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Find video protocols related to scientific articles indexed in Pubmed.
NILVAD protocol: a European multicentre double-blind placebo-controlled trial of nilvadipine in mild-to-moderate Alzheimer's disease.
BMJ Open
PUBLISHED: 10-11-2014
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This study is a European multicentre, randomised, double-blind, placebo-controlled trial investigating the efficacy and safety of nilvadipine as a disease course modifying treatment for mild-to-moderate Alzheimer's disease (AD) in a phase III study that will run for a period of 82?weeks with a treatment period of 78?weeks.
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CERAD neuropsychological compound scores are accurate in detecting prodromal alzheimer's disease: a prospective AddNeuroMed study.
J. Alzheimers Dis.
PUBLISHED: 10-07-2014
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The Consortium to Establish a Registry for Alzheimer's Disease Neuropsychological Battery (CERAD-NB) is a widely used tool in screening for Alzheimer's disease (AD), however, it does not include a validated total score for delayed memory. Our aim was to develop clinically applicable memory compound scores for CERAD-NB and examine whether they and global cognitive total scores could detect prodromal AD and cognitive progression in MCI. One year follow-up data of 201 subjects with a baseline diagnosis of MCI (46 progressed to AD; 155 remained stable) and 212 controls in the European multicenter AddNeuroMed study were analyzed. Two previously described cognitive total scores and two memory compound scores were tabulated for CERAD-NB. Receiver Operating Characteristic analysis was applied in the group discrimination at baseline and the annual change for different compound scores was examined. Normative cut-offs for CERAD compound scores were tabulated in the Finnish CERAD sample of 306 controls. Country adjusted CERAD compound scores (AUC 0.95-0.96) were more accurate than Word List Recall (AUC 0.93) and Mini-Mental State Examination (AUC 0.90) in discriminating progressive mild cognitive impairment (MCI) subjects from controls. With normative cut-off values CERAD total scores yielded to 87-89% sensitivity and 84-86% specificity in screening for prodromal AD in a separate multinational population. The annual deterioration in all CERAD compound scores was significant in the progressive (p ? 0.001) but not in the stable MCI group (p > 0.08). CERAD total scores are a practical way of screening for prodromal AD and assessing cognitive progression in MCI. The new memory compound scores were more accurate than CERAD subtests in predicting AD conversion.
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Generalizability of the Disease State Index Prediction Model for Identifying Patients Progressing from Mild Cognitive Impairment to Alzheimer's Disease.
J. Alzheimers Dis.
PUBLISHED: 09-10-2014
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Background: The Disease State Index (DSI) prediction model measures the similarity of patient data to diagnosed stable and progressive mild cognitive impairment (MCI) cases to identify patients who are progressing to Alzheimer's disease. Objectives: We evaluated how well the DSI generalizes across four different cohorts: DESCRIPA, ADNI, AddNeuroMed, and the Kuopio MCI study. Methods: The accuracy of the DSI in predicting progression was examined for each cohort separately using 10 × 10-fold cross-validation and for inter-cohort validation using each cohort as a test set for the model built from the other independent cohorts using bootstrapping with 10 repetitions. Altogether 875 subjects were included in the analysis. The analyzed data included a comprehensive set of age and gender corrected magnetic resonance imaging (MRI) features from hippocampal volumetry, multi-template tensor-based morphometry, and voxel-based morphometry as well as Mini-Mental State Examination (MMSE), APOE genotype, and additional cohort specific data from neuropsychological tests and cerebrospinal fluid measurements (CSF). Results: The DSI model was used to classify the patients into stable and progressive MCI cases. AddNeuroMed had the highest classification results of the cohorts, while ADNI and Kuopio MCI exhibited the lowest values. The MRI features alone achieved a good classification performance for all cohorts. For ADNI and DESCRIPA, adding MMSE, APOE genotype, CSF, and neuropsychological data improved the results. Conclusions: The results reveal that the prediction performance of the combined cohort is close to the average of the individual cohorts. It is feasible to use different cohorts as training sets for the DSI, if they are sufficiently similar.
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Genetic predisposition to increased blood cholesterol and triglyceride lipid levels and risk of Alzheimer disease: a mendelian randomization analysis.
PLoS Med.
PUBLISHED: 09-01-2014
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Although altered lipid metabolism has been extensively implicated in the pathogenesis of Alzheimer disease (AD) through cell biological, epidemiological, and genetic studies, the molecular mechanisms linking cholesterol and AD pathology are still not well understood and contradictory results have been reported. We have used a Mendelian randomization approach to dissect the causal nature of the association between circulating lipid levels and late onset AD (LOAD) and test the hypothesis that genetically raised lipid levels increase the risk of LOAD.
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The use of biomarkers for the etiologic diagnosis of MCI in Europe: An EADC survey.
Alzheimers Dement
PUBLISHED: 08-20-2014
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We investigated the use of Alzheimer's disease (AD) biomarkers in European Alzheimer's Disease Consortium centers and assessed their perceived usefulness for the etiologic diagnosis of mild cognitive impairment (MCI). We surveyed availability, frequency of use, and confidence in diagnostic usefulness of markers of brain amyloidosis (amyloid positron emission tomography [PET], cerebrospinal fluid [CSF] A?42) and neurodegeneration (medial temporal atrophy [MTA] on MR, fluorodeoxyglucose positron emission tomography [FDG-PET], CSF tau). The most frequently used biomarker is visually rated MTA (75% of the 37 responders reported using it "always/frequently") followed by CSF markers (22%), FDG-PET (16%), and amyloid-PET (3%). Only 45% of responders perceive MTA as contributing to diagnostic confidence, where the contribution was rated as "moderate". Seventy-nine percent of responders felt "very/extremely" comfortable delivering a diagnosis of MCI due to AD when both amyloid and neuronal injury biomarkers were abnormal (P < .02 versus any individual biomarker). Responders largely agreed that a combination of amyloidosis and neuronal injury biomarkers was a strongly indicative AD signature.
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Predicting progression of Alzheimer's disease using ordinal regression.
PLoS ONE
PUBLISHED: 08-20-2014
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We propose a novel approach to predicting disease progression in Alzheimer's disease (AD)--multivariate ordinal regression--which inherently models the ordered nature of brain atrophy spanning normal aging (CTL) to mild cognitive impairment (MCI) to AD. Ordinal regression provides probabilistic class predictions as well as a continuous index of disease progression--the ORCHID (Ordinal Regression Characteristic Index of Dementia) score. We applied ordinal regression to 1023 baseline structural MRI scans from two studies: the US-based Alzheimer's Disease Neuroimaging Initiative (ADNI) and the European based AddNeuroMed program. Here, the acquired AddNeuroMed dataset was used as a completely independent test set for the ordinal regression model trained on the ADNI cohort providing an optimal assessment of model generalizability. Distinguishing CTL-like (CTL and stable MCI) from AD-like (MCI converters and AD) resulted in balanced accuracies of 82% (cross-validation) for ADNI and 79% (independent test set) for AddNeuroMed. For prediction of conversion from MCI to AD, balanced accuracies of 70% (AUC of 0.75) and 75% (AUC of 0.81) were achieved. The ORCHID score was computed for all subjects. We showed that this measure significantly correlated with MMSE at 12 months (? =? -0.64, ADNI and ? = ?-0.59, AddNeuroMed). Additionally, the ORCHID score can help fractionate subjects with unstable diagnoses (e.g. reverters and healthy controls who later progressed to MCI), moderately late converters (12-24 months) and late converters (24-36 months). A comparison with results in the literature and direct comparison with a binary classifier suggests that the performance of this framework is highly competitive.
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The role of ABCA1 gene sequence variants on risk of Alzheimer's disease.
J. Alzheimers Dis.
PUBLISHED: 08-19-2014
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The ATP-binding cassette, sub-family A, member 1 gene (ABCA1) is a candidate risk gene for late onset Alzheimer's disease (LOAD) as a consequence of its role in cholesterol transport and metabolism, which is implicated in LOAD risk. ABCA1 has been shown in mouse models to enable the clearance of amyloid-? peptide from the brain, through its role in the lipidation of apolipoprotein (APOE). Although recent large scale genome wide association studies (GWAS) have failed to find significant associations with common genetic variants in this gene and LOAD, rare variants in ABCA1 have been shown to influence plasma high-density lipoprotein cholesterol levels. Using next generation sequencing of pooled DNA samples, we sequenced all the coding regions of ABCA1 in 311 LOAD cases and 360 control individuals drawn from the Greek population to identify low frequency non-synonymous variation. There were a significantly higher proportion of rare non-synonymous variants in control individuals compared to AD cases, suggestive of a protective effect. These findings provide new evidence of an effect of ABCA1 variants on AD risk. In addition they highlight the importance of high throughput sequencing in the identification of rare variation undetected by GWAS, but with the potential to have a strong effect on risk of LOAD.
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Circulating Proteomic Signatures of Chronological Age.
