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02/2018 journal articles

Editorials

PREVENTION OF ALZHEIMER’S DISEASE IN CHINESE POPULATIONS: STATUS, CHALLENGES AND DIRECTIONS

L. Feng, J. Li, J.-T. Yu, C. Zhang, B. Yang, B. Vellas, C. Li

J Prev Alz Dis 2018;5(2):90-94

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CITATION:
L. Feng ; J. Li ; J.-T. Yu ; C. Zhang ; B. Yang ; B. Vellas ; C. Li (2018): Prevention of Alzheimer’s Disease in Chinese Populations: Status, Challenges and Directions. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2018.14

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DIABETES MELLITUS AND COGNITIVE DECLINE – PREVENTION SHOULD NOT BE DELAYED!

A.J. Sinclair, B. Vellas

J Prev Alz Dis 2018;5(2):95-97

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CITATION:
A.J. Sinclair ; B. Vellas (2018): Diabetes Mellitus and Cognitive Decline – Prevention Should Not Be Delayed!. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2018.9

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CTAD Task Force

IDENTIFYING BETTER OUTCOME MEASURES TO IMPROVE TREATMENT OF AGITATION IN DEMENTIA: A REPORT FROM THE EU/US/CTAD TASK FORCE

M. Sano, M. Soto, M. Carrillo, J. Cummings, S. Hendrix, J. Mintzer, A. Porsteinsson, P. Rosenberg, L. Schneider, J. Touchon, P. Aisen, B. Vellas, C. Lyketsos, and the EU/US/CTAD Task Force members

J Prev Alz Dis 2018;5(2):98-102

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For the second time in the past 3 years, the EU-US CTAD Task Force addressed challenges related to designing clinical trials for agitation in dementia, which is one of the most disruptive aspects of the condition for both patients and caregivers. Six recommendations emerged from the Task Force meeting: 1 – Operationalizing agitation criteria established by the IPA; 2 – Combining clinician- and caregiver-derived outcomes as primary outcome measures; 3 – Using global ratings to define clinically meaningful effects and power studies; 4 – Improving the accuracy of caregiver reports by better training and education of caregivers; 5 – Employing emerging technologies to collect near real-time behavioral data; and 6 – Utilizing innovative trial designs and increasing the use of biomarkers to maximize the productivity of clinical trials for neuropsychiatric symptoms.

CITATION:
M. Sano ; M. Soto ; M. Carrillo ; J. Cummings ; S. Hendrix ; J. Mintzer ; A. Porsteinsson ; P. Rosenberg ; L. Schneider ; J. Touchon ; P. Aisen ; B. Vellas ; C. Lyketsos ; and the EU/US/CTAD Task Force members (2018): Identifying Better Outcome Measures to Improve Treatment of Agitation in Dementia: 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.2018.15

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Brief Report

BIOMARKER AND CLINICAL TRIAL DESIGN SUPPORT FOR DISEASE-MODIFYING THERAPIES: REPORT OF A SURVEY OF THE EU/US: ALZHEIMER’S DISEASE TASK FORCE

J. Cummings, N. Fox, B. Vellas, P. Aisen, G. Shan, for the EU/US Alzheimer’ Disease Task Force

J Prev Alz Dis 2018;5(2):103-109

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BACKGROUND: Disease-modifying therapies are urgently needed for the treatment of Alzheimer’s disease (AD). The European Union/United States (EU/US) Task Force represents a broad range of stakeholders including biopharma industry personnel, academicians, and regulatory authorities. OBJECTIVES: The EU/US Task Force represents a community of knowledgeable individuals who can inform views of evidence supporting disease modification and the development of disease-modifying therapies (DMTs). We queried their attitudes toward clinical trial design and biomarkers in support of DMTs. DESIGN/SETTING/PARTICIANTS: A survey of members of the EU/US Alzheimer’s Disease Task Force was conducted. Ninety-three members (87%) responded. The details were analyzed to understand what clinical trial design and biomarker data support disease modification. MEASUREMENTS/RESULTS/CONCLUSIONS: Task Force members favored the parallel group design compared to delayed start or staggered withdrawal clinical trial designs to support disease modification. Amyloid biomarkers were regarded as providing mild support for disease modification while tau biomarkers were regarded as providing moderate support. Combinations of biomarkers, particularly combinations of tau and neurodegeneration, were regarded as providing moderate to marked support for disease modification and combinations of all three classes of biomarkers were regarded by a majority as providing marked support for disease modification. Task Force members considered that evidence derived from clinical trials and biomarkers supports clinical meaningfulness of an intervention, and when combined with a single clinical trial outcome, nearly all regarded the clinical trial design or biomarker evidence as supportive of disease modification. A minority considered biomarker evidence by itself as indicative of disease modification in prevention trials. Levels of evidence (A,B,C) were constructed based on these observations. CONCLUSION: The survey indicates the view of knowledgeable stakeholders regarding evidence derived from clinical trial design and biomarkers in support of disease modification. Results of this survey can assist in designing clinical trials of DMTs.

