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03/2015 journal articles

Editorials

NEUROPSYCHIATRIC SYMPTOMS IN DEMENTIA: OVERVIEW AND MEASUREMENT CHALLENGES

C.G. Lyketsos

J Prev Alz Dis 2015;2(3):155-156

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CITATION:
C.G. Lyketsos (2015): NEUROPSYCHIATRIC SYMPTOMS IN DEMENTIA: OVERVIEW AND MEASUREMENT CHALLENGES. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2015.60

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Comments

STUDIES OF AGITATION / AGGRESSION IN ALZHEIMER’S DISEASE – SCIENTIFIC AND OPERATIONAL CHALLENGES

K. Siegfried, V. Legrand

J Prev Alz Dis 2015;2(3):157-159

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The paper addresses important questions and challenges of protocol features and conditions of efficacy and safety studies of agitation / aggression in patients with Alzheimer’s Disease (AD). Specifically, questions of patient selection criteria, study settings (outpatient, nursing home studies) and study design features are discussed. The comments and advices provided were based on inquiries conducted with an international group of 24 clinical experts in AD (from Asia, Europe, Latin America and the US). There was a good agreement on study duration and the basic study design features, whereas different views were expressed on the types of allowable concomitant medication and (partially also) on study settings. Decisions on most of these protocol features will have major operational consequences (e.g. on recruitment rates, recruitment strategies) which need to be considered in a reasonable trade-off with methodological requirements to make the study feasible and at the same time ensure the highest scientific standards possible.

CITATION:
K. Siegfried ; V. Legrand ; (2015): Studies of Agitation / Aggression in Alzheimer’s Disease – Scientific and Operational Challenges. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2015.51

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Point of View

NEW IPA CRITERIA FOR AGITATION IN COGNITIVE IMPAIRMENT

J. Cummings

J Prev Alz Dis 2015;2(3):160-162

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The International Psychogeriatric Association (IPA) recently formed an Agitation Definition Working Group (ADWG) to craft a consensus definition of agitation in order to advance basic and clinical research. The provisional definition created by this international group of experts on the neuropsychiatric aspects of Alzheimer’s disease (AD) defines agitation as a clinical syndrome distinct from other conditions such as psychosis or depression. Patients must meet criteria for cognitive impairment and exhibit behaviors such as excessive activity and verbal or physical aggression severe enough to produce disability in social, or interpersonal functions, or activities of daily living. These symptoms should not be attributable to other psychiatric or medical disorders, suboptimal environment, or drug effects. Future validation studies are needed to confirm or revise the definition. This definition will facilitate clinical trials and other types of clinical and translational research.

CITATION:
J. Cummings (2015): New IPA Criteria for Agitation in Cognitive Impairment. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2015.65

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TRIAL DESIGN FOR THE EVALUATION OF NEUROPSYCHIATRIC SYMPTOMS IN ALZHEIMER’S DISEASE: CONSIDERATIONS AND RECOMMENDATIONS

J. Bell

J Prev Alz Dis 2015;2(3):163-164

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CITATION:
J. Bell (2015): Trial Design for the Evaluation of Neuropsychiatric Symptoms in Alzheimer’s Disease: Considerations and Recommendations. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2015.48

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Original Research

POST HOC EVIDENCE FOR AN ADDITIVE EFFECT OF MEMANTINE AND DONEPEZIL: CONSISTENT FINDINGS FROM DOMINO-AD STUDY AND MEMANTINE CLINICAL TRIAL PROGRAM