J. Gerontol. A Biol. Sci. Med. Sci.
PUBLISHED: 08-14-2014
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To elucidate the proteomic features of aging in plasma, the subproteome targeted by the SOMAscan assay was profiled in blood samples from 202 females from the TwinsUK cohort. Findings were replicated in 677 independent individuals from the AddNeuroMed, Alzheimer's Research UK, and Dementia Case Registry cohorts. Results were further validated using RNAseq data from whole blood in TwinsUK and the most significant proteins were tested for association with aging-related phenotypes after adjustment for age. Eleven proteins were associated with chronological age and were replicated at protein level in an independent population. These were further investigated at gene expression level in 384 females from the TwinsUK cohort. The two most strongly associated proteins were chordin-like protein 1 (meta-analysis ? [SE] = 0.013 [0.001], p = 3.66 × 10(-46)) and pleiotrophin (0.012 [0.005], p = 3.88 × 10(-41)). Chordin-like protein 1 was also significantly correlated with birthweight (0.06 [0.02], p = 0.005) and with the individual Framingham 10-years cardiovascular risk scores in TwinsUK (0.71 [0.18], p = 9.9 × 10(-5)). Pleiotrophin is a secreted growth factor with a plethora of functions in multiple tissues and known to be a marker for cardiovascular risk and osteoporosis. Our study highlights the importance of proteomics to identify some molecular mechanisms involved in human health and aging.
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Alleles that increase risk for type 2 diabetes mellitus are not associated with increased risk for Alzheimer's disease.
Neurobiol. Aging
PUBLISHED: 07-24-2014
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Although epidemiological studies suggest that type 2 diabetes mellitus (T2DM) increases the risk of late-onset Alzheimer's disease (LOAD), the biological basis of this relationship is not well understood. The aim of this study was to examine the genetic comorbidity between the 2 disorders and to investigate whether genetic liability to T2DM, estimated by a genotype risk scores based on T2DM associated loci, is associated with increased risk of LOAD. This study was performed in 2 stages. In stage 1, we combined genotypes for the top 15 T2DM-associated polymorphisms drawn from approximately 3000 individuals (1349 cases and 1351 control subjects) with extracted and/or imputed data from 6 genome-wide studies (>10,000 individuals; 4507 cases, 2183 controls, 4989 population controls) to form a genotype risk score and examined if this was associated with increased LOAD risk in a combined meta-analysis. In stage 2, we investigated the association of LOAD with an expanded T2DM score made of 45 well-established variants drawn from the 6 genome-wide studies. Results were combined in a meta-analysis. Both stage 1 and stage 2 T2DM risk scores were not associated with LOAD risk (odds ratio = 0.988; 95% confidence interval, 0.972-1.004; p = 0.144 and odds ratio = 0.993; 95% confidence interval, 0.983-1.003; p = 0.149 per allele, respectively). Contrary to expectation, genotype risk scores based on established T2DM candidates were not associated with increased risk of LOAD. The observed epidemiological associations between T2DM and LOAD could therefore be a consequence of secondary disease processes, pleiotropic mechanisms, and/or common environmental risk factors. Future work should focus on well-characterized longitudinal cohorts with extensive phenotypic and genetic data relevant to both LOAD and T2DM.
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Candidate blood proteome markers of Alzheimer's disease onset and progression: a systematic review and replication study.
J. Alzheimers Dis.
PUBLISHED: 07-18-2014
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A blood-based protein biomarker, or set of protein biomarkers, that could predict onset and progression of Alzheimer's disease (AD) would have great utility; potentially clinically, but also for clinical trials and especially in the selection of subjects for preventative trials. We reviewed a comprehensive list of 21 published discovery or panel-based (> 100 proteins) blood proteomics studies of AD, which had identified a total of 163 candidate biomarkers. Few putative blood-based protein biomarkers replicate in independent studies but we found that some proteins do appear in multiple studies; for example, four candidate biomarkers are found to associate with AD-related phenotypes in five independent research cohorts in these 21 studies: ?-1-antitrypsin, ?-2-macroglobulin, apolipoprotein E, and complement C3. Using SomaLogic's SOMAscan proteomics technology, we were able to conduct a large-scale replication study for 94 of the 163 candidate biomarkers from these 21 published studies in plasma samples from 677 subjects from the AddNeuroMed (ANM) and the Alzheimer's Research UK/Maudsley BRC Dementia Case Registry at King's Health Partners (ARUK/DCR) research cohorts. Nine of the 94 previously reported candidates were found to associate with AD-related phenotypes (False Discovery Rate (FDR) q-value < 0.1). These proteins show sufficient replication to be considered for further investigation as a biomarker set. Overall, we show that there are some signs of a replicable signal in the range of proteins identified in previous studies and we are able to further replicate some of these. This suggests that AD pathology does affect the blood proteome with some consistency.
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Automated Hippocampal Subfield Measures as Predictors of Conversion from Mild Cognitive Impairment to Alzheimer's Disease in Two Independent Cohorts.
Brain Topogr
PUBLISHED: 06-25-2014
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Previous studies have shown that hippocampal subfields may be differentially affected by Alzheimer's disease (AD). This study used an automated analysis technique and two large cohorts to (1) investigate patterns of subfield volume loss in mild cognitive impairment (MCI) and AD, (2) determine the pattern of subfield volume loss due to age, gender, education, APOE ?4 genotype, and neuropsychological test scores, (3) compare combined subfield volumes to hippocampal volume alone at discriminating between AD and healthy controls (HC), and predicting future MCI conversion to AD at 12 months. 1,069 subjects were selected from the AddNeuroMed and Alzheimer's disease neuroimaging initiative (ADNI) cohorts. Freesurfer was used for automated segmentation of the hippocampus and hippocampal subfields. Orthogonal partial least squares to latent structures (OPLS) was used to train models on AD and HC subjects using one cohort for training and the other for testing and the combined cohort was used to predict MCI conversion. MANCOVA and linear regression analyses showed multiple subfield volumes including Cornu Ammonis 1 (CA1), subiculum and presubiculum were atrophied in AD and MCI and were related to age, gender, education, APOE ?4 genotype, and neuropsychological test scores. For classifying AD from HC, combined subfield volumes achieved comparable classification accuracy (81.7 %) to total hippocampal (80.7 %), subiculum (81.2 %) and presubiculum (80.6 %) volume. For predicting MCI conversion to AD combined subfield volumes and presubiculum volume were more accurate (81.1 %) than total hippocampal volume. (76.7 %).
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Depression and anxiety levels increase chronic musculoskeletal pain in patients with Alzheimer's disease.
Curr Alzheimer Res
PUBLISHED: 05-26-2014
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During the next decades a rapid increase is expected in the number of patients with dementia suffering from pain who often take less medication compared to normal elderly, due to several diagnostic barriers. Comorbid mood disorders result in great difficulties in pain assessment and further treatment.
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Dementia and depression in older adults: a southeast European perspective: summary of a dementia psychogeriatric symposium held in Ohrid, Macedonia, 23 May 2013.
J. Alzheimers Dis.
PUBLISHED: 05-03-2014
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We present a report on the recent symposium on dementia and depression in older adults, held in Ohrid, Macedonia and discuss the urgent need for development of psychogeriatric and affiliated services in the Southeast European region. The limited epidemiological data from nine countries in this region suggest high variability of prevalence rates for mental health problems in older adults (>65 years of age). At the moment, there are over 520,000 older adults in the region living with dementia alone. The prevalence rates for dementia (%) are either similar to those of the developed countries (9-9.6% in build-up northern Greece and Albania, respectively) or substantially lower (3.6-4% in rural northern Greece and Montenegro, respectively). The latter may be due to either cultural diversity or lack of adequate medical health service provision and expertise to recognize and diagnose dementia. Indeed, there is a lack of organized specialized services for older adults with mental health problem in the region. The symposium raised the awareness of this problem in the region and called for networking between isolated individuals working in this field to improve the current situation and facilitate further development of adequate clinical services to meet the growing needs of the older adults in the countries of the Southeast Europe.
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Alzheimer's disease biomarker discovery using SOMAscan multiplexed protein technology.
Alzheimers Dement
PUBLISHED: 04-29-2014
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Blood proteins and their complexes have become the focus of a great deal of interest in the context of their potential as biomarkers of Alzheimer's disease (AD). We used a SOMAscan assay for quantifying 1001 proteins in blood samples from 331 AD, 211 controls, and 149 mild cognitive impaired (MCI) subjects. The strongest associations of protein levels with AD outcomes were prostate-specific antigen complexed to ?1-antichymotrypsin (AD diagnosis), pancreatic prohormone (AD diagnosis, left entorhinal cortex atrophy, and left hippocampus atrophy), clusterin (rate of cognitive decline), and fetuin B (left entorhinal atrophy). Multivariate analysis found that a subset of 13 proteins predicted AD with an accuracy of area under the curve of 0.70. Our replication of previous findings provides further evidence that levels of these proteins in plasma are truly associated with AD. The newly identified proteins could be potential biomarkers and are worthy of further investigation.
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The cerebrospinal fluid "Alzheimer profile": Easily said, but what does it mean?
Alzheimers Dement
PUBLISHED: 04-12-2014
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We aimed to identify the most useful definition of the "cerebrospinal fluid Alzheimer profile," based on amyloid-ß1-42 (A?42), total tau, and phosphorylated tau (p-tau), for diagnosis and prognosis of Alzheimer's disease (AD).
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Plasma proteins predict conversion to dementia from prodromal disease.
Alzheimers Dement
PUBLISHED: 02-24-2014
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The study aimed to validate previously discovered plasma biomarkers associated with AD, using a design based on imaging measures as surrogate for disease severity and assess their prognostic value in predicting conversion to dementia.
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Multisite longitudinal reliability of tract-based spatial statistics in diffusion tensor imaging of healthy elderly subjects.
