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Publisher: Elsevier   (Total: 3031 journals)

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Showing 1 - 200 of 3031 Journals sorted alphabetically
AASRI Procedia     Open Access   (Followers: 15)
Academic Pediatrics     Hybrid Journal   (Followers: 20, SJR: 1.402, h-index: 51)
Academic Radiology     Hybrid Journal   (Followers: 16, SJR: 1.008, h-index: 75)
Accident Analysis & Prevention     Partially Free   (Followers: 79, SJR: 1.109, h-index: 94)
Accounting Forum     Hybrid Journal   (Followers: 22, SJR: 0.612, h-index: 27)
Accounting, Organizations and Society     Hybrid Journal   (Followers: 27, 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: 302, 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  
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: 195, 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: 9, 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: 2)
Acta Poética     Open Access   (Followers: 4)
Acta Psychologica     Hybrid Journal   (Followers: 21, SJR: 1.365, h-index: 73)
Acta Sociológica     Open Access  
Acta Tropica     Hybrid Journal   (Followers: 5, 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: 3, SJR: 0.383, h-index: 19)
Actas Urológicas Españolas (English Edition)     Full-text available via subscription   (Followers: 2)
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)
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: 5)
Additive Manufacturing     Hybrid Journal   (Followers: 7, SJR: 1.039, h-index: 5)
Additives for Polymers     Full-text available via subscription   (Followers: 20)
Advanced Drug Delivery Reviews     Hybrid Journal   (Followers: 119, 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: 16, SJR: 0.739, h-index: 33)
Advances in Accounting     Hybrid Journal   (Followers: 8, 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: 24, 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: 10, SJR: 0.801, h-index: 26)
Advances in Applied Microbiology     Full-text available via subscription   (Followers: 21, 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: 26, 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 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: 24, 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: 8, SJR: 1.268, h-index: 45)
Advances in Clinical Chemistry     Full-text available via subscription   (Followers: 28, 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 Developmental Biology     Full-text available via subscription   (Followers: 11)
Advances in Digestive Medicine     Open Access   (Followers: 4)
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: 39, SJR: 3.25, h-index: 43)
Advances in Engineering Software     Hybrid Journal   (Followers: 25, 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: 38, 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: 41, SJR: 0.674, h-index: 38)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 14)
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: 18, SJR: 0.906, h-index: 24)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 8, SJR: 0.497, h-index: 31)
Advances in Human Factors/Ergonomics     Full-text available via subscription   (Followers: 22)
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: 33, 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: 4)
Advances in Intl. Accounting     Full-text available via subscription   (Followers: 4)
Advances in Life Course Research     Hybrid Journal   (Followers: 7, SJR: 0.764, h-index: 15)
Advances in Lipobiology     Full-text available via subscription   (Followers: 1)
Advances in Magnetic and Optical Resonance     Full-text available via subscription   (Followers: 8)
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: 5, 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: 21)
Advances in Molecular and Cellular Endocrinology     Full-text available via subscription   (Followers: 10)
Advances in Molecular Toxicology     Full-text available via subscription   (Followers: 6, SJR: 0.324, h-index: 8)
Advances in Nanoporous Materials     Full-text available via subscription   (Followers: 3)
Advances in Oncobiology     Full-text available via subscription   (Followers: 3)
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: 20, SJR: 0.4, h-index: 28)
Advances in Pharmaceutical Sciences     Full-text available via subscription   (Followers: 14)
Advances in Pharmacology     Full-text available via subscription   (Followers: 13, SJR: 1.718, h-index: 58)
Advances in Physical Organic Chemistry     Full-text available via subscription   (Followers: 7, 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: 18)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 17, SJR: 1.5, h-index: 62)
Advances in Psychology     Full-text available via subscription   (Followers: 56)
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: 1, SJR: 0.1, h-index: 2)
Advances in Space Research     Full-text available via subscription   (Followers: 332, SJR: 0.606, h-index: 65)
Advances in Structural Biology     Full-text available via subscription   (Followers: 7)
Advances in Surgery     Full-text available via subscription   (Followers: 6, SJR: 0.823, h-index: 27)
Advances in the Study of Behavior     Full-text available via subscription   (Followers: 28, SJR: 1.321, h-index: 56)
Advances in Veterinary Medicine     Full-text available via subscription   (Followers: 14)
Advances in Veterinary Science and Comparative Medicine     Full-text available via subscription   (Followers: 12)
Advances in Virus Research     Full-text available via subscription   (Followers: 5, SJR: 1.878, h-index: 68)
Advances in Water Resources     Hybrid Journal   (Followers: 42, 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: 303, 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: 4, SJR: 0.344, h-index: 6)
Ageing Research Reviews     Hybrid Journal   (Followers: 7, SJR: 3.289, h-index: 78)
Aggression and Violent Behavior     Hybrid Journal   (Followers: 389, SJR: 1.385, h-index: 72)
Agri Gene     Hybrid Journal  
Agricultural and Forest Meteorology     Hybrid Journal   (Followers: 15, SJR: 2.18, h-index: 116)
Agricultural Systems     Hybrid Journal   (Followers: 29, SJR: 1.275, h-index: 74)
Agricultural Water Management     Hybrid Journal   (Followers: 36, SJR: 1.546, h-index: 79)
Agriculture and Agricultural Science Procedia     Open Access  
Agriculture and Natural Resources     Open Access   (Followers: 1)
Agriculture, Ecosystems & Environment     Hybrid Journal   (Followers: 48, 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: 3, 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: 9, SJR: 0.922, h-index: 66)
Alcoholism and Drug Addiction     Open Access   (Followers: 5)
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  
Algal Research     Partially Free   (Followers: 7, 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: 5, SJR: 0.776, h-index: 35)
ALTER - European J. of Disability Research / Revue Européenne de Recherche sur le Handicap     Full-text available via subscription   (Followers: 6, SJR: 0.158, h-index: 9)
Alzheimer's & Dementia     Hybrid Journal   (Followers: 45, SJR: 4.289, h-index: 64)
Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring     Open Access   (Followers: 5)
Alzheimer's & Dementia: Translational Research & Clinical Interventions     Open Access   (Followers: 3)
American Heart J.     Hybrid Journal   (Followers: 45, SJR: 3.157, h-index: 153)
American J. of Cardiology     Hybrid Journal   (Followers: 47, SJR: 2.063, h-index: 186)
American J. of Emergency Medicine     Hybrid Journal   (Followers: 34, SJR: 0.574, h-index: 65)
American J. of Geriatric Pharmacotherapy     Full-text available via subscription   (Followers: 6, 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: 25, SJR: 1.259, h-index: 81)
American J. of Kidney Diseases     Hybrid Journal   (Followers: 31, SJR: 2.313, h-index: 172)
American J. of Medicine     Hybrid Journal   (Followers: 48, 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: 173, SJR: 2.255, h-index: 171)
American J. of Ophthalmology     Hybrid Journal   (Followers: 51, SJR: 2.803, h-index: 148)
American J. of Ophthalmology Case Reports     Open Access   (Followers: 2)
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: 22, SJR: 0.59, h-index: 45)
American J. of Pathology     Hybrid Journal   (Followers: 23, SJR: 2.653, h-index: 228)
American J. of Preventive Medicine     Hybrid Journal   (Followers: 21, SJR: 2.764, h-index: 154)
American J. of Surgery     Hybrid Journal   (Followers: 32, SJR: 1.286, h-index: 125)
American J. of the Medical Sciences     Hybrid Journal   (Followers: 13, SJR: 0.653, h-index: 70)
Ampersand : An Intl. J. of General and Applied Linguistics     Open Access   (Followers: 5)
Anaerobe     Hybrid Journal   (Followers: 4, SJR: 1.066, h-index: 51)
Anaesthesia & Intensive Care Medicine     Full-text available via subscription   (Followers: 52, SJR: 0.124, h-index: 9)
Anaesthesia Critical Care & Pain Medicine     Full-text available via subscription   (Followers: 3)
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: 2, SJR: 2.577, h-index: 7)
Analytica Chimica Acta     Hybrid Journal   (Followers: 38, SJR: 1.548, h-index: 152)
Analytical Biochemistry     Hybrid Journal   (Followers: 152, SJR: 0.725, h-index: 154)
Analytical Chemistry Research     Open Access   (Followers: 7, SJR: 0.18, h-index: 2)
Analytical Spectroscopy Library     Full-text available via subscription   (Followers: 10)
Anesthésie & Réanimation     Full-text available via subscription  
Anesthesiology Clinics     Full-text available via subscription   (Followers: 21, 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: 141, SJR: 1.907, h-index: 126)
Animal Feed Science and Technology     Hybrid Journal   (Followers: 5, SJR: 1.151, h-index: 83)
Animal Reproduction Science     Hybrid Journal   (Followers: 5, SJR: 0.711, h-index: 78)
Annales d'Endocrinologie     Full-text available via subscription   (SJR: 0.394, h-index: 30)
Annales d'Urologie     Full-text available via subscription  
Annales de Cardiologie et d'Angéiologie     Full-text available via subscription   (SJR: 0.177, h-index: 13)
Annales de Chirurgie de la Main et du Membre Supérieur     Full-text available via subscription  
Annales de Chirurgie Plastique Esthétique     Full-text available via subscription   (Followers: 2, SJR: 0.354, h-index: 22)
Annales de Chirurgie Vasculaire     Full-text available via subscription   (Followers: 1)

