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Aeolian Research     Hybrid Journal   (Followers: 5, SJR: 0.973, h-index: 22)
Aerospace Science and Technology     Hybrid Journal   (Followers: 325, SJR: 0.816, h-index: 49)
AEU - Intl. J. of Electronics and Communications     Hybrid Journal   (Followers: 8, SJR: 0.318, h-index: 36)
African J. of Emergency Medicine     Open Access   (Followers: 5, SJR: 0.344, h-index: 6)
Ageing Research Reviews     Hybrid Journal   (Followers: 8, SJR: 3.289, h-index: 78)
Aggression and Violent Behavior     Hybrid Journal   (Followers: 405, SJR: 1.385, h-index: 72)
Agri Gene     Hybrid Journal  
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Agriculture and Natural Resources     Open Access   (Followers: 1)
Agriculture, Ecosystems & Environment     Hybrid Journal   (Followers: 54, SJR: 1.879, h-index: 120)
Ain Shams Engineering J.     Open Access   (Followers: 5, SJR: 0.434, h-index: 14)
Air Medical J.     Hybrid Journal   (Followers: 5, SJR: 0.234, h-index: 18)
AKCE Intl. J. of Graphs and Combinatorics     Open Access   (SJR: 0.285, h-index: 3)
Alcohol     Hybrid Journal   (Followers: 10, SJR: 0.922, h-index: 66)
Alcoholism and Drug Addiction     Open Access   (Followers: 8)
Alergologia Polska : Polish J. of Allergology     Full-text available via subscription   (Followers: 1)
Alexandria Engineering J.     Open Access   (Followers: 1, SJR: 0.436, h-index: 12)
Alexandria J. of Medicine     Open Access  
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ALTER - European J. of Disability Research / Revue Européenne de Recherche sur le Handicap     Full-text available via subscription   (Followers: 8, SJR: 0.158, h-index: 9)
Alzheimer's & Dementia     Hybrid Journal   (Followers: 48, SJR: 4.289, h-index: 64)
Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring     Open Access   (Followers: 6)
Alzheimer's & Dementia: Translational Research & Clinical Interventions     Open Access   (Followers: 5)
American Heart J.     Hybrid Journal   (Followers: 49, SJR: 3.157, h-index: 153)
American J. of Cardiology     Hybrid Journal   (Followers: 47, SJR: 2.063, h-index: 186)
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American J. of Geriatric Pharmacotherapy     Full-text available via subscription   (Followers: 8, SJR: 1.091, h-index: 45)
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American J. of Human Genetics     Hybrid Journal   (Followers: 31, SJR: 8.769, h-index: 256)
American J. of Infection Control     Hybrid Journal   (Followers: 25, SJR: 1.259, h-index: 81)
American J. of Kidney Diseases     Hybrid Journal   (Followers: 32, SJR: 2.313, h-index: 172)
American J. of Medicine     Hybrid Journal   (Followers: 45, SJR: 2.023, h-index: 189)
American J. of Medicine Supplements     Full-text available via subscription   (Followers: 3)
American J. of Obstetrics and Gynecology     Hybrid Journal   (Followers: 237, SJR: 2.255, h-index: 171)
American J. of Ophthalmology     Hybrid Journal   (Followers: 57, SJR: 2.803, h-index: 148)
American J. of Ophthalmology Case Reports     Open Access   (Followers: 5)
American J. of Orthodontics and Dentofacial Orthopedics     Full-text available via subscription   (Followers: 6, SJR: 1.249, h-index: 88)
American J. of Otolaryngology     Hybrid Journal   (Followers: 25, SJR: 0.59, h-index: 45)
American J. of Pathology     Hybrid Journal   (Followers: 26, SJR: 2.653, h-index: 228)
American J. of Preventive Medicine     Hybrid Journal   (Followers: 22, SJR: 2.764, h-index: 154)
American J. of Surgery     Hybrid Journal   (Followers: 34, SJR: 1.286, h-index: 125)
American J. of the Medical Sciences     Hybrid Journal   (Followers: 12, SJR: 0.653, h-index: 70)
Ampersand : An Intl. J. of General and Applied Linguistics     Open Access   (Followers: 5)
Anaerobe     Hybrid Journal   (Followers: 4, SJR: 1.066, h-index: 51)
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Analytic Methods in Accident Research     Hybrid Journal   (Followers: 4, SJR: 2.577, h-index: 7)
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Angiologia e Cirurgia Vascular     Open Access  
Animal Behaviour     Hybrid Journal   (Followers: 160, SJR: 1.907, h-index: 126)
Animal Feed Science and Technology     Hybrid Journal   (Followers: 5, SJR: 1.151, h-index: 83)
Animal Reproduction Science     Hybrid Journal   (Followers: 5, SJR: 0.711, h-index: 78)
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Journal Cover Alzheimer's & Dementia: Translational Research & Clinical Interventions
  [5 followers]  Follow
  This is an Open Access Journal Open Access journal
   ISSN (Online) 2352-8737
   Published by Elsevier Homepage  [3043 journals]
  • Alzheimer's disease drug development pipeline: 2017

    • Authors: Jeffrey Cummings; Garam Lee; Travis Mortsdorf; Aaron Ritter; Kate Zhong
      Pages: 367 - 384
      Abstract: Publication date: September 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions, Volume 3, Issue 3
      Author(s): Jeffrey Cummings, Garam Lee, Travis Mortsdorf, Aaron Ritter, Kate Zhong
      Introduction There is an urgent need to develop new treatments for Alzheimer's disease (AD) and to understand the drug development process for new AD therapies. Methods We assessed the agents in the AD pipeline as documented in for phase I, phase II, and phase III, accessed 1/5/2017. Results There are 105 agents in the AD treatment development pipeline, of which 25 agents are in 29 trials in phase I, 52 agents are in 68 trials in phase II, and 28 agents are in 42 trials in phase III. Seventy percent of drugs in the AD pipeline are disease-modifying therapies (DMTs). Fourteen percent are symptomatic cognitive enhancers, and 13% are symptomatic agents addressing neuropsychiatric and behavioral changes (2% have undisclosed mechanisms). Most trials are sponsored by the biopharmaceutical industry. Trials include patients with preclinical AD (cognitively normal with biomarker evidence of AD), prodromal AD (mild cognitive symptoms and biomarker evidence of AD), and AD dementia. Biomarkers are included in many drug development programs particularly those for DMTs. Thirteen of 46 phase II DMT trials have amyloid imaging as an entry criterion, and 10 of 28 phase III trials incorporate amyloid imaging for diagnosis and entry. A large number of participants are needed for AD clinical trials; in total, 54,073 participants are required for trials spanning preclinical AD to AD dementia. When compared with the 2016 pipeline, there are eight new agents in phase I, 16 in phase II, and five in phase III. Discussion The AD drug development pipeline has 105 agents divided among phase I, phase II, and phase III. The trials include a wide range of clinical trial populations, many mechanisms of action, and require a substantial number of clinical trial participants. Biomarkers are increasingly used in patient identification and as outcome measures, particularly in trials of DMTs.

      PubDate: 2017-09-30T08:25:01Z
      DOI: 10.1016/j.trci.2017.05.002
  • Neuropsychiatric signs and symptoms of Alzheimer's disease:
           New treatment paradigms

    • Authors: Krista L. Lanctôt; Joan Amatniek; Sonia Ancoli-Israel; Steven E. Arnold; Clive Ballard; Jiska Cohen-Mansfield; Zahinoor Ismail; Constantine Lyketsos; David S. Miller; Erik Musiek; Ricardo S. Osorio; Paul B. Rosenberg; Andrew Satlin; David Steffens; Pierre Tariot; Lisa J. Bain; Maria C. Carrillo; James A. Hendrix; Heidi Jurgens; Brendon Boot
      Pages: 440 - 449
      Abstract: Publication date: September 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions, Volume 3, Issue 3
      Author(s): Krista L. Lanctôt, Joan Amatniek, Sonia Ancoli-Israel, Steven E. Arnold, Clive Ballard, Jiska Cohen-Mansfield, Zahinoor Ismail, Constantine Lyketsos, David S. Miller, Erik Musiek, Ricardo S. Osorio, Paul B. Rosenberg, Andrew Satlin, David Steffens, Pierre Tariot, Lisa J. Bain, Maria C. Carrillo, James A. Hendrix, Heidi Jurgens, Brendon Boot
      Neuropsychiatric symptoms (NPSs) are hallmarks of Alzheimer's disease (AD), causing substantial distress for both people with dementia and their caregivers, and contributing to early institutionalization. They are among the earliest signs and symptoms of neurocognitive disorders and incipient cognitive decline, yet are under-recognized and often challenging to treat. With this in mind, the Alzheimer's Association convened a Research Roundtable in May 2016, bringing together experts from academia, industry, and regulatory agencies to discuss the latest understanding of NPSs and review the development of therapeutics and biomarkers of NPSs in AD. This review will explore the neurobiology of NPSs in AD and specific symptoms common in AD such as psychosis, agitation, apathy, depression, and sleep disturbances. In addition, clinical trial designs for NPSs in AD and regulatory considerations will be discussed.

      PubDate: 2017-09-30T08:25:01Z
      DOI: 10.1016/j.trci.2017.07.001
  • Guide to enable health charities to increase recruitment to clinical
           trials on dementia

    • Authors: Larry W. Chambers; Megan Harris; Elizabeth Lusk; Debbie Benczkowski
      Abstract: Publication date: Available online 27 September 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Larry W. Chambers, Megan Harris, Elizabeth Lusk, Debbie Benczkowski
      Introduction The Alzheimer Society embarked on a project to improve ways that the 60 provincial and local Societies in Canada can work with local researchers to support recruitment of volunteers to clinical trials and studies. A Guide to assist these offices was produced to design ethical recruitment of research volunteers within their client populations. Methods Consultations with individuals from provincial and local Societies, as well as researchers and leaders from health-related organizations, were conducted to identify in what ways these organizations are involved in study volunteer recruitment, what is and is not working, and what would be helpful to support future efforts. The Guide prototype used scenarios to illustrate study volunteer recruitment practices as they have been or could be applied in Societies. An implementable version of the Guide was produced with input from multiple internal and external reviewers including subject-matter experts and target users from Societies. Results Society staff reported that benefits of using the Guide were that it served as a catalyst for conversation and reflection and identified the need for a policy. Also, it enabled Society readiness to respond to requests by persons with dementia and their caregivers wishing to participate in research. A majority (94%) of participating Society staff across Canada agreed that they would increase their capacity to support research recruitment. Discussion Charitable organizations that raise funds for research have a role in promoting the recruitment of persons with dementia and their caregivers into clinical trials and studies. The Guide was produced to facilitate organizational change to both create a positive culture regarding research as well as practical solutions that can help organizations achieve this goal.

      PubDate: 2017-09-30T08:25:01Z
      DOI: 10.1016/j.trci.2017.08.008
  • Proton pump inhibitors and the risk of severe cognitive impairment:
           The role of posttraumatic stress disorder

    • Authors: Sean A.P. Clouston; Oren Shapira; Roman Kotov; Lan Lei; Monika Waszczuk; Evelyn J. Bromet; Benjamin J. Luft
      Abstract: Publication date: Available online 23 September 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Sean A.P. Clouston, Oren Shapira, Roman Kotov, Lan Lei, Monika Waszczuk, Evelyn J. Bromet, Benjamin J. Luft
      Introduction Proton pump inhibitors (PPIs), a common treatment for gastroesophageal reflux disease, were recently associated with increased risk of dementia. However, severe or chronic stress including, for example, posttraumatic stress disorder (PTSD) was not accounted for. This study examined whether PPI use was associated with severe cognitive impairment (SCI) and whether PTSD explained this association in a cohort of World Trade Center (WTC) responders. Method A prospective cohort study of 3779 WTC responders attending a university-based monitoring and treatment program. Prescriptions for PPIs and SCI determined using the Montreal Cognitive Assessment were the focus of the analysis. Results Overall, 1451 (38.4%) responders were dispensed PPIs, and 83 (2.2%) had SCI. Bivariable analyses revealed significant associations between being-dispensed PPIs in relation to SCI. After adjusting for PTSD, major depressive disorder, WTC exposures, age, and sex, being-dispensed PPIs were significantly associated with odds of SCI (adjusted odds ratio = 1.67 95% confidence interval = 1.054–2.643). Conclusions Being-dispensed PPIs were associated with SCI in this analysis of WTC responders. Results suggest that clinicians treating gastroesophageal reflux disease may seek to both understand patients' mental health history and monitor cognitive functioning when designing treatment routines. Overall, results confirmed that this is an important area of investigation with potential direct clinical implications.

