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Find video protocols related to scientific articles indexed in Pubmed.
Couples' experiences with early-onset dementia: An interpretative phenomenological analysis of dyadic dynamics.
Dementia (London)
PUBLISHED: 10-12-2014
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The growing interest in early-onset dementia has attracted attention to the situation and experiences of the caregiver, most often the spouse. Several qualitative studies on caregiving spouses have underlined the importance of the feeling of loss, the change of role reported by the caregiving spouses, and the strategies used to protect the person with dementia, all of which raise the question of the relational dynamics at play in these dyads. The present study on 16 couples examines the experiences of each partner, as well as the kinds of interactions taking place within the dyad and how they have evolved since the disease began.
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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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Animal spotting in Alzheimer's disease: an eye tracking study of object categorization.
J. Alzheimers Dis.
PUBLISHED: 09-04-2014
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We investigated rapid object categorization and, more specifically, the ability to detect a target object within a natural scene in people with mild Alzheimer's disease (AD) using a saccadic choice task. It has been suggested that the anatomical pathway likely used to initiate rapid oculomotor responses in the saccadic choice task could involve the Frontal Eye Field, a structure that is part of the dorsal attentional network, in which connectivity is disrupted in AD. Seventeen patients with mild AD and 23 healthy age-matched controls took part in the study. A group of 24 young healthy observers was included as it has been reported that normal aging affects eye movements. Participants were presented with pairs of colored photographs of natural scenes, one containing an animal (the target) and one containing various objects (distracter), displayed for 1 s left and right of fixation. They were asked to saccade to the scene containing an animal. Neither pathology nor age affected temporal (saccade latencies and durations) and spatial (saccade amplitude) parameters of eye movements. Patients with AD were significantly less accurate than age-matched controls, and older participants were less accurate than young observers. The results are interpreted in terms of noisier sensory information and increased uncertainty in relation to deficits in the magnocellular pathway. The results suggest that, even at a mild stage of the pathology, people exhibit difficulties in selecting relevant objects.
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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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JAK2 and MPL protein levels determine TPO-induced megakaryocyte proliferation vs differentiation.
Blood
PUBLISHED: 08-20-2014
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Megakaryopoiesis is a 2-step differentiation process, regulated by thrombopoietin (TPO), on binding to its cognate receptor myeloproliferative leukemia (MPL). This receptor associates with intracytoplasmic tyrosine kinases, essentially janus kinase 2 (JAK2), which regulates MPL stability and cell-surface expression, and mediates TPO-induced signal transduction. We demonstrate that JAK2 and MPL mediate TPO-induced proliferation arrest and megakaryocytic differentiation of the human megakaryoblastic leukemia cell line UT7-MPL. A decrease in JAK2 or MPL protein expression, and JAK2 chemical inhibition, suppress this antiproliferative action of TPO. The expression of JAK2 and MPL, which progressively increases along normal human megakaryopoiesis, is decreased in platelets of patients diagnosed with JAK2- or MPL-mutated essential thrombocytemia and primary myelofibrosis, 2 myeloproliferative neoplasms in which megakaryocytes (MKs) proliferate excessively. Finally, low doses of JAK2 chemical inhibitors are shown to induce a paradoxical increase in MK production, both in vitro and in vivo. We propose that JAK2 and MPL expression levels regulate megakaryocytic proliferation vs differentiation in both normal and pathological conditions, and that JAK2 chemical inhibitors could promote a paradoxical thrombocytosis when used at suboptimal doses.
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Survival and early recourse to care for dementia: A population based study.
Alzheimers Dement
PUBLISHED: 08-14-2014
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A large proportion of dementia cases are still undiagnosed. Although early dementia care has been hypothesized to benefit both patients and families, evidence-based benefits are lacking. Thus, investigating the benefits for newly demented persons according to their recourse to care in the "real life" appears critical.
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Contribution of ATXN2 intermediary polyQ expansions in a spectrum of neurodegenerative disorders.
Neurology
PUBLISHED: 08-06-2014
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The aim of this study was to establish the frequency of ATXN2 polyglutamine (polyQ) expansion in large cohorts of patients with amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP), and to evaluate whether ATXN2 could act as a modifier gene in patients carrying the C9orf72 expansion.
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Impact of harmonization of collection tubes on Alzheimer's disease diagnosis.
Alzheimers Dement
PUBLISHED: 08-05-2014
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The objective of this study was to analyze differences in biomarker outcomes before and after harmonization of cerebrospinal fluid (CSF) collection tubes in Alzheimer's disease (AD) diagnosis.
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Validation of the Test Your Memory (F-TYM Test) in a French memory clinic population.
Clin Neuropsychol
PUBLISHED: 08-04-2014
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The Test Your Memory (TYM) test has been proposed for screening dementia. We present a French version and its validation in memory clinics. F-TYM was administered to 201 patients with memory complaints visiting five secondary referral hospital centers. Final diagnosis was dementia in 34%, amnestic mild cognitive impairment (MCI) in 32%, non-amnestic MCI in 11%, absence of cognitive disorder in 23% and F-TYM scores were respectively (M ± SD) 30.9 ± 7.6, 40.5 ± 6.3, 44.3 ± 4.5 and 43.5 ± 6.6 (p < .0001). F-TYM showed high correlation with MMSE (r = .78), excellent internal consistency, no effect of educational level, sex, or mood but a significant effect of age (p = .004). A F-TYM score ? 39 had 0.90 sensitivity and 0.70 specificity for diagnosis of dementia. F-TYM was unable to discriminate MCI and patients without cognitive disorders. F-TYM could be proposed for screening of dementia in patients with memory complaints.
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Differential processing of natural scenes in posterior cortical atrophy and in Alzheimer's disease, as measured with a saccade choice task.
Front Integr Neurosci
PUBLISHED: 07-25-2014
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Atrophy of the medial temporal lobe structures that support scene perception and the binding of an object to its context (i.e., the hippocampus and the parahippocampal cortex) appears early in the course of Alzheimer's disease (AD). However, few studies have investigated scene perception in people with AD. Here, we assessed the ability to find a target object within a natural scene in people with AD and in people with posterior cortical atrophy (PCA, a variant of AD). Pairs of color photographs were displayed on the left and right of a fixation cross for 1 s. In separate blocks of trials, participants were asked to categorize the target (an animal) by either moving their eyes toward the photograph containing the target (the saccadic choice task) or pressing a key corresponding to the target's location (the manual choice task). Isolated objects and objects within scenes were studied in both tasks. Participants with PCA were more impaired in detection of a target within a scene than participants with AD. The latter's performance pattern was more similar to that of age-matched controls in terms of accuracy, saccade latencies and the benefit gained from contextual information. Participants with PCA benefited less from contextual information in both the saccade and the manual choice tasks-suggesting that people with posterior brain lesions have impairments in figure/ground segregation and are more sensitive to object crowding.
