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Showing 1 - 200 of 3080 Journals sorted alphabetically
A Practical Logic of Cognitive Systems     Full-text available via subscription   (Followers: 7)
AASRI Procedia     Open Access   (Followers: 15)
Academic Pediatrics     Hybrid Journal   (Followers: 25, SJR: 1.402, h-index: 51)
Academic Radiology     Hybrid Journal   (Followers: 22, SJR: 1.008, h-index: 75)
Accident Analysis & Prevention     Partially Free   (Followers: 86, SJR: 1.109, h-index: 94)
Accounting Forum     Hybrid Journal   (Followers: 25, SJR: 0.612, h-index: 27)
Accounting, Organizations and Society     Hybrid Journal   (Followers: 30, SJR: 2.515, h-index: 90)
Achievements in the Life Sciences     Open Access   (Followers: 4)
Acta Anaesthesiologica Taiwanica     Open Access   (Followers: 5, SJR: 0.338, h-index: 19)
Acta Astronautica     Hybrid Journal   (Followers: 363, SJR: 0.726, h-index: 43)
Acta Automatica Sinica     Full-text available via subscription   (Followers: 3)
Acta Biomaterialia     Hybrid Journal   (Followers: 25, SJR: 2.02, h-index: 104)
Acta Colombiana de Cuidado Intensivo     Full-text available via subscription   (Followers: 1)
Acta de Investigación Psicológica     Open Access   (Followers: 2)
Acta Ecologica Sinica     Open Access   (Followers: 8, SJR: 0.172, h-index: 29)
Acta Haematologica Polonica     Free   (SJR: 0.123, h-index: 8)
Acta Histochemica     Hybrid Journal   (Followers: 3, SJR: 0.604, h-index: 38)
Acta Materialia     Hybrid Journal   (Followers: 229, SJR: 3.683, h-index: 202)
Acta Mathematica Scientia     Full-text available via subscription   (Followers: 5, SJR: 0.615, h-index: 21)
Acta Mechanica Solida Sinica     Full-text available via subscription   (Followers: 9, SJR: 0.442, h-index: 21)
Acta Oecologica     Hybrid Journal   (Followers: 10, SJR: 0.915, h-index: 53)
Acta Otorrinolaringologica (English Edition)     Full-text available via subscription   (Followers: 1)
Acta Otorrinolaringológica Española     Full-text available via subscription   (Followers: 3, SJR: 0.311, h-index: 16)
Acta Pharmaceutica Sinica B     Open Access   (Followers: 1)
Acta Poética     Open Access   (Followers: 4)
Acta Psychologica     Hybrid Journal   (Followers: 24, SJR: 1.365, h-index: 73)
Acta Sociológica     Open Access  
Acta Tropica     Hybrid Journal   (Followers: 6, SJR: 1.059, h-index: 77)
Acta Urológica Portuguesa     Open Access  
Actas Dermo-Sifiliograficas     Full-text available via subscription   (Followers: 4)
Actas Dermo-Sifiliográficas (English Edition)     Full-text available via subscription   (Followers: 3)
Actas Urológicas Españolas     Full-text available via subscription   (Followers: 4, SJR: 0.383, h-index: 19)
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Actualites Pharmaceutiques     Full-text available via subscription   (Followers: 5, SJR: 0.141, h-index: 3)
Actualites Pharmaceutiques Hospitalieres     Full-text available via subscription   (Followers: 4, SJR: 0.112, h-index: 2)
Acupuncture and Related Therapies     Hybrid Journal   (Followers: 4)
Acute Pain     Full-text available via subscription   (Followers: 13)
Ad Hoc Networks     Hybrid Journal   (Followers: 11, SJR: 0.967, h-index: 57)
Addictive Behaviors     Hybrid Journal   (Followers: 15, SJR: 1.514, h-index: 92)
Addictive Behaviors Reports     Open Access   (Followers: 6)
Additive Manufacturing     Hybrid Journal   (Followers: 7, SJR: 1.039, h-index: 5)
Additives for Polymers     Full-text available via subscription   (Followers: 21)
Advanced Drug Delivery Reviews     Hybrid Journal   (Followers: 132, SJR: 5.2, h-index: 222)
Advanced Engineering Informatics     Hybrid Journal   (Followers: 11, SJR: 1.265, h-index: 53)
Advanced Powder Technology     Hybrid Journal   (Followers: 17, SJR: 0.739, h-index: 33)
Advances in Accounting     Hybrid Journal   (Followers: 9, SJR: 0.299, h-index: 15)
Advances in Agronomy     Full-text available via subscription   (Followers: 15, SJR: 2.071, h-index: 82)
Advances in Anesthesia     Full-text available via subscription   (Followers: 26, SJR: 0.169, h-index: 4)
Advances in Antiviral Drug Design     Full-text available via subscription   (Followers: 3)
Advances in Applied Mathematics     Full-text available via subscription   (Followers: 6, SJR: 1.054, h-index: 35)
Advances in Applied Mechanics     Full-text available via subscription   (Followers: 11, SJR: 0.801, h-index: 26)
Advances in Applied Microbiology     Full-text available via subscription   (Followers: 22, SJR: 1.286, h-index: 49)
Advances In Atomic, Molecular, and Optical Physics     Full-text available via subscription   (Followers: 16, SJR: 3.31, h-index: 42)
Advances in Biological Regulation     Hybrid Journal   (Followers: 4, SJR: 2.277, h-index: 43)
Advances in Botanical Research     Full-text available via subscription   (Followers: 3, SJR: 0.619, h-index: 48)
Advances in Cancer Research     Full-text available via subscription   (Followers: 25, SJR: 2.215, h-index: 78)
Advances in Carbohydrate Chemistry and Biochemistry     Full-text available via subscription   (Followers: 9, SJR: 0.9, h-index: 30)
Advances in Catalysis     Full-text available via subscription   (Followers: 5, SJR: 2.139, h-index: 42)
Advances in Cell Aging and Gerontology     Full-text available via subscription   (Followers: 4)
Advances in Cellular and Molecular Biology of Membranes and Organelles     Full-text available via subscription   (Followers: 12)
Advances in Chemical Engineering     Full-text available via subscription   (Followers: 27, SJR: 0.183, h-index: 23)
Advances in Child Development and Behavior     Full-text available via subscription   (Followers: 10, SJR: 0.665, h-index: 29)