Neuroimage
PUBLISHED: 02-19-2014
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Large-scale longitudinal neuroimaging studies with diffusion imaging techniques are necessary to test and validate models of white matter neurophysiological processes that change in time, both in healthy and diseased brains. The predictive power of such longitudinal models will always be limited by the reproducibility of repeated measures acquired during different sessions. At present, there is limited quantitative knowledge about the across-session reproducibility of standard diffusion metrics in 3T multi-centric studies on subjects in stable conditions, in particular when using tract based spatial statistics and with elderly people. In this study we implemented a multi-site brain diffusion protocol in 10 clinical 3T MRI sites distributed across 4 countries in Europe (Italy, Germany, France and Greece) using vendor provided sequences from Siemens (Allegra, Trio Tim, Verio, Skyra, Biograph mMR), Philips (Achieva) and GE (HDxt) scanners. We acquired DTI data (2 × 2 × 2 mm(3), b = 700 s/mm(2), 5 b0 and 30 diffusion weighted volumes) of a group of healthy stable elderly subjects (5 subjects per site) in two separate sessions at least a week apart. For each subject and session four scalar diffusion metrics were considered: fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD) and axial (AD) diffusivity. The diffusion metrics from multiple subjects and sessions at each site were aligned to their common white matter skeleton using tract-based spatial statistics. The reproducibility at each MRI site was examined by looking at group averages of absolute changes relative to the mean (%) on various parameters: i) reproducibility of the signal-to-noise ratio (SNR) of the b0 images in centrum semiovale, ii) full brain test-retest differences of the diffusion metric maps on the white matter skeleton, iii) reproducibility of the diffusion metrics on atlas-based white matter ROIs on the white matter skeleton. Despite the differences of MRI scanner configurations across sites (vendors, models, RF coils and acquisition sequences) we found good and consistent test-retest reproducibility. White matter b0 SNR reproducibility was on average 7 ± 1% with no significant MRI site effects. Whole brain analysis resulted in no significant test-retest differences at any of the sites with any of the DTI metrics. The atlas-based ROI analysis showed that the mean reproducibility errors largely remained in the 2-4% range for FA and AD and 2-6% for MD and RD, averaged across ROIs. Our results show reproducibility values comparable to those reported in studies using a smaller number of MRI scanners, slightly different DTI protocols and mostly younger populations. We therefore show that the acquisition and analysis protocols used are appropriate for multi-site experimental scenarios.
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Computerized Cognitive Testing for Older Adults: A review.
Am J Alzheimers Dis Other Demen
PUBLISHED: 02-13-2014
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Objective:This article is a review of computerized tests and batteries used in the cognitive assessment of older adults.Method:A literature search on Medline followed by cross-referencing yielded a total of 76 citations.Results:Seventeen test batteries were identified and categorized according to their scope. Computerized adaptive testing (CAT) and the Cambridge Cognitive Examination CAT battery as well as 3 experimental batteries and an experimental test are discussed in separate sections. All batteries exhibit strengths associated with computerized testing such as standardization of administration, accurate measurement of many variables, automated record keeping, and savings of time and costs. Discriminant validity and test-retest reliability were well documented for most batteries while documentation of other psychometric properties varied.Conclusion:The large number of available batteries can be beneficial to the clinician or researcher; however, care should be taken in order to choose the correct battery for each application.
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Cognitive and physical training for the elderly: evaluating outcome efficacy by means of neurophysiological synchronization.
Int J Psychophysiol
PUBLISHED: 01-17-2014
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Recent neuroscientific research has demonstrated that both healthy and pathological aging induces alterations in the co-operative capacity of neuronal populations in the brain. Both compensatory and neurodegenerative mechanisms contribute to neurophysiological synchronization patterns, which provide a valuable marker for age-related cognitive decline. In this study, we propose that neuroplasticity-based training may facilitate coherent interaction of distant brain regions and consequently enhance cognitive performance in elderly people. If this is true, this would make neurophysiological synchronization a valid outcome measure to assess the efficacy of non-pharmacological interventions to prevent or delay age-related cognitive decline. The present study aims at providing an objective, synchronization-based tool to assess cognitive and/or physical interventions, adopting the notion of Relative Wavelet Entropy. This mathematical model employs a robust and parameter-free synchronization metric. By using data mining techniques, a distance value was computed for all participants so as to quantify the proximity of their individual profile to the mean group synchronization increase. In support of our hypothesis, results showed a significant increase in synchronization, for four electrode pairs, in the intervention group as compared to the active control group. It is concluded that the novel introduction of neurophysiological synchronization features could be used as a valid and reliable outcome measure; while the distance-based analysis could provide a reliable means of evaluating individual benefits.
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Electroencephalogram and Alzheimer's disease: clinical and research approaches.
Int J Alzheimers Dis
PUBLISHED: 01-15-2014
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Alzheimer's disease (AD) is a neurodegenerative disorder that is characterized by cognitive deficits, problems in activities of daily living, and behavioral disturbances. Electroencephalogram (EEG) has been demonstrated as a reliable tool in dementia research and diagnosis. The application of EEG in AD has a wide range of interest. EEG contributes to the differential diagnosis and the prognosis of the disease progression. Additionally such recordings can add important information related to the drug effectiveness. This review is prepared to form a knowledge platform for the project entitled "Cognitive Signal Processing Lab," which is in progress in Information Technology Institute in Thessaloniki. The team tried to focus on the main research fields of AD via EEG and recent published studies.
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Legal capacity of the elderly in Greece.
Hell J Nucl Med
PUBLISHED: 01-07-2014
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Legal capacity of the elderly people in Greece is of great legal, medical and social importance, but has received little attention till now from medical literature. This paper aims to study whether elderly people with dementia are able to participate in legal contracts like sales, purchases, loans, leases, donations and testaments. We tried to introduce a new test for the above legal-financial contracts and show some preliminary findings. The test consists of six examined relevant domains concerning basic monetary skills, cash transactions, bank statement management, financial conceptual knowledge, knowledge of potential heirs (beneficiaries) and assets/estate and finally the decision making process for different dilemmas on sales, purchases, loans, leases, donations and testaments. We studied 203 people. Eighty three people were healthy, 64 with Alzheimer's disease (AD) (10 with severe AD, 22 with moderate, and 32 with mild AD), 10 with Parkinson's disease (PD), and 46 with amnestic Mild Cognitive Impairment (aMCI). Individuals were included in the study only if they were aged 60 and over and only if they had a partner or a guardian who could give information on the individual's daily living. The exclusion criteria were predefined as follows: history of any other mental health disease and/or any other serious somatic health disease except for their official diagnosis of dementia. Results showed statistically significant differences with all three groups of patients characterized as incapable for legal-financial actions. Patients with severe AD (P<0.001), patients with moderate AD (P<0.001), patients with mild AD (P<0.001), patients with PD (P<0.001) and aMCI patients (P<0.001) differed significantly from healthy controls. Further research should include more extensive sampling of elderly patients with varying demographic characteristics in Greece, to confirm and expand our initial findings. In conclusion, our new test which is based on Marson's theoretical model of financial capacity seems to be highly correlated with the so far use of MMSE/HMSE scores, but it gives more specific information that is of interest in the field of civil forensics for characterizing someone as legally (in) capable for large and/or small scale financial acts. Our preliminary results show for the first time in Greece that: a) four groups of elderly people (suffering from Alzheimer's disease at different stages, Parkinson's disease and amnestic Mild Cognitive Impairment and healthy elders) show a significantly different profile on all examined domains of this new test according to their diagnosis, b) people with MCI from Greece do face problems in the domains outlined above (mainly financial decision making problems), and that c) subsequent changes in the Greek law should be made.
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Can a novel computerized cognitive screening test provide additional information for early detection of Alzheimer's disease?
Alzheimers Dement
PUBLISHED: 01-02-2014
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Virtual reality testing of everyday activities is a novel type of computerized assessment that measures cognitive, executive, and motor performance as a screening tool for early dementia. This study used a virtual reality day-out task (VR-DOT) environment to evaluate its predictive value in patients with mild cognitive impairment (MCI).
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Functional disorganization of small-world brain networks in mild Alzheimer's Disease and amnestic Mild Cognitive Impairment: an EEG study using Relative Wavelet Entropy (RWE).
Front Aging Neurosci
PUBLISHED: 01-01-2014
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Previous neuroscientific findings have linked Alzheimer's Disease (AD) with less efficient information processing and brain network disorganization. However, pathological alterations of the brain networks during the preclinical phase of amnestic Mild Cognitive Impairment (aMCI) remain largely unknown. The present study aimed at comparing patterns of the detection of functional disorganization in MCI relative to Mild Dementia (MD). Participants consisted of 23 cognitively healthy adults, 17 aMCI and 24 mild AD patients who underwent electroencephalographic (EEG) data acquisition during a resting-state condition. Synchronization analysis through the Orthogonal Discrete Wavelet Transform (ODWT), and directional brain network analysis were applied on the EEG data. This computational model was performed for networks that have the same number of edges (N = 500, 600, 700, 800 edges) across all participants and groups (fixed density values). All groups exhibited a small-world (SW) brain architecture. However, we found a significant reduction in the SW brain architecture in both aMCI and MD patients relative to the group of Healthy controls. This functional disorganization was also correlated with the participant's generic cognitive status. The deterioration of the network's organization was caused mainly by deficient local information processing as quantified by the mean cluster coefficient value. Functional hubs were identified through the normalized betweenness centrality metric. Analysis of the local characteristics showed relative hub preservation even with statistically significant reduced strength. Compensatory phenomena were also evident through the formation of additional hubs on left frontal and parietal regions. Our results indicate a declined functional network organization even during the prodromal phase. Degeneration is evident even in the preclinical phase and coexists with transient network reorganization due to compensation.