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Frontotemporal dementia and its subtypes: a genome-wide association study.
Raffaele Ferrari, Dena G Hernandez, Michael A Nalls, Jonathan D Rohrer, Adaikalavan Ramasamy, John B J Kwok, Carol Dobson-Stone, William S Brooks, Peter R Schofield, Glenda M Halliday, John R Hodges, Olivier Piguet, Lauren Bartley, Elizabeth Thompson, Eric Haan, Isabel Hernández, Agustin Ruíz, Mercè Boada, Barbara Borroni, Alessandro Padovani, Carlos Cruchaga, Nigel J Cairns, Luisa Benussi, Giuliano Binetti, Roberta Ghidoni, Gianluigi Forloni, Daniela Galimberti, Chiara Fenoglio, Maria Serpente, Elio Scarpini, Jordi Clarimón, Alberto Lleó, Rafael Blesa, Maria Landqvist Waldö, Karin Nilsson, Christer Nilsson, Ian R A Mackenzie, Ging-Yuek R Hsiung, David M A Mann, Jordan Grafman, Christopher M Morris, Johannes Attems, Timothy D Griffiths, Ian G McKeith, Alan J Thomas, P Pietrini, Edward D Huey, Eric M Wassermann, Atik Baborie, Evelyn Jaros, Michael C Tierney, Pau Pastor, Cristina Razquin, Sara Ortega-Cubero, Elena Alonso, Robert Perneczky, Janine Diehl-Schmid, Panagiotis Alexopoulos, Alexander Kurz, Innocenzo Rainero, Elisa Rubino, Lorenzo Pinessi, Ekaterina Rogaeva, Peter St George-Hyslop, Giacomina Rossi, Fabrizio Tagliavini, Giorgio Giaccone, James B Rowe, Johannes C M Schlachetzki, James Uphill, John Collinge, Simon Mead, Adrian Danek, Vivianna M Van Deerlin, Murray Grossman, John Q Trojanowski, Julie van der Zee, William Deschamps, Tim Van Langenhove, Marc Cruts, Christine Van Broeckhoven, Stefano F Cappa, Isabelle Le Ber, Didier Hannequin, Véronique Golfier, Martine Vercelletto, Alexis Brice, Benedetta Nacmias, Sandro Sorbi, Silvia Bagnoli, Irene Piaceri, Jørgen E Nielsen, Lena E Hjermind, Matthias Riemenschneider, Manuel Mayhaus, Bernd Ibach, Gilles Gasparoni, Sabrina Pichler, Wei Gu, Martin N Rossor, Nick C Fox, Jason D Warren, Maria Grazia Spillantini, Huw R Morris, Patrizia Rizzu, Peter Heutink, Julie S Snowden, Sara Rollinson, Anna Richardson, Alexander Gerhard, Amalia C Bruni, Raffaele Maletta, Francesca Frangipane, Chiara Cupidi, Livia Bernardi, Maria Anfossi, Maura Gallo, Maria Elena Conidi, Nicoletta Smirne, Rosa Rademakers, Matt Baker, Dennis W Dickson, Neill R Graff-Radford, Ronald C Petersen, David Knopman, Keith A Josephs, Bradley F Boeve, Joseph E Parisi, William W Seeley, Bruce L Miller, Anna M Karydas, Howard Rosen, John C van Swieten, Elise G P Dopper, Harro Seelaar, Yolande A L Pijnenburg, Philip Scheltens, Giancarlo Logroscino, Rosa Capozzo, Valeria Novelli, Annibale A Puca, Massimo Franceschi, Alfredo Postiglione, Graziella Milan, Paolo Sorrentino, Mark Kristiansen, Huei-Hsin Chiang, Caroline Graff, Florence Pasquier, Adeline Rollin, Vincent Deramecourt, Florence Lebert, Dimitrios Kapogiannis, Luigi Ferrucci, Stuart Pickering-Brown, Andrew B Singleton, John Hardy, Parastoo Momeni.
Lancet Neurol
PUBLISHED: 06-20-2014
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Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes-MAPT, GRN, and C9orf72--have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder.
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Primary care management of non-institutionalized elderly diabetic patients: The S.AGES cohort - Baseline data.
Prim Care Diabetes
PUBLISHED: 05-26-2014
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S.AGES is a multicenter prospective cohort study of non-institutionalized patients aged 65 and over with atrial fibrillation, type 2 diabetes or chronic pain. Its objective is to describe the medical management in primary care. This article presents the baseline characteristics of subjects in the diabetes subcohort and compares the results to those from cohorts of older diabetic patients.
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Advancing research diagnostic criteria for Alzheimer's disease: the IWG-2 criteria.
Lancet Neurol
PUBLISHED: 05-23-2014
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In the past 8 years, both the International Working Group (IWG) and the US National Institute on Aging-Alzheimer's Association have contributed criteria for the diagnosis of Alzheimer's disease (AD) that better define clinical phenotypes and integrate biomarkers into the diagnostic process, covering the full staging of the disease. This Position Paper considers the strengths and limitations of the IWG research diagnostic criteria and proposes advances to improve the diagnostic framework. On the basis of these refinements, the diagnosis of AD can be simplified, requiring the presence of an appropriate clinical AD phenotype (typical or atypical) and a pathophysiological biomarker consistent with the presence of Alzheimer's pathology. We propose that downstream topographical biomarkers of the disease, such as volumetric MRI and fluorodeoxyglucose PET, might better serve in the measurement and monitoring of the course of disease. This paper also elaborates on the specific diagnostic criteria for atypical forms of AD, for mixed AD, and for the preclinical states of AD.
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Treatment of sleep apnoea syndrome decreases cognitive decline in patients with Alzheimer's disease.
J. Neurol. Neurosurg. Psychiatr.
PUBLISHED: 05-14-2014
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It is essential to detect and then treat factors that aggravate Alzheimer's disease (AD). Here, we sought to determine whether or not continuous positive airway pressure (CPAP) therapy for sleep apnoea syndrome (SAS) slows the rate of cognitive decline in mild-to-moderate AD patients.
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Thrombolytic therapy for stroke in patients with preexisting cognitive impairment.
Neurology
PUBLISHED: 05-14-2014
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We aimed to evaluate the influence of prestroke cognitive impairment (PSCI) on outcomes in stroke patients treated with IV recombinant tissue plasminogen activator (rtPA).
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Consequences of dextropropoxyphene market withdrawal in elderly patients with chronic pain.
Eur. J. Clin. Pharmacol.
PUBLISHED: 03-26-2014
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Describe the consequences of dextropropoxyphene (DXP) market withdrawal on analgesic prescriptions and on the quality of therapeutic management of chronic pain.
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Diagnostic criteria for vascular cognitive disorders: a VASCOG statement.