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Journal Cover Alzheimer's & Dementia: Translational Research & Clinical Interventions
  [3 followers]  Follow
    
  This is an Open Access Journal Open Access journal
   ISSN (Online) 2352-8737
   Published by Elsevier Homepage  [3031 journals]
  • Effect of physical exercise on markers of neuronal dysfunction in
           cerebrospinal fluid in patients with Alzheimer's disease

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

      PubDate: 2017-02-26T06:22:51Z
      DOI: 10.1016/j.trci.2017.01.005
       
  • The prevalence and biomarkers’ characteristic of rapidly progressive
           Alzheimer's disease from ADNI database

    • Authors: Maowen Ba; Xiaofeng Li; Kok Pin Ng; Tharick Ali Pascoal; Sulantha Mathotaarachchi; Pedro Rosa-Neto; Serge Gauthier
      Abstract: Publication date: Available online 9 February 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Maowen Ba, Xiaofeng Li, Kok Pin Ng, Tharick Ali Pascoal, Sulantha Mathotaarachchi, Pedro Rosa-Neto, Serge Gauthier
      Introduction The prevalence and detailed biomarkers’ characteristic of rapidly progressive Alzheimer's disease (rpAD) remain incompletely understood. Methods A total of 312 mild AD patients from Alzheimer's Disease Neuroimaging Initiative database were chosen and dichotomized into rpAD and non-rpAD groups. We performed the prevalence and comprehensive biomarker evaluation. Results The prevalence of rpAD was 17.6% in mild AD. Compared with non-rpAD, there were no differences in APOE ε4/ε4, APOE ε3/ε4, and APOE ε2/ε4 genotype distribution, cerebrospinal fluid tau, phosphorylated tau (p-tau), amyloid-β, hippocampus volume, and amyloid deposition in rpAD. Yet, a lower p-tau/tau ratio was observed in rpAD (P = .04). rpAD showed region-specific hypometabolism ([18F]fluorodeoxyglucose-positron emission tomography [FDG-PET]) (P = .001). Receiver-operating characteristic analysis of FDG-PET demonstrated that left angular and left temporal cortices were the regions with higher area under the curve and predictive value for identifying clinical at-risk rpAD. Discussion We identified that rpAD commonly existed in mild AD. Cerebral hypometabolism could provide potential clinical differential value for rpAD in the short-term follow-up period.