      PubDate: 2017-09-24T05:28:27Z
      DOI: 10.1016/j.trci.2017.08.007
  • Potential implications of practice effects in Alzheimer prevention trials

    • Authors: Diane M. Jacobs; M. Colin Ard; David P. Salmon; Douglas R. Galasko; Mark W. Bondi; Steven D. Edland
      Abstract: Publication date: Available online 19 September 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Diane M. Jacobs, M. Colin Ard, David P. Salmon, Douglas R. Galasko, Mark W. Bondi, Steven D. Edland
      Introduction Practice effects (PEs) present a potential confound in clinical trials with cognitive outcomes. A single-blind placebo run-in design, with repeated cognitive outcome assessments before randomization to treatment, can minimize effects of practice on trial outcome. Methods We investigated the potential implications of PEs in Alzheimer's disease prevention trials using placebo arm data from the Alzheimer's Disease Cooperative Study donepezil/vitamin E trial in mild cognitive impairment. Frequent ADAS-Cog measurements early in the trial allowed us to compare two competing trial designs: a 19-month trial with randomization after initial assessment, versus a 15-month trial with a 4-month single-blind placebo run-in and randomization after the second administration of the ADAS-Cog. Standard power calculations assuming a mixed-model repeated-measure analysis plan were used to calculate sample size requirements for a hypothetical future trial designed to detect a 50% slowing of cognitive decline. Results On average, ADAS-Cog 13 scores improved at first follow-up, consistent with a PE and progressively worsened thereafter. The observed change for a 19-month trial (1.18 points) was substantively smaller than that for a 15-month trial with 4-month run-in (1.79 points). To detect a 50% slowing in progression under the standard design (i.e., a 0.59 point slowing), a future trial would require 3.4 times more subjects than would be required to detect the comparable percent slowing (i.e., 0.90 points) with the run-in design. Discussion Assuming the improvement at first follow-up observed in this trial represents PEs, the rate of change from the second assessment forward is a more accurate representation of symptom progression in this population and is the appropriate reference point for describing treatment effects characterized as percent slowing of symptom progression; failure to accommodate this leads to an oversized clinical trial. We conclude that PEs are an important potential consideration when planning future trials.

      PubDate: 2017-09-24T05:28:27Z
      DOI: 10.1016/j.trci.2017.08.010
  • Toward common mechanisms for risk factors in Alzheimer's syndrome

    • Authors: Miguel Medina; Zaven S. Khachaturian; Martin Rossor; Jesús Avila; Angel Cedazo-Minguez
      Abstract: Publication date: Available online 19 September 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Miguel Medina, Zaven S. Khachaturian, Martin Rossor, Jesús Avila, Angel Cedazo-Minguez
      The global strategic goal of reducing health care cost, especially the prospects for massive increases due to expanding markets for health care services demanded by aging populations and/or people with a wide range of chronic disorders-disabilities, is a complex and formidable challenge with many facets. Current projections predict marked increases in the demand for health driven by both the exponential climb in the prevalence of chronic disabilities and the increases in the absolute numbers of people in need of some form of health care. Thus, the looming predicament for the economics of health care systems worldwide mandates the formulation of a strategic goal to foster significant expansion of global R&D efforts to discover and develop wide-ranging interventions to delay and/or prevent the onset of chronic disabling conditions. The rationale for adopting such a tactical objective is based on the premise that the costs and prevalence of chronic disabling conditions will be reduced by half even if a modest delay of 5 years in the onset of disability is obtained by a highly focused multinational research initiative. Because of the recent history of many failures in drug trials, the central thesis of this paper is to argue for the exploration-adoption of novel mechanistic ideas, theories, and paradigms for developing wide range and/or types of interventions. Although the primary focus of our discussion has been on biological approaches to therapy, we recognize the importance of emerging knowledge on nonpharmacological interventions and their potential impact in reducing health care costs. Although we may not find a drug to cure or prevent dementia for a long time, research is starting to demonstrate the potential contributes of nonpharmacological interventions toward the economics of health care in terms of rehabilitation, promoting autonomy, and potential to delay institutionalization, thus promoting healthy aging and reductions in the cost of care.

      PubDate: 2017-09-24T05:28:27Z
      DOI: 10.1016/j.trci.2017.08.009
  • Biomathematical screening of amyloid positron emission tomography
           radiotracers with clinical usefulness index

    • Authors: Ying-Hwey Nai; Miho Shidahara; Chie Seki; Hiroshi Watabe
      Abstract: Publication date: Available online 19 September 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Ying-Hwey Nai, Miho Shidahara, Chie Seki, Hiroshi Watabe
      Introduction To facilitate radiotracers' development, a screening methodology using a biomathematical model and clinical usefulness index (CUI) was proposed to evaluate radiotracers' diagnostic capabilities. Methods A total of 31 amyloid positron emission tomography radiotracers were evaluated. A previously developed biomathematical model was used to simulate 1000 standardized uptake value ratios with population and noise simulations, which were used to determine the integrated receiver operating characteristics curve (Az), effect size (Es), and standardized uptake value ratio (Sr) of conditions-pairs of healthy control–mild cognitive impaired and mild cognitive impaired–Alzheimer's disease. CUI was obtained from the product of averaged Az ( Az ¯ ) , Es ( Es ¯ ) , and Sr ( Sr ¯ ) . Results The relationships of Az ¯ , Es ¯ , and Sr ¯ with CUI were different, suggesting that they assessed different radiotracer properties. The combination of Az, Es, and Sr complemented each other and resulted in CUI of 0.10 to 5.72, with clinically applied amyloid positron emission tomography radiotracers having CUI greater than 3.0. Discussion The CUI rankings of clinically applied radiotracers were close to their reported clinical results, attesting to the applicability of the screening methodology.

      PubDate: 2017-09-24T05:28:27Z
      DOI: 10.1016/j.trci.2017.08.006
  • Characterization of APOE and TOMM40 allele frequencies in the Japanese

    • Authors: Akira Nishimura; Hidenori Nonomura; Shingo Tanaka; Michihiro Yoshida; Yuka Maruyama; Yutaka Aritomi; Ann M. Saunders; Daniel K. Burns; Michael W. Lutz; Grant Runyan; Eric Lai; Kumar Budur; Allen D. Roses
      Abstract: Publication date: Available online 6 September 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Akira Nishimura, Hidenori Nonomura, Shingo Tanaka, Michihiro Yoshida, Yuka Maruyama, Yutaka Aritomi, Ann M. Saunders, Daniel K. Burns, Michael W. Lutz, Grant Runyan, Eric Lai, Kumar Budur, Allen D. Roses
      Introduction Dementia is one of the major health threats to our aging society, and Alzheimer's disease (AD) is the leading cause. In Japan, ∼15% of the elderly population has dementia. The apolipoprotein E (APOE) genotype and a polymorphism (rs10524523) in the translocase of outer mitochondrial membrane 40 (TOMM40) gene have been associated with the age of onset of AD. However, differences in allele frequencies of these markers in different ethnic populations are not well known. Methods Whole blood samples were collected from 300 Japanese subjects, and genomic DNA was extracted to determine APOE alleles and TOMM40 rs10524523 genotypes. Results Our results indicated that the APOE-ε3–TOMM40′523 short haplotype is less frequent in Japanese subjects than in Caucasians, whereas the APOE-ε3–TOMM40′523 long and APOE-ε3–TOMM40′523 very long haplotypes are more frequent in Japanese subjects than in Caucasians. We also showed that the APOE-ε4–TOMM40′523 short haplotype, which was noted to be frequently observed in African Americans, was also found in the Japanese population, although it is extremely rare in the Caucasian population. Discussion A biomarker risk assignment algorithm, using a combination of APOE, TOMM40′523 genotype, and age, has been developed to assign near-term risk for developing the onset of mild cognitive impairment due to AD and is being used as an enrichment tool in an ongoing delay-of-onset clinical trial. Understanding the characterization of APOE and TOMM40 allele frequencies in the Japanese population is the first step in developing a risk algorithm for AD research and clinical applications for AD prevention in Japan.

      PubDate: 2017-09-12T03:13:05Z
      DOI: 10.1016/j.trci.2017.07.003
  • Concise informed consent to increase data and biospecimen access may
           accelerate innovative Alzheimer's disease treatments

    • Authors: Ann M. Hake; Penny A. Dacks; Stephen P. Arnerić
      Abstract: Publication date: Available online 1 September 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Ann M. Hake, Penny A. Dacks, Stephen P. Arnerić
      Introduction Informed consent forms that restrict the distribution of data and samples have been an impediment to advancing Alzheimer's disease (AD) understandings and treatments. The Coalition Against Major Disease public-private partnership developed concise addenda to responsibly broaden data access of informed consent forms. Methods Coalition Against Major Disease members identified key elements for ensuring data and biospecimen access, and patient privacy protection according to applicable US law. Collaboration with the Alzheimer's Association established the understandability and relevance of the addenda with AD patients and Care Partners. Results Two key findings are (1) patients with dementia and Care Partners were shocked that their data and samples are not broadly shared and (2) with diverse feedback, two concise addenda were created to enable data and sample sharing both within and outside future sponsored studies (see Boxes). Discussion Increasing the access of valuable anonymized patient-level clinical trial data has the potential to inform the foundational and regulatory science required to deliver innovative treatments for AD.

      PubDate: 2017-09-06T01:41:07Z
      DOI: 10.1016/j.trci.2017.08.003
  • The effect of diagnostic criteria on outcome measures in preclinical and
           prodromal Alzheimer's disease: Implications for trial design

    • Authors: Daniela Bertens; Betty M. Tijms; Lisa Vermunt; Niels D. Prins; Philip Scheltens; Pieter Jelle Visser
      Abstract: Publication date: Available online 30 August 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Daniela Bertens, Betty M. Tijms, Lisa Vermunt, Niels D. Prins, Philip Scheltens, Pieter Jelle Visser
      Introduction We investigated the influence of different inclusion criteria for preclinical and prodromal Alzheimer's disease (AD) on changes in biomarkers and cognitive markers and on trial sample size estimates. Methods We selected 522 cognitively normal subjects and 872 subjects with mild cognitive impairment from the Alzheimer's Disease Neuroimaging Initiative study. Compared inclusion criteria were (1) preclinical or prodromal AD (amyloid marker abnormal); (2) preclinical or prodromal AD stage-1 (amyloid marker abnormal, injury marker normal); and (3) preclinical or prodromal AD stage-2 (amyloid and injury markers abnormal). Outcome measures were amyloid, neuronal injury, and cognitive markers. Results In both subjects with preclinical and prodromal AD stage-2, inclusion criteria resulted in the largest observed decline in brain volumetric measures on magnetic resonance imaging and cognitive markers. Discussion Inclusion criteria influence the observed rate of worsening in outcome measures. This has implications for trial design.

