Combined treatment with memantine and galantamine-CR compared with galantamine-CR only in antidementia drug naive patients with mild-to-moderate Alzheimer's disease

Introduction: Several studies have tested the N-methyl-D-aspartate–receptor antagonist memantine as an add-on to pre-existing treatment with acetylcholinesterase inhibitors. The objective of this study was to evaluate the efficacy and safety of a combined memantine and galantamine-CR de novo regimen compared with galantamine-CR only treatment in never treated patients with mild-to-moderate Alzheimer's disease (AD). Methods: Antidementia drug–naïve participants (n = 232) with probable, mild-to-moderate AD, and mini-mental state examination scores between 15 and 26 (inclusive) were randomized to receive either 20 mg/day memantine plus 24 mg/day galantamine-CR or 24 mg/day galantamine-CR plus placebo in a 52-week, prospective, double-blind, controlled trial. The primary outcome measurement was the change on the Alzheimer's disease assessment scale-cognition score. Secondary measures comprised the Alzheimer's Disease Cooperative Study-activities of daily living inventory and the clinical dementia rating. Results: At the end of the trial, there were no statistically significant differences between the galantamine-CR/memantine combination and galantamine-CR only group in primary and secondary outcome measurements. The incidence and the severity of adverse events were similar between the groups. Discussion: In this trial, memantine in combination with galantamine-CR did not show an advantage with respect to cognition, function, and behavior in previously never treated patients with mild-to-moderate AD. There were no significant differences in tolerability and safety between the groups. Thus, a de novo combination treatment results in no significant improvement in disease progression (current controlled trials number: NCT01921972)

WHEDA study: Effectiveness of occupational therapy at home for older people with dementia and their caregivers - the design of a pragmatic randomised controlled trial evaluating a Dutch programme in seven German centres

Contains fulltext : 80941.pdf (publisher's version ) (Open Access)BACKGROUND: A recent Dutch mono-centre randomised controlled trial has shown that occupational therapy improves daily functioning in dementia. The aim of this present study is to compare the effects of the Dutch community occupational therapy programme with a community occupational therapy consultation on daily functioning in older people with mild or moderate dementia and their primary caregivers in a German multi-centre context. METHODS/DESIGN: A multi-centre single blind randomised controlled trial design is being used in seven health care centres (neurological, psychiatric and for older people) in urban regions. Patients are 1:1 randomised to treatment or control group. Assessors are blind to group assignment and perform measurements on both groups at baseline, directly after intervention at 6 weeks and at 16, 26 and 52 weeks follow-up. A sample of 140 community dwelling older people (aged >65 years) with mild or moderate dementia and their primary caregivers is planned. The experimental intervention consists of an evidence-based community occupational therapy programme including 10 sessions occupational therapy at home. The control intervention consists of one community occupational therapy consultation based on information material of the Alzheimer Society. Providers of both interventions are occupational therapists experienced in treatment of cognitively impaired older people and trained in both programmes. 'Community' indicates that occupational therapy intervention occurs in the person's own home. The primary outcome is patients' daily functioning assessed with the performance scale of the Interview for Deterioration in Daily Living Activities in Dementia and video tapes of daily activities rated by external raters blind to group assignment using the Perceive, Recall, Plan and Perform System of Task Analysis. Secondary outcomes are patients' and caregivers' quality of life, mood and satisfaction with treatment; the caregiver's sense of competence, caregiver's diary (medication, resource utilisation, time of informal care); and the incidence of long-term institutionalisation. Process evaluation is performed by questionnaires and focus group discussion. DISCUSSION: The transfer from the Dutch mono-centre design to the pragmatic multi-site trial in a German context implicates several changes in design issues including differences in recruitment time, training of interventionists and active control group treatment.The study is registered under DRKS00000053 at the German register of clinical trials, which is connected to the International Clinical Trials Registry Platform

