained significant in sensitivity analyses. Exploratory analyses indicate that most BZRAs may be associated with an increased mortality among patients hospitalised for COVID-19, except for diazepam, which may be associated with a reduced mortality compared with any other BZRA treatment. Conclusions BZRA use may be associated with an increased mortality among patients hospitalised for COVID-19, suggesting the potential benefit of decreasing dose or tapering off gradually these medications when possible.

Background: In several randomized controlled trials (RCT) acetylcholinesterase-inhibitors (AChE-I) were tested in patients with mild cognitive impairment (MCI) but were ineffective in delaying disease progression as determined by neuropsychological testing only. Here we present data from an open label observational extension of a multicenter RCT in order to assess if biomarkers are providing useful additional information about a drug’s efficacy. We followed 83 amnestic MCI patients and performed correlational analyses of Aβ 1-42 and total-Tau in the cerebrospinal fluid (CSF), hippocampal and amygdala volume at baseline, the total duration of blinded and open label AChE-I treatment and the outcome 24 months after inclusion into the RCT. Twelve out of 83 amnestic MCI (14%) had progressed to Alzheimer’s disease (AD). Overall, worsening and disease progression as measured by the Alzheimer’s Disease Assessment Scale – cognitive subscale (ADAS-cog), Alzheimer’s Disease Cooperative Study – Activities of Daily Living (ADCS-ADL) and Clinical Dementia Rating (CDR) did not correlate with the duration of AChE-I treatment. However, a specific multidimensional biomarker profile at baseline indicated more reliably than cognitive testing alone progression to AD. We conclude that pharmacological RCTs testing symptomatic treatment effects in MCI should include biomarker assessment.

© 2015, Elsevier Inc. All rights reserved. Background: Late-onset Alzheimer's disease (AD) is heritable with 20 genes showing genome-wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis. Methods: The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. Results: ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (P = 3.27 × 10-12 after multiple testing correction for pathways), regulation of endocytosis (P = 1.31 × 10-11), cholesterol transport (P = 2.96 × 10-9), and proteasome-ubiquitin activity (P = 1.34 × 10-6). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P =.002-.05). Conclusions: The immune response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics., Medical Research Council, Alzheimer’s Research UK, and theWelsh Assembly Government. ADGC and CHARGE were supported by the National Institutes of Health, National Institute on Aging (NIH-NIA). CHARGE was also supported by Erasmus Medical Center and Erasmus University. IGAP was funded by the French National Foundation on Alzheimer’s Disease and Related Disorders, the Centre National de Genotypage and the Institut Pasteur de Lille, Inserm, FRC (Fondation pour la Recherche sur le Cerveau), and Rotary. This work has been developed and supported by the LABEX (Laboratory of Excellence Program Investment for the Future) DISTALZ grant (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer’s disease).

Hintergrund: Zum achtzigsten Male jahrt sich der erzwungene Rucktritt (1.3.1934) Gustav Kolbs (1870 – 1938). Er gilt als Begrunder des „Erlanger Systems“ der offenen Fursorge. Der nachfolgende Artikel soll Gustav Kolbs „Lebenswerk“ wurdigen durch Aufzeigen des Aufbaus, der Blutezeit sowie des Niedergangs seines „Erlanger Systems“ im zeitgeschichtlichen Kontext. Methode: Relevantes archivarisches Material sowie Sekundarliteratur wurden ausgewertet. Ergebnisse: An der psychiatrischen Anstalt in Erlangen fuhrte Gustav Kolb als Direktor (1911 – 1934) ab 1914 die Unterbringung psychisch Kranker in ihrer eigenen Familie ein. 1930 unterstanden in einem Fursorgegebiet von circa 3200 Quadratkilometer 4200 Menschen der insgesamt 770 000 Anwohner der offenen Fursorge. Das „Erlanger System“ stellte die groste Organisation dieser Art in Deutschland dar. Kolb vertrat zwar eugenische Leitgedanken, widersetzte sich jedoch der nationalsozialistischen Gesundheitspolitik. Er zog sich 1933 beruflich zuruck und verstarb funf Jahre spater. Diskussion: Im Spannungsfeld der offenen Fursorge zwischen Hilfsinstitution fur und Kontrollinstanz uber psychisch kranke Menschen gab es in der Weimarer Zeit noch eine relativ ausgewogene Balance. Spater bot Gustav Kolbs organisatorische Grundlichkeit mit dem Anlegen einer Zentralkartei der Erlanger Ausenfursorge reichlich erbbiologisches Informationsmaterial. Tragischerweise wurde dies im Rahmen der Durchfuhrung des nationalsozialistischen Gesetzes zur Verhutung erbkranken Nachwuchses (14.7.1933) als wichtige Hinweisquelle missbraucht. Mehrere Aspekte trugen dazu bei, dass Kolbs freiheitliches System zu einem Erfassungsinstrument der Nationalsozialisten zweckentfremdet werden konnte. Schlussbemerkung: Vereinzelte Bemuhungen, nach 1945 erneut offene Fursorge-Einrichtungen zu etablieren, wurden nicht umgesetzt. Erst im Rahmen der sozialpsychiatrischen Bewegung in den 68ern erlebte Kolbs Konzept eine damals unbenannte und unerkannte Renaissance.