      PubDate: 2017-02-13T05:19:29Z
      DOI: 10.1016/j.trci.2016.12.005
       
  • A composite measure of cognitive and functional progression in Alzheimer's
           disease: Design of the Capturing Changes in Cognition study

    • Authors: Roos J. Jutten; John Harrison; Frank Jan de Jong; André Aleman; Craig W. Ritchie; Philip Scheltens; Sietske A.M. Sikkes
      Abstract: Publication date: Available online 9 February 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Roos J. Jutten, John Harrison, Frank Jan de Jong, André Aleman, Craig W. Ritchie, Philip Scheltens, Sietske A.M. Sikkes
      Introduction Cognitive testing in Alzheimer's disease (AD) is essential for establishing diagnosis, monitoring progression, and evaluating treatments. Assessments should ideally be brief, reliable, valid, and reflect clinically meaningful changes. There is a lack of instruments that meet all these criteria. In the Capturing Changes in Cognition (Catch-Cog) study, we seek to correct these deficiencies through the development and validation of a composite measure combining cognition and function: the cognitive-functional composite (CFC). We expect that the CFC is able to detect clinically relevant changes over time in early dementia stages of AD. Methods/Design We will include patients (n = 350) with mild cognitive impairment or mild dementia due to AD from memory clinics in the Netherlands and the United Kingdom. We will include cognitively healthy volunteers (n = 30) as a control group. The CFC is based on the “cognitive composite” and the Amsterdam instrumental activities of daily living questionnaire. We will investigate test–retest reliability with baseline and 2- to 3-week follow-up assessments (n = 50 patients and n = 30 healthy controls). We will involve experts and participants to evaluate the initial feasibility and refine the CFC if needed. Subsequently, we will perform a longitudinal construct validation study in a prospective cohort (n = 300) with baseline, 3-, 6-, and 12-month follow-up assessments. The main outcome is cognitive and functional progression measured by the CFC. Reference measures for progression include traditional cognitive and functional tests, disease burden measures, and brain imaging methods. Using linear mixed modeling, we will investigate longitudinal changes on the CFC and relate these to the reference measures. Using linear regression analyses, we will evaluate the influence of possible confounders such as age, gender, and education on the CFC. Conclusion By performing an independent longitudinal construct validation, the Catch-Cog study of the novel CFC will contribute to the improvement of disease monitoring and treatment evaluation in mild AD.

      PubDate: 2017-02-13T05:19:29Z
      DOI: 10.1016/j.trci.2017.01.004
       
  • Bladder antimuscarinics and cognitive decline in elderly patients

    • Authors: Daniela C. Moga; Erin L. Abner; Qishan Wu; Gregory A. Jicha
      Abstract: Publication date: Available online 9 February 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Daniela C. Moga, Erin L. Abner, Qishan Wu, Gregory A. Jicha
      Introduction The evidence on the impact of bladder antimuscarinics initiation on cognitive function in older adults is inconsistent. Methods A retrospective analysis of data from the National Alzheimer's Coordinating Center (NACC) on enrollees 65 years and older evaluated the association between antimuscarinic initiation and cognitive decline. We defined decline from baseline (yes/no) for cognitive assessments included in the NACC Uniform Data Set 2.0 battery. New users were matched on year of enrollment and time in the cohort to randomly selected nonusers. Analyses were conducted using inverse probability of treatment weights based on baseline propensity scores. Results Our analyses included 698 new users and 7037 nonusers. The odds ratio (OR) and 95% confidence interval for cognitive decline in users as compared to nonusers was 1.4 (1.19–1.65) for Mini–Mental State Examination (MMSE), and 1.21 (1.03–1.42) for Clinical Dementia Rating; in addition, the odds of decline were 20% higher in users compared to nonusers for semantic memory/language and executive function. The effect estimate for MMSE was 1.94 (1.3–2.91) for those with mild cognitive impairment, 1.26 (0.99–1.62) in those with normal cognition, and 1.44 (1.04–1.99) in those with dementia at baseline. Discussion Our results show that antimuscarinic initiation is associated with cognitive decline and raise questions about their use, especially in those with impaired cognition.

      PubDate: 2017-02-13T05:19:29Z
      DOI: 10.1016/j.trci.2017.01.003
       
  • The effect of statins on rate of cognitive decline in mild cognitive
           impairment

    • 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
       
  • Intermittent hypoxic–hyperoxic training on cognitive performance in
           geriatric patients

    • Authors: Urike Bayer; Rudolf Likar; Georg Pinter; Haro Stettner; Susanne Demschar; Brigitte Trummer; Stefan Neuwersch; Oleg Glazachev; Martin Burtscher
      Abstract: Publication date: Available online 8 February 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Urike Bayer, Rudolf Likar, Georg Pinter, Haro Stettner, Susanne Demschar, Brigitte Trummer, Stefan Neuwersch, Oleg Glazachev, Martin Burtscher
      Introduction Intermittent hypoxic–hyperoxic training (IHHT) may complement a multimodal training intervention (MTI) for improving cognitive function and exercise tolerance in geriatric patients. Methods Thirty-four patients (64–92 years) participated in this randomized controlled trial. Before and after the 5- to 7-week intervention period (MTI + IHHT vs. MTI + ambient air), cognitive function was assessed by the Dementia-Detection Test (DemTect) and the Sunderland Clock-Drawing Test (CDT), and functional exercise capacity by the total distance of the 6-Minute Walk Test (6MWT). Results DemTect and CDT indicated significantly larger improvements after MTI + IHHT (+16.7% vs. −0.39%, P < .001) and (+10.7% vs. −8%, P = .031) which was also true for the 6MWT (+24.1% vs. +10.8%, P = .021). Discussion IHHT turned out to be easily applicable to and well tolerated by geriatric patients up to 92 years. IHHT contributed significantly to improvements in cognitive function and functional exercise capacity in geriatric patients performing MTI.