CITATION:
J. Cummings ; N. Fox ; B. Vellas ; P. Aisen ; G. Shan ; for the EU/US Alzheimer’ Disease Task Force (2018): Biomarker and Clinical Trial Design Support for Disease-Modifying Therapies: Report of a Survey of the EU/US: Alzheimer’s Disease Task Force. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2018.13

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MINIMIZING THE SAMPLE SIZES OF CLINICAL TRIALS ON PRECLINICAL AND EARLY SYMPTOMATIC STAGE OF ALZHEIMER DISEASE

J. Luo, H. Weng, J.C. Morris, C. Xiong

J Prev Alz Dis 2018;5(2):110-119

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Background: Clinical trials of investigational drugs for Alzheimer disease (AD) increasingly focus on the prodromal (symptomatic) stage of the illness and now its preclinical (asymptomatic) stage. Sensitive and specific cognitive and functional endpoints are needed to track subtle cognitive and functional changes in the early and preclinical stages to minimize sample sizes in these trials. Objectives: To identify informative items in a standard clinical assessment protocol and a psychometric battery that are predictive of onset of dementia symptom. Design: Longitudinal retrospective study. Setting: Washington University (WU) Knight Alzheimer Disease Research Center (ADRC). Participants: A total of 735 individuals at least 65 years old and cognitively normal at baseline from a longitudinal clinical cohort at the WU Knight ADRC. Measurements: The annual clinical assessment included a wide spectrum of functional and cognitive domains; a comprehensive psychometric battery was completed about 2 weeks after the clinical evaluation. Psychometricians are blinded to the results of the clinical evaluation and to the prior performance of the participants on the psychometric tests. Results: The mean age at baseline of the 735 participants was 74.30 and 62.31% were female. 240 individuals developed prodromal dementia symptoms (consistent with mild cognitive impairment due to AD and with very mild AD dementia) during longitudinal follow-up (mean follow-up=6.79 years). Among a total of 562 items in the clinical and cognitive assessments under analysis, 292 (52%) were identified as informative because their longitudinal changes were predictive of symptomatic onset. When these items were used to form the functional and cognitive composites, the longitudinal rates of changes were free of a learning effect and captured subtle longitudinal progression prior to symptomatic onset. The rates of change were much greater right after the symptomatic onset than those from the functional and cognitive composites formed using non-informative items. Although the sample sizes for prevention trials (prior to symptomatic onset) using the informative items still yield large numbers, the sample sizes for early treatment trial (after symptomatic onset) was much smaller than those derived from all the items or from the non-informative items alone. Conclusions: The antecedent longitudinal changes in nearly half of the items in a clinical assessment protocol and a comprehensive cognitive battery did not show statistically significant ability to predict the dementia symptom onset, and hence may be non-informative to track the preclinical functional and cognitive progression of AD. The remaining items, on the other hand, captured some of the preclinical changes prior to the symptom onset, but performed much better right after the symptom onset. Currently ongoing prevention trials on preclinical AD of elderly individuals may need to re-assess the sample sizes and statistical power.

CITATION:
J. Luo ; H. Weng ; J.C. Morris ; C. Xiong (2018): Minimizing the Sample Sizes of Clinical Trials on Preclinical and Early Symptomatic Stage of Alzheimer Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2018.16

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A LITERATURE REVIEW OF METHODOLOGIES USED IN RANDOMIZED CLINICAL TRIALS OF AGITATION IN ALZHEIMER’S DISEASE

S. Dubé, J.T. Megerian, R. Malamut

J Prev Alz Dis 2018;5(2):120-133

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Agitation is a common and burdensome symptom associated with Alzheimer’s disease (AD). This is a narrative literature review of the designs and methods used in randomized clinical trials of agitation in patients with AD; sources range from published, to completed but not published, to ongoing studies in the past 10 years. Selection for review included blinded, randomized trials conducted to assess the effect of a pharmacological intervention for which agitation in patients with AD was among the prespecified end points. Key criteria for exclusion included open-label studies, trials of dementia not specific to AD, or mixed populations of AD and unspecified dementia. A search of PubMed and clinicaltrials.gov databases identified 36 trials for which agitation was among the prespecified end points: 18 were published trials and 18 were completed but not published or ongoing. There was significant heterogeneity among AD studies in terms of diagnostic criteria, assessment of severity of disease and agitation, sample size and powering assumptions, treatment duration, patient age and cognitive status, and outcomes measurements. Few studies used a mitigation strategy for placebo response. Accumulating evidence suggests that it is important to consider the following in trial design: thresholds for baseline severity of agitation and AD; use of prespecified accepted criteria to define agitation; and use of standardized, validated tools to measure treatment effects during a trial. Adoption of these design strategies might help improve signal detection and bring us closer to identifying the most appropriate, effective, and safe treatments for agitation in patients with AD.