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Application of a MRI based index to longitudinal atrophy change in Alzheimer disease, mild cognitive impairment and healthy older individuals in the AddNeuroMed cohort.
Front Aging Neurosci
PUBLISHED: 01-01-2014
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Cross sectional studies of patients at risk of developing Alzheimer disease (AD) have identified several brain regions known to be prone to degeneration suitable as biomarkers, including hippocampal, ventricular, and whole brain volume. The aim of this study was to longitudinally evaluate an index based on morphometric measures derived from MRI data that could be used for classification of AD and healthy control subjects, as well as prediction of conversion from mild cognitive impairment (MCI) to AD. Patients originated from the AddNeuroMed project at baseline (119 AD, 119 MCI, 110 controls (CTL)) and 1-year follow-up (62 AD, 73 MCI, 79 CTL). Data consisted of 3D T1-weighted MR images, demographics, MMSE, ADAS-Cog, CERAD and CDR scores, and APOE e4 status. We computed an index using a multivariate classification model (AD vs. CTL), using orthogonal partial least squares to latent structures (OPLS). Sensitivity, specificity and AUC were determined. Performance of the classifier (AD vs. CTL) was high at baseline (10-fold cross-validation, 84% sensitivity, 91% specificity, 0.93 AUC) and at 1-year follow-up (92% sensitivity, 74% specificity, 0.93 AUC). Predictions of conversion from MCI to AD were good at baseline (77% of MCI converters) and at follow-up (91% of MCI converters). MCI carriers of the APOE e4 allele manifested more atrophy and presented a faster cognitive decline when compared to non-carriers. The derived index demonstrated a steady increase in atrophy over time, yielding higher accuracy in prediction at the time of clinical conversion. Neuropsychological tests appeared less sensitive to changes over time. However, taking the average of the two time points yielded better correlation between the index and cognitive scores as opposed to using cross-sectional data only. Thus, multivariate classification seemed to detect patterns of AD changes before conversion from MCI to AD and including longitudinal information is of great importance.
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Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease.
Valentina Escott-Price, Celine Bellenguez, Li-San Wang, Seung-Hoan Choi, Denise Harold, Lesley Jones, Peter Holmans, Amy Gerrish, Alexey Vedernikov, Alexander Richards, Anita L Destefano, Jean-Charles Lambert, Carla A Ibrahim-Verbaas, Adam C Naj, Rebecca Sims, Gyungah Jun, Joshua C Bis, Gary W Beecham, Benjamin Grenier-Boley, Giancarlo Russo, Tricia A Thornton-Wells, Nicola Denning, Albert V Smith, Vincent Chouraki, Charlene Thomas, M Arfan Ikram, Diana Zelenika, Badri N Vardarajan, Yoichiro Kamatani, Chiao-Feng Lin, Helena Schmidt, Brian Kunkle, Melanie L Dunstan, Maria Vronskaya, , Andrew D Johnson, Agustin Ruíz, Marie-Therese Bihoreau, Christiane Reitz, Florence Pasquier, Paul Hollingworth, Olivier Hanon, Annette L Fitzpatrick, Joseph D Buxbaum, Dominique Campion, Paul K Crane, Clinton Baldwin, Tim Becker, Vilmundur Gudnason, Carlos Cruchaga, David Craig, Najaf Amin, Claudine Berr, Oscar L Lopez, Philip L De Jager, Vincent Deramecourt, Janet A Johnston, Denis Evans, Simon Lovestone, Luc Letenneur, Isabel Hernández, David C Rubinsztein, Gudny Eiriksdottir, Kristel Sleegers, Alison M Goate, Nathalie Fiévet, Matthew J Huentelman, Michael Gill, Kristelle Brown, M Ilyas Kamboh, Lina Keller, Pascale Barberger-Gateau, Bernadette McGuinness, Eric B Larson, Amanda J Myers, Carole Dufouil, Stephen Todd, David Wallon, Seth Love, Ekaterina Rogaeva, John Gallacher, Peter St George-Hyslop, Jordi Clarimón, Alberto Lleó, Anthony Bayer, Debby W Tsuang, Lei Yu, Magda Tsolaki, Paola Bossù, Gianfranco Spalletta, Petra Proitsi, John Collinge, Sandro Sorbi, Florentino Sanchez Garcia, Nick C Fox, John Hardy, Maria Candida Deniz Naranjo, Paolo Bosco, Robert Clarke, Carol Brayne, Daniela Galimberti, Elio Scarpini, Ubaldo Bonuccelli, Michelangelo Mancuso, Gabriele Siciliano, Susanne Moebus, Patrizia Mecocci, Maria Del Zompo, Wolfgang Maier, Harald Hampel, Alberto Pilotto, Ana Frank-García, Francesco Panza, Vincenzo Solfrizzi, Paolo Caffarra, Benedetta Nacmias, William Perry, Manuel Mayhaus, Lars Lannfelt, Hakon Hakonarson, Sabrina Pichler, Minerva M Carrasquillo, Martin Ingelsson, Duane Beekly, Victoria Alvarez, Fanggeng Zou, Otto Valladares, Steven G Younkin, Eliecer Coto, Kara L Hamilton-Nelson, Wei Gu, Cristina Razquin, Pau Pastor, Ignacio Mateo, Michael J Owen, Kelley M Faber, Palmi V Jonsson, Onofre Combarros, Michael C O'Donovan, Laura B Cantwell, Hilkka Soininen, Deborah Blacker, Simon Mead, Thomas H Mosley, David A Bennett, Tamara B Harris, Laura Fratiglioni, Clive Holmes, Renée F A G de Bruijn, Peter Passmore, Thomas J Montine, Karolien Bettens, Jerome I Rotter, Alexis Brice, Kevin Morgan, Tatiana M Foroud, Walter A Kukull, Didier Hannequin, John F Powell, Michael A Nalls, Karen Ritchie, Kathryn L Lunetta, John S K Kauwe, Eric Boerwinkle, Matthias Riemenschneider, Mercè Boada, Mikko Hiltunen, Eden R Martin, Reinhold Schmidt, Dan Rujescu, Jean-Francois Dartigues, Richard Mayeux, Christophe Tzourio, Albert Hofman, Markus M Nöthen, Caroline Graff, Bruce M Psaty, Jonathan L Haines, Mark Lathrop, Margaret A Pericak-Vance, Lenore J Launer, Christine Van Broeckhoven, Lindsay A Farrer, Cornelia M van Duijn, Alfredo Ramírez, Sudha Seshadri, Gerard D Schellenberg, Philippe Amouyel, Julie Williams.
PLoS ONE
PUBLISHED: 01-01-2014
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Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls.
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Evidence of altered phosphatidylcholine metabolism in Alzheimers disease.
Neurobiol. Aging
PUBLISHED: 05-24-2013
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Abberant lipid metabolism is implicated in Alzheimers disease (AD) pathophysiology, but the connections between AD and lipid metabolic pathways are not fully understood. To investigate plasma lipids in AD, a multiplatform screen (n = 35 by liquid chromatography-mass spectrometry and n = 35 by nuclear magnetic resonance) was developed, which enabled the comprehensive analysis of plasma from 3 groups (individuals with AD, individuals with mild cognitive impairment (MCI), and age-matched controls). This screen identified 3 phosphatidylcholine (PC) molecules that were significantly diminished in AD cases. In a subsequent validation study (n = 141), PC variation in a bigger sample set was investigated, and the same 3 PCs were found to be significantly lower in AD patients: PC 16:0/20:5 (p < 0.001), 16:0/22:6 (p < 0.05), and 18:0/22:6 (p < 0.01). A receiver operating characteristic (ROC) analysis of the PCs, combined with apolipoprotein E (ApoE) data, produced an area under the curve predictive value of 0.828. Confirmatory investigations into the background biochemistry indiciated no significant change in plasma levels of 3 additional PCs of similar structure, total choline containing compounds or total plasma omega fatty acids, adding to the evidence that specific PCs play a role in AD pathology.
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Different multivariate techniques for automated classification of MRI data in Alzheimers disease and mild cognitive impairment.
Psychiatry Res
PUBLISHED: 03-29-2013
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Automated structural magnetic resonance imaging (MRI) processing pipelines and different multivariate techniques are gaining popularity for Alzheimers disease (AD) research. We used four supervised learning methods to classify AD patients and controls (CTL) and to prospectively predict the conversion of mild cognitive impairment (MCI) to AD from baseline MRI data. A total of 345 participants from the AddNeuroMed cohort were included in this study; 116 AD patients, 119 MCI patients and 110 CTL individuals. High resolution sagittal 3D MP-RAGE datasets were acquired and MRI data were processed using FreeSurfer. We explored the classification ability of orthogonal projections to latent structures (OPLS), decision trees (Trees), artificial neural networks (ANN) and support vector machines (SVM). Applying 10-fold cross-validation demonstrated that SVM and OPLS were slightly superior to Trees and ANN, although not statistically significant for distinguishing between AD and CTL. The classification experiments resulted in up to 83% sensitivity and 87% specificity for the best techniques. For the prediction of conversion of MCI patients at baseline to AD at 1-year follow-up, we obtained an accuracy of up to 86%. The value of the multivariate models derived from the classification of AD vs. CTL was shown to be robust and efficient in the identification of MCI converters.
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Prediction of Alzheimer disease in subjects with amnestic and nonamnestic MCI.