Advances in Chronic Kidney Disease     Full-text available via subscription   (Followers: 9, SJR: 1.268, h-index: 45)
Advances in Clinical Chemistry     Full-text available via subscription   (Followers: 29, SJR: 0.938, h-index: 33)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 18, SJR: 2.314, h-index: 130)
Advances in Computers     Full-text available via subscription   (Followers: 16, SJR: 0.223, h-index: 22)
Advances in Dermatology     Full-text available via subscription   (Followers: 12)
Advances in Developmental Biology     Full-text available via subscription   (Followers: 11)
Advances in Digestive Medicine     Open Access   (Followers: 7)
Advances in DNA Sequence-Specific Agents     Full-text available via subscription   (Followers: 5)
Advances in Drug Research     Full-text available via subscription   (Followers: 22)
Advances in Ecological Research     Full-text available via subscription   (Followers: 45, SJR: 3.25, h-index: 43)
Advances in Engineering Software     Hybrid Journal   (Followers: 26, SJR: 0.486, h-index: 10)
Advances in Experimental Biology     Full-text available via subscription   (Followers: 7)
Advances in Experimental Social Psychology     Full-text available via subscription   (Followers: 43, SJR: 5.465, h-index: 64)
Advances in Exploration Geophysics     Full-text available via subscription   (Followers: 3)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 8)
Advances in Food and Nutrition Research     Full-text available via subscription   (Followers: 51, SJR: 0.674, h-index: 38)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 16)
Advances in Genetics     Full-text available via subscription   (Followers: 15, SJR: 2.558, h-index: 54)
Advances in Genome Biology     Full-text available via subscription   (Followers: 11)
Advances in Geophysics     Full-text available via subscription   (Followers: 6, SJR: 2.325, h-index: 20)
Advances in Heat Transfer     Full-text available via subscription   (Followers: 22, SJR: 0.906, h-index: 24)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 9, SJR: 0.497, h-index: 31)
Advances in Human Factors/Ergonomics     Full-text available via subscription   (Followers: 26)
Advances in Imaging and Electron Physics     Full-text available via subscription   (Followers: 2, SJR: 0.396, h-index: 27)
Advances in Immunology     Full-text available via subscription   (Followers: 36, SJR: 4.152, h-index: 85)
Advances in Inorganic Chemistry     Full-text available via subscription   (Followers: 9, SJR: 1.132, h-index: 42)
Advances in Insect Physiology     Full-text available via subscription   (Followers: 3, SJR: 1.274, h-index: 27)
Advances in Integrative Medicine     Hybrid Journal   (Followers: 6)
Advances in Intl. Accounting     Full-text available via subscription   (Followers: 4)
Advances in Life Course Research     Hybrid Journal   (Followers: 8, SJR: 0.764, h-index: 15)
Advances in Lipobiology     Full-text available via subscription   (Followers: 2)
Advances in Magnetic and Optical Resonance     Full-text available via subscription   (Followers: 9)
Advances in Marine Biology     Full-text available via subscription   (Followers: 16, SJR: 1.645, h-index: 45)
Advances in Mathematics     Full-text available via subscription   (Followers: 10, SJR: 3.261, h-index: 65)
Advances in Medical Sciences     Hybrid Journal   (Followers: 6, SJR: 0.489, h-index: 25)
Advances in Medicinal Chemistry     Full-text available via subscription   (Followers: 5)
Advances in Microbial Physiology     Full-text available via subscription   (Followers: 4, SJR: 1.44, h-index: 51)
Advances in Molecular and Cell Biology     Full-text available via subscription   (Followers: 22)
Advances in Molecular and Cellular Endocrinology     Full-text available via subscription   (Followers: 10)
Advances in Molecular Toxicology     Full-text available via subscription   (Followers: 8, SJR: 0.324, h-index: 8)
Advances in Nanoporous Materials     Full-text available via subscription   (Followers: 4)
Advances in Oncobiology     Full-text available via subscription   (Followers: 3)
Advances in Organ Biology     Full-text available via subscription   (Followers: 2)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 15, SJR: 2.885, h-index: 45)
Advances in Parallel Computing     Full-text available via subscription   (Followers: 7, SJR: 0.148, h-index: 11)
Advances in Parasitology     Full-text available via subscription   (Followers: 7, SJR: 2.37, h-index: 73)
Advances in Pediatrics     Full-text available via subscription   (Followers: 24, SJR: 0.4, h-index: 28)
Advances in Pharmaceutical Sciences     Full-text available via subscription   (Followers: 13)
Advances in Pharmacology     Full-text available via subscription   (Followers: 15, SJR: 1.718, h-index: 58)
Advances in Physical Organic Chemistry     Full-text available via subscription   (Followers: 8, SJR: 0.384, h-index: 26)
Advances in Phytomedicine     Full-text available via subscription  
Advances in Planar Lipid Bilayers and Liposomes     Full-text available via subscription   (Followers: 3, SJR: 0.248, h-index: 11)
Advances in Plant Biochemistry and Molecular Biology     Full-text available via subscription   (Followers: 8)
Advances in Plant Pathology     Full-text available via subscription   (Followers: 5)
Advances in Porous Media     Full-text available via subscription   (Followers: 4)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 17)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 20, SJR: 1.5, h-index: 62)
Advances in Psychology     Full-text available via subscription   (Followers: 62)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 5, SJR: 0.478, h-index: 32)
