Search

In old age, the chronic use of substances such as alcohol and sedatives, and more recently opioids, is a major public health and personal problem. Despite this, relatively little attention has been paid to the disorders associated with the use of these substances. These recommendations have been formulated by the Swiss Society for Elderly Psychiatry and Psychotherapy (SPPA) in collaboration with the Swiss Nurses' Association (SNA) and the Swiss Society for Addiction Medicine (SSAM). They provide a summary of the knowledge about addiction disorders in old age for the benefit of those working with patients, with the aim of strengthening prevention, early detection and appropriate interventions.À l’âge avancé, la consommation chronique de substances comme l’alcool et les sédatifs, et plus récemment les opioïdes, représente un important problème pour les personnes concernées et de santé publique. Malgré cela, relativement peu d’attention a été accordée aux troubles associés à la consommation de ces substances. Les présentes recommandations ont été formulées par la Société suisse de psychiatrie et psychothérapie de la personne âgée (SPPA) en collaboration avec l’Association suisse des infirmières et infirmiers (ASI) et la Société suisse de médecine de l’addiction (SSMA). Elles mettent à la disposition des intervenants auprès des patients un résumé des connaissances au sujet des troubles addictifs à l’âge avancé, avec comme objectif de renforcer la prévention et le dépistage précoce, et des interventions adaptées.

The G4C2-repeat expansion in C9orf72 is the most common cause of frontotemporal dementia and of amyotrophic lateral sclerosis. The variability of age at onset and phenotypic presentations is a hallmark of C9orf72 disease. In this study, we aimed to identify modifying factors of disease onset in C9orf72 carriers using a family-based approach, in pairs of C9orf72 carrier relatives with concordant or discordant age at onset. Linkage and association analyses provided converging evidence for a locus on chromosome Xq27.3. The minor allele A of rs1009776 was associated with an earlier onset (P = 1 × 10−5). The association with onset of dementia was replicated in an independent cohort of unrelated C9orf72 patients (P = 0.009). The protective major allele delayed the onset of dementia from 5 to 13 years on average depending on the cohort considered. The same trend was observed in an independent cohort of C9orf72 patients with extreme deviation of the age at onset (P = 0.055). No association of rs1009776 was detected in GRN patients, suggesting that the effect of rs1009776 was restricted to the onset of dementia due to C9orf72. The minor allele A is associated with a higher SLITRK2 expression based on both expression quantitative trait loci (eQTL) databases and in-house expression studies performed on C9orf72 brain tissues. SLITRK2 encodes for a post-synaptic adhesion protein. We further show that synaptic vesicle glycoprotein 2 and synaptophysin, two synaptic vesicle proteins, were decreased in frontal cortex of C9orf72 patients carrying the minor allele. Upregulation of SLITRK2 might be associated with synaptic dysfunctions and drives adverse effects in C9orf72 patients that could be modulated in those carrying the protective allele. How the modulation of SLITRK2 expression affects synaptic functions and influences the disease onset of dementia in C9orf72 carriers will require further investigations. In summary, this study describes an original approach to detect modifier genes in rare diseases and reinforces rising links between C9orf72 and synaptic dysfunctions that might directly influence the occurrence of first symptoms.

Recommendations for the Prevention, Diagnostics and Therapy of Addiction Disorders in the Elderly

Obwohl der chronische Konsum einzelner Substanzen wie z.B. Alkohol und Sedativa, sowie zunehmend auch Opioide, im Alter ein grosses Problem mit erheblichen Folgeschäden für die Betroffenen darstellt, ist den entsprechenden Störungsbildern bisher wenig Beachtung geschenkt worden. Die vorliegenden Empfehlungen sind unter der Federführung der Schweizerischen Gesellschaft für Alterspsychiatrie- und Psychotherapie (SGAP) in Zusammenarbeit mit dem Schweizer Berufsverband für Pflegefachpersonal (SBK) und der Schweizerischen Gesellschaft für Suchtmedizin (SSAM) entstanden, mit dem Ziel, den aktuellen Stand des Wissens über die Abhängigkeitserkrankungen im Alter sowie über die Möglichkeiten der Diagnostik und Therapie zusammenzufassen und den interprofessionellen, klinischen Teams zur Verfügung zu stellen. Sie sollen helfen, die Prävention und Frühdiagnostik zu stärken, und stellen bewusst die Psychotherapie und pflegerischen Interventionsmöglichkeiten in den Vordergrund., Although the chronic consumption of alcohol and sedatives, and increasingly opioids, represents a major problem in old age with consequential damage for those affected, little attention has been paid to the substance abuse disorders in old age. The aim of the present recommendations, a collaboration work of the Swiss Society for Geriatric Psychiatry and Psychotherapy (SGAP), Swiss Nurses Association (SBK) and Swiss Society of Addiction Medicine (SSAM), is to summarize the current state of knowledge in prevention, diagnostics and therapy of substance abuse disorders in old age for an interprofessional clinical team. They are intended to help strengthen prevention and early diagnosis, and consciously emphasize psychotherapy and nursing intervention options., La consommation chronique à l’âge avancé de substances comme l’alcool et les sédativfs, et plus récemment d’opioïdes, représente un important problème avec des conséquences à court et à long terme. Malgré cela, peu d’attention a été accordée aux troubles associés à la consommation de ces produits. Les présentes recommandations ont été formulées par la Société Suisse de Psychiatrie et Psychothérapie de la Personne Agée (SPPA) en collaboration avec l’Association suisse des infirmières et infirmiers (ASI) et la Société Suisse de Médedine de l’Addicition (SSMA). Elles ont comme objectif de mettre à la disposition des intervenants des connaissances au sujet des troubles addictifs à l’âge avancé et les options préventives, diagnostiques et thérapeutiques. Elles sont sensées renforcer la prévention et le dépistage précoce et mettent en avant les interventions psychothérapeutiques et les soins.