Hintergrund: Dem Internisten, Neurologen und Psychiater Adolf Bingel kommt bei der Etablierung der Elektrokonvulsionstherapie (EKT) in Deutschland eine entscheidende Bedeutung zu. Ihm ist es zu verdanken, dass die Psychiatrische- und Nervenklinik der Universitat Erlangen als erstes Institut Deutschlands das Verfahren der EKT ausfuhrte. Methode: Relevantes archivarisches Material sowie Sekundarliteratur wurden ausgewertet. Ergebnisse: Im Zuge der Entnazifizierung wurde der EKT-Pionier Adolf Bingel/Erlangen von der Spruchkammer in Heidelberg als „Mitlaufer“ eingestuft. Er siedelte 1946 als anerkannter deutscher Wissenschaftler im Rahmen der „Operation Paperclip“ in die USA aus. Diskussion: Die wiederholt erfolgte Verwechslung mit dem Pionier der Luftenzephalografie Adolf Bingel/Braunschweig muss berichtigt werden. Schlussfolgerung: 1957 bekam Bingel von der Universitat Erlangen den Titel „Dozent a. D.“ verliehen. 1959 wurde Bingel auserordentlicher Professor fur Neurologie am Baylor University College in Houston/Texas.

Hintergrund: Von der 1846 eroffneten „Kreis-Irrenanstalt Erlangen“ sind aktuell noch zwei Gebaude erhalten. Durch deren Abriss soll Bauplatz fur ein modernes „Translational Research Center“ (TRC) entstehen. Vor diesem Hintergrund mochten wir an die Entstehungsgeschichte der ersten psychiatrischen Anstalt Bayerns erinnern. Als deutschlandweite Einzigartigkeit soll das anstaltsarchitektonisch realisierte panoptische Bauprinzip gewurdigt werden. Methode: Relevante Primarquellen und Sekundarliteratur sowie ausgewahlte Abbildungen wurden ausgewertet und vor dem Hintergrund der psychiatriehistorischen Entwicklung interpretiert. Ergebnisse: Auserhalb Grosbritanniens wurde das panoptische System bzgl. Anstaltsbaus in Frankreich, Italien und Deutschland jeweils nur einmal realisiert, namlich in Avignon, Genua und Erlangen. Der panoptische Architekturtypus ermoglichte eine Patientenbeaufsichtigung mit minimalem Aufwand an Personal: Von zentralem Beobachtungszimmer aus konnte die gesamte Station ubersehen werden. Dank der fachkundigen Beratung des Arztes Johann Michael Leupoldt (1794 – 1874) konnte das Projekt der ersten bayerischen Heil- und Pflegeanstalt binnen zwolf Jahren realisiert werden. Diskussion: Obwohl seit 1818 die H-Form einer Anstalt als architektonisch vollkommener beurteilt wurde, zog man in Erlangen einen kreuzformigen Plan vor. Ob finanzielle Engpasse hierzu notigten, bleibt im Spekulativen. Weder die Aktenlage noch Leupoldts Selbstbiografie geben Aufschluss hieruber. Schlussfolgerung: Mag das realisierte TRC-Bauprojekt ein Dokument fur bislang deutschlandweit singularen medizinischen Fortschritt darstellen, so gilt es umso mehr, die „Kreis-Irrenanstalt Erlangen“ als einen Markstein in der Entwicklung psychiatrischer Architektur zu wurdigen.

Few data are available concerning the role of risk markers for Alzheimer's disease (AD) in progression to AD dementia among subjects with mild cognitive impairment (MCI). We therefore investigated the role of well-known AD-associated single-nucleotide polymorphism (SNP) in the progression from MCI to AD dementia. Four independent MCI data sets were included in the analysis: (a) the German study on Aging, Cognition and Dementia in primary care patients (n=853); (b) the German Dementia Competence Network (n=812); (c) the Fundació ACE from Barcelona, Spain (n=1245); and (d) the MCI data set of the Amsterdam Dementia Cohort (n=306). The effects of single markers and combined polygenic scores were measured using Cox proportional hazards models and meta-analyses. The clusterin (CLU) locus was an independent genetic risk factor for MCI to AD progression (CLU rs9331888: hazard ratio (HR)=1.187 (1.054-1.32); P=0.0035). A polygenic score (PGS1) comprising nine established genome-wide AD risk loci predicted a small effect on the risk of MCI to AD progression in APOE-ϵ4 (apolipoprotein E-ϵ4) carriers (HR=1.746 (1.029-2.965); P=0.038). The novel AD loci reported by the International Genomics of Alzheimer's Project were not implicated in MCI to AD dementia progression. SNP-based polygenic risk scores comprising currently available AD genetic markers did not predict MCI to AD progression. We conclude that SNPs in CLU are potential markers for MCI to AD progression.