Alzheimer Dis Assoc Disord
PUBLISHED: 03-18-2014
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Several sets of diagnostic criteria have been published for vascular dementia since the 1960s. The continuing ambiguity in vascular dementia definition warrants a critical reexamination.
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Who needs cerebrospinal biomarkers? A national survey in clinical practice.
J. Alzheimers Dis.
PUBLISHED: 03-01-2014
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Cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) are well validated in clinical research but less in clinical practice. Using a questionnaire, we evaluated the reasons for prescriptions and clinician's expectations concerning CSF biomarkers. The results show that CSF AD biomarkers are mainly required in case of atypical dementia and diagnosis uncertainty that are different from indications in clinical research. In the future, clinicians wish to get new biomarkers that could improve differential diagnosis and could have a good pronostic value. Further studies in routine practice are necessary to precise the role of these biomarkers in the management of patients.
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Unusual features of Creutzfeldt-Jakob disease followed-up in a memory clinic.
J. Neurol.
PUBLISHED: 01-08-2014
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Sporadic Creutzfeldt-Jakob disease (sCJD) generally manifests itself by cognitive or rapidly progressive motor symptoms. An atypical onset or an unusual evolution may delay the diagnosis. Among patients with a confirmed diagnosis of sCJD following a post-mortem neuropathological examination at the Neuropathology Centre of Lille, France, those who had presented with atypical cognitive disorders at onset were included in the study. Four patients were included. The first patient (64-years-old) presented early language disorders, later accompanied by apathy and behavioral disorders. The prolonged course suggested a diagnosis of progressive primary aphasia. The second patient (68-years-old) presented with aphasia, apraxia, and ataxia of the right upper limb with parkinsonian syndrome, suggesting corticobasal degeneration. In the two last patients (58- and 61-years-old), the onset was marked by an anxiety-depression syndrome, falls, visual hallucinations, extra-pyramidal syndrome, and fluctuating cognitive decline. The diagnosis raised was probable Lewy body dementia. The 14.3.3 protein was found in two of the four cases. The clinical elements found may initially suggest focal atrophy or Lewy body dementia. A very rapid clinical deterioration generally suggests sCJD, but in the last case, the evolution was particularly slow. The diagnosis of sCJD must be considered in cases of rapid-onset dementia, even if all of the clinical criteria are not present. The detection of the 14.3.3 protein and multifold increase in total-Tau with normal or slightly increased phosphorylated-Tau in the CSF are additional arguments to reinforce the diagnosis. The post-mortem neuropathological examination is important to confirm the diagnosis.
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Effects of the PPAR-? agonist fenofibrate on acute and short-term consequences of brain ischemia.
J. Cereb. Blood Flow Metab.
PUBLISHED: 01-08-2014
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In stroke, there is an imperative need to develop disease-modifying drugs able to (1) induce neuroprotection and vasculoprotection, (2) modulate recovery and brain plasticity, and (3) limit the short-term motor and cognitive consequences. We hypothesized that fenofibrate, a peroxisome proliferator-activated receptor-? (PPAR-?) agonist, could exert a beneficial effect on immediate and short-term poststroke consequences related to its pleiotropic mechanisms. Rats or mice were subjected to focal ischemia to determine the effects of acute treatment by fenofibrate on (i) motor and memory impairment, (2) both cerebral and vascular compartments, (3) inflammation, (4) neurogenesis, and (5) amyloid cascade. We show that fenofibrate administration results in both neuronal and vascular protection and prevents the short-term motor and cognitive poststroke consequences by interaction with several mechanisms. Modulation of PPAR-? generates beneficial effects in the immediate poststroke consequences by mechanisms involving the interactions between polynuclear neutrophils and the vessel wall, and microglial activation. Fenofibrate modulates mechanisms involved in neurorepair and amyloid cascade. Our results suggest that PPAR-? agonists could check the key points of a potential disease-modifying effect in stroke.
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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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Microbleeds in postmortem brains of patients with Alzheimer disease: a T2*-weighted gradient-echo 7.0 T magnetic resonance imaging study.
Alzheimer Dis Assoc Disord
PUBLISHED: 12-24-2013
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This study aims to determine the distribution and to quantify microbleeds (MBs) in postmortem brains of patients with Alzheimer disease (AD) on T2*-weighted gradient-echo 7.0 T magnetic resonance imaging. Twenty-eight AD brains were compared with 5 controls. The AD brains were subdivided further: 18 without and 10 with additional severe cerebral amyloid angiopathy (AD-CAA). The distribution and the number of cortical focal signal intensity losses, representing MBs, were assessed on coronal sections at the frontal, the central, and the occipital level of a cerebral hemisphere. MBs prevailed in the central sections (P=0.005) of AD brains without CAA, whereas in AD-CAA brains, they were more frequent in all coronal sections (P?0.002). They prevailed in the deep cortical layers of the AD brains and of the controls (P?0.03). They were significantly increased in all cortical layers of the AD-CAA brains (P?0.04), compared with the controls. MBs prevalence in brains of AD patients had a different topographic distribution according to the absence or presence of severe CAA.
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A new decision tree combining Abeta 1-42 and p-Tau levels in Alzheimers diagnosis.
Curr Alzheimer Res
PUBLISHED: 11-06-2013
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The objective of this work was to improve the clinical diagnosis of Alzheimers disease (AD) by proposing a simple decision tree based on three major biomarkers of AD found in the cerebrospinal fluid (CSF): amyloid peptide A?1- 42, total Tau (t-Tau) and Tau phosphorylated at Thr181 (p-Tau). Two consecutive cohorts comprising 548 patients in total were recruited by the Memory and Neurology Clinics at Lille University Hospital (France). These included 293 patients with AD, 171 patients with other dementias and 84 healthy controls. All patients underwent lumbar puncture for the assessment of CSF concentrations of A?1-42, t-Tau and p-Tau. International criteria for dementias were used for diagnosis by investigators blind to CSF test results. To identify the combination of biomarkers that best predicted the 3 diagnoses, we used the CHAID decision tree method with the first cohort. Our analysis yielded a two-step decision tree, with a first stratification step based on the A?1-42/p-Tau ratio of the CSF, and a second step based on CSF p-Tau concentrations. The second cohort was then used to determine the power (0.618), sensitivity (82%) and specificity (81%) of this tree in AD diagnosis. These were found to be at least as high as those of other known algorithms based on the three CSF biomarkers, A?1-42, t-Tau and p-Tau.For the first time, diagnostic rules for AD based on CSF variables were compared in a single study. Our findings indicate that the measurement of A?1-42 and p-Tau levels in the CSF is sufficient to diagnose AD.
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Impact of cerebro-spinal fluid biomarkers of Alzheimers disease in clinical practice: a multicentric study.
