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Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer’s disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8074; replication n = 5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aβ42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple Aβ42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume. This work was supported by a grant (European Alzheimer DNA BioBank, EADB) from the EU Joint Programme, Neurodegenerative Disease Research (JPND). Amsterdam dementia Cohort (ADC): Research of the Alzheimer center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. The Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting VUmc fonds. The clinical database structure was developed with funding from Stichting Dioraphte. Genotyping of the Dutch case-control samples was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND FP-829-029 (ZonMW project number 733051061). Part of the work described in this study was carried out in the context of the Parelsnoer Institute (PSI). PSI was part of and funded by the Dutch Federation of University Medical Centers and has received initial funding from the Dutch Government (from 2007-2011). Since 2020, this work was carried out in the context of Parelsnoer clinical biobanks at Health-RI (https://www.health-ri.nl/initiatives/parelsnoer).Part of the genotyping included in this work was funded by the JPND EADB grant (German Federal Ministry of Education and Research (BMBF) grant: 01ED1619A). Alfredo Ramirez is also supported by the German Research Foundation (DFG) grants Nr: RA 1971/6-1, RA1971/7-1, and RA 1971/8-1. We would like to thank patients and controls who participated in this project. The Genome Research @ Fundacio ACE project (GR@ACE) is supported by Grifols SA, Fundacion bancaria 'La Caixa', Fundacio ACE, and CIBERNED. A.R. and M.B. receive support from the European Union/EFPIA Innovative Medicines Initiative Joint undertaking ADAPTED and MOPEAD projects (grant numbers 115975 and 115985, respectively). M.B. and A.R. are also supported by national grants PI13/02434, PI16/01861, PI17/01474, PI19/01240 and PI19/01301. Accion Estrategica en Salud is integrated into the Spanish National R + D + I Plan and funded by ISCIII (Instituto de Salud Carlos III)-Subdireccion General de Evaluacion and the Fondo Europeo de Desarrollo Regional (FEDER-'Una manera de hacer Europa'). The position held by I.dR. is funded by grant. FI20/00215. PFIS Contratos Predoctorales de Formacion en Investigacion en Salud. We would like to thank UCL Genomics, London, UK, for performing the genotyping analyses of the samples within the Gothenburg H70 Birth Cohort Studies and Clinical AD Sweden. The recruitment and clinical characterization of research participants at Washington University were supported by NIH P30AG066444, and P01AG003991. This work was supported by access to equipment made possible by the Hope Center for Neurological Disorders, the Neurogenomics and Informatics Center (NGI: https://neurogenom ics.wustl.edu/)and the Departments of Neurology and Psychiatry at Washington University School of Medicine. Research at the Belgian EADB site is funded in part by the Alzheimer Research Foundation (SAO-FRA), The Research Foundation Flanders (FWO), and the University of Antwerp Research Fund. FK is supported by a BOF DOCPRO fellowship of the University of Antwerp Research Fund. The work of Valdecilla was supported by grants from the Instituto de Salud Carlos III (Fondo de Investigacion Sanitario, PI08/0139, PI12/02288, PI16/01652, and PI20/01011), the JPND (DEMTEST PI11/03028), the CIBERNED, and the Siemens Healthineers. We thank the Valdecilla Biobank (PT17/0015/0019), integrated into the Spanish Biobank Network, for their support and collaboration in sample collection and management. Our heartfelt thanks to the participants of the Valdecilla Cohort for their generosity. The work of ADGEN was supported by EU Joint Programme-Neurodegenerative Disease Research (301220) and the Academy of Finland (338182). The DELCODE study (Study-ID:BN012) was supported and conducted by the German Center for Neurodegenerative Diseases (DZNE). The data samples were provided by the DELCODE study group. Details and participating sites can be found at www.dzne.de/en/research/studies/clinical-studies/delco de. The German Dementia Competence Network (KND) is funded by the German Federal Ministry of Education and Research (BMBF) grants Number: 01G10102, 01GI0420, 01GI0422, 01GI0423, 01GI0429, 01GI0431, 01GI0433, 04GI0434, 01GI0711. WF, SvdL, HHolstege, CT and PhS are recipients of ABOARD, which is a public-private partnership receiving funding from ZonMW (#73305095007) and HealthHolland, Topsector Life Sciences & Health (PPP-allowance; #LSHM20106). More than 30 partners participate in ABOARD (www.aboard-project.nl).ABOARD also receives funding from de Hersenstichting, Edwin Bouw Fonds and Gieskes-Strijbisfonds. IEJ was partially supported by NWO Gravitation program BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (NWO: 024.004.012). AZ was supported by the Swedish Alzheimer Foundation (AF-939988, AF-930582, AF-646061, AF-741361), and the Dementia Foundation (2020-04-13, 2021-0417). ISk was supported by the Swedish state under the agreement between the Swedish government and the county councils, the ALFagreement (ALF 716681), the Swedish Research Council (no 11267, 825-2012-5041, 2013-8717, 2015-02830, 2017-00639, 2019-01096), Swedish Research Council for Health, Working Life and Welfare (no 2001-2646, 2001-2835, 2001-2849, 2003-0234, 2004-0150, 20050762, 2006-0020, 2008-1229, 2008-1210, 2012-1138, 2004-0145, 2006-0596, 2008-1111, 2010-0870, 2013-1202, 2013-2300, 20132496), Swedish Brain Power, Hjarnfonden, Sweden (FO2016-0214, FO2018-0214, FO2019-0163), the Alzheimer's Association Zenith Award (ZEN-01-3151), the Alzheimer's Association Stephanie B. Overstreet Scholars (IIRG-00-2159), the Alzheimer's Association (IIRG-03-6168, IIRG-09-131338) and the Bank of Sweden Tercentenary Foundation. SK was supported by the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (ALFGBG-81392, ALF GBG-771071), the Swedish Alzheimer Foundation (AF-842471, AF-737641, AF-939825), and the Swedish Research Council (2019-02075). MW was supported by the Swedish Research Council 2016-01590. DP was supported by BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (grant no. 024.004.012), and a European Research Council advanced grant (Grant No, ERC-2018-AdG GWAS2FUNC 834057. HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (2018-02532), the European Research Council (681712), Swedish State Support for Clinical Research (ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (2018092016862), the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 860197 (MIRIADE), and the UK Dementia Research Institute at UCL. KB was supported by the Swedish Research Council (#2017-00915), the Alzheimer Drug Discovery Foundation (ADDF), USA (#RDAPB201809-2016615), the Swedish Alzheimer Foundation (#AF-742881), Hjarnfonden, Sweden (#FO2017-0243), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986), the European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236), the National Institute of Health (NIH), USA, (grant #1R01AG06839801), and the Alzheimer's Association 2021 Zenith Award (ZEN-21848495). CC receives support from the National Institutes of Health (R01AG044546, R01AG064877, RF1AG053303, R01AG058501, U01AG058922, RF1AG058501, R01AG064614), and the Chuck Zuckerberg Initiative (CZI).

