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To investigate the association of the change in practice of leisure and social activities with dementia risk taking into account the evolution of cognitive performances. From the PAQUID prospective cohort re-examined every 2 years until the 20-year follow-up since 1988, 1461 subjects were seen at 10th year of follow-up. Engagement in 10 leisure and social activities was collected at baseline and at the 10-year follow-up visit for 805 subjects. Four categories of change in activity engagement were considered: subjects who remained active; remained inactive; became inactive and became active. Adjustment on confounders (age, gender, educational level, diabetes, stroke and depression) and rate of evolution of cognitive performances was made with the multivariate Cox proportional hazards model. Time to incident cases of dementia occurring between the 10th and the 20th year of follow-up. A total of 258 incident dementia cases were documented. The risk of dementia was lower for subjects remaining or becoming active (cumulative risk of dementia: 30%) compared to those remaining or becoming inactive (52% and 42%, respectively) (p

A better knowledge of long-term trajectories of cognitive decline is a central feature of the study of the process leading to Alzheimer's dementia. Several factors may mitigate such decline, among which is education, a major risk factor for Alzheimer's disease. The aim of our work was to compare the pattern and duration of clinical trajectories before Alzheimer's dementia in individuals with low and high education within the PAQUID cohort involving 20 years of follow-up. The sample comprises 442 participants with incident Alzheimer's disease (27.2% were male)--171 with low education (mean age=86.2 years; standard deviation=5.3 years) and 271 with higher education (mean age=86.5; standard deviation=5.4)--and 442 control subjects matched according to age, sex and education. At each visit and up to the 20-year follow-up visit, several cognitive and clinical measures were collected and incident cases of Alzheimer's disease clinically diagnosed. The evolution of clinical measures in pre-demented subjects and matched controls was analysed with a semi-parametric extension of the mixed effects linear model. The results show that the first signs of cognitive decline occurred 15 to 16 years before achieving dementia threshold in higher-educated subjects whereas signs occurred at 7 years before dementia in low-educated subjects. There seemed to be two successive periods of decline in higher-educated subjects. Decline started ∼15 to 16 years before dementia with subtle impairment restricted to some cognitive tests and with no impact during the first 7 to 8 years on global cognition, cognitive complaints, or activities of daily living scales. Then, ∼7 years before dementia, global cognitive abilities begin to deteriorate, along with difficulties dealing with complex activities of daily living, the increase in self-perceived difficulties and depressive symptoms. By contrast, lower-educated subjects presented a single period of decline lasting ∼7 years, characterized by decline concomitantly affecting specific and more global cognitive function along with alteration in functional abilities. This study demonstrates how early cognitive symptoms may emerge preceding Alzheimer's dementia particularly in higher-educated individuals, for whom decline occurred up to 16 years before dementia. It also demonstrates the protective role of education in the clinical trajectory preceding Alzheimer's dementia. We suggest that the initial decline in cognition occurs at the onset of comparable Alzheimer's disease pathology in both groups, and is associated with immediate decline to dementia in the lower education group. In contrast, higher education protects against further cognitive decline for ∼7 years until pathology becomes more severe.

Background/Aims: This study was designed to develop a practical risk score for predicting 5-year survival after the diagnosis of dementia. Methods: Using the Paquid Study (prospective, population-based, long-term cohort study), we created a prognosis score with incident cases of dementia and validated it in another prospective, population-based, long-term cohort study, the Three City Study. -Results: Among the 3,777 subjects enrolled in the Paquid Study, 454 incident cases of dementia were included in this study. After a 5-year follow-up period, 319 (70.3%) were deceased. The score was constructed from three independent prognostic variables (gender, age at diagnosis and number of ADL restricted). The discriminant ability of the score was good with a c index of 0.754. Sensitivity was 64.7% and specificity 76.3%. In the validation cohort, the discriminant ability of the prognostic score with c statistics was 0.700. Sensitivity was 26.3% and specificity 95.4%. Conclusions: The prognostic factors selected in the predictive model are easily assessable, so this simple score could provide helpful information for the management of dementia, particularly to identify patients with duration of the disease greater than 5 years.

BACKGROUND AND PURPOSE: Stroke volume, an increasingly used end point in phase II trials, is considered stationary at least 30 days after the ictus. We investigated whether information conveyed by MR imaging measurements of the “final” infarct volume could be assessed as early as the subacute stage (days 3–6), rather than waiting for the chronic stage (days 30–45). MATERIALS AND METHODS: Ninety-five patients with middle cerebral artery stroke prospectively included in a multicenter study underwent MR imaging during the first 12 hours (MR imaging-1), between days 3 and 6 (MR imaging-2), and between days 30 and 45 (MR imaging-3). We first investigated the relationship between subacute (FLAIR-2) and chronic volumes (FLAIR-3), by using a linear regression model. We then tested the relationship between FLAIR volumes (either FLAIR-2 or FLAIR-3) and functional disability, measured by the mRS at the time of MR imaging-3, by using logistic regression. The performances of the models were assessed by using the AUC in ROC. RESULTS: A linear association between log FLAIR-2 and log FLAIR-3 volumes was observed. The proportion of FLAIR-3 variation, explained by FLAIR-2, was high (R2 = 81%), without a covariate that improved this percentage. Both FLAIR-2 and FLAIR-3 were independent predictors of mRS (OR, 0.79 and 0.73; 95% CI, 0.64–0.97 and 0.56–0.96; P = .026 and .023). The performances of the models for the association between either FLAIR volume and mRS did not differ (AUC = 0.897 for FLAIR-2 and 0.888 for FLAIR-3). CONCLUSIONS: Stroke damage may be assessed by a subacute volume because subacute volume predicts the “true” final volume and provides the same clinical prognosis.