      PubDate: 2017-09-06T01:41:07Z
      DOI: 10.1016/j.trci.2017.08.005
  • Measuring brain synaptic vesicle protein 2A with positron emission
           tomography and [18F]UCB-H

    • Authors: Mohamed Ali Bahri; Alain Plenevaux; Joël Aerts; Christine Bastin; Guillaume Becker; Joël Mercier; Anne Valade; Tim Buchanan; Nathalie Mesdagh; Didier Ledoux; Alain Seret; André Luxen; Eric Salmon
      Abstract: Publication date: Available online 30 August 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Mohamed Ali Bahri, Alain Plenevaux, Joël Aerts, Christine Bastin, Guillaume Becker, Joël Mercier, Anne Valade, Tim Buchanan, Nathalie Mesdagh, Didier Ledoux, Alain Seret, André Luxen, Eric Salmon
      Introduction Brain distribution of synaptic vesicle protein 2A was measured with [18F]UCB-H and positron emission tomography (PET). Methods Images of synaptic density were acquired in healthy volunteers (two young participants and two seniors). Input function was measured by arterial blood sampling (arterial input function) and derived from PET images using carotid activity (image-derived input function). Logan graphical analysis was used to estimate regional synaptic vesicle protein 2A distribution volume. Results [18F]UCB-H uptake was ubiquitous in cortical and subcortical gray matter. Arterial input function and image-derived input function provided regional distribution volume with a high linear relationship. Discussion The cerebral distribution of [18F]UCB-H is similar to that recently observed with [11C]UCB-J. An accurate [18F]UCB-H quantification can be performed without invasive arterial blood sampling when no suitable reference region is available, using dynamic PET carotid activity. Brain synaptic density can be studied in vivo in normal and pathological aging.

      PubDate: 2017-09-06T01:41:07Z
      DOI: 10.1016/j.trci.2017.08.004
  • A general neurologist's perspective on the urgent need to apply resilience
           thinking to the prevention and treatment of Alzheimer's disease

    • Authors: Grazyna Pomorska; Judith K. Ockene
      Abstract: Publication date: Available online 30 August 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Grazyna Pomorska, Judith K. Ockene
      The goal of this article was to look at the problem of Alzheimer's disease (AD) through the lens of a socioecological resilience-thinking framework to help expand our view of the prevention and treatment of AD. This serious and complex public health problem requires a holistic systems approach. We present the view that resilience thinking, a theoretical framework that offers multidisciplinary approaches in ecology and natural resource management to solve environmental problems, can be applied to the prevention and treatment of AD. Resilience thinking explains a natural process that occurs in all complex systems in response to stressful challenges. The brain is a complex system, much like an ecosystem, and AD is a disturbance (allostatic overload) within the ecosystem of the brain. Resilience thinking gives us guidance, direction, and ideas about how to comprehensively prevent and treat AD and tackle the AD epidemic.

      PubDate: 2017-09-06T01:41:07Z
      DOI: 10.1016/j.trci.2017.08.001
  • An 8-week, open-label, dose-finding study of nimodipine for the treatment
           of progranulin insufficiency from GRN gene mutations

    • Authors: Sharon J. Sha; Zachary A. Miller; Sang-won Min; Yungui Zhou; Jesse Brown; Laura L. Mitic; Anna Karydas; Mary Koestler; Richard Tsai; Chiara Corbetta-Rastelli; Sophie Lin; Emma Hare; Scott Fields; Kirsten E. Fleischmann; Ryan Powers; Ryan Fitch; Lauren Herl Martens; Mehrdad Shamloo; Anne M. Fagan; Robert V. Farese; Rodney Pearlman; William Seeley; Bruce L. Miller; Li Gan; Adam L. Boxer
      Abstract: Publication date: Available online 30 August 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Sharon J. Sha, Zachary A. Miller, Sang-won Min, Yungui Zhou, Jesse Brown, Laura L. Mitic, Anna Karydas, Mary Koestler, Richard Tsai, Chiara Corbetta-Rastelli, Sophie Lin, Emma Hare, Scott Fields, Kirsten E. Fleischmann, Ryan Powers, Ryan Fitch, Lauren Herl Martens, Mehrdad Shamloo, Anne M. Fagan, Robert V. Farese, Rodney Pearlman, William Seeley, Bruce L. Miller, Li Gan, Adam L. Boxer
      Introduction Frontotemporal lobar degeneration–causing mutations in the progranulin (GRN) gene reduce progranulin protein (PGRN) levels, suggesting that restoring PGRN in mutation carriers may be therapeutic. Nimodipine, a Food and Drug Administration–approved blood-brain barrier-penetrant calcium channel blocker, increased PGRN levels in PGRN-deficient murine models. We sought to assess safety and tolerability of oral nimodipine in human GRN mutation carriers. Methods We performed an open-label, 8-week, dose-finding, phase 1 clinical trial in eight GRN mutation carriers to assess the safety and tolerability of nimodipine and assayed fluid and radiologic markers to investigate therapeutic endpoints. Results There were no serious adverse events; however, PGRN concentrations (cerebrospinal fluid and plasma) did not change significantly following treatment (percent changes of −5.2 ± 10.9% in plasma and −10.2 ± 7.8% in cerebrospinal fluid). Measurable atrophy within the left middle frontal gyrus was observed over an 8-week period. Discussion While well tolerated, nimodipine treatment did not alter PGRN concentrations or secondary outcomes.

      PubDate: 2017-09-06T01:41:07Z
      DOI: 10.1016/j.trci.2017.08.002
  • Gamma rhythm low field magnetic stimulation alleviates neuropathologic
           changes and rescues memory and cognitive impairments in a mouse model of
           Alzheimer's disease

    • Authors: Junli Zhen; Yanjing Qian; Xiechuan Weng; Wenting Su; Jianliang Zhang; Lihui Cai; Lin Dong; Haiting An; Ruijun Su; Jiang Wang; Yan Zheng; Xiaomin Wang
      Abstract: Publication date: Available online 30 August 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Junli Zhen, Yanjing Qian, Xiechuan Weng, Wenting Su, Jianliang Zhang, Lihui Cai, Lin Dong, Haiting An, Ruijun Su, Jiang Wang, Yan Zheng, Xiaomin Wang
      Introduction The abnormal amyloid β (Aβ) accumulation and Aβ-related neural network dysfunction are considered central to the pathogenesis of Alzheimer's disease (AD) at the early stage. Deep-brain reachable low field magnetic stimulation (DMS), a novel noninvasive approach that was designed to intervene the network activity in brains, has been found to alleviate stress-related cognitive impairments. Methods Amyloid precursor protein/presenilin-1 transgenic mice (5XFAD) were treated with DMS, and cognitive behavior and AD-like pathologic changes in the neurochemical and electrophysiological properties in 5XFAD mice were assessed. Results We demonstrate that DMS treatment enhances cognitive performances, attenuates Aβ load, upregulates postsynaptic density protein 95 level, and promotes hippocampal long-term potentiation in 5XFAD mouse brain. Intriguingly, the gamma burst magnetic stimulation reverses the aberrant gamma oscillations in the transgenic hippocampal network. Discussion This work establishes a solid foundation for the effectiveness of DMS in treating AD and proposes a future study of gamma rhythm stimulation on reorganizing rhythmic neural activity in AD brain.

      PubDate: 2017-09-06T01:41:07Z
      DOI: 10.1016/j.trci.2017.07.002
  • A comprehensive approach to reablement in dementia

    • Authors: Christopher J. Poulos; Antony Bayer; Lauren Beaupre; Linda Clare; Roslyn G. Poulos; Rosalie H. Wang; Sytse Zuidema; Katherine S. McGilton
      Abstract: Publication date: Available online 27 July 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Christopher J. Poulos, Antony Bayer, Lauren Beaupre, Linda Clare, Roslyn G. Poulos, Rosalie H. Wang, Sytse Zuidema, Katherine S. McGilton
      As society grapples with an aging population and increasing prevalence of disability, “reablement” as a means of maximizing functional ability in older people is emerging as a potential strategy to help promote independence. Reablement offers an approach to mitigate the impact of dementia on function and independence. This article presents a comprehensive reablement approach across seven domains for the person living with mild-to-moderate dementia. Domains include assessment and medical management, cognitive disability, physical function, acute injury or illness, assistive technology, supportive care, and caregiver support. In the absence of a cure or ability to significantly modify the course of the disease, the message for policy makers, practitioners, families, and persons with dementia needs to be “living well with dementia”, with a focus on maintaining function for as long as possible, regaining lost function when there is the potential to do so, and adapting to lost function that cannot be regained. Service delivery and care of persons with dementia must be reoriented such that evidence-based reablement approaches are integrated into routine care across all sectors.

      PubDate: 2017-07-30T18:17:30Z
      DOI: 10.1016/j.trci.2017.06.005
  • Midlife anticholinergic drug use, risk of Alzheimer's disease, and brain
           atrophy in community-dwelling older adults

    • Authors: Yi-Fang Chuang; Palchamy Elango; Christopher E. Gonzalez; Madhav Thambisetty
      Abstract: Publication date: Available online 19 July 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Yi-Fang Chuang, Palchamy Elango, Christopher E. Gonzalez, Madhav Thambisetty
      Introduction We examined how long-term anticholinergic (AC) drug use beginning at midlife affects risk of Alzheimer's disease (AD) and rates of brain atrophy in cognitively normal older adults. Methods We followed 723 individuals (mean baseline age 52.3 years; mean follow-up interval 20.1 years) in the Baltimore Longitudinal Study of Aging. The AC drug exposure was defined using the Anticholinergic Cognitive Burden Scale: Nonusers (n = 404), as well as participants exposed to medications with AC activity but without known clinically relevant negative cognitive effects (i.e., “possible AC users”; n = 185) and those exposed to AC drugs with established and clinically relevant negative cognitive effects (i.e., “definite AC users”; n = 134). The neuroimaging sample included 93 participants who remained cognitively normal through follow-up and underwent serial magnetic resonance imaging (n = 93, 724 brain scans, mean follow-up interval 8.2 years, and baseline age 68.6 years). Results Possible AC users, but not definite AC users, showed increased risk of incident AD compared with nonusers (hazard ratio, 1.63; 95% confidence interval, 1.02–2.61; P = .04) and greater rates of atrophy in total cortical gray matter volume compared with nonusers (β = −0.74, P = .018). Faster rates of brain atrophy were also observed among possible AC users in the right posterior cingulate, as well as right middle frontal and left superior temporal gyri. Data on frequency and duration of medication use were available in only approximately half of the sample. Among these participants, definite AC users had both shorter duration and lower frequency of medication use relative to possible AC users. Discussion Long-term exposure to medications with mild AC activity during midlife is associated with increased risk of AD and accelerated brain atrophy.

      PubDate: 2017-07-24T17:45:10Z
      DOI: 10.1016/j.trci.2017.06.004
  • Serum concentrations of vitamin E and carotenoids are altered in
           Alzheimer's disease: A case-control study

    • Authors: Kathryn Mullan; Michael A. Williams; Chris R. Cardwell; Bernadette McGuinness; Peter Passmore; Giuliana Silvestri; Jayne V. Woodside; Gareth J. McKay
      Abstract: Publication date: Available online 19 July 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Kathryn Mullan, Michael A. Williams, Chris R. Cardwell, Bernadette McGuinness, Peter Passmore, Giuliana Silvestri, Jayne V. Woodside, Gareth J. McKay
      Introduction Oxidative stress has been implicated in the pathogenesis of Alzheimer's disease (AD). We investigated associations between serum levels of lipophilic antioxidants and AD. Methods Serum concentrations of retinol, two forms of vitamin E (α- and γ-tocopherol) and six carotenoids were quantified by high-performance liquid chromatography from patients with AD (n = 251) and cognitively intact controls (n = 308) and assessed by regression analyses. Results Serum levels of α-tocopherol and all six carotenoids were significantly lower in patients with AD compared with cognitively intact controls (P < .001). In contrast, γ-tocopherol was significantly higher in the serum of patients with AD (odds ratio = 1.17 [confidence intervals: 1.05–1.31]). Discussion Our findings implicate compromised serum antioxidant defenses in AD pathogenesis and differing biological roles for vitamin E isoforms. This highlights the need for improved understanding in the balanced upregulation of exogenous antioxidants related to dietary intake or supplement use in future nutritional intervention studies.