      PubDate: 2017-02-13T05:19:29Z
      DOI: 10.1016/j.trci.2017.01.002
       
  • Design of pilot studies to inform the construction of composite
           outcome measures

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

      PubDate: 2017-01-25T02:34:23Z
      DOI: 10.1016/j.trci.2016.12.004
       
  • An amylin analog used as a challenge test for Alzheimer's disease

    • Authors: Haihao Zhu; Robert A. Stern; Qiushan Tao; Alexandra Bourlas; Maritza D. Essis; Meenakshi Chivukula; James Rosenzweig; Devin Steenkamp; Weiming Xia; Gustavo A. Mercier; Yorghos Tripodis; Martin Farlow; Neil Kowall; Wei Q. Qiu
      Abstract: Publication date: Available online 21 January 2017
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Haihao Zhu, Robert A. Stern, Qiushan Tao, Alexandra Bourlas, Maritza D. Essis, Meenakshi Chivukula, James Rosenzweig, Devin Steenkamp, Weiming Xia, Gustavo A. Mercier, Yorghos Tripodis, Martin Farlow, Neil Kowall, Wei Q. Qiu
      Introduction Preclinical studies demonstrate the potential of amylin in the diagnosis of Alzheimer's disease (AD). We aimed to lay the foundation for repurposing the amylin analog and a diabetes drug, pramlintide, for AD in humans. Methods We administered a single subcutaneous injection of 60 μg of pramlintide to nondiabetic subjects under fasting conditions. Results None of the participants developed hypoglycemia after the injection of pramlintide. The pramlintide challenge induced a significant surge of amyloid-β peptide and a decrease in total tau in the plasma of AD subjects but not in control participants. The pramlintide injection provoked an increase in interleukin 1 receptor antagonist and a decrease in retinol-binding protein 4, which separates AD subjects from control subjects. Discussion Pramlintide use appeared to be safe in the absence of diabetes. The biomarker changes as a result of the pramlintide challenge, which distinguished AD from control subjects and mild cognitive impairment.

      PubDate: 2017-01-25T02:34:23Z
      DOI: 10.1016/j.trci.2016.12.002
       
  • NPT088 reduces both amyloid-β and tau pathologies in transgenic mice

    • Authors: Jonathan M. Levenson; Sally Schroeter; Jenna C. Carroll; Valerie Cullen; Eva Asp; Ming Proschitsky; Charlotte H.-Y. Chung; Sharon Gilead; Muhammad Nadeem; Hemraj B. Dodiya; Shadiyat Shoaga; Elliott J. Mufson; Haim Tsubery; Rajaraman Krishnan; Jason Wright; Beka Solomon; Richard Fisher; Kimberley S. Gannon
      Pages: 141 - 155
      Abstract: Publication date: Available online 14 July 2016
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Jonathan M. Levenson, Sally Schroeter, Jenna C. Carroll, Valerie Cullen, Eva Asp, Ming Proschitsky, Charlotte H.-Y. Chung, Sharon Gilead, Muhammad Nadeem, Hemraj B. Dodiya, Shadiyat Shoaga, Elliott J. Mufson, Haim Tsubery, Rajaraman Krishnan, Jason Wright, Beka Solomon, Richard Fisher, Kimberley S. Gannon
      Introduction Alzheimer's disease (AD) is characterized by appearance of both extracellular senile plaques and intracellular neurofibrillary tangles, comprised of aggregates of misfolded amyloid-β (Aβ) and hyper-phosphorylated tau, respectively. In a previous study, we demonstrated that g3p, a capsid protein from bacteriophage M13, binds to and remodels misfolded aggregates of proteins that assume an amyloid conformation. We engineered a fusion protein (“NPT088”) consisting of the active fragment of g3p and human-IgG1-Fc. Methods Aged Tg2576 mice or rTg4510 mice received NPT088 weekly via IP injection. Cognitive and/or functional motor endpoints were monitored during dosing. Pathology was quantified biochemically and immunohistochemically. Results NPT088-lowered Aβ plaque and improved cognitive performance of aged Tg2576 mice. Moreover, NPT088 reduced phospho-tau pathology, reduced brain atrophy, and improved cognition in rTg4510 mice. Discussion These observations establish NPT088 as a novel therapeutic approach and potential drug class that targets both Aβ and tau, the hallmark pathologies of AD.

      PubDate: 2016-07-16T06:54:17Z
      DOI: 10.1016/j.trci.2016.06.004
      Issue No: Vol. 2, No. 3 (2016)
       
  • B-vitamins are potentially a cost-effective population health strategy to
           tackle dementia: Too good to be true'

    • Authors: Apostolos Tsiachristas; A. David Smith
      Pages: 156 - 161
      Abstract: Publication date: Available online 11 August 2016
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Apostolos Tsiachristas, A. David Smith
      Introduction To respond to the threat of dementia to public health and the economy, we need to prioritize research resources on strategies that would be the most effective. In relation to the prevention of dementia, this article considers whether lowering plasma homocysteine by B-vitamin supplementation is one of the top priority and cost-effective treatments. Method A decision model was constructed to calculate the lifetime costs and quality-adjusted life years (QALYs) of providing B-vitamin treatment to people in the United Kingdom over 60 years with high levels (>13 μmol/L) of plasma homocysteine, which was compared to the lifetime costs and outcomes of not providing them with the treatment. Results Treatment with B-vitamins will save £60,021 per QALY gained and so is highly cost-effective. Discussion We anticipate that this provocative finding will be debated by scientists, clinicians, and policy makers and eventually be tested in future clinical trials.

