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02/2016 journal articles

Editorials

BARRIERS FOR PREVENTION AND PRODROMAL AD TRIALS

R.C. Petersen

J Prev Alz Dis 2016;3(2):66-67

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CITATION:
R.C. Petersen (2016): Barriers for Prevention and Prodromal AD Trials. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2016.96

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CTAD Task Force

REGISTRIES AND COHORTS TO ACCELERATE EARLY PHASE ALZHEIMER’S TRIALS. A REPORT FROM THE E.U./U.S. CLINICAL TRIALS IN ALZHEIMER’S DISEASE TASK FORCE

P. Aisen, J. Touchon, S. Andrieu, M. Boada, R. Doody, R.L. Nosheny, J.B. Langbaum, L. Schneider, S. Hendrix, G. Wilcock, J.L. Molinuevo, C. Ritchie, P.-J. Ousset, J. Cummings, R. Sperling, S.T. DeKosky, S. Lovestone, H. Hampel, R. Petersen, V. Legrand, M. Egan, C. Randolph, S. Salloway, M. Weiner, B. Vellas, and Task Force Members

J Prev Alz Dis 2016;3(2):68-74

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The EU/US/CTAD Task Force, an international collaboration of AD investigators from industry and academia, met in Barcelona, Spain, on November 4th, 2015, to explore existing and planned patient registries and other clinical trial infrastructure meant to expedite recruitment of large numbers of participants into clinical trials and improve their productivity. The Task Force identified a number of approaches currently being tested around the world, including the use of predictive algorithms to identify individuals likely to have prodromal or preclinical AD, the establishment of clinical trial networks to streamline trials, and reforming the informed consent process to make it less burdensome to both investigators and trial participants. Multi-national systems such as the European Prevention of Alzheimer’s Dementia (EPAD) and the Global Alzheimer’s Platform (GAP) offer value for sponsors, trial sites, and patients by optimizing efforts to find effective disease-modifying and symptomatic treatments.

CITATION:
P. Aisen ; J. Touchon ; S. Andrieu ; M. Boada ; R. Doody ; R.L. Nosheny ; J.B. Langbaum ; L. Schneider ; S. Hendrix ; G. Wilcock ; J.L. Molinuevo ; C. Ritchie ; P.-J. Ousset ; J. Cummings ; R. Sperling ; S.T. DeKosky ; S. Lovestone ; H. Hampel ; R. Petersen ; V. Legrand ; M. Egan ; C. Randolph ; S. Salloway ; M. Weiner ; B. Vellas ; and Task Force Members (2016): Registries and Cohorts to Accelerate Early Phase Alzheimer’s Trials. A Report from the E.U./U.S. Clinical Trials in Alzheimer’s Disease Task Force. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2016.97

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Original Research

VANUTIDE CRIDIFICAR (ACC-001) AND QS-21 ADJUVANT IN INDIVIDUALS WITH EARLY ALZHEIMER’S DISEASE: AMYLOID IMAGING POSITRON EMISSION TOMOGRAPHY AND SAFETY RESULTS FROM A PHASE 2 STUDY

C.H. van Dyck, C. Sadowsky, G. Le Prince Leterme, K. Booth, Y. Peng, K. Marek, N. Ketter, E. Liu, B.T. Wyman, N. Jackson, M. Slomkowski, J. M. Ryan

J Prev Alz Dis 2016;3(2):75-84

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BACKGROUNDd: ACC-001 is an investigational therapeutic vaccine designed to elicit antibodies against the N-terminal peptide 1-7 of the amyloid-beta peptide, believed to be important in the pathogenesis of Alzheimer’s disease. OBJECTIVES: To evaluate safety, immunogenicity, impact on brain amyloid, and other exploratory endpoints in participants receiving ACC-001. DESIGN: Randomized, phase 2, interventional study. Trial registration: Clinicaltrials.gov ID NCT01227564. PARTICIPANTS: Individuals with early Alzheimer’s disease (Mini-Mental State Examination scores ≥25, a global Clinical Dementia Rating of 0.5, and evidence of elevated baseline brain amyloid burden). Intervention: Participants were randomized to ACC-001 3 µg or 10 µg with QS-21 adjuvant (50 µg), or placebo. MEASUREMENTS: The primary endpoint was change in brain amyloid burden by 18F-florbetapir positron emission tomography in composite cortical standard uptake value ratio. RESULTS: A total of 63 participants were randomized and 51 completed the study. At week 104, no significant differences were observed in 18F-florbetapir positron emission tomography composite cortical standard uptake value ratio between either ACC-001 dose compared with placebo. In both ACC-001 + QS-21 treatment groups, following the initial immunization, the anti-amyloid-beta geometric mean titers increased after each subsequent vaccination and then declined, with less apparent decline after the later compared with earlier immunizations. The majority of treatment-emergent adverse events in the ACC-001 + QS-21 groups were injection site reactions, which occurred at a greater rate in active treatment groups than in the placebo group. No amyloid-related imaging abnormalities of edema or effusion were reported. CONCLUSION: No statistically significant differences were observed between groups in the change from baseline brain amyloid burden despite apparently robust systemically measured anti-amyloid-beta antibody response at both dose levels. Insufficient antibody titers, poor quality immune response, short duration of treatment, or small sample size may have resulted in these findings. The safety and tolerability profile was acceptable.

