02/2014 journal articles
EDITORIAL : THE BRAINHEALTHREGISTRY.ORG: USING THE INTERNET FOR IDENTIFICATION, ASSESSMENT, SCREENING, RECRUITMENT, AND LONGITUDINAL MONITORING OF SUBJECTS FOR NEUROSCIENCE AND ALZHEIMER’S DISEASE STU
J Prev Alz Dis 2014;1(2):59-61Show summaryHide summary
M.W. Weiner (2014): EDITORIAL : THE BRAINHEALTHREGISTRY.ORG: USING THE INTERNET FOR IDENTIFICATION, ASSESSMENT, SCREENING, RECRUITMENT, AND LONGITUDINAL MONITORING OF SUBJECTS FOR NEUROSCIENCE AND ALZHEIMER’S DISEASE STU. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2014.9
EDITORIAL : DEMENTIA PREVENTION STRATEGIES – BEYOND THE RANDOMIZED CONTROLLED TRIAL?
E. Richard, C. Brayne
J Prev Alz Dis 2014;1(2):62-64Show summaryHide summary
E. Richard ; C. Brayne (2014): EDITORIAL : DEMENTIA PREVENTION STRATEGIES – BEYOND THE RANDOMIZED CONTROLLED TRIAL?. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2014.10
COMMENT : E.U./U.S. CTAD TASK FORCE ON ALZHEIMER\'S TRIAL POPULATIONS FOR STUDY
J Prev Alz Dis 2014;1(2):66-67Show summaryHide summary
J.M. Cedarbaum (2014): COMMENT : E.U./U.S. CTAD TASK FORCE ON ALZHEIMER'S TRIAL POPULATIONS FOR STUDY. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2014.11
COMMENT : A NEW ERA: DISEASE MODIFYING ALZHEIMER DISEASE PREVENTION TRIALS
R.J. Bateman, J.C. Morris
J Prev Alz Dis 2014;1(2):68Show summaryHide summary
R.J. Bateman ; J.C. Morris (2014): COMMENT : A NEW ERA: DISEASE MODIFYING ALZHEIMER DISEASE PREVENTION TRIALS . The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2014.12
COMMENT : ALZHEIMER’S DISEASE DRUG DEVELOPMENT: TRIAL-READY COHORTS SHOULD HELP
J Prev Alz Dis 2014;1(2):69-70Show summaryHide summary
M. Grundman (2014): COMMENT : ALZHEIMER’S DISEASE DRUG DEVELOPMENT: TRIAL-READY COHORTS SHOULD HELP. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2014.13
COMMENT : CLINICAL TRIALS FOR ALZHEIMER’S DISEASE TURNED A CORNER IN 2013’
J Prev Alz Dis 2014;1(2):71-73Show summaryHide summary
C.W. Ritchie (2014): COMMENT : CLINICAL TRIALS FOR ALZHEIMER’S DISEASE TURNED A CORNER IN 2013. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2014.14
ARIZONA ALZHEIMER’S REGISTRY: STRATEGY AND OUTCOMES OF A STATEWIDE RESEARCH RECRUITMENT REGISTRY
K.T. Saunders, J.B. Langbaum, C.J. Holt, W. Chen, N. High, C. Langlois, M. Sabbagh, P.N. Tariot
J Prev Alz Dis 2014;1(2):74-79Show summaryHide summary
Background:The Arizona Alzheimer’s Consortium (AAC) created the Arizona Alzheimer’s Registry, a screening and referral process for people interested in participating in Alzheimer’s disease related research. The goals of the Registry were to increase awareness of Alzheimer's disease research and accelerate enrollment into AAC research studies.
Methods: Participation was by open invitation to adults 18 and older. Those interested provided consent and completed a written questionnaire. A subset of Registrants underwent an initial telephone cognitive assessment. Referral to AAC sites was based on medical history, telephone cognitive assessment, and research interests.
Results: A total of 1257 people consented and 1182 underwent an initial cognitive screening. Earned media (38.7%) was the most effective recruitment strategy. Participants had a mean age of 68.1 (SD 10.6), 97% were Caucasian, had 15.2 (SD 2.7) mean years of education, and 60% were female. 30% reported a family history of dementia and 70% normal cognition. Inter-rater agreement between self-reported memory status and the initial telephone cognitive assessment had a kappa of 0.31-0.43. 301 were referred to AAC sites.