BACKGROUND: The contribution of potential treatable dementia aetiologies diagnosed using cerebral imaging varied considerably in previous studies and was not evaluated in a recent larger German sample of patients from a memory clinic. MATERIAL AND METHODS: MRI images of 502 patients were retrospectively reassessed. Beside the proportion of potentially treatable dementia aetiology, the extent of whole brain atrophy (semiquantitative) and vascular white matter lesions were assessed. RESULTS: Mean age of the patients was 63.7 ± 13.1 years; 49 % were female, mean MMST was 24.2 ± 5.5. In 74 % there was an agreement between the clinical dementia syndrome and MRI. 9 % (45 patients) had clearly discrepant imaging results, according to MRI criteria (21 × ischaemia, 20 × normal pressure hydrocephalus (NPH), 4 × intracerebral haemorrhage). These patients could not not be differentiated using age and MMST alone as clinical criteria. There was a significant correlation between global brain atrophy and MMST (r = -0.32; p < 0.001) and white matter lesion score (r = 0.28; p < 0.001). CONCLUSION: In 9 % there was a clear discrepancy between MRI results and the clinical syndrome diagnosis in memory-clinic patients. As known from earlier studies and current German 3 rd generation guidelines, it is reasonable to perform MRI imaging in dementia to improve the aetiological and differential diagnoses and to detect a different aetiology that can be missed using the clinical dementia criteria alone.

Die neurochemische Demenzdiagnostik (NDD) ist ein Routineinstrument in der Diagnostik neurodegenerativer Erkrankungen wie der Alzheimer-Erkrankung (Alzheimer’s disease, AD). Gegenwartig werden zwei Biomarkergruppen verwendet, die im Liquor cerebrospinalis („cerebrospinal fluid“, CSF) gemessen werden. Es handelt sich um Amyloid-β-Peptide (Aβ) und Tau-Proteine einschlieslich hyperphosphorylierte Formen (pTau). Aktuell geht die Entwicklung der NDD in folgende Richtungen: 1. Suche nach neuen Biomarkern mit verbesserter diagnostischer Leistung; 2. Suche nach Biomarkern im Blut; 3. Anwendung neuer Technologien zur okonomischeren Handhabung der Patientenproben; 4. Optimierung der Bestimmung bereits verwendeter Biomarker (z. B. durch verbesserte Qualitatskontrolle und Vergleichbarkeit der Ergebnisse unterschiedlicher Labore). In diesem Artikel geben wir einen kurzen Uberblick uber die gegenwartige Situation auf dem Gebiet der liquorbasierten NDD und fassen einige Hypothesen zur moglichen zukunftigen Entwicklung zusammen.

A survey in specialties other than psychiatry showed that "emergency room"-patients have factors other than the presenting disease that determine the usage of urgent medical evaluation. In the following prospective study 104 outpatients presenting at daytime in a university psychiatric emergency care unit were included over 6 months. Apart from social and epidemiological data, illnesses according to ICD-10, reason for presentation from the patient's point of view and in this regard the physician's evaluation were included. The most prevalent diagnoses were depression, adjustment disorders and anxiety disorders, comprising together 75 %. Organic disorders or addictive disorders were less frequent; psychoses were found in 8 %. Concerning the presentation as an emergency, 70 % of patients reported a subjective clinical deterioration but only 44 % were regarded as an urgent need in the responsible physician's point of view (Cohen's kappa 0.39). Our findings show that patients presenting as "psychiatric emergency cases" without appointment mainly suffer from depression, adjustment disorders and panic disorders. Furthermore, the layperson's point of view of clinical deterioration justifying an emergency presentation differs from physician's evaluation. The most likely cause for this disagreement between physicians and patients in the assessment to utilise a medical emergency care service in psychiatry might be dysfunctional or, respectively, negative-biased cognitions accompanying depressive syndromes.

Hintergrund Multiple-Choice-Fragen spielen in der Aus- und Weiterbildung eine wichtige Rolle. Seit 2002 gibt es in Der Nervenarzt CME („continuing medical education”) -Artikel mit meist 10 Multiple-Choice-Fragen. Untersuchungen aus anderen Fachgebieten zeigten, dass CME-Fragen haufig formal-didaktisch ungunstige Formate enthalten. In der vorliegenden Studie haben wir die CME-Fragen aus Der Nervenarzt auf ihre formal-didaktische Qualitat untersucht.