Advances in Radiation Oncology     Open Access  
Advances in Small Animal Medicine and Surgery     Hybrid Journal   (Followers: 2, SJR: 0.1, h-index: 2)
Advances in Space Biology and Medicine     Full-text available via subscription   (Followers: 5)
Advances in Space Research     Full-text available via subscription   (Followers: 360, SJR: 0.606, h-index: 65)
Advances in Structural Biology     Full-text available via subscription   (Followers: 8)
Advances in Surgery     Full-text available via subscription   (Followers: 7, SJR: 0.823, h-index: 27)
Advances in the Study of Behavior     Full-text available via subscription   (Followers: 30, SJR: 1.321, h-index: 56)
Advances in Veterinary Medicine     Full-text available via subscription   (Followers: 16)
Advances in Veterinary Science and Comparative Medicine     Full-text available via subscription   (Followers: 13)
Advances in Virus Research     Full-text available via subscription   (Followers: 5, SJR: 1.878, h-index: 68)
Advances in Water Resources     Hybrid Journal   (Followers: 44, SJR: 2.408, h-index: 94)
Aeolian Research     Hybrid Journal   (Followers: 5, SJR: 0.973, h-index: 22)
Aerospace Science and Technology     Hybrid Journal   (Followers: 331, 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: 417, SJR: 1.385, h-index: 72)
Agri Gene     Hybrid Journal  
Agricultural and Forest Meteorology     Hybrid Journal   (Followers: 16, SJR: 2.18, h-index: 116)
Agricultural Systems     Hybrid Journal   (Followers: 30, SJR: 1.275, h-index: 74)
Agricultural Water Management     Hybrid Journal   (Followers: 40, SJR: 1.546, h-index: 79)
Agriculture and Agricultural Science Procedia     Open Access  
Agriculture and Natural Resources     Open Access   (Followers: 2)
Agriculture, Ecosystems & Environment     Hybrid Journal   (Followers: 55, 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: 11, 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   (Followers: 1)
Algal Research     Partially Free   (Followers: 8, SJR: 2.05, h-index: 20)
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 3)
Allergologia et Immunopathologia     Full-text available via subscription   (Followers: 1, SJR: 0.46, h-index: 29)
Allergology Intl.     Open Access   (Followers: 4, SJR: 0.776, h-index: 35)
Alpha Omegan     Full-text available via subscription   (SJR: 0.121, h-index: 9)
ALTER - European J. of Disability Research / Revue Européenne de Recherche sur le Handicap     Full-text available via subscription   (Followers: 9, SJR: 0.158, h-index: 9)
Alzheimer's & Dementia     Hybrid Journal   (Followers: 46, SJR: 4.289, h-index: 64)
Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring     Open Access   (Followers: 4)
Alzheimer's & Dementia: Translational Research & Clinical Interventions     Open Access   (Followers: 4)
Ambulatory Pediatrics     Hybrid Journal   (Followers: 5)
American Heart J.     Hybrid Journal   (Followers: 49, SJR: 3.157, h-index: 153)
American J. of Cardiology     Hybrid Journal   (Followers: 48, SJR: 2.063, h-index: 186)
American J. of Emergency Medicine     Hybrid Journal   (Followers: 40, SJR: 0.574, h-index: 65)
American J. of Geriatric Pharmacotherapy     Full-text available via subscription   (Followers: 9, SJR: 1.091, h-index: 45)
American J. of Geriatric Psychiatry     Hybrid Journal   (Followers: 14, SJR: 1.653, h-index: 93)
American J. of Human Genetics     Hybrid Journal   (Followers: 32, SJR: 8.769, h-index: 256)
American J. of Infection Control     Hybrid Journal   (Followers: 26, 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: 46, 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: 199, SJR: 2.255, h-index: 171)
American J. of Ophthalmology     Hybrid Journal   (Followers: 59, SJR: 2.803, h-index: 148)
American J. of Ophthalmology Case Reports     Open Access   (Followers: 6)
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: 27, SJR: 2.653, h-index: 228)
American J. of Preventive Medicine     Hybrid Journal   (Followers: 25, SJR: 2.764, h-index: 154)
American J. of Surgery     Hybrid Journal   (Followers: 35, 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: 6)
Anaerobe     Hybrid Journal   (Followers: 4, SJR: 1.066, h-index: 51)
Anaesthesia & Intensive Care Medicine     Full-text available via subscription   (Followers: 58, SJR: 0.124, h-index: 9)
Anaesthesia Critical Care & Pain Medicine     Full-text available via subscription   (Followers: 12)
Anales de Cirugia Vascular     Full-text available via subscription  
Anales de Pediatría     Full-text available via subscription   (Followers: 2, SJR: 0.209, h-index: 27)
Anales de Pediatría (English Edition)     Full-text available via subscription  
Anales de Pediatría Continuada     Full-text available via subscription   (SJR: 0.104, h-index: 3)
Analytic Methods in Accident Research     Hybrid Journal   (Followers: 4, SJR: 2.577, h-index: 7)
Analytica Chimica Acta     Hybrid Journal   (Followers: 37, SJR: 1.548, h-index: 152)
Analytical Biochemistry     Hybrid Journal   (Followers: 166, SJR: 0.725, h-index: 154)
Analytical Chemistry Research     Open Access   (Followers: 8, SJR: 0.18, h-index: 2)
Analytical Spectroscopy Library     Full-text available via subscription   (Followers: 12)
Anesthésie & Réanimation     Full-text available via subscription   (Followers: 1)
Anesthesiology Clinics     Full-text available via subscription   (Followers: 22, SJR: 0.421, h-index: 40)
Angiología     Full-text available via subscription   (SJR: 0.124, h-index: 9)
Angiologia e Cirurgia Vascular     Open Access  
Animal Behaviour     Hybrid Journal   (Followers: 172, SJR: 1.907, h-index: 126)

