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02/2015 journal articles

Editorials

ACTIVE IMMUNOTHERAPY FOR ALZHEIMER’S DISEASE: THE ROAD AHEAD

M.S. Rafii

J Prev Alz Dis 2015;2(2):78-79

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CITATION:
M.S. Rafii (2015): Active Immunotherapy for Alzheimer’s Disease: The Road Ahead. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2015.59

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IMMUNOTHERAPY OF AD: ALUM DEMAIN?

R. Liblau, A. Saoudi

J Prev Alz Dis 2015;2(2):80-81

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CITATION:
R. Liblau ; A. Saoudi (2015): Immunotherapy of AD: Alum Demain?. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2015.64

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COGNITIVE/CLINICAL ENDPOINTS FOR PRE-DEMENTIA AD TRIALS

P.S. Aisen

J Prev Alz Dis 2015;2(2):82-84

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CITATION:
P.S. Aisen (2015): Cognitive/Clinical Endpoints for Pre-Dementia AD Trials. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2015.62

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Point of View

ESTABLISHING CLINICAL RELEVANCE IN PRECLINICAL ALZHEIMER’S DISEASE

R.A. Sperling, R.E. Amariglio, G.A. Marshall, D.M. Rentz

J Prev Alz Dis 2015;2(2):85-87

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CITATION:
R.A. Sperling ; R.E. Amariglio ; G.A. Marshall ; D.M. Rentz (2015): Establishing Clinical Relevance in Preclinical Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2015.56

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POSSIBLE ENDPOINTS IN A PRODROMAL ALZHEIMER’S DISEASE TRIAL

A.M. Wessels, S.W. Andersen, P. Castelluccio, Z. Zhang, P. Yu

J Prev Alz Dis 2015;2(2):88-90

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CITATION:
A.M. Wessels ; S.W. Andersen ; P. Castelluccio ; Z. Zhang ; P. Yu (2015): POSSIBLE ENDPOINTS IN A PRODROMAL ALZHEIMER’S DISEASE TRIAL. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2015.52

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Original Research

METHODOLOGICAL ASPECTS OF THE PHASE II STUDY AFF006 EVALUATING AMYLOID-BETA -TARGETING VACCINE AFFITOPE® AD02 IN EARLY ALZHEIMER’S DISEASE – PROSPECTIVE USE OF NOVEL COMPOSITE SCALES