INTRODUCTION: Postpartal affective disorders are with a prevalence between 8 % and 15 % highly frequent maternal diseases after childbirth. An undetected and untreated postpartum depression causes a wide range of negative consequences such as risk of a chronic manifestation of a major depression, social retreat, limitations in the bonding behavior, and behavioral disorders of the child. Therefore, an early detection of pregnant women at risk is warranted. METHODS: Within a prospective study (FRAMES: Franconian Maternal Health Evaluation Studies), 1,100 pregnant women were interviewed with standardized questionnaires at three points of time: Prepartal (U1): from the 30 th week of pregnancy onwards, 48 - 72 hours (U2) postpartum (pp) und 6 - 8 months pp (U3). 554 women were included in the substudy Blue FRAMES, where an additional telephone interview at the 10 th day pp was conducted with a focus on symptoms relating to Baby Blues such as mood instability, irritability and concentration deficits. The Edinburgh Postnatal Depression Scale (EPDS) and the Hamilton Rating Scale For Depression (HAMD) were used for quantification of depressivity at each point of time. RESULTS: EPDS values differed significantly (Friedman Test; χ 2 = 110.8; df = 2, p < 0,001) between the different examination points (Wilcoxon Test; U1 - U2: Z = -11.0; p < 0.001; U1 - U3: Z = -6.6; p < 0.001; U2 - U3: Z = -4,5; p < 0,001). Regarding EPDS values, higher values were observed prepartum (U1). After a decrease after two to three days postpartum (U2), values increased again. However, EPDS values six months postpartum (U3) were still lower than prepartum (U1). DISCUSSION: The observed EPDS values postpartum are comparable to results of other studies. The higher EPDS values prepartum have a good predictive value. There is a great need and possibility for improved prevention of postpartal disorders, when appropriately addressed in the prepartum period.

Cognitive decline is a frequent clinical symptom in elderly patients. In particular, memory disturbances are an early sign and a risk factor for subsequent development of neurodegenerative dementia. At the same time, elderly patients often receive multiple medications due to an increasing number of acquired diseases. Certain drugs have adverse side effects on cognition due to interference with the cholinergic or GABA-ergic system. This could lead to underestimation of the actual cognitive status at initial clinical presentation. In the present study we included 221 patients (mean age 68,5 years) who presented for the first time in a specialized memory-clinic and who had or developed dementia during follow up. Most patients had mixed vascular-degenerative dementia (57 %). On average, patients took 2.1 drugs. 19.9 % of the patients had medications with potential adverse effects on cognition. Patients with medication affecting cognition had a worse cognitive performance than patients with a medication not influencing cognitive functioning (Mini-Mental vs. 18.8. 22.01, p = 0.01) in univariate analysis. Psychotropic drugs were used less frequently (38 %) than primary non-CNS medication. The results remained unchanged even after performing a case-control study with the mixed dementia population with age and gender matched patients. However, in multivariate analysis, only the absolute number of medication taken remained as an independent factor. Our data highlight the clinical importance of medication history in the diagnostic work-up of cognitive impairment. The absolute number of medication taken seems to be more important than medication with possible adverse side effects on cognition.

The diagnosis of Alzheimer's dementia is currently changing from a late and exclusion diagnosis towards a pathophysiology-based early and positive diagnosis. Especially advances in neuro-chemical dementia diagnostics in the cerebrospinal fluid (NDD-CSF) and imaging techniques like PET, SPECT or MRI are of particular interest. Unfortunately, many studies investigated only either one or other technique. In the present study 56 patients (average 67.1 years; average mini-mental status test (MMST) 22.2) were examined with the clinical diagnosis of Alzheimer's dementia. All patients both underwent NDD-CSF as well as 99mTc-SPECT. Only the SPECT, but not the NDD-CSF correlated with disease severity. Sensitivity of NDD-CSF was 89 % and SPECT 48 % for all patients and 93 % resp. 61 % for patients with MMST < 24. Below MMST 20 both methods had equal sensitivity. Both diagnostic techniques showed no statistic coherence (p = 0.27), neither after correction for subgroups like disease severity or the APOE genotype. Our results are compatible with the hypothesis that the NDD-CSF reflects beta-amyloid-aggregation and Tau-Protein pathology as a pathophysiologic biomarker. Our results suggest that SPECT is rather a state parameter for the rCBF changes following cortical neurodegeneration.