S. Hendrix, N. Ellison, S. Stanworth, V. Otcheretko, P.N. Tariot

J Prev Alz Dis 2015;2(3):165-171

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Background: Several randomized trials have demonstrated superiority of memantine-cholinesterase inhibitor combination therapy in patients with moderate to severe Alzheimer’s disease, yet a recent publication reported no additional benefit of add-on memantine therapy compared to donepezil alone. Objectives: In this post hoc analysis, we sought to re-evaluate the results from the DOMINO study using common statistical tools and to apply the statistical models used in the DOMINO study to a pooled data set of 24- to 28-week randomized trials of memantine in patients with moderate to severe AD in order to explore the robustness of the primary findings from the DOMINO study. Design: DOMINO study: Randomized, double-blind, placebo-controlled trial (Current Controlled Trial number, ISRCTN49545035); Memantine Clinical Trial Program: Pooled analysis from four randomized, double-blind, placebo-controlled trials. Setting: DOMINO study: United Kingdom; Memantine Clinical Trial Program: Multinational. Participants: DOMINO study: 295 participants enrolled during the period of February 2008 to March 2010; Memantine Clinical Trial Program: 1417 participants enrolled between August 1998 and January 2008. Measurements: In the DOMINO study, the co-primary outcome measures were scores on the Standardized Mini-Mental State Examination and the Bristol Activities of Daily Living Scale; Neuropsychiatric Inventory was a secondary measure. In the Memantine Clinical Trial Program, outcome measures included the Severe Impairment Battery, the 19-item Alzheimer’s Disease Cooperative Study – Activities of Daily Living scale, Neuropsychiatric Inventory, and a 4-Domain Composite Index (Z-score; a post hoc assessment). Results: Both the pooled analysis of the Memantine Clinical Trial Program and the re-assessment of the DOMINO study with common statistical tools showed that adding memantine to donepezil therapy is associated with benefits across multiple clinical domains. Conclusions: The current analyses suggest that the results of the DOMINO study do not contradict previous studies which investigated the combined effects of memantine-cholinesterase inhibitor treatment.

CITATION:
S. Hendrix ; N. Ellison ; S. Stanworth ; V. Otcheretko ; P.N. Tariot (2015): Post Hoc Evidence for an Additive Effect of Memantine and Donepezil: Consistent Findings from DOMINO-AD Study and Memantine Clinical Trial Program. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2015.66

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AN OPEN-LABEL TRIAL OF YOKUKANSAN ON SLEEP DISTURBANCE IN ALZHEIMER’S DISEASE AND OTHER DEMENTIA

Y. Hayashi, Y. Ishida, K. Okahara, Y. Mitsuyama

J Prev Alz Dis 2015;2(3):172-177

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Background: An effective hypnotic drug with a low risk of adverse reactions is required for Alzheimer’s disease (AD) patients, because the therapeutic interventions to improve sleep quality may help alleviate some symptoms of AD including cognitive function. Objective: The aim of this study was to investigate the efficacy and safety of Yokukansan in sleep disturbances in patients with AD and other dementia. Design: An open-label trial. Setting: Two sites consist of university and hospital in Japan. Participants: Thirteen patients (7 men and 6 women, average age = 76.0 ± 7.2 (mean ± SD) years old) including 12 AD and 1 frontotemporal dementia. Intervention: Treatment with Yokukansan (5–7.5 g/day) was given for 8 weeks. Measurements: The primary outcome measure was the Sleep Disorder Inventory (SDI) based on the Neuropsychiatric Inventory, an instrument developed by the Alzheimer’s Disease Cooperative Study. Secondary outcome measures included the objective actigraphic evaluations, Neuropsychiatric Inventory-Questionnaire (NPI-Q), MINI-Mental State Examination (MMSE). These assessments were evaluated at baseline, and weeks 4 and 8. Results: After 4 and 8 weeks treatment with Yokukansan, significant improvements were observed in the SDI total score, caregivers’ distress score, and NPI-Q total score. In actigraph data, wake after sleep onset (WASO) time (min), was significantly improved. The MMSE score did not change during the treatment. No serious adverse events were caused by YKS. Conclusion: The present results suggest that Yokukansan is safe and beneficial in the treatment of sleep disturbances and that it can possibly reduce the burden of care of demented patients.