Conclusion: IThe Registry created an infrastructure and process to screen and refer a high volume of eager Registrants. These methods were found to be effective at prescreening individuals for studies, which facilitated AAC research recruitment. The established infrastructure and experiences gained from the Registry have served as the prototype for the web-based Alzheimer’s Prevention Registry, a national registry focusing on Alzheimer's disease prevention research.
K.T. Saunders; J.B. Langbaum; C.J. Holt; W. Chen; N. High; C. Langlois; M. Sabbagh; P.N. Tariot(2014): ARIZONA ALZHEIMER’S REGISTRY: STRATEGY AND OUTCOMES OF A STATEWIDE RESEARCH RECRUITMENT REGISTRY.The Journal of Prevention of Alzheimer’s Disease (JPAD).http://dx.doi.org/10.14283/jpad.2014.1
CURCUMIN MICELLES IMPROVE MITOCHONDRIAL FUNCTION IN A MOUSE MODEL OF ALZHEIMER’S DISEASE
S. Hagl, M. Heinrich, A. Kocher, C. Schiborr, J. Frank, G.P. Eckert
J Prev Alz Dis 2014;1(2):80-83Show summaryHide summary
Preventive strategies for late-onset Alzheimer’s disease (AD) should start early at a prodromal stage. Mitochondrial dysfunction has been found to play an important role in the initiation of both aging and the pathogenesis of Alzheimer’s disease. Curcumin, a widely used spice and food-coloring agent, is a polyphenol derived from the rhizome of Curcuma longa. It is known to have anti-oxidant, anti-inflammatory, and anti-protein-aggregate activities which are usually considered beneficial for mitochondrial function. We assessed brain mitochondrial function and concentrations of soluble Aβ40 in a mouse model of AD (Thy1-APP751SL transgenic mice) after 3-week administration of curcumin micelles. Curcumin micelles are a newly developed formulation that account for increased curcumin bioavailability. Curcumin treatment had positive effects on mitochondrial membrane potential and respiratory control ratio. Additionally, it decreased levels of soluble Aβ40 in brains of Thy1-APPSL transgenic mice. Hence, curcumin micelles are a promising neutraceutical for the prevention of AD.
S. Hagl ; M. Heinrich ; A. Kocher ; C. Schiborr ; J. Frank ; G.P. Eckert(2014): CURCUMIN MICELLES IMPROVE MITOCHONDRIAL FUNCTION IN A MOUSE MODEL OF ALZHEIMER’S DISEASE.The Journal of Prevention of Alzheimer’s Disease (JPAD).http://dx.doi.org/10.14283/jpad.2014.2
NEUROPROTECTIVE EFFECTS OF A VARIETY OF POMEGRANATE JUICE EXTRACTS (PJE) AGAINST THE EXCITOTOXIN QUINOLINIC ACID IN HUMAN PRIMARY NEURONS
N. Braidy, S. Subash, M.M. Essa, R. Vaishnav, S. Al-Adawi, A. Al-Asmi, H. Al-Senawi, A.A.R. Alobaidy, R. Lakhtakia, G.J. Guillemin
J Prev Alz Dis 2014;1(2):84-90Show summaryHide summary
Background: Quinolinic acid (QUIN) excitotoxicity is mediated by elevated intracellular Ca2+ levels, and nitric oxide (NO•) mediated oxidative stress leading to DNA damage, and cell death due to energy restriction.
Methods: We evaluated the effect of a series of pomegranate juice extracts (PJE), Helow, Malasi, Qusum, and Hamedh, with antioxidant properties on QUIN induced excitotoxicity on primary cultures of human neurons.
Results: We showed that Helow and Malasi can attenuate QUIN-induced excitotoxicity to a greater extent than Qusum and Hamedh from Oman. Similarly, both Helow and Malasi were able to attenuate QUIN-induced Ca2+ influx and nNOS activity to a greater extent compared to Qusum, and Hamedh. All extracts reduced the oxidative effects of increased NO• production, and hence preventing NAD+ depletion and cell death.
Conclusion: In addition to the well-known antioxidant properties of these natural phytochemicals, the inhibitory effect of some of these compounds on specific excitotoxic processes such as calcium influx provides additional evidence for the beneficial health effects of PJE in excitable tissue, particularly within the CNS.