There are more than 100 memory clinics established in Germany, Austria and German-speaking Switzerland. We compared the impact of the structure of two German memory clinics (Erlangen and Nuremberg) on therapeutic outcome. 483 patients suffering from dementia with indication for antidementive therapy were included in this study. The data ascertainment included patient-related data, the mini mental score, comorbidity as well as psychiatric drug therapy. After a mean follow-up of 3.7 years, we performed a single cross-sectional survey covering over 90 % of patients to assess clinical course and adherence to therapy. The patients of the Erlangen University Memory Clinic were significantly younger (69.8 +/- 9.49 vs. 74.6 +/- 10.7 years; p = 0.01) and had a better mini mental score at their first presentation (20.9 +/- 9.4 vs. 19.5 +/- 5.9; p = 0.02). They showed a non-significantly faster disease progression (as measured by mini mental decline per year), than the patients from Nuremberg. Concerning the allocationof diagnosis, more late onset-dementias and dementias of a mixed type were treated at the Nuremberg clinic. At the university clinic, more dementias were of unclassified origin. Concomitant drug therapies, death rates and therapy adherence (53 %) were not different between the two clinics. The two memory clinics under investigation differed in patient age, disease severity and diagnostic assessment. Still, parameters of therapeutic outcome showed converging results.

Objective: To better understand the seemingly contradictory plasma beta-amyloid (A beta) results in Alzheimer's disease (AD) patients by using a newly developed plasma A beta assay, the INNO-BIA plasma A beta forms, in a multicenter study. Methods: A combined retrospective analysis of plasma A beta isoforms on mild cognitive impairment (MCI) from three large cross-sectional studies involving 643 samples from the participating German and Swedish centers. Results: Detection modules based on two different amino (N)-terminal specific A beta monoclonal antibodies demonstrated that A beta in plasma could be reliable quantified using a sandwich immunoassay technology with high precision, even for low A beta 42 plasma concentrations. A beta 40 and A beta 42 concentrations varied consistently with the ApoE genotype, while the A beta 42/A beta 40 ratio did not. Irrespective of the decrease of the A beta 42/A beta 40 ratio with age and MMSE, this parameter was strongly associated with AD, as defined in this study by elevated hyperphosphorylated (P-tau181P) levels in cerebrospinal fluid (CSF). Conclusion: A highly robust assay for repeatedly measuring A beta forms in plasma such as INNO-BIA plasma A beta forms might be a useful tool in a future risk assessment of AD. (Less)

O envelhecimento da população e o aumento da expectativa de vida resultam em um número cada vez maior de pacientes com demência. Os déficits cognitivos podem ser manifestações de uma doença curável do sistema nervoso central (por exemplo, neuroinflamação), como também de uma doença atualmente considerada irreversível, como a doença de Alzheimer (DA). Tendo em vista as novas abordagens terapêuticas para a DA, em que se avalia o potencial modificador da patogenia, torna-se necessário o estabelecimento de um diagnóstico confiável em vida. Embora a análise do líquido cefalorraquidiano (LCR) e do soro seja realização de rotina em doenças neuroinflamatórias, ainda necessita de padronização para ser usada como instrumento auxiliar no diagnóstico clínico da DA. Vários parâmetros relacionados à DA (tau total, formas fosforiladas de tau, peptídeos Aβ, genótipo ApoE, p97 etc.) podem ser determinados no LCR. A combinação de alguns desses parâmetros proporciona sensibilidade e especificidade na faixa de 85% para o diagnóstico da DA, um valor usualmente atribuído a um bom instrumento de diagnóstico. Nesta revisão, são discutidas as publicações mais recentes sobre os marcadores neuroquímicos para o diagnóstico clínico das demências, com ênfase no diagnóstico precoce e diferencial da DA. Discutem-se brevemente as novas perspectivas oferecidas por tecnologias recentes, tais como a FCS (fluorescence correlation spectroscopy) e a técnica de espectrometria de massa pelo método SELDI-TOF (surface enhanced laser desorption/ionization time-of-flight mass spectrometry).Aging of population, and increasing life expectancy result in an increasing number of patients with dementia. This symptom can be a part of a completely curable disease of the central nervous system (e.g, neuroinflammation), or a disease currently considered irreversible (e.g, Alzheimer's disease, AD). In the latter case, several potentially successful treatment approaches are being tested now, demanding reasonable standards of pre-mortem diagnosis. Cerebrospinal fluid and serum analysis (CSF/serum analysis), whereas routinely performed in neuroinflammatory diseases, still requires standardization to be used as an aid to the clinically based diagnosis of AD. Several AD-related CSF parameters (total tau, phosphorylated forms of tau, Aß peptides, ApoE genotype, p97, etc.) tested separately or in a combination provide sensitivity and specificity in the range of 85%, the figure commonly expected from a good diagnostic tool. In this review, recently published reports regarding progress in neurochemical pre-mortem diagnosis of dementias are discussed with a focus on an early and differential diagnosis of AD. Novel perspectives offered by recently introduced technologies, e.g, fluorescence correlation spectroscopy (FCS) and surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) are briefly discussed.