J. Neurol.
PUBLISHED: 09-27-2013
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CSF biomarkers of Alzheimers disease are well validated in clinical research; however, their pragmatic utility in daily practice is still unappreciated. These biomarkers are used in routine practice according to Health Authority Recommendations. In 604 consecutive patients explored for cognitive disorders, questionnaires were prospectively proposed and filled. Before and after CSF biomarker results, clinicians provided a diagnosis and an estimate of their diagnostic confidence. Analysis has compared the frequency of diagnosis before and after CSF biomarker results using the net reclassification improvement (NRI) method. We have evaluated external validity comparing with data of French Bank National of AD (BNA). A total of 561 patients [Alzheimers disease (AD), n = 253; non-AD, n = 308] were included (mean age, 68.6 years; women, 52 %). Clinically suspected diagnosis and CSF results were concordant in 65.2 % of cases. When clinical hypothesis and biological results were discordant, a reclassification occurred in favour of CSF biomarkers results in 76.9 %. The NRI was 39.5 %. In addition, the results show a statistically significant improvement in clinician confidence for their diagnosis. In comparison with BNA data, patients were younger and more frequently diagnosed with AD. Clinicians tend to heavily rely on the CSF AD biomarkers results and are more confident in their diagnoses using CSF AD biomarkers. Thus, these biomarkers appear as a key tool in clinical practice.
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Reasons that prevent the inclusion of Alzheimers disease patients in clinical trials.
Br J Clin Pharmacol
PUBLISHED: 09-21-2013
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To assess reasons that prevent Alzheimers disease (AD) patients from being included in clinical trials.
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National observatory on the therapeutic management in ambulatory care patients aged 65 and over, with type 2 diabetes, chronic pain or atrial fibrillation.
Therapie
PUBLISHED: 08-28-2013
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The primary objective of the S.AGES cohort is to describe the real-life therapeutic care of elderly patients. Patients and methods. This is a prospective observational cohort study of 3 700 non-institutionalized patients over the age of 65 years with either type 2 diabetes mellitus (T2DM), chronic pain or atrial fibrillation (AF) recruited by French general practitioners (GPs). Follow-up is planned for 3 years. Baseline characteristics. In the chronic pain sub-cohort, 33% of patients are treated with only grade 1 analgesics, 29% with grade 2 analgesics and 3% with grade 3 analgesics, and 22% have no pain treatment. In the T2DM sub-cohort, 61% of patients have well-controlled diabetes (Hb1c<7%) and 18% are treated with insulin. In the AF sub-cohort, 65% of patients have a CHADS2 score greater than 2, 77% are treated with oral anticoagulants, 17% with platelet inhibitors, 40% with antiarrhythmic drugs and 56% with rate slowing medications. Conclusion. The S.AGES cohort presents a unique opportunity to clarify the real-life therapeutic management of ambulatory elderly subjects and will help to identify the factors associated with the occurrence of major clinical events.
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Memory loss during lenalidomide treatment: a report on two cases.
BMC Pharmacol Toxicol
PUBLISHED: 06-11-2013
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There are many reports of cognitive dysfunction in patients receiving chemotherapy or targeted therapies. Many antineoplastic agents may be involved in the condition also known as "chemo brain" or "chemo fog".
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Clinical efficacy of second generation tyrosine kinase inhibitor and 5-azacytidine combination in chronic myelogenous leukaemia in myeloid blast crisis.
Eur. J. Cancer
PUBLISHED: 05-22-2013
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Even in the tyrosine kinase inhibitors era, the prognosis of patients with chronic myeloid leukaemia in myeloid blast crisis remains dismal with few patients surviving longer than 6 months. Here we report the cases of 5 patients treated with the combination of 5-azacytidine and tyrosine kinase inhibitors for myeloid blast crisis CML. All patients achieved a complete haematological response including two with a complete cytogenetic and major molecular response. Two patients underwent an allogeneic stem cell transplantation. One died from relapse 34 months from diagnosis. The second is alive and free from disease at 11 months from diagnosis. The other 3 patients are still in complete haematological response after 15, 24 and 33 months of follow-up. These results suggest that the combination has a significant activity in myeloid blast crisis and may increase survival.
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C9orf72 repeat expansions are a rare genetic cause of parkinsonism.
Brain
PUBLISHED: 02-16-2013
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The recently identified C9orf72 gene accounts for a large proportion of amyotrophic lateral sclerosis and frontotemporal lobar degenerations. As several forms of these disorders are associated with parkinsonism, we hypothesized that some patients with Parkinsons disease or other forms of parkinsonism might carry pathogenic C9orf72 expansions. Therefore, we looked for C9orf72 repeat expansions in 1446 unrelated parkinsonian patients consisting of 1225 patients clinically diagnosed with Parkinsons disease, 123 with progressive supranuclear palsy, 21 with corticobasal degeneration syndrome, 43 with Lewy body dementia and 25 with multiple system atrophy-parkinsonism. Of the 1446 parkinsonian patients, five carried C9orf72 expansions: three patients with typical Parkinsons disease, one with corticobasal degeneration syndrome and another with progressive supranuclear palsy. This study shows that (i) although rare, C9orf72 repeat expansions may be associated with clinically typical Parkinsons disease and also with other parkinsonism; (ii) in several patients, parkinsonism was levodopa-responsive and remained pure, without associated dementia, for >10 years and (iii) interestingly, all C9orf72 repeat expansion carriers had positive family histories of parkinsonism, degenerative dementias or amyotrophic lateral sclerosis. This study also provides the tools for identifying parkinsonian patients with C9orf72 expansions, with important consequences for genetic counselling.
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Emotional and psychological implications of early AD diagnosis.
Med. Clin. North Am.
PUBLISHED: 02-06-2013
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This article reviews the current recommendations in early diagnosis and the desires of the patients and their relatives, put in perspective with the reality of the clinical practices. More specific situations covered are: (1) the issue of young diseased patients, taking into account the psychological implications of the early occurrence of the disease in life and of the longer delay for these patients between the first observable signs and the diagnosis and (2) the issue of genetic testing, taking into account the implications of this extremely early form of bad news on the individuals existence and on the family structure.
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Action and noun fluency testing to distinguish between Alzheimers disease and dementia with Lewy bodies.
J Clin Exp Neuropsychol
PUBLISHED: 02-04-2013
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The objective of the present study was to establish whether performance in an action fluency task is of value in the differential diagnosis of Alzheimers disease (AD) and dementia with Lewy bodies (DLB). After collecting normative data on performance in an action fluency task and a conventional animal fluency task in a cohort of French-speaking healthy controls, we assessed AD and DLB patients. Only the action fluency score differed significantly between the two demented groups, with DLB patients performing worse than AD patients. However, a composite action and animal fluency score was found to be more effective for discriminating between these two groups.
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Exacerbated CSF abnormalities in younger patients with Alzheimers disease.
Neurobiol. Dis.