Neurology
PUBLISHED: 02-27-2013
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To compare the predictive accuracy of ?-amyloid (A?)1-42 and total tau in CSF, hippocampal volume (HCV), and APOE genotype for Alzheimer disease (AD)-type dementia in subjects with amnestic mild cognitive impairment (aMCI) and nonamnestic mild cognitive impairment (naMCI).
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Alzheimers disease susceptibility variants in the MS4A6A gene are associated with altered levels of MS4A6A expression in blood.
Neurobiol. Aging
PUBLISHED: 02-18-2013
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An increased risk of developing Alzheimers disease (AD) has previously been found to be associated with variants at the MS4A6A locus. We sought to identify which genes and transcripts in this region have altered expression in AD and mild cognitive impairment (MCI) and are influenced by the AD risk variant(s), as a first step to understanding the molecular basis of AD susceptibility at this locus. Common variants located within highly expressed MS4A6A transcripts were significantly associated with AD and MS4A6A expression levels in blood from MCI and AD subjects (p < 0.05, rs610932, rs7232, rs583791). More copies of the protective (minor) allele were associated with lower MS4A6A expression of each transcript (e.g., p = 0.019; rs610932-total MS4A6A). Furthermore, in heterozygous AD subjects, relative expression of the protective allele of V4-MS4A6A transcripts was lower (p < 0.008). Irrespective of genotype, MS4A6A transcripts were increased in blood from people with AD (p < 0.003), whereas lower expression of full length V1-MS4A6A (p = 0.002) and higher expression of V4-MS4A6A (p = 1.8 × 10(-4)) were observed in MCI, relative to elderly controls. The association between genotype and expression was less consistent in brain, although BA9 did have a similar genotype association with V4-MS4A6A transcripts as in blood. MS4A6A transcripts were widely expressed in tissues and cells, with the exception of V4-MS4A6A, which was not expressed in neuronal cells. Together these results suggest that high levels of MS4A6A in emerging AD pathology are detrimental. Persons with MCI may lower MS4A6A expression to minimize detrimental disease associated MS4A6A activity. However, those with the susceptibility allele appear unable to decrease expression sufficiently, which may explain their increased risk for developing AD. Inhibiting MS4A6A may therefore promote a more neuroprotective phenotype, although further work is needed to establish whether this is the case.
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The deletion variant of ?2b-adrenergic receptor is associated with decreased risk in Alzheimers disease and mild cognitive impairment.
J. Neurol. Sci.
PUBLISHED: 02-04-2013
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A common genetic polymorphism of the ?2b-adrenergic receptor (ADRA2B) resulting in a deletion of three glutamic acids located on the third intracellular loop of the protein, has been associated with memory formation enhanced by emotional events. Additionally, there are several studies documenting the involvement of this polymorphism in other types of cognition, such as episodic memory. The aim of this study was to investigate the possible relationship of this genetic variance with a common memory affecting disease, Alzheimers disease. Our study was carried out in a total number of 311 Greek subjects, including 119 sporadic AD patients, 95 MCI cases and 97 controls. Genomic DNA was extracted from whole blood and the fragments containing the polymorphism were amplified by PCR analysis. A genotypic analysis of the APOE polymorphism was also carried out. A significant difference in the frequency of the ADRA2B genetic variation among the three groups was observed. Specifically, the deletion variant is more prevalent in controls than in AD and MCI patients. Our data demonstrate for the first time an independent contribution of the ADRA2B genetic polymorphism to memory impairment and we further suggest a possible protective role of the deletion variant against the disease development.
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Inflammatory proteins in plasma are associated with severity of Alzheimers disease.
PLoS ONE
PUBLISHED: 01-01-2013
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Markers of Alzheimers disease (AD) are being widely sought with a number of studies suggesting blood measures of inflammatory proteins as putative biomarkers. Here we report findings from a panel of 27 cytokines and related proteins in over 350 subjects with AD, subjects with Mild Cognitive Impairment (MCI) and elderly normal controls where we also have measures of longitudinal change in cognition and baseline neuroimaging measures of atrophy. In this study, we identify five inflammatory proteins associated with evidence of atrophy on MR imaging data particularly in whole brain, ventricular and entorhinal cortex measures. In addition, we observed six analytes that showed significant change (over a period of one year) in people with fast cognitive decline compared to those with intermediate and slow decline. One of these (IL-10) was also associated with brain atrophy in AD. In conclusion, IL-10 was associated with both clinical and imaging evidence of severity of disease and might therefore have potential to act as biomarker of disease progression.
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Plasma biomarkers of brain atrophy in Alzheimers disease.
PLoS ONE
PUBLISHED: 09-20-2011
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Peripheral biomarkers of Alzheimers disease (AD) reflecting early neuropathological change are critical to the development of treatments for this condition. The most widely used indicator of AD pathology in life at present is neuroimaging evidence of brain atrophy. We therefore performed a proteomic analysis of plasma to derive biomarkers associated with brain atrophy in AD. Using gel based proteomics we previously identified seven plasma proteins that were significantly associated with hippocampal volume in a combined cohort of subjects with AD (N?=?27) and MCI (N?=?17). In the current report, we validated this finding in a large independent cohort of AD (N?=?79), MCI (N?=?88) and control (N?=?95) subjects using alternative complementary methods-quantitative immunoassays for protein concentrations and estimation of pathology by whole brain volume. We confirmed that plasma concentrations of five proteins, together with age and sex, explained more than 35% of variance in whole brain volume in AD patients. These proteins are complement components C3 and C3a, complement factor-I, ?-fibrinogen and alpha-1-microglobulin. Our findings suggest that these plasma proteins are strong predictors of in vivo AD pathology. Moreover, these proteins are involved in complement activation and coagulation, providing further evidence for an intrinsic role of these pathways in AD pathogenesis.
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A Web services-based exergaming platform for senior citizens: the Long Lasting Memories project approach to e-health care.
Conf Proc IEEE Eng Med Biol Soc
PUBLISHED: 08-29-2011
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This piece of research describes an innovative e-health service that supports the cognitive and physical training of senior citizens and promotes their active ageing. The approach is adopted by the Long Lasting Memories (LLM) project, elements of which are discussed herein in the light of the functionalities provided to the users and the therapists. The aim of this work is to describe those technical elements that demonstrate the unique and integrative character of the LLM service, which is based on a modular Web service architecture, rendering the system available in different settings like the homes of seniors. The underlying database as well as the remote user interface empower therapists to set personalized training schemes, to view the progress of training sessions, as well as, adding new games and exercises into the system, thereby increasing the services sustainability and marketability.
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Tocopherols and tocotrienols plasma levels are associated with cognitive impairment.
Neurobiol. Aging
PUBLISHED: 07-20-2011
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Vitamin E includes 8 natural compounds (4 tocopherols, 4 tocotrienols) with potential neuroprotective activity. ?-Tocopherol has mainly been investigated in relation to cognitive impairment. We examined the relation of all plasma vitamin E forms and markers of vitamin E damage (?-tocopherylquinone, 5-nitro-?-tocopherol) to mild cognitive impairment (MCI) and Alzheimers disease (AD). Within the AddNeuroMed-Project, plasma tocopherols, tocotrienols, ?-tocopherylquinone, and 5-nitro-?-tocopherol were assessed in 168 AD cases, 166 MCI, and 187 cognitively normal (CN) people. Compared with cognitively normal subjects, AD and MCI had lower levels of total tocopherols, total tocotrienols, and total vitamin E. In multivariable-polytomous-logistic regression analysis, both MCI and AD cases had 85% lower odds to be in the highest tertile of total tocopherols and total vitamin E, and they were, respectively, 92% and 94% less likely to be in the highest tertile of total tocotrienols than the lowest tertile. Further, both disorders were associated with increased vitamin E damage. Low plasma tocopherols and tocotrienols levels are associated with increased odds of MCI and AD.
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The AddNeuroMed framework for multi-centre MRI assessment of Alzheimers disease: experience from the first 24 months.
Int J Geriatr Psychiatry
PUBLISHED: 04-28-2011
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To describe the AddNeuroMed imaging framework for multi-centre magnetic resonance imaging (MRI) assessment of longitudinal changes in Alzheimers disease and report on early results from the first 24 months of the project.
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Sensitivity and specificity of medial temporal lobe visual ratings and multivariate regional MRI classification in Alzheimers disease.
PLoS ONE
PUBLISHED: 04-14-2011
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Visual assessment rating scales for medial temporal lobe (MTL) atrophy have been used by neuroradiologists in clinical practice to aid the diagnosis of Alzheimers disease (AD). Recently multivariate classification methods for magnetic resonance imaging (MRI) data have been suggested as alternative tools. If computerized methods are to be implemented in clinical practice they need to be as good as, or better than experienced neuroradiologists and carefully validated. The aims of this study were: (1) To compare the ability of MTL atrophy visual assessment rating scales, a multivariate MRI classification method and manually measured hippocampal volumes to distinguish between subjects with AD and healthy elderly controls (CTL). (2) To assess how well the three techniques perform when predicting future conversion from mild cognitive impairment (MCI) to AD.
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Life events and dementia: what is the nature of their relationship?
Psychiatry Res
PUBLISHED: 03-25-2011
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The current study analyzed the life events reported by 1271 demented patients vs. 140 cognitively healthy elderly subjects. The Life Change Unit (LCU) method was used to quantify the results. When all the events were included in the analysis, the two groups had similar LCU scores (61.26 vs. 63.42). However, when events causally related to dementia (e.g. stroke) are excluded, demented patients were found to experience half of the LCU load in comparison to controls (30.70 vs. 63.42). In both groups the level of LCU load is far below 100 which is the threshold suggested for the induction of psychosomatic disorders. Conclusively, the current study suggests that there is no causal role for life events in the etiopathogenesis of dementia. On the contrary, demented patients even the last few months before the clinical onset of dementia experience low life-events-related stress, possibly because of subclinical impairment which is already present.