Es werden Verbesserungsschritte in Planung, Durchfuhrung und Auswertung von Multiple-Choice-Prufungen in den Fachern Psychiatrie, Psychosomatik, Psychotherapie und Neurologie beschrieben. 640 Fragen von 1419 Studierenden wurden uber 4 Jahre analysiert. Veranderungen betrafen die Abschaffung problematischer Multiple-Choice-Fragetypen, Einfuhrung von reformierten validen Multiple-Choice-Frageformaten, automatisiertes Einlesen und Auswerten der Antworten; Erweiterung der fallbasierten Fragen, Verlangerung der Fragenstamme, quantitative Auswertung der Fragen und Einfuhrung eines Peer-review-Systems. Folgen waren eine Zunahme des Schweregrades um 18%, Zunahme der Trennscharfe um 67% und Abnahme der Auswertungszeiten auf wenige Stunden. Als Nachteil des Prozesses kam es durch das Peer-review-Verfahren zu einer Zunahme der Vorbereitungszeit, was jedoch von den Beteiligten als positiv empfunden wurde, da die Fragenqualitat verbessert werden konnte.

Benzodiazepines are very often prescribed because of their anxiolytic, sedative and hypnotic properties. However, long term treatment is associated with development of benzodiazepine dependence. Besides development of physical dependence, which is linked to a typical benzodiazepine withdrawal syndrome when drug intake is discontinued, also behavioural addiction to benzodiazepines has been described. Benzodiazepines are known to enhance GABAergic neurotransmission. Counter regulation of enhanced GABAergic neurotransmission by enhancement of glutamatergic neurotransmission is thought to be one reason underlying the typical symptoms of benzodiazepine withdrawal. Also alterations in the expression of neuropeptides like Corticotropin Releasing Hormone and Neuropeptide Y are thought to be involved in the development of benzodiazepine dependence. However, until today the knowledge of neural mechanisms underlying the development of benzodiazepine dependence remains incomplete. Because even long term treatment with small doses of benzodiazepines is associated with adverse reactions like cognitive dysfunctions withdrawal from benzodiazepines should be aimed. Anticonvulsants and antidepressants seem to reduce the intensity of benzodiazepine withdrawal and to enhance long term prognosis of dependence.

Der vorliegende Bericht beschreibt ein vom Bundesministerium für Gesundheit gefördertes Vorhaben zum «Leuchtturmprojekt Demenz» im Themenfeld 1 «Therapie und Pflegemaßnahmen: Wirksamkeit unter Alltagsbedingungen». Hierbei handelt es sich um eine multizentrische randomisierte Interventionsstudie, die den Einfluss von Sport (multimodale sportliche Aktivität) unter kontrollierten Bedingungen auf die kognitive Entwicklung von Alzheimer-Patienten im frühen Stadium prüft. In einem zweiarmigen Design werden je 150 Patienten mit früher AD unter Verum- bzw. Kontroll-Bedingungen untersucht. Die Verum-Gruppe erhält ein spezifisches sportliches Trainingsprogramm. In der Kontrollgruppe werden lediglich Dehnungsübungen durchgeführt. Primäre Endpunkte der Studie sind die kognitive Leistung der Patienten sowie deren Alltagskompetenz im Verlauf. Die gesundheitsbezogene Lebensqualität der Patienten sowie etwaige Verhaltensstörungen und depressive Symptome werden als sekundäre Endpunkte erfasst. Darüber hinaus werden die Angehörigen zur krankheitsbezogenen Belastung befragt und auf depressive Symptome untersucht. Angelehnt an die Hypothesen der «Initiative Demenzversorgung in der Allgemeinmedizin» (IDA) sollen entsprechende nicht-medikamentöse Versorgungsangebote dazu beitragen, dass Patienten länger in ihrem gewohnten häuslichen Umfeld leben. Im Sinne der Nachhaltigkeit der zu erwartenden Ergebnisse wird ein «Do it yourself»-Manual erstellt, mit dem das Trainingsprogramm auch ohne professionelle Anleitung, z. B. im Rahmen von Selbsthilfegruppen durchgeführt werden kann. Die weitere Implementierung (z. B. in Internetforen und weiteren Medien) wird durch einen Beirat der lokalen Krankenkassen, Gesundheitsämter und der Deutschen Alzheimer-Gesellschaft unterstützt.