S. Hendrix, N. Ellison, S. Stanworth, L. Tierney, F. Mattner, W. Schmidt, B. Dubois, A. Schneeberger

J Prev Alz Dis 2015;2(2):91-102

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BACKGROUND: Optimized scales and composite outcomes have been proposed as a way to more accurately measure Alzheimer’s disease related decline. AFFITOPE® AD02, is an amyloid-beta (Aβ)-targeting vaccine to elicit anti-Aβ antibodies. IMM-AD04, commonly known as Alum, originally designated as a control agent, appeared to have disease-modifying activity in a multicenter, parallel group phase II study in early AD patients. OBJECTIVES: To develop adapted outcomes for cognition, function and a composite scale with improved sensitivity to decline and treatment effects in early AD (mild plus prodromal AD) based on historical data and to assess these adapted outcomes in this phase II study. DESIGN: Data from public datasets was analyzed using a partial least squares model in order to identify an optimally weighted cognitive outcome, Adapted ADAS-cog, and an optimally weighted ADL outcome, Adapted ADCS-ADL which were prospectively defined as co-primary endpoints for the study and were also combined into a composite scale. Data from 162 patients in the placebo groups of ADCS studies and 156 mild patients in the ADNI I study were pooled for this analysis. The Adapted ADAS-cog scale considered 13 ADAS-cog items as well as several Neuropsychological test items and CogState items, the Adapted ADCS-ADL considered all ADCS-ADL items. After the pre-specified analyses were complete, additional adapted and composite scales were investigated in a post-hoc manner. Evaluation of the adapted and composite scales was performed on Phase II trial data for AFFITOPE® AD02 (AFF006, Clinical Trial Identifier: NCT01117818) and historic data in early AD. Least square means, standard deviations, and least squares mean to standard deviation ratios were compared among adapted and composite scales and traditional scales for the 5 treatment groups in the phase II study and overall for the historic data. Treatment effect sizes and p-values were also compared for the phase II study. RESULTS: Cognitive items that were selected for the adapted cognitive scale (aADAS-cog) and had the highest weights were Word Recall, Word Recognition, and Orientation. Delayed Word Recall and Digit Cancellation were among the items excluded due to lack of improved sensitivity to decline. Highly weighted ADL items included in the adapted functional scale (aADCS-ADL) were using the telephone, traveling, preparing a meal/snack, selecting clothing, shopping and using appliances. Excluded items were primarily basic ADLs such as eating, walking, toileting and bathing. Comparisons between traditional scales and primary outcome adapted scales show improved sensitivity to group differences with the adapted scales in the phase II trial. Most of the improvement in the sensitivity of the aADAS-cog and the aADCS-ADL is due to a larger treatment difference observed rather than the improved sensitivity to decline in the comparison groups. CONCLUSION: To our knowledge, this is the first study to prospectively use optimized scales as primary endpoints and to demonstrate the superior power of optimized scales and composites in early disease. Although it is possible that the treatment difference between randomized groups is due to a factor other than the treatment itself, for instance baseline imbalance, the improved power to detect these differences still argues in favor of the adapted scales. The issue of oversensitivity to detect treatment effects is controlled by selection of the alpha level for significance, and in our case will happen less than 5% of the time. Clinical relevance of the treatment difference should be assessed separately from statistical significance, and in this phase II study, is supported by significant or similar sizes of effect on function, behaviour and quality of life outcomes, which are important to patients and caregivers.

CITATION:
S. Hendrix ; N. Ellison ; S. Stanworth ; L. Tierney ; F. Mattner ; W. Schmidt ; B. Dubois ; A. Schneeberger ; (2015): METHODOLOGICAL ASPECTS OF THE PHASE II STUDY AFF006 EVALUATING AMYLOID-BETA -TARGETING VACCINE AFFITOPE® AD02 IN EARLY ALZHEIMER’S DISEASE – PROSPECTIVE USE OF NOVEL COMPOSITE SCALES. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2015.67

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RESULTS FROM A PHASE II STUDY TO ASSESS THE CLINICAL AND IMMUNOLOGICAL ACTIVITY OF AFFITOPE® AD02 IN PATIENTS WITH EARLY ALZHEIMER’S DISEASE

A. Schneeberger, S. Hendrix, M. Mandler, N. Ellison, V. Bürger, M. Brunner, L. Frölich, N. Mimica, J. Hort, M. Rainer, D. Imarhiagbe, A. Kurz, O. Peters, H.-J. Gertz, L. Tierney, F. Mattner, W. Schmidt, B. Dubois, for the investigators of CT AFF006