Purpose To evaluate the reproducibility of fluid attenuated inversion recovery (FLAIR) and four other magnetic resonance imaging (MRI) sequences in the quantitative assessment of final cerebral infarct volume. Materials and Methods FLAIR, T1-3D, magnetization transfer ratio (MTR)-map, diffusion-weighted trace (DWI)-trace, and apparent diffusion coefficient (ADC)-map, were acquired and measured in 33 patients 30–45 days after onset of a first-ever ischemic stroke. The infarct area was visually detected and manually delineated two times by two readers separately after images and sequences randomization. The reliability was assessed by using an intraclass correlation coefficient (ICC) and its two-sided 95% confidence interval (95% CI). Results DWI-trace had the best reliability, with an ICC of 0.96 (95% CI = 0.93–0.98). FLAIR had an ICC of 0.86 (95% CI = 0.73–0.93), and a much higher volume. T1-3D, MTR-map and ADC-map had lower reliability or excessive volume values equal to 0 in comparison to DWI-trace. Conclusion DWI-trace performed within 30th and 45th day following onset of acute ischemic stroke was the most reliable sequence for final infarct volume quantification. This sequence should be added to FLAIR evaluation to strengthen the statistical results of the pharmacological trials and reduce their variability. J. Magn. Reson. Imaging 2009;29:1280–1284. © 2009 Wiley-Liss, Inc.

The primary objective of the open-label extension was to evaluate the long-term safety and tolerability of a transdermal rivastigmine patch up to 1 year, as a novel approach to treatment in Alzheimer disease. This was a 28-week extension to a 24-week, double-blind, double-dummy, placebo-controlled, and active-controlled study evaluating rivastigmine patches [9.5 mg/24 h (10 cm2) and 17.4 mg/24 h (20 cm2)] and oral capsules (3 to 6 mg twice-daily). Patients entering the extension were switched directly to 9.5 mg/ 24 h rivastigmine patch and increased to 17.4 mg/24 h patch, irrespective of their double-blind study treatment. Primary measures included safety and tolerability assessments, including adverse events and serious adverse events. Of 1195 patients randomized to treatment, 870 (72.8%) completed the double-blind study and entered the open-label extension. During weeks 1 to 4 of the extension, 9.5 mg/24 h rivastigmine patch was well tolerated overall by patients formerly randomized to rivastigmine capsule or patch groups: < or =2.5% reported nausea and < or =1.9% reported vomiting. No unexpected safety issues arose, and skin tolerability was good; similar to the double-blind study. During the 28-week, open-label extension phase, the patch seemed to be well tolerated with a favorable safety profile.

Objective Whereas cognitive deficits are known to be detectable long before the typical symptoms of Alzheimer's disease (AD) are evident, previous studies have failed to determine when cognitive functioning actually begins to decline before dementia. Utilizing the long follow-up of the PAQUID study, we examined the emergence of the first clinical symptoms over a 14-year period of follow-up before the dementia phase of AD. Methods This study relies on a case–control sample selected from the PAQUID cohort. Of the 3,777 initial subjects of the cohort, 350 subjects experienced development of AD during the 14 years of follow-up. The cases were matched to 350 elderly control subjects. The evolution of scores on cognitive, functional, and depression scales was described throughout the 14-year follow-up using a semiparametric extension of the mixed-effects linear model. Results The first decline in cognitive performances appeared as early as 12 years before dementia in measures of semantic memory and conceptual formation. Then, more global deficits appeared that were concomitant with an increase in memory complaints and depressive symptoms. About 2 years later, as a consequence of cognitive dysfunction, the subjects started to become slightly dependent in their activities of daily living. In the last 3 years, the impairment significantly worsened until the subjects reached the dementia phase. Interpretation This approach, describing the 14 years preceding dementia, provides a clear illustration of the particularly long and progressive prodromal phase of AD, and shows the successive emergence of cognitive deficits, depressive symptoms, and functional impairment during this phase. Ann Neurol 2008;64:492–498

Resume Cette revue presente divers aspects des demences vasculaires (DV), dont la definition a bien evolue depuis la demence par infarctus multiple de Hachinski. Nous avons aborde plus particulierement les criteres diagnostiques actuels des demences vasculaires, leur histoire naturelle encore mal connue, leurs aspects neuroradiologiques morphologiques et fonctionnels, les difficultes de l’epidemiologie de ces affections, la notion recente de liens avec la maladie d’Alzheimer et le probleme des demences dites mixtes. L’evolution du concept de demences vasculaires vers une notion plus large de « desordres cognitifs d’origine vasculaire », incluant un stade de trouble cognitif vasculaire dans lequel le sujet n’est pas dement, est evoquee. Enfin, une breve revue des traitements actuels est presentee.