CITATION:
C.H. van Dyck ; C. Sadowsky ; G. Le Prince Leterme ; K. Booth ; Y. Peng ; K. Marek ; N. Ketter ; E. Liu ; B.T. Wyman ; N. Jackson ; M. Slomkowski ; J. M. Ryan (2016): Vanutide Cridificar (ACC-001) and QS-21 Adjuvant in Individuals with Early Alzheimer’s Disease: Amyloid Imaging Positron Emission Tomography and Safety Results from a Phase 2 Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2016.91

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THE EFFECT OF VASCULAR NEUROPATHOLOGY ON LATE-LIFE COGNITION: RESULTS FROM THE SMART PROJECT

R.J. Kryscio, E.L. Abner, P.T. Nelson, D. Bennett, J. Schneider, L. Yu, L.S. Hemmy, K.O. Lim, K. Masaki, N. Cairns, C. Xiong, R. Woltjer, H.H. Dodge, S. Tyas, D.W. Fardo, W. Lou, L. Wan, F.A. Schmitt

J Prev Alz Dis 2016;3(2):85-91

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Background: Cerebral vascular pathology may contribute to cognitive decline experienced by some elderly near death. Given evidence for mixed neuropathologies in advanced age, preventing or reducing cerebrovascular burden in late life may be beneficial. Objective: To correlate measures of cerebral vascular pathology with cognitive trajectories. Setting: Observational study. Participants: A cohort of 2,274 individuals who came to autopsy at a mean age of 89.3 years and 82 percent of whom had at least two cognitive assessments within the last six years of life was compiled from six centers conducting longitudinal studies. Measurements: For each cognitive domain: immediate and delayed memory, language, and naming, three trajectories were examined: good, intermediate, and poor cognition. The probability of a participant belonging to each trajectory was associated with measures of cerebral vascular pathology after adjustment for demographics, APOE, and Alzheimer neuropathology. Results: A large proportion of the cohort (72-94%) experienced good or intermediate cognition in the four domains examined. The presence of arteriolosclerosis and the presence of lacunar infarcts doubled the odds of belonging to the poor cognitive trajectory for language when compared to the good trajectory. The presence of lacunar infarcts increased the odds of an intermediate or poor trajectory for immediate and delayed recall while the presence of large artery infarcts increased the odds of poor trajectories for all four cognitive domains examined. Microinfarcts and cerebral amyloid angiopathy had little effect on the trajectories. Conclusion: Indicators of cerebral vascular pathology act differently on late life cognition.

CITATION:
R.J. Kryscio ; E.L. Abner ; P.T. Nelson ; D. Bennett ; J. Schneider ; L. Yu ; L.S. Hemmy ; K.O. Lim ; K. Masaki ; N. Cairns ; C. Xiong ; R. Woltjer ; H.H. Dodge ; S. Tyas ; D.W. Fardo ; W. Lou ; L. Wan ; F.A. Schmitt (2016): The Effect of Vascular Neuropathology on Late-life Cognition: Results from the SMART Project. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2016.95

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LONGITUDINAL TRAJECTORIES OF CLINICAL DECLINE IN AMYLOID POSITIVE AND NEGATIVE POPULATIONS

P.T. Trzepacz, H. Hochstetler, S. Wang, P. Yu, M. Case, D.B. Henley, E. Degenhardt, J.-M. Leoutsakos, C.G. Lyketsos, for the Alzheimer’s Disease Neuroimaging Initiative