J Prev Alz Dis 2015;2(2):103-114

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OBJECTIVES: The primary objective of this clinical trial was to assess the clinical activity of various doses and formulations of AFFITOPE® AD02 following its repeated s.c. administration to patients with early Alzheimer´s disease (AD), based on the evaluation of cognitive and functional domains. DESIGN: It was designed as a randomized, placebo-controlled, parallel group, double blind, multicenter phase II trial with 10 regular outpatient visits and 6 telephone interviews. SETTING: The trial was performed at 32 sites in six countries. PARTICIPANTS: A total of 332 patients were enrolled and 265 patients completed the trial in 3 treatment groups with AD02 and 2 control groups with aluminum oxihydroxide, here named IMM-AD04. Patients were randomly assigned to 5 groups: two doses of IMM-AD04, 25µg AD02 (in two different formulations) and 75µg AD02. INTERVENTION: At months 0, 1, 2, 3, 9 and 15, each patient received a single s.c. injection of the corresponding preparations of AFFITOPE® AD02 or the control, IMM-AD04. MEASUREMENTS: Co-primary efficacy outcomes included a measure of cognition (adapted AD Assessment Scale cognitive [aADAS cog]), and a measure of function (adapted AD Cooperative Trial Activities of Daily Living [aADCS-ADL]). A primary composite score was the sum of these two scores. RESULTS: Treatments were generally well tolerated and adverse events (AEs) were seen at similar rates across all treatment groups, with the exception that more injection site reactions were seen in the groups with a higher level of adjuvant. None of the AD02 groups showed a benefit over the IMM-AD04 controls for primary or exploratory efficacy outcomes. The control groups differed on aADCS-ADL and therefore couldn’t be pooled (p=0.039). Unexpectedly, the 2mg IMM-AD04 showed statistically significant effects over the other groups on several clinical outcomes including: aADAS-cog, aADL, Composite, ADAS-cog, CDR-sb, and QOL-AD Caregiver as well as two biomarker outcomes: right and total hippocampal volume (all p<0.05). 48% of patients in the IMM-AD04 2mg group had no decline in the composite outcome over 18 months compared to 17%-31% in the other groups, which is consistent with historical placebo groups. CONCLUSION: No significant treatment effects were seen for the investigational compound AD02. However, the IMM-AD04 2mg group showed statistically significant effects over all other groups on several clinical outcomes as well as a slowing of decline on right hippocampal volume. The data support further development of IMM-AD04 as a disease modifying agent in line with EMA/FDA definitions.

CITATION:
A. Schneeberger ; S. Hendrix ; M. Mandler ; N. Ellison ; V. Bürger ; M. Brunner ; L. Frölich ; N. Mimica ; J. Hort ; M. Rainer ; D. Imarhiagbe ; A. Kurz ; O. Peters ; H.-J. Gertz ; L. Tierney ; F. Mattner ; W. Schmidt ; B. Dubois ; for the investigators of CT AFF006 (2015): Results from a Phase II Study to Assess the Clinical and Immunological Activity of AFFITOPE® AD02 in Patients with Early Alzheimer’s Disease . The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2015.63

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CLINICAL AND ECONOMIC CHARACTERISTICS OF MILESTONES ALONG THE CONTINUUM OF ALZHEIMER’S DISEASE: TRANSFORMING FUNCTIONAL SCORES INTO LEVELS OF DEPENDENCE

K. Kahle-Wrobleski, J.S. Andrews, M. Belger, S. Gauthier, Y. Stern, D.M. Rentz, D. Galasko

J Prev Alz Dis 2015;2(2):115-120

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BACKGROUND: Because Alzheimer’s disease (AD) is characterized by a gradual decline, it can be difficult to identify distinct clinical milestones that signal disease advancement. Adapting a functional scale may be a useful way of staging disease progression that is more informative for healthcare systems. Objectives: To adapt functional scale scores into discrete levels of dependence as a way of staging disease progression that is more informative to care providers and stakeholders who rely on the functional impact of diseases to determine access to supportive services and interventions. Design: Analysis of data from the GERAS study. Setting: GERAS is an 18-month prospective, multicenter, naturalistic, observational cohort study reflecting the routine care of patients with AD in France, Germany, and the United Kingdom. Participants: Data were from baseline results of 1497 community-living patients, aged ≥55 years, diagnosed with probable AD and their caregivers. Measurements: We used data from the Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory (ADCS-ADL) and mapped items onto established categories of functional dependence, validated using clinical and economic measures. Cognitive function, behavioral symptoms, caregiver burden, and cost were assessed. Based on stages of functional dependence described by the Dependence Scale, individual ADCS-ADL items were used to approximate 6 dependence levels. Results: There was a significant relationship between assigned level of dependence derived from the ADCS-ADL score and cognitive severity category. As the assigned level of dependence increased, the associated clinical and economic indicators demonstrated a pattern of greater disease severity. Conclusions: This mapping provides initial support for dependence levels as appropriate interim clinical milestones that characterize the functional deficits associated with AD.