CITATION:
S. Dubé ; J.T. Megerian ; R. Malamut (2018): A Literature Review of Methodologies Used in Randomized Clinical Trials of Agitation in Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2018.17

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Original Research

THE INTEGRATED ALZHEIMER’S DISEASE RATING SCALE (IADRS) FINDINGS FROM THE EXPEDITION3 TRIAL

A.M. Wessels, S.W. Andersen, S.A. Dowsett, E.R. Siemers

J Prev Alz Dis 2018;5(2):134-136

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The Integrated Alzheimer’s Disease (AD) Rating Scale (iADRS) is a composite tool that combines scores from the AD Assessment Scale-Cognitive subscale (ADAS-Cog) and the AD Cooperative Study - instrumental Activities of Daily Living (ADCS-iADL). It demonstrates acceptable psychometric properties, and is effective in capturing both disease progression and separation of placebo and active drug effect. We assessed the performance of iADRS in the solanezumab EXPEDITION3 study, an 80-week, placebo-controlled study of individuals with mild AD dementia. A statistically significant difference between placebo and active drug was observed for iADRS score change from baseline at Week 28 (p=0.028) through Week 80 (p=0.015). Across the Phase 3 solanezumab trials, iADRS was the only tool that consistently differentiated between solanezumab and placebo groups. These findings suggest that the iADRS is a useful integrated measurement tool for treatment trials of individuals with mild AD dementia.

CITATION:
A.M. Wessels ; S.W. Andersen ; S.A. Dowsett ; E.R. Siemers (2018): The Integrated Alzheimer’s Disease Rating Scale (iADRS) Findings from the EXPEDITION3 Trial. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2018.10

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ADHERENCE TO THE MEDITERRANEAN DIET IS NOT RELATED TO BETA-AMYLOID DEPOSITION: DATA FROM THE WOMEN’S HEALTHY AGEING PROJECT

E. Hill, C. Szoeke, L. Dennerstein, S. Campbell, P. Clifton

J Prev Alz Dis 2018;5(2):137-141

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Background: Research has indicated the neuroprotective potential of the Mediterranean diet. Adherence to the Mediterranean diet has shown preventative potential for Alzheimer’s disease incidence and prevalence, yet few studies have investigated the impact of Mediterranean diet adherence on the hallmark protein; beta-amyloid. Objectives: To investigate the association between Mediterranean diet adherence and beta-amyloid deposition in a cohort of healthy older Australian women. Design: This study was a cross-sectional investigation of participants from the longitudinal, epidemiologically sourced Women’s Healthy Ageing Project which is a follow-up of the Melbourne Women’s Midlife Health Project. Setting: Assessments were conducted at the Centre for Medical Research, Royal Melbourne Hospital in Melbourne, Australia. F-18 Florbetaben positron emission tomography scanning was conducted at the Austin Centre for PET in Victoria, Australia. Participants: One hundred and eleven Women’s Healthy Ageing Project participants were included in the study. Measurements: Mediterranean diet adherence scores for all participants were calculated from the administration of a validated food frequency questionnaire constructed by the Cancer Council of Victoria. Beta-amyloid deposition was measured using positron emission tomography standardised uptake value ratios. Results: Gamma regression analysis displayed no association between Mediterranean diet adherence and beta-amyloid deposition. This result was consistent across APOE-ε4 +/- cohorts and with the inclusion of covariates such as age, education, body mass index and cognition. Conclusions: This study found no association between adherence to the Mediterranean diet and beta-amyloid deposition in a cohort of healthy Australian women.

CITATION:
E. Hill ; C. Szoeke ; L. Dennerstein ; S. Campbell ; P. Clifton (2018): Adherence to the Mediterranean Diet Is not Related to Beta-Amyloid Deposition: Data from the Women’s Healthy Ageing Project. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2018.12

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STRONG RELATIONSHIP BETWEEN MALNUTRITION AND COGNITIVE FRAILTY IN THE SINGAPORE LONGITUDINAL AGEING STUDIES (SLAS-1 AND SLAS-2)