PUBLISHED: 01-14-2013
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Increasing age is the most important risk factor for developing Alzheimers disease (AD). The aim of this study was to investigate the relationships between age and cerebrospinal fluid (CSF) levels of ?-amyloid (A? 1-42), total Tau and phosphorylated Tau (pTau-181), in AD and non-AD patients explored for cognitive disorders. 966 patients (AD, n=528; non-AD, n=438) were included between January 2008 and December 2010 (mean age, 69.5years; mean MMSE, 20.2) from three French memory centers. Multivariable linear regression models were used to study the relationship between CSF biomarker levels and age in AD and non-AD patients. The capacity of each CSF biomarker in discriminating patients was evaluated using the area under the receiver-operating characteristic (ROC) curves by quartile of distribution of age. In AD patients, older age was associated with higher CSF A? 1-42 and lower Tau levels. Conversely, in non-AD patients, age was associated with lower CSF A? 1-42, higher Tau, and higher pTau-181 levels. In sex-stratified analysis, these relationships were significant only in women. Using ROC curve analysis, CSF AD biomarkers were more discriminant in younger patients than in older ones. In this clinically-based study, younger patients with AD had exacerbated CSF anomalies compared to older patients with AD. CSF biomarkers were more discriminant in younger patients than in older ones for the diagnosis of AD, especially in women. These results support the idea of an overlap in AD neuropathological lesions in oldest subjects with or without AD.
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Early onset dementia: characteristics in a large cohort from academic memory clinics.
Alzheimer Dis Assoc Disord
PUBLISHED: 12-15-2011
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To describe the characteristics of early-onset dementia (EOD) in a cohort from 3 memory clinics.
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Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia.
Brain
PUBLISHED: 08-02-2011
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Based on the recent literature and collective experience, an international consortium developed revised guidelines for the diagnosis of behavioural variant frontotemporal dementia. The validation process retrospectively reviewed clinical records and compared the sensitivity of proposed and earlier criteria in a multi-site sample of patients with pathologically verified frontotemporal lobar degeneration. According to the revised criteria, possible behavioural variant frontotemporal dementia requires three of six clinically discriminating features (disinhibition, apathy/inertia, loss of sympathy/empathy, perseverative/compulsive behaviours, hyperorality and dysexecutive neuropsychological profile). Probable behavioural variant frontotemporal dementia adds functional disability and characteristic neuroimaging, while behavioural variant frontotemporal dementia with definite frontotemporal lobar degeneration requires histopathological confirmation or a pathogenic mutation. Sixteen brain banks contributed cases meeting histopathological criteria for frontotemporal lobar degeneration and a clinical diagnosis of behavioural variant frontotemporal dementia, Alzheimers disease, dementia with Lewy bodies or vascular dementia at presentation. Cases with predominant primary progressive aphasia or extra-pyramidal syndromes were excluded. In these autopsy-confirmed cases, an experienced neurologist or psychiatrist ascertained clinical features necessary for making a diagnosis according to previous and proposed criteria at presentation. Of 137 cases where features were available for both proposed and previously established criteria, 118 (86%) met possible criteria, and 104 (76%) met criteria for probable behavioural variant frontotemporal dementia. In contrast, 72 cases (53%) met previously established criteria for the syndrome (P?
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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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Steroid and nonsteroidal anti-inflammatory drugs, cognitive decline, and dementia.
Neurobiol. Aging
PUBLISHED: 03-09-2011
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The aim of this study was to evaluate the effects of anti-inflammatory intake on cognitive function in 7234 community-dwelling elderly persons. Cognitive performance, clinical diagnosis of dementia, and anti-inflammatory use were evaluated at baseline, and 2, 4, and 7 years later. Multivariate logistic regression analyses were adjusted for sociodemographic, behavioral, physical, mental health variables, and genetic vulnerability (apolipoprotein E ?4). Elderly women taking inhaled corticosteroids were at increased risk for cognitive decline over 7 years in executive functioning (odds ratio, 1.76; 95% confidence interval, 1.14-2.71; p = 0.04); the effect being increased after continuous use (odds ratio, 3.15; 95% confidence interval, 1.29-7.68; p = 0.01) and not found after discontinuation of treatment. In men, no significant associations were observed. Corticosteroid use was not significantly associated with an increase risk of incident dementia over 7 years. Nonsteroidal anti-inflammatory drug use was not significantly associated with either dementia incidence or cognitive decline in both sexes. The association may be related to hypothalamic-pituitary-adrenal corticotropic axis dysfunctioning rather than a direct anti-inflammatory mechanism. Long-term use of inhaled corticosteroids may constitute a form of reversible cognitive disorder in elderly women. Physicians should check this possibility before assuming neurodegenerative changes.
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[Molecular actors in Alzheimers disease: which diagnostic and therapeutic consequences?].
Therapie
PUBLISHED: 12-13-2010
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Alzheimers disease is a neurodegenerative disorder characterized by neuropathological lesions: amyloid deposits and neurofibrillary degeneration. However, the links between these two brain hallmarks are still poorly understood. Until now, mainly amyloid pathology has been targeted un many clinical trials without any success. Both new therapeutic strategies and diagnosis improvement are needed.
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Revising the definition of Alzheimers disease: a new lexicon.
Lancet Neurol
PUBLISHED: 10-09-2010
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Alzheimers disease (AD) is classically defined as a dual clinicopathological entity. The recent advances in use of reliable biomarkers of AD that provide in-vivo evidence of the disease has stimulated the development of new research criteria that reconceptualise the diagnosis around both a specific pattern of cognitive changes and structural/biological evidence of Alzheimers pathology. This new diagnostic framework has stimulated debate about the definition of AD and related conditions. The potential for drugs to intercede in the pathogenic cascade of the disease adds some urgency to this debate. This paper by the International Working Group for New Research Criteria for the Diagnosis of AD aims to advance the scientific discussion by providing broader diagnostic coverage of the AD clinical spectrum and by proposing a common lexicon as a point of reference for the clinical and research communities. The cornerstone of this lexicon is to consider AD solely as a clinical and symptomatic entity that encompasses both predementia and dementia phases.
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Biomarkers for the early stages of clinical development in Alzheimers disease.
Therapie
PUBLISHED: 09-21-2010
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As the failure of several recent Phase III drug development programmes bears witness, the clinical development of "disease-modifying" drugs in Alzheimers disease has been confronted with challenging methodological difficulties. Taking into account the financial stakes involved taking drug candidates to the Phase III stage of development, and the risk of investing time and resources fruitlessly in the evaluation of poor candidate drugs, the crucial decision remains whether to proceed from Phase II to Phase III (Go/Nogo). The aim of Phase II studies is to select a molecule likely to be effective in Phase III, but also to eliminate candidate-drugs with an inadequate effect. No consensus currently exists on the best possible design of Phase II studies to inform the Go/Nogo decision optimally. The challenges in choosing the best study design relate to the target population, the end-point criteria used, in particular the use of biomarkers, the experimental protocol, and the study duration. The objective of the Round Table (RT) was to gather the opinions of French experts from the academic, industrial, and regulatory world in order to arrive at a consensus recommendation for the best possible design to be used in Phase II studies in Alzheimers disease.