Background: The etiology of frontotemporal dementia (FTD) is poorly understood. To identify genes with predicted expression levels associated with FTD, we integrated summary statistics with external reference gene expression data using a transcriptome-wide association study approach. Methods: FUSION software was used to leverage FTD summary statistics (all FTD: n = 2154 cases, n = 4308 controls; behavioral variant FTD: n = 1337 cases, n = 2754 controls; semantic dementia: n = 308 cases, n = 616 controls; progressive nonfluent aphasia: n = 269 cases, n = 538 controls; FTD with motor neuron disease: n = 200 cases, n = 400 controls) from the International FTD-Genomics Consortium with 53 expression quantitative loci tissue type panels (n = 12,205; 5 consortia). Significance was assessed using a 5% false discovery rate threshold. Results: We identified 73 significant gene–tissue associations for FTD, representing 44 unique genes in 34 tissue types. Most significant findings were derived from dorsolateral prefrontal cortex splicing data (n = 19 genes, 26%). The 17q21.31 inversion locus contained 23 significant associations, representing 6 unique genes. Other top hits included SEC22B (a gene involved in vesicle trafficking), TRGV5, and ZNF302. A single gene finding (RAB38) was observed for behavioral variant FTD. For other clinical subtypes, no significant associations were observed. Conclusions: We identified novel candidate genes (e.g., SEC22B) and previously reported risk regions (e.g., 17q21.31) for FTD. Most significant associations were observed in dorsolateral prefrontal cortex splicing data despite the modest sample size of this reference panel. This suggests that our findings are specific to FTD and are likely to be biologically relevant highlights of genes at different FTD risk loci that are contributing to the disease pathology.

Funder: QingLan Research Project of Jiangsu for Outstanding Young Teachers, Funder: Project funded by Postdoctoral Science Foundation of Xuzhou Medical University, Funder: Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD) for Xuzhou Medical University, We employed Mendelian randomization (MR) to evaluate the causal relationship between leukocyte telomere length (LTL) and amyotrophic lateral sclerosis (ALS) with summary statistics from genome-wide association studies (n = ~ 38,000 for LTL and ~ 81,000 for ALS in the European population; n = ~ 23,000 for LTL and ~ 4,100 for ALS in the Asian population). We further evaluated mediation roles of lipids in the pathway from LTL to ALS. The odds ratio per standard deviation decrease of LTL on ALS was 1.10 (95% CI 0.93–1.31, p = 0.274) in the European population and 0.75 (95% CI 0.53–1.07, p = 0.116) in the Asian population. This null association was also detected between LTL and frontotemporal dementia in the European population. However, we found that an indirect effect of LTL on ALS might be mediated by low density lipoprotein (LDL) or total cholesterol (TC) in the European population. These results were robust against extensive sensitivity analyses. Overall, our MR study did not support the direct causal association between LTL and the ALS risk in neither population, but provided suggestive evidence for the mediation role of LDL or TC on the influence of LTL and ALS in the European population.

Der Bedarf an spezifischen Therapiemoglichkeiten fur altere Menschen mit Abhangigkeitserkrankungen steigt aufgrund der zunehmenden Lebenserwartung. Evidenzen zu psychotherapeutischen Therapiekonzepten sowie medikamentosen und pflegerischen Optionen gibt es lediglich aus der Suchtforschung mit jungeren Erwachsenen.