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Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimers disease.
Paul Hollingworth, Denise Harold, Rebecca Sims, Amy Gerrish, Jean-Charles Lambert, Minerva M Carrasquillo, Richard Abraham, Marian L Hamshere, Jaspreet Singh Pahwa, Valentina Moskvina, Kimberley Dowzell, Nicola Jones, Alexandra Stretton, Charlene Thomas, Alex Richards, Dobril Ivanov, Caroline Widdowson, Jade Chapman, Simon Lovestone, John Powell, Petroula Proitsi, Michelle K Lupton, Carol Brayne, David C Rubinsztein, Michael Gill, Brian Lawlor, Aoibhinn Lynch, Kristelle S Brown, Peter A Passmore, David Craig, Bernadette McGuinness, Stephen Todd, Clive Holmes, David Mann, A David Smith, Helen Beaumont, Donald Warden, Gordon Wilcock, Seth Love, Patrick G Kehoe, Nigel M Hooper, Emma R L C Vardy, John Hardy, Simon Mead, Nick C Fox, Martin Rossor, John Collinge, Wolfgang Maier, Frank Jessen, Eckart Rüther, Britta Schürmann, Reiner Heun, Heike Kölsch, Hendrik van den Bussche, Isabella Heuser, Johannes Kornhuber, Jens Wiltfang, Martin Dichgans, Lutz Frölich, Harald Hampel, John Gallacher, Michael Hüll, Dan Rujescu, Ina Giegling, Alison M Goate, John S K Kauwe, Carlos Cruchaga, Petra Nowotny, John C Morris, Kevin Mayo, Kristel Sleegers, Karolien Bettens, Sebastiaan Engelborghs, Peter P De Deyn, Christine Van Broeckhoven, Gill Livingston, Nicholas J Bass, Hugh Gurling, Andrew McQuillin, Rhian Gwilliam, Panagiotis Deloukas, Ammar Al-Chalabi, Christopher E Shaw, Magda Tsolaki, Andrew B Singleton, Rita Guerreiro, Thomas W Mühleisen, Markus M Nöthen, Susanne Moebus, Karl-Heinz Jöckel, Norman Klopp, H-Erich Wichmann, V Shane Pankratz, Sigrid B Sando, Jan O Aasly, Maria Barcikowska, Zbigniew K Wszolek, Dennis W Dickson, Neill R Graff-Radford, Ronald C Petersen, , Cornelia M van Duijn, Monique M B Breteler, M Arfan Ikram, Anita L Destefano, Annette L Fitzpatrick, Oscar Lopez, Lenore J Launer, Sudha Seshadri, Claudine Berr, Dominique Campion, Jacques Epelbaum, Jean-Francois Dartigues, Christophe Tzourio, Annick Alpérovitch, Mark Lathrop, Thomas M Feulner, Patricia Friedrich, Caterina Riehle, Michael Krawczak, Stefan Schreiber, Manuel Mayhaus, S Nicolhaus, Stefan Wagenpfeil, Stacy Steinberg, Hreinn Stefansson, Kari Stefansson, Jón Snaedal, Sigurbjorn Bjornsson, Palmi V Jonsson, Vincent Chouraki, Benjamin Genier-Boley, Mikko Hiltunen, Hilkka Soininen, Onofre Combarros, Diana Zelenika, Marc Delepine, María J Bullido, Florence Pasquier, Ignacio Mateo, Ana Frank-García, Elisa Porcellini, Olivier Hanon, Eliecer Coto, Victoria Alvarez, Paolo Bosco, Gabriele Siciliano, Michelangelo Mancuso, Francesco Panza, Vincenzo Solfrizzi, Benedetta Nacmias, Sandro Sorbi, Paola Bossù, Paola Piccardi, Beatrice Arosio, Giorgio Annoni, Davide Seripa, Alberto Pilotto, Elio Scarpini, Daniela Galimberti, Alexis Brice, Didier Hannequin, Federico Licastro, Lesley Jones, Peter A Holmans, Thorlakur Jonsson, Matthias Riemenschneider, Kevin Morgan, Steven G Younkin, Michael J Owen, Michael O'Donovan, Philippe Amouyel, Julie Williams.
Nat. Genet.
PUBLISHED: 03-10-2011
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We sought to identify new susceptibility loci for Alzheimers disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimers Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ? 1 × 10(-5). We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10(-17); including ADGC data, meta P = 5.0 × 10(-21)) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10(-14); including ADGC data, meta P = 1.2 × 10(-16)) are new Alzheimers disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10(-4); including ADGC data, meta P = 8.6 × 10(-9)), CD33 (GERAD+, P = 2.2 × 10(-4); including ADGC data, meta P = 1.6 × 10(-9)) and EPHA1 (GERAD+, P = 3.4 × 10(-4); including ADGC data, meta P = 6.0 × 10(-10)).
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Detection of elevated antibodies against SR protein kinase 1 in the serum of Alzheimers disease patients.
J. Neuroimmunol.
PUBLISHED: 03-08-2011
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Autoantibodies targeting specific cellular antigens are often present in sera and cerebrospinal fluids (CSFs) of patients with Alzheimers disease (AD) and could play a role in the onset and/or progression of the disease. In this study we identified SR Protein Kinase 1 (SRPK1) as a new autoantigen elevated in AD. SRPK1, the prototype of the serine/arginine family of kinases, has been implicated in the regulation of multiple cellular processes such as pre-mRNA splicing, cell proliferation, chromatin structure, nuclear import and germ cell development. Using an ELISA assay, anti-SRPK1 antibodies, targeting mainly the first catalytic domain of the kinase, were detected in sera of patients with AD, at significantly elevated levels as compared to control subjects. The findings of this study document for the first time the existence of antibodies targeting SRPK1 in human sera and are indicative of a correlation between the levels of a-SRPK1 antibodies and the incidence of AD.
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Clinical efficacy of aniracetam, either as monotherapy or combined with cholinesterase inhibitors, in patients with cognitive impairment: a comparative open study.
CNS Neurosci Ther
PUBLISHED: 02-26-2011
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Dementia constitutes an increasingly prevalent cognitive disorder with serious socioeconomic implications.
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AddNeuroMed and ADNI: similar patterns of Alzheimers atrophy and automated MRI classification accuracy in Europe and North America.
Neuroimage
PUBLISHED: 02-14-2011
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The European Union AddNeuroMed program and the US-based Alzheimer Disease Neuroimaging Initiative (ADNI) are two large multi-center initiatives designed to collect and validate biomarker data for Alzheimers disease (AD). Both initiatives use the same MRI data acquisition scheme. The current study aims to compare and combine magnetic resonance imaging (MRI) data from the two study cohorts using an automated image analysis pipeline and a multivariate data analysis approach. We hypothesized that the two cohorts would show similar patterns of atrophy, despite demographic differences and could therefore be combined. MRI scans were analyzed from a total of 1074 subjects (AD=295, MCI=444 and controls=335) using Freesurfer, an automated segmentation scheme which generates regional volume and regional cortical thickness measures which were subsequently used for multivariate analysis (orthogonal partial least squares to latent structures (OPLS)). OPLS models were created for the individual cohorts and for the combined cohort to discriminate between AD patients and controls. The ADNI cohort was used as a replication dataset to validate the model created for the AddNeuroMed cohort and vice versa. The combined cohort model was used to predict conversion to AD at baseline of MCI subjects at 1 year follow-up. The AddNeuroMed, the ADNI and the combined cohort showed similar patterns of atrophy and the predictive power was similar (between 80 and 90%). The combined model also showed potential in predicting conversion from MCI to AD, resulting in 71% of the MCI converters (MCI-c) from both cohorts classified as AD-like and 60% of the stable MCI subjects (MCI-s) classified as control-like. This demonstrates that the methods used are robust and that large data sets can be combined if MRI imaging protocols are carefully aligned.
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Deep sequencing of the Nicastrin gene in pooled DNA, the identification of genetic variants that affect risk of Alzheimers disease.
PLoS ONE
PUBLISHED: 01-27-2011
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Nicastrin is an obligatory component of the ?-secretase; the enzyme complex that leads to the production of A? fragments critically central to the pathogenesis of Alzheimers disease (AD). Analyses of the effects of common variation in this gene on risk for late onset AD have been inconclusive. We investigated the effect of rare variation in the coding regions of the Nicastrin gene in a cohort of AD patients and matched controls using an innovative pooling approach and next generation sequencing. Five SNPs were identified and validated by individual genotyping from 311 cases and 360 controls. Association analysis identified a non-synonymous rare SNP (N417Y) with a statistically higher frequency in cases compared to controls in the Greek population (OR 3.994, CI 1.105-14.439, p = 0.035). This finding warrants further investigation in a larger cohort and adds weight to the hypothesis that rare variation explains some of genetic heritability still to be identified in Alzheimers disease.
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Automated hippocampal shape analysis predicts the onset of dementia in mild cognitive impairment.