Many studies address the neurobiological mechanisms of alcohol craving. The study results obtained so far show that there may be at least three subtypes of craving, which may be linked to changes in different neurotransmitter systems. Actually in Germany acamprosate and disulfiram are approved for clinical use for the prevention of alcohol relapse. Also off-label therapy with naltrexone is possible. However studies show that these substances are not effective in all patients. In the light of hypothetical changes in different neurotransmitter systems, subtype specific therapy may be necessary for successful prevention of alcohol relapse. Therefore new therapy options are needed in order to treat alcohol dependent persons. Substances that seem to have efficacy in preclinical or preliminary clinical studies are baclofen, topiramate, odansetron, rimonabant and memantine.

Despite the advances in the psychopharmacology, the treatment of depressive disorder is still not satisfactory. All current pharmacological substances are affecting the monoamines in the central nervous system. The present review discusses advances in the field of monoaminergic antidepressants as well as new treatment alternatives. The new monoaminergic substances include metabolites of known antidepressants, direct serotonin-agonists, and triple-reuptake inhibitors, blocking the transport of serotonin, norepinephrine, and dopamine. Non-monoaminergic strategies include substances affecting melatonin or neuropeptides. Glutamate modulating agents such as ketamine or riluzole are another promising approach in the treatment of depression. Some advances have also been achieved in the field of HPA-axis modulation.

Biomarkers for differential diagnosis of the three most frequent degenerative forms of dementia, Alzheimer's disease (AD), dementia with Lewy bodies (DLB) and frontotemporal dementias (FTD), are currently under intensive investigation, but disease-specific biomarkers for FTD and DLB are still lacking. We analyzed 303 cerebrospinal fluid (CSF) samples of 71 AD, 32 DLB and 36 FTD patients in comparison to 93 various other dementias (OD), 20 peripheral neurologic disease (PND) controls, 25 neurodegenerative disorders without dementia (ND) and 26 depressive cognitive complainers (DCC) for distinct CSF amyloid-beta (Abeta) peptide patterns, using the quantitative Abeta-SDS-PAGE/immunoblot. Additionally, the novel electrochemiluminescence technique (MSD) was used to validate the measures on Abeta1-38. The main outcome measures were a striking decrease of Abeta1-42 in AD (P=7.4 x 10(-19)), and most interestingly a pronounced decrease of Abeta1-38 in FTD (P=9.6 x 10(-7)). Moreover, a novel peptide that most probably represents an oxidized alpha-helical form of Abeta1-40 (Abeta1-40(ox)) displayed a highly significant increase in DLB (P=3.7 x 10(-3)) as compared to non-demented disease controls. The overall diagnostic accuracy of percentage Abeta peptide abundances (Abeta1-X%) was clearly superior to absolute CSF Abeta levels. Abeta1-42% and Abeta1-38% enabled contrasts of 85% or beyond to distinguish AD and FTD, respectively, from all other investigated subjects. Abeta1-40(ox)% yielded a diagnostic sensitivity and specificity of 88 and 73% for the detection of DLB among all other investigated patients. We found a strong correlation between Abeta1-38 levels as measured by the Abeta-SDS-PAGE/immunoblot and MSD, respectively. CSF Abeta peptides may reflect disease-specific impact of distinct neurodegenerative processes on Abeta peptide metabolism and represent a potential diagnostic biomarker for AD, FTD and DLB.

In the last years, numerous studies have been performed on neurobiological mechanisms in alcohol craving. Changes in the hypothalamic cortisol pathway and the leptin metabolism, which is also associated with pharmacological interventions, have been of special interest. With acamprosate and naltrexone two substances exist for pharmacotherapy, but recent results about the efficacy are controversial. The clinical profit of disulfiram has been shown, at least in a subgroup of patients. Besides, there are several promising candidate substances. Current investigations focus on a differentiated pharmacotherapy of alcohol dependence, including psychological and genetic factors.

ZusammenfassungDie vorliegende Arbeit soll eine Übersicht über innovative diagnostische Ansätze der Neurochemischen Demenzdiagnostik (NDD) geben. Eine verbesserte Früh- und Differenzialdiagnostik demenzieller Erkrankungen ist unter dem Aspekt sich entwickelnder kausal orientierter Therapiestrategien für die Alzheimer-Demenz (AD) von Bedeutung. Dies betrifft insbesondere Patienten mit leichter kognitiver Beeinträchtigung, wo ein AD-typisches Demenzbiomarkerprofil die drohende AD bereits mindestens vier bis sieben Jahre vor Ausbruch des Demenzstadiums anzeigen kann. Ebenso besteht Bedarf an zusätzlichen Demenzbiomarkern für die verbesserte Differenzialdiagnostik anderer Frühstadien neurodegenerativer Demenzerkrankungen, wie frontotemporale Demenzen, Demenz mit Lewy-Körperchen und Parkinson-Demenz, oder aber für Demenzbiomarker, die eng mit dem Schweregrad der Demenz im Verlauf korrelieren. Bezüglich neuerer Forschungsansätze werden wir auch erste Ansätze einer blutbasierten NDD diskutieren und innovative methodische Ansätze der multiparametischen Diagnostik (Multiplex Assays) vorstellen.