      PubDate: 2017-07-24T17:45:10Z
      DOI: 10.1016/j.trci.2017.06.006
  • Lower brain and blood nutrient status in AD: Results from meta-analyses

    • Authors: Martijn C. de Wilde; Bruno Vellas; Elodie Girault; Aysun Cetinyurek Yavuz; John W. Sijben
      Abstract: Publication date: Available online 24 June 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Martijn C. de Wilde, Bruno Vellas, Elodie Girault, Aysun Cetinyurek Yavuz, John W. Sijben
      Introduction Alzheimer's disease (AD) patients are at risk of nutritional insufficiencies because of physiological and psychological factors. Recently, we showed the results of the meta-analyses indicating lower plasma levels of vitamins A, B12, C, E, and folate in AD patients compared with cognitively intact elderly controls (controls). Now, additional and more extensive literature searches were performed selecting studies which compare blood and brain/cerebrospinal fluid (CSF) levels of vitamins, minerals, trace elements, micronutrients, and fatty acids in AD patients versus controls. Methods The literature published after 1980 in Cochrane Central Register of Controlled Trials, Medline, and Embase electronic databases was systematically analyzed using Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines to detect studies meeting the selection criteria. Search terms used are as follows: AD patients, Controls, vitamins, minerals, trace elements, micronutrients, and fatty acids. Random-effects meta-analyses using a linear mixed model with correction for age differences between AD patients and controls were performed when four or more publications were retrieved for a specific nutrient. Results Random-effects meta-analyses of 116 selected publications showed significant lower CSF/brain levels of docosahexaenoic acid (DHA), choline-containing lipids, folate, vitamin B12, vitamin C, and vitamin E. In addition, AD patients showed lower circulatory levels of DHA, eicosapentaenoic acid, choline as phosphatidylcholine, and selenium. Conclusion The current data show that patients with AD have lower CSF/brain availability of DHA, choline, vitamin B12, folate, vitamin C, and vitamin E. Directionally, brain nutrient status appears to parallel the lower circulatory nutrient status; however, more studies are required measuring simultaneously circulatory and central nutrient status to obtain better insight in this observation. The brain is dependent on nutrient supply from the circulation, which in combination with nutrient involvement in AD-pathophysiological mechanisms suggests that patients with AD may have specific nutritional requirements. This hypothesis could be tested using a multicomponent nutritional intervention.

      PubDate: 2017-07-04T15:42:20Z
      DOI: 10.1016/j.trci.2017.06.002
  • Determining the impact of psychosis on rates of false-positive and
           false-negative diagnosis in Alzheimer's disease

    • Authors: Corinne E. Fischer; Winnie Qian; Tom A. Schweizer; Zahinoor Ismail; Eric E. Smith; Colleen P. Millikin; David G. Munoz
      Abstract: Publication date: Available online 21 June 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Corinne E. Fischer, Winnie Qian, Tom A. Schweizer, Zahinoor Ismail, Eric E. Smith, Colleen P. Millikin, David G. Munoz
      Introduction The rate of clinical misdiagnosis of Alzheimer's disease (AD) and how psychosis impacts that clinical judgment is unclear. Methods Using data from National Alzheimer's Coordinating Center, we compared the clinical and neuropathologic diagnosis in patients with a diagnosis of AD with autopsy and in neuropathology-confirmed AD cases (n = 961). We determined the rate of true positives, false positives, and false negatives in patients with and without psychosis. Results A total of 76% received a correct AD diagnosis, 11.9% had a false-negative diagnosis, and 12.1% had a false-positive diagnosis of AD. Psychotic patients had a higher rate of false-negative diagnosis and a lower rate of false-positive diagnosis of AD compared with nonpsychotic patients. Discussion Patients with psychosis were five times more likely to be misdiagnosed as dementia with Lewy bodies, whereas patients without psychosis were more likely to be falsely diagnosed with AD when vascular pathology is the underlying neuropathologic cause of dementia.

      PubDate: 2017-06-23T14:25:49Z
      DOI: 10.1016/j.trci.2017.06.001
  • A randomized feasibility pilot trial of hearing treatment for reducing
           cognitive decline: Results from the Aging and Cognitive Health Evaluation
           in Elders Pilot Study

    • Authors: Jennifer A. Deal; Marilyn S. Albert; Michelle Arnold; Shrikant I. Bangdiwala; Theresa Chisolm; Sonia Davis; Ann Eddins; Nancy W. Glynn; Adele M. Goman; Melissa Minotti; Thomas Mosley; George W. Rebok; Nicholas Reed; Elizabeth Rodgers; Victoria Sanchez; A. Richey Sharrett; Josef Coresh; Frank R. Lin
      Abstract: Publication date: Available online 21 June 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Jennifer A. Deal, Marilyn S. Albert, Michelle Arnold, Shrikant I. Bangdiwala, Theresa Chisolm, Sonia Davis, Ann Eddins, Nancy W. Glynn, Adele M. Goman, Melissa Minotti, Thomas Mosley, George W. Rebok, Nicholas Reed, Elizabeth Rodgers, Victoria Sanchez, A. Richey Sharrett, Josef Coresh, Frank R. Lin
      Introduction Hearing loss (HL) is prevalent and independently related to cognitive decline and dementia. There has never been a randomized trial to test if HL treatment could reduce cognitive decline in older adults. Methods A 40-person (aged 70–84 years) pilot study in Washington County, MD, was conducted. Participants were randomized 1:1 to a best practices hearing or successful aging intervention and followed up for 6 months. Identifier: NCT02412254. Results Aging and Cognitive Health Evaluation in Elders Pilot (ACHIEVE-P) Study demonstrated feasibility in recruitment, retention, and implementation of interventions with no treatment-related adverse events. A clear efficacy signal of the hearing intervention was observed in perceived hearing handicap (mean of 0.11 to −1.29 standard deviation [SD] units; lower scores better) and memory (mean of −0.10 SD to 0.38 SD). Discussion ACHIEVE-P sets the stage for the full-scale ACHIEVE trial (N = 850, recruitment beginning November 2017), the first randomized trial to determine efficacy of a best practices hearing (vs. successful aging) intervention on reducing cognitive decline in older adults with HL.

      PubDate: 2017-06-23T14:25:49Z
      DOI: 10.1016/j.trci.2017.06.003
  • Ponezumab in mild-to-moderate Alzheimer's disease: Randomized phase II
           PET-PIB study

    • Authors: Jaren W. Landen; Niels Andreasen; Carol L. Cronenberger; Pamela F. Schwartz; Anne Börjesson-Hanson; Henrik Östlund; Catherine A. Sattler; Brendon Binneman; Martin M. Bednar
      Abstract: Publication date: Available online 8 June 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Jaren W. Landen, Niels Andreasen, Carol L. Cronenberger, Pamela F. Schwartz, Anne Börjesson-Hanson, Henrik Östlund, Catherine A. Sattler, Brendon Binneman, Martin M. Bednar
      Background The safety, pharmacokinetics, and effect on peripheral and central amyloid beta (Aβ) of multiple doses of ponezumab, an anti-Aβ monoclonal antibody, were characterized in subjects with mild-to-moderate Alzheimer's disease treated for 1 year. Methods Subjects were aged ≥50 years with Mini–Mental State Examination scores 16 to 26. Cohort Q was randomized to ponezumab 10 mg/kg (n = 12) or placebo (n = 6) quarterly. Cohort M was randomized to a loading dose of ponezumab 10 mg/kg or placebo, followed by monthly ponezumab 7.5 mg/kg (n = 12) or placebo (n = 6), respectively. Results Ponezumab was generally well tolerated. Plasma concentrations increased dose dependently, but cerebrospinal fluid (CSF) penetration was low. Plasma Aβ increased dose dependently with ponezumab, but CSF biomarkers, brain amyloid burden, cognition, and function were not affected. Conclusions Both ponezumab dosing schedules were generally safe and well tolerated but did not alter CSF biomarkers, brain amyloid burden, or clinical outcomes.

      PubDate: 2017-06-13T13:03:50Z
      DOI: 10.1016/j.trci.2017.05.003
  • The effects of noncoding aquaporin-4 single-nucleotide polymorphisms on
           cognition and functional progression of Alzheimer's disease

    • Authors: Kevin G. Burfeind; Charles F. Murchison; Shawn K. Westaway; Matthew J. Simon; Deniz Erten-Lyons; Jeffrey A. Kaye; Joseph F. Quinn; Jeffrey J. Iliff
      Abstract: Publication date: Available online 26 May 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Kevin G. Burfeind, Charles F. Murchison, Shawn K. Westaway, Matthew J. Simon, Deniz Erten-Lyons, Jeffrey A. Kaye, Joseph F. Quinn, Jeffrey J. Iliff
      Introduction The glymphatic system is a brain-wide perivascular network that facilitates clearance of proteins, including amyloid β, from the brain interstitium through the perivascular exchange of cerebrospinal fluid and interstitial fluid. The astrocytic water channel aquaporin-4 (AQP4) is required for glymphatic system function, and impairment of glymphatic function in the aging brain is associated with altered AQP4 expression and localization. In human cortical tissue, alterations in AQP4 expression and localization are associated with Alzheimer's disease (AD) status and pathology. Although this suggests a potential role for AQP4 in the development or progression of AD, the relationship between of naturally occurring variants in the human AQP4 gene and cognitive function has not yet been evaluated. Methods Using data from several longitudinal aging cohorts, we investigated the association between five AQP4 single-nucleotide polymorphisms (SNPs) and the rate of cognitive decline in participants with a diagnosis of AD. Results None of the five SNPs were associated with different rates of AD diagnosis, age of dementia onset in trial subjects. No association between AQP4 SNPs with histological measures of AD pathology, including Braak stage or neuritic plaque density was observed. However, AQP4 SNPs were associated with altered rates of cognitive decline after AD diagnosis, with two SNPS (rs9951307 and rs3875089) associated with slower cognitive decline and two (rs3763040 and rs3763043) associated with more rapid cognitive decline after AD diagnosis. Discussion These results provide the first evidence that variations in the AQP4 gene, whose gene product AQP4 is vital for glymphatic pathway function, may modulate the progression of cognitive decline in AD.

      PubDate: 2017-05-29T16:18:36Z
      DOI: 10.1016/j.trci.2017.05.001
  • Power analysis to detect treatment effects in longitudinal clinical trials
           for Alzheimer's disease

    • Authors: Zhiyue Huang; Graciela Muniz-Terrera; Brian D.M. Tom
      Abstract: Publication date: Available online 24 May 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Zhiyue Huang, Graciela Muniz-Terrera, Brian D.M. Tom
      Introduction Assessing cognitive and functional changes at the early stage of Alzheimer's disease (AD) and detecting treatment effects in clinical trials for early AD are challenging. Methods Under the assumption that transformed versions of the Mini–Mental State Examination, the Clinical Dementia Rating Scale–Sum of Boxes, and the Alzheimer's Disease Assessment Scale–Cognitive Subscale tests'/components' scores are from a multivariate linear mixed-effects model, we calculated the sample sizes required to detect treatment effects on the annual rates of change in these three components in clinical trials for participants with mild cognitive impairment. Results Our results suggest that a large number of participants would be required to detect a clinically meaningful treatment effect in a population with preclinical or prodromal Alzheimer's disease. We found that the transformed Mini–Mental State Examination is more sensitive for detecting treatment effects in early AD than the transformed Clinical Dementia Rating Scale–Sum of Boxes and Alzheimer's Disease Assessment Scale–Cognitive Subscale. The use of optimal weights to construct powerful test statistics or sensitive composite scores/endpoints can reduce the required sample sizes needed for clinical trials. Conclusion Consideration of the multivariate/joint distribution of components' scores rather than the distribution of a single composite score when designing clinical trials can lead to an increase in power and reduced sample sizes for detecting treatment effects in clinical trials for early AD.