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Journal Cover Alzheimer's & Dementia: Translational Research & Clinical Interventions
  [4 followers]  Follow
  This is an Open Access Journal Open Access journal
   ISSN (Online) 2352-8737
   Published by Elsevier Homepage  [3049 journals]
  • Tangled tau: Active pathology or footprint of disease'

    • Authors: James P. Higham
      Pages: 658 - 659
      Abstract: Publication date: November 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions, Volume 3, Issue 4
      Author(s): James P. Higham

      PubDate: 2017-12-10T12:40:25Z
      DOI: 10.1016/j.trci.2017.10.007
  • Integrating sex and gender into neurodegeneration research: A
           six-component strategy

    • Authors: Mary C. Tierney; Ashley F. Curtis; Howard Chertkow; R. Jane Rylett
      Pages: 660 - 667
      Abstract: Publication date: November 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions, Volume 3, Issue 4
      Author(s): Mary C. Tierney, Ashley F. Curtis, Howard Chertkow, R. Jane Rylett
      Introduction Despite important sex differences, there remains a paucity of studies examining sex and gender differences in neurodegeneration. The Canadian Consortium on Neurodegeneration in Aging (CCNA), a national network of researchers, provides an ideal platform to incorporate sex and gender. Methods CCNA's Women, Gender, Sex and Dementia program developed and implemented a six-component strategy involving executive oversight, training, research collaboration, progress report assessment, results dissemination, and ongoing manuscript review. The inclusion of sex and gender in current and planned CCNA projects was examined in two progress reporting periods in 2016. Results Sex and gender research productivity increased substantially for both preclinical (36%–45%) and human (56%–60%) cohorts. The main barrier was lack of funding. Discussion The Women, Gender, Sex and Dementia strategy resulted in a major increase of sex and gender into research on neurodegenerative disorders. This best practice model could be utilized by a wide variety of large multidisciplinary groups.

      PubDate: 2017-12-10T12:40:25Z
      DOI: 10.1016/j.trci.2017.10.006
  • 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: 2017-11-18T12:07:30Z
      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: 2017-11-18T12:07:30Z
      DOI: 10.1016/j.trci.2017.07.001
  • Person-centered care for older people with dementia in the acute hospital

    • Authors: Felicia Hui En Tay; Claire L. Thompson; Chih Ming Nieh; Chih Chiang Nieh; Hui Mien Koh; Jessie Joon Cheen Tan; Philip Lin Kiat Yap
      Abstract: Publication date: Available online 6 December 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Felicia Hui En Tay, Claire L. Thompson, Chih Ming Nieh, Chih Chiang Nieh, Hui Mien Koh, Jessie Joon Cheen Tan, Philip Lin Kiat Yap
      Introduction Patients with dementia (PWDs) are often subjected to enforced dependency and experience functional decline and emotional distress during hospital stay. Person-centered care (PCC) with specialized psychosocial interventions, minimally obtrusive medical care, and physical restraints-free practice holds potential to improve patient outcomes. We evaluate the effectiveness of an acute hospital dementia unit (Care for Acute Mentally Infirm Elders [CAMIE]) that adopts a PCC protocol. Methods Prospective naturalistic cohort study whereby PWDs in the CAMIE unit (n = 170) were compared with a control group in usual care wards (n = 60) over 6 months. Assessments included patient demographics, dementia type and stage, comorbidities (Charlson's Comorbidity Index), acute illness severity, Well-Being, Ill-Being, functional status (Modified Barthel Index), agitation levels (Pittsburgh Agitation Scale), and quality of life (EuroQoL), assessed on admission and discharge. Multivariate analysis of covariance examined the effect of CAMIE versus usual care on pre-post outcomes. Results CAMIE patients showed statistically significant greater gains in Modified Barthel Index function and Well-Being, decreased Ill-Being and agitation, and greater improvement in EuroQoL index score (effect size: Δ = 0.18) after adjusting for baseline differences that translated to a quality-adjusted life years gain of 0.045, assuming stability over 3 months. Estimating added cost of CAMIE stay over usual care at SGD 1500 (USD 1040) for average length of stay of 15 days per patient, the incremental cost-effectiveness ratio fell within the threshold for cost-effectiveness at USD 23,111. Discussion PCC for PWDs in acute hospitals not only improves clinical outcomes for patients but is also cost-effective. The results support the adoption of PCC on a wider scale for better care of PWDs.