Alzheimer disease (AD) has a significant impact on caregivers. Administering and managing medications is one of their many daily tasks. More effective modes of drug administration may benefit patient and caregiver, and may improve compliance. A prospective outcome of the IDEAL (Investigation of TransDermal Exelon in ALzheimer's disease) trial was to evaluate caregiver preference for rivastigmine patches compared with capsules. The 24-week, randomized, double-blind, double-dummy, placebo- and active-controlled IDEAL trial investigated once-daily rivastigmine patches vs twice-daily capsules in moderate AD patients. Caregivers rated patch adhesion throughout. The AD Caregiver Preference Questionnaire (ADCPQ) assessed patch vs capsule from caregivers' perspective, based on expectations, preferences, and satisfaction with treatment. A total of 1,059 caregivers completed the ADCPQ while their respective patients were on study drug. More than 70% of caregivers preferred the patch to capsules overall. The patch was preferred to capsules with respect to ease of use (p < 0.0001) and ease of following the schedule (p < 0.0001). Caregivers indicated greater satisfaction overall (p < 0.0001) and less interference with daily life (p < 0.01) with the patch vs capsules. The preference substudy of the IDEAL trial demonstrated that caregivers of AD patients preferred patches to capsules for drug delivery. Preference for the patch may indicate reduced caregiver stress, substantiated by greater satisfaction and less interference with daily life. These benefits may lead to improved compliance.

Large prospective studies have established that sleep-disordered breathing (SDB) is associated with an increased incidence of cardiovascular and cerebrovascular diseases. Heterogeneous results have been published about SDB and ischaemic stroke mechanism. The aim of this study was to evaluate the relationship between poststroke apneic syndrome and stroke aetiologies according to the ASCO classification.A total of 134 patients with acute ischaemic cerebrovascular events were prospectively included. Patients with severe or infratentorial infarctions were excluded. Stroke risk factors and clinical characteristics were recorded in all patients. An overnight polygraphy was recorded (Embletta PDS). Apneic patients were defined if the polygraphy reported an apnea-hypopnea index ≥15. A standardized diagnosis workup, including serum biological investigation, evaluation of extra and intracranial arteries and heart morphology and function, was performed. Stroke mechanism was defined using ASCO and TOAST classifications.A proportion of 42% (56 of 134) of the patients were diagnosed as having sleep apneas. Apneic patients were older (p 0.001), had higher BMI (p = 0.02), and more were hypertensive (p 0.001). Using ASCO classification, a major cardioembolic source of stroke, mainly atrial fibrillation, was more frequently observed in apneic patients (41.1% vs. 20.5%, p 0.05), while no difference was observed when considering atherosclerosis or small-vessel disease mechanisms. Univariate analysis showed that cardioembolic stroke depends on sex, age, left atrial size and OSA; however, age remained the only significant factor in multivariate analysis.This study confirms the high prevalence of sleep apneas in stroke-affected patients and identifies atrial fibrillation as a major source of stroke in this population. The strong correlation between age and SDB seems to drive the increased frequency of stroke related to atrial fibrillation in this population.

Summary Background Intravenous tissue plasminogen activator is the only approved specific treatment for acute ischaemic stroke. Ancrod, a natural defibrinogenating agent from snake venom, has proved to have a favourable effect when given within 3 h after an acute ischaemic stroke. The European Stroke Treatment with Ancrod Trial was undertaken to assess the effects of ancrod when given within 6 h. Methods 1222 patients with an acute ischaemic stroke were included in this randomised double-blind placebo-controlled trial. Brain CT scans were done to exclude intracranial haemorrhages and large evolving ischaemic infarctions. Patients were randomly assigned ancrod (n=604) or placebo (n=618). The primary outcome was functional success at 3 months (survival, Barthel Index of 95 or 100, or return to prestroke level). The analysis was by intention-to-treat. This trial is registered with ClinicalTrials.gov, trial number NCT00343174. Findings Functional success at 3 months did not differ between patients given ancrod (42%) and those given placebo (42%) (p=0·94, OR=0·99, 95% CI, 0·76–1·29). Interpretation On the basis of our findings, ancrod should not be recommended for use in acute ischaemic stroke beyond 3 h.

Better knowledge of the preclinical phase of Alzheimer's disease would be an important advance to allow earlier treatment of this ominous disease. This prodromal period was investigated in the Paquid cohort by analysing change in cognitive performances at five time points over a 9 year period. Neuropsychological measures including global cognitive functioning (Mini-Mental State Examination), visuo-spatial memory (Benton Visual Retention Test), verbal fluency (Isaacs Set Test) and abstract thinking (Wechsler Similarities Test) were assessed in 215 future Alzheimer's disease subjects and 1050 individuals without dementia. The results showed that cognitive performances of the pre-morbid subjects at baseline were already lower than those of individuals without dementia (1.4 points less on the Mini-Mental State Examination; 1.8 points less on the Benton Visual Retention Test; 4 points less on the Isaacs Set Test and 0.8 points less on the Wechsler Similarities Test). For some neuropsychological tests, an acceleration of the decline occurred approximately 3 years before the diagnosis and, for each test, the course of decline was modulated by education level. These findings show that abnormally low performances can be evidenced 9 years before the clinical diagnosis of Alzheimer's disease in several domains of cognition beyond memory and that cognitive change over time can be influenced by education.

Resume Introduction L’expression clinique des lymphomes cerebraux primitifs peut etre polymorphe. Observation Nous rapportons le cas d’une patiente ayant presente des episodes neurologiques recidivants evocateurs d’une pathologie ischemique arterielle avec imagerie cerebrale normale. Tardivement, l’IRM mit en evidence une lesion pedonculaire dont la biopsie permit de porter le diagnostic de lymphome cerebral primitif de type B de haut grade de malignite. Conclusion Ce cas illustre la difficulte diagnostique de cette affection rare et de mauvais pronostic.