N. Braidy, ; S. Subash ; M.M. Essa ; R. Vaishnav ; S. Al-Adawi ; A. Al-Asmi ; H. Al-Senawi ; A.A.R. Alobaidy ; R. Lakhtakia ; G.J. Guillemin(2014): NEUROPROTECTIVE EFFECTS OF A VARIETY OF POMEGRANATE JUICE EXTRACTS (PJE) AGAINST THE EXCITOTOXIN QUINOLINIC ACID IN HUMAN PRIMARY NEURONS.The Journal of Prevention of Alzheimer’s Disease (JPAD).http://dx.doi.org/10.14283/jpad.2014.3
ALZHEIMER’S PREVENTION EDUCATION: IF WE BUILD IT, WILL THEY COME? www.AlzU.org
R.S. Isaacson, N. Haynes, A. Seifan, D. Larsen, S. Christiansen, J.C. Berger, J.E. Safdieh, A.M. Lunde, A. Luo, M. Kramps, M. McInnis, C.N. Ochner
J Prev Alz Dis 2014;1(2):91-98Show summaryHide summary
Background: Internet-based educational interventions may be useful for impacting knowledge and behavioral change. However, in AD prevention, little data exists about which educational tools work best in terms of learning and interest in participating in clinical trials.
Objectives: Primary: Assess effectiveness of interactive webinars vs. written blog-posts on AD prevention learning. Secondary: Evaluate the effect of AD prevention education on interest in participating in clinical trials; Assess usability of, and user perceptions about, an online AD education research platform; Classify target populations (demographics, learning needs, interests). Design: Observational Setting: Online Participants: Men/Women, aged 25+, recruited via facebook.com Intervention: Alzheimer’s Universe (www.AlzU.org) education research platform Measurements: Pre/post-test performance, self-reported Likert-scale ratings, completion rates
Results: Over two-weeks, 4268 visits were generated. 503 signed-up for a user account (11.8% join rate), 196 participated in the lessons (39.0%) and 100 completed all beta-testing steps (19.9%). Users randomized to webinar instruction about AD prevention and the stages of AD demonstrated significant increases (p=0.01) in pre vs. post-testing scores compared to blog-post intervention. Upon joining, 42% were interested in participating in a clinical trial in AD prevention. After completing all beta-test activities, interest increased to 86%. Users were primarily women and the largest category was children of AD patients. 66.3% joined to learn more about AD prevention, 65.3% to learn more about AD treatment.
Conclusions: Webinar-based education led to significant improvements in learning about AD prevention and the stages of AD. AlzU.org participation more than doubled interest in AD prevention clinical trial participation. Subjects were quickly and cost-effectively recruited, and highly satisfied with the AD education research platform. Based on these data, we will further refine AlzU.org prior to public launch and aim to study the effectiveness of 25 interactive webinar-based vs. blog-post style lessons on learning and patient outcomes, in a randomized, within-subjects design trial.
R.S. Isaacson ; N. Haynes ; A. Seifan ; D. Larsen ; S. Christiansen ; J.C. Berger ; J.E. Safdieh ; A.M. Lunde ; A. Luo ; M. Kramps ; M. McInnis ; C.N. Ochner(2014): ALZHEIMER’S PREVENTION EDUCATION: IF WE BUILD IT, WILL THEY COME? www.AlzU.org.The Journal of Prevention of Alzheimer’s Disease (JPAD).http://dx.doi.org/10.14283/jpad.2014.4
A NOVEL STUDY PARADIGM FOR LONG-TERM PREVENTION TRIALS IN ALZHEIMER DISEASE: THE PLACEBO GROUP SIMULATION APPROACH (PGSA). APPLICATION TO MCI DATA FROM THE NACC DATABASE
M. Berres, W.A. Kukull, A.R. Miserez, A.U. Monsch, S.E. Monsell, R. Spiegel, for the Alzheimer’s Disease Neuroimaging Initiative
J Prev Alz Dis 2014;1(2):99-109Show summaryHide summary
INTRODUCTION: The PGSA (Placebo Group Simulation Approach) aims at avoiding problems of sample representativeness and ethical issues typical of placebo-controlled secondary prevention trials with MCI patients. The PGSA uses mathematical modeling to forecast the distribution of quantified outcomes of MCI patient groups based on their own baseline data established at the outset of clinical trials. These forecasted distributions are then compared with the distribution of actual outcomes observed on candidate treatments, thus substituting for a concomitant placebo group. Here we investigate whether a PGSA algorithm that was developed from the MCI population of ADNI 1*, can reliably simulate the distribution of composite neuropsychological outcomes from a larger, independently selected MCI subject sample.