      PubDate: 2017-05-29T16:18:36Z
      DOI: 10.1016/j.trci.2017.04.007
  • Phase II clinical trials of anti–β-amyloid antibodies: When is
           enough, enough?

    • Authors: Michael Gold
      Abstract: Publication date: Available online 17 May 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Michael Gold
      Efforts to develop new therapies to combat Alzheimer's disease suffer from extraordinarily high failure rates that make it difficult to justify continued investment in the field. Although there are a number of plausible explanations for this extremely high attrition rate, one of the explanations that has received little attention is the lack of compelling data from Phase II studies for compounds that have been pushed into Phase III trials and then have failed. An analysis of publicly available data from the Phase II studies for bapineuzumab and solanezumab indicates that neither compound produced compelling evidence of drug-like behavior that would justify their progression into pivotal trials. The published data suggest that sponsors took decisions to move these compounds into Phase III on the basis of vastly limited data that were rife with type I error and probably driven by commercial concerns. The continued push to move compounds that are not likely to succeed in later stage clinical trials threatens to erode trust in the clinical research enterprise making it much harder to properly test truly promising compounds.

      PubDate: 2017-05-19T15:24:16Z
      DOI: 10.1016/j.trci.2017.04.005
  • The BDNF Val66Met polymorphism moderates the effect of cognitive reserve
           on 36-month cognitive change in healthy older adults

    • Authors: David D. Ward; Ross Andel; Nichole L. Saunders; Megan E. Thow; Shannon Z. Klekociuk; Aidan D. Bindoff; James C. Vickers
      Abstract: Publication date: Available online 15 May 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): David D. Ward, Ross Andel, Nichole L. Saunders, Megan E. Thow, Shannon Z. Klekociuk, Aidan D. Bindoff, James C. Vickers
      Introduction Cognitive reserve (CR) and BDNF Val66Met are independently associated with the rate of cognitive decline in preclinical Alzheimer's disease. This study was designed to investigate the interactive effects of these variables on 36-month cognitive change in cognitively intact older adults. Methods Data for this investigation were obtained from 445 community-residing participants of the Tasmanian Healthy Brain Project, who underwent genetic screening and annual assessment of neuropsychological, health, and psychosocial function. Results Our main result was that BDNF Val66Met moderated the relationship between baseline CR and change in executive function performance, in that CR-related differences in function decreased across the follow-up period in BDNF Val homozygotes, but became more pronounced in BDNF Met carriers. Similar effects were not observed within the other memory- and language-related cognitive domains. Discussion Inheritance of BDNF Met may be associated with a detrimental influence on the relationship between CR and cognitive change in cognitively intact older adults, but this effect may be restricted to the executive function domain.

      PubDate: 2017-05-19T15:24:16Z
      DOI: 10.1016/j.trci.2017.04.006
  • Combined mnemonic strategy training and high-definition transcranial
           direct current stimulation for memory deficits in mild cognitive

    • Authors: Benjamin M. Hampstead; K. Sathian; Marom Bikson; Anthony Y. Stringer
      Abstract: Publication date: Available online 15 May 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Benjamin M. Hampstead, K. Sathian, Marom Bikson, Anthony Y. Stringer
      Introduction Memory deficits characterize Alzheimer's dementia and the clinical precursor stage known as mild cognitive impairment. Nonpharmacologic interventions hold promise for enhancing functioning in these patients, potentially delaying functional impairment that denotes transition to dementia. Previous findings revealed that mnemonic strategy training (MST) enhances long-term retention of trained stimuli and is accompanied by increased blood oxygen level–dependent signal in the lateral frontal and parietal cortices as well as in the hippocampus. The present study was designed to enhance MST generalization, and the range of patients who benefit, via concurrent delivery of transcranial direct current stimulation (tDCS). Methods This protocol describes a prospective, randomized controlled, four-arm, double-blind study targeting memory deficits in those with mild cognitive impairment. Once randomized, participants complete five consecutive daily sessions in which they receive either active or sham high definition tDCS over the left lateral prefrontal cortex, a region known to be important for successful memory encoding and that has been engaged by MST. High definition tDCS (active or sham) will be combined with either MST or autobiographical memory recall (comparable to reminiscence therapy). Participants undergo memory testing using ecologically relevant measures and functional magnetic resonance imaging before and after these treatment sessions as well as at a 3-month follow-up. Primary outcome measures include face-name and object-location association tasks. Secondary outcome measures include self-report of memory abilities as well as a spatial navigation task (near transfer) and prose memory (medication instructions; far transfer). Changes in functional magnetic resonance imaging will be evaluated during both task performance and the resting-state using activation and connectivity analyses. Discussion The results will provide important information about the efficacy of cognitive and neuromodulatory techniques as well as the synergistic interaction between these promising approaches. Exploratory results will examine patient characteristics that affect treatment efficacy, thereby identifying those most appropriate for intervention.

      PubDate: 2017-05-19T15:24:16Z
      DOI: 10.1016/j.trci.2017.04.008
  • Clinicians' views on conversations and shared decision making in
           diagnostic testing for Alzheimer's disease—The ABIDE project

    • Authors: Marleen Kunneman; Ellen M.A. Smets; Femke H. Bouwman; Niki S.M. Schoonenboom; Marissa D. Zwan; Ruth Pel-Littel; Wiesje M. van der Flier
      Abstract: Publication date: Available online 10 May 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Marleen Kunneman, Ellen M.A. Smets, Femke H. Bouwman, Niki S.M. Schoonenboom, Marissa D. Zwan, Ruth Pel-Littel, Wiesje M. van der Flier
      Introduction This study explores clinicians' views on and experiences with when, how, and by whom decisions about diagnostic testing for Alzheimer's disease are made and how test results are discussed with patients. Methods Following a preparatory focus group with 13 neurologists and geriatricians, we disseminated an online questionnaire among 200 memory clinic clinicians. Results Respondents were 95 neurologists and geriatricians (response rate 47.5%). Clinicians (74%) indicated that decisions about testing are made before the first encounter, yet they favored a shared decision-making approach. Patient involvement seems limited to receiving information. Clinicians with less tolerance for uncertainty preferred a bigger say in decisions (P < .05). Clinicians indicated to always communicate the diagnosis (94%), results of different tests (88%–96%), and risk of developing dementia (66%). Discussion Clinicians favor patient involvement in deciding about diagnostic testing, but conversations about decisions and test results can be improved and supported.

      PubDate: 2017-05-14T14:54:28Z
      DOI: 10.1016/j.trci.2017.03.009
  • Technology for home dementia care: A prototype locating system put to the

    • Authors: Herlind Megges; Silka Dawn Freiesleben; Natalie Jankowski; Brigitte Haas; Oliver Peters
      Abstract: Publication date: Available online 10 May 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Herlind Megges, Silka Dawn Freiesleben, Natalie Jankowski, Brigitte Haas, Oliver Peters
      Introduction The user experience of persons with dementia and their primary caregivers with locating systems is not firmly established. Methods Eighteen dyads used a prototype locating system during 4 weeks. Primary outcome measures were ratings of usability, and product functions and features. Secondary outcome measures were caregiver burden, perceived self-efficacy, frequency of use, and willingness to purchase the prototype. Changes in scores between baseline (T1) and end of testing period (T2) were compared by performing independent and dependent samples correlations and descriptive statistics. Results Seventeen dyads made up the final sample. Ratings of usability and product functions and features were fair, but usability ratings were significantly reduced after 4 weeks. Although the prototype was used infrequently by majority of the samples, most caregivers would be willing to purchase the prototype, with men more willing than women. No significant change in technological willingness, caregiver burden, or perceived self-efficacy was found between T1 and T2. Perceived self-efficacy significantly negatively correlated with willingness to purchase the prototype after 4 weeks. Discussion Results highlight the importance of including end users in the research and development phase of locating systems to improve the user experience in home dementia care. Necessary indications for further research are carrying out randomized controlled trials with larger, more representative samples and developing innovative software and hardware solutions.

      PubDate: 2017-05-14T14:54:28Z
      DOI: 10.1016/j.trci.2017.04.004
  • Multiple-dose ponezumab for mild-to-moderate Alzheimer's disease: Safety
           and efficacy

    • Authors: Jaren W. Landen; Sharon Cohen; Clare B. Billing; Carol Cronenberger; Scot Styren; Aaron H. Burstein; Catherine Sattler; Jae-Hong Lee; Clifford R. Jack; Kejal Kantarci; Pamela F. Schwartz; William T. Duggan; Qinying Zhao; Ken Sprenger; Martin M. Bednar; Brendon Binneman
      Abstract: Publication date: Available online 10 May 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Jaren W. Landen, Sharon Cohen, Clare B. Billing, Carol Cronenberger, Scot Styren, Aaron H. Burstein, Catherine Sattler, Jae-Hong Lee, Clifford R. Jack, Kejal Kantarci, Pamela F. Schwartz, William T. Duggan, Qinying Zhao, Ken Sprenger, Martin M. Bednar, Brendon Binneman
      Background Multiple intravenous doses of ponezumab, an anti-amyloid antibody, were evaluated in subjects with mild-to-moderate Alzheimer's disease (AD). Methods In part A, 77 subjects were randomized to ponezumab 0.1, 0.5, or 1 mg/kg (75 treated) and 26 to placebo (24 treated). In part B, 63 subjects were randomized and treated with ponezumab 3 or 8.5 mg/kg and 32 with placebo. Subjects received 10 infusions over 18 months and were followed for 6 months thereafter. Results Ponezumab was generally safe and well tolerated. Most common adverse events were fall (16.7% ponezumab, 21.4% placebo), headache (13.8%, 21.4%), and cerebral microhemorrhage (13.8%, 19.6%). Plasma ponezumab increased dose-dependently with limited accumulation. Cerebrospinal fluid penetration was low. Plasma Aβ1–x and Aβ1–40 showed robust increases, but cerebrospinal fluid biomarkers showed no dose response. Ponezumab had no effects on cognitive/functional outcomes or brain volume. Conclusions Multiple-dose ponezumab was generally safe, but not efficacious, in mild-to-moderate AD.

      PubDate: 2017-05-14T14:54:28Z
      DOI: 10.1016/j.trci.2017.04.003
  • Patients' and caregivers' views on conversations and shared decision
           making in diagnostic testing for Alzheimer's disease—The ABIDE project

    • Authors: Marleen Kunneman; Ruth Pel-Littel; Femke H. Bouwman; Freek Gillissen; Niki S.M. Schoonenboom; Jules J. Claus; Wiesje M. van der Flier; Ellen M.A. Smets
      Abstract: Publication date: Available online 10 May 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Marleen Kunneman, Ruth Pel-Littel, Femke H. Bouwman, Freek Gillissen, Niki S.M. Schoonenboom, Jules J. Claus, Wiesje M. van der Flier, Ellen M.A. Smets
      Introduction This study aims to assess patients' and caregivers' views on and experiences with (1) decisions about diagnostic testing for Alzheimer's disease (AD) and (2) receiving test results. Methods We conducted separate focus groups with patients from three hospitals who underwent diagnostic testing for AD (N = 11) and their caregivers (N = 11). Audio recordings were transcribed verbatim and analyzed using MaxQDA. Results Patients and caregivers preferred and perceived active involvement in decision making, but the decision to initiate diagnostic testing seems to be made before the clinician-patient encounter. Patients and caregivers indicate that decisions are driven by a strong need to explain the patient's symptoms. They missed information on why different diagnostic tests were used, what the results of these tests were, and to what extent these results were (ab)normal. Discussion The decision-making process around diagnostic testing for AD and the information provision before and after diagnostic testing could be improved.