Background and Purpose— UK-279,276 (neutrophil inhibitory factor) reduced infarct volume in a rat middle cerebral artery occlusion reperfusion model. ASTIN (Acute Stroke Therapy by Inhibition of Neutrophils) was an adaptive phase 2 dose-response–finding, proof-of-concept study to establish whether UK-279,276 improves recovery in acute ischemic stroke. The prime objective was to determine the dose that gave a clinically relevant effect in patients. Methods— A Bayesian sequential design with real-time efficacy data capture and continuous reassessment of the dose response allowed double-blind, randomized, adaptive allocation to 1 of 15 doses (dose range, 10 to 120 mg) or placebo and early termination for efficacy or futility. The primary end point was change from baseline to day 90 on the Scandinavian Stroke Scale (ΔSSS), adjusted for baseline SSS, aiming for a 3-point additional mean recovery above placebo. Results— Nine hundred sixty-six acute stroke patients (887 ischemic, 204 cotreated with intravenous tissue plasminogen activator; mean baseline SSS score, 28; range, 10 to 40) were treated within 6 hours of symptom onset. Mean ΔSSS was approximately +17 points of improvement on SSS for the overall evaluable population. There was no treatment effect for UK-279,276 (posterior probability of futility, 0.89). The trial was stopped early for futility. Post hoc analysis indicated a mean 1.6-point additional improvement on ΔSSS in the tissue plasminogen activator–treated subset (credible interval=0.5, 2.6). UK-279,276 was generally well tolerated, with no increased incidence of infections. Conclusions— UK-279,276 did not improve recovery in acute ischemic stroke patients but was devoid of serious side effects. The adaptive design facilitated early termination for futility.

All trials require a principal investigator to take the lead role and act as main contact amongst the various groups of participants. His role ranges from assistance in protocol design; through selection of investigators, monitoring of study conduct and responding to Safety Committee recommendations; to involvement in study reporting and in maintaining access to the data set after the conclusion of the trial. This article describes the role of the principal investigator and Steering Committee in more detail and discusses the issues that arise out of the organisational requirements of modern clinical trials and the potential tensions between the various participating groups.

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 position emission tomography [PET], cerebrospinal fluid [CSF] A beta 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. (C) 2015 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

Contains fulltext : 153394.pdf (Publisher’s version ) (Open Access) INTRODUCTION: There is a growing body of evidence that subtle deficits in instrumental activities of daily living (IADL) may be present in mild cognitive impairment (MCI). However, it is not clear if there are IADL domains that are consistently affected across patients with MCI. In this systematic review, therefore, we aimed to summarize research results regarding the performance of MCI patients in specific IADL (sub)domains compared with persons who are cognitively normal and/or patients with dementia. METHODS: The databases PsycINFO, PubMed and Web of Science were searched for relevant literature in December 2013. Publications from 1999 onward were considered for inclusion. Altogether, 497 articles were retrieved. Reference lists of selected articles were searched for potentially relevant articles. After screening the abstracts of these 497 articles, 37 articles were included in this review. RESULTS: In 35 studies, IADL deficits (such as problems with medication intake, telephone use, keeping appointments, finding things at home and using everyday technology) were documented in patients with MCI. Financial capacity in patients with MCI was affected in the majority of studies. Effect sizes for group differences between patients with MCI and healthy controls were predominantly moderate to large. Performance-based instruments showed slight advantages (in terms of effect sizes) in detecting group differences in IADL functioning between patients with MCI, patients with Alzheimer's disease and healthy controls. CONCLUSION: IADL requiring higher neuropsychological functioning seem to be most severely affected in patients with MCI. A reliable identification of such deficits is necessary, as patients with MCI with IADL deficits seem to have a higher risk of converting to dementia than patients with MCI without IADL deficits. The use of assessment tools specifically designed and validated for patients with MCI is therefore strongly recommended. Furthermore, the development of performance-based assessment instruments should be intensified, as they allow a valid and reliable assessment of subtle IADL deficits in MCI, even if a proxy is not available. Another important point to consider when designing new scales is the inclusion of technology-associated IADL. Novel instruments for clinical practice should be time-efficient and easy to administer.

A growing number of studies report a deterioration of the executive function (EF) in dementia of the Alzheimer type (DAT). To evaluate EFs in DAT, a new version of the Tower of London (TOL) task, originally developed by Shallice (1982), was adapted. The new version of the test was built up in its easiest possible feature in order to be administrable to early- or middle-stage demented patients. Seventeen DAT patients, and 17 controls matched for age and sex, were administered the TOL. The protocol followed a “hierarchical paradigm,” that is, simpler problems were embedded in more complex, subsequent problems. Results showed that DAT patients were impaired compared to controls. Both control and DAT groups showed a decrease in percentage of success rate in relation to the number of movements required by the task. On the more complex problems, the performance of DAT subjects was proportionally more impaired. Qualitative analysis revealed that rule breaking was a salient performance feature of the DAT group. These findings are consistent with the presence of an EF deficit in DAT.