CITATION:
Y. Hayashi ; Y. Ishida ; K. Okahara ; Y. Mitsuyama (2015): An Open-Label Trial of Yokukansan on Sleep Disturbance in Alzheimer’s Disease and Other Dementia. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2015.70

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THE RELATIONSHIP OF HEMOGLOBIN LEVELS, DELIRIUM AND COGNITIVE STATUS IN HOSPITALIZED GERIATRIC PATIENTS: RESULTS FROM THE CRIME STUDY

G. Brombo, L. Bianchi, E. Savino, S. Magon, A. Cherubini, A. Corsonello, G. Zuliani, G. Onder, S. Volpato

J Prev Alz Dis 2015;2(3):178-183

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Objective: Delirium is a frequent clinical complication in geriatric patients admitted to the hospital, because of the simultaneous presence and synergistic effect of predisposing and precipitating factors. Also anaemia is a common concern in geriatric population. The aim of this study was to investigate the association between anaemia (precipitating factor) and delirium in a sample of Italian older hospitalized patients with different degree of cognitive impairment (predisposing factor). Design, setting, participants: Cross-sectional analysis of 1069 participants enrolled in the CRIME study, with assessment of hemoglobin levels at hospital admission. Measurements: Delirium was assessed using DSM-IV criteria, whereas cognitive status was categorized as dementia, cognitive impairment or normal, according to clinical history, specific treatment and MMSE score. Anaemia was defined according to sex-specific WHO criteria. The association of hemoglobin levels and delirium was investigated with multivariable logistic regression models. Results: Mean age of study participants was 81.4±7.2 years, 52.2% had prevalent anaemia, 6.1% had delirium. According to cognitive status 20.8% had dementia and 40.9% had cognitive impairment. Overall there was no association between anaemia and delirium. However, among patients with cognitive impairment (MMSE <24, no dementia) anaemia was significantly associated with the likelihood of delirium (p<0.006). Multivariate logistic regression analysis, adjusted for potential confounders, showed in these patients a graded increased risk of delirium according to anaemia severity with an almost six-fold increased risk of delirium in moderate-severe anaemia (OR 5.95, 95% CI:1.15-30.73). Conclusion: In older patients with cognitive impairment moderate-severe anaemia is independently associated with the likelihood of delirium. Further studies should investigate if anaemia correction would translate in delirium risk reduction.

CITATION:
G. Brombo ; L. Bianchi ; E. Savino ; S. Magon ; A. Cherubini ; A. Corsonello ; G. Zuliani ; G. Onder ; S. Volpato (2015): The Relationship of Hemoglobin Levels, Delirium and Cognitive Status in Hospitalized Geriatric Patients: Results from the CRIME Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2015.49

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Review Articles

PROGRESS IN TREATMENT DEVELOPMENT FOR NEUROPSYCHIATRIC SYMPTOMS IN ALZHEIMER’S DISEASE: FOCUS ON AGITATION AND AGGRESSION. A REPORT FROM THE EU/US/CTAD TASK FORCE

M. Soto, S. Abushakra, J. Cummings, J. Siffert, P. Robert, B. Vellas, C.G. Lyketsos, and Task Force Members

J Prev Alz Dis 2015;2(3):184-188

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Background: The management of neuropsychiatric symptoms (NPS) such as agitation and aggression is a major priority in caring for people with Alzheimer’s disease (AD). Agitation and aggression (A/A) are among the most disruptive symptoms, and given their impact, they are increasingly an important target for development of effective treatments. Considerable progress has been made in the last years with a growing number of randomized controlled trials (RCTs) of drugs for NPS. The limited benefits reported in some RCTs may be accounted for by the absence of a biological link of the tested molecule to NPS and also by key methodological issues. In recent RCTs of A/A, a great heterogeneity design was found. Designing trials for dementia populations with NPS presents many challenges, including identification of appropriate participants for such trials, engagement and compliance of patients and caregivers in the trials and the choice of optimal outcome measures to demonstrate treatment effectiveness. The EU/US -CTAD Task Force, an international collaboration of investigators from academia, industry, non-profit foundations, and regulatory agencies met in Philadelphia on November 19, 2014 to address some of these challenges. Despite potential heterogeneity in clinical manifestations and neurobiology, agitation and aggression seems to be accepted as an entity for drug development. The field appears to be reaching a consensus in using both agitation and aggression (or other NPS)-specific quantitative measures plus a global rating of change for agitation outcomes based on clinician judgment as the main outcomes.