      PubDate: 2017-05-14T14:54:28Z
      DOI: 10.1016/j.trci.2017.04.002
  • Diagnostic dilemmas in Alzheimer's disease: Room for shared decision

    • Authors: Wiesje M. van der Flier; Marleen Kunneman; Femke H. Bouwman; Ronald C. Petersen; Ellen M.A. Smets
      Abstract: Publication date: Available online 9 May 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Wiesje M. van der Flier, Marleen Kunneman, Femke H. Bouwman, Ronald C. Petersen, Ellen M.A. Smets
      The launch of the NIA-AA research criteria for Alzheimer's disease (AD) diagnosis illustrates the large advances that have been made in the field of AD diagnosis. These new possibilities however also introduce new dilemmas into the consulting room, and this provides room for shared decision making (SDM). SDM refers to clinicians and patients (and/or their caregivers) working together to decide which care plan best fits individual patients and their lives, when there is more than one reasonable option. Here, we describe how SDM in the diagnosis of AD promotes patient-centered care, as it helps to adapt the diagnostic process to the patients' values and preferences. We provide an outline for a research agenda, as SDM in the diagnosis of dementia should be studied intensively incorporating the views of both patients and caregivers.

      PubDate: 2017-05-14T14:54:28Z
      DOI: 10.1016/j.trci.2017.03.008
  • Sedentary behavior as a risk factor for cognitive decline: A focus on the
           influence of glycemic control in brain health

    • Authors: Michael J. Wheeler; Paddy C. Dempsey; Megan S. Grace; Kathryn A. Ellis; Paul A. Gardiner; Daniel J. Green; David W. Dunstan
      Abstract: Publication date: Available online 2 May 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Michael J. Wheeler, Paddy C. Dempsey, Megan S. Grace, Kathryn A. Ellis, Paul A. Gardiner, Daniel J. Green, David W. Dunstan
      Cognitive decline leading to dementia represents a global health burden. In the absence of targeted pharmacotherapy, lifestyle approaches remain the best option for slowing the onset of dementia. However, older adults spend very little time doing moderate to vigorous exercise and spend most of time in sedentary behavior. Sedentary behavior has been linked to poor glycemic control and increased risk of all-cause mortality. Here, we explore a potential link between sedentary behavior and brain health. We highlight the role of glycemic control in maintaining brain function and suggest that reducing and replacing sedentary behavior with intermittent light-intensity physical activity may protect against cognitive decline by reducing glycemic variability. Given that older adults find it difficult to achieve current exercise recommendations, an additional practical strategy may be to reduce and replace sedentary behavior with intermittent light-intensity physical activity. However, more research is needed to understand the impact of poor glycemic control on brain function and whether practical interventions aimed at reducing sedentary behavior can help slow cognitive decline.

      PubDate: 2017-05-04T13:07:09Z
      DOI: 10.1016/j.trci.2017.04.001
  • Effect of physical exercise on markers of neuronal dysfunction in
           cerebrospinal fluid in patients with Alzheimer's disease

    • Authors: Camilla Steen Jensen; Erik Portelius; Peter Høgh; Lene Wermuth; Kaj Blennow; Henrik Zetterberg; Steen Gregers Hasselbalch; Anja Hviid Simonsen
      Abstract: Publication date: Available online 17 April 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Camilla Steen Jensen, Erik Portelius, Peter Høgh, Lene Wermuth, Kaj Blennow, Henrik Zetterberg, Steen Gregers Hasselbalch, Anja Hviid Simonsen
      Introduction Physical exercise has gained increasing focus as a potential mean to maintain cognitive function in patients with Alzheimer's disease (AD). Alongside the markers of specific AD pathology (amyloid-β and tau), other pathologies such as neuronal damage and synaptic loss have been proposed as markers of the disease. Here, we study the effect of physical exercise on biomarkers of neuronal and synaptic integrity. Methods Cerebrospinal fluid (CSF) from 51 AD subjects who participated in the randomized controlled trial ADEX was analyzed for the concentration of neurofilament light (NFL), neurogranin (Ng), visinin-like protein-1 (VILIP-1), and chitinase-3–like protein 1 (YKL-40). Participants were subjected to either 16 weeks of moderate- to high-intensity exercise (n = 25) or treatment as usual (control group, n = 26), and CSF was collected before and after intervention. Results No significant differences in CSF concentrations of VILIP-1, YKL-40, NFL, and Ng were observed when comparing mean change from baseline between the exercise and control groups. Similarly, when classifying subjects based on their exercise levels, no significant changes were observed for the biomarkers in the control group compared with the high-exercise group (attending 80% of the exercise sessions with an intensity of 70% of maximum heart rate or above). Discussion These results are not supportive of a modulatory effect of physical exercise on the selected biomarkers of neuronal and synaptic integrity in patients with AD.

      PubDate: 2017-04-20T17:27:42Z
      DOI: 10.1016/j.trci.2017.03.007
  • Accelerating drug development for Alzheimer's disease through the use of
           data standards

    • Authors: Jon Neville; Steve Kopko; Klaus Romero; Brian Corrigan; Bob Stafford; Elizabeth LeRoy; Steve Broadbent; Martin Cisneroz; Ethan Wilson; Eric Reiman; Hugo Vanderstichele; Stephen P. Arnerić; Diane Stephenson
      Abstract: Publication date: Available online 15 April 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Jon Neville, Steve Kopko, Klaus Romero, Brian Corrigan, Bob Stafford, Elizabeth LeRoy, Steve Broadbent, Martin Cisneroz, Ethan Wilson, Eric Reiman, Hugo Vanderstichele, Stephen P. Arnerić, Diane Stephenson
      Introduction The exceedingly high rate of failed trials in Alzheimer's disease (AD) calls for immediate attention to improve efficiencies and learning from past, ongoing, and future trials. Accurate, highly rigorous standardized data are at the core of meaningful scientific research. Data standards allow for proper integration of clinical data sets and represent the essential foundation for regulatory endorsement of drug development tools. Such tools increase the potential for success and accuracy of trial results. Methods The development of the Clinical Data Interchange Standards Consortium (CDISC) AD therapeutic area data standard was a comprehensive collaborative effort by CDISC and Coalition Against Major Disease, a consortium of the Critical Path Institute. Clinical concepts for AD and mild cognitive impairment were defined and a data standards user guide was created from various sources of input, including data dictionaries used in AD clinical trials and observational studies. Results A comprehensive collection of AD-specific clinical data standards consisting of clinical outcome measures, leading candidate genes, and cerebrospinal fluid and imaging biomarkers was developed. The AD version 2.0 (V2.0) Therapeutic Area User Guide was developed by diverse experts working with data scientists across multiple consortia through a comprehensive review and revision process. The AD CDISC standard is a publicly available resource to facilitate widespread use and implementation. Discussion The AD CDISC V2.0 data standard serves as a platform to catalyze reproducible research, data integration, and efficiencies in clinical trials. It allows for the mapping and integration of available data and provides a foundation for future studies, data sharing, and long-term registries in AD. The availability of consensus data standards for AD has the potential to facilitate clinical trial initiation and increase sharing and aggregation of data across observational studies and among clinical trials, thereby improving our understanding of disease progression and treatment.

      PubDate: 2017-04-20T17:27:42Z
      DOI: 10.1016/j.trci.2017.03.006
  • UB-311, a novel UBITh amyloid-β peptide vaccine for mild Alzheimer's

    • Authors: Chang Yi Wang; Pei-Ning Wang; Ming-Jang Chiu; Connie L. Finstad; Feng Lin; Shugene Lynn; Yuan-Hung Tai; Xin De Fang; Kesheng Zhao; Chung-Ho Hung; Yiting Tseng; Wen-Jiun Peng; Jason Wang; Chih-Chieh Yu; Be-Sheng Kuo; Paul A. Frohna
      Abstract: Publication date: Available online 14 April 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Chang Yi Wang, Pei-Ning Wang, Ming-Jang Chiu, Connie L. Finstad, Feng Lin, Shugene Lynn, Yuan-Hung Tai, Xin De Fang, Kesheng Zhao, Chung-Ho Hung, Yiting Tseng, Wen-Jiun Peng, Jason Wang, Chih-Chieh Yu, Be-Sheng Kuo, Paul A. Frohna
      Introduction A novel amyloid-β (Aβ) synthetic peptide vaccine (UB-311) has been evaluated in a first-in-human trial with patients of mild-to-moderate Alzheimer's disease. We describe translational research covering vaccine design, preclinical characterization, and phase-I clinical trial with supportive outcome that advances UB-311 into an ongoing phase-II trial. Methods UB-311 is constructed with two synthetic Aβ1–14–targeting peptides (B-cell epitope), each linked to different helper T-cell peptide epitopes (UBITh) and formulated in a Th2-biased delivery system. The hAPP751 transgenic mouse model was used to perform the proof-of-concept study. Baboons and macaques were used for preclinical safety, tolerability, and immunogenicity evaluation. Patients with mild-to-moderate Alzheimer's disease (AD) were immunized by intramuscular route with 3 doses of UB-311 at weeks 0, 4, and 12, and monitored until week 48. Safety and immunogenicity were assessed per protocol, and preliminary efficacy was analyzed by Alzheimer's Disease Assessment Scale–Cognitive Subscale (ADAS-Cog), Mini–Mental State Examination (MMSE), and Alzheimer's Disease Cooperative Study–Clinician's Global Impression of Change. Results UB-311 covers a diverse genetic background and facilitates strong immune response with high responder rate. UB-311 reduced the levels of Aβ1–42 oligomers, protofibrils, and plaque load in hAPP751 transgenic mice. Safe and well-tolerated UB-311 generated considerable site-specific (Aβ1–10) antibodies across all animal species examined. In AD patients, UB-311 induced a 100% responder rate; injection site swelling and agitation were the most common adverse events (4/19 each). A slower rate of increase in ADAS-Cog from baseline to week 48 was observed in the subgroup of mild AD patients (MMSE ≥ 20) compared with the moderate AD subgroup, suggesting that UB-311 may have a potential of cognition improvement in patients with early stage of Alzheimer's dementia. Discussion The UBITh platform can generate a high-precision molecular vaccine with high responder rate, strong on-target immunogenicity, and a potential of cognition improvement, which support UB-311 for active immunotherapy in early-to-mild AD patients currently enrolled in a phase-II trial (NCT02551809).

      PubDate: 2017-04-20T17:27:42Z
      DOI: 10.1016/j.trci.2017.03.005
  • A dopamine receptor genetic variant enhances perceptual speed in cognitive
           healthy subjects

    • Authors: Sandra Barral; Christian Habeck; Elaine Gazes; Philip L. De Jager; David A. Bennett; Yaakov Stern
      Abstract: Publication date: Available online 8 April 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Sandra Barral, Christian Habeck, Elaine Gazes, Philip L. De Jager, David A. Bennett, Yaakov Stern
      Cognition is under strong genetic control, yet the specific genes are unknown. To investigate genetic influences on specific cognitive domains, 153 cognitive healthy subjects of European ancestry from the Reference Abilities Study (Reference Ability Neural Network) were genotyped for 1160 variants within 446 neuropsychiatric genes. Adjusted linear regression models evaluated the association between the genetic variants and four reference abilities, which capture variance in age-related cognitive function (vocabulary, episodic memory, perceptual speed, and reasoning). One hundred and fifty-nine variants nominally significant in the Reference Ability Neural Network cohort were then re-evaluated in an independent cohort of 868 cognitive healthy subjects from the Religious Orders Study and Rush Memory Aging Project. Meta-analysis yielded a Bonferroni adjusted statistically significant association between perceptual speed and a variant located in the promoter of the dopamine receptor D4 gene, rs3756450 (β = 0.23, standard error = 0.05, P meta  = 2.3 × 10−5). Our data suggest that genetic variation in a dopamine pathway gene influences perceptual speed performance in cognitively healthy individuals.