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What are the causes of pre-existing dementia in patients with intracerebral haemorrhages?
Brain
PUBLISHED: 09-17-2010
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In intracerebral haemorrhage, the most frequent underlying vasculopathies are cerebral amyloid angiopathy and hypertensive vasculopathy. Although both are associated with cognitive impairment, no study has focused on pre-existing dementia in patients with intracerebral haemorrhage. Therefore, we aimed to determine prevalence and mechanisms of pre-existing dementia in a large cohort of patients with an intracerebral haemorrhage. In a cohort of 417 patients, we evaluated the cognitive status before intracerebral haemorrhage with the Informant Questionnaire on Cognitive Decline in the Elderly. The cut-off to diagnose cognitive impairment with no dementia was 53 and 64 for pre-existing dementia. We determined factors associated with pre-existing dementia in multivariate analyses in the overall cohort and among patients with lobar only or deep only intracerebral haemorrhages. We performed post-mortem examinations when possible. Of 417 patients (median age 72 years, interquartile range 58-79), 58 (14%; 95% CI 11-18%) patients had cognitive impairment with no dementia and 65 had pre-existing dementia (16%; 95% CI 12-19%). In lobar intracerebral haemorrhage, the prevalence was 23%, and factors associated with pre-existing dementia were increasing age (odds ratio: 1.09 per year; 95% CI 1.02-1.15), having <8 years of education (odds ratio: 8.37; 95% CI 1.91-36.65) and increasing cortical atrophy (odds ratio: 3.34 per step; 95% CI 1.40-7.96). The five autopsied patients had Alzheimers disease with cerebral amyloid angiopathy. In deep intracerebral haemorrhage, factors associated with pre-existing dementia were presence of old territorial vascular lesions (odds ratio: 4.52; 95% CI 1.18-17.42) and increasing severity of leucoaraiosis (odds ratio: 4.11 per step; 95% CI 1.73-9.75); the autopsied patient had small-vessel disease without Alzheimers disease. These findings support the fact that pre-existing dementia is frequent in patients with intracerebral haemorrhage and may be the consequence of two different mechanisms: neurodegeneration with Alzheimers disease and cerebral amyloid angiopathy in lobar intracerebral haemorrhage versus vascular process in deep intracerebral haemorrhage. These findings may contribute to the improvement of prevention and management of patients with intracerebral haemorrhages.
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A senescence-like cell-cycle arrest occurs during megakaryocytic maturation: implications for physiological and pathological megakaryocytic proliferation.
PLoS Biol.
PUBLISHED: 07-28-2010
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Thrombopoietin (TPO) via signaling through its cognate receptor MPL is a key cytokine involved in the regulation of megakaryocyte differentiation leading to platelet production. Mature megakaryocytes are polyploid cells that have arrested DNA replication and cellular proliferation but continue sustained protein synthesis. Here, we show that TPO induces cell-cycle arrest in the megakaryocytic UT7-MPL cell line by the activation of the ERK/MAPK pathway, induction of p21CIP transcription, and senescence markers through EGR1 activation. A similar senescence-like process was also detected in normal primary postmitotic megakaryocytes. In contrast, senescence was not observed in malignant megakaryocytes derived from primary myelofibrosis patients (a form of chronic myeloid hemopathy). Our data indicate that polyploid mature megakaryocytes receive signals from TPO to arrest cell proliferation and enter a senescent-like state. An escape from this physiological process may be associated with certain myeloproliferative neoplasms leading to abnormal megakaryocytic proliferation.
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Prevalence of small cerebral bleeds in patients with a neurodegenerative dementia: a neuropathological study.
J. Neurol. Sci.
PUBLISHED: 06-18-2010
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Small cerebral bleeds are frequently observed on magnetic resonance imaging in patients with Alzheimer dementia (AD). Histological confirmations in post-mortem brains are scarce. This study describes the prevalence of cerebrovascular lesions and the quantification of the "bleeding load" in post-mortem brains of patients with neurodegenerative dementias.
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An analysis of communication in conversation in patients with dementia.
Neuropsychologia
PUBLISHED: 04-27-2010
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Patients with degenerative dementia often show language disorders, but little is known about their verbal (VC) and non-verbal communication (NVC). Our aim was to analyse VC and NVC in patients with standard criteria of mild-moderately severe dementia (MMSE ?14/30) resulting from Alzheimers disease (AD; 29 cases), behavioural variant of frontotemporal dementia (FTD; 16), or dementia with Lewy bodies (DLB; 13). We used the Lille Communication Test, which addresses three domains: participation in communication (PC: greeting, attention, participation), VC (verbal comprehension, speech outflow, intelligibility, word production, syntax, verbal pragmatics and verbal feedback), and NVC (understanding gestures, affective expressivity, producing gestures, pragmatics and feedback). Patients were compared with 47 matching control subjects. AD patients were partially impaired (p?0.01) in PC (greeting), and more definitely in VC, especially by verbal comprehension and word finding difficulties and to a much lesser degree in verbal pragmatics (responding to open questions, presenting new information), while NVC was mostly preserved. FTD patients were severely impaired in PC. VC difficulties were related to lexical-semantic, syntactic and more specifically pragmatic problems. NVC was impaired by difficulties in affective expressivity, pragmatics and feedback management. DLB patients showed modest difficulties with VC. PC, VC and NVC strongly correlated with performance in the dementia rating scale. In conclusion, the profile of communication difficulties was quite different between groups. FTD patients showed most severe difficulties in PC and verbal and non-verbal pragmatics, in relation to their frontal lesions. AD patients had prominent impairment of lexical-semantic operations.
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CHMP2B mutations are rare in French families with frontotemporal lobar degeneration.
J. Neurol.
PUBLISHED: 03-22-2010
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Two C-truncating CHMP2B (chromatin modifying protein 2B) mutations were recently found in Danish and Belgian families with autosomal dominant forms of frontotemporal lobar degeneration (FTLD). In addition, few CHMP2B missense mutations of uncertain pathogenic role were reported in several families with FTLD or FTLD associated with motoneuron disease (FTLD-MND). In order to determine the genetic contribution of CHMP2B mutations in FTLD and FTLD-MND families, we analyzed the CHMP2B gene in 198 French probands with familial FTLD and FTLD-MND. One CHMP2B missense variant was found in a proband with familial FTLD (0.8%). The pathogenic role of CHMP2B missense variants is unclear, however the pSer194Leu substitution, located in the C-terminal domain of the protein, was predicted to alter the stability of the protein by in silico analyses. We conclude that CHMP2B mutations represent a rare cause of familial FTLD and they are not implicated in familial FTLD-MND in French patients. The previously reported C-truncating CHMP2B mutations may be private to the Danish and Belgian pedigrees.