Objective:Studies of frailty have tended to focus on adverse outcomes. This study aims to develop a short instrument that identifies a positive outcome, namely, the level of well-being in older adults at risk of frailty.Method:871 older adults (49.4% women; mean age 75.72 years; SD = 8.05) with a frailty risk profile participated in the first wave of the D-SCOPE study. The possible domains of well-being were identified using a bottom-up approach. Exploratory Structural Equation Modeling (ESEM) and multidimensional Item Response Theory (IRT) analysis of 17 items in 4 domains measuring well-being was performed on a calibration sample (n = 435) to develop the instrument. The instrument was subsequently corroborated by confirmatory factor analysis and convergent/divergent relations with relevant external measures in a validation sample (n = 436).Results:The ESEM three-factor solution, with the subdimensions of sense of mastery, meaning in life, and life satisfaction, displayed good fit to the data (RMSEA = 0.070). For each dimension, the three best discriminating items were retained for the instrument following IRT analysis. Internal consistency of these dimensions was good in the validation sample (sense of mastery α = 0.864, meaning in life α = 0.715, and life satisfaction α = 0.782). The confirmatory factor analysis (CFA) three-factor model also showed good fit to the data (RMSEA = 0.064). Small to large zero-order correlations with the external measures were as expected.Conclusions:Using a bottom-up approach, this study developed a short instrument to identify levels of well-being in vulnerable or frail older adults. The instrument can be applied in primary care and prevention programs.

Introduction: In this multicenter study on subjective cognitive decline (SCD) in community-based and memory clinic settings, we assessed the (1) incidence of Alzheimer's disease (AD) and non-AD dementia and (2) determinants of progression to dementia.Methods: Eleven cohorts provided 2978 participants with SCD and 1391 controls. We estimated dementia incidence and identified risk factors using Cox proportional hazards models.Results: In SCD, incidence of dementia was 17.7 (95% Poisson confidence interval 15.2-20.3)/1000 person-years (AD: 11.5 [9.6-13.7], non-AD: 6.1 [4.7-7.7]), compared with 14.2 (11.3-17.6) in controls (AD: 10.1 [7.7-13.0], non-AD: 4.1 [2.6-6.0]). The risk of dementia was strongly increased in SCD in a memory clinic setting but less so in a community-based setting. In addition, higher age (hazard ratio 1.1 [95% confidence interval 1.1-1.1]), lower Mini-Mental State Examination (0.7 [0.66-0.8]), and apolipoprotein E epsilon 4 (1.8 [1.3-2.5]) increased the risk of dementia.Discussion: SCD can precede both AD and non-AD dementia. Despite their younger age, individuals with SCD in a memory clinic setting have a higher risk of dementia than those in community-based cohorts. (C) 2018 The Authors. Published by Elsevier Inc.

Even though the involvement of serotonin (5-hydroxytryptamine; 5-HT) and its receptors in Alzheimer's disease (AD) is widely accepted, data on the expression and the role of 5-HT7 receptors in AD is relatively limited. Therefore, the objective of the present work was to study the expression of serotonergic 5-HT7 receptors in postmortem samples of AD brains and correlate it with neurotransmitter levels, cognition and behavior. The study population consisted of clinically well-characterized and neuropathologically confirmed AD patients (n = 42) and age-matched control subjects (n = 18). Reverse-transcription quantitative polymerase chain reaction (RT-qPCR) and high-performance liquid chromatography were performed on Brodmann area (BA) 7, BA10, BA22, BA24, hippocampus, amygdala, thalamus and cerebellum to measure mRNA levels of 5-HT7 receptors (HTR7), as well as the concentrations of various monoamine neurotransmitters and their metabolites. Decreased levels of HTR7 mRNA were observed in BA10. A significant association was observed between HTR7 levels in BA10 and BEHAVE-AD cluster B (hallucinations) (rs(28) = 0.444, P < 0.05). In addition, a negative correlation was observed between HTR7 levels in BA10 and both MHPG concentrations in this brain region (rs(45) = -0.311; P < 0.05), and DOPAC levels in the amygdala (rs(42) = -0.311; P < 0.05). Quite surprisingly, no association was found between HTR7 levels and cognitive status. Altogether, this study supports the notion of the involvement of 5-HT7 receptors in psychotic symptoms in AD, suggesting the interest of testing antagonist acting at this receptor to specifically treat psychotic symptoms in this illness.

Parkinson’s disease (PD) is a progressive neurodegenerative brain disease presenting with a variety of motor and non-motor symptoms, loss of midbrain dopaminergic neurons in the substantia nigra pars compacta and the occurrence of α-synuclein-positive Lewy bodies in surviving neurons. Here, we performed whole exome sequencing in 52 early-onset PD patients and identified 3 carriers of compound heterozygous mutations in the ATP10B P4-type ATPase gene. Genetic screening of a Belgian PD and dementia with Lewy bodies (DLB) cohort identified 4 additional compound heterozygous mutation carriers (6/617 PD patients, 0.97%; 1/226 DLB patients, 0.44%). We established that ATP10B encodes a late endo-lysosomal lipid flippase that translocates the lipids glucosylceramide (GluCer) and phosphatidylcholine (PC) towards the cytosolic membrane leaflet. The PD associated ATP10B mutants are catalytically inactive and fail to provide cellular protection against the environmental PD risk factors rotenone and manganese. In isolated cortical neurons, loss of ATP10B leads to general lysosomal dysfunction and cell death. Impaired lysosomal functionality and integrity is well known to be implicated in PD pathology and linked to multiple causal PD genes and genetic risk factors. Our results indicate that recessive loss of function mutations in ATP10B increase risk for PD by disturbed lysosomal export of GluCer and PC. Both ATP10B and glucocerebrosidase 1, encoded by the PD risk gene GBA1, reduce lysosomal GluCer levels, emerging lysosomal GluCer accumulation as a potential PD driver. Electronic supplementary material The online version of this article (10.1007/s00401-020-02145-7) contains supplementary material, which is available to authorized users.