      PubDate: 2017-04-14T10:55:40Z
      DOI: 10.1016/j.trci.2017.03.004
  • Inferior parietal tDCS with training improves cognition in anomic AD and

    • Authors: Carlos Roncero; Heike Kniefel; Erik Service; Alexander Thiel; Stephan Probst; Howard Chertkow
      Abstract: Publication date: Available online 24 March 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Carlos Roncero, Heike Kniefel, Erik Service, Alexander Thiel, Stephan Probst, Howard Chertkow
      Introduction We evaluated whether transcranial direct current stimulation (tDCS) can improve picture-naming abilities in subjects with anomic Alzheimer or frontotemporal dementias. Methods Using a double-blind crossover design, 10 participants were trained on picture naming over a series of 10 sessions with either 30 minutes of anodal (2 mA) tDCS stimulation to the left inferior parieto-temporal region (P3) or sham stimulation. We evaluated performance on a trained picture-naming list, an equivalent untrained list, and additional neuropsychological tasks. Results Participants improved significantly more receiving real stimulation rather than sham stimulation (40% vs. 19%, P < .01), lasting at least 2 weeks after stimulation. Furthermore, these participants showed a small increase for untrained picture-naming items and digit span when they received real stimulation but a decrease when sham stimulation was received. Discussion tDCS stimulation has promise as a treatment for anomia in demented individuals and the effect can generalize to unstudied items as well as other cognitive abilities.

      PubDate: 2017-03-30T09:18:07Z
      DOI: 10.1016/j.trci.2017.03.003
  • Differential medial temporal lobe morphometric predictors of relational
           and item-encoded memories in healthy individuals and in individuals with
           mild cognitive impairment or Alzheimer's disease

    • Authors: Jesus J. Gomar; J. Daniel Ragland; Aziz M. Uluğ; Amber Sousa; Edward D. Huey; Concepcion Conejero-Goldberg; Peter Davies; Terry E. Goldberg
      Abstract: Publication date: Available online 23 March 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Jesus J. Gomar, J. Daniel Ragland, Aziz M. Uluğ, Amber Sousa, Edward D. Huey, Concepcion Conejero-Goldberg, Peter Davies, Terry E. Goldberg
      Introduction Episodic memory processes are supported by different subregions of the medial temporal lobe (MTL). In contrast to a unitary model of memory recognition supported solely by the hippocampus, a current model suggests that item encoding engages perirhinal cortex, whereas relational encoding engages parahippocampal cortex and the hippocampus. However, this model has not been examined in the context of aging, neurodegeneration, and MTL morphometrics. Methods Forty-four healthy subjects (HSs) and 18 cognitively impaired subjects (nine mild cognitive impairment [MCI] and nine Alzheimer's disease [AD] patients) were assessed with the relational and item-specific encoding task (RISE) and underwent 3T magnetic resonance imaging. The RISE assessed the differential contribution of relational and item-specific memory. FreeSurfer was used to obtain measures of cortical thickness of MTL regions and hippocampus volume. Results Memory accuracies for both item and relational memory were significantly better in the HS group than in the MCI/AD group. In MCI/AD group, relational memory was disproportionately impaired. In HSs, hierarchical regressions demonstrated that memory was predicted by perirhinal thickness after item encoding and by hippocampus volume after relational encoding (both at trend level) and significantly by parahippocampal thickness at associative recognition. The same brain morphometry profiles predicted memory accuracy in MCI/AD although more robustly perirhinal thickness for item encoding (R2 = 0.31) and hippocampal volume and parahippocampal thickness for relational encoding (R2 = 0.31). Discussion Our results supported a model of episodic memory in which item-specific encoding was associated with greater perirhinal cortical thickness, while relational encoding was associated with parahippocampal and hippocampal morphometrics. We identified these relationships not only in HSs but also in individuals with MCI and AD. In the subjects with cognitive impairment, reductions in hippocampal volume and impairments in relational memory were especially prominent.

      PubDate: 2017-03-23T21:18:40Z
      DOI: 10.1016/j.trci.2017.03.002
  • Associations between social relationship measures, serum brain-derived
           neurotrophic factor, and risk of stroke and dementia

    • Authors: Joel Salinas; Alexa Beiser; Jayandra J. Himali; Claudia L. Satizabal; Hugo J. Aparicio; Galit Weinstein; Farrah J. Mateen; Lisa F. Berkman; Jonathan Rosand; Sudha Seshadri
      Abstract: Publication date: Available online 22 March 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Joel Salinas, Alexa Beiser, Jayandra J. Himali, Claudia L. Satizabal, Hugo J. Aparicio, Galit Weinstein, Farrah J. Mateen, Lisa F. Berkman, Jonathan Rosand, Sudha Seshadri
      Introduction Mechanisms underlying social determinants of stroke and dementia are unclear and brain-derived neurotrophic factor (BDNF) may contribute as a molecular link. Methods Using the Framingham Study, we examined social relationship measures as predictors of higher serum BDNF level and cumulative incidence of stroke and dementia. Results Among 3294 participants, controlling for age and sex, isolation trended with lower BDNF (odds ratio = 0.69 [0.47–1.00]). Participants with more companionship had reduced risk for stroke (hazard ratio [HR] = 0.59 [0.41–0.83]) and dementia (HR = 0.67 [0.49–0.92]). Greater emotional support was associated with higher BDNF (odds ratio = 1.27 [1.04–1.54]), reduced dementia risk (HR = 0.69 [0.51–0.94], and among smokers, reduced stroke risk (HR = 0.23 [0.10–0.57]). Associations persisted after additional adjustments. BDNF partly mediated the total effect between emotional support and dementia risk. Conclusions Availability of social support appears to be associated with increased BDNF levels and, in certain subsets, reduce risk of subsequent dementia and stroke, thus warranting study of these pathways to understand their role in neuroprotection.

      PubDate: 2017-03-23T21:18:40Z
      DOI: 10.1016/j.trci.2017.03.001
  • Recruiting to preclinical Alzheimer's disease clinical trials through

    • Authors: Joshua D. Grill
      Abstract: Publication date: Available online 14 March 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Joshua D. Grill
      Participant registries are repositories of individuals who have expressed willingness to learn about studies for which they may be eligible. Registries are increasingly being used to improve recruitment to preclinical Alzheimer's disease (AD) clinical trials, which require large screening efforts to identify adequate number of participants who meet enrollment criteria. Recruiting to preclinical AD trials from registries is made more efficient through registry collection of data that permits exclusion of those who will not be eligible and identifies individuals most likely to qualify for trials. Such data could include self-reported disease family history or other risk factors but could also include cognitive, genetic, or biomarker testing outcomes. Few data are available to guide investigators overseeing registries and important ethical questions are likely to arise related to their conduct, especially in registries collecting AD risk information. This article outlines three areas of consideration for registry investigators: informed consent, disclosure, and sponsorship.

      PubDate: 2017-03-18T02:09:29Z
      DOI: 10.1016/j.trci.2017.02.004
  • Effects of traumatic brain injury and posttraumatic stress disorder on
           development of Alzheimer's disease in Vietnam Veterans using the
           Alzheimer's Disease Neuroimaging Initiative: Preliminary report

    • Authors: Michael W. Weiner; Danielle Harvey; Jacqueline Hayes; Susan M. Landau; Paul S. Aisen; Ronald C. Petersen; Duygu Tosun; Dallas P. Veitch; Clifford R. Jack; Charles Decarli; Andrew J. Saykin; Jordan Grafman; Thomas C. Neylan
      Abstract: Publication date: Available online 12 March 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Michael W. Weiner, Danielle Harvey, Jacqueline Hayes, Susan M. Landau, Paul S. Aisen, Ronald C. Petersen, Duygu Tosun, Dallas P. Veitch, Clifford R. Jack, Charles Decarli, Andrew J. Saykin, Jordan Grafman, Thomas C. Neylan
      Introduction Traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD) have previously been reported to be associated with increased risk of Alzheimer's disease (AD). We are using biomarkers to study Vietnam Veterans with/without mild cognitive impairment with a history of at least one TBI and/or ongoing PTSD to determine whether these contribute to the development of AD. Methods Potential subjects identified by Veterans Administration records underwent an initial telephone screen. Consented subjects underwent clinical evaluation, lumbar puncture, structural magnetic resonance imaging, and amyloid positron emission tomography (PET) scans. Results We observed worse cognitive functioning in PTSD and TBI + PTSD groups, worse global cognitive functioning in the PTSD group, lower superior parietal volume in the TBI + PTSD group, and lower amyloid positivity in the PTSD group, but not the TBI group compared to controls without TBI/PTSD. Medial temporal lobe atrophy was not increased in the PTSD and/or TBI groups. Discussion Preliminary results do not indicate that TBI or PTSD increase the risk for AD measured by amyloid PET. Additional recruitment, longitudinal follow-up, and tau-PET scans will provide more information in the future.

      PubDate: 2017-03-18T02:09:29Z
      DOI: 10.1016/j.trci.2017.02.005
  • Study design: The effect of aerobic exercise on cerebral perfusion in
           patients with vascular cognitive impairment

    • Authors: Anna E. Leeuwis; Astrid M. Hooghiemstra; Raquel Amier; Doeschka A. Ferro; Leonie Franken; Robin Nijveldt; Joost P.A. Kuijer; Anne-Sophie G.T. Bronzwaer; Johannes J. van Lieshout; Marc B. Rietberg; Janne M. Veerbeek; Rosalie J. Huijsmans; Frank J.G. Backx; Charlotte E. Teunissen; Esther E. Bron; Frederik Barkhof; Niels D. Prins; Rahil Shahzad; Wiro J. Niessen; Albert de Roos; Matthias J.P. van Osch; Albert C. van Rossum; Geert J. Biessels; Wiesje M. van der Flier
      Abstract: Publication date: Available online 6 March 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Anna E. Leeuwis, Astrid M. Hooghiemstra, Raquel Amier, Doeschka A. Ferro, Leonie Franken, Robin Nijveldt, Joost P.A. Kuijer, Anne-Sophie G.T. Bronzwaer, Johannes J. van Lieshout, Marc B. Rietberg, Janne M. Veerbeek, Rosalie J. Huijsmans, Frank J.G. Backx, Charlotte E. Teunissen, Esther E. Bron, Frederik Barkhof, Niels D. Prins, Rahil Shahzad, Wiro J. Niessen, Albert de Roos, Matthias J.P. van Osch, Albert C. van Rossum, Geert J. Biessels, Wiesje M. van der Flier
      Introduction There is evidence for a beneficial effect of aerobic exercise on cognition, but underlying mechanisms are unclear. In this study, we test the hypothesis that aerobic exercise leads to increased cerebral blood flow in patients with vascular cognitive impairment (VCI). Methods This study is a multicenter single-blind randomized controlled trial among 80 patients with VCI. Most important inclusion criteria are a diagnosis of VCI with Mini-Mental State Examination ≥22 and Clinical Dementia Rating ≤0.5. Participants are randomized into an aerobic exercise program group or a control group. The aerobic exercise program aims to improve cardiorespiratory fitness and takes 14 weeks, with a frequency of three times a week. Participants are provided with a bicycle ergometer at home. The control group receives two information meetings. Primary outcome measure is change in cerebral blood flow in rest, measured with arterial spin labeling magnetic resonance imaging. Discussion We expect exercise on cerebral perfusion in patients with VCI to provide insight into the potential mechanism by which aerobic exercise improves hemodynamic status.