CITATION:
M. Soto ; S. Abushakra ; J. Cummings ; J. Siffert ; P. Robert ; B. Vellas ; C.G. Lyketsos ; and Task Force Members (2015): Progress in Treatment Development for Neuropsychiatric Symptoms in Alzheimer’s Disease: Focus on Agitation and Aggression. A Report from the EU/US/CTAD Task Force. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2015.77

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BRIDGING THE TRANSLATION GAP: FROM DEMENTIA RISK ASSESSMENT TO ADVICE ON RISK REDUCTION

K.J. Anstey, R. Eramudugolla, D.E. Hosking, N.T. Lautenschlager, R.A. Dixon

J Prev Alz Dis 2015;2(3):189-198

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Dementia risk reduction is a global health and fiscal priority given the current lack of effective treatments and the projected increased number of dementia cases due to population ageing. There are often gaps among academic research, clinical practice, and public policy. We present information on the evidence for dementia risk reduction and evaluate the progress required to formulate this evidence into clinical practice guidelines. This narrative review provides capsule summaries of current evidence for 25 risk and protective factors associated with AD and dementia according to domains including biomarkers, demographic, lifestyle, medical, and environment. We identify the factors for which evidence is strong and thereby especially useful for risk assessment with the goal of personalising recommendations for risk reduction. We also note gaps in knowledge, and discuss how the field may progress towards clinical practice guidelines for dementia risk reduction.

CITATION:
K.J. Anstey ; R. Eramudugolla ; D.E. Hosking ; N.T. Lautenschlager ; R.A. Dixon (2015): Bridging the Translation Gap: From Dementia Risk Assessment to Advice on Risk Reduction. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2015.75

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THE ROAD AHEAD TO CURE AND PREVENT ALZHEIMER’S DISEASE: IMPLEMENTING PREVENTION INTO PRIMARY CARE

B. Fougère, B. Vellas, J. Delrieu, A.J. Sinclair, A. Wimo, C.J. Herman, H. Fillit, S. Gauthier, S. Oustric

J Prev Alz Dis 2015;2(3):199-211

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Most old adults receive their health care from their primary care practitioner; as a consequence, as the population ages, the manifestations and complications of cognitive impairment and dementia impose a growing burden on providers of primary care. Current guidelines do not recommend routine cognitive screening for older persons by primary care physicians, although the vast majority recommend a cognitive status assessment and neurological examination for subjects with a cognitive complaint. Also, no clinical practice guidelines recommend interventions in older adults with cognitive impairment in primary care settings. However, primary care physicians need to conduct a review of risks and protective factors associated with cognitive decline and organize interventions to improve or maintain cognitive function. Recent epidemiological studies have indicated numerous associations between lifestyle-related risk factors and incidental cognitive impairment. The development of biomarkers could also help in diagnosis, prognosis, selection for clinical trials, and objective assessment of therapeutic responses. Interventions aimed at cognitive impairment prevention should be pragmatic and easy to implement on a large scale in different health care systems, without generating high additional costs or burden on participants, medical and social care teams.

CITATION:
B. Fougère ; B. Vellas ; J. Delrieu ; A.J. Sinclair ; A. Wimo ; C.J. Herman ; H. Fillit ; S. Gauthier ; S. Oustric (2015): The Road Ahead To Cure And Prevent Alzheimer’s Disease: Implementing Prevention into Primary Care. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2015.73

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Letter to the Editor

NEW FINDINGS WITH REANALYSIS OF THE DOMINO TRIAL ?

J.F. Dartigues

J Prev Alz Dis 2015;2(3):212

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CITATION:
J.F. Dartigues (2015): New findings with reanalysis of the Domino trial ?. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2015.76

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