      PubDate: 2016-08-12T09:00:59Z
      DOI: 10.1016/j.trci.2016.07.002
      Issue No: Vol. 2, No. 3 (2016)
       
  • Poor cerebrovascular function is an early marker of cognitive decline in
           healthy postmenopausal women

    • Authors: Rachel H.X. Wong; Hamish M. Evans; Peter R.C. Howe
      Pages: 162 - 168
      Abstract: Publication date: Available online 3 August 2016
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Rachel H.X. Wong, Hamish M. Evans, Peter R.C. Howe
      Introduction Impairment of cerebrovascular function becomes evident after menopause. No study has yet explored relationships between deficits in cerebrovascular function, cognitive performance, and mood in postmenopausal women. Method Cerebrovascular function was assessed in 80 healthy postmenopausal women by monitoring blood flow velocity (BFV) in the middle and posterior cerebral arteries using transcranial Doppler ultrasound at rest, following a hypercapnic challenge, and during performance of a cognitive test battery; the latter assessed domains of memory and executive functions. Various measures of mood (i.e., Profile of Mood States and Center for Epidemiological Studies Depression Scale) were also assessed. Results Cerebral artery elasticity and BFV responsiveness to cognitive tests (neurovascular coupling) correlated with cognitive performance but not with depressive symptoms or mood states. Mood deficits were related to poor cognitive performance. Conclusion These results highlight the importance of adequate cerebral perfusion for optimized cognitive function in healthy postmenopausal women. Preventative strategies to attenuate accelerated cognitive decline should also consider restoring cerebrovascular function.

      PubDate: 2016-08-07T08:37:25Z
      DOI: 10.1016/j.trci.2016.07.003
      Issue No: Vol. 2, No. 3 (2016)
       
  • First-in-human, double-blind, placebo-controlled, single-dose escalation
           study of aducanumab (BIIB037) in mild-to-moderate Alzheimer's disease

    • Authors: James Ferrero; Leslie Williams; Heather Stella; Kate Leitermann; Alvydas Mikulskis; John O'Gorman; Jeff Sevigny
      Pages: 169 - 176
      Abstract: Publication date: Available online 20 June 2016
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): James Ferrero, Leslie Williams, Heather Stella, Kate Leitermann, Alvydas Mikulskis, John O'Gorman, Jeff Sevigny
      Introduction Aducanumab (BIIB037), a human monoclonal antibody selective for aggregated forms of amyloid beta, is being investigated as a disease-modifying treatment for Alzheimer's disease (AD). Methods This randomized, double-blind, placebo-controlled single ascending-dose study investigated the safety, tolerability, and pharmacokinetics (PK) of aducanumab in patients with mild-to-moderate AD. Eligible patients were sequentially randomized 6:2 to aducanumab (0.3, 1, 3, 10, 20, 30, and 60 mg/kg) or placebo. Results The primary outcome was safety and tolerability. Doses ≤30 mg/kg were generally well tolerated with no severe or serious adverse events (SAEs). All three patients who received 60-mg/kg aducanumab developed SAEs of symptomatic amyloid-related imaging abnormalities, which completely resolved by weeks 8–15. Aducanumab Cmax, AUC0–last, and AUCinf increased in a dose-proportional manner. Discussion In this single-dose study, aducanumab demonstrated an acceptable safety and tolerability profile and linear PK at doses ≤30 mg/kg (clinicaltrials.gov NCT01397539).

      PubDate: 2016-06-26T02:31:50Z
      DOI: 10.1016/j.trci.2016.06.002
      Issue No: Vol. 2, No. 3 (2016)
       
  • Proof of concept demonstration of optimal composite MRI endpoints for
           clinical trials

    • Authors: Steven D. Edland; M. Colin Ard; Jaiashre Sridhar; Derin Cobia; Adam Martersteck; M.-Marsel Mesulam; Emily J. Rogalski
      Pages: 177 - 181
      Abstract: Publication date: Available online 4 July 2016
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Steven D. Edland, M. Colin Ard, Jaiashre Sridhar, Derin Cobia, Adam Martersteck, M. Marsel Mesulam, Emily J. Rogalski
      Background Atrophy measures derived from structural MRI are promising outcome measures for early phase clinical trials, especially for rare diseases such as primary progressive aphasia (PPA), where the small available subject pool limits our ability to perform meaningfully powered trials with traditional cognitive and functional outcome measures. Methods We investigated a composite atrophy index in 26 PPA participants with longitudinal MRIs separated by 2 years. Rogalski et al. [Neurology 2014;83:1184–1191] previously demonstrated that atrophy of the left perisylvian temporal cortex (PSTC) is a highly sensitive measure of disease progression in this population and a promising endpoint for clinical trials. Using methods described by Ard et al. [Pharmaceutical Statistics 2015;14:418–426], we constructed a composite atrophy index composed of a weighted sum of volumetric measures of 10 regions of interest within the left perisylvian cortex using weights that maximize signal-to-noise and minimize sample size required of trials using the resulting score. Sample size required to detect a fixed percentage slowing in atrophy in a 2-year clinical trial with equal allocation of subjects across arms and 90% power was calculated for the PSTC and optimal composite surrogate biomarker endpoints. Results The optimal composite endpoint required 38% fewer subjects to detect the same percent slowing in atrophy than required by the left PSTC endpoint. Conclusions Optimal composites can increase the power of clinical trials and increase the probability that smaller trials are informative, an observation especially relevant for PPA but also for related neurodegenerative disorders including Alzheimer's disease.

