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BackgroundThe 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.MethodsFUSION 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.ResultsWe 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.ConclusionsWe 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.

BackgroundFrontotemporal 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.MethodsWe 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

Introduction While lithium (Li) has been well established for the treatment of bipolar disorder, geriatric patients require special attention when it comes to issues of drug safety. Declining renal function, amongst other medical conditions, and polypharmacy may pose increased risks. Only a few previous studies have addressed the management of Li in geriatric patients. Methods Twenty-four German medical experts on geriatric medicine and Li treatment participated in a Delphi survey, consisting of two rounds of questionnaires and a final formulation of treatment recommendations. Three major issues of Li therapy were outlined: initiation of treatment, monitoring of ongoing therapy, and withdrawal due to medical reasons. Final recommendations were consented to at a threshold of at least 80% expert agreement. Results Final consensus was achieved on 21 clinical recommendations. The approved recommendations covered aspects of necessary laboratory checks, concomitant medication, and target Li serum concentration in geriatric patients. Concerning the termination of Li therapy, an agreement was reached on the appropriate time span for tapering and on potential alternatives to Li. No consensus was achieved on whether concomitant dementia or frailty should be considered contraindications for Li treatment and the appropriate threshold of the estimated glomerular function rate for withdrawing Li. Conclusion According to the view of German experts, Li may be used in geriatric patients, but it should be monitored carefully. However, the lack of consent in several specific treatment situations underlines the need for research on specific issues of Li therapy. [ABSTRACT FROM AUTHOR]

Copyright of Praxis (16618157) is the property of Aerzteverlag medinfo AG and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Praxis (16618157) is the property of Aerzteverlag medinfo AG and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Lithium augmentation compared with phenelzine in treatment-resistant depression in the elderly: an open, randomized controlled trial. Correct is: "In a randomized controlled trial, Li was the more effective treatment option for therapy-resistant major depression compared to the monoamine oxidase inhibitor phenelzine. [Extracted from the article]

The present study utilized functional magnetic resonance imaging (fMRI) to examine the neural processing of concurrently presented emotional stimuli under varying explicit and implicit attention demands. Specifically, in separate trials, participants indicated the category of either pictures or words. The words were placed over the center of the pictures and the picture-word compound-stimuli were presented for 1500 ms in a rapid event-related design. The results reveal pronounced main effects of task and emotion: the picture categorization task prompted strong activations in visual, parietal, temporal, frontal, and subcortical regions; the word categorization task evoked increased activation only in left extrastriate cortex. Furthermore, beyond replicating key findings regarding emotional picture and word processing, the results point to a dissociation of semantic-affective and sensory-perceptual processes for words: while emotional words engaged semantic-affective networks of the left hemisphere regardless of task, the increased activity in left extrastriate cortex associated with explicitly attending to words was diminished when the word was overlaid over an erotic image. Finally, we observed a significant interaction between Picture Category and Task within dorsal visual-associative regions, inferior parietal, and dorsolateral, and medial prefrontal cortices: during the word categorization task, activation was increased in these regions when the words were overlaid over erotic as compared to romantic pictures. During the picture categorization task, activity in these areas was relatively decreased when categorizing erotic as compared to romantic pictures. Thus, the emotional intensity of the pictures strongly affected brain regions devoted to the control of task-related word or picture processing. These findings are discussed with respect to the interplay of obligatory stimulus processing with task-related attentional control mechanisms. [ABSTRACT FROM AUTHOR]

Objective: Cholinergic therapy is used in mild-to-moderate Alzheimer’s disease (AD) and antiglutamatergic therapy in moderate-to-severe AD. Global scales, as commonly used in clinical trials, blur specifics of disease progression and drug effects. The objective was to assess combination therapy of rivastigmine plus memantine by specific neuropsychological tests in patients with mild-to-moderate AD. Methods: 12-week-short multicenter open-label pilot study. Ninety patients with mild-to-moderate AD already on stable medication with rivastigmine (3–6 mg b.i.d.) additionally received memantine for 12 weeks. Subscales of the Alzheimer’s Disease Assessment Scale (ADAS-cog), the Mini-Mental State Examination (MMSE) and additional neuropsychological tests (e.g. span tasks, semantic fluency) were assessed. Results: The scores in the ADAS-cog memory subscale, the MMSE score, and digit span and semantic fluency significantly improved on combination therapy. Conclusion: Memory improvement was correlated with ADAS-cog memory score at baseline and inversely with age at onset of treatment. The data suggest that improvement on combination therapy results from an improvement of attention/executive function with secondary memory improvement, which will need to be confirmed in a subsequent double-blind study on a larger number of patients. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

