01/2014 journal articles
Editorials
EDITORIAL: JOURNAL OF PREVENTION OF ALZHEIMER’S DISEASE (JPAD): BUILDING A “FLEET” AGAINST ALZHEIMER’S DISEASE
B. Vellas, J. Touchon, P. Aisen, M.C. Carrillo
J Prev Alz Dis 2014;1(1):2-3
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B. Vellas ; J. Touchon ; P. Aisen ; M.C. Carrillo (2014): EDITORIAL: JOURNAL OF PREVENTION OF ALZHEIMER’S DISEASE (JPAD): BUILDING A “FLEET” AGAINST ALZHEIMER’S DISEASE. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2014.22
EDITORIAL : MULTI-DOMAIN PREVENTION FOR A MULTI-FACTORIAL DISEASE
E. Richard, A.S. Khachaturiani
J Prev Alz Dis 2014;1(1):4-5
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E. Richard ; A.S. Khachaturiani (2014): EDITORIAL : MULTI-DOMAIN PREVENTION FOR A MULTI-FACTORIAL DISEASE. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2014.23
Comments
COMMENT: IS ALZHEIMER’S DISEASE DRUG DEVELOPMENT BROKEN? WHAT MUST BE IMPROVED?
R.S. Doody
J Prev Alz Dis 2014;1(1):6-7
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R.S. Doody (2014): COMMENT: IS ALZHEIMER’S DISEASE DRUG DEVELOPMENT BROKEN? WHAT MUST BE IMPROVED?. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2014.24
COMMENT: IS ALZHEIMER’S DISEASE DRUG DEVELOPMENT BROKEN? WHAT MUST BE IMPROVED
E. Siemers
J Prev Alz Dis 2014;1(1):8-10
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E. Siemers (2014): COMMENT: IS ALZHEIMER’S DISEASE DRUG DEVELOPMENT BROKEN? WHAT MUST BE IMPROVED. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2014.15
COMMENT: HIGH ALZHEIMER’S DISEASE STUDY COMPLEXITY - LOW SUCCESS RATE
P. Schüler
J Prev Alz Dis 2014;1(1):11-12
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P. Schüler (2014): COMMENT: HIGH ALZHEIMER’S DISEASE STUDY COMPLEXITY - LOW SUCCESS RATE. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2014.16
Original Research
MAPT STUDY: A MULTIDOMAIN APPROACH FOR PREVENTING ALZHEIMER’S DISEASE: DESIGN AND BASELINE DATA
B. Vellas, I. Carrie, S. Gillette-Guyonnet, J. Touchon, T. Dantoine, J.F. Dartigues, M.N. Cuffi, S. Bordes, Y. Gasnier, P. Robert, L. Bories, O. Rouaud, F. Desclaux, K. Sudres, M. Bonnefoy, A. Pesce, C. Dufouil, S. Lehericy, M. Chupin, J.F. Mangin, P. Payoux, D. Adel, P. Legrand, D. Catheline, C. Kanony, M. Zaim, L. Molinier, N. Costa, J. Delrieu, T. Voisin, C. Faisant, F. Lala, F. Nourhashemi, Y. Rolland, G. Abellan Van Kan, C. Dupuy, C. Cantet, P. Cestac, S. Belleville, S. Willis, M. Cesari, M.W. Weiner, M.E. Soto, P.J. Ousset, S. Andrieu
J Prev Alz Dis 2014;1(1):13-22
Show summaryHide summaryObjective: The Multidomain Alzheimer Preventive Trial (MAPT study) was designed to assess the efficacy of isolated supplementation with omega-3 fatty acid, an isolated multidomain intervention (consisting of nutritional counseling, physical exercise, cognitive stimulation) or a combination of the two interventions on the change of cognitive functions in frail subjects aged 70 years and older for a period of 3 years. Ancillary neuroimaging studies were additionally implemented to evaluate the impact of interventions on cerebral metabolism (FDG PET scans) and atrophy rate (MRIs), as well as brain amyloïd deposit (AV45 PET scans).
Design, patients: 1680 subjects (mean age: 75.3 years; female: 64.8 %), enrolled by 13 memory clinics, were randomized into one of the following four groups: omega-3 supplementation alone, multidomain intervention alone, omega-3 plus multidomain intervention, or placebo. Participants underwent cognitive, functional and biological assessments at M6, M12, M24 and M36 visits. The primary endpoint is a change of memory function at 3 years, as assessed by the Free and Cued Selective Reminding test. All participants will be followed for 2 additional years after the 3-years intervention (MAPT PLUS extension study).