      PubDate: 2016-07-06T04:43:12Z
      DOI: 10.1016/j.trci.2016.05.002
      Issue No: Vol. 2, No. 3 (2016)
       
  • Vitamin E family: Role in the pathogenesis and treatment of Alzheimer's
           disease

    • Authors: Virginia Boccardi; Marta Baroni; Francesca Mangialasche; Patrizia Mecocci
      Pages: 182 - 191
      Abstract: Publication date: Available online 30 August 2016
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Virginia Boccardi, Marta Baroni, Francesca Mangialasche, Patrizia Mecocci
      Introduction Vitamin E family, composed by tocopherols and tocotrienols, is a group of compounds with neuroprotective properties. The exact role in the pathogenesis and the benefit of vitamin E as treatment for Alzheimer's disease (AD) are still under debate. Methods A literature search in PubMed, Medline, and Cochrane databases has been carried out. All types of studies, from bench and animal models to clinical, were included. Results High plasma vitamin E levels are associated with better cognitive performance, even if clear evidence of their ability to prevent or delay cognitive decline in AD is still lacking. Each vitamin E form is functionally unique and shows specific biological functions. Tocotrienols seem to have superior antioxidant and anti-inflammatory properties compared with tocopherols. Discussion The benefit of vitamin E as a treatment for AD is still under debate, mainly because of the inconsistent findings from observational studies and the methodological limitations of clinical trials.

      PubDate: 2016-09-01T11:23:00Z
      DOI: 10.1016/j.trci.2016.08.002
      Issue No: Vol. 2, No. 3 (2016)
       
  • Quantile regression to characterize solanezumab effects in Alzheimer's
           disease trials

    • Authors: Yun-Fei Chen; Xiwen Ma; Karen Sundell; Karla Alaka; Kory Schuh; Joel Raskin; Robert A. Dean
      Pages: 192 - 198
      Abstract: Publication date: Available online 17 August 2016
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Yun-Fei Chen, Xiwen Ma, Karen Sundell, Karla Alaka, Kory Schuh, Joel Raskin, Robert A. Dean
      Introduction In two solanezumab trials for mild-to-moderate Alzheimer's disease (AD) dementia, 27% of patients had biomarker confirmation of amyloid status. Of these, approximately 25% of mild patients and approximately 10% of moderate patients were amyloid negative and, as a group, did not exhibit clinical progression typical of AD. This post-hoc analysis describes a statistical surrogate for amyloid status. Methods Quantile regression was used to examine solanezumab treatment effects at fixed percentiles of varying degrees of clinical progression, with lowest percentiles (minimal progression atypical of AD) and higher percentiles acting as surrogates for amyloid negativity or positivity, respectively. Results In mild patients, solanezumab treatment effect was greater in higher percentiles of progression and less in lowest percentiles (AD-atypical). In moderate patients, solanezumab did not show effects across most percentiles. Discussion Results are compatible with design of the ongoing solanezumab EXPEDITION 3 trial that limits patients to those with mild AD dementia and evidence of amyloid pathology.

      PubDate: 2016-08-17T09:27:09Z
      DOI: 10.1016/j.trci.2016.07.005
      Issue No: Vol. 2, No. 3 (2016)
       
  • Profiling the dynamics of CSF and plasma Aβ reduction after treatment
           with JNJ-54861911, a potent oral BACE inhibitor

    • Authors: Maarten Timmers; Bianca Van Broeck; Steven Ramael; John Slemmon; Katja De Waepenaert; Alberto Russu; Jennifer Bogert; Hans Stieltjes; Leslie M. Shaw; Sebastiaan Engelborghs; Dieder Moechars; Marc Mercken; Enchi Liu; Vikash Sinha; John Kemp; Luc Van Nueten; Luc Tritsmans; Johannes Rolf Streffer
      Pages: 202 - 212
      Abstract: Publication date: Available online 24 August 2016
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Maarten Timmers, Bianca Van Broeck, Steven Ramael, John Slemmon, Katja De Waepenaert, Alberto Russu, Jennifer Bogert, Hans Stieltjes, Leslie M. Shaw, Sebastiaan Engelborghs, Dieder Moechars, Marc Mercken, Enchi Liu, Vikash Sinha, John Kemp, Luc Van Nueten, Luc Tritsmans, Johannes Rolf Streffer
      Objectives Safety, tolerability, pharmacokinetics, and pharmacodynamics of a novel β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor, JNJ-54861911, were assessed after single and multiple dosing in healthy participants. Methods Two randomized, placebo-controlled, double-blind studies were performed using single and multiple ascending JNJ-54861911 doses (up to 14 days) in young and elderly healthy participants. Regular blood samples and frequent CSF samples were collected up to 36 hours after last dose to assess the pharmacokinetic and pharmacodynamic (Aβ, sAPPα,β,total levels) profiles of JNJ-54861911. Results JNJ-54861911 was well-tolerated, adverse events that were uncommon and unrelated to JNJ-54861911. JNJ-54861911 showed dose-proportional CSF and plasma pharmacokinetic profiles. Plasma- and CSF-Aβ and CSF-sAPPβ were reduced in a dose-dependent manner. Aβ reductions (up to 95%) outlasted exposure to JNJ-54861911. APOE ε4 carrier status and baseline Aβ levels did not influence Aβ/sAPPβ reductions. Conclusion JNJ-54861911, a potent brain-penetrant BACE1 inhibitor, achieved high and stable Aβ reductions after single and multiple dosing in healthy participants.

