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02/2017 journal articles

Editorials

GETTING MORE CLINICALLY MEANINGFUL MEASURES OF FUNCTIONAL IMPAIRMENT FOR ALZHEIMER’S DISEASE

H. Fillit

J Prev Alz Dis 2017;4(2):67-68

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CITATION:
H. Fillit (2017): Getting More Clinically Meaningful Measures of Functional Impairment for Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.11

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EXPANDING THE TOOLKIT FOR STUDIES OF AGING

A.S. Buchman, P.A. Boyle, D.A. Bennett

J Prev Alz Dis 2017;4(2):69-70

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CITATION:
A.S. Buchman ; P.A. Boyle ; D.A. Bennett (2017): Expanding the Toolkit for Studies of Aging. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.14

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Original Research

DEPENDENCE LEVELS AS INTERIM CLINICAL MILESTONES ALONG THE CONTINUUM OF ALZHEIMER’S DISEASE: 18-MONTH RESULTS FROM THE GERAS OBSERVATIONAL STUDY

K. Kahle-Wrobleski, J.S. Andrews, M. Belger, W. Ye, S. Gauthier, D.M. Rentz, D. Galasko

J Prev Alz Dis 2017;4(2):72-80

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Background: While functional loss forms part of the current diagnostic criteria used to identify dementia due to Alzheimer’s disease, the gradual and progressive nature of the disease makes it difficult to recognize clinically relevant signposts that could be helpful in making treatment and management decisions. Having previously observed a significant relationship between stages of functional dependence (the level of assistance patients require consequent to Alzheimer’s disease deficits, derived from the Alzheimer’s Disease Cooperative Study – Activities of Daily Living Scale) and cognitive severity, we investigated whether measures of functional dependence could be utilized to identify clinical milestones of Alzheimer’s disease progression. OBJECTIVES: To describe the patterns of change in dependence over the course of 18 months in groups stratified according to cognitive Alzheimer’s disease dementia severity (determined using the Mini-Mental State Examination score) and to identify characteristics associated with patients showing worsening dependence (progressors) versus those showing no change or improvement (non-progressors). DESIGN: Analysis of longitudinal data from the GERAS study. SETTING: GERAS is an 18-month prospective, multicenter, naturalistic, observational cohort study reflecting the routine care of patients with Alzheimer’s disease in France, Germany, and the United Kingdom. PARTICIPANTS: 1495 community-living patients, aged ≥55 years, diagnosed with probable Alzheimer’s disease dementia, and their caregivers. MEASUREMENTS: Dependence levels, cognitive function, behavioral symptoms, caregiver burden, and cost were assessed at baseline and at 18 months. RESULTS: Of 971 patients having both baseline and 18-month data, 42% (408) were progressors and 563 (58%) were non-progressors. This general pattern held for all three levels of baseline Alzheimer’s disease dementia severity – mild (Mini-Mental State Examination score 21–26), moderate (15–20) or moderately severe/severe (<15) – with 40–45% of each group identified as progressors and 55–60% as non-progressors. No baseline differences were seen between progressors and non-progressors in cognitive scores or behavioral symptoms, although progressors had significantly shorter times since diagnosis and showed milder functional impairment. Baseline factors predictive of increasing dependence over 18 months included more severe cognitive impairment, living with others, and having multiple caregivers. A higher level of initial dependence was associated with less risk of dependence progression. Total societal costs of care also increased with greater dependence. CONCLUSIONS: In this large cohort, 42% of Alzheimer’s disease dementia patients at all levels of cognitive severity became more dependent within 18 months of observation while 58% did not progress. Dependence levels may be considered as meaningful interim clinical milestones that reflect Alzheimer’s disease-related functional deficits, although a time frame that extends beyond 18 months may be necessary to observe changes if used in clinical trials or other longitudinal studies. Recognition of predictors of greater dependence offers opportunities for intervention.