Background and Purpose — Based on the hypothesis of glutamate-induced neurotoxicity (excitotoxicity) in cerebral ischemia, this study examined the efficacy and tolerability of memantine, an uncompetitive N -methyl- d -aspartate antagonist, in the treatment of mild to moderate vascular dementia. Methods — In this multicenter, 28-week trial carried out in France, 321 patients received 10 mg/d memantine or placebo twice a day; 288 patients were valid for intent-to-treat analysis. Patients had to meet the criteria for probable vascular dementia and have a Mini-Mental State (MMSE) score between 12 and 20 at inclusion. The 2 primary end points were the cognitive subscale of the Alzheimers Disease Assessment Scale (ADAS-cog) and the global Clinician’s Interview Based Impression of Change (CIBIC-plus). Results — After 28 weeks, the mean ADAS-cog scores were significantly improved relative to placebo. In the intention-to-treat population, the memantine group mean score had gained an average of 0.4 points, whereas the placebo group mean score had declined by 1.6 points, ie, a difference of 2.0 points (95% confidence interval, 0.49 to 3.60). The response rate for CIBIC-plus, defined as improved or stable, was 60% with memantine compared with 52% with placebo ( P =0.227, intention to treat). Among the secondary efficacy parameters, which were analyzed in the per-protocol subset, MMSE was significantly improved with memantine compared with deterioration with placebo ( P =0.003). The Gottfries-Brane-Steen Scale intellectual function subscore and the Nurses’ Observation Scale for Geriatric Patients disturbing behavior dimension also showed differences in favor of memantine ( P =0.04 and P =0.07, respectively). Memantine was well tolerated with a frequency of adverse events comparable to placebo. Conclusions — In patients with mild to moderate vascular dementia, memantine 20 mg/d improved cognition consistently across different cognitive scales, with at least no deterioration in global functioning and behavior. It was devoid of concerning side effects.

Several recent studies have provided substantial support for the proposal that a decrease in inhibitory processing may play an important role in cognitive changes occurring in the early stages of Dementia of the Alzheimer Type (DAT). The question addressed by the present study was whether these deficits are the result of the failure of a general inhibitory mechanism, or whether DAT is associated with selective decreases in a subset of inhibitory processes. For this, a computerized battery of tasks assessing several inhibitory mechanisms was administered to 28 mild DAT patients and 28 matched elderly adults. The results showed that DAT patients failed to produce Negative Priming effects and were severely impaired in the Stroop task. However, no evidence was found for an impairment on the Go-No go task and only limited impairment on the Stop Signal task, suggesting that in the early stages of the disease, not all inhibitory mechanisms are uniformly impaired.

International audience; Alzheimer's disease and other related disorders (ADRD) represent a major challenge for health care systems within the aging population. It is therefore important to develop better instruments to assess the disease severity and progression, as well as to improve its treatment, stimulation, and rehabilitation. This is the underlying idea for the development of Serious Games (SG). These are digital applications specially adapted for purposes other than entertaining; such as rehabilitation, training and education. Recently, there has been an increase of interest in the use of SG targeting patients with ADRD. However, this field is completely uncharted, and the clinical, ethical, economic and research impact of the employment of SG in these target populations has never been systematically addressed. The aim of this paper is to systematically analyze the Strengths, Weaknesses, Opportunities, and Threats (SWOT) of employing SG with patients with ADRD in order to provide practical recommendations for the development and use of SG in these populations. These analyses and recommendations were gathered, commented on and validated during a 2-round workshop in the context of the 2013 Clinical Trial of Alzheimer's Disease (CTAD) conference, and endorsed by stakeholders in the field. The results revealed that SG may offer very useful tools for professionals involved in the care of patients suffering from ADRD. However, more interdisciplinary work should be done in order to create SG specifically targeting these populations. Furthermore, in order to acquire more academic and professional credibility and acceptance, it will be necessary to invest more in research targeting efficacy and feasibility. Finally, the emerging ethical challenges should be considered a priority.

Dieser Artikel fasst die Empfehlungen zur Behandlung des Schlaganfalls der Europaischen Schlaganfall-Initiative (EUSI) fur das Europaische Schlaganfall-Council (ESC), die Europaische Neurologische Gesellschaft (ENS) und die Europaische Forderation Neurologischer Gesellschaften (EFNS) zusammen.

Summary Background Low-molecular-weight heparins and heparinoids are superior to unfractionated heparin in the prevention and treatment of venous thromboembolism, but their safety and efficacy in acute ischaemic stroke are inadequately defined. Methods This randomised, double-blind, aspirin-controlled trial tested the safety and efficacy of treatment with highdose tinzaparin (175 anti-Xa IU/kg daily; 487 patients), medium-dose tinzaparin (100 anti-Xa IU/kg daily; 508 patients), or aspirin (300 mg daily; 491 patients) started within 48 h of acute ischaemic stroke and given for up to 10 days. Primary intracerebral haemorrhage was excluded by computed tomography. Outcome was assessed, with treatment allocation concealed, by the modified Rankin scale at 6 months (independence [scores 0–2] vs dependence or death [scores 3–6]). Findings Of 1486 randomised patients, two did not receive treatment and 46 were lost to follow-up. The proportions independent at 6 months were similar in the groups assigned high-dose tinzaparin (194/468 [41·5%]), mediumdose tinzaparin (206/486 [42·4%]), or aspirin (205/482 [42·5%]). There was no difference in effect in any predefined subgroup, including patients with presumed cardioembolic stroke. Other outcome measures were similar between the treatment groups (disability, casefatality, and neurological deterioration rates). During the inhospital treatment period no patient assigned high-dose tinzaparin developed a symptomatic deep-vein thrombosis compared with nine assigned aspirin. Conversely, seven patients assigned high-dose tinzaparin developed symptomatic intracerebral haemorrhage compared with one in the aspirin group. Interpretation Treatment with tinzaparin, at high or medium dose, within 48 h of acute ischaemic stroke did not improve functional outcome compared with aspirin. Although high-dose tinzaparin was superior in preventing deep-vein thrombosis, it was associated with a higher rate of symptomatic intracranial haemorrhage.