J Prev Alz Dis 2016;3(2):92-100

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BACKGROUND: Brain beta-amyloid status portends different trajectories of clinical decline. OBJECTIVE: Determine trajectories and predictive baseline variable(s). DESIGN: Longitudinal, up to 24 months. SETTING: ADNI sites. PARTICIPANTS: Healthy control (n=325), early and late mild cognitive impairment (n=279; n=372), and Alzheimer’s dementia (n=216) subjects from ADNI-1/GO/2. MEASUREMENTS: Baseline amyloid status was based on first available CSF Aβ1-42 or, [11C]PiB or [18F]florbetapir (FBP) PET. Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog13) and Functional Activities Questionnaire (FAQ) were co-analyzed using Growth Mixture Modeling (GMM) to define latent class trajectories for each amyloid group. Classification and Regression Tree (CART) analysis determined which variables best predicted trajectory class membership using a number of variables available to clinicians. RESULTS: GMMs found two trajectory classes (C1, C2) each for amyloid-positive (P; n=722) and negative (N; n=470) groups. Most (90%) in the negative group were C2N with mildly impaired baseline ADAS-Cog13, normal FAQ and nonprogression; 10% were C1N with moderately impaired baseline FAQ and ADAS-Cog13 and trajectory of moderately worsening scores on the FAQ. C1P (26%) had more impaired baseline FAQ and ADAS-Cog13 than C2P (74%) and a steeper declining trajectory. CART yielded 4 decision nodes (FAQ <10.5, FAQ <6.5, MMSE ≥26.5, age <75.5) in positive and 1 node (FAQ <6.5) in negative groups, with 91.4% and 92.8% accuracy for class assignments, respectively. CONSLUSIONS: The trajectory pattern of greater decline in amyloid positive subjects was predicted by greater baseline impairment of cognition and function. While most amyloid-negative subjects had nonprogression irrespective of their diagnosis, a subgroup declined similarly to the gradually declining amyloid-positive group. CART predicted likely trajectory class, with known amyloid status, using variables accessible in a clinical setting, but needs replication.

CITATION:
P.T. Trzepacz ; H. Hochstetler ; S. Wang ; P. Yu ; M. Case ; D.B. Henley ; E. Degenhardt ; J.-M. Leoutsakos ; C.G. Lyketsos ; for the Alzheimer’s Disease Neuroimaging Initiative (2016): Longitudinal Trajectories of Clinical Decline in Amyloid Positive and Negative Populations. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2016.90

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A NOVEL EIGENVECTOR-BASED METHOD TO DETECT MILD ALZHEIMER’S DISEASE USING EVENT-RELATED POTENTIALS

B.L. Brown, S.B. Hendrix, M. Cecchi, J.M. Scott, J.W. Silcox, K.D. Brighton, D. Hedges

J Prev Alz Dis 2016;3(2):101-104

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Event-related potentials (ERPs) are a physiological measure of cognitive function that have shown diagnostic and prognostic utility in Alzheimer’s disease (AD). In this study, we used a novel eigenvector-based technique to better understand brain electrophysiological differences between subjects with mild AD and healthy controls (HC). Using ERPs from 75 subjects with mild AD and 95 HC, we first calculated cognitive task eigenvectors within each subject from three conditions and then calculated second-order eigenvector components to compare the AD group to the HC group. A MANOVA of the three second-level components discriminated between AD and HC multivariately (Wilks’ lambda=.4297, p<0.0001, R2 = .5703), and also on each of the three components univariately (all 3 p-values<0.0001). The eigenvector-based technique used in this study accurately discriminated between the mild AD group and HC. As such, this analysis method adds to our understanding of the differences in ERP signal between AD and HC, and could provide a sensitive biomarker for diagnosis and monitoring of AD progression.