Matrix metalloproteinases (MMPs) are a multigene family of proteinases regulating the functions of a large number of signaling and scaffolding molecules that are involved in neuro-inflammation, synaptic dysfunction and neuronal death. MMPs have been associated with neurological conditions, such as Alzheimer's disease (AD), through a sudden and massive upregulation of particular members of the MMP family. Evidence for this hypothesis can be found in the clinical observation of increased MMP1 and MMP3 expression levels in plasma of AD patients compared to control individuals and in the proamyloidogenic effects that have been described for additional MMP family members like MMP13, MT1-MMP, and MT5-MMP. Consequently, we investigated the role of MMP1, 3, 13, MT1-MMP, and MT5-MMP in the genetic etiology of AD. We performed full exonic resequencing of these 5 MMPs in 1278 AD patients (mean age at onset [AAO]: 74.88 I 9.10, range: 29-96) and 797 age-matched control individuals (mean age at inclusion [AAI]: 74.92 I 6.48, range: 65-100) from Flanders-Belgium and identified MMP13 as most promising candidate gene. We identified 6 ultra-rare (

People with Down syndrome (DS) are prone to develop Alzheimer's disease (AD). Behavioral and psychological symptoms of dementia (BPSD) are core features, but have not been comprehensively evaluated in DS. In a European multidisciplinary study, the novel Behavioral and Psychological Symptoms of Dementia in Down Syndrome (BPSD-DS) scale was developed to identify frequency and severity of behavioral changes taking account of life-long characteristic behavior. 83 behavioral items in 12 clinically defined sections were evaluated. The central aim was to identify items that change in relation to the dementia status, and thus may differentiate between diagnostic groups. Structured interviews were conducted with informants of persons with DS without dementia (DS, n = 149), with questionable dementia (DS+Q, n = 65), and with diagnosed dementia (DS+AD, n = 67). First exploratory data suggest promising interrater, test-retest, and internal consistency reliability measures. Concerning item relevance, group comparisons revealed pronounced increases in frequency and severity in items of anxiety, sleep disturbances, agitation & stereotypical behavior, aggression, apathy, depressive symptoms, and eating/drinking behavior. The proportion of individuals presenting an increase was highest in DS+AD, intermediate in DS+Q, and lowest in DS. Interestingly, among DS+Q individuals, a substantial proportion already presented increased anxiety, sleep disturbances, apathy, and depressive symptoms, suggesting that these changes occur early in the course of AD. Future efforts should optimize the scale based on current results and clinical experiences, and further study applicability, reliability, and validity. Future application of the scale in daily care may aid caregivers to understand changes, and contribute to timely interventions and adaptation of caregiving.

Background Neutrophil Gelatinase-Associated Lipocalin (NGAL) is an inflammatory protein with gaining increasing interest for its use as marker in blood and cerebrospinal fluid (CSF) for several chronic diseases. Its biochemical properties make it an attractive marker. However, changes in blood and CSF NGAL concentrations during the diurnal rhythm in the elderly are unknown. This information is important for its optimal use as marker in studies with older people. Methods Serial paired plasma and CSF samples were obtained from 8 healthy elderly males over a 30 hour period. NGAL and cortisol were quantified with ELISA. Results No significant changes in plasma and CSF NGAL concentrations over time were found, whereas cortisol (included as internal control) concentrations displayed significant changes over time. Significant circadian patterns were found for plasma NGAL and for cortisol in both plasma and CSF. However, CSF NGAL concentrations did not follow a diurnal pattern in elderly males. Conclusions This study illustrates the temporal regulation of NGAL in plasma and CSF, which potentially is a useful reference for studies measuring NGAL as biomarker in older individuals. This article is protected by copyright. All rights reserved.

The underlying pathophysiology of primary open-angle glaucoma remains unclear, but the lamina cribrosa seems to be the primary site of injury and raised intraocular pressure is a major risk factor. In recent years, a decreased intracranial pressure, leading to an abnormally high trans-lamina cribrosa pressure difference, has gained interest as a new risk factor for glaucoma. New research now lends support to the hypothesis that a paravascular transport system is present in the eye analogous to the recently discovered glymphatic system in the brain, which is a functional waste clearance pathway that promotes elimination of interstitial solutes, including amyloid-β, from the brain along paravascular channels. Given that amyloid-β has been reported to increase by chronic elevation of intraocular pressure in glaucomatous animal models and to cause retinal ganglion cell death, the discovery of a paravascular clearance system in the eye may provide powerful new insights into the pathophysiology of primary open-angle glaucoma. In this review, we provide a new conceptual framework for understanding the pathogenesis of primary open-angle glaucoma, present supporting preliminary data from our own post-mortem study, and hypothesize that the disease may result from restriction of normal glymphatic flow at the level of the lamina cribrosa due to a low intracranial pressure and/or a high trans-lamina cribrosa pressure gradient. If confirmed, this viewpoint could offer new perspectives for the development of novel diagnostic and therapeutic strategies for this devastating disorder.

Obestatin is a ghrelin-associated peptide hormone with presumed anorexigenic and inhibitory effect on gastric propulsive motility activity. Recent literature, however, discloses much contestation over satiety and gastrointestinal motility-related functionalities of obestatin. In addition, antidipsinogenic effects in rodents by obestatin were recently reported. The present study was set up to bring more clarity into the contested effects of obestatin on food and water intake. Additionally, the stability of obestatin in brain tissue homogenate was investigated. The in vitro incubation of obestatin in brain homogenates revealed disappearance half-life times of 19 min for crude brain homogenate to 27 min for brain membrane homogenate. For the behavioural studies, male C57Bl/6 mice were intracerebroventricularly treated with 0.2 nmol murine amidated obestatin or vehicle at the age of 3 months. An additional group of mice was treated with 0.3 nmol of corticotropin releasing factor (CRF) as a positive control of suppression of food intake. Food and water intake were studied over a period of 5 h in metabolic cages. Under our experimental conditions, no suppressive effects of obestatin on food or water intake were observed, whereas CRF evoked a significant suppression of food intake, which proves the internal validity of the study design.

A new study describes a biomarker profile based on cerebrospinal fluid (CSF) tau and amyloid-β142 in a uniquely large population with a variety of dementia diagnoses. This study confirms the differential diagnostic value of CSF biomarkers and further highlights the important neuropathological overlap between dementia aetiologies.