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

Objective: At present, inhibition of cholines-terase is the treatment of choice for subjects with mild-to-moderate Alzheimer's disease (AD). Memantine, a noncompetitive antagonist at N-methyl-d-aspartate receptors, is currently used to treat subjects with moderate-to-severe AD. The goal of this multicenter, open-label pilot study was to investigate whether combination therapy with memantine added to rivastigmine is safe and beneficial in subjects with mild-to-moderate AD., Method: Patients with a DSM-IV diagnosis of dementia of the Alzheimer's type (N = 95), who were treated with rivastigmine (6-12 mg/day) for a maximum duration of 24 weeks prior to baseline, received memantine (5-20 mg/day) in combination with rivastigmine for 12 weeks. The primary efficacy variable was the change in the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) total score at the end of 12 weeks compared with baseline. The study was conducted between September 15, 2003, and May 27, 2004., Results: There was a statistically significant difference between baseline and week 12 for the ADAS-cog total score, showing a positive effect of combination therapy. Combination therapy did not evidence any unexpected safety concerns and was well-tolerated by most patients., Conclusion: Memantine in combination with rivastigmine appears to be safe and beneficial in patients with mild-to-moderate AD. Our results need to be confirmed in a large, long-term, randomized, double-blind, placebo-controlled clinical trial.

Objective: This open-label, prospective, observational, Post-Marketing Surveillance (PMS) study assessed the efficacy and safety of donepezil in patients who had been switched from therapies currently used in Germany to treat Alzheimer's disease (AD), such as memantine and nootropics, due to insufficient efficacy or poor tolerability. A treatment-naive population was included as a comparator., Research Design and Methods: Patients with AD were treated with donepezil and observed for a period of approximately 3 months. A cognitive assessment was made using the Mini-Mental State Examination (MMSE). Quality of life (QoL) was assessed by the investigators who answered the question 'How did therapy with donepezil influence the QoL of the patient and/or his family over the observation period?' and was graded using three ratings: improved/unchanged/worsened. Adverse events (AEs) were also monitored., Results: A total of 913 patients entered the study (mean +/- SD MMSE score 18.03 +/- 5.34). Efficacy assessments were analyzed for three groups: an overall group of patients who had received any form of prior AD drug therapy (N+ group; n = 709); a subgroup of patients from the N+ group who had received prior memantine therapy only (M+ group; n = 111) and patients who were drug treatment naive (N- group; n = 204). In the evaluable population donepezil improved MMSE scores by 2.21 +/- 3.47 points on average, with similar improvements observed in all three groups. QoL was judged to be improved in at least 70% of patients, again with similar results obtained for all three groups. Donepezil was well tolerated, with 85 of 913 (9.3%) patients reporting AEs. The most common AEs were those typically seen with cholinergic therapies (i.e., diarrhoea, vomiting and nausea)., Conclusions: In this observational PMS study, donepezil was shown to be efficacious and well tolerated in patients who were being insufficiently treated with memantine or nootropic therapy. The magnitude of response was similar to that observed in patients who were previously treatment naive, suggesting prior medication does not effect donepezil's efficacy.

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

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.

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.

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.

Alzheimer's Disease (AD) is the most common cause for dementia in our ageing population, which leads to a slowly progressive, irretrievable ruination of mental function. The destructive, primarily degenerative condition is neuropathologically characterized by the formation of amyloid plaques, neurofibrillary tangles and loss of neurons and synapses as well. Research during the past twenty years revealed early in the disease course a degeneration of cholinergic nuclei localised in the basal forebrain. Impairment of this cholinergic system, which projects into large areas of the limbic system and the neocortex is followed by disturbance of attentional processes and cognitive decline. The link between the cholinergic dysfunction and cognitive impairment has focused large scientific efforts to understand the neurobiology of cognition and to develop therapeutic tools for the fight against Alzheimer's Disease. Acetylcholinesterase inhibitors are currently the best established treatment for this devastating disease. This review describes historical aspects and the vast range of use of cholinesterase inhibitors in traditional societies and industrial nations. Second, the rational basis will be outlined for their development as medication, the so-called cholinergic hypotheses of AD. Third, acetylcholinesterase inhibitors currently available for the treatment of AD will be reviewed. This includes donepezil, galanthamine and rivastigmine. Tacrine, the first acetylcholinesterase inhibitor who became available in 1993 as a treatment for AD, does not play an essential role anymore besides his historical value, because of its hepatotoxicity. Although acetylcholinesterase inhibitors are no cure, these drugs can delay the progress of mental deterioration, reduce neuropsychiatric symptoms and therefore represent a rational therapeutic approach to the treatment of Alzheimer's Disease.

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.

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 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.

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.

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 6th 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.