ATENCIÓ: la correcció està també al DDD, cal relacionar??? https://ddd.uab.cat/record/226203 Altres ajuts: The following studies and consortia have contributed to this manuscript. Amsterdam dementia Cohort (ADC): Research of the Alzheimer center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. The Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting VUmc fonds. The clinical database structure was developed with funding from Stichting Dioraphte. Genotyping of the Dutch case-control samples was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND FP-829-029 (ZonMW projectnumber 733051061). 100-Plus study: We are grateful for the collaborative efforts of all participating centenarians and their family members and/or relations. This work was supported by Stichting Alzheimer Nederland (WE09.2014-03), Stichting Diorapthe, horstingstuit foundation, Memorabel (ZonMW projectnumber 733050814) and Stichting VUmc Fonds. Genotyping of the 100-Plus Study was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND FP-829-029 (ZonMW projectnumber 733051061). German Study on Ageing, Cognition and Dementia in Primary Care Patients (AgeCoDe): This study/publication is part of the German Research Network on Dementia (KND), the German Research Network on Degenerative Dementia (KNDD; German Study on Ageing, Cognition and Dementia in Primary Care Patients; AgeCoDe), and the Health Service Research Initiative (Study on Needs, health service use, costs and health-related quality of life in a large sample of oldest-old primary care patients (85+; AgeQualiDe)) and was funded by the German Federal Ministry of Education and Research (grants KND: 01GI0102, 01GI0420, 01GI0422, 01GI0423, 01GI0429, 01GI0431, 01GI0433, 01GI0434; grants KNDD: 01GI0710, 01GI0711, 01GI0712, 01GI0713, 01GI0714, 01GI0715, 01GI0716; grants Health Service Research Initiative: 01GY1322A, 01GY1322B, 01GY1322C, 01GY1322D, 01GY1322E, 01GY1322F, 01GY1322G). Alfredo Ramirez was partly supported by the ADAPTED consortium: Alzheimer's disease Apolipoprotein Pathology for Treatment Elucidation and Development, which has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115975. Brain compendium: This work was funded by the UK Medical Research Council (13044). P.F.C. is a Wellcome Trust principal Fellow (212219/Z/18/Z) and a UK NIHR Senior Investigator, who receives support from the Medical Research Council Mitochondrial Biology Unit (MC_UU_00015/9), and the National Institute for Health Research (NIHR) Biomedical Research Centre based at Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health.Clinical AD, Sweden: We would like to thank UCL Genomics for performing the genotyping analyses. Danish data: The studies behind the Danish long-lived cases received funding from The National Program for Research Infrastructure 2007 (grant no. 09-063256), the Danish Agency for Science Technology and Innovation, the Velux Foundation, the US National Institute of Health (P01 AG08761), the Danish Agency for Science, Technology and Innovation/The Danish Council for Independent Research (grant no. 11-107308), the European Union's Seventh Framework Programme (FP7/2007-2011) under grant agreement no. 259679, the INTERREG 4 A programme Syddanmark-Schleswig-K.E.R.N. (by EU funds from the European Regional Development Fund), the CERA Foundation (Lyon), the AXA Research Fund, Paris, and The Health Foundation (Helsefonden), Copenhagen, Denmark. The GOYA study was conducted as part of the activities of the Danish Obesity Research Centre (DanORC, www.danorc.dk) and The MRC centre for Causal Analyses in Translational Epidemiology (MRC CAiTE). The genotyping for GOYA was funded by the Wellcome Trust (WT 084762). GOYA is a nested study within The Danish National Birth Cohort which was established with major funding from the Danish National Research Foundation. Additional support for this cohort has been obtained from the Pharmacy Foundation, the Egmont Foundation, The March of Dimes Birth Defects Foundation, the Augustinus Foundation, and the Health Foundation. Fundació ACE (FACE): We would like to thank patients and controls who participated in this project. We are indebted to Trinitat Port-Carbó and her family for their support of Fundació ACE research programs. Fundació ACE collaborates with the Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, Spain) and is one of the participating centers of the Dementia Genetics Spanish Consortium (DEGESCO). Agustín Ruiz has received support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking ADAPTED Grant No. 115975 and by grants PI13/02434 and PI16/01861. Acción Estratégica en Salud, integrated in the Spanish National R + D + I Plan and financed by ISCIII (Instituto de Salud Carlos III)-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER- "Una manera de Hacer Europa"), by Fundación bancaria "La Caixa" and Grifols SA (GR@ACE project). Genetics of Healthy Ageing Study (GEHA - NL): The work described in this paper was funded mainly by the EU GEHA Project contract no. LSHM-CT-2004-503-270. Gothenburg Birth Cohort (GBC) Studies: We would like to thank UCL Genomics for performing the genotyping analyses. The studies were supported by The Stena Foundation, The Swedish Research Council (2015-02830, 2013-8717), The Swedish Research Council for Health, Working Life and Wellfare (2013-1202, 2005-0762, 2008-1210, 2013-2300, 2013-2496, 2013-0475), The Brain Foundation, Sahlgrenska University Hospital (ALF), The Alzheimer's Association (IIRG-03-6168), The Alzheimer's Association Zenith Award (ZEN-01-3151), Eivind och Elsa K:son Sylvans Stiftelse, The Swedish Alzheimer Foundation. International FTD-Genomics Consortium (IFGC): International FTD-Genomics Consortium (IFGC): The authors thank the IFGC for providing relevant data to support the analyses presented in this manuscript. Further acknowledgments for IFGC (https://ifgcsite.wordpress.com/), e.g. full members list and affiliations, are found in the online supplementary files. IPDGC (​The International Parkinson Disease Genomics Consortium): We also would like to thank all members of the International Parkinson Disease Genomics Consortium (IPDGC). See for a complete overview of members, acknowledgements and funding http://pdgenetics.org/partners. Kompetenznetz Multiple Sklerose (KKNMS): This work was supported by the German Ministry for Education and Research (BMBF) as part of the "German Competence Network Multiple Sclerosis" (KKNMS) (grant nos. 01GI0916 and 01GI0917) and the Munich Cluster for Systems Neurology (SyNergy). TA was supported by the BMBF through the Integrated Network IntegraMent, under the auspices of the e:Med Programme (01ZX1614J). BH was supported by the EU Horizon 2020 project MultipleMS.Longitudinal Aging Study Amsterdam (LASA) is largely supported by a grant from the Netherlands Ministry of Health, Welfare and Sports, Directorate of Long-Term Care. The authors are grateful to all LASA participants, the fieldwork team and all researchers for their ongoing commitment to the study. Leiden Longevity Study: This study was supported by a grant from the Innovation-Oriented Research Program on Genomics (SenterNovem IGE05007), the Centre for Medical Systems Biology, and the Netherlands Consortium for Healthy Ageing (Grant 050-060-810), all in the framework of the Netherlands Genomics Initiative/Netherlands Organization for Scientific Research (NWO) and by Unilever Colworth.Maria Carolina Dalmasso: Georg Forster Research Award (Alexander von Humboldt Foundation). Mayo Clinic AD, DLB, PD, PSP: We thank the patients and their families for their participation, without whom these studies would not have been possible. Funding for this work was supported by National Institute on Aging [RF AG051504 to NET.; U01 AG046139 to NET]; and National Institute of Neurological Disorders and Stroke [R01 NS080820 to NET; P50 NS072187]. The Mayo Clinic is a Lewy Body Dementia Association (LBDA) Research Center of Excellence, American Parkinson Disease Association (APDA) Information and Referral Center and Center for Advanced Research, NINDS Tau Center without Walls (U54-NS100693) and is supported by Mayo Clinic AD and related dementias genetics program, The Little Family Foundation, the Mangurian Foundation for Lewy body research and NINDS R01 NS078086 (to OAR). The PD program at the Mayo Clinic Florida is also supported by the Mayo Clinic Center for Regenerative Medicine, Mayo Clinic Center for Individualized Medicine, Mayo Clinic Neuroscience Focused Research Team (Cecilia and Dan Carmichael Family Foundation, and the James C. and Sarah K. Kennedy Fund for Neurodegenerative Disease Research at Mayo Clinic in Florida), the gift from Carl Edward Bolch, Jr., and Susan Bass Bolch, and The Sol Goldman Charitable Trust. Samples included in this study are from the brain bank at Mayo Clinic in Jacksonville which is supported by CurePSP The online version of this article (10.1007/s00401-019-02026-8) contains supplementary material, which is available to authorized users.