Weight loss and undernutrition are commonly described in patients with Alzheimers disease (AD) and have been associated with various adverse outcomes. Therefore, it is important to know what the best approach is to community-dwelling AD patients with a risk of developing a poor nutritional status; however, there is currently no evidence on which to base nutritional recommendations. Expert based recommendations are that the nutritional status should be part of the work-up of all AD patients. If weight loss of 5 % or more has occurred in 36 months or if the mini-nutritional assessment (MNA) classifies a patient as undernourished, a nutritional intervention should be started. The intervention should be multifactorial and encompass treatment of the underlying proposed causes and risk factors of weight loss and undernutrition as well as improvement of the nutritional status by increasing energy and protein intake combined with daily physical activity.

Background The ability to identify individuals at increased genetic risk for Alzheimer's disease (AD) may streamline biomarker and drug trials and aid clinical and personal decision making. Methods We evaluated the discriminative ability of a genetic risk score (GRS) covering 22 published genetic risk loci for AD in 1162 Flanders-Belgian AD patients and 1019 controls and assessed correlations with family history, onset age, and cerebrospinal fluid (CSF) biomarkers (Aβ142, T-Tau, P-Tau181P). Results A GRS including all single nucleotide polymorphisms (SNPs) and age-specific APOE ε4 weights reached area under the curve (AUC) 0.70, which increased to AUC 0.78 for patients with familial predisposition. Risk of AD increased with GRS (odds ratio, 2.32 (95% confidence interval 2.082.58 per unit; P < 1.0e−15). Onset age and CSF Aβ142 decreased with increasing GRS (Ponset_age = 9.0e−11; PAβ = 8.9e−7). Conclusions The discriminative ability of this 22-SNP GRS is still limited, but these data illustrate that incorporation of age-specific weights improves discriminative ability. GRS-phenotype correlations highlight the feasibility of identifying individuals at highest susceptibility.

ObjectiveWith a prevalence that varies between 20% and 65%, poststroke depression (PSD) is a frequent sequel of stroke. The aim of this study was to determine incidence and risk factors for PSD 18months after stroke. MethodsAs part of the Middelheim Interdisciplinary Stroke Study, patients were followed up for 18months in this prospective and longitudinal epidemiological study. Clinically significant signs and symptoms of PSD were quantified by means of the Cornell Scale for Depression (CSD) and the Montgomery and angstrom sberg Depression Rating Scale. Activities, including social activities, were measured with the Stroke Impact Scale (SIS). Relational problems since stroke onset were defined by a questionnaire. ResultsData analysis was performed on 125 patients who completed follow-up assessments. Depression (CSD score 8) was diagnosed in 28% of the patients. Patients with PSD were more dependent for activities of daily living and displayed more physical and cognitive impairment than patients without PSD. The risk to become depressed decreased with 5% when the patient's activities increased with one unit on the SIS (odds ratio (OR)=0.95; 95% confidence interval (CI)=0.93-0.97). Patients with persistent relational problems since stroke onset had approximately four and a half times greater risk of becoming depressed than patients without (OR=4.48; 95%CI=1.17-16.87). ConclusionsMultiple regression models indicated that the most determining features for developing PSD at 18months poststroke include reduced activity and relationship problems due to stroke. Further studies on risk factors for PSD are essential, including psychosocial aspects, given its negative impact on rehabilitation and quality of life. Copyright (c) 2013 John Wiley & Sons, Ltd.

Objectives: The objective of this study is to clarify the role of (G 4 C 2 ) n expansions in the etiology of Parkinson disease (PD) in the worldwide multicenter Genetic Epidemiology of Parkinson9s Disease (GEO-PD) cohort. Methods: C9orf72 (G 4 C 2 ) n repeats were assessed in a GEO-PD cohort of 7,494 patients diagnosed with PD and 5,886 neurologically healthy control individuals ascertained in Europe, Asia, North America, and Australia. Results: A pathogenic (G 4 C 2 ) n>60 expansion was detected in only 4 patients with PD (4/7,232; 0.055%), all with a positive family history of neurodegenerative dementia, amyotrophic lateral sclerosis, or atypical parkinsonism, while no carriers were detected with typical sporadic or familial PD. Meta-analysis revealed a small increase in risk of PD with an increasing number of (G 4 C 2 ) n repeats; however, we could not detect a robust association between the C9orf72 (G 4 C 2 ) n repeat and PD, and the population attributable risk was low. Conclusions: Together, these findings indicate that expansions in C9orf72 do not have a major role in the pathogenesis of PD. Testing for C9orf72 repeat expansions should only be considered in patients with PD who have overt symptoms of frontotemporal lobar degeneration/amyotrophic lateral sclerosis or apparent family history of neurodegenerative dementia or motor neuron disease.

Background: Autosomal dominant dopa-responsive dystonia (AD-DRD) is caused by a biochemical defect primarily resulting from guanosine triphosphate cyclohydrolase 1 gene (GCH1) mutations. Few families have been reported without mutations in GCH1. Methods: Genome-wide linkage analysis and positional cloning to identify the genetic defect in a Belgian AD-DRD family was carried out. Results and Conclusion: In this study, we report on the identification and characterization of a novel 24-kb deletion spanning exon 1 and the 5′ regulatory region of GCH1 causing a wide spectrum of motor and nonmotor symptoms in a large Belgian AD-DRD family. This large-scale deletion of regulatory sequences leads to decreased GCH1 activity in all carriers, most probably resulting from allelic loss of transcription. We mapped the breakpoints of this deletion to the nucleotide level, allowing the development of a straightforward polymerase chain reaction assay for fast, efficient detection of this large deletion, which will prove valuable for preimplantation genetic diagnosis.

Aims: Cognitive impairment and dementia are common features of Parkinson's disease (PD). Patients with Parkinson's disease dementia (PDD) often have significant cholinergic defects, which may be treated with cholinesterase inhibitors (ChEIs). The objective of this review was to consider available efficacy, tolerability, and safety data from studies of ChEIs in PDD. Discussions: A literature search resulted in the identification of 20 relevant publications. Of these, the treatment of PD patients with rivastigmine, donepezil, or galantamine was the focus of six, eleven, and two studies respectively, while one study reported use of both tacrine and donepezil. The majority of studies were small (

Background: Stroke in the young has not been thoroughly investigated with most previous studies based on a small number of patients from single centers. Furthermore, recent reports indicate that Fabry disease may be a significant cause for young stroke. The primary aim of our study was to determine the prevalence of Fabry disease in young stroke patients, while the secondary aim was to describe patterns of stroke in young patients. Methods: We initiated the Stroke in Young Fabry Patients (sifap1) study as a multinational prospective European study of stroke patients aged 18–55 years and collected a broad range of clinical, laboratory, and radiological data using stringent standardized methods. All patients were tested for Fabry disease and blood was stored for future genetic testing. Results: We managed to enroll 5,024 eligible young stroke patients in 15 countries and 47 centers across Europe between April 2007 and January 2010. The median number of patients included per center was 98 with a range between 8 and 315. The average duration of patient recruitment per center was 22 months, ranging between 5 and 33 months. The database was closed in July 2010. This paper describes protocol and methodology of the sifap1 study. Conclusion: The sifap1 study included the largest series of young stroke patients so far and will allow for analyses on a large number of aspects of stroke in the young.