Interventions: 1/ Omega-3 supplementation: two soft capsules daily as a single dose, containing a total of 400 mg docosahexaenoic acid (DHA), i.e., 800 mg docosahexaenoic acid per day, for 3 years. 2/ Multidomain intervention: collective training sessions conducted in small groups (6–8 participants) in twelve 120-minute sessions over the first 2 months (two sessions a week for the first month, and one session a week the second month) then a 60-minute session per month in the following three areas: nutrition, physical activity, and cognition until the end of the 3 years. In addition to the collective sessions, individualized preventive outpatient visits exploring possible risk factors for cognitive decline are performed at baseline, M12 and M24.
Baseline population: For cognition, the mean MMSE at baseline was 28.1 (± 1.6). About 58% and 42% of participants had a CDR score equal to 0 and 0.5, respectively. Regarding mobility status, 200 (11.9%) had a 4-m gait speed lower or equal to 0.8 m/s. According to the Fried criteria, 673 (42.1%) participants were considered pre frail, and 51 (3.2%) frail. The red blood cell DHA content was 26.1 ± 8.1 µg/g. Five hundred and three participants underwent baseline MRI. AV45 PET scans were performed in 271 individuals and preliminary results showed that 38.0% had a cortical SUVR > 1.17, which gave an indication of significant brain amyloïd deposit.
Discussion: The MAPT trial is presently the first largest and longest multidomain preventive trial relevant to cognitive decline in older adults with subjective memory complaints. The multidomain intervention designed for the MAPT trial is likely to be easily implemented within the general population.
CITATION:
B. Vellas ; I. Carrie ; S. Gillette-Guyonnet ; J. Touchon ; T. Dantoine ; J.F. Dartigues ; M.N. Cuffi ; S. Bordes ; Y. Gasnier ; P. Robert ; L. Bories ; O. Rouaud ; F. Desclaux ; K. Sudres ; M. Bonnefoy ; A. Pesce ; C. Dufouil ; S. Lehericy ; M. Chupin ; J.F. Mangin ; P. Payoux ; D. Adel ; P. Legrand ; D. Catheline ; C. Kanony ; M. Zaim ; L. Molinier ; N. Costa ; J. Delrieu ; T. Voisin ; C. Faisant ; F. Lala ; F. Nourhashemi ; Y. Rolland ; G. Abellan Van Kan ; C. Dupuy ; C. Cantet ; P. Cestac ; S. Belleville ; S. Willis ; M. Cesari ; M.W. Weiner ; M.E. Soto ; P.J. Ousset ; S. Andrieu (2014): MAPT STUDY: A MULTIDOMAIN APPROACH FOR PREVENTING ALZHEIMER’S DISEASE: DESIGN AND BASELINE DATA. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2014.34
MEDITERRANEAN DIET AND MAGNETIC RESONANCE IMAGING-ASSESSED BRAIN ATROPHY IN COGNITIVELY NORMAL INDIVIDUALS AT RISK FOR ALZHEIMER’S DISEASE
L. Mosconi, J. Murray, W.H. Tsui, Y. Li, M. Davies, S. Williams, E. Pirraglia, N. Spector, R.S. Osorio, L. Glodzik, P. McHugh, M.J. de Leon
J Prev Alz Dis 2014;1(1):23-32
Show summaryHide summaryOBJECTIVES: Epidemiological evidence linking diet, one of the most important modifiable environmental factors, and risk of Alzheimer’s disease (AD) is rapidly increasing. Several studies have shown that higher adherence to a Mediterranean diet (MeDi) is associated with reduced risk of AD. This study examines the associations between high vs. lower adherence to a MeDi and structural MRI-based brain atrophy in key regions for AD in cognitively normal (NL) individuals with and without risk factors for AD.
DESIGN: Cross-sectional study. SETTING: Manhattan (broader area).
PARTICIPANTS: Fifty-two NL individuals (age 54+12 y, 70% women) with complete dietary information and cross-sectional, 3D T1-weighted MRI scans were examined.
MEASUREMENTS: Subjects were dichotomized into those showing higher vs. lower adherences to the MeDi using published protocols. Estimates of cortical thickness for entorhinal cortex (EC), inferior parietal lobe, middle temporal gyrus, orbitofrontal cortex (OFC) and posterior cingulate cortex (PCC) were obtained by use of automated segmentation tools (FreeSurfer). Multivariate general linear models and linear regressions assessed the associations of MeDi with MRI measures.
RESULTS: Of the 52 participants, 20 (39%) showed higher MeDi adherence (MeDi+) and 32 (61%) showed lower adherence (MeDi-). Groups were comparable for clinical, neuropsychological measures, presence of a family history of AD (FH), and frequency of Apolipoprotein E (APOE) ε4 genotype. With and without controlling for age and total intracranial volume, MeDi+ subjects showed greater thickness of AD-vulnerable ROIs as compared to MeDi- subjects (Wilk’s Lambda p=0.026). Group differences were most pronounced in OFC (p=0.001), EC (p=0.03) and PCC (p=0.04) of the left hemisphere. Adjusting for gender, education, FH, APOE status, BMI, insulin resistance scores and presence of hypertension did not attenuate the relationship.
CONCLUSION: NL individuals showing lower adherence to the MeDi had cortical thinning in the same brain regions as clinical AD patients compared to those showing higher adherence. These data indicate that the MeDi may have a protective effect against tissue loss, and suggest that dietary interventions may play a role in the prevention of AD.
CITATION:
L. Mosconi ; J. Murray ; W.H. Tsui ; Y. Li ; M. Davies ; S. Williams ; E. Pirraglia ; N. Spector ; R.S. Osorio ; L. Glodzik ; P. McHugh ; M.J. de Leon (2014): MEDITERRANEAN DIET AND MAGNETIC RESONANCE IMAGING-ASSESSED BRAIN ATROPHY IN COGNITIVELY NORMAL INDIVIDUALS AT RISK FOR ALZHEIMER’S DISEASE. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2014.17
THE TIMECOURSE OF GLOBAL COGNITIVE GAINS FROM SUPERVISED COMPUTER-ASSISTED COGNITIVE TRAINING: A RANDOMISED, ACTIVE-CONTROLLED TRIAL IN ELDERLY WITH MULTIPLE DEMENTIA RISK FACTORS
A. Lampit, H. Hallock, R. Moss, S. Kwok, M. Rosser, M. Lukjanenko, A. Kohn, S. Naismith, H. Brodaty, M. Valenzuela
J Prev Alz Dis 2014;1(1):33-39
Show summaryHide summaryBackground: Home-based computerised cognitive training (CCT) is ineffective at enhancing global cognition, a key marker of cognitive ageing.
Objectives: To test the effectiveness of supervised, group-based, multidomain CCT on global cognition in older adults and to characterise the dose-response relationship during and after training.
Design: A randomised, double-blind, longitudinal, active-controlled trial.
Setting: Community-based training centre in Sydney, Australia
Participants: Eighty nondemented community-dwelling older adults (mean age = 72.1, 68.8% females) with multiple dementia risk factors but no major neuropsychiatric or sensory disorder. Of the 80 participants admitted to the study, 65 completed post-training assessment and 55 were followed up one year after training cessation.
Interventions: Thirty-six group-based sessions over three months of either CCT targeting memory, speed, attention, language and reasoning tasks, or active control training comprising audiovisual educational exercises.
Measurements: Primary outcome was change from baseline in global cognition as defined by a composite score of memory, speed and executive function. Secondary outcome was 15-month change in Bayer Activities of Daily Living from baseline to one year post-training.
Results: Intention-to-treat analyses revealed significant effects on global cognition in the cognitive training group compared to active control after three weeks of training (ES = 0.33, P=.039) that increased after 3 months of training (ES = 0.49, P=.003) and persisted three months after training cessation (ES = 0.30, P=0.023). Significant and durable improvements were also noted in memory and processing speed. Dose-response characteristics differed among cognitive domains. Training effects waned gradually but residual gains were noted twelve months post-training. No significant effects on activities of daily living were noted and there were no adverse effects.
Conclusions: In older adults with multiple dementia risk factors, group-based CCT is a safe and effective intervention for enhancing overall cognition, memory and processing speed. Dose-response relationships vary for each cognitive domain, vital information for clinical and community implementation and further trial design.