Mutations in the microtubule-associated protein tau (MAPT) gene cause autosomal dominant frontotemporal lobar degeneration with tau inclusions (FTLD-tau). MAPT p.R406W carriers present clinically with progressive memory loss and neuropathologically with neuronal and glial tauopathy. However, the pathogenic events triggered by the expression of the mutant tau protein remain poorly understood. To identify the genes and pathways that are dysregulated in FTLD-tau, we performed transcriptomic analyses in induced pluripotent stem cell (iPSC)–derived neurons carrying MAPT p.R406W and CRISPR/Cas9-corrected isogenic controls. We found that the expression of the MAPT p.R406W mutation was sufficient to create a significantly different transcriptomic profile compared with that of the isogeneic controls and to cause the differential expression of 328 genes. Sixty-one of these genes were also differentially expressed in the same direction between MAPT p.R406W carriers and pathology-free human control brains. We found that genes differentially expressed in the stem cell models and human brains were enriched for pathways involving gamma-aminobutyric acid (GABA) receptors and pre-synaptic function. The expression of GABA receptor genes, including GABRB2 and GABRG2, were consistently reduced in iPSC-derived neurons and brains from MAPT p.R406W carriers. Interestingly, we found that GABA receptor genes, including GABRB2 and GABRG2, are significantly lower in symptomatic mouse models of tauopathy, as well as in brains with progressive supranuclear palsy. Genome wide association analyses reveal that common variants within GABRB2 are associated with increased risk for frontotemporal dementia (P −3). Thus, our systems biology approach, which leverages molecular data from stem cells, animal models, and human brain tissue can reveal novel disease mechanisms. Here, we demonstrate that MAPT p.R406W is sufficient to induce changes in GABA-mediated signaling and synaptic function, which may contribute to the pathogenesis of FTLD-tau and other primary tauopathies.

Storungsmodelle in der Alterspsychotherapie beziehen neben schulenspezifischen Storungs- und Behandlungsmodellen auch gerontologische Konzepte mit ein. Daher werden zunachst das Alters- und storungsspezifische Rahmenmodell sowie das Modell der selektiven Optimierung mit Kompensation dargestellt. Sie zeigen, dass nicht nur erschwerende Faktoren (wie Multimorbiditat, Verluste, Fahigkeitseinschrankungen) sondern auch erleichternde Faktoren (wie Bewaltigungs- und Lebenserfahrung, angepasste Wohlbefindensregulation) relevant sind. Allgemeine altersbezogene Modifizierungen psychotherapeutischer Techniken werden beschrieben. Schwerpunkt ist die Darstellung verhaltenstherapeutischer Interventionen bei korperlichen Veranderungen und Krankheiten sowie bei kognitiver Beeintrachtigung und Fruhdemenz. Dabei wird erlautert, wie in der Alterspsychotherapie das klassische Patient-Therapeut-Setting erweitert wird mit Angeboten fur Angehorige der Patienten und Supervision fur Pflegepersonen. Erganzt wird dieser Beitrag durch einen Uberblick uber die Behandlung von Depression und Angststorungen im Alter.

Introduction The objective of this open-label study was to evaluate treatment benefits of risperidone long-acting injectable (RLAI) in patients with schizophrenia following direct transition from oral risperidone (RIS) compared with transition from other oral second generation antipsychotics. Methods Stable in- or outpatients (n=206) receiving RIS or OQAZ (olanzapine, quetiapine, amisulpride, ziprasidone) were transitioned to RLAI for 12 weeks. The primary outcome was the between-group treatment difference in change in PANSS total score from baseline to endpoint. Secondary outcomes included health-related quality-of-life and therapeutic alliance. Results Mean between-group difference in the change in PANSS total score from baseline to endpoint was -6.1 (CI: -17.6, 5.4), suggesting greater improvement in OQAZ than RIS patients. Due to the pre-specified non-inferiority margin of 5.1, it could not be concluded that OQAZ pre-treatment results in an at least non-inferior PANSS reduction versus RIS pre-treatment. Patient satisfaction with medication and change in quality-of-life subscores showed advantages for OQAZ patients. Discussion Compared to RIS pre-treatment, clinically stable patients with schizophrenia who are pre-treated with OQAZ might draw a stronger clinical benefit from direct transition to RLAI.