      PubDate: 2017-03-10T07:27:36Z
      DOI: 10.1016/j.trci.2017.02.002
  • Zfra restores memory deficits in Alzheimer's disease triple-transgenic
           mice by blocking aggregation of TRAPPC6AΔ, SH3GLB2, tau, and amyloid β,
           and inflammatory NF-κB activation

    • Authors: Ming-Hui Lee; Yao-Hsiang Shih; Sing-Ru Lin; Jean-Yun Chang; Yu-Hao Lin; Chun-I Sze; Yu-Min Kuo; Nan-Shan Chang
      Abstract: Publication date: Available online 6 March 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Ming-Hui Lee, Yao-Hsiang Shih, Sing-Ru Lin, Jean-Yun Chang, Yu-Hao Lin, Chun-I Sze, Yu-Min Kuo, Nan-Shan Chang
      Introduction Zinc finger-like protein that regulates apoptosis (Zfra) is a naturally occurring 31-amino-acid protein. Synthetic peptides Zfra1–31 and Zfra4–10 are known to effectively block the growth of many types of cancer cells. Methods Ten-month-old triple-transgenic (3×Tg) mice for Alzheimer's disease (AD) received synthetic Zfra peptides via tail vein injections, followed by examining restoration of memory deficits. Results Zfra significantly downregulated TRAPPC6AΔ, SH3GLB2, tau, and amyloid β (Αβ) aggregates in the brains of 3×Tg mice and effectively restored their memory capabilities. Zfra inhibited melanoma-induced neuronal death in the hippocampus and plaque formation in the cortex. Mechanistically, Zfra blocked the aggregation of amyloid β 42 and many serine-containing peptides in vitro, suppressed tumor necrosis factor–mediated NF-κB activation, and bound cytosolic proteins for accelerating their degradation in ubiquitin/proteasome-independent manner. Discussion Zfra peptides exhibit a strong efficacy in blocking tau aggregation and Αβ formation and restore memory deficits in 3×Tg mice, suggesting its potential for treatment of AD.

      PubDate: 2017-03-10T07:27:36Z
      DOI: 10.1016/j.trci.2017.02.001
  • Impact of programs to reduce antipsychotic and anticholinergic use in
           nursing homes

    • Authors: Ryan M. Carnahan; Grant D. Brown; Elena M. Letuchy; Linda M. Rubenstein; Brian M. Gryzlak; Marianne Smith; Jeffrey C. Reist; Michael W. Kelly; Susan K. Schultz; Michelle T. Weckmann; Elizabeth A. Chrischilles
      Abstract: Publication date: Available online 6 March 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Ryan M. Carnahan, Grant D. Brown, Elena M. Letuchy, Linda M. Rubenstein, Brian M. Gryzlak, Marianne Smith, Jeffrey C. Reist, Michael W. Kelly, Susan K. Schultz, Michelle T. Weckmann, Elizabeth A. Chrischilles
      Introduction Antipsychotics are used for behavioral and psychological symptoms of dementia (BPSD), but have risks. Anticholinergics can worsen outcomes in dementia. The Improving Antipsychotic Appropriateness in Dementia Patients (IA-ADAPT) educational program and Centers for Medicare and Medicaid Services' Partnership to Improve Dementia Care (CMS Partnership) promote improved care for BPSD. The purpose of this study was to evaluate the impact of these programs on medication use and BPSD among nursing home residents. Methods This quasi-experimental longitudinal study used Medicare and assessment data for Iowa nursing home residents from April 2011 to December 2012. Antipsychotic and anticholinergic use was evaluated on a monthly basis, and changes in BPSD were tracked using assessment data. Results are presented as odds ratios per month after exposure to IA-ADAPT or the start of the CMS Partnership. Results Of 427 eligible Iowa nursing homes, 114 were exposed to IA-ADAPT in 2012. Nursing home exposure to IA-ADAPT was associated with reduced antipsychotic use (OR, 0.93; 95% CI, 0.91–0.96) and anticholinergic use (OR, 0.96; 95% CI, 0.94–0.99), reduced use of excessive antipsychotic doses per CMS guidance (OR, 0.88; 95% CI, 0.82–0.93), and increased odds of a potentially appropriate indication among antipsychotic users (OR, 1.06; 95% CI, 1.02–1.11). The CMS Partnership was associated with reduced antipsychotic use (OR, 0.97; 95% CI, 0.95–0.99). IA-ADAPT was associated with increased documentation of delusions (OR, 1.04; 95% CI, 1.01–1.07) and delirium (OR, 1.03; 95% CI, 1.00–1.05), and there was a trend toward increased documentation of physical aggression (OR, 1.03; 95% CI, 1.00–1.06; P = .051). However, with the exception of delusions these increases primarily occurred in residents without dementia, who were not the subject of the intervention. Discussion This study suggests that IA-ADAPT and the CMS Partnership improved medication use. IA-ADAPT effects on BPSD are more difficult to interpret.

      PubDate: 2017-03-10T07:27:36Z
      DOI: 10.1016/j.trci.2017.02.003
  • Predicting mild cognitive impairment from spontaneous spoken utterances

    • Authors: Meysam Asgari; Jeffrey Kaye; Hiroko Dodge
      Abstract: Publication date: Available online 27 February 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Meysam Asgari, Jeffrey Kaye, Hiroko Dodge
      Introduction Trials in Alzheimer's disease are increasingly focusing on prevention in asymptomatic individuals. We hypothesized that indicators of mild cognitive impairment (MCI) may be present in the content of spoken language in older adults and be useful in distinguishing those with MCI from those who are cognitively intact. To test this hypothesis, we performed linguistic analyses of spoken words in participants with MCI and those with intact cognition participating in a clinical trial. Methods Data came from a randomized controlled behavioral clinical trial to examine the effect of unstructured conversation on cognitive function among older adults with either normal cognition or MCI ( NCT01571427). Unstructured conversations (but with standardized preselected topics across subjects) were recorded between interviewers and interviewees during the intervention sessions of the trial from 14 MCI and 27 cognitively intact participants. From the transcription of interviewees recordings, we grouped spoken words using Linguistic Inquiry and Word Count (LIWC), a structured table of words, which categorizes 2500 words into 68 different word subcategories such as positive and negative words, fillers, and physical states. The number of words in each LIWC word subcategory constructed a vector of 68 dimensions representing the linguistic features of each subject. We used support vector machine and random forest classifiers to distinguish MCI from cognitively intact participants. Results MCI participants were distinguished from those with intact cognition using linguistic features obtained by LIWC with 84% classification accuracy which is well above chance 60%.

      PubDate: 2017-03-05T06:43:37Z
      DOI: 10.1016/j.trci.2017.01.006
  • Targeting butyrylcholinesterase for preclinical SPECT imaging of
           Alzheimer's disease

    • Authors: D.R. DeBay; G.A. Reid; I.R. Pottie; E. Martin; C.V. Bowen; S. Darvesh
      Abstract: Publication date: Available online 24 February 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): D.R. DeBay, G.A. Reid, I.R. Pottie, E. Martin, C.V. Bowen, S. Darvesh
      Introduction Diagnosis of Alzheimer's disease (AD) in vivo, by molecular imaging of amyloid or tau, is constrained because similar changes can be found in brains of cognitively normal individuals. Butyrylcholinesterase (BChE), which becomes associated with these structures in AD, could elevate the accuracy of AD diagnosis by focusing on BChE pathology in the cerebral cortex, a region of scant BChE activity in healthy brain. Methods N-methylpiperidin-4-yl 4-[123I]iodobenzoate, a BChE radiotracer, was injected intravenously into 5XFAD mice and their wild-type (WT) counterparts for comparative SPECT studies. SPECT, computed tomography, and magnetic resonance imaging enabled comparison of whole brain and regional retention of the BChE radiotracer in both mouse strains. Results Retention of the BChE radiotracer was consistently higher in the 5XFAD mouse than in WT, and differences were particularly evident in the cerebral cortex. Discussion Cerebral cortical BChE imaging with SPECT can distinguish 5XFAD mouse model from the WT counterpart.

      PubDate: 2017-02-26T06:22:51Z
      DOI: 10.1016/j.trci.2017.01.005
  • The effect of statins on rate of cognitive decline in mild cognitive

    • Authors: Kyle B. Smith; Paul Kang; Marwan N. Sabbagh
      Abstract: Publication date: Available online 9 February 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Kyle B. Smith, Paul Kang, Marwan N. Sabbagh
      Introduction This study's aims are to identify whether a relationship between statin use and rate of cognitive decline exists. The relationship between statins and mild cognitive impairment (MCI) has been investigated in the past with the evidence showing mixed results. Methods Seven hundred sixty-eight subjects were identified with MCI. Subjects were stratified into six possible groups according to ApoE4 status and statin use and assessed for decline in cognitive function. Results All cognitive assessments trended toward less decline with statin use. Alzheimer’s Disease Assessment Scale 11 (ADAS 11) showed the biggest difference in mean change between statin users and nonusers (−0.82 vs. −1.22, respectively). Change reached marginal significance on the ADAS 11 when stratified by ApoE4-negative subjects. Discussion All cognitive assessments trended toward less decline when subjects were concurrently treated with a statin, supporting the position that statins do not have a net negative effect on cognitive assessment and suggests a potential treatment benefit.

      PubDate: 2017-02-13T05:19:29Z
      DOI: 10.1016/j.trci.2017.01.001
  • Design of pilot studies to inform the construction of composite
           outcome measures

    • Authors: Steven D. Edland; M. Colin Ard; Weiwei Li; Lingjing Jiang
      Abstract: Publication date: Available online 23 January 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Steven D. Edland, M. Colin Ard, Weiwei Li, Lingjing Jiang
      Background Composite scales have recently been proposed as outcome measures for clinical trials. For example, the Prodromal Alzheimer's Cognitive Composite (PACC) is the sum of z-score normed component measures assessing episodic memory, timed executive function, and global cognition. Alternative methods of calculating composite total scores using the weighted sum of the component measures that maximize signal-to-noise ratio of the resulting composite score have been proposed. Optimal weights can be estimated from pilot data, but it is an open question as how large a pilot trial is required to calculate reliably optimal weights. Methods We describe the calculation of optimal weights and use large-scale computer simulations to investigate the question as how large a pilot study sample is required to inform the calculation of optimal weights. The simulations are informed by the pattern of decline observed in cognitively normal subjects enrolled in the Alzheimer's Disease Cooperative Study Prevention Instrument cohort study, restricting to n = 75 subjects aged 75 years and older with an ApoE E4 risk allele and therefore likely to have an underlying Alzheimer neurodegenerative process. Results In the context of secondary prevention trials in Alzheimer's disease and using the components of the PACC, we found that pilot studies as small as 100 are sufficient to meaningfully inform weighting parameters. Regardless of the pilot study sample size used to inform weights, the optimally weighted PACC consistently outperformed the standard PACC in terms of statistical power to detect treatment effects in a clinical trial. Pilot studies of size 300 produced weights that achieved near-optimal statistical power and reduced required sample size relative to the standard PACC by more than half. Discussion These simulations suggest that modestly sized pilot studies, comparable to that of a phase 2 clinical trial, are sufficient to inform the construction of composite outcome measures. Although these findings apply only to the PACC in the context of prodromal Alzheimer's disease, the observation that weights only have to approximate the optimal weights to achieve near-optimal performance should generalize. Performing a pilot study or phase 2 trial to inform the weighting of proposed composite outcome measures is highly cost-effective. The net effect of more efficient outcome measures is that smaller trials will be required to test novel treatments. Alternatively, second generation trials can use prior clinical trial data to inform weighting, so that greater efficiency can be achieved as we move forward.

      PubDate: 2017-01-25T02:34:23Z
      DOI: 10.1016/j.trci.2016.12.004
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