      PubDate: 2017-12-10T12:40:25Z
      DOI: 10.1016/j.trci.2017.11.003
  • Feasibility and efficacy data from a ketogenic diet intervention in
           Alzheimer's disease

    • Authors: Matthew K. Taylor; Debra K. Sullivan; Jonathan D. Mahnken; Jeffrey M. Burns; Russell H. Swerdlow
      Abstract: Publication date: Available online 6 December 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Matthew K. Taylor, Debra K. Sullivan, Jonathan D. Mahnken, Jeffrey M. Burns, Russell H. Swerdlow
      Introduction We assessed the feasibility and cognitive effects of a ketogenic diet (KD) in participants with Alzheimer's disease. Methods The Ketogenic Diet Retention and Feasibility Trial featured a 3-month, medium-chain triglyceride–supplemented KD followed by a 1-month washout in clinical dementia rating (CDR) 0.5, 1, and 2 participants. We obtained urine acetoacetate, serum β-hydroxybutyrate, food record, and safety data. We administered the Alzheimer's Disease Assessment Scale-cognitive subscale and Mini–Mental State Examination before the KD, and following the intervention and washout. Results We enrolled seven CDR 0.5, four CDR 1, and four CDR 2 participants. One CDR 0.5 and all CDR 2 participants withdrew citing caregiver burden. The 10 completers achieved ketosis. Most adverse events were of medium-chain triglyceride–related. Among the completers, the mean of the Alzheimer's Disease Assessment Scale-cognitive subscale score improved by 4.1 points during the diet (P = .02) and reverted to baseline after the washout. Conclusion This pilot trial justifies KD studies in mild Alzheimer's disease.

      PubDate: 2017-12-10T12:40:25Z
      DOI: 10.1016/j.trci.2017.11.002
  • Unmasking the benefits of donepezil via psychometrically precise
           identification of mild cognitive impairment: A secondary analysis of the
           ADCS vitamin E and donepezil in MCI study

    • Authors: Emily C. Edmonds; M. Colin Ard; Steven D. Edland; Douglas R. Galasko; David P. Salmon; Mark W. Bondi
      Abstract: Publication date: Available online 1 December 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Emily C. Edmonds, M. Colin Ard, Steven D. Edland, Douglas R. Galasko, David P. Salmon, Mark W. Bondi
      Introduction Criteria for mild cognitive impairment (MCI) used in many clinical trials are susceptible to “false-positive (FP)” errors that can be avoided by an “actuarial” psychometric approach. Methods Cluster analysis was applied to baseline neuropsychological test data from 756 MCI participants in the Alzheimer's Disease Cooperative Study donepezil trial. Treatment groups were compared after “FP” MCI cases were removed. Results Cluster analyses revealed three groups: “single-domain amnestic MCI” (31%), “multidomain amnestic MCI” (39%), and “FP MCI” (30%). After removing FP MCI cases, the donepezil treatment group had a lower rate of progression to Alzheimer's disease and better performance on cognitive tests than the placebo/vitamin E group. Discussion Removal of “FP” MCI diagnoses unmasked beneficial effects of donepezil, despite a 30% reduction in sample size. MCI subject selection based on actuarial methods with comprehensive neuropsychological test data can result in more efficient clinical trials and improved ability to detect treatment effects.

      PubDate: 2017-12-10T12:40:25Z
      DOI: 10.1016/j.trci.2017.11.001
  • Longitudinal patterns of potentially inappropriate medication use
           following incident dementia diagnosis

    • Authors: Christine M. Ramsey; Danijiela Gnjidic; George O. Agogo; Heather Allore; Daniela Moga
      Abstract: Publication date: Available online 26 November 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Christine M. Ramsey, Danijiela Gnjidic, George O. Agogo, Heather Allore, Daniela Moga
      Introduction Potentially inappropriate medication (PIM) use in older adults with dementia is an understudied area. We assessed longitudinal changes in PIM exposure by dementia type following dementia diagnosis. Methods We followed 2448 participants aged ≥65 years (52% women, 85.5% Caucasian, mean age 80.9 ± 7.5 years) diagnosed with dementia after enrollment in the National Alzheimer's Coordinating Center (2005–2014). We estimated the association between dementia type and PIM annually for 2 years after diagnosis, using Generalized Estimating Equations. Results Participants with Lewy body dementia had more PIM use, and participants with frontotemporal dementia had less PIM use than participants with Alzheimer's disease. In the first year following diagnosis, total number of medications increased, on average, by 10% for Alzheimer's disease and 15% for Lewy body dementia (P < .05 for both). Discussion A tailored approach aimed at optimizing drug therapy is needed to mitigate PIM exposure to improve medical care for individuals with dementia.

      PubDate: 2017-12-10T12:40:25Z
      DOI: 10.1016/j.trci.2017.10.008
  • Drug discovery and development: Role of basic biological research

    • Authors: Richard C. Mohs; Nigel H. Greig
      Abstract: Publication date: Available online 11 November 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Richard C. Mohs, Nigel H. Greig
      This article provides a brief overview of the processes of drug discovery and development. Our aim is to help scientists whose research may be relevant to drug discovery and/or development to frame their research report in a way that appropriately places their findings within the drug discovery and development process and thereby support effective translation of preclinical research to humans. One overall theme of our article is that the process is sufficiently long, complex, and expensive so that many biological targets must be considered for every new medicine eventually approved for clinical use and new research tools may be needed to investigate each new target. Studies that contribute to solving any of the many scientific and operational issues involved in the development process can improve the efficiency of the process. An awareness of these issues allows the early implementation of measures to increase the opportunity for success. As editors of the journal, we encourage submission of research reports that provide data relevant to the issues presented.