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Rapid categorization of faces and objects in a patient with impaired object recognition.
Neurocase
PUBLISHED: 01-25-2010
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We tested rapid-categorization in a patient who was impaired in face and object recognition. Photographs of natural scenes were displayed for 100 ms. Participants had to press a key when they saw an animal among various objects as distractors or human faces among animal faces as distractors. Though the patient was impaired at figure/ground segregation, recognized very few objects and faces, she categorized animals and faces with a performance ranging between 70 and 86% correct. Displaying pictures in isolation did not improve performance. The results suggest that rapid categorization can be accomplished on the basis of coarse information without overt recognition.
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Treatment of vascular risk factors is associated with slower decline in Alzheimer disease.
Neurology
PUBLISHED: 09-02-2009
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There is growing evidence that vascular risk factors (VRF) contribute to cognitive decline. Whether their treatment can slow down the progression of Alzheimer disease (AD) remains unsettled. The aim of this observational study was to evaluate whether the treatment of VRF is associated with a slower cognitive decline in patients who have AD without cerebrovascular disease (CVD).
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A study of the association between the ADAM12 and SH3PXD2A (SH3MD1) genes and Alzheimers disease.
Neurosci. Lett.
PUBLISHED: 08-14-2009
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Several observations suggest that neurotoxicity in Alzheimers disease (AD) can be partly attributed to beta-amyloid (Abeta) and senile plaques. Recent work has suggested that the FISH (five SH3 domains) adapter protein and ADAM12 (a disintegrin and metalloprotease) may mediate the neurotoxic effect of Abeta. Both genes are located on chromosome 10, within a region linked to AD (for SH3PXD2A) or nearby (for ADAM12). A recent study reported a statistically significant interaction between 2 variants of these genes (rs3740473 for SH3PXD2A and rs11244787 for ADAM12) with respect to the risk of developing AD. With a view to replicating this observation, we genotyped the two SNPs in four European case-control cohorts of Caucasian origin (1913 cases and 1468 controls) but were unable to confirm the initial results.
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Drugs with anticholinergic properties, cognitive decline, and dementia in an elderly general population: the 3-city study.
Arch. Intern. Med.
PUBLISHED: 07-29-2009
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Despite the high intake of medications with anticholinergic properties by community-dwelling elderly persons, the effects on cognitive decline and dementia have rarely been evaluated.
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Bilateral temporal glioma presenting as a paraneoplastic limbic encephalitis with pure cognitive impairment.
Neurologist
PUBLISHED: 07-11-2009
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Memory impairment caused by bilateral hippocampal primitive brain tumor is rarely reported. Clinical and MRI features can mimic paraneoplastic limbic encephalitis (PLE), and the differential diagnosis between these 2 entities may be difficult.
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Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimers disease.
Nat. Genet.
PUBLISHED: 05-12-2009
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The gene encoding apolipoprotein E (APOE) on chromosome 19 is the only confirmed susceptibility locus for late-onset Alzheimers disease. To identify other risk loci, we conducted a large genome-wide association study of 2,032 individuals from France with Alzheimers disease (cases) and 5,328 controls. Markers outside APOE with suggestive evidence of association (P < 10(-5)) were examined in collections from Belgium, Finland, Italy and Spain totaling 3,978 Alzheimers disease cases and 3,297 controls. Two loci gave replicated evidence of association: one within CLU (also called APOJ), encoding clusterin or apolipoprotein J, on chromosome 8 (rs11136000, OR = 0.86, 95% CI 0.81-0.90, P = 7.5 x 10(-9) for combined data) and the other within CR1, encoding the complement component (3b/4b) receptor 1, on chromosome 1 (rs6656401, OR = 1.21, 95% CI 1.14-1.29, P = 3.7 x 10(-9) for combined data). Previous biological studies support roles of CLU and CR1 in the clearance of beta amyloid (Abeta) peptide, the principal constituent of amyloid plaques, which are one of the major brain lesions of individuals with Alzheimers disease.
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Is the ornithine transcarbamylase gene a genetic determinant of Alzheimers disease?
Neurosci. Lett.
PUBLISHED: 04-16-2009
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Expression of ornithine transcarbamylase (OTC) is strongly induced in the brain of individuals suffering from Alzheimers Disease (AD). Association studies in a population from northern France have revealed that two SNPs -389 G/A (rs5963409) and -241 A/G (rs5963411) located in the promoter of the OTC gene are associated with the risk of developing AD. In the present work, these association studies were extended to a population of 2113 AD cases and 1580 controls from northern France, western France, the United Kingdom and Italy. The rs5963409 minor allele was weakly but significantly associated with an increased risk of developing AD (OR=1.19, p=0.004). This association was independent of age and ApoE status. Our results support that the OTC gene may be a minor genetic determinant of AD.
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Study of thyroid hormone receptor alpha gene polymorphisms on Alzheimers disease.
Neurobiol. Aging
PUBLISHED: 01-09-2009
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Because the action of thyroid hormone (T3) is involved in adult cognitive functions, we wanted to assess the association between THRA gene polymorphisms, which encodes the T3 nuclear receptor TR?1, and Alzheimers disease (AD) risk. We analysed 5 single nucleotide polymorphisms (SNPs) of THRA, covering the known common genetic variability of the gene, in the Lille AD case-control study (710 cases/597 controls). We observed that subjects bearing the rs939348 TT genotype had a tendency to have a higher risk of developing AD (adjusted OR [95%CI]=1.71 [0.99-2.95] p=0.06). We extended our finding to three other independent AD case-control studies and observed similar trends. When combining the 4 studies (1749 cases/1339 controls), we observed an overall significant higher risk of AD in TT subjects (adjusted OR [95%CI]=1.42 [1.03-1.96], p=0.03) compared with C allele bearers. However, when combining our data with the available data coming from 2 American genome wide association studies on AD, we observed a weak and not significant association (OR=1.19 [0.97-1.45], p=0.10). The relationship between the genetic variability of the THRA gene and AD risk remains uncertain but cannot be entirely excluded.
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Prevalence of cerebrovascular lesions in patients with Lewy body dementia: a neuropathological study.
Clin Neurol Neurosurg
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The co-existence of vascular pathology in patients with Lewy body dementia (LBD) is still a matter of debate. This study analyses the prevalence and the severity of cerebrovascular lesions in post-mortem brains of patients with LBD.
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My belief or yours? Differential theory of mind deficits in frontotemporal dementia and Alzheimers disease.