Alzheimer disease (AD) is the most frequent cause of dementia in developed Western countries. Over time, affected patients invariably develop cognitive and functional decline, and most develop early or later behavioral disturbances. Declining cognitive and functional abilities contribute to loss of independent living and feelings of denial, confusion, fear and guilt until, finally, the patient loses most abilities to think, move, speak, or perceive. As patients' dependency on assistance increases, the level of caregiver strain rises. The caregiver may develop feelings of anger, grief, loneliness and resentment, and the health and well-being of most caregivers are often affected. Approximately 3-4 million people currently have AD in the USA, at an annual cost of up to US$100 billion, and the disease is expected to reach epidemic proportions by 2020. To achieve a clinically relevant, long-term outcome, pharmacotherapy must have sustained favorable effects on cognitive, functional and behavioral symptoms of AD. Slowing the development of these features of the disease will mean a long-term improvement in quality of life for patients and caregivers. Postponing the emergence of behavioral symptoms would bring about direct beneficial effects on patients with AD and their families, help delay long-term care placement and lower costs.

The traditional aim of Alzheimer's disease treatment in clinical trials has been to improve cognitive abilities. It has become increasingly clear, however, that other aspects are important in assessing treatment responses. A group of 10 physicians recently gathered to review the current criteria for assessing treatment success in Alzheimer's disease. While cognition has been previously viewed as the primary measure of efficacy, areas such as functional abilities, behaviour, caregiver burden, quality of life and resource utilization all need to be comprehensively assessed to fully evaluate treatment effects in patients with Alzheimer's disease, as well as their impacts on caregivers and society. Postponing or slowing decline in any of these areas may represent an important benefit and should be considered as an outcome measure in clinical trials, clinical practice and decision-making about healthcare budgets. Accepted instruments are available for assessing outcomes in each aspect of Alzheimer's disease, but they need to be selected carefully to provide valid, meaningful data. Some of the most frequently used outcome measures in Alzheimer's disease are reviewed. Using expanded criteria for treatment success and clinically relevant outcome measures, data from currently available studies show that cholinesterase inhibitors produce clinically meaningful long-term benefits in multiple domains in patients with Alzheimer's disease.

Stroke-like Migraine Attacks after Radiation Therapy (SMART) syndrome is a rare complication of cranial irradiation. Radiation is well-known to impair vascular vessel architecture and function. We investigated the hypothesis of radiation-induced cerebral vascular reserve dysfunction as the underlying mechanism of SMART. Interictal cerebrovascular reactivity was investigated using Tc-99m hexamethylpropyleneamine oxime-SPECT and acetazolamide challenge in 3 patients. We found interictal hypoperfusion and normal cerebrovascular reactivity in all patients. Neither ictal restriction of the apparent diffusion coefficient nor MR angiography abnormalities were observed. These findings do not support a vascular mechanism in SMART syndrome. Postradiation neuronal dysfunction may be the underlying mechanism. Further investigations on larger series are needed to confirm this hypothesis.

The European Stroke Initiative (EUSI) is the common body of stroke-related activities within the European Federation of Neurological Societies (EFNS), the European Neurological Society (ENS) and the European Stroke Council (ESC). The Executive committee of the EUSI has authorized the writing committee of the EUSI to create recommendations for stroke management covering all areas of stroke treatment. The recommendations are listed according to levels of evidence pre-specified and modified according to several proposals in the literature. The recommendations have been approved by the executive committees of the EUSI, the ESC, the EFNS and the ENS. They are called recommendations rather than guidelines in order to underline the large amount of individual decision making due to the fact that for many important questions, no data of high evidence level is available. The EUSI plans to review and update the recommendations on a regular basis.

Decline in functional abilities is a major component of the dementia syndrome. The definition of dementia in the International Classification of Diseases (10th rev.) requires a cognitive impairment sufficient to impair personal activities of daily living (ADL). The Diagnostic and Statistical Manual of Mental Disorders (4th ed.) also requires cognitive deficits sufficiently severe to cause impairment in occupational or social functioning and must represent a decline from a higher level of functioning. However, the term disability is more appropriate than impairment to describe a loss in activities, as opposed to a loss of elementary functions, and is consistent with World Health Organization definitions of impairment, disability, and handicap. There is no doubt that ADL outcomes are required in therapeutic drug studies on vascular dementia, and there is a good rationale and some evidence for the use of ADL scales developed for therapeutic research in Alzheimer disease, favoring scales devoid of items sensitive to physical disabilities. Similarly, ADL-related clinical milestones could be used for longer-term studies aiming predominantly at slowing progression of disease in both early and later stages of dementia. Slower decline in ADL and delay in reaching ADL-related clinical milestones should be considered as valid outcomes by regulatory bodies in the process of dementia drug approval.