Macrophages in Alzheimer’s disease: the blood-borne identity

Alzheimer’s disease (AD) is a progressive and incurable neurodegenerative disorder clinically characterized by cognitive decline involving loss of memory, reasoning and linguistic ability. The amyloid cascade hypothesis holds that mismetabolism and aggregation of neurotoxic amyloid-β (Aβ) peptides, which are deposited as amyloid plaques, are the central etiological events in AD. Recent evidence from AD mouse models suggests that blood-borne mononuclear phagocytes are capable of infiltrating the brain and restricting β-amyloid plaques, thereby limiting disease progression. These observations raise at least three key questions: (1) what is the cell of origin for macrophages in the AD brain, (2) do blood-borne macrophages impact the pathophysiology of AD and (3) could these enigmatic cells be therapeutically targeted to curb cerebral amyloidosis and thereby slow disease progression? This review begins with a historical perspective of peripheral mononuclear phagocytes in AD, and moves on to critically consider the controversy surrounding their identity as distinct from brain-resident microglia and their potential impact on AD pathology

Over de rups van Papilio machaon

Volume: 2Start Page: 129End Page: 13

Eigenschappen van twee exotische Lepidoptera

Volume: 1Start Page: 131End Page: 13

Molecular mechanisms and therapeutic application of nsaids and derived compounds in alzheimer's disease

Alzheimer's disease (AD) is the most common form of neurodegenerative dementias worldwide. Amyloid-beta deposition, neurofibrillary tangle formation and Neuroinflammation are the major pathogenetic mechanisms that in concert lead to memory dysfunction and decline of cognition. To date, there is no curative treatment for AD. Epidemiological analysis support the notion that sustained intake of non-steroidal anti-inflammatory drugs (NSAIDs) reduce the risk and delay the onset of AD. In contrast, therapeutic studies testing NSAID efficacy in AD patients have not yielded positive results. This suggests that either the investigated drugs have not addressed the mechanism of action required for mediating beneficial effects or that NSAIDs are effective at stages way before clinical onset of symptoms. The NSAIDs concerned are pleiotrophic in nature and interact with more than one pathomechanism. Therefore evidence for more than one neuroprotective action of NSAIDs has been put forward and it seems likely that some of the drugs act at multiple levels through more than one molecular mechanism. Some, even may not only be beneficial, but negative actions may be overruled by protective effects. Within these mechanisms, modulation of gamma-secretase activity, the activation of the peroxisome proliferator-activated receptor-gamma, binding to prostaglandin receptors or interactions at the blood-brain barrier may account for the observed protection from AD. This article reviews the current knowledge and views on the above mechanisms and critically discusses current obstacles and the potential as future AD therapeutics

Main Group Tellurium Heterocycles Anchored by a (P2N2)-N-V Scaffold and Their Sulfur/Selenium Analogues

A comprehensive investigation of reactions of alkali-metal derivatives of the ditelluro dianion [TePV((NBu)-Bu-t)(mu-(NBu)-Bu-t)](2)(2-) (L2-, E = Te) with p-block element halides produced a series of novel heterocycles incorporating (P2N2)-N-V rings, tellurium, and group 13-16 elements. The dianion engages in Te,Te'-chelation to the metal center in Ph2Ge and R2Sn (R = Bu-t, Bu-n, Ph) derivatives; similar behavior was noted for group 14 derivatives of L2- (E = S, Se). In the case of group 13 trihalides MCl3 (M = Ga, In), neutral spirocyclic complexes (L)M[(NBu)-Bu-t(Te)P-v(mu-(NBu)-Bu-t)(2)(PN)-N-III(H)Bu-t)] (M = Ga, In) comprised of a Te,Te'-chelated ligand L2- and a N,Te-bonded ligand resulting from loss of Te and monoprotonation were obtained. In reactions with RPCl2 (R = Bu-t, Ad, (Pr2N)-Pr-i) a significant difference was observed between Se- and S-containing systems. In the former case, Se,Se'-chelated derivatives were formed in high yields, whereas the N,S-chelated isomers predominated for sulfur. All complexes were characterized by multinudear (H-1, P-31, Se-77, Sn-119, and Te-123) NMR spectroscopy; this technique was especially useful in the analysis of the mixture of (L) (Se) and (L)(SeSe) obtained from the reaction of Se2Cl2 with L2- (E = Te). Single-crystal X-ray structures were obtained for the spirocydic In complex (9), (L)GePh2 (E = Te, 10), (L)(SnBu2)-Bu-t = Te, 12a); E = Se, 12aSe, E = S, 12aS) and (L)(mu-SeSe) (E = Te, 16)

Atrophy outcomes in multicentre clinical trials on Alzheimer's disease: effect of different processing and analysis approaches on sample sizes

Structural MRI markers may serve as surrogate endpoints in clinical trials on disease modification in Alzheimer's disease (AD). Here, we used a longitudinal MRI data set of total brain and cortical grey matter volumes from 66 patients with AD recruited across seven centres of the German Dementia Competence Network. We compared effect size estimates for the detection of a 25% reduction of atrophy progression between a priori segmentation of brain tissue, implementing an anatomical model of brain tissue distribution, and a posteriori segmentation that was not informed by an anatomical model. Additionally, we compared effect size estimates between fixed effects analysis and a mixed effects model, implementing a random effects term to account for variable spacing of observation times. A priori segmentation reduced the required sample size by 50%. Introducing a random effects term for time led to an additional 50% reduction of required samples sizes compared to fixed effects analysis. In summary, using a priori segmentation with mixed effects analysis reduced the sample size to detect clinically relevant treatment effects more than fourfold. The implementation of mixed effects models will enhance the power to detect treatment effects also with other classes of biological endpoints including molecular biomarkers of disease

Left anterior temporal lobe sustains naming in Alzheimer's dementia and mild cognitive impairment

Cognitive decline in degenerative dementia is paralleled by progressive brain atrophy, with the localization of atrophy reflecting specific cognitive impairment. Confrontation naming deficits are frequently observed in dementia across etiologies. In this study we aimed to identify the brain regions underlying this deficit. In patients with clinically diagnosed dementia or mild cognitive impairment (MCI) we investigated the relationship between gray matter volume (GMV) and performance on a standardized confrontation naming test. 268 patients with one of three probable etiologies were included: Alzheimer's Dementia (AD), AD with signs of cerebrovascular pathology, and frontotemporal dementia. Applying voxel-based morphometry using a diffeomorphic registration algorithm we contrasted GMV of patients performing within the normal range with those of patients with pathological performance. Further, differential effects of gray matter atrophy on impaired performance in AD versus MCI of AD type were investigated. Results revealed significantly reduced GMV in the left anterior temporal lobe (ATL) in pathological performers compared to normal performers. The subgroup analysis confined to MCI of AD type and AD patients confirmed this relationship. While left ATL atrophy is known to be implicated in naming deficits in semantic dementia, our data confirm the same in AD and MCI of AD type

Amyloidβ peptide ratio 42/40 but not Aβ42 correlates with phospho-Tau in patients with low- and high-CSF Aβ40 load

Neurochemical dementia diagnostics (NDD) can significantly improve the clinically based categorization of patients with early dementia disorders, and the cerebrospinal fluid (CSF) concentrations of amyloid beta peptides ending at the amino acid position of 42 (A{beta}x-42 and A{beta}1-42) are widely accepted biomarkers of Alzheimer's disease (AD). However, in subjects with constitutively high- or low-CSF concentrations of total A{beta} peptides (tA{beta}), the NDD interpretation might lead to erroneous conclusions as these biomarkers seem to correlate better with the total A{beta} load than with the pathological status of a given patient in such cases. In this multicenter study, we found significantly increased CSF concentrations of phosphorylated Tau (pTau181) and total Tau in the group of subjects with high CSF A{beta}x-40 concentrations and decreased A{beta}x-42/x-40 concentration ratio compared with the group of subjects with low CSF A{beta}x-40 and normal A{beta} ratio (p<0.001 in both cases). Furthermore, we observed significantly decreased A{beta} ratio (p<0.01) in the group of subjects with APOE epsilon 4 allele compared with the group of subjects without this allele. Surprisingly, patients with low-A{beta}x-40 and the decreased A beta ratio characterized with decreased pTau181 (p<0.05), and unaltered total Tau compared with the subjects with high A{beta}x-40 and the A{beta}ratio in the normal range. We conclude that the amyloid{beta} concentration ratio should replace the 'raw' concentrations of corresponding A{beta} peptides to improve reliability of the neurochemical dementia diagnosis