      PubDate: 2016-08-27T10:42:40Z
      DOI: 10.1016/j.trci.2016.08.001
      Issue No: Vol. 2, No. 3 (2016)
       
  • Dissociation of Down syndrome and Alzheimer's disease effects
           with imaging

    • Authors: Dawn C. Matthews; Ana S. Lukic; Randolph D. Andrews; Boris Marendic; James Brewer; Robert A. Rissman; Lisa Mosconi; Stephen C. Strother; Miles N. Wernick; William C. Mobley; Seth Ness; Mark E. Schmidt; Michael S. Rafii
      Pages: 69 - 81
      Abstract: Publication date: Available online 8 March 2016
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Dawn C. Matthews, Ana S. Lukic, Randolph D. Andrews, Boris Marendic, James Brewer, Robert A. Rissman, Lisa Mosconi, Stephen C. Strother, Miles N. Wernick, William C. Mobley, Seth Ness, Mark E. Schmidt, Michael S. Rafii
      Introduction Down Syndrome (DS) adults experience accumulation of Alzheimer's disease (AD)–like amyloid plaques and tangles and a high incidence of dementia and could provide an enriched population to study AD-targeted treatments. However, to evaluate effects of therapeutic intervention, it is necessary to dissociate the contributions of DS and AD from overall phenotype. Imaging biomarkers offer the potential to characterize and stratify patients who will worsen clinically but have yielded mixed findings in DS subjects. Methods We evaluated 18F fluorodeoxyglucose positron emission tomography (PET), florbetapir PET, and structural magnetic resonance (sMR) image data from 12 nondemented DS adults using advanced multivariate machine learning methods. Results Our results showed distinctive patterns of glucose metabolism and brain volume enabling dissociation of DS and AD effects. AD-like pattern expression corresponded to amyloid burden and clinical measures. Discussion These findings lay groundwork to enable AD clinical trials with characterization and disease-specific tracking of DS adults.

      PubDate: 2016-04-30T18:37:36Z
      DOI: 10.1016/j.trci.2016.02.004
      Issue No: Vol. 2, No. 2 (2016)
       
  • The ALFA project: A research platform to identify early pathophysiological
           features of Alzheimer's disease

    • Authors: José Luis Molinuevo; Nina Gramunt; Juan Domingo Gispert; Karine Fauria; Manel Esteller; Carolina Minguillon; Gonzalo Sánchez-Benavides; Gema Huesa; Sebastián Morán; Rafael Dal-Ré; Jordi Camí
      Pages: 82 - 92
      Abstract: Publication date: Available online 3 March 2016
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): José Luis Molinuevo, Nina Gramunt, Juan Domingo Gispert, Karine Fauria, Manel Esteller, Carolina Minguillon, Gonzalo Sánchez-Benavides, Gema Huesa, Sebastián Morán, Rafael Dal-Ré, Jordi Camí
      Introduction The preclinical phase of Alzheimer's disease (AD) is optimal for identifying early pathophysiological events and developing prevention programs, which are shared aims of the ALFA project, including the ALFA registry and parent cohort and the nested ALFA+ cohort study. Methods The ALFA parent cohort baseline visit included full cognitive evaluation, lifestyle habits questionnaires, DNA extraction, and MRI. The nested ALFA+ study adds wet and imaging biomarkers for deeper phenotyping. Results A total of 2743 participants aged 45 to 74 years were included in the ALFA parent cohort. We show that this cohort, mostly composed of cognitively normal offspring of AD patients, is enriched for AD genetic risk factors. Discussion The ALFA project represents a valuable infrastructure that will leverage with different studies and trials to prevent AD. The longitudinal ALFA + cohort will serve to untangle the natural history of the disease and to model the preclinical stages to develop successful trials.

      PubDate: 2016-04-30T18:37:36Z
      DOI: 10.1016/j.trci.2016.02.003
      Issue No: Vol. 2, No. 2 (2016)
       
  • Cross-validation of optimized composites for preclinical Alzheimer

    • Authors: Michael Donohue; Chung-Kai Sun Rema Raman Philip Insel Paul Aisen
      Abstract: Publication date: Available online 27 December 2016
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Michael C. Donohue, Chung-Kai Sun, Rema Raman, Philip S. Insel, Paul S. Aisen
      Introduction We discuss optimization and validation of composite end points for presymptomatic Alzheimer clinical trials. Optimized composites offer hope of substantial gains in statistical power or reduction in sample size. But there is tradeoff between optimization and face validity such that optimization should only be considered if there is a convincing rationale. As with statistically derived regions of interest in neuroimaging, validation on independent data sets is essential. Methods Using four data sets, we consider the optimized weighting of four components of a cognitive composite which includes measures of (1) global cognition, (2) semantic memory, (3) episodic memory, and (4) executive function. Weights are optimized to either discriminate amyloid positivity or maximize power to detect a treatment effect in an amyloid-positive population. We apply repeated 5 × 3-fold cross-validation to quantify the out-of-sample performance of optimized composite end points. Results We found the optimized weights varied greatly across the folds of the cross-validation with either optimization method. Both optimization methods tend to down-weight the measures of global cognition and executive function. However, when these optimized composites were applied to the validation sets, they did not provide consistent improvements in power. In fact, overall, the optimized composites performed worse than those without optimization. Discussion We find that component weight optimization does not yield valid improvements in sensitivity of this composite to detect treatment effects.