Methods: Data available from the National Alzheimer's Coordinating Center (NACC) were used. We included 1523 patients with single or multiple domain amnestic mild cognitive impairment (aMCI) and at least two follow-ups after baseline. In order to strengthen the analysis and to verify whether there was a drift over time in the neuropsychological outcomes, the NACC subject sample was split into 3 subsamples of similar size. The previously described PGSA algorithm for the trajectory of a composite neuropsychological test battery (NTB) score was adapted to the test battery used in NACC. Nine demographic, clinical, biological and neuropsychological candidate predictors were included in a mixed model; this model and its error terms were used to simulate trajectories of the adapted NTB.
Results The distributions of empirically observed and simulated data after 1, 2 and 3 years were very similar, with some over-estimation of decline in all 3 subgroups. The by far most important predictor of the NTB trajectories is the baseline NTB score. Other significant predictors are the MMSE baseline score and the interactions of time with ApoE4 and FAQ (functional abilities). These are essentially the same predictors as determined for the original NTB score.
Conclusion: An algorithm comprising a small number of baseline variables, notably cognitive performance at baseline, forecasts the group trajectory of cognitive decline in subsequent years with high accuracy. The current analysis of 3 independent subgroups of aMCI patients from the NACC database supports the validity of the PGSA longitudinal algorithm for a NTB. Use of the PGSA in long-term secondary AD prevention trials deserves consideration.
M. Berres, ; W.A. Kukull, ; A.R. Miserez, ; A.U. Monsch, ; S.E. Monsell, ; R. Spiegel (for the Alzheimer’s Disease Neuroimaging Initiative)(2014): A NOVEL STUDY PARADIGM FOR LONG-TERM PREVENTION TRIALS IN ALZHEIMER DISEASE: THE PLACEBO GROUP SIMULATION APPROACH (PGSA). APPLICATION TO MCI DATA FROM THE NACC DATABASE.The Journal of Prevention of Alzheimer’s Disease (JPAD).http://dx.doi.org/10.14283/jpad.2014.5
E.U./U.S. CTAD TASK FORCE ON ALZHEIMER\'S TRIAL POPULATIONS
B. Vellas, C. Sampaio, R. Bateman, A. Boxer, M.C. Carrillo, J. Cummings, B. Dubois, H. Hampel, R. Katz, Z. Khachaturian, S. Gauthier, K. Johnson, J. Karlawish, M. Mintun, R. Petersen, M. Rafii, P. Robert, L.S. Schneider, E. Siemers, R. Sperling, P. Tariot, J. Touchon, M. Weiner, S. Andrieu, P. Aisen, Task Force Members
J Prev Alz Dis 2014;1(2):110-116Show summaryHide summary
Successful therapeutic trials require well-targeted populations to demonstrate the effectiveness of a drug candidate. Most trials in the field of Alzheimer’s disease (AD) have been conducted in patients with mild to moderate dementia. However, the advent of amyloid PET imaging has demonstrated that a significant proportion of individuals enrolled in such studies do not have evidence of brain amyloidosis and may in fact not have Alzheimer’s disease. Further, dementia represents an advanced stage of neurodegeneration, perhaps too late for significant benefits of disease-modifying interventions. The successful development of effective disease-slowing therapies requires a study population selected in accordance with the mechanism of the specific intervention. An international task force of investigators from academia, industry, non-profit foundations, and regulatory agencies met in San Diego, California, USA, on November 13, 2013, to address issues related to screening and identification of clinical trial participants, and the ramifications of decisions made in this regard for drug development in AD and other dementias.