Neuroimage
PUBLISHED: 01-14-2011
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The hippocampus is involved at the onset of the neuropathological pathways leading to Alzheimers disease (AD). Individuals with mild cognitive impairment (MCI) are at increased risk of AD. Hippocampal volume has been shown to predict which MCI subjects will convert to AD. Our aim in the present study was to produce a fully automated prognostic procedure, scalable to high throughput clinical and research applications, for the prediction of MCI conversion to AD using 3D hippocampal morphology. We used an automated analysis for the extraction and mapping of the hippocampus from structural magnetic resonance scans to extract 3D hippocampal shape morphology, and we then applied machine learning classification to predict conversion from MCI to AD. We investigated the accuracy of prediction in 103 MCI subjects (mean age 74.1 years) from the longitudinal AddNeuroMed study. Our model correctly predicted MCI conversion to dementia within a year at an accuracy of 80% (sensitivity 77%, specificity 80%), a performance which is competitive with previous predictive models dependent on manual measurements. Categorization of MCI subjects based on hippocampal morphology revealed more rapid cognitive deterioration in MMSE scores (p<0.01) and CERAD verbal memory (p<0.01) in those subjects who were predicted to develop dementia relative to those predicted to remain stable. The pattern of atrophy associated with increased risk of conversion demonstrated initial degeneration in the anterior part of the cornus ammonis 1 (CA1) hippocampal subregion. We conclude that automated shape analysis generates sensitive measurements of early neurodegeneration which predates the onset of dementia and thus provides a prognostic biomarker for conversion of MCI to AD.
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Effectiveness of nonpharmacological approaches in patients with mild cognitive impairment.
Neurodegener Dis
PUBLISHED: 08-20-2010
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Mild cognitive impairment (MCI) patients are at increased risk of developing dementia. There is a conflict if cognitive interventions can improve cognitive and functional performances in order to delay the development of dementia.
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Memantine for patients with Parkinsons disease dementia or dementia with Lewy bodies: a randomised, double-blind, placebo-controlled trial.
Lancet Neurol
PUBLISHED: 08-20-2010
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Previous studies have suggested that patients with Lewy-body-related dementias might benefit from treatment with the N-methyl D-aspartate receptor antagonist memantine, but further data are needed. Therefore, the efficacy and safety of memantine were investigated in patients with mild to moderate Parkinsons disease dementia (PDD) or dementia with Lewy bodies (DLB).
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Association between white matter hyperintensities and executive decline in mild cognitive impairment is network dependent.
Neurobiol. Aging
PUBLISHED: 07-13-2010
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White matter hyperintensities (WMH) in Mild Cognitive Impairment (MCI) have been associated with impaired executive functioning, although contradictory findings have been reported. The aim of this study was to examine whether WMH location influenced the relation between WMH and executive functioning in MCI participants (55-90 years) in the European multicenter memory-clinic-based DESCRIPA study, who underwent MRI scanning at baseline (N = 337). Linear mixed model analysis was performed to test the association between WMH damage in three networks (frontal-parietal, frontal-subcortical and frontal-parietal-subcortical network) and change in executive functioning over a 3-year period. WMH in the frontal-parietal and in the frontal-parietal-subcortical network were associated with decline in executive functioning. However, the frontal-subcortical network was not associated with change in executive functioning. Our results suggest that parietal WMH are a significant contributor to executive decline in MCI and that investigation of WMH in the cerebral networks supporting cognitive functions provide a new way to differentiate stable from cognitive declining MCI individuals.
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Multivariate analysis of MRI data for Alzheimers disease, mild cognitive impairment and healthy controls.
Neuroimage
PUBLISHED: 06-03-2010
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We have used multivariate data analysis, more specifically orthogonal partial least squares to latent structures (OPLS) analysis, to discriminate between Alzheimers disease (AD), mild cognitive impairment (MCI) and elderly control subjects combining both regional and global magnetic resonance imaging (MRI) volumetric measures. In this study, 117 AD patients, 122 MCI patients and 112 control subjects (from the AddNeuroMed study) were included. High-resolution sagittal 3D MP-RAGE datasets were acquired from each subject. Automated regional segmentation and manual outlining of the hippocampus were performed for each image. Altogether this yielded volumes of 24 different anatomically defined structures which were used for OPLS analysis. 17 randomly selected AD patients, 12 randomly selected control subjects and the 22 MCI subjects who converted to AD at 1-year follow up were excluded from the initial OPLS analysis to provide a small external test set for model validation. Comparing AD with controls we found a sensitivity of 87% and a specificity of 90% using hippocampal measures alone. Combining both global and regional measures resulted in a sensitivity of 90% and a specificity of 94%. This increase in sensitivity and specificity resulted in an increase of the positive likelihood ratio from 9 to 15. From the external test set, the model predicted 82% of the AD patients and 83% of the control subjects correctly. Finally, 73% of the MCI subjects which converted to AD at 1 year follow-up were shown to resemble AD patients more closely than controls. This method shows potential for distinguishing between different patient groups. Combining the different MRI measures together resulted in a significantly better classification than using them separately. OPLS also shows potential for predicting conversion from MCI to AD.
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Drug profile: transdermal rivastigmine patch in the treatment of Alzheimer disease.
CNS Neurosci Ther
PUBLISHED: 04-16-2010
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Cholinesterase inhibitors constitute one of the mainstays of treatment of Alzheimer disease (AD). Gastrointestinal side effects, difficulty accessing therapeutic doses and poor patient compliance have been identified as barriers to effective treatment with these substances. The rivastigmine transdermal patch provides continuous delivery of drug through the skin into the bloodstream, avoiding the fluctuations in plasma concentration associated with oral administration. This pharmacokinetic profile is associated with reduced side effects, resulting in easier access to expected target doses. These benefits, along with other practical advantages of the transdermal patch, may contribute to enhanced patient compliance. Here, we present a review of the current literature on rivastigmine patch, and offer advice based on our own collective clinical experience. Rivastigmine patch provides an efficient option for managing patients with AD, to be considered among the first line therapies for the disease.
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Cerebrospinal fluid proteins in the diagnosis of Alzheimers disease.
Recent Pat CNS Drug Discov
PUBLISHED: 03-01-2010
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Alzheimers disease (AD) is rapidly grooving incidence that affects millions of people worldwide, therefore there is an immediate need for its early and accurate diagnosis. Many research studies have been performed on possible accurate and reliable diagnostic biomarkers of AD. This review study provides an overview on the cerebrospinal fluid (CSF) proteins that are used as biochemical markers for the early diagnosis of AD and their future prospects, as well as relevant patents.
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Depression, extrapyramidal symptoms, dementia and an unexpected outcome: a case report.
Cases J
PUBLISHED: 02-02-2010
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The diagnosis of Parkinsons disease is mainly clinical. DaT SCAN may help in difficult cases. Depression is also a clinical diagnosis and is common and persistent symptom in Parkinsons disease. Dementia is very often in Parkinsons disease, but usually not at the first stages. The treatment of each of the above symptoms is difficult and a lot of times individualized.
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Analysis of regional MRI volumes and thicknesses as predictors of conversion from mild cognitive impairment to Alzheimers disease.
Neurobiol. Aging
PUBLISHED: 01-25-2010
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We determined predictors of conversion to Alzheimers disease (AD) from mild cognitive impairment (MCI) with automated magnetic resonance imaging (MRI) regional cortical volume and thickness measures. One hundred amnestic MCI subjects, 118 AD patients, and 94 age-matched healthy controls were selected from AddNeuroMed study. Twenty-four regional cortical volumes and 34 cortical thicknesses were measured with automated image processing software at baseline. Twenty-one subjects converted from MCI to AD determined with the cognitive tests at baseline and 1 year later. The hippocampus, amygdala, and caudate volumes were significantly smaller in progressive MCI subjects than in controls and stable MCI subjects. The cortical volumes achieved higher predictive accuracy than did cognitive tests or cortical thickness. Combining the volumes, thicknesses, and cognitive tests did not improve the accuracy. The volume of amygdala and caudate were independent variables in predicting conversion from MCI to AD. We conclude that regional cortical volume measures are more powerful than those common cognitive tests we used in identifying AD patients at the very earliest stage of the disease.
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Severely stressful events and dementia: a study of an elderly Greek demented population.
Psychiatry Res
PUBLISHED: 01-15-2010
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There is evidence that proneness to experience psychological distress is a risk factor for Alzheimers disease (AD). In the present study, an attempt is made to examine the possible association between stressful events and cognitive impairment of the elderly, based on a sample of 1271 patients (500 male, 771 female) diagnosed with dementia according to the DSM-IV criteria and 140 age- and gender-matched cognitive healthy subjects. All patients were recruited from the Memory and Dementia Outpatient Clinic of the 3rd University Department of Neurology in "G. Papanikolaou" General Hospital, Thessaloniki, and examined over a period of 7 years. The majority of patients reported a history of a stressful event before the onset of dementia (n=990, 77.9%), while fewer patients reported insidious onset (n=281, 22.1%). The most frequently reported event was the announcement of a life threatening disease (n=472, 37.1%), followed by problems within the family (n=157, 12.4%), spouse death (n = 100, 7.9%), death of a sibling or other beloved person (n=77, 6.1%). Only 55% of the control subjects encountered stressful events, which is significantly different from the percentage of the study group. Our results demonstrate that a stressful event in the elderly could potentially trigger a cognitive decline.
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MRI measures of Alzheimers disease and the AddNeuroMed study.
Ann. N. Y. Acad. Sci.