      PubDate: 2016-12-30T00:46:10Z
       
  • Preclinical Alzheimer disease and longitudinal driving decline

    • Authors: Catherine Roe; Ganesh Babulal Denise Head Sarah Stout Elizabeth Vernon
      Abstract: Publication date: Available online 23 December 2016
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Catherine M. Roe, Ganesh M. Babulal, Denise M. Head, Sarah H. Stout, Elizabeth K. Vernon, Nupur Ghoshal, Brad Garland, Peggy P. Barco, Monique M. Williams, Ann Johnson, Rebecca Fierberg, M. Scot Fague, Chengjie Xiong, Elizabeth Mormino, Elizabeth A. Grant, David M. Holtzman, Tammie L.S. Benzinger, Anne M. Fagan, Brian R. Ott, David B. Carr, John C. Morris
      Introduction Links between preclinical Alzheimer disease (AD) and driving difficulty onset would support the use of driving performance as an outcome in primary and secondary prevention trials among older adults (OAs). We examined whether AD biomarkers predicted the onset of driving difficulties among OAs. Methods One hundred four OAs (65+ years) with normal cognition took part in biomarker measurements, a road test, clinical and psychometric batteries, and self-reported their driving habits. Results Higher values of cerebrospinal fluid (CSF) tau/Aβ42 and phosphorylated tau (ptau181)/Aβ42 ratios, but not uptake on Pittsburgh compound B amyloid imaging (P = .12), predicted time to a rating of marginal or fail on the driving test using Cox proportional hazards models. Hazards ratios (95% confidence interval) were 5.75 (1.70–19.53), P = .005 for CSF tau/Aβ42; 6.19 (1.75–21.88), and P = .005 for CSF ptau181/Aβ42. Discussion Preclinical AD predicted time to receiving a marginal or fail rating on an on-road driving test. Driving performance shows promise as a functional outcome in AD prevention trials.

      PubDate: 2016-12-30T00:46:10Z
       
  • Active Aβ immunotherapy CAD106 in Alzheimer disease: A phase-2b study

    • Authors: Rik Vandenberghe; Marie-Emmanuelle Riviere; Angelika Caputo; Judit Sovago; R. Paul Maguire; Martin Farlow; Giovanni Marotta; Raquel Sanchez-Valle; Philip Scheltens; J. Michael Ryan; Ana Graf
      Abstract: Publication date: Available online 23 December 2016
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Rik Vandenberghe, Marie-Emmanuelle Riviere, Angelika Caputo, Judit Sovago, R. Paul Maguire, Martin Farlow, Giovanni Marotta, Raquel Sanchez-Valle, Philip Scheltens, J. Michael Ryan, Ana Graf
      Introduction This randomized, double-blind, placebo-controlled, 90-week study assessed safety, tolerability, and immunogenicity of CAD106 with/without adjuvant in patients with mild Alzheimer disease. Methods One hundred twenty-one patients received up to seven intramuscular injections of CAD106 (150 μg or 450 μg) or placebo ± adjuvant over 60 weeks. An amyloid positron emission tomography (PET) substudy was also conducted. Results CAD106 induced strong serological responses (amyloid-beta [Aβ]-IgG) in 55.1% (150 μg) and 81.1% (450 μg) of patients (strong serological responders [SSRs]). Serious adverse events (SAEs) were reported in 24.5% (95% confidence interval [CI] 16.7–33.8) of the patients in the active treatment group and in 6.7% (95% CI 0.2–31.9) in the placebo group. Three of the SAEs were classified as possibly related to study drug by the investigators. No evidence of central nervous system inflammation was found. Amyloid-related imaging abnormalities (ARIAs) occurred in six cases, all of them were strong serological responders. None of the ARIAs were symptomatic. Serum Aβ-IgG titer area under the curves correlated negatively with amyloid PET standardized uptake value ratio percentage change from baseline to week 78 within the CAD-treated patients (r = −0.84, P = .0004). Decrease in cortical gray-matter volume from baseline to week 78 was larger in SSRs than in controls (P = .0077). Discussion Repeated CAD106 administration was generally well tolerated. CAD106 450 μg with alum adjuvant demonstrated the best balance between antibody response and tolerability.

      PubDate: 2016-12-30T00:46:10Z
      DOI: 10.1016/j.trci.2016.12.003
       
  • Social interaction and cognitive decline: Results of a 7-year community
           intervention

    • Authors: Hiroyuki Hikichi; Katsunori Kondo; Tokunori Takeda; Ichiro Kawachi
      Abstract: Publication date: Available online 21 December 2016
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Hiroyuki Hikichi, Katsunori Kondo, Tokunori Takeda, Ichiro Kawachi
      Introduction There are few intervention studies that demonstrated linking social participation to lower risk of cognitive decline. We examined prospectively the protective effect of a community intervention program promoting social participation on the incidence of cognitive disability. Methods The baseline was established in a survey of community-dwelling older people aged 65 years old or more in July 2006 (2793 respondents, response rate 48.5%). The setting was Taketoyo town in Japan, where municipal authorities launched an intervention that was based on the establishment of community-based centers called “salons,” where the town's senior residents could congregate and participate in social activities, ranging from arts and crafts, games, and interactive activities with preschool children. Three salons were established in May 2010, and a total of 10 salons were in operation by 2013. We recorded the frequency of salon participation among survey respondents till 2013 and conducted two follow-up surveys (in 2010 and 2013) to collect information about health status and behaviors. The onset of cognitive disability was followed from May 2007 to January 2014. We used the marginal structural models to evaluate the effect of program. Results The range of prevalence of cognitive disability was from 0.2% to 2.5% during the observation period. The proportion of respondents who participates to salons increased over time to about 11.7%. The frequency of salon participation was protectively associated with cognitive decline, even after adjusting for time-dependent covariates and attrition (odds ratio = 0.73, 95% