Lithium Therapy in Old Age: Recommendations from a Delphi Survey.

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.

[Recommendations for the Prevention, Diagnostics and Therapy of Addiction Disorders in the Elderly]. / Empfehlungen für die Prävention, Diagnostik und Therapie der Abhängigkeitserkrankungen im Alter.

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.

Implicit and Explicit Attention to Pictures and Words: An fMRI-Study of Concurrent Emotional Stimulus Processing.

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.

A visual [18F]FDG-PET rating scale for the differential diagnosis of frontotemporal lobar degeneration.

This study presents a visual rating scale for the assessment of cerebral [(18)F]fluoro-2-deoxy-D: -glucose positron emission tomography (FDG-PET) scans to characterize typical findings in dementias associated with frontotemporal lobar degeneration (FTLD) and to differentiate individual patients with FTLD compared to Alzheimer's disease (AD) and mild cognitive impairment (MCI). A total of 43 cerebral PET scans from patients with FTLD (n = 16, mean age 58.4 years), AD (n = 16, 59.9 years) and MCI (n = 11, 57.9 years) were analysed. Every PET data set was visually rated for seven brain regions on each hemisphere (frontal lobe, temporal lobe, parietal lobe, occipital lobe, basal ganglia, thalamus and cerebellum). The extent of the impairment in metabolism was classified as absent, mild, medium or strong. Using this four-stage visual rating scale, characteristic profiles of metabolic impairment in FTLD, AD, MCI and the FTLD-subgroup FTD (n = 9) could be demonstrated. Patients with FTLD showed a significantly lower metabolism in the left frontal lobe and in the left basal ganglia when compared to AD and to MCI. Complementary analyses using statistical parametric mapping (SPM2) supported the findings of the visual analysis. In detecting FTLD with visual rating, sensitivity/specificity was 81/94% compared to AD and 81/64% compared to MCI. Patients with FTD were correctly attributed to a diagnosis of FTLD with a sensitivity of 89%. This visual rating scale may facilitate the differential diagnosis of FTLD in clinical routine.

Memory performance correlates with gray matter density in the ento-/perirhinal cortex and posterior hippocampus in patients with mild cognitive impairment and healthy controls--a voxel based morphometry study.

Voxel based morphometry (VBM) is a useful tool to assess differences in brain morphology between groups of patients and healthy controls. In addition, VBM enables the performance of regression analyses to determine potential correlations between performance on cognitive tests and variations in local brain morphology. Prior VBM studies investigating patients with mild cognitive impairment (MCI) have revealed different patterns of local brain atrophy. In order to extend previous findings, we investigated 18 patients with MCI and 18 age- and gender-matched healthy controls. All participants underwent extensive neuropsychological testing in addition to undergoing anatomical scanning with magnetic resonance imaging (MRI). Cohort analysis revealed bilateral decreases in gray matter density in the medial temporal lobes (MTLs) and neocortical regions of the temporal lobes in patients with MCI. Moreover, regression analyses demonstrated a correlation between immediate verbal recall and gray matter density in the left perirhinal/entorhinal cortex, while delayed free recall correlated with gray matter density in the left hippocampus. It has been proposed that performance in the immediate recall is supported by the so-called "episodic buffer", a component of working memory that contributes to the maintenance of integrated memory traces. Accordingly, our results suggest that anatomical regions associated with verbal long-term and verbal working memory are structurally segregated within the left MTL.

No association of TDP-43 with sporadic frontotemporal dementia.

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.

No association of common VCP variants with sporadic frontotemporal dementia.

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.

Neural correlates of emotional working memory in patients with mild cognitive impairment.

Emotional stimuli can have beneficial effects on memory in healthy aged subjects and partly on patients with dementia. So far, no experimental study has explored the effects of memory for emotional stimuli in patients with mild cognitive impairment (MCI), a concept that describes a transitional state between normal aging and dementia. The present fMRI study explored working memory for emotional stimuli in 16 patients with amnestic MCI (aMCI) and 16 healthy aged participants. Subjects performed an n-back task (2-back) with neutral, positive, and negative emotional pictures. The analysis focused on target processing. Results showed that groups did not differ in working memory performance. In healthy aged participants emotional targets had no significant impact on working memory. In patients with aMCI a negativity bias was observed, indicating that negative targets were better remembered compared to neutral and positive targets. Regarding fMRI results, both groups showed an increase in functional activity in prefrontal and lateral parietal brain regions associated with target processing. As a key result, we observed significant group by emotion interaction effects in the precuneus. Healthy aged participants showed a signal decrease in the left precuneus for positive compared to neutral targets. The precuneus deactivation in healthy aged participants may indicate a disengagement of self-referential processes towards task-related processes. Patients with aMCI revealed a signal increase in the right precuneus for negative compared to neutral targets. This increase in precuneus activity, combined with a behavioural facilitation effect, may indicate a mechanism to compensate disease related processes in aMCI.

Association of the tau haplotype H2 with age at onset and functional alterations of glucose utilization in frontotemporal dementia.

OBJECTIVE: 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). METHOD: 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. RESULTS: 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. CONCLUSIONS: 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.

Domain-specific improvement of cognition on memantine in patients with Alzheimer's disease treated with rivastigmine.

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.

No association of chromatin-modifying protein 2B with sporadic frontotemporal dementia.

Mutations of the chromatin modifying protein 2B gene (CHMP2B) were identified, in a Danish pedigree, to cause familial frontotemporal dementia (FTD). To explore the possible genetic contribution of common CHMP2B variants in sporadic FTD, we analyzed 14 single nucleotide polymorphisms covering the entire genomic region of CHMP2B. After adjustment for multiple testing single marker and haplotype analysis revealed no significant association with sporadic FTD. Thus, we conclude that CHMP2B can be excluded as a susceptibility gene conferring risk to sporadic forms of FTD.

Cerebrospinal fluid tau and beta-amyloid in Alzheimer patients, disease controls and an age-matched random sample.

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.

Adding memantine to rivastigmine therapy in patients with mild-to-moderate alzheimer's disease: results of a 12-week, open-label pilot study.

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.

Performance of diadochokinetic movements in schizophrenic patients.

Motor deficits are common and disabling symptoms in schizophrenic patients, which have enormous impact on the long-term outcome of the disease by affecting work performance and daily functioning. They are attributed to the disorder itself, as well as to treatment with dopamine-blocking antipsychotics. This study assessed the kinematic parameters of motor performance of a diadochokinetic hand movement in 20 drug-naïve, 20 conventionally treated (haloperidol or fluphenazine), and 20 atypically treated (olanzapine) patients, as well as in 20 healthy controls using a three-dimensional ultrasonic movement analysis system. It also tested differences in motor enhancement as induced by an attentional strategy and in dexterity advantages of motor performance for the dominant hand between the four study groups. Amplitude and peak velocity of diadochokinetic hand movements were significantly reduced in all patient groups compared to the controls, while frequency of the repetitive movement remained unaffected. The reduction was most pronounced in the conventionally treated patients. In addition, movement automation was impaired, primarily under conventional antipsychotic treatment. The study also revealed weaker effects of an attentional enhancing strategy on the movement amplitude in atypically and conventionally treated patients compared to both controls and drug-naïve patients. Alterations of dexterity could not be detected either in the drug-naïve or in the treated patients. The results indicate that patients with schizophrenia suffer from a specific primary motor deficit in diadochokinesia with reduction of amplitude and peak velocity. This deficit is significantly worsened by conventional antipsychotic treatment. Antipsychotic treatment additionally reduces the enhancing effect of an attentional strategy on motor performance.

Effect of donepezil in patients with Alzheimer's disease previously untreated or treated with memantine or nootropic agents in Germany: an observational study.

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.

[Genetic tau-variants in patients with frontotemporal dementia]. / Tau-assoziierte genetische Polymorphismen bei frontotemporaler Demenz.

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.

[Differences in cerebral glucose metabolism between frontotemporal lobar degeneration and Alzheimer's disease]. / Unterschiede im zerebralen Glukosestoffwechsel zwischen frontotemporaler lobärer Degeneration und der Alzheimer-Krankheit.

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.