CITATION:
K. Kahle-Wrobleski ; J.S. Andrews ; M. Belger ; W. Ye ; S. Gauthier ; D.M. Rentz ; D. Galasko (2017): Dependence Levels as Interim Clinical Milestones Along the Continuum of Alzheimer’s Disease: 18-Month Results from the GERAS Observational Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.2

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ACTIVITIES OF DAILY LIVING MEASURED BY THE HARVARD AUTOMATED PHONE TASK TRACK WITH COGNITIVE DECLINE OVER TIME IN NON-DEMENTED ELDERLY

G.A. Marshall, S.L. Aghjayan, M. Dekhtyar, J.J. Locascio, K. Jethwani, R.E. Amariglio, K.A. Johnson, R.A. Sperling, D.M. Rentz

J Prev Alz Dis 2017;4(2):81-86

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Background: Impairment in activities of daily living is a major burden to both patients and caregivers. Mild impairment in instrumental activities of daily living is often seen at the stage of mild cognitive impairment. The field of Alzheimer’s disease is moving toward earlier diagnosis and intervention and more sensitive and ecologically valid assessments of instrumental or complex activities of daily living are needed. The Harvard Automated Phone Task, a novel performance-based activities of daily living instrument, has the potential to fill this gap. Objective: To further validate the Harvard Automated Phone Task by assessing its longitudinal relationship to global cognition and specific cognitive domains in clinically normal elderly and individuals with mild cognitive impairment. Design: In a longitudinal study, the Harvard Automated Phone Task was associated with cognitive measures using mixed effects models. The Harvard Automated Phone Task’s ability to discriminate across diagnostic groups at baseline was also assessed. Setting: Academic clinical research center. Participants: Two hundred and seven participants (45 young normal, 141 clinically normal elderly, and 21 mild cognitive impairment) were recruited from the community and the memory disorders clinics at Brigham and Women’s Hospital and Massachusetts General Hospital. Measurements: Participants performed the three tasks of the Harvard Automated Phone Task, which consist of navigating an interactive voice response system to refill a prescription (APT-Script), select a new primary care physician (APT-PCP), and make a bank account transfer and payment (APT-Bank). The 3 tasks were scored based on time, errors, repetitions, and correct completion of the task. The primary outcome measure used for each of the tasks was total time adjusted for correct completion. Results: The Harvard Automated Phone Task discriminated well between young normal, clinically normal elderly, and mild cognitive impairment participants (APT-Script: p<0.001; APT-PCP: p<0.001; APT-Bank: p=0.04). Worse baseline Harvard Automated Phone Task performance or worsening Harvard Automated Phone Task performance over time tracked with overall worse performance or worsening performance over time in global cognition, processing speed, executive function, and episodic memory. Conclusions: Prior cross-sectional and current longitudinal analyses have demonstrated the utility of the Harvard Automated Phone Task, a new performance-based activities of daily living instrument, in the assessment of early changes in complex activities of daily living in non-demented elderly at risk for Alzheimer’s disease. Future studies will focus on cross-validation with other sensitive activities of daily living tests and Alzheimer’s disease biomarkers.

CITATION:
G.A. Marshall ; S.L. Aghjayan ; M. Dekhtyar ; J.J. Locascio ; K. Jethwani ; R.E. Amariglio ; K.A. Johnson ; R.A. Sperling ; D.M. Rentz (2017): Activities of Daily Living Measured by the Harvard Automated Phone Task Track with Cognitive Decline over Time in Non-Demented Elderly. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.10

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SHORT-TERM PRACTICE EFFECTS AND AMYLOID DEPOSITION: PROVIDING INFORMATION ABOVE AND BEYOND BASELINE COGNITION

K. Duff, D.B. Hammers, B.C.A. Dalley, K.R. Suhrie, T.J. Atkinson, K.M. Rasmussen, K.P. Horn, B.E. Beardmore, L.D. Burrell, N.L. Foster, J. M. Hoffman