Using 8- and 18-month-old AβPP23 mice, we investigated the involvement of high-affinity glutamate transporters (GLAST, GLT-1, EAAC1), vesicular glutamate transporters (VGLUT1-3) and xCT, the specific subunit of system xc-, in Alzheimers disease (AD) pathogenesis. Transporter expression was studied in cortical and hippocampal tissue and linked to extracellular glutamate and glutamate reuptake activity as measured using in vivo microdialysis. In 8-month-old animals, we could not observe plaque formation or gliosis. Yet, in hippocampus as well as cortex GLAST and GLT-1 expression was decreased. Whereas in cortex this was accompanied by upregulated VGLUT1 expression, extracellular glutamate concentrations were decreased. Surprisingly, inhibiting glutamate reuptake with TBOA revealed increased glutamate reuptake activity in cortex of AβPP23 mice, despite decreased GLAST and GLT-1 expression, and resulted in status epilepticus in all AβPP23 mice, contrary to wildtype littermates. In hippocampus of 8-month-old AβPP23 mice, we observed increased EAAC1 expression besides the decrease in GLAST and GLT-1. Yet, glutamate reuptake activity was drastically decreased according to the decreased GLAST and GLT-1 expression. In 18-month-old AβPP23 mice, plaque formation and gliosis in cortex and hippocampus were accompanied by decreased GLT-1 expression. We also showed, for the first time, increased cortical expression of VGLUT3 and xCT together with a strong tendency towards increased cortical extracellular glutamate levels. VGLUT2 expression remained unaltered in all conditions. The present findings support the hypothesis that alterations in transport of glutamate, and more particular via GLT-1, may be involved in AD pathogenesis.

During the past decades, the role of the cerebellum as sole modulator of motor coordination, balance and motor speech has been substantially redefined. Results from neuroanatomical, neuroimaging and clinical studies have extended the functional role of the cerebellum to cognitive and affective regulation. Neuroanatomical studies convincingly demonstrated cerebellar connectivity with the supratentorial association areas involved in higher cognitive functioning, whereas functional neuroimaging studies provided evidence of cerebellar activation during a variety of cognitive tasks. In this contribution, a concise overview of the cerebellar role in various cognitive processes, such as executive functioning, memory, learning, attention, visuospatial regulation, language and behavioralaffective modulation, is presented. In addition, cerebellar syndromes such as the cerebellar cognitive affective syndrome (CCAS) and the posterior fossa syndrome (PFS) will be discussed. Although extensive research has substantially broadened the insights into the cognitive and affective role of the cerebellum, the precise nature of the cerebellar contribution to cognitive, linguistic and affective processing is not yet clear. In this review, clinical and functional neuroimaging data will be discussed that substantiate some of the current hypotheses dealing with the presumed neurobiological mechanisms underlying the cognitive and affective modulatory role of the cerebellum.

Background and Purpose— High blood pressure (BP) is present in ≈80% of patients with acute ischemic stroke and is independently associated with poor outcome. There are few data examining the relationship between admission BP and acute CT findings. Methods— TAIST was a randomized controlled trial assessing 10 days of treatment with tinzaparin versus aspirin in 1489 patients with acute ischemic stroke ( Results— Higher systolic BP (SBP) was associated with abnormal CT scans because of independent associations with chronic changes of leukoariosis (OR, 1.12; 95% CI, 1.05–1.17) and old infarction (OR, 1.12; 95% CI, 1.06–1.17) at baseline, and signs of visible infarction at day 10 (OR, 1.06; 95% CI, 1.00–1.13). A lower SBP was associated with signs of acute infarction (OR, 0.94; 95% CI, 0.89–0.99). Hemorrhagic transformation, dense middle cerebral artery sign, mass effect, and cerebral edema at day 10 were not independently associated with baseline BP. Conclusion— Although high baseline BP is independently associated with a poor outcome after stroke, this was not shown to be through an association with increased hemorrhagic transformation, cerebral edema, or mass effect; trial design may be suboptimal to detect this. Higher SBP is associated with visible infarction on day 10 scans. The influence of changing BP in acute stroke on CT findings is still to be ascertained.

Background Associations between low levels of folate and vitamin B-12 and cognitive impairment inpatients with dementia have been reported. Some studies revealed correlations between low levels of vitamin B-12 and behavioural and psychological signs and symptoms of dementia (BPSD) in Alzheimer's disease (AD) patients. Given the lack of studies in frontotemporal dementia (FrD) and on folate and given the methodological shortcomings of former publications, we set up a prospective study. Methods At inclusion, AD (n = 152) and FTD (n = 28) patients underwent a neuropsychological examination. Behaviour was assessed using a battery of behavioural assessment scales. Determination of serum vitamin B-12 and red cell folate levels were performed within a time frame of two weeks of inclusion. Results In both patient groups, significantly negative correlations between levels of serum vitamin B-12 and red cell folate and the degree of cognitive deterioration were found. No correlations with BPSD were found in the AD patient group. In FTD patients, levels of vitamin B-12 were negatively correlated with both hallucinations (p = 0.022) and diurnal rhythm disturbances (p = 0.036). Conclusions The observed negative correlations between levels of vitamin B-12 and folate and cognitive impairment in both AD and FrD patients, raise the possibility of a non-specific etiological role. Although levels of vitamin B-12 and folate did not correlate with BPSD in AD patients, negative correlations between serum vitamin B-12 levels and BPSD in FrD patients were revealed. Decreased serum vitamin B-12 levels may predispose FTD patients to develop hallucinations and diurnal rhythm disturbances. Copyright (C) 2004 John Wiley Sons, Ltd.