PUBLISHED: 11-13-2009
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Here we describe the AddNeuroMed multicenter magnetic resonance imaging (MRI) study for longitudinal assessment in Alzheimers disease (AD). The study is similar to a faux clinical trial and has been established to assess longitudinal MRI changes in AD, mild cognitive impairment (MCI), and healthy control subjects using an image acquisition protocol compatible with the Alzheimers Disease Neuroimaging Initiative (ADNI). The approach consists of a harmonized MRI acquisition protocol across centers, rigorous quality control, a central data analysis hub, and an automated image analysis pipeline. Comprehensive quality control measures have been established throughout the study. An intelligent web-accessible database holds details on both the raw images and data processed using a sophisticated image analysis pipeline. A total of 378 subjects were recruited (130 AD, 131 MCI, 117 healthy controls) of which a high percentage (97.3%) of the T1-weighted volumes passed the quality control criteria. Measurements of normalized whole brain volume, whole brain cortical thickness, and point-by-point group-based cortical thickness measurements, demonstrating the power of the automated image analysis techniques employed, are reported.
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AddNeuroMed--the European collaboration for the discovery of novel biomarkers for Alzheimers disease.
Ann. N. Y. Acad. Sci.
PUBLISHED: 11-13-2009
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There is an urgent need for Alzheimers disease (AD) biomarkers-especially in the context of clinical trials. Biomarkers for early diagnosis, disease progression, and prediction are most critical, and disease-modification therapy development may depend on the discovery and validation of such markers. AddNeuroMed is a cross European, public/private consortium developed for AD biomarker discovery. We report here the development and design of AddNeuroMed and the progress toward the development of plasma markers. Despite the obstacles to such markers, we have identified a range of markers including CFH and A2M, both of which have been independently replicated. The experience of AddNeuroMed leads us to three overall conclusions. First, collaboration is essential. Second, design is paramount and combining modalities, such as imaging and proteomics, may be informative. Third, animal models are valuable in biomarker research. Most importantly, we have learned that plasma markers are feasible.
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Long-term treatment of patients with Alzheimers disease in primary and secondary care: results from an international survey.
Curr Med Res Opin
PUBLISHED: 10-27-2009
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The International Outcomes Survey in Dementia (IOSID) was initiated to observe the effects of current standard of care for Alzheimers disease (AD) on patient outcomes and caregiver burden in a real-life setting.
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Prevalence and prognostic value of CSF markers of Alzheimers disease pathology in patients with subjective cognitive impairment or mild cognitive impairment in the DESCRIPA study: a prospective cohort study.
Lancet Neurol
PUBLISHED: 06-10-2009
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Alzheimers disease (AD) pathology is common in patients with amnestic mild cognitive impairment (aMCI) without dementia, but the prevalence of AD pathology in patients with subjective cognitive impairment (SCI) and non-amnestic mild cognitive impairment (naMCI) is unknown. AD is characterised by decreased CSF concentrations of Abeta(42) and increased concentrations of tau. We investigated the prevalence of a CSF AD profile in patients with SCI, naMCI, or aMCI and the association of this profile with cognitive outcome in each group.
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Combination analysis of neuropsychological tests and structural MRI measures in differentiating AD, MCI and control groups--the AddNeuroMed study.
Neurobiol. Aging
PUBLISHED: 05-19-2009
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To study the ability of neuropsychological tests, manual MRI hippocampal volume measures, regional volume and cortical thickness measures to identify subjects with Alzheimers disease (AD), mild cognitive impairment (MCI), and healthy age-matched controls. Neuropsychological tests, manual hippocampal volume, automated regional volume and regional cortical thickness measures were performed in 120 AD patients, 120 MCI subjects, and 111 controls. The regional cortical thickness and volumes in MCI subjects were significantly decreased in limbic/paralimbic areas and temporal lobe compared to controls. Atrophy was much more extensive in the AD patients compared to MCI subjects and controls. The combination of neuropsychological tests and volumes revealed the highest accuracy (82% AD vs. MCI; 94% AD vs. control; 83% MCI vs. control). Adding regional cortical thicknesses into the discriminate analysis did not improve accuracy. We conclude that regional cortical thickness and volume measures provide a panoramic view of brain atrophy in AD and MCI subjects. A combination of neuropsychological tests and regional volumes are important when discriminating AD from healthy controls and MCI.
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Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimers disease.
Nat. Genet.
PUBLISHED: 04-28-2009
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We undertook a two-stage genome-wide association study (GWAS) of Alzheimers disease (AD) involving over 16,000 individuals, the most powerful AD GWAS to date. In stage 1 (3,941 cases and 7,848 controls), we replicated the established association with the apolipoprotein E (APOE) locus (most significant SNP, rs2075650, P = 1.8 x 10(-157)) and observed genome-wide significant association with SNPs at two loci not previously associated with the disease: at the CLU (also known as APOJ) gene (rs11136000, P = 1.4 x 10(-9)) and 5 to the PICALM gene (rs3851179, P = 1.9 x 10(-8)). These associations were replicated in stage 2 (2,023 cases and 2,340 controls), producing compelling evidence for association with Alzheimers disease in the combined dataset (rs11136000, P = 8.5 x 10(-10), odds ratio = 0.86; rs3851179, P = 1.3 x 10(-9), odds ratio = 0.86).
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Rivastigmine for Alzheimers disease.
Cochrane Database Syst Rev
PUBLISHED: 04-17-2009
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Alzheimers disease (AD) is the commonest cause of dementia affecting older people. One of the therapeutic strategies aimed at ameliorating the clinical manifestations of Alzheimers disease is to enhance cholinergic neurotransmission in relevant parts of the brain by the use of cholinesterase inhibitors to delay the breakdown of acetylcholine released into synaptic clefts. Tacrine, the first of the cholinesterase inhibitors to undergo extensive trials for this purpose, was associated with significant adverse effects including hepatotoxicity. Other cholinesterase inhibitors, including rivastigmine, with superior properties in terms of specificity of action and low risk of adverse effects, have now been introduced. Rivastigmine has received approval for use in 60 countries including all member states of the European Union and the USA.
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Eradication of Helicobacter pylori may be beneficial in the management of Alzheimers disease.
J. Neurol.
PUBLISHED: 02-25-2009
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Infectious agents have been proposed as potential causes of Alzheimers disease (AD). Recently, we documented a high prevalence of Helicobacter pylori (Hp) infection in patients with AD. We aim to access the effect of Hp eradication on the AD cognitive (MMSE: Mini Mental State Examination and CAMCOG: Cambridge Cognitive Examination for the Elderly) and functional (FRSSD: Functional Rating Scale for Symptoms of Dementia) status parameters. In the first part of the study, a total of 50 consecutive patients with AD and 30 age-matched anaemic controls underwent an upper gastrointestinal endoscopy, and gastric mucosal biopsies were obtained to detect the presence of Hp infection by histologic analysis and rapid urease test. Serum anti-Hp-specific IgG level was analysed by enzyme-linked immunosorbent assay. In the second part, Hp-positive AD patients received a triple eradication regimen (omeprazole, clarithromycin and amoxicillin), and all patients were followed up for 2 years, while under the same treatment with cholinesterase inhibitors. Hp was detected in 88% of AD patients and in 46.7% of controls (P < 0.001). Hp eradication was successful in 84.8% of treated patients. At the 2-year clinical endpoint, cognitive and functional status parameters improved in the subgroup of patients where Hp eradication was successful (P < 0.001 and P = 0.049 for MMSE and CAMCOG, respectively; P < 0.001 for FRSSD), but not in the other patients. Hp eradication may positively influence AD manifestations, suggesting a possible common link between Hp and AD.
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Male patient with mild cognitive impairment and extremely high P300 and Slow-wave latencies: a case report.
Cases J
PUBLISHED: 02-23-2009
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We present a case of a 74-year-old Greek male who suffered from paraphasias, memory and orientation problems. The patient was assessed with neuropsychometric tests, auditory event-related potentials and cerebrospinal fluid proteins and was diagnosed with mild cognitive impairment. The emphasis on the case is on the unexplained high levels of P300 and Slow wave of the auditory event-related potentials. P300 is believed to be delayed in Alzheimers Disease (AD), however in our case it was extremely prolonged in baseline and follow-up examinations without AD being diagnosed. This might suggest that AD is a complex and multifactorial disease.
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Alzheimers dementia and post-traumatic stress disorder differences and similarities in neuroimaging.
Hell J Nucl Med
PUBLISHED: 02-07-2009
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There are studies supporting the suggestion that a severe psychological stress in the elderly can be the risk factor of Alzheimers dementia (AB) and other types of dementia. We have reviewed the findings of single photon emission tomography, positron emission tomography, magnetic resonance imaging and functional magnetic resonance imaging (fMRI), related to brain function and structure in AD and in post traumatic stress disorder (PTSD). There is evidence that prefrontal and orbitofrontal cortices dysfunction contributes to PTSD symptomatology. Similarities between the two different aforementioned diseases exist in the areas of (a) medial temporal lobe, (b) hippocampus and (c) cingulated cortex.
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Alzheimers disease biomarker discovery using in silico literature mining and clinical validation.
J Transl Med
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Alzheimers Disease (AD) is the most widespread form of dementia in the elderly but despite progress made in recent years towards a mechanistic understanding, there is still an urgent need for disease modification therapy and for early diagnostic tests. Substantial international efforts are being made to discover and validate biomarkers for AD using candidate analytes and various data-driven omics approaches. Cerebrospinal fluid is in many ways the tissue of choice for biomarkers of brain disease but is limited by patient and clinician acceptability, and increasing attention is being paid to the search for blood-based biomarkers. The aim of this study was to use a novel in silico approach to discover a set of candidate biomarkers for AD.
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