CITATION:
A. Lampit ; H. Hallock ; R. Moss ; S. Kwok ; M. Rosser ; M. Lukjanenko ; A. Kohn ; S. Naismith ; H. Brodaty ; M. Valenzuela (2014): THE TIMECOURSE OF GLOBAL COGNITIVE GAINS FROM SUPERVISED COMPUTER-ASSISTED COGNITIVE TRAINING: A RANDOMISED, ACTIVE-CONTROLLED TRIAL IN ELDERLY WITH MULTIPLE DEMENTIA RISK FACTORS. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2014.18
Review Articles
IS ALZHEIMER’S DISEASE DRUG DEVELOPMENT BROKEN? WHAT MUST BE IMPROVED
P.-J.Ousset, J. Cummings, J. Delrieu, V. Legrand, N. Prins, B. Winblad, J. Touchon, M.W. Weiner, B. Vellas
J Prev Alz Dis 2014;1(1):40-45
Show summaryHide summaryDuring the decade from 2002 to 2012, 99.6% of the 244 agents tested for efficacy in slowing the progression of Alzheimer’s’ disease (AD) failed to achieve their primary endpoints. At a CTAD symposium on November 14, 2013, in San Diego, USA, an international group of AD researchers met to discuss the evolution of trials over the past 10 years and proposed a number of changes intended to streamline and enhance the efficiency of clinical trials. Approximately 1,031 AD trials were conducted between 2000 and 2012. The number of patients per trial site tended to decrease over time necessitating a larger number of sites. The use of biomarkers for enrichment purposes, or as measures of target engagement or surrogate outcomes, results in higher screen failure and drop-out rates, adding to trial duration and/or costs. Present disease modifying AD trials ask for increasing logistical and technical requirements, necessitating the creation of highly specialized trial facilities and limiting the participation of smaller sites. Due to heavy administrative and regulatory task, only about 13% of the team's time is used for the essential recruitment. Proposals and perspectives: Strategies suggested to improve the efficiency of recruitment include establishing “ready to go cohorts” in advance of trials using biomarkers and clinical measures. Simplification and harmonization of administrative procedures, including harmonization of certification procedures, are urgently needed. Alternative approaches, such as using the Internet to screen volunteers for possible inclusion needs to be evaluated. The AD drug development enterprise from discovery through clinical trials requires re-examination and re-organization if new drugs are to be delivered to patients in a timely way.
CITATION:
P.-J.Ousset ; J. Cummings ; J. Delrieu ; V. Legrand ; N. Prins ; B. Winblad ; J. Touchon ; M.W. Weiner ; B. Vellas (2014): IS ALZHEIMER’S DISEASE DRUG DEVELOPMENT BROKEN? WHAT MUST BE IMPROVED. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2014.19
INTER-SPECIES GLIA DIFFERENCES: IMPLICATIONS FOR SUCCESSFUL TRANSLATION OF TRANSGENIC RODENT ALZHEIMER’S DISEASE MODEL TREATMENT USING BEXAROTENE
G. Bartzokis
J Prev Alz Dis 2014;1(1):46-50
Show summaryHide summaryDespite a multitude of efficacious treatments for the cognitive symptoms and pathology in transgenic mouse models of Alzheimer’s disease (AD), success in human trials has been elusive. Rodent-human brain dissimilarities may help explain failures of past human trials and improve outcomes of future ones. This review highlights the essential role of the human brain’s exceptional myelination in achieving and maintaining optimal brain functions, as well as underlying its vulnerability to age-related myelin breakdown and the degenerative brain diseases that process can trigger. This alternative myelin-centered perspective is used herein to help explain key disconnects in the existing treatment literature by focusing on recent reports on brain effects of bexarotene, the only marketed retinoid X receptor (RXR) agonist. The myelin perspective exposes significant yet underexplored opportunities for novel treatment and prevention interventions that have the potential to considerably reduce the tremendous burden of degenerative brain diseases.
CITATION:
G. Bartzokis (2014): INTER-SPECIES GLIA DIFFERENCES: IMPLICATIONS FOR SUCCESSFUL TRANSLATION OF TRANSGENIC RODENT ALZHEIMER’S DISEASE MODEL TREATMENT USING BEXAROTENE. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2014.20
PREVENTION: HOW THE PARADIGM IS SHIFTING
P. Whitehouse, D.R. George
J Prev Alz Dis 2014;1(1):51-55
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P. Whitehouse ; D.R. George (2014): PREVENTION: HOW THE PARADIGM IS SHIFTING. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2014.21