The uremic syndrome is a complex mixture of organ dysfunctions, which is attributed to the retention of a myriad of compounds that under normal condition are excreted by the healthy kidneys (uremic toxins). In the area of identification and characterization of uremic toxins and in the knowledge of their pathophysiologic importance, major steps forward have been made during recent years. The present article is a review of several of these steps, especially in the area of information about the compounds that could play a role in the development of cardiovascular complications. It is written by those members of the Uremic Toxins Group, which has been created by the European Society for Artificial Organs (ESAO). Each of the 16 authors has written a state of the art in his/her major area of interest.

Neurodegenerative disorders (NDDs) pose an ever-increasing healthcare burden on society. Studying neurochemical disturbances in these diseases could help identify novel targets of interest and pinpoint disease biomarkers. This thesis focused on the neurochemical characterization of Alzheimer’s disease (AD), frontotemporal lobar degeneration (FTLD), dementia with Lewy bodies/Parkinson’s disease dementia (DLB/PDD) and amyotrophic lateral sclerosis (ALS), primarily with respect to monoaminergic neurotransmitter systems. In addition, we addressed several methodological issues, including the influence of circadian rhythm on monoamines in cerebrospinal fluid (CSF) and plasma and the rostrocaudal concentration gradient (RCG) in CSF. We also verified whether B elements, a type of short interspersed nuclear elements, could be applied as a normalization strategy in reverse transcription quantitative PCR (RT-qPCR) experiments. We found an influence of circadian rhythm on homovanillic acid (HVA), and identified the presence of a RCG for HVA and 5-hydroxyindoleacetic acid. These findings underscored the importance of standardization of pre-analytical procedures. Furthermore, we could conclude that B elements could be adopted as normalization factors in hippocampus, but less so in cortex. We further investigated monoaminergic systems in AD and behavioral variant FTLD and found that these two NDDs are characterized by distinct serotonergic and noradrenergic systems. Next, we analyzed CSF and serum samples from patients with AD, FTLD, DLB/PDD and CONTR and noted altered 3-methoxy-4-hydroxyphenylglycol levels in DLB/PDD subjects. In addition, we confirmed that CSF and serum levels of this noradrenergic metabolite improved the AD versus DLB/PDD differential diagnosis. Because of considerable clinical, genetic and neuropathological overlap between FTLD and ALS, we analyzed CSF and serum samples for monoaminergic and kynurenergic content. A general dopaminergic disturbance was observed in FTLD and ALS subjects, while the KP did not appear to be altered in the ALS-FTLD continuum. The expression of G protein-coupled receptors (GPCRs) in brain tissue of AD and CONTR subjects was assessed using RT-qPCR. Our results indicated alterations in serotonergic and noradrenergic GPCR expression levels in limbic and frontal brain areas of AD subjects. Glutamatergic and cholinergic GPCR expression levels in the hippocampus of APP23 mice were influenced by age, but not by genotype. Protein-level analyses of the 5-HT6 receptor in the APP23 model did not show any age- or genotype effects. Taken together, this dissertation offers more insight into the neurochemical imbalance in several NDDs. Our hypotheses regarding neurochemical underpinnings of NDDs remain to be strengthened, and the biomarker potential of the investigated neurochemicals should be further confirmed.

Neurodegenerative diseases are often associated with comorbidities that worsen the disease phenotype. As our society might benefit from more effective therapeutic strategies for these comorbidities, we sought to provide a better characterization of the underlying mechanisms that play a role in their development. In this doctoral thesis, we focused on two comorbidities in particular, namely epilepsy and sleep disturbances. Epilepsy is more prevalent in certain neurodegenerative diseases. Patients are more prone to the development of seizures and epilepsy than aged control individuals. As many of these neurodegenerative disorders are characterized by the presence of pathologic forms of tau and neurofibrillary tangles, studying the effects of tau pathology on the development of epilepsy might prove rewarding. To gain more insight into the relation between tau pathology and epileptogenesis, the Tau58/4 tauopathy mouse model was subjected to a seizure susceptibility analysis. We reported increased seizure susceptibility in young Tau58/4 mice, which are still in an early pathologic stage, but not in old Tau58/4 mice with full-blown tau pathology. Therefore, we hypothesized a crucial role for pre-fibrillar hyperphosphorylated tau in increasing the sensitivity towards PTZ-induced seizures. Aside from epilepsy, many patients also suffer from other comorbidities, including sleep and circadian rhythm disturbances. In contrast to epilepsy, sleep abnormalities are among the first noticeable symptoms of the disease. To gain a better understanding of how certain dementia-specific pathologic proteins interact with sleep-regulating brain centers and influence cognition, two different transgenic mouse models were studied. We found that, at advanced stages of pathology, both models display severe sleep deficits. In APP23 mice, the sleep and activity profile hints towards a hyperactive condition during the dark phase. In Tau58/4 mice sleep time was reduced during both photoperiods. Most remarkably, disturbances in rapid eye movement sleep were already present from a young age. Based on the pathologic spread in the APP23 model and the spectral data of the EEG, we concluded that A? probably has toxic effects at the level of the cortex, resulting in disrupted patterns of cortical activation and sleep loss. By contrast, tau pathology might be more detrimental for the central regulation of sleep, regulated by sleep centers in the brainstem, because sleep disturbances are photoperiod-independent and arise around the time pathologic tau starts to accumulate in pontine regions. To conclude, A? and tau obviously have differential effects on sleep in these two distinct models.

Progressive supranuclear palsy (PSP) is a movement disorder with prominent tau neuropathology. Brain diseases with abnormal tau deposits are called tauopathies, the most common being Alzheimer’s disease. Environmental causes of tauopathies include repetitive head trauma associated with some sports. To identify common genetic variation contributing to risk for tauopathies, we carried out a genome-wide association study of 1,114 PSP cases and 3,247 controls (Stage 1) followed up by a second stage where 1,051 cases and 3,560 controls were genotyped for Stage 1 SNPs that yielded P ≤ 10−3. We found significant novel signals (P < 5 × 10−8) associated with PSP risk at STX6, EIF2AK3, and MOBP. We confirmed two independent variants in MAPT affecting risk for PSP, one of which influences MAPT brain expression. The genes implicated encode proteins for vesicle-membrane fusion at the Golgi-endosomal interface, for the endoplasmic reticulum unfolded protein response, and for a myelin structural component., T.G. serves as an editorial board member of Movement Disorders and Parkinsonism and Related Disorders and is funded by Novartis Pharma, the Federal Ministry of Education and Research (BMBF) (NGFN-Plus and ERA-Net NEURON), the Helmholtz Association (HelMA, Helmholtz Alliance for Health in an Ageing Society) and the European Community (MeFoPa, Medndelian Forms of Parkinsonism). T.G. received speakers honoraria from Novartis, Merck-Serono, Schwarz Pharma, Boehringer Ingelheim and Valeant Pharma and royalties for his consulting activities from Cefalon Pharma and Merck-Serono. T.G. holds a patent concerning the LRRK2 gene and neurodegenerative disorders. J.H. is consulting for Merck Serono and Eisai. I.Litvan is the founder of the Litvan Neurological Research Foundation, whose mission is to increase awareness, determine the cause/s and search for a cure for neurodegenerative disorders presenting with either parkinsonian or dementia symptoms (501c3).