ZusammenfassungDie vorliegende Arbeit soll eine Übersicht über das sich schnell entwickelnde Gebiet der Neurochemischen Demenzdiagnostik (NDD) geben, wobei der Schwerpunkt auf Anwendungen liegen soll, die zwischenzeitlich bereits Eingang in die Routinediagnostik gefunden haben oder wo dies bald zu erwarten ist. Demenzbiomarker, die in unabhängigen größeren Studien multizentrisch an mehreren tausend Patienten und Probanden validiert wurden, liegen bisher nur für folgende Parameter im lumbalen Liquor vor (liquorbasierte neurochemische Demenzdiagnostik, LiquorNDD): beta-Amyloidpeptide, Gesamt-Tau und hyperphosphorylierte Tau-Proteine (phospho-Tau). Diese Studien belegen eindrucksvoll, dass die CSF-NDD zwischenzeitlich eine hohe Relevanz für die verbesserte Frühund Differenzialdiagnostik demenzieller Erkrankungen erlangt hat und für die Alzheimer-Demenz eine prädiktive Diagnostik bietet.

Glutamate is the most important excitatory transmitter in the central nervous system. A tremendous complexity in the actions of this excitatory transmitter was found and an equally great complexity in the molecular structures of the receptors activated by glutamate. The glutamate receptor system influences nearly all other neurotransmitter systems. Glutamate also plays a central role in important processes of the central nervous system like the long-term potentiation in the hippocampus and the central sensitization for pain stimuli in the spinal cord, which is predominantly mediated by NMDA-receptors. But there are actions of glutamate beyond its function as an excitatory transmitter. Glutamate also has a trophic influence on neurons--depending upon the developmental stage. The excitotoxicity of glutamate mediated by NMDA-receptors is the common ultimate mechanism of acute and chronic nerve cell death and plays an important role in many acute neurologic diseases. The modulation of the glutamate system for example by antagonist of the glutamate-receptors might be a possible way in therapy of many different diseases of the central nervous system.

Health services research aims to generate knowledge about care processes of people with illnesses who access health-care services. In addition, the consequences of those processes in the care routine concerning the involved persons and the health system are analyzed. CONCEPT OF THE THEORETICAL WORK: In the first part of the manuscript, an overview concerning the current definitions and subsumptions of the concept of health services research is given. The second part of the manuscript focuses on demonstrating how evidence-based health services research can be used to enable optimization of the care system. The concept is called the "circle of care optimization". In the first step the current care situation concerning its deficits and their reasons is analyzed. In the second step a relevant care goal is defined. In the third step an improvement of an existing care process is developed to achieve the defined care goal. In the fourth step, a comparative empirical study with a high-quality study design is carried out, to assess whether the improved care process is superior to the current care as usual. A health economic evaluation will be performed if applicable. If the results show no or only small advantages, the "circle" starts again with step 3. However, if the results show a significant effect in favour of the new care process and are relevant for the delivery of care and efficient in the context of health economics, a fifth step will be performed which involves developing and testing strategies for implementation. Where relevant, the consequences of implementation are investigated in a sixth step. A "best-practice" practical example is demonstrated to illustrate the "circle of care optimization".conclusions are derived by illustrating future challenges for health services research.

Background: About 30% of psychiatric patients don't take their drugs as advised, which can lead to treatment failure and relapses [1]. Pharmacists' interventions improved medication adherence in other indications such as diabetes, [2] but it is unclear if psychiatric patients benefit from pharmacist counseling during hospitalization and particularly after discharge from hospital. Methods: To assess the impact of pharmacists' interventions on patient adherence, a controlled clinical trial in the department of psychiatry and psychotherapy at the university hospital of Erlangen was planned. Control patients receive usual care whereas patients in the intervention group benefit from education services offered by pharmacists during their stay and after discharge. Adherence is measured by “Medication Adherence Rating Scale” (MARS). The MARS is conducted at admission, discharge and 3 months after discharge. Results: So far, 114 control patients have been included in the control phase. During hospitalization, patient adherence improved from admission to discharge. First results from follow-up measurement indicate that adherence declines after discharge. Conclusion: Although follow-up data is still incomplete, it becomes apparent that some patients discontinue their drugs after discharge. The intervention phase will show if pharmacists can improve patients' adherence. 1. Burkhart P et al, Journal of Nurs Scholarsh 2003;35:207 2. Shah M et al, Journal of Pharm Practice 2013;26:120 – 124