CITATION:
B.L. Brown ; S.B. Hendrix ; M. Cecchi ; J.M. Scott ; J.W. Silcox ; K.D. Brighton ; D. Hedges (2015): A Novel Eigenvector-Based Method to Detect Mild Alzheimer’s Disease Using Event-Related Potentials. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2015.79

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MODERATE, REGULAR ALCOHOL CONSUMPTION IS ASSOCIATED WITH HIGHER COGNITIVE FUNCTION IN OLDER COMMUNITY-DWELLING ADULTS

E.T. Reas, G.A. Laughlin, D. Kritz-Silverstein, E. Barrett-Connor, L.K. McEvoy

J Prev Alz Dis 2016;3(2):105-113

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Background: Evidence suggests that moderate alcohol consumption may protect against cognitive decline and dementia. However, uncertainty remains over the patterns of drinking that are most beneficial. Objective: To examine associations between amount and frequency of alcohol consumption with multiple domains of cognitive function in a well-characterized cohort of older community-dwelling adults in southern California. Design: Observational, cross-sectional cohort study. Setting: A research visit between 1988-1992 in Rancho Bernardo, California. Participants: 1624 participants of the Rancho Bernardo Study (mean age ± SD = 73.2 ± 9.3 years). Measurements: Participants completed a neuropsychological test battery, self-administered questionnaires on alcohol consumption and lifestyle, and a clinical health evaluation. We classified participants according to average amount of alcohol intake into never, former, moderate, heavy and excessive drinkers, and according to frequency of alcohol intake, into non-drinkers, rare, infrequent, frequent and daily drinkers. We examined the association between alcohol intake and cognitive function, controlling for age, sex, education, exercise, smoking, waist-hip ratio, hypertension and self-assessed health. Results: Amount and frequency of alcohol intake were significantly associated with cognitive function, even after controlling for potentially related health and lifestyle variables. Global and executive function showed positive linear associations with amount and frequency of alcohol intake, whereas visual memory showed an inverted U-shaped association with alcohol intake, with better performance for moderate and infrequent drinkers than for non-drinkers, excessive drinkers or daily drinkers. Conclusions: In several cognitive domains, moderate, regular alcohol intake was associated with better cognitive function relative to not drinking or drinking less frequently. This suggests that beneficial cognitive effects of alcohol intake may be achieved with low levels of drinking that are unlikely to be associated with adverse effects in an aging population.

CITATION:
E.T. Reas ; G.A. Laughlin ; D. Kritz-Silverstein ; E. Barrett-Connor ; L.K. McEvoy (2016): Moderate, Regular Alcohol Consumption is Associated with Higher Cognitive Function in Older Community-Dwelling Adults . The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2016.89

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Review Articles

RE-ENGINEERING ALZHEIMER CLINICAL TRIALS: GLOBAL ALZHEIMER’S PLATFORM NETWORK

J. Cummings, P. Aisen, R. Barton, J. Bork, R. Doody, J. Dwyer, J. C. Egan, H. Feldman, D. Lappin, L. Truyen, S. Salloway, R. Sperling, G. Vradenburg, for the GAP-NET Working Groups

J Prev Alz Dis 2016;3(2):114-120

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Alzheimer’s disease (AD) drug development is costly, time-consuming, and inefficient. Trial site functions, trial design, and patient recruitment for trials all require improvement. The Global Alzheimer Platform (GAP) was initiated in response to these challenges. Four GAP work streams evolved in the US to address different trial challenges: 1) registry-to-cohort web-based recruitment; 2) clinical trial site activation and site network construction (GAP-NET); 3) adaptive proof-of-concept clinical trial design; and 4) finance and fund raising. GAP-NET proposes to establish a standardized network of continuously funded trial sites that are highly qualified to perform trials (with established clinical, biomarker, imaging capability; certified raters; sophisticated management system. GAP-NET will conduct trials for academic and biopharma industry partners using standardized instrument versions and administration. Collaboration with the Innovative Medicines Initiative (IMI) European Prevention of Alzheimer’s Disease (EPAD) program, the Canadian Consortium on Neurodegeneration in Aging (CCNA) and other similar international initiatives will allow conduct of global trials. GAP-NET aims to increase trial efficiency and quality, decrease trial redundancy, accelerate cohort development and trial recruitment, and decrease trial costs. The value proposition for sites includes stable funding and uniform training and trial execution; the value to trial sponsors is decreased trial costs, reduced time to execute trials, and enhanced data quality. The value for patients and society is the more rapid availability of new treatments for AD.

CITATION:
J. Cummings ; P. Aisen ; R. Barton ; J. Bork ; R. Doody ; J. Dwyer ; J. C. Egan ; H. Feldman ; D. Lappin ; L. Truyen ; S. Salloway ; R. Sperling ; G. Vradenburg ; for the GAP-NET Working Groups (2016): Re-Engineering Alzheimer Clinical Trials: Global Alzheimer’s Platform Network. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2016.93

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