Zusammenfassung: Der vorliegende Artikel diskutiert den potenziellen Nutzen und die Risiken einer neuroleptischen Behandlung von neuropsychiatrischen Symptomen bei Patienten mit Demenz. Verhaltensauffälligkeiten und psychosenahe Phänomene sind während des gesamten Krankheitsverlaufs hoch prävalent und belasten sowohl die Patienten als auch deren Angehörige. Die individuelle Berücksichtigung von Komorbiditäten und einer in der Regel vorhandenen Komedikation sind ebenso wie eine Symptomanalyse bereits vor Beginn einer neuroleptischen Therapie unentbehrlich. Neuroleptika gehören zu den bestuntersuchten Psychopharmaka überhaupt, verfügen über unterschiedliche pharmakologische Profile und werden sehr oft bei älteren Menschen verordnet. Neuere Studienergebnisse machen deutlich, dass Neuroleptika zwar wirksam sind, deren Anwendung jedoch aufgrund ihrer Nebenwirkungsprofile auf Patienten mit schweren klinischen Symptomen beschränkt bleiben sollte.

The microtubule-associated protein tau gene (MAPT) contains two extended haplotypes, H1 and H2, which have been linked with sporadic tauopathies. However, there is little evidence as to how these haplotypes may influence the clinical features of the disease. The aim of this study was to investigate the MAPT haplotypes in relation to risk for, and functional alterations of glucose metabolism in, patients with frontotemporal dementia (FTD).The authors investigated MAPT haplotypes in 142 individuals with FTD and 292 comparison subjects. Additionally, in a subset of 41 individuals with FTD and 16 comparison subjects, the authors undertook functional [ (18)F]fluorodeoxyglucose positron emission tomography (PET) imaging.MAPT haplotype distribution did not differ significantly between individuals with FTD and comparison subjects. However, the H2 haplotype was clinically associated with an earlier age at onset of FTD, which presented in a dose-dependent manner. Correspondingly, PET analysis revealed functional differences in glucose utilization patterns between MAPT haplotypes, with H2 carriers having a more pronounced hypometabolism in frontal brain areas than H1 carriers, which could not be accounted for by differences in duration of illness.While the extended MAPT H1 and H2 haplotypes do not appear to confer risk for disease development, the H2 haplotype appears to modify age at onset and functionally shows a more severe decline of glucose utilization in frontal brain areas.

Alzheimer's disease and associated disorders are characterized by a high prevalence of severe psychological symptoms. Behavioural disturbances complicate the disease course and significantly impact patients' and caregivers' condition. Second generation antipsychotics (SGA) have been shown in several well-designed trials to be moderately effective in treating severe behavioural pathology and psychotic symptoms. These results are contrasted by increased risk for cerebrovascular events and mortality. Hazards may be alleviated by individual choice of SGA, that consider existing co-morbidities and common polypharmacy in the elderly. Making the decision for a treatment with SGA in dementia should rather be individualized by agreement with the relatives and the patient himself, if possible instead of exlusively relying on clinical trial evidence. Early application of acetylcholinesterase inhibitors may exert positive long-term influence on psychopathology and thus contribute to alleviate the problematic issue of behavioural disturbances.

We prospectively evaluated the diagnostic accuracy of cerebrospinal fluid (CSF)-beta-amyloid1-42 (Abeta42), -total-tau (tau) and -phosphorylated-tau181 (p-tau181) as measured by sandwich ELISAs in the clinical routine of a community state hospital to discriminate between patients with Alzheimer's disease (AD), healthy controls (HC), non-AD-dementias, a group composed of various psychiatric disorders (non-AD-dementias, mental diseases) and an age-matched random sample (RS) (total N=219). By comparing patients with AD to HC as reference, tau revealed sensitivity (sens)/specificity (spec) of 88%/80%, p-tau(181) 88%/80%, tau/Abeta42-ratio 81%/85% and phospho-tau(181)/Abeta42-ratio 81%/78%. Discriminative power between HC and all dementias under investigation was estimated lower for tau (78%/77%) and p-tau(181) (73%/79%). Relative to patients with AD, ROC analysis for the RS revealed highest sens/spec for p-tau181 (79%/77%) and p-tau181/Abeta42 ratio (78%/75%). Differentiation between AD versus a group made of patients with various psychiatric disorders was optimised by using CSF-p-tau181 (80%/77%). Under clinical routine conditions current CSF-biomarkers show a substantial capacity to discriminate between AD and HC as reference and to mark off AD patients from RS and heterogeneous diagnostic groups composed of non-AD dementias and other psychiatric conditions. Despite a residual substantial overlap between the groups, we conclude that current CSF markers are well suited to support AD-related diagnostic procedures in every-day clinics.

Dementia with frontotemporal lobar degeneration (FTLD) is clinically characterized by the occurrence of various psychiatric symptoms. In a recent study, the hospital-based prevalence of FTLD and the circumstances of the patients’ admission to German psychiatric state hospitals were estimated. On the basis of further continuous assessment, this original FTLD group (n = 33) has been enlarged to 58 patients. The authors here present demographic and clinical data, and reasons for admission to geriatric psychiatry hospitals in comparison with 17 patients, who primarily attended the Memory Disorders Clinic of the University of Regensburg. The results implicate that both institutions see patients with different clinical syndromes: (1) patients were primarily referred to the Memory Disorders Clinic presenting memory and/or speech difficulties as the leading symptoms; (2) major reasons for hospitalisation of patients with FTLD in geriatric psychiatry hospitals were behavioural disturbances; (3) late-onset FTLD (>65 years) was more common than previously assumed in both institutions, and (4) increasing age at admission increased the likelihood to obtain a limited diagnostic approach of brain imaging (only cranial computer tomography) to evaluate the cause of dementia.