      PubDate: 2017-11-12T08:26:12Z
      DOI: 10.1016/j.trci.2017.10.005
  • Optimizing the preclinical Alzheimer's cognitive composite with semantic
           processing: The PACC5

    • Authors: Kathryn V. Papp; Dorene M. Rentz; Irina Orlovsky; Reisa A. Sperling; Elizabeth C. Mormino
      Abstract: Publication date: Available online 10 November 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Kathryn V. Papp, Dorene M. Rentz, Irina Orlovsky, Reisa A. Sperling, Elizabeth C. Mormino
      Introduction Amyloid-related decline in semantic memory was recently shown to be observable in the preclinical period of Alzheimer's disease. Cognitive composites designed to be sensitive to cognitive change in preclinical Alzheimer's disease (e.g., preclinical Alzheimer's cognitive composite [PACC]) and currently used in secondary prevention trials do not currently integrate measures of semantic processing. Our objective was to determine whether a standard semantic measure (i.e., category fluency [CAT] to animals, fruits, and vegetables) adds independent information above and beyond Aβ-related decline captured by the PACC. Methods Clinically normal older adults from the Harvard Aging Brain Study were identified at baseline as Aβ+ (n = 70) or Aβ− (n = 209) using Pittsburgh compound B–positron emission tomography imaging and followed annually with neuropsychological testing for 3.87 ± 1.09 years. The relationships between PACC, CAT, and variations of the PACC including/excluding CAT were examined using linear mixed models controlling for age, sex, and education. We additionally examined decline on CAT by further grouping Aβ+ participants into preclinical stage 1 and stage 2 on the basis of neurodegeneration markers. Results CAT explained unique variance in amyloid-related decline, with Aβ+'s continuing to decline relative to Aβ−'s in CAT even after controlling for overall PACC decline. In addition, removal of CAT from the PACC resulted in a longitudinal Aβ+/− effect size reduction of 20% at 3-year follow-up and 12% at 5-year follow-up. Finally, both stage 1 and stage 2 participants declined on CAT in comparison with stage 0, suggesting CAT declines early within the preclinical trajectory. Conclusion Addition of CAT to the PACC provides unique information about early cognitive decline not currently captured by the episodic memory, executive function, and global cognition components and may therefore improve detection of early Aβ-related cognitive decline.

      PubDate: 2017-11-12T08:26:12Z
      DOI: 10.1016/j.trci.2017.10.004
  • Computerized cognitive training for older diabetic adults at risk of
           dementia: Study protocol for a randomized controlled trial

    • Authors: Rachel Bloom; Michal Schnaider-Beeri; Ramit Ravona-Springer; Anthony Heymann; Dabush Hai; Lior Bar; Shirel Slater; Yuri Rassovsky; Alex Bahar-Fuchs
      Abstract: Publication date: Available online 10 November 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Rachel Bloom, Michal Schnaider-Beeri, Ramit Ravona-Springer, Anthony Heymann, Dabush Hai, Lior Bar, Shirel Slater, Yuri Rassovsky, Alex Bahar-Fuchs
      Background Older adults with type 2 diabetes are at high risk of cognitive decline and dementia and form an important target group for dementia risk reduction studies. Despite evidence that computerized cognitive training (CCT) may benefit cognitive performance in cognitively healthy older adults and those with mild cognitive impairment, whether CCT may benefit cognitive performance or improve disease self-management in older diabetic adults has not been studied to date. In addition, whether adaptive difficulty levels and tailoring of interventions to individuals' cognitive profile are superior to generic training remains to be established. Method Ninety community-dwelling older (age ≥ 65) diabetic adults are recruited and randomized into a tailored and adaptive computerized cognitive training condition or to a generic, nontailored, or adaptive CCT condition. Both groups complete an 8-week training program using the commercially available CogniFit program. The intervention is augmented by a range of behavior-change techniques, and participants in each condition are further randomized into a global or cognition-specific phone-based self-efficacy (SE) condition, or a no-SE condition. The primary outcome is global cognitive performance immediately after the intervention. Secondary outcomes include diabetes self-management, meta-memory, mood, and SE. Discussion This pilot study is the first trial evaluating the potential benefits of home-based tailored and adaptive CCT in relation to cognitive and disease self-management in older diabetic adults. Methodological strengths of this trial include the double-blind design, the clear identification of the proposed active ingredients of the intervention, and the use of evidence-based behavior-change techniques. Results from this study will indicate whether CCT has the potential to lower the risk of diabetes-related cognitive decline. The outcomes of the trial will also advance our understanding of essential intervention parameters required to improve or maintain cognitive function and enhance disease self-management in this at-risk group.