J Prev Alz Dis 2017;4(2):87-92

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Background: Practice effects, which are improvements in cognitive test scores due to repeated exposure to testing materials, may provide information about Alzheimer’s disease pathology, which could be useful for clinical trials enrichment. Objectives: The current study sought to add to the limited literature on short-term practice effects on cognitive tests and their relationship to amyloid deposition on neuroimaging. Participants: Twenty-seven, non-demented older adults (9 cognitively intact, 18 with mild cognitive impairment) received amyloid imaging with 18F-Flutemetamol, and two cognitive testing sessions across one week to determine practice effects. Results: A composite measure of 18F-Flutemetamol uptake correlated significantly with all seven cognitive tests scores on the baseline battery (r’s = -0.61 – 0.59, all p’s<0.05), with higher uptake indicating poorer cognition. Practice effects significantly added to the relationship (above and beyond the baseline associations) with 18F-Flutemetamol uptake on 4 of the 7 cognitive test scores (partial r’s = -0.45 – 0.44, p’s<0.05), with higher uptake indicating poorer practice effects. The odds ratio of being “amyloid positive” was 13.5 times higher in individuals with low practice effects compared to high practice effects. Conclusions: Short-term practice effects over one week may be predictive of progressive dementia and serve as an affordable screening tool to enrich samples for preventative clinical trials in Alzheimer’s disease.

CITATION:
K. Duff ; D.B. Hammers ; B.C.A. Dalley ; K.R. Suhrie ; T.J. Atkinson ; K.M. Rasmussen ; K.P. Horn ; B.E. Beardmore ; L.D. Burrell ; N.L. Foster ; J. M. Hoffman (2017): Short-Term Practice Effects and Amyloid Deposition: Providing Information Above and Beyond Baseline Cognition. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.9

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FACEHBI: A PROSPECTIVE STUDY OF RISK FACTORS, BIOMARKERS AND COGNITION IN A COHORT OF INDIVIDUALS WITH SUBJECTIVE COGNITIVE DECLINE. STUDY RATIONALE AND RESEARCH PROTOCOLS

O. Rodriguez-Gomez, A. Sanabria, A. Perez-Cordon, D. Sanchez-Ruiz, C. Abdelnour, S. Valero, I. Hernandez, M. Rosende-Roca, A. Mauleon, L. Vargas, M. Alegret, A. Espinosa, G. Ortega, M. Guitart, A. Gailhajanet, O. Sotolongo-Grau, S. Moreno-Grau, S. Ruiz, M. Tarragona, J. Serra, E. Martin, E. Peleja, F. Lomeña, F. Campos, A. Vivas, M.Gomez-Chiari, M.A. Tejero, J. Giménez, P. Pesini, M. Sarasa, G.Martinez, A. Ruiz, L. Tarraga, M.Boada

J Prev Alz Dis 2017;4(2):100-108

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Background: Long-term longitudinal studies with multimodal biomarkers are needed to delve into the knowledge of preclinical AD. Subjective cognitive decline has been proposed as a risk factor for the development of cognitive impairment. Thus, including individuals with SCD in observational studies may be a cost-effective strategy to increase the prevalence of preclinical AD in the sample. Objectives: To describe the rationale, research protocols and baseline characteristics of participants in the Fundació ACE Healthy Brain Initiative (FACEHBI). Design: FACEHBI is a clinical trial (EudraCT: 2014-000798-38) embedded within a long-term observational study of individuals with SCD. Setting: Participants have been recruited at the memory clinic of Fundació ACE (Barcelona) from two different sources: patients referred by a general practitioner and individuals from an Open House Initiative. Participants: 200 individuals diagnosed with SCD with a strictly normal performance in a comprehensive neuropsychological battery. Measurements: Individuals will undergo an extensive neuropsychological protocol, risk factor assessment and a set of multimodal biomarkers including florbetaben PET, structural and functional MRI, diffusion tensor imaging, determination of amyloid species in plasma and neurophthalmologic assessment with optical coherence tomography. Results: Two hundred individuals have been recruited in 15 months. Mean age was 65.9 years; mean MMSE was 29.2 with a mean of 14.8 years of education. Conclusions: FACEHBI is a long-term study of cognition, biomarkers and lifestyle that has been designed upon an innovative symptom-based approach using SCD as target population. It will shed light on the pathophysiology of preclinical AD and the role of SCD as a risk marker for the development of cognitive impairment.

CITATION:
O. Rodriguez-Gomez ; A. Sanabria ; A. Perez-Cordon ; D. Sanchez-Ruiz ; C. Abdelnour ; S. Valero ; I. Hernandez ; M. Rosende-Roca ; A. Mauleon ; L. Vargas ; M. Alegret ; A. Espinosa ; G. Ortega ; M. Guitart ; A. Gailhajanet ; O. Sotolongo-Grau ; S. Moreno-Grau ; S. Ruiz ; M. Tarragona ; J. Serra ; E. Martin ; E. Peleja ; F. Lomeña ; F. Campos ; A. Vivas ; M.Gomez-Chiari ; M.A. Tejero ; J. Giménez ; P. Pesini ; M. Sarasa ; G.Martinez ; A. Ruiz ; L. Tarraga ; M. Boada (2016): FACEHBI: A Prospective Study of Risk Factors, Biomarkers and Cognition in a Cohort of Individuals with Subjective Cognitive Decline. Study Rationale and Research Protocols. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2016.122

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ALBUMIN, HEMOGLOBIN, AND THE TRAJECTORY OF COGNITIVE FUNCTION IN COMMUNITY-DWELLING OLDER JAPANESE: A 13-YEAR LONGITUDINAL STUDY

H. Murayama, S. Shinkai, M. Nishi, Y. Taniguchi, H. Amano, S. Seino, Y. Yokoyama, H. Yoshida, Y. Fujiwara, H. Ito

J Prev Alz Dis 2017;4(2):93-99

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Background: Cognitive function can substantially decline over a long period, and understanding the trajectory of cognitive function is important. However, little is known about the linkage between nutritional biomarkers and long-term cognitive change. Objectives: We analyzed 13-year longitudinal data for older Japanese to examine the associations of serum albumin and hemoglobin levels with the trajectory of cognitive function. Design: Longitudinal study. Setting: Community-based. Participants: A total of 1,744 community-dwelling adults aged 65 years or older who participated in annual health examinations in Kusatsu town, Gunma Prefecture, Japan, from 2002–2014. Measurements: Cognitive function was assessed annually by the Mini-Mental State Examination (MMSE). Albumin and hemoglobin levels at baseline (the year when a respondent first participated in the health examination) were divided into quartiles. Hierarchical linear modeling was used to analyze intrapersonal and interpersonal differences in cognitive function. Results: Participants’ MMSE scores decreased at an accelerated rate over the 13-year period. Participants with the lowest baseline albumin level (below the first quartile line) showed a greater accelerated decline in MMSE scores over time, compared with those with the highest level (above the third quartile line). Moreover, MMSE scores in participants with a lower hemoglobin level and lower MMSE score at baseline tended to decline faster over time at an accelerated rate. Conclusions: These findings yield new insights about the complex and diverse roles of these nutritional biomarkers on the trajectory of cognitive function in old age.

CITATION:
H. Murayama ; S. Shinkai ; M. Nishi ; Y. Taniguchi ; H. Amano ; S. Seino ; Y. Yokoyama ; H. Yoshida ; Y. Fujiwara ; H. Ito (2016): Albumin, Hemoglobin, and the Trajectory of Cognitive Function in Community-Dwelling Older Japanese: A 13-Year Longitudinal Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2016.113

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Review Articles

DEFINING DISEASE MODIFYING THERAPY FOR ALZHEIMER’S DISEASE

J. Cummings, N. Fox

J Prev Alz Dis 2017;4(2):109-115

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Background: Disease-modifying therapies (DMTs) are urgently needed to treat the growing number of individuals with Alzheimer’s disease (AD) or at immanent risk for AD. A definition of DMT is required to facilitate the process of DMT drug development. Process: This is a review of the state of the science with regard to definition and development of DMTs. Results: A DMT is as an intervention that produces an enduring change in the clinical progression of AD by interfering in the underlying pathophysiological mechanisms of the disease process that lead to cell death. Demonstration of DMT efficacy is garnered through clinical trial designs and biomarkers. Evidence of disease modification in the drug development process is based on trial designs such as staggered start and delayed withdrawal showing an enduring effect on disease course or on combined clinical outcomes and correlated biomarker evidence of an effect on the underlying pathophysiological processes of the disease. Analytic approaches such as showing change in slope of cognitive decline, increasing drug-placebo difference over time, and delay of disease milestones are not conclusive by themselves but support the presence of a disease modifying effect. Neuroprotection is a related concept whose demonstration depends on substantiating disease modification. No single type of evidence in itself is sufficient to prove disease modification – consistency, robustness, and variety of sources of data will all contribute to convincing stakeholders that an agent is a DMT. Conclusion: DMT is defined by its enduring effect on processes leading to cell death. A variety of types of data can be used to support the hypothesis that disease modification has occurred.

CITATION:
J. Cummings ; N. Fox (2017): Defining Disease Modifying Therapy for Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.12

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EU/US/CTAD TASK FORCE: LESSONS LEARNED FROM RECENT AND CURRENT ALZHEIMER’S PREVENTION TRIALS

P. Aisen, J. Touchon, R. Amariglio, S. Andrieu, R. Bateman, J. Breitner, M. Donohue, B. Dunn, R. Doody, N. Fox, S. Gauthier, M. Grundman, S. Hendrix, C. Ho, M. Isaac, R. Raman, P. Rosenberg, R. Schindler, L. Schneider, R.A. Sperling, P. Tariot, K. Welsh-Bohmer, M. Weiner, B. Vellas, and Task Force Members

J Prev Alz Dis 2017;4(2):116-124

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At a meeting of the EU/US/Clinical Trials in Alzheimer’s Disease (CTAD) Task Force in December 2016, an international group of investigators from industry, academia, and regulatory agencies reviewed lessons learned from ongoing and planned prevention trials, which will help guide future clinical trials of AD treatments, particularly in the pre-clinical space. The Task Force discussed challenges that need to be addressed across all aspects of clinical trials, calling for innovation in recruitment and retention, infrastructure development, and the selection of outcome measures. While cognitive change provides a marker of disease progression across the disease continuum, there remains a need to identify the optimal assessment tools that provide clinically meaningful endpoints. Patient- and informant-reported assessments of cognition and function may be useful but present additional challenges. Imaging and other biomarkers are also essential to maximize the efficiency of and the information learned from clinical trials.

CITATION:
P. Aisen ; J. Touchon ; R. Amariglio ; S. Andrieu ; R. Bateman ; J. Breitner ; M. Donohue ; B. Dunn ; R. Doody ; N. Fox ; S. Gauthier ; M. Grundman ; S. Hendrix ; C. Ho ; M. Isaac ; R. Raman ; P. Rosenberg ; R. Schindler ; L. Schneider ; R. Sperling ; P. Tariot ; K. Welsh-Bohmer ; M. Weiner ; B. Vellas ; and Task Force Members (2017): EU/US/CTAD Task Force: Lessons Learned from Recent and Current Alzheimer’s Prevention Trials. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.13

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ETHICAL ISSUES IN THE DEVELOPMENT OF READINESS COHORTS IN ALZHEIMER’S DISEASE RESEARCH

R. Milne, E. Bunnik, K. Tromp, S. Bemelmans, S. Badger, D.Gove, M. Maman, M. Schermer, L. Truyen, C. Brayne, E. Richard

J Prev Alz Dis 2017;4(2):125-131

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There is growing interest in the development of novel approaches to secondary prevention trials in Alzheimer’s disease to facilitate screening and recruitment of research participants and to reduce the time and costs associated with clinical trials. Several international research collaborations are setting up research infrastructures that link existing research cohorts, studies or patient registries to establish ‘trial-ready’ or ‘readiness’ cohorts. From these cohorts, individuals are recruited into clinical trial platforms. In setting up such research infrastructures, researchers must make ethically challenging design decisions in at least three areas: re-contacting participants in existing research studies, obtaining informed consent for participation in a readiness cohort, and disclosure of Alzheimer’s disease-related biomarkers. These ethical considerations have been examined by a dedicated workgroup within the European Prevention of Alzheimer’s Dementia (EPAD) project, a trans-European longitudinal cohort and adaptive proof-of-concept clinical trial platform. This paper offers recommendations for the ethical management of re-contact, informed consent and risk disclosure which may be of value to other research collaborations in the process of developing readiness cohorts for prevention trials in Alzheimer’s disease and other disease areas.

CITATION:
R. Milne ; E. Bunnik ; K. Tromp ; S. Bemelmans ; S. Badger ; D. Gove ; M. Maman ; M. Schermer ; L. Truyen ; C. Brayne ; E. Richard (2017): Ethical Issues in the Development of Readiness Cohorts in Alzheimer’s Disease Research. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.5

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