Test results (raw scores) are composed of an unknown true score and an error term. The error term can be estimated by means of test reliability which is defined by the ratio of true variance and obtained variance. Different estimates of reliability either based on single measurements (e. g. Cronbach's coefficient, split half reliability, Kuder Richardson method) or two measurements (test/retest, inter- or intrarater reliability) are available. Parallel test reliability depends on the correlation of two different tests obtained in one session. Canonical correlation methods allow an extension of the parallel test situation and split half technique. Two or more tests are performed in a sample of subjects. Randomized subsets are correlated using canonical correlation technique. The objective of this study is to estimate the homogeneity of test batteries. 94 patients (64 f, 30 m; age: 54 - 89 ys.) supposed to have dementia were tested using the clocktest (CT, scores: 1 - 5), MMSE (mini mental state examination) and SKT (Syndrom Kurztest). Four (i, j: 1 - 4) subsets of 20 patients each were determined by random and the following characteristics were calculated: Empiric correlation coefficient for n = 94 (R), canonical correlation coefficient (Rcan), eigenvalues (EV) and redundancy (Rnd) of corresponding variable sets. The results of canonical analysis showed canonical correlation coefficients in order of 0.8 to 0.9 (p-values < 0,001). This high internal consistency can be interpreted as a measure of reliability of the test batteries. In conclusion, canonical correlation based on parallel tests splitted in subsets gives information on consistency, i. e. reliability, of test batteries in addition to conventional correlation methods.

The concept of frontotemporal lobar degeneration comprises a heterogenous group of cortical dementias, including frontotemporal dementia, as the major clinical variant. Because of their highly variable clinical presentation, to establish the diagnosis of frontotemporal dementia could be a diagnostic challenge for the clinician. Here we report a 53 years old caucasian male patient who was admitted for hospitalization due to acute severe schizophrenia-like symptoms. The leading symptomatology comprised acoustic and bizarre optical hallucinations with euphoria and self-overestimation. Remission of the psychotic symptoms demasked the clinical picture of a rapidly progressive frontotemporal dementia with marked apathy, indifference, emotional blunting, loss of insight, change of personality and typical cognitive impairment. The diagnosis was supported by the results of cerebral MRI and FDG-18 PET. This first clinical manifestation of a schizophrenia-like syndrome in the 6 (th) life decade implicates frontotemporal dementia as an important differential diagnosis of schizophrenic disorders in late life. In addition of basically thinking about frontotemporal dementia, a detailed medical history, cognitive testing, neuroimaging and eventually the evaluation of the further disease course are necessary to establish a diagnosis of frontotemporal dementia.

Wir berichten uber den ersten Fall von polyzystischer lipomembranoser Osteodysplasie oder “brain, bone and fat disease” in Deutschland. Die nach dem Erstbeschreibern auch als Morbus Jarvi-Hakola-Nasu bezeichnete Erkrankung ist bisher vor allem in Japan und in Finnland beschrieben worden. Einzelne Falle wurden aus Schweden, Norwegen, Italien, Sudafrika, Belgien und den USA berichtet. Im deutschsprachigen Raum ist bisher ein Fall aus O veroffentlicht worden.

Niemann-Pick disease type C (NPC) is an inherited neuro-degenerative disorder associated with intracellular cholesterol trafficking defects. Mutations in two distinct genes, NPC1 and HE1, have recently been shown to cause this disease. We have analysed the NPC1 gene in five German patients with NPC from four unrelated families. We identified a total of five novel mutations in the coding region of the NPC1 gene (G231V, D874V, 1642M, 11094T and R116stop). All affected individuals displayed compound heterozygosity. The mutated alleles were transmitted by the nonaffected parents with the exception of one patient, in whom a de novo mutation (G231V) had occurred. Interestingly, the G231V/P237S NPC1 genotype in this individual is associated with an early-onset form of NPC. In contrast, we found that the D874V/D948N genotype, observed in another NPC patient, is characterized by a late onset of clinical symptoms that presents with a pronounced white-matter disease. Our results will contribute to defining the association between the clinical phenotypes and the genetic abnormalities in Niemann-Pick C disease.

Alois Alzheimer evaluated five cases of Alzheimer's disease in the early 20th century. We focused on the family of "Johann F.," Alzheimer's second patient, who died in October 1910 at age 57 years, and whose brain pathology is typical of a subgroup of Alzheimer's disease, the so-called "plaque-only type." It was perhaps Emil Kraepelin's personal knowledge of this patient and the histological data of the other four cases that influenced Kraepelin to coin the term Alzheimer's disease. The church archive in Passau has a genealogical database drawn from sacramental registers dating from approximately 1580 to 1900. The genealogical data of the "Johann F." family, which comes from villages in Lower Bavaria, extends as far back as 1670. We found documentation starting around 1830 about cause of death in the church records, which shows a familial predisposition to dementia. Affected family members include the mother, maternal grandfather, maternal great-aunt, maternal great-grandfather as well as three of Johann F.'s eight siblings. The offspring (children and grandchildren) of these affected siblings also were affected by mental illness. We conclude that "Johann F." represents the index case of a family with a predisposition to presenile dementia with variable age of onset (30s to 60s).

Mutations in the gene for valosin containing protein (VCP) cause autosomal dominant inclusion body myopathy associated with Paget disease and frontotemporal dementia (IBMPFD). To investigate the role of this novel gene in sporadic forms of frontotemporal dementia (FTD), we genotyped 27 single nucleotide polymorphisms covering the entire VCP genomic region in 198 patients with sporadic FTD and 184 matched controls from Germany. No significant association could be demonstrated. There is no evidence, that common variants in VCP confer a strong risk to the development of sporadic FTD.