CITATION:
K. Kahle-Wrobleski ; J.S. Andrews ; M. Belger ; S. Gauthier ; Y. Stern ; D.M. Rentz ; D. Galasko (2015): Clinical and Economic Characteristics of Milestones along the Continuum of Alzheimer’s Disease: Transforming Functional Scores into Levels of Dependence. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2015.53

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ASSESSMENT OF AGE-RELATED DIFFERENCES IN FUNCTIONAL CAPACITY USING THE VIRTUAL REALITY FUNCTIONAL CAPACITY ASSESSMENT TOOL (VRFCAT)

A.S. Atkins, I. Stroescu, N.B. Spagnola, V.G. Davis, T.D. Patterson, M. Narasimhan, P.D. Harvey, R.S.E. Keefe

J Prev Alz Dis 2015;2(2):121-127

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Clinical trials for primary prevention and early intervention in preclinical AD require measures of functional capacity with improved sensitivity to deficits in healthier, non-demented individuals. To this end, the Virtual Reality Functional Capacity Assessment Tool (VRFCAT) was developed as a direct performance-based assessment of functional capacity that is sensitive to changes in function across multiple populations. Using a realistic virtual reality environment, the VRFCAT assesses a subject’s ability to complete instrumental activities associated with a shopping trip. The present investigation represents an initial evaluation of the VRFCAT as a potential co-primary measure of functional capacity in healthy aging and preclinical MCI/AD by examining test-retest reliability and associations with cognitive performance in healthy young and older adults. The VRFCAT was compared and contrasted with the UPSA-2-VIM, a traditional performance-based assessment utilizing physical props. Results demonstrated strong age-related differences in performance on each VRFCAT outcome measure, including total completion time, total errors, and total forced progressions. VRFCAT performance showed strong correlations with cognitive performance across both age groups. VRFCAT Total Time demonstrated good test-retest reliability (ICC=.80 in young adults; ICC=.64 in older adults) and insignificant practice effects, indicating the measure is suitable for repeated testing in healthy populations. Taken together, these results provide preliminary support for the VRFCAT as a potential measure of functionally relevant change in primary prevention and preclinical AD/MCI trials.

CITATION:
A.S. Atkins ; I. Stroescu ; N.B. Spagnola ; V.G. Davis ; T.D. Patterson ; M. Narasimhan ; P.D. Harvey ; R.S.E. Keefe (2015): ASSESSMENT OF AGE-RELATED DIFFERENCES IN FUNCTIONAL CAPACITY USING THE VIRTUAL REALITY FUNCTIONAL CAPACITY ASSESSMENT TOOL (VRFCAT). The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2015.61

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Review Articles

ENDPOINTS FOR PRE-DEMENTIA AD TRIALS: A REPORT FROM THE EU/US/CTAD TASK FORCE

B. Vellas, R. Bateman, K. Blennow , G. Frisoni , K. Johnson, R. Katz , J. Langbaum, D. Marson , R. Sperling, A. Wessels, S. Salloway, R. Doody, P. Aisen, Task Force Members

J Prev Alz Dis 2015;2(2):128-135

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For Alzheimer’s disease treatment trials that focus on the pre-dementia stage of disease, outcome measures are needed that will enable assessment of disease progression in patients who are clinically normal. The EU/US CTAD Task Force, an international collaboration of investigators from industry, academia, non-profit foundations, and regulatory agencies, met in Philadelphia, Pennsylvania, USA, on November 19, 2014 to discuss existing and novel outcome assessments that may be useful in pre-dementia trials. Composite measures that assess changes in episodic memory, executive function, global cognition, and global function have recently been developed by a number of groups and appear to be sensitive at this stage. Functional measures that involve real-life complex tasks also appear to capture early subtle changes in pre-dementia subjects and have the advantage of representing clinically meaningful change. Patient reported outcomes and novel CSF and imaging biomarkers have also shown promise. More studies are needed to validate all of these tests in the pre-dementia population. Many of them have been incorporated as exploratory measures in ongoing or planned trials.