B. Vellas ; C. Sampaio ; R. Bateman ; A. Boxer ; M.C. Carrillo ; J. Cummings ; B. Dubois ; H. Hampel ; R. Katz ; Z. Khachaturian ; S. Gauthier ; K. Johnson ; J. Karlawish ; M. Mintun ; R. Petersen ; M. Rafii ; P. Robert ; L.S. Schneider ; E. Siemers ; R. Sperling ; P. Tariot ; J. Touchon ; M. Weiner ; S. Andrieu ; P. Aisen ; Task Force Members(2014): E.U./U.S. CTAD TASK FORCE ON ALZHEIMER'S TRIAL POPULATIONS.The Journal of Prevention of Alzheimer’s Disease (JPAD).http://dx.doi.org/10.14283/jpad.2014.6
DEMENTIA PREVENTION: OPTIMIZING THE USE OF OBSERVATIONAL DATA FOR PERSONAL, CLINICAL, AND PUBLIC HEALTH DECISION-MAKING
P.A. Dacks, S. Andrieu, D. Blacker, A.J. Carman, A.M. Green, F. Grodstein, V.W. Henderson , B.D. James, R.F. Lane, J. Lau, P.-J. Lin, B.C. Reeves, R.C. Shah, B. Vellas, K. Yaffe, K. Yurko-Mauro, D.W. Shineman, H.M. Fillit, D.A. Bennett
J Prev Alz Dis 2014;1(2):117-123Show summaryHide summary
Worldwide, over 35 million people suffer from Alzheimer’s disease and related dementias. This number is expected to triple over the next 40 years. How can we improve the evidence supporting strategies to reduce the rate of dementia in future generations? The risk of dementia is likely influenced by modifiable factors such as exercise, cognitive activity, and the clinical management of diabetes and hypertension. However, the quality of evidence is limited and it remains unclear whether specific interventions to reduce these modifiable risk factors can, in turn, reduce the risk of dementia. Although randomized controlled trials are the gold-standard for causality, the majority of evidence for long-term dementia prevention derives from, and will likely continue to derive from, observational studies. Observational research has some unavoidable limitations, but its utility for dementia prevention might be improved by, for example, better distinction between confirmatory and exploratory research, higher reporting standards, investment in effectiveness research enabled by increased data-pooling, and standardized exposure and outcome measures. Informed decision-making by the general public on low-risk health choices that could have broad potential benefits could be enabled by internet-based tools and decision-aids to communicate the evidence, its quality, and the estimated magnitude of effect.
P.A. Dacks ; S. Andrieu ; D. Blacker ; A.J. Carman ; A.M. Green ; F. Grodstein ; V.W. Henderson ; B.D. James ; R.F. Lane ; J. Lau ; P.-J. Lin ; B.C. Reeves ; R.C. Shah ; B. Vellas ; K. Yaffe ; K. Yurko-Mauro ; D.W. Shineman ; D.A. Bennett ; H.M. Fillit (2014): Dementia Prevention: Optimizing the Use of Observational Data for Personal, Clinical, and Public Health Decision-Making. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2014.35
HIPPOCAMPAL ASTROCYTES AND ALZHEIMER’S DISEASE
J Prev Alz Dis 2014;1(2):124-128Show summaryHide summary
Considerable progress has been made in elucidating the molecules involved in the pathology of Alzheimer's disease (AD). However, it is still uncertain why the hippocampus is the focus of this pathology, since these molecules (amyloid precursor protein, beta secretase, apolipoprotein E) are not more abundant within the hippocampus than in other, undamaged brain areas. Several unique features of the hippocampus may make it more vulnerable to this age-related pathology. These include 1) a specialized metabolism that enhances damaging effects of oxidative stress, 2) a capacity for neurogenesis, and 3) specializations in mitochondrial and metal homeostasis. The thesis of this paper is that an unusual subset of hippocampal astrocytes makes a fundamental contribution to all three of these hippocampal features and allows different and seemingly conflicting risk factors for AD to be viewed in a unified manner. These astrocytes participate in neurogenesis, produce fatty acid binding protein 7, unlike most astrocytes in the mature brain, and undergo an age-related mitochondrial degeneration. Degeneration of astrocyte mitochondria appears due to oxidative stress arising from fatty acid metabolism. This mitochondrial degeneration produces intracellular deposits of iron and copper, metals that have been shown to harmfully interact with cleavage products of amyloid precursor protein. Pharmacological and dietary manipulations that protect these astrocytes from age-related oxidative stress may prove to be useful strategies in combatting the progression of AD.
J. Young (2014): HIPPOCAMPAL ASTROCYTES AND ALZHEIMER’S DISEASE. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2014.8