Studies on cytochrome P450 2B (CYP2B) in the brain have essentially been focused on protein characterization and regional distribution. Due to the high sequence homology between the closely related CYP2B1 and 2B2 isoforms and the low amounts of the corresponding mRNAs few efforts have been made to analyze the expression, regulation, and inducibility of these P450 genes in a specific cell type. In the present study, we investigated CYP2B mRNA expression in primary rat astrocyte cultures under the influence of the anti-epileptic drug phenytoin, which is known to be a CYP2B inducing agent in liver. In situ hybridization with a digoxigenin (DIG)-labeled cRNA probe demonstrated that 30–40% of the astrocytes strongly expressed a CYP2B mRNA-specific signal within the first week of cultivation. With increasing age (>14 days) a greater percentage of cells (>90%) expressed mRNA for P450 2B. However, the level of transcriptional activity was substantially lower than in younger cultures. To discriminate between the 2B1 and 2B2 isoforms the reverse transcription/ polymerase chain reaction (RT/ PCR) procedures were proved for rat hepatic mRNA as a control assay. Subsequently, the application of this method on cultured astrocytes confirmed that these brain cells may express CYP2B1 mRNA. CYP2B2 mRNA could not be detected in astrocyte cultures at any age examined. Phenytoin led to the down regulation of CYP2B1 mRNA, which contrasts with the drug inducing effect on hepatic CYP2B1 and 2B2 levels. After 4 hr of exposure of phenytoin to the astrocytes no amplification product could be detected at all. Phenytoin did not induce either CYP2B1 or 2B2 expression. J. Neurosci. Res. 54:402–411, 1998. © 1998 Wiley-Liss, Inc.

Summary Background Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes— MAPT , GRN , and C9orf72 —have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder. Methods We did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with FTD and 9402 healthy controls. To reduce genetic heterogeneity, all participants were of European ancestry. In the discovery phase (samples from 2154 patients with FTD and 4308 controls), we did separate association analyses for each FTD subtype (behavioural variant FTD, semantic dementia, progressive non-fluent aphasia, and FTD overlapping with motor neuron disease [FTD-MND]), followed by a meta-analysis of the entire dataset. We carried forward replication of the novel suggestive loci in an independent sample series (samples from 1372 patients and 5094 controls) and then did joint phase and brain expression and methylation quantitative trait loci analyses for the associated (p −8 ) single-nucleotide polymorphisms. Findings We identified novel associations exceeding the genome-wide significance threshold (p −8 ). Combined (joint) analyses of discovery and replication phases showed genome-wide significant association at 6p21.3, HLA locus (immune system), for rs9268877 (p=1·05 × 10 −8 ; odds ratio=1·204 [95% CI 1·11–1·30]), rs9268856 (p=5·51 × 10 −9 ; 0·809 [0·76–0·86]) and rs1980493 (p value=1·57 × 10 −8 , 0·775 [0·69–0·86]) in the entire cohort. We also identified a potential novel locus at 11q14, encompassing RAB38 / CTSC (the transcripts of which are related to lysosomal biology), for the behavioural FTD subtype for which joint analyses showed suggestive association for rs302668 (p=2·44 × 10 −7 ; 0·814 [0·71–0·92]). Analysis of expression and methylation quantitative trait loci data suggested that these loci might affect expression and methylation in cis . Interpretation Our findings suggest that immune system processes (link to 6p21.3) and possibly lysosomal and autophagy pathways (link to 11q14) are potentially involved in FTD. Our findings need to be replicated to better define the association of the newly identified loci with disease and to shed light on the pathomechanisms contributing to FTD. Funding The National Institute of Neurological Disorders and Stroke and National Institute on Aging, the Wellcome/MRC Centre on Parkinson's disease, Alzheimer's Research UK, and Texas Tech University Health Sciences Center.

OBJECTIVE [corrected] To evaluate tau-associated genetic polymorphisms in patients with sporadic frontotemporal dementia (FTD) and healthy control subjects. METHOD Tau-gene sequence of 30 patients with FTD and 30 healthy controls was analysed by polymerase-chain-reaction (PCR). Subsequent sequencing was performed to identify exonic and intronic differences between both groups. RESULTS The following polypmorphisms, which are localized closely to each exon-intron-border, have been identified: In 37 % (n = 11) of the control subjects three different intronic polymorphisms occur simultaneously (Intron 2, 263, C --> Y; Intron 3, 590, A --> R; Intron 11, 150, G --> A). In the FTD group, this coexistance has been observed only in 17 % (n = 5). CONCLUSIONS In how far there exists a significant correlation between the newly identified triple polymorphism in the Tau gene and an alternated risk for FTD must be evaluated in a lager population. The proximity of these polymorphisms to the exon-intron border would facilitate functional influences on gene expression patterns. These preliminary results described, above potentially point to further pathogenetic factors in the genesis of FTD.

The diurnal variation of pain threshold was studied in 13 healthy volunteers (age: 21 - 27 ys) using the tourniquet pain model. A tourniquet was inflated above systolic blood pressure for 1 minute and pain scores and heart rate were recorded at 0.5, 1.0, 1.5 and 2.0 minutes. The test was repeated during a study day at 6.00 h, 12.00 h, 18.00 h and 24.00 h. Significant differences of pain scores between clocktimes were found 1 minutes after inflation and after 1.5 minutes with regard to heart rate. Generally, the highest pain scores were found at 24.00 h.