CITATION:
B. Vellas ; R. Bateman ; K. Blennow ; G. Frisoni ; K. Johnson ; R. Katz ; J. Langbaum ; D. Marson ; R. Sperling ; A. Wessels ; S. Salloway ; R. Doody ; P. Aisen ; and Task Force Members ; (2015): Endpoints for Pre-Dementia AD Trials: 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.2015.55

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TEA FOR ALZHEIMER PREVENTION

L. Feng, M.-S. Chong, W.-S. Lim, T.-S. Lee, E.-H. Kua, T.-P. Ng

J Prev Alz Dis 2015;2(2):136-141

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The availability of empirical data from human studies in recent years have lend credence to the old axiomatic wisdom that health benefits of tea drinking extend to the area of cognition. Specifically, there is increasing interest as to whether tea drinking can delay or even prevent the onset of Alzheimer’s disease (AD). Data from several cross-sectional studies have consistently shown that tea drinking is associated with better performance on cognitive tests. This association is supported by longitudinal data from the Singapore Longitudinal Aging Study, the Chinese Longitudinal Healthy Longevity Survey and the Cardiovascular Health Study. The only two published longitudinal analyses on clinical outcome reported conflicting results: one study reported that mid-life tea drinking was not associated with risk reduction of Alzheimer’s disease in late life while the other one found that green tea consumption reduced the incidence of dementia or mild cognitive impairment. Two small trials from Korea and Japan reported encouraging but preliminary results. While the existing evidence precludes a definite conclusion as to whether tea drinking can be an effective and simple lifestyle preventive measure for AD, further research involving longer-term longitudinal studies and randomized controlled trials is clearly warranted to shed light on this topic of immense public health interest. Biological markers of tea consumption and Alzheimer diseases should be employed in future research to better delineate the underlying mechanisms of tea drinking’s protective effect on cognition.

CITATION:
L. Feng ; M.-S. Chong ; W.-S. Lim ; T.-S. Lee ; E.-H. Kua ; T.-P. Ng (2015): Tea for Alzheimer Prevention. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2015.57

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COGNITIVE REHABILITATION IN ALZHEIMER’S DISEASE – A CONCEPTUAL AND METHODOLOGICAL REVIEW

E. Kasper, S. Ochmann, W. Hoffmann, W. Schneider, E. Cavedo, H. Hampel, S. Teipel

J Prev Alz Dis 2015;2(2):142-152

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Within the last 20 years, several standardized cognitive trainings have been developed aiming at the delay of cognitive decline in older people who are at risk of Alzheimer’s Disease (AD) or in mild stages of dementia. The transfer of cognitive training effects into activities of daily living was very limited in most previous studies. Therefore, multimodal Cognitive Rehabilitation approaches have been designed that aim to improve the activities of daily living. These approaches also attempt to integrate the patient’s psychopathological and behavioral status as well as social relationships into the treatment plan. Contrary to other approaches, CR mainly focuses on compensation rather than restoration of impaired functionality. In this review, we define CR conceptually, and derive specific criteria to evaluate current CR approaches for individuals with mild cognitive impairment (MCI) and AD dementia. In addition, we perform a critical, methodical analysis of available CR studies, reviewing their short- and long-term treatment effects. Findings suggest that CR approaches improve memory performance and competence of activity of daily living (ADL) in mildly cognitively impaired subjects (MCI), when compensatory, integrative, as well as interactive elements and domain specificity are taken into account. Interactive and individual aspects also appear to be relevant to sustain long-term effects. In AD dementia, similar results emerged, although with smaller effect sizes. The efficacy of individualized CR approaches was comparable with theory-based, manual-guided concepts as long as promoting interaction was part of the treatment. So far, only few randomized controlled studies of sufficient sample size are available. Future systematic efficacy studies need to consider precisely defined outcome variables. This is necessary before one can draw conclusions of how CR can be used for secondary prevention of AD dementia as well as AD treatment.

CITATION:
E. Kasper ; S. Ochmann ; W. Hoffmann ; W. Schneider ; E. Cavedo ; H. Hampel ; S. Teipel (2015): Cognitive Rehabilitation in Alzheimer’s Disease – A Conceptual and Methodological Review. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2015.58

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