Summary Background Blockade of the endocannabinoid receptor reduces obesity and improves metabolic abnormalities such as triglycerides, HDL cholesterol, and fasting blood glucose. We assessed whether rimonabant would improve major vascular event-free survival. Methods This double-blind, placebo-controlled trial was undertaken in 974 hospitals in 42 countries. 18 695 patients with previously manifest or increased risk of vascular disease were randomly assigned to receive either rimonabant 20 mg (n=9381) or matching placebo (n=9314). Randomisation was stratified by centre, implemented with an independent interactive voice response system, and all study personnel and participants were masked to group assignment. The primary endpoint was the composite of cardiovascular death, myocardial infarction, or stroke, as determined via central adjudication. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00263042. Findings At a mean follow-up of 13·8 months (95% CI 13·6–14·0), the trial was prematurely discontinued because of concerns by health regulatory authorities in three countries about suicide in individuals receiving rimonabant. All randomised participants were analysed. At the close of the trial (Nov 6, 2008), the composite primary endpoint of cardiovascular death, myocardial infarction, or stroke occurred in 364 (3·9%) patients assigned to rimonabant and 375 (4·0%) assigned to placebo (hazard ratio 0·97, 95% CI 0·84–1·12, p=0·68). With rimonabant, gastrointestinal (3038 [33%] vs 2084 [22%]), neuropsychiatric (3028 [32%] vs 1989 [21%]), and serious psychiatric side-effects (232 [2·5%] vs 120 [1·3%]) were significantly increased compared with placebo. Four patients in the rimonabant group and one in the placebo group committed suicide. Interpretation The premature termination of this trial has important lessons for drug development. A drug that was being marketed for weight loss, but being tested for improving cardiovascular outcomes, induced a level of serious neuropsychiatric effects that was deemed unacceptable by regulatory authorities, and both the drug and the trial were abruptly terminated. Funding Sanofi-Aventis.

Item does not contain fulltext BACKGROUND: In the ARISTOTLE trial, the rate of stroke or systemic embolism was reduced by apixaban compared with warfarin in patients with atrial fibrillation (AF). Patients with AF and previous stroke or transient ischaemic attack (TIA) have a high risk of stroke. We therefore aimed to assess the efficacy and safety of apixaban compared with warfarin in prespecified subgroups of patients with and without previous stroke or TIA. METHODS: Between Dec 19, 2006, and April 2, 2010, patients were enrolled in the ARISTOTLE trial at 1034 clinical sites in 39 countries. 18,201 patients with AF or atrial flutter were randomly assigned to receive apixaban 5 mg twice daily or warfarin (target international normalised ratio 2.0-3.0). The median duration of follow-up was 1.8 years (IQR 1.4-2.3). The primary efficacy outcome was stroke or systemic embolism, analysed by intention to treat. The primary safety outcome was major bleeding in the on-treatment population. All participants, investigators, and sponsors were masked to treatment assignments. In this subgroup analysis, we estimated event rates and used Cox models to compare outcomes in patients with and without previous stroke or TIA. The ARISTOTLE trial is registered with ClinicalTrials.gov, number NTC00412984. FINDINGS: Of the trial population, 3436 (19%) had a previous stroke or TIA. In the subgroup of patients with previous stroke or TIA, the rate of stroke or systemic embolism was 2.46 per 100 patient-years of follow-up in the apixaban group and 3.24 in the warfarin group (hazard ratio [HR] 0.76, 95% CI 0.56 to 1.03); in the subgroup of patients without previous stroke or TIA, the rate of stroke or systemic embolism was 1.01 per 100 patient-years of follow-up with apixaban and 1.23 with warfarin (HR 0.82, 95% CI 0.65 to 1.03; p for interaction=0.71). The absolute reduction in the rate of stroke and systemic embolism with apixaban versus warfarin was 0.77 per 100 patient-years of follow-up (95% CI -0.08 to 1.63) in patients with and 0.22 (-0.03 to 0.47) in those without previous stroke or TIA. The difference in major bleeding with apixaban compared with warfarin was 1.07 per 100 patient-years (95% CI 0.09-2.04) in patients with and 0.93 (0.54-1.32) in those without previous stroke or TIA. INTERPRETATION: The effects of apixaban versus warfarin were consistent in patients with AF with and without previous stroke or TIA. Owing to the higher risk of these outcomes in patients with previous stroke or TIA, the absolute benefits of apixaban might be greater in this population. FUNDING: Bristol-Myers Squibb and Pfizer. 01 juni 2012

Background BG-12 (dimethyl fumarate) was shown to have antiinflammatory and cytoprotective properties in preclinical experiments and to result in significant reductions in disease activity on magnetic resonance imaging (MRI) in a phase 2, placebo-controlled study involving patients with relapsingremitting multiple sclerosis. Methods We conducted a randomized, double-blind, placebo-controlled phase 3 study involving patients with relapsingremitting multiple sclerosis. Patients were randomly assigned to receive oral BG-12 at a dose of 240 mg twice daily, BG-12 at a dose of 240 mg three times daily, or placebo. The primary end point was the proportion of patients who had a relapse by 2 years. Other end points included the annualized relapse rate, the time to confirmed progression of disability, and findings on MRI. Results The estimated proportion of patients who had a relapse was significantly lower in the two BG-12 groups than in the placebo group (27% with BG-12 twice daily and 26% with BG-12 thrice daily vs. 46% with placebo, P