Brain
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Theory of mind reasoning-the ability to understand someone elses mental states, such as beliefs, intentions and desires-is crucial in social interaction. It has been suggested that a theory of mind deficit may account for some of the abnormalities in interpersonal behaviour that characterize patients affected by behavioural variant frontotemporal dementia. However, there are conflicting reports as to whether understanding someone elses mind is a key difference between behavioural variant frontotemporal dementia and other neurodegenerative conditions such as Alzheimers disease. Literature data on the relationship between theory of mind abilities and executive functions are also contradictory. These disparities may be due to underestimation of the fractionation within theory of mind components. A recent theoretical framework suggests that taking someone elses mental perspective requires two distinct processes: inferring someone elses belief and inhibiting ones own belief, with involvement of the temporoparietal and right frontal cortices, respectively. Therefore, we performed a neuropsychological and neuroimaging study to investigate the hypothesis whereby distinct cognitive deficits could impair theory of mind reasoning in patients with Alzheimers disease and patients with behavioural variant frontotemporal dementia. We used a three-option false belief task to assess theory of mind components in 11 patients with behavioural variant frontotemporal dementia, 12 patients with Alzheimers disease and 20 healthy elderly control subjects. The patients with behavioural variant frontotemporal dementia and those with Alzheimers disease were matched for age, gender, education and global cognitive impairment. [(18)F]-fluorodeoxyglucose-positron emission tomography imaging was used to investigate neural correlates of theory of mind reasoning deficits. Performance in the three-option false belief task revealed differential impairments in the components of theory of mind reasoning; patients with Alzheimers disease had a predominant deficit in inferring someone elses belief, whereas patients with behavioural variant frontotemporal dementia were selectively impaired in inhibiting their own mental perspective. Moreover, inhibiting ones own perspective was strongly correlated with inhibition in a Stroop task but not with other subprocesses of executive functions. This finding suggests that self-perspective inhibition may depend on cognitive processes that are not specific to the social domain. Last, the severity of the deficit in inferring someone elses beliefs correlated significantly over all subjects with hypometabolism in the left temporoparietal junction, whereas the severity of the deficit in self-perspective inhibition correlated significantly with hypometabolism in the right lateral prefrontal cortex. In conclusion, our findings provided clinical and imaging evidence to support differential deficits in two components of theory of mind reasoning (subserved by distinct brain regions) in patients with Alzheimers disease and patients with behavioural variant frontotemporal dementia.
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Dissociated responses to newer antimyeloma drugs identify a subset of refractory patients with an extremely poor prognosis.
Eur. J. Cancer
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We describe the striking and unexpected evolution of 10 patients with de novo multiple myeloma treated with novel-agent based induction therapy, who displayed a dissociated evolution characterised by an apparent good response contrasting with the concomitant development of aggressive non-secreting plasmocytomas immediately before, or just after, autologous stem cell transplantation. Patients did not respond to salvage therapies. Eight of them died from progression less than 12 months after diagnosis. This unusual evolution in the era of novel agents warrants further scrutiny.
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Long-term use of standardised Ginkgo biloba extract for the prevention of Alzheimers disease (GuidAge): a randomised placebo-controlled trial.
Lancet Neurol
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Prevention strategies are urgently needed to tackle the growing burden of Alzheimers disease. We aimed to assess efficacy of long-term use of standardised ginkgo biloba extract for the reduction of incidence of Alzheimers disease in elderly adults with memory complaints.
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[Alzheimers disease and related disorders: specificity of young onset patients, including ethical aspects].
Geriatr Psychol Neuropsychiatr Vieil
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The number of patients with young onset dementia (YOD) (that is before age 65) is estimated at 32,000 in France, and 5000 with onset dementia before 60 years. These patients differ from older ones by the greater number of rares causes (29%), heterogeneity of the presentation among the usual diseases, such as non-amnestic phenotypes of Alzheimers disease, high frequency of frontal symptoms, and possible genetic origin. These aspects must be taken into account for the diagnosis, often more difficult than in older ones because patients have a little knowledge of the YOD, excepted in the genetics forms. YOD patients can still work or drive a car, and we should choose between the respect for autonomy and the security for the patient and their carers. YOD patients can be more often included in pharmacological trials because they have lower associated disorders. Individual non-pharmacological treatment should be priviledged because they dont easily accept collective activities with other patients over 60 years of age. Excepted for the very young patients (onset before 45), the survival is longer than in late onset dementia, with sometimes severe behavioral problems related to frontal syndrome. In France, the caregiving at home has been improved since the possibility for the YOD patients to receive a financial assistance reserved for the disabled patients, but admission to a nursing home before 60 is very difficult and increases the caregiver burden and perception of unfairness. There is a discrimination between young or older demented patients related to the great difficulty to meet the needs of younger patients, due to the rigidity of the medical and social systems. The presentation of a limited offer for the YOD patients must initiate reflections on our capacities to respect the autonomy and the dignity of the Alzheimers patients regardless of age.
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Both common variations and rare non-synonymous substitutions and small insertion/deletions in CLU are associated with increased Alzheimer risk.
Mol Neurodegener
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We have followed-up on the recent genome-wide association (GWA) of the clusterin gene (CLU) with increased risk for Alzheimer disease (AD), by performing an unbiased resequencing of all CLU coding exons and regulatory regions in an extended Flanders-Belgian cohort of Caucasian AD patients and control individuals (n = 1930). Moreover, we have replicated genetic findings by targeted resequencing in independent Caucasian cohorts of French (n = 2182) and Canadian (n = 573) origin and by performing meta-analysis combining our data with previous genetic CLU screenings.
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Therapeutic drug monitoring of aminoglycosides in acute myeloid leukaemia patients.
Scand. J. Infect. Dis.
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International guidelines limit the use of aminoglycosides in febrile neutropenia to severe situations. We retrospectively reviewed the use of aminoglycosides in adult acute myeloid leukaemia patients admitted in 2009. Our guidelines include precise indications (severe sepsis, shock, drug resistance), dosing regimens (once-daily 20 mg/kg/day amikacin, 5 mg/kg/day gentamicin), durations of treatment, drug monitoring timing, and target C(max) concentrations (40 mg/l amikacin, 20 mg/l gentamicin). Thirty-one patients received 46 aminoglycoside courses: 31 amikacin and 15 gentamicin. The mean prescribed dosage was 19 ± 2.8 mg/kg/day for amikacin and 4.7 ± 0.9 mg/kg/day for gentamicin. The mean duration of use was 2.9 days for both drugs. The mean C(max) for amikacin was 47 ± 13 mg/l and for gentamicin was 13.6 ± 7.5 mg/l. In compliant regimens, all amikacin patients and a third of gentamicin patients had adequate C(max). Among 23 isolated pathogens, 65.5% were susceptible to both drugs and 11.5% to amikacin only. This vindicates the 20 mg/kg/day amikacin dosage and suggests a need to increase the gentamicin dosage.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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