Vascular dementia (VaD) is the second most frequent cause of organic acquired cognitive dysfunction in the Western world and is probably the first cause in some Asian countries. Therefore, it represents an important target for drug trials in dementia. This report puts in perspective methodological issues in VaD trials, as opposed to Alzheimer disease (AD), and reproduces in extenso the European Medicinal Products Evaluation Agency (EMEA) guidelines for trials of symptomatic treatments of dementia, particularly in AD. There are no explicit guidelines for VaD trials, but many of the recommendations for AD are already applicable to VaD for drugs aiming at alleviating symptoms of dementia. However, VaD can be viewed as being one of the many possible consequences of cerebrovascular diseases, so that there is more to expect from secondary prevention strategies for VaD than for AD (in which both the etiology and the pathophysiological mechanisms are largely unknown). So it seems logical to put more emphasis on the stabilization of the symptoms of VaD, by preventing progression or recurrence insofar as the vascular risk factors for VaD can often be identified and controlled, than in attempting to improve the existing clinical manifestations of established vascular brain damage. Even if purely symptomatic drugs are developed to improve the symptoms of VaD, they will have to be studied in the context of a tight control of existing vascular risk factors. For secondary prevention, trials of at least 1 year seem advisable.

Background. Metrifonate is a long-lasting acetylcholinesterase inhibitor being developed for the symptomatic treatment of Alzheimer's disease (AD). Objectives. This study compared the efficacy, tolerability and safety of two doses of metrifonate in patients with mild-to-moderate AD, over a 26-week treatment period. Methods. Six hundred and five patients were randomized to placebo (n = 208), a 40/50 mg dose (40 or 50 mg by weight; n = 200) or a 60/80 mg dose (60 or 80 mg by weight; n = 197) metrifonate. Patients randomized to receive metrifonate were administered a once-daily loading dose of 80 or 120 mg based on weight for 2 weeks, followed by the relevant maintenance dose for 24 weeks. Four main clinical domains of AD were assessed: cognition (ADAS-cog and MMSE), psychiatric and behavioural symptoms (ADAS-noncog and NPI), instrumental and basic activities of daily living (DAD) and global functioning (CIBIC-plus, CIBIS-plus and GDS). Results. ADAS-cog performance was significantly improved in the 60/80 mg and 40/50 mg dose groups, compared with placebo, in the intention-to-treat (ITT) population. In addition, statistically significant treatment differences were demonstrated between the 60/80 mg dose group and placebo on MMSE, ADAS-noncog, the NPI subitems of hallucinations and apathy, DAD, CIBIC-plus, CIBIS-plus and the GDS. The performance of the 40/50 mg dose group was also significantly superior to placebo on the CIBIS-plus and the NPI subitem aberrant motor behaviour. Conclusions. Metrifonate significantly improved a wide range of symptoms across all four clinical domains of AD in a dose-dependent manner, and was safe and well tolerated at both doses studied.

Several studies have reported low performances of patients with dementia of the Alzheimer Type (DAT) on the Trial Making Test (TMT), however, these studies were not designed to identify specific operations underlying this impairment. To better understand the attentional disorder in DAT, we analyzed the performances of patients with DAT and matched elderly adults on the TMT, with a detailed analysis of error types. The analysis showed that 67% of patients' errors were related to an inhibitory deficit versus only 24% in normal elderly adults. Therefore, it was suggested that inefficient inhibitory mechanisms are responsible, to a large extent, for the poor TMT performance of patients with DAT, supporting the hypothesis of an inhibitory dysfunction in DAT.

Our aim was to evaluate the association between magnetisation transfer imaging (MTI) parameters measured 30 to 45 days after a cerebrovascular insult and post-stroke functional outcome at the same time. MTI offers the opportunity to depict subtle microstructural changes in infarcted areas. The clinical significance of the heterogeneity of brain damage within ischaemic stroke lesions is unknown. We prospectively included 58 patients with acute middle cerebral artery stroke. Diffusion-weighted imaging was performed within 12 hours after onset and the final infarct was documented by MRI with fluid-attenuated inversion recovery (FLAIR) and MTI at 30 to 45 days follow-up. We evaluated the association between MTI histogram parameters and the clinical outcome assessed by dichotomised (threshold2) modified rankin scale (mRS) using multivariable logistic regression models adjusted on baseline characteristics. In multivariable analyses, stroke outcome was mostly driven by initial National Institutes of Health Stroke Scale (odds ratio [OR]=1.23; 95% confidence interval [CI]=1.07-1.41; p0.01) while after adjustment of initial stroke severity magnetisation transfer ratio peak position was the only MRI parameter associated with functional status at 30 to 45 days post-stroke (OR=0.86; 95% CI=0.75-0.98; p=0.02); lower peak position values associated with higher mRS. Conversely, stroke volume measured on FLAIR sequence was not associated with stroke prognosis (p=0.87). The intensity of microstructural changes within the infarct core measured at 30 to 45 days follow-up is independently associated with the functional status evaluated at the same time. MTI and related parameters could be used as surrogate markers of treatment response in stroke clinical trials.