AZD3480 is a selective agonist of the central 42 and 22 neuronal icotinic cholinergic receptors (NNRs). Its effects on cognition were investigated in 567 patients with mild-to-moderate Alzheimers disease (AD) (Mini Mental State Examination [MMSE] 1226). Mean baseline MMSE was 21 (SD ± 3.7), with 61% of patients having mild disease (MMSE 2126). Mean age was 74 (range 5885) years. Patients were randomized to one of 5 treatment groups: AZD3480 5 mg, 20 mg or 35/100 mg, donepezil 10 mg (active comparator) or placebo, and treated once daily for 12 weeks. The primary outcome measure was change from baseline at Week 12 on the AD Assessment Scale-Cognitive Subscale (ADAS-Cog). Neither AZD3480 nor donepezil showed a statistically significant improvement versus placebo on ADAS-Cog. Improvements in a number of secondary outcome measures (MMSE, AD Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) and Disability Assessment for Dementia [DAD]) were observed for AZD3480 and for donepezil. A post-hoc analysis on ADAS-Cog, excluding patients with very mild AD (MMSE 2526) indicated improvement versus placebo for AZD3480 20 mg (−1.4, 95% CI: −3.0; 0.2) and donepezil (−1.0, 95% CI: −2.3; 0.3). AZD3480 was well tolerated. The study did not meet proof of concept criteria, since neither AZD3480 nor donepezil were statistically significantly superior to placebo on ADAS-Cog and was considered to be inconclusive. Further studies are required to determine the therapeutic potential of stimulating 42 receptors with NNRs in AD patients.

BACKGROUND: Background The leucine-rich repeat kinase 2 gene (LRRK2) harbours highly penetrant mutations that are linked to familial parkinsonism. However, the extent of its polymorphic variability in relation to risk of Parkinson's disease (PD) has not been assessed systematically. We therefore assessed the frequency of LRRK2 exonic variants in individuals with and without PD, to investigate the role of the variants in PD susceptibility. METHODS: LRRK2 was genotyped in patients with PD and controls from three series (white, Asian, and Arab-Berber) from sites participating in the Genetic Epidemiology of Parkinson's Disease Consortium. Genotyping was done for exonic variants of LRRK2 that were identified through searches of literature and the personal communications of consortium members. Associations with PD were assessed by use of logistic regression models. For variants that had a minor allele frequency of 0.5% or greater, single variant associations were assessed, whereas for rarer variants information was collapsed across variants. FINDINGS: 121 exonic LRRK2 variants were assessed in 15 540 individuals: 6995 white patients with PD and 5595 controls, 1376 Asian patients and 962 controls, and 240 Arab-Berber patients and 372 controls. After exclusion of carriers of known pathogenic mutations, new independent risk associations were identified for polymorphic variants in white individuals (M1646T, odds ratio 1.43, 95% CI 1.15-1.78; p=0.0012) and Asian individuals (A419V, 2.27, 1.35-3.83; p=0.0011). A protective haplotype (N551K-R1398H-K1423K) was noted at a frequency greater than 5% in the white and Asian series, with a similar finding in the Arab-Berber series (combined odds ratio 0.82, 0.72-0.94; p=0.0043). Of the two previously reported Asian risk variants, G2385R was associated with disease (1.73, 1.20-2.49; p=0.0026), but no association was noted for R1628P (0.62, 0.36-1.07; p=0.087). In the Arab-Berber series, Y2189C showed potential evidence of risk association with PD (4.48, 1.33-15.09; p=0.012). INTERPRETATION: The results for LRRK2 show that several rare and common genetic variants in the same gene can have independent effects on disease risk. LRRK2, and the pathway in which it functions, is important in the cause and pathogenesis of PD in a greater proportion of patients with this disease than previously believed. These results will help discriminate those patients who will benefit most from therapies targeted at LRRK2 pathogenic activity. FUNDING: Michael J Fox Foundation and National Institutes of Health. Lancet Neurol

Item does not contain fulltext BACKGROUND: Vitamin K antagonists are highly effective in preventing stroke in patients with atrial fibrillation but have several limitations. Apixaban is a novel oral direct factor Xa inhibitor that has been shown to reduce the risk of stroke in a similar population in comparison with aspirin. METHODS: In this randomized, double-blind trial, we compared apixaban (at a dose of 5 mg twice daily) with warfarin (target international normalized ratio, 2.0 to 3.0) in 18,201 patients with atrial fibrillation and at least one additional risk factor for stroke. The primary outcome was ischemic or hemorrhagic stroke or systemic embolism. The trial was designed to test for noninferiority, with key secondary objectives of testing for superiority with respect to the primary outcome and to the rates of major bleeding and death from any cause. RESULTS: The median duration of follow-up was 1.8 years. The rate of the primary outcome was 1.27% per year in the apixaban group, as compared with 1.60% per year in the warfarin group (hazard ratio with apixaban, 0.79; 95% confidence interval [CI], 0.66 to 0.95; P

Background and Purpose— Fewer than 5% of patients with acute ischemic stroke are currently treated, and there is need for additional treatment options. A novel catheter treatment (NeuroFlo) that increases cerebral blood flow was tested to 14 hours. Methods— The Safety and Efficacy of NeuroFlo in Acute Ischemic Stroke trial is a randomized trial of the safety and efficacy of NeuroFlo treatment in improving neurological outcome versus standard medical management. The primary safety end point was the incidence of serious adverse events through 90 days. The primary efficacy end point on a modified intent-to-treat population was a global disability end point at 90 days. Secondary end points included mortality, intracranial hemorrhage, modified Rankin scale score outcome of 0 to 2, and modified Rankin scale shift analysis. Results— Between October 2005 and January 2010, 515 patients were enrolled at 68 centers in 9 countries. The primary efficacy end point did not reach statistical significance (OR, 1.17; CI, 0.81–1.67; P =0.407). The primary safety end point did not show a difference in serious adverse events ( P =0.923). Ninety-day mortality was 11.3% (26/230) in treatment and 16.3% (42/257) in control ( P =0.087). Post hoc analyses showed that patients presenting within 5 hours (OR, 3.33; CI, 1.31–8.48), with NIHSS score 8 to 14 (OR, 1.80; CI, 0.99–3.30), or older than age 70 years (OR, 2.02; CI, 1.02–4.03) had better modified Rankin scale score outcomes of 0 to 2; additionally, there were fewer stroke-related deaths in treatment compared to control groups (7.4%=17/230; 14.4%=37/257). Conclusions— The trial met its primary safety end point but not its primary efficacy end point. Signals of treatment effect were suggested on all-cause mortality, in patients presenting early, older than age 70 years, or with moderate strokes, but these require confirmation. Clinical Trial Registration Information— URL: http://clinicaltrials.gov . Unique identifier: NCT00119717.