L. Chye, K. Wei, M.S.Z. Nyunt, Q. Gao, S.L. Wee, T.P. Ng

J Prev Alz Dis 2018;5(2):142-148

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Background: Physical frailty is well known to be strongly associated with malnutrition, but the combined impact of physical frailty and cognitive impairment among non-demented older persons (cognitive frailty) on malnutrition prevalence is not well documented. Design: Cross-sectional cohort study. Setting and Participants: Community-dwelling older Singaporeans aged ≥55y (n=5414) without dementia in the Singapore Longitudinal Ageing Study (SLAS-1 and SLAS-2). Measurements: The Mini Nutritional Assessment – short form (MNA-SF) and Nutrition Screening Initiative (NSI) Determine Checklist were used to determine their nutritional status. Participants were categorized as cognitive normal (CN) or cognitive impaired (CI) by Mini Mental State Examination (MMSE<=23), as pre-frail (PF) (score=1-2) or frail (F) (score=3-5) using Fried’s criteria, and as cognitive pre-frail (PF+CI) or cognitive frail (F+CI). Results: The prevalence of cognitive frailty was 1.6%, and cognitive pre-frailty was 5.5% (total, 7.1%). The prevalence of MNA malnutrition was 2.4%, and NSI high nutritional risk was 6.3%. The prevalence of MNA malnutrition was lowest among Robust-CN and highest among Frail-CI (0.5% in Robust-CN, 0.6% in Robust-CI, 2.8% in Pre-frail-CN, 7.3% in Pre-frail-CI, 15.4% in Frail-CN, and 23.1% in Frail-CI). Similarly, the prevalence of NSI high nutritional risk was lowest in Robust-CN (3.7%) and highest in Frail-CI (13.6%). Adjusted for sociodemographic and health status, pre-frailty/frailty-CI versus Robust-CN was associated with the highest odds ratio of association with MNA malnutrition (OR=8.16, p<0.001), although not the highest with NSI high nutritional risk (OR=1.48, p=0.017). Conclusions: An extraordinary high prevalence of malnutrition was observed among older adults with cognitive frailty who should be specially targeted for active intervention.

CITATION:
L. Chye ; K. Wei ; M.S.Z. Nyunt ; Q. Gao ; S.L. Wee ; T.P. Ng (2017): Strong Relationship between Malnutrition and Cognitive Frailty in the Singapore Longitudinal Ageing Studies (SLAS-1 and SLAS-2). The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.46

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Review Articles

DEVELOPMENT OF AZELIRAGON, AN ORAL SMALL MOLECULE ANTAGONIST OF THE RECEPTOR FOR ADVANCED GLYCATION ENDPRODUCTS, FOR THE POTENTIAL SLOWING OF LOSS OF COGNITION IN MILD ALZHEIMER’S DISEASE

A.H. Burstein, M. Sabbagh, R. Andrews, C. Valcarce, I. Dunn, L. Altstiel

J Prev Alz Dis 2018;5(2):149-154

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Increasing evidence supports the role of the Receptor for Advanced Glycation Endproducts (RAGE) in the pathology of Alzheimer’s disease. Azeliragon (TTP488) is an orally bioavailable small molecule inhibitor of RAGE in Phase 3 development as a potential treatment to slow disease progression in patients mild AD. Preclinical studies in animal models of AD (tgAPPSwedish/London) have shown azeliragon to decrease Aβ plaque deposition; reduce total Aβ brain concentration while increasing plasma Aβ levels; decreases sAPPβ while increasing sAPPα; reduce levels of inflammatory cytokines; and slow cognitive decline and improve cerebral blood flow. In the Phase 2b study, 18-months treatment in patients with mild-to-moderate AD indicated a baseline to endpoint change in ADAS-cog of 3.1 points in favor of drug. A greater magnitude of effect was evident in the sub-group of patients with mild AD (MMSE 21-26) with a baseline to endpoint change of 4 points on the ADAS-cog in favor of azeliragon and a 1 point change in CDR-sb in favor of drug. Azeliragon 5 mg/day delayed time to cognitive deterioration (7-point change in ADAS-cog from baseline, logrank p=0.0149). Based on promising results from the Phase 2b study, a Phase 3 registration program (STEADFAST) is being conducted under a Special Protocol Assessment from FDA. The ongoing Phase 3 program, if successful may demonstrate azeliragon can slow cognitive decline in mild AD patients.

CITATION:
A.H. Burstein ; M. Sabbagh ; R. Andrews ; C. Valcarce ; I. Dunn ; L. Altstiel (2018): Development of Azeliragon, an Oral Small Molecule Antagonist of the Receptor for Advanced Glycation Endproducts, for the Potential Slowing of Loss of Cognition in Mild Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2018.18

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Letter to the Editor

NANOROBOTS THE FUTURE OF NEUROLOGY: A PERSPECTIVE ON ALZHEIMER’S DISEASE

C. Hooper, S. Layé

J Prev Alz Dis 2018;5(2):155-156

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CITATION:
C. Hooper ; S. Layé ; (2018): Nanorobots the Future of Neurology: A Perspective on Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2018.6

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