Background and Purpose Piracetam, a nootropic agent with neuroprotective properties, has been reported in pilot studies to increase compromised regional cerebral blood flow in patients with acute stroke and, given soon after onset, to improve clinical outcome. We performed a multicenter, randomized, double-blind trial to test whether piracetam conferred benefit when given within 12 hours of the onset of acute ischemic stroke to a large group of patients. Methods Patients received placebo or 12 g piracetam as an initial intravenous bolus, 12 g daily for 4 weeks and 4.8 g daily for 8 weeks. The primary end point was neurologic outcome after 4 weeks as assessed by the Orgogozo scale. Functional status at 12 weeks as measured by the Barthel Index was the major secondary outcome. CT scan was performed within 24 hours of the onset of stroke but not necessarily before treatment. Analyses based on the intention to treat were performed in all randomized patients (n=927) and in an “early treatment” population specified in the protocol as treatment within 6 hours of the onset of stroke but subsequently redefined as less than 7 hours after onset (n=452). Results In the total population, outcome was similar with both treatments (the mean Orgogozo scale after 4 weeks: piracetam 57.7, placebo 57.6; the mean Barthel Index after 12 weeks: piracetam 55.8, placebo 53.1). Mortality at 12 weeks was 23.9% (111/464) in the piracetam group and 19.2% (89/463) in the placebo group (relative risk 1.24, 95% confidence interval, 0.97 to 1.59; P =.15). Deaths were fewer in the piracetam group in those patients in the intention-to-treat population admitted with primary hemorrhagic stroke. Post hoc analyses in the early treatment subgroup showed differences favoring piracetam relative to placebo in mean Orgogozo scale scores after 4 weeks (piracetam 60.4, placebo 54.9; P =.07) and Barthel Index scores at 12 weeks (piracetam 58.6, placebo 49.4; P =.02). Additional analyses within this subgroup, confined to 360 patients with moderate and severe stroke (initial Orgogozo scale score P Conclusions Piracetam did not influence outcome when given within 12 hours of the onset of acute ischemic stroke. Post hoc analyses suggest that piracetam may confer benefit when given within 7 hours of onset, particularly in patients with stroke of moderate and severe degree. A randomized, placebo-controlled, multicenter study, the Piracetam Acute Stroke Study II (PASS II) will soon begin.

Calcified aortic stenosis (CAS) is an unusual cause of cerebral infarct. The presence of cerebral intra-vascular or intra-parenchymatous calcifications, symptomatic or not, is suggestive of the diagnosis of CAS. We report two patients who experienced stroke induced by spontaneous calcic emboli from a calcified aortic valve and underline the importance of brain CT scan.

Antiplatelet drugs (APD) are widely used in the prevention of ischemic cardio- and cerebrovascular diseases. The authors studied the frequency of stroke occurring after APD discontinuation, the cause of discontinuation, and the delay between APD disruption and stroke. Only 4.49% of strokes were related to a recent APD discontinuation, but all cases occurred between 6 and 10 days after drug discontinuation (p < 0.0001). This temporal pattern has biologic plausibility because the inhibited platelets circulate in the blood for about 10 days.

International audience; PURPOSE: To compare perfusion-weighted (PW) imaging and apparent diffusion coefficient (ADC) maps in prediction of infarct size and growth in patients with acute middle cerebral artery infarct. MATERIALS AND METHODS: This study was approved by the local institutional review board. Written informed consent was obtained from all 80 patients. Subsequent infarct volume and growth on follow-up magnetic resonance (MR) images obtained within 6 days were compared with the predictions based on PW images by using a time-to-peak threshold greater than 4 seconds and ADC maps obtained less than 12 hours after middle cerebral artery infarct. ADC- and PW imaging-predicted infarct growth areas and infarct volumes were correlated with subsequent infarct growth and follow-up diffusion-weighted (DW) imaging volumes. The impact of MR imaging time delay on the correlation coefficient between the predicted and subsequent infarct volumes and individual predictions of infarct growth by using receiver operating characteristic curves were assessed. RESULTS: The infarct volume measurements were highly reproducible (concordance correlation coefficient [CCC] of 0.965 and 95% confidence interval [CI]: 0.949, 0.976 for acute DW imaging; CCC of 0.995 and 95% CI: 0.993, 0.997 for subacute DW imaging). The subsequent infarct volume correlated (P

Paquid (personnes âgees quid) is a population-based cohort specifically designed to study the epidemiology of brain aging and dependency in activities of daily living in elderly people. At baseline screening, 3.777 subjects older than 65 were randomly selected in 75 different parishes from Gironde and Dordogne, and two administrative districts around Bordeaux in South-Western France. The participation rate was 68%. Subjects were followed up every two to three years with repeated measures of cognition, instrumental and basic activities of daily living collected by a trained psychologist, and a systematic detection of incident cases of dementia. The participation rate of each follow-up screening was around 75%. The detection of dementia was conducted with a two-stage design, with a first stage conducted by the psychologist and the confirmation of the diagnosis made at home by a physician, specialist in Alzheimer disease and related disorders (ADRD). Over 20 years of follow-up more than 800 subjects developed incident dementia and more than 2.500 died. Paquid remains the only representative cohort of elderly people living at home in France, giving estimations of prevalence, incidence and duration of ADRD and dependency. Thirty six risk factors of dementia and/or AD have been studied. On the basis of the Paquid data, we have shown that the prodromal phase of AD was longer than ten years and that dementia represented the major cause of dependency in the elderly.

We examined the relationship between tobacco consumption and Alzheimer's disease (AD), cognitive deficit, and memory performances in elderly community residents of southwestern France. Subjects were considered to have a cognitive deficit if they scored under 24 on the French version of the Mini-Mental State Examination, and poor memory performances if they scored under 8 on the Benton Visual Retention Test. Among the 3770 subjects who gave information about their smoking habits, only 356 (9.5%) were current smokers, 998 (26.5%) were past smokers, and 2416 (64%) were never smokers. Current smokers (odds ratio (OR) = 0.52, P < 0.001) and past smokers (OR = 0.54, P < 0.001) had a lower risk of cognitive deficit than did never smokers. However, this significant relationship disappeared after adjustment for potential confounding factors such as occupational category (OR = 0.91 (not significant) for current smokers and OR = 0.87 (not significant) for past smokers). Similar results were obtained for the risk of AD and of poor memory performances. The apparent protective effect of smoking habits on cognitive abilities could be due to a confounding effect of occupational category.