      PubDate: 2017-11-12T08:26:12Z
      DOI: 10.1016/j.trci.2017.10.003
  • A randomized, exploratory molecular imaging study targeting amyloid beta
           with a novel 8-OH quinoline in Alzheimer's disease (The PBT2-204 IMAGINE

    • Authors: V.L. Villemagne; C.C. Rowe; K.J. Barnham; R. Cherny; M. Woodward; S. Bozinosvski; O. Salvado; P. Bourgeat; K. Perez; C. Fowler; A. Rembach; P. Maruff; C. Ritchie; R. Tanzi; C.L. Masters
      Abstract: Publication date: Available online 9 November 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): V.L. Villemagne, C.C. Rowe, K.J. Barnham, R. Cherny, M. Woodward, S. Bozinosvski, O. Salvado, P. Bourgeat, K. Perez, C. Fowler, A. Rembach, P. Maruff, C. Ritchie, R. Tanzi, C.L. Masters
      Introduction We are developing a second generation 8-OH quinoline (2-(dimethylamino) methyl-5, 7-dichloro-8-hydroxyquinoline [PBT2, Prana Biotechnology]) for targeting amyloid beta (Aβ) in Alzheimer's disease (AD). In an earlier phase IIa, 3 month trial, PBT2 lowered CSF Aβ by 13% and improved cognition (executive function) in a dose-related fashion in early AD. We, therefore, sought to learn whether PBT2 could alter the Aβ-PET signal in subjects with prodromal or mild AD, in an exploratory randomized study over a 12-month phase in a double-blind and a 12-month open label extension phase trial design. Methods For inclusion, the usual clinical criteria for prodromal or probable AD, Mini–Mental State Examination ≥20, and global Pittsburgh compound B (PiB)-PET standardized uptake volume ratio (SUVR) >1.7 were used. As this was an exploratory study, we included contemporaneous matched control data from the Australian Imaging Biomarker and Lifestyle Study (AIBL). Other measures included FDG-PET, magnetic resonance imaging volumetrics, blood Aβ biomarkers, and cognition and function. Results Forty subjects completed the first 12-month double-blind phase (placebo = 15, PBT2 = 25), and 27 subjects completed the 12-month open label extension phase (placebo = 11, PBT2 = 16). Overall, PTB2 250 mg/day was safe and well tolerated. The mean PiB-PET SUVR at baseline was 2.51 ± 0.59. After adjusting for baseline SUVR, in the double-blind phase, the placebo group showed a nonsignificant decline in PiB-PET SUVR, whereas the PBT2 group declined significantly (P = .048). Subjects who did not enter or complete the extension study had a significantly higher 12-month Aβ-PET SUVR (2.68 ± 0.55) compared with those who completed (2.29 ± 0.48). Both groups differed significantly from the rate of change over 12 months in the AIBL control group. In the open label 12-month exclusion study, the PiB-SUVR stabilized. There were no significant differences between PBT2 and controls in FDG-PET, magnetic resonance imaging volumetrics, blood Aβ biomarkers, or cognition/function over the course of the double-blind phase. Discussion There was no significant difference between PBT2 and controls at 12 months, likely due to the large individual variances over a relatively small number of subjects. PBT2 was associated with a significant 3% PiB-PET SUVR decline in the double-blind phase and a stabilization of SUVR in the open-label phase. From this exploratory study, we have learned that the entry criterion of SUVR should have been set at ≥ 1.5 and <2.0, where we know from the AIBL study that subjects in this band are accumulating Aβ in a linear fashion and that subjects who withdrew from this type of study have much higher SUVRs, which if not taken into account, could distort the final results. Because of large individual variations in SUVR, future studies of PBT2 will require larger numbers of subjects (n > 90 per arm) over a longer period (18 months or more). Further evaluation of higher doses of PBT2 in earlier stages of AD is warranted. Trial Registration ACTRN 12611001008910 and ACTRN 12613000777796.

      PubDate: 2017-11-12T08:26:12Z
      DOI: 10.1016/j.trci.2017.10.001
  • Protective effect of antirheumatic drugs on dementia in rheumatoid
           arthritis patients

    • Authors: Andy Judge; Cesar Garriga; Nigel K. Arden; Simon Lovestone; Dani Prieto-Alhambra; Cyrus Cooper; Christopher J. Edwards
      Abstract: Publication date: Available online 9 November 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Andy Judge, Cesar Garriga, Nigel K. Arden, Simon Lovestone, Dani Prieto-Alhambra, Cyrus Cooper, Christopher J. Edwards
      Introduction Rheumatoid arthritis is a systemic inflammatory disease, and classical disease-modifying antirheumatic drugs (cDMARDs) have proven efficacy. It is unknown what impact cDMARDs might have on dementia as an outcome. Methods Incident diagnoses of rheumatoid arthritis in persons over 18 years from 1995 to 2011 were identified from the UK Clinical Practice Research Datalink. There were 3876 cDMARD users and were propensity score matched to 1938 nonusers, on a wide range of confounders. Impact on dementia was assessed using survival models. Results cDMARD users were at reduced risk of dementia (hazard ratio: 0.60; 95% confidence interval: 0.42–0.85). The effect was strongest in methotrexate users (hazard ratio: 0.52; 95% confidence interval; 0.34–0.82). Discussion The strong effect of cDMARD use on halving of dementia risk requires replication in a trial and may provide an important therapeutic pharmacological treatment.