OBJECTIVE To describe differences in cerebral glucose metabolism between frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD). METHODS 14 patients with FTLD (7 f/7 m, mean age 60.1 years) and 14 patients with AD (7 f/7 m, mean age 59.5 years) were examined. [18F]FDG positron emission tomography (PET) scans were analysed with statistical nonparametric mapping (SnPM) and statistical parametric mapping (SPM99). RESULTS Significant decreases in glucose metabolism in FTLD compared to AD were detected in the left insula/left inferior frontal gyrus (Brodman area [BA]13, 45 and 47) and in the medial frontal gyrus bilaterally (BA10). A significant decrease in AD compared to FTLD was identified in the right middle temporal gyrus (BA39). CONCLUSION Cerebral PET could be a promising tool to discriminate FTLD from AD.

Schizophrenic disorders as well as neuroleptic treatment can affect locomotion. The study assessed the influence of neuroleptic treatment on externally triggered gait on a treadmill at three different velocities via ultrasonic topometric gait analysis. Spatial and temporal gait parameters were assessed in two groups of schizophrenic patients either under treatment with conventional neuroleptics (n = 12) or without neuroleptic treatment (n = 10) and re-assessed after treatment change to the atypical neuroleptic olanzapine in a repeated measures design. After switch from conventional neuroleptics to olanzapine patients showed an increase of step length and decrease of cadence at the low (p

Caregiver counselling is an indispensable feature of current concepts for dementia treatment. Self-support groups and psychoeducative programms for caregivers of patients with Alzheimer's disease may reduce the burden of nursing and psychological strain. Specific caregiver needs from patients with frontotemporal lobar dementia (FTLD [frontotemporal dementia, semantic dementia, progressive aphasia, corticobasal degeneration]) are only partially taken into account. We conducted a German wide epidemiologic study which revealed that specific counselling for supporting relatives and caregivers of patients with FTLD is only fragmentary in hospital services for old age psychiatry. In most cases, they are referred to the local Alzheimer's disease Associations (89 %). Besides that, the existence of large hospital care units has significant negative repercussions on psychosocial supply for caregivers of patients with FTLD. To establish decentralized support units by these hospitals would lead to a significant improvement of medical and social care in this field.

The antiepileptic drug phenytoin is known to be substrate as well as inducer of cytochrome P450 (P450) in the mammalian liver. We were able to show the expression of P450 species immunorelated to the main phenytoin-induced hepatic isoforms in mice (CYP2C29) and rats (CYP2B1,2) also in the central and peripheral nervous system and primary cultures of cell types from the brain. The 2B1,2 related protein showed only a weak constitutive expression in vivo and in vitro analyzed by immunocytochemistry, in situ hybridization, Northern blot and RT/polymerase chain reaction (PCR). Contrary, the CYP2C29 related form is inducible by phenytoin at about 1.5-fold starting from an already higher constitutive level. This protein is characterized by a remarkable tendency to dissociate from the endomembranes during tissue homogenization. The supernatant of microsomal pellet is able to metabolize phenytoin in a reconstitutive system.

The total number per month of prescribed antibiotics or psychiatric drugs during one year (1998) was assessed by means of sine wave models [Y(t) = M + A x sin(2 x pi x t/tau + Phi)]. M (no. of prescriptions per month) denotes mean frequency over one period, A (no. per month) denotes amplitude, tau (month) corresponds to the period and Phi (month) to the phase of the fitted curve. Data were evaluated descriptively and chronograms including 95 %-confidence limits were given. Significant nonlinear regression models could be calculated for amoxicillin, paroxetine, citalopram, amitriptyline and buspirone prescription behaviour. Both circannual and ultra-annual (period shorter than one year) rhythms of prescription were found. Peak values for antibiotic drug prescription during fall and winter is probably associated with higher incidence of infectious diseases. Antidepressant drug prescription has maxima in spring and fall, which is in keeping with the epidemiology of depressive disorders. The seasonality of buspirone prescription may reflect a basic periodicity of anxiety disorders. In conclusion, the chronopharmaco-epidemiological data of antibiotic and antidepressant drug prescription with circannual and ultra-annual rhythms may reflect the periodicity of infectious and psychiatric diseases.

A hyperphosphorylated, ubiquitinated form of TDP-43, known as pathologic TDP-43, was shown to be a central component of ubiquitin-positive, tau-negative and alpha-synuclein-negative inclusions in frontotemporal lobar degeneration (FTLD-U) and amytrophic lateral sclerosis (ALS). To investigate the role of the TDP-43 gene in sporadic forms of frontotemporal dementia (FTD), we genotyped 10 single nucleotide polymorphisms covering the entire TDP-43 genomic region, including the MASP2 gene in 173 patients with sporadic FTD (including 7 patients that were diagnosed with FTD and ALS) and 184 matched controls from Germany. Although we could observe a weak trend towards a potential disease association in a few FTD/ALS patients, no significant association with sporadic FTD could be demonstrated. There is no evidence, that common variants in TDP-43 confer a strong risk to the development of sporadic FTD.

The H1 haplotype of the tau gene, MAPT, has been linked to the sporadic tauopathies corticobasal degeneration and progressive supranuclear palsy; however, there have been inconsistent findings regarding association with frontotemporal dementia (FTD). We investigated MAPT haplotype diversity, in 171 sporadic FTD and 186 healthy controls individuals, and report no single marker or haplotype association with increased risk or changes in age at onset. These findings do not support an association of MAPT with FTD but do not rule out its association with other tauopathies.