      PubDate: 2017-11-12T08:26:12Z
      DOI: 10.1016/j.trci.2017.10.002
  • Speed of processing training results in lower risk of dementia

    • Authors: Jerri D. Edwards; Huiping Xu; Daniel O. Clark; Lin T. Guey; Lesley A. Ross; Frederick W. Unverzagt
      Abstract: Publication date: Available online 7 November 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Jerri D. Edwards, Huiping Xu, Daniel O. Clark, Lin T. Guey, Lesley A. Ross, Frederick W. Unverzagt
      Introduction Cognitive training improves cognitive performance and delays functional impairment, but its effects on dementia are not known. We examined whether three different types of cognitive training lowered the risk of dementia across 10 years of follow-up relative to control and if greater number of training sessions attended was associated with lower dementia risk. Methods The Advanced Cognitive Training in Vital Elderly (NCT00298558) study was a randomized controlled trial (N = 2802) among initially healthy older adults, which examined the efficacy of three cognitive training programs (memory, reasoning, or speed of processing) relative to a no-contact control condition. Up to 10 training sessions were delivered over 6 weeks with up to four sessions of booster training delivered at 11 months and a second set of up to four booster sessions at 35 months. Outcome assessments were taken immediately after intervention and at intervals over 10 years. Dementia was defined using a combination of interview- and performance-based methods. Results A total of 260 cases of dementia were identified during the follow-up. Speed training resulted in reduced risk of dementia (hazard ratio [HR] 0.71, 95% confidence interval [CI] 0.50–0.998, P = .049) compared to control, but memory and reasoning training did not (HR 0.79, 95% CI 0.57–1.11, P = .177 and HR 0.79, 95% CI 0.56–1.10, P = .163, respectively). Each additional speed training session was associated with a 10% lower hazard for dementia (unadjusted HR, 0.90; 95% CI, 0.85–0.95, P < .001). Discussion Initially, healthy older adults randomized to speed of processing cognitive training had a 29% reduction in their risk of dementia after 10 years of follow-up compared to the untreated control group.

      PubDate: 2017-11-12T08:26:12Z
      DOI: 10.1016/j.trci.2017.09.002
  • Traumatic exposures, posttraumatic stress disorder, and cognitive
           functioning in World Trade Center responders

    • Authors: Sean Clouston; Robert H. Pietrzak; Roman Kotov; Marcus Richards; Avron Spiro; Stacey Scott; Yael Deri; Soumyadeep Mukherjee; Candace Stewart; Evelyn Bromet; Benjamin J. Luft
      Abstract: Publication date: Available online 19 October 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Sean Clouston, Robert H. Pietrzak, Roman Kotov, Marcus Richards, Avron Spiro, Stacey Scott, Yael Deri, Soumyadeep Mukherjee, Candace Stewart, Evelyn Bromet, Benjamin J. Luft
      Introduction This study examined whether World Trade Center (WTC)-related exposures and posttraumatic stress disorder (PTSD) were associated with cognitive function and whether WTC responders' cognition differed from normative data. Methods A computer-assisted neuropsychological battery was administered to a prospective cohort study of 1193 WTC responders with no history of stroke or WTC-related head injuries. Data were linked to information collected prospectively since 2002. Sample averages were compared to published norms. Results Approximately 14.8% of sampled responders had cognitive dysfunction. WTC responders had worse cognitive function compared to normative data. PTSD symptom severity and working >5 weeks on-site was associated with lower cognition. Discussion Results from this sample highlight the potential for WTC responders to be experiencing an increased burden of cognitive dysfunction and linked lowered cognitive functioning to physical exposures and to PTSD. Future research is warranted to understand the extent to which cognitive dysfunction is evident in neural dysfunction.

      PubDate: 2017-10-29T07:36:55Z
      DOI: 10.1016/j.trci.2017.09.001
  • Study protocol of the Intense Physical Activity and Cognition study: The
           effect of high-intensity exercise training on cognitive function in older

    • Authors: Belinda M. Brown; Stephanie R. Rainey-Smith; Natalie Castalanelli; Nicole Gordon; Shaun Markovic; Hamid R. Sohrabi; Michael Weinborn; Simon M. Laws; James Doecke; Kaikai Shen; Ralph N. Martins; Jeremiah J. Peiffer
      Abstract: Publication date: Available online 19 October 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Belinda M. Brown, Stephanie R. Rainey-Smith, Natalie Castalanelli, Nicole Gordon, Shaun Markovic, Hamid R. Sohrabi, Michael Weinborn, Simon M. Laws, James Doecke, Kaikai Shen, Ralph N. Martins, Jeremiah J. Peiffer
      Inconsistent results from previous studies of exercise and cognitive function suggest that rigorously designed randomized controlled trials are urgently needed. Here, we describe the design of the Intense Physical Activity and Cognition (IPAC) study, which will assess the impact of a 6-month high-intensity exercise intervention on cognitive function and biomarkers of dementia risk, compared with a 6-month moderate-intensity exercise intervention and control group (no study-related exercise). One-hundred and five cognitively healthy men and women aged between 60 and 80 years are randomized into a high-intensity exercise, moderate-intensity exercise, or control group. Individuals randomized to an exercise intervention undertake 6 months of cycle-based exercise twice a week, at 50 minutes per session. All participants undergo comprehensive neuropsychological testing, blood sampling, brain magnetic resonance imaging, fitness testing, and a body composition scan at baseline, 6 months (immediately after intervention), and 18 months (12 months after intervention). The IPAC study takes a multidisciplinary approach to investigating the role of exercise in maintaining a healthy brain throughout aging. Rigorous monitoring of exertion and adherence throughout the intervention, combined with repeated measures of fitness, is vital in ensuring an optimum exercise dose is reached. Results from the IPAC study will be used to inform a large-scale multicentre randomized controlled trial, with the ultimate aim of pinpointing the frequency, duration, and intensity of exercise that provides the most benefit to the brain, in terms of enhancing cognitive function and reducing dementia risk in older adults.

      PubDate: 2017-10-29T07:36:55Z
      DOI: 10.1016/j.trci.2017.09.003
  • 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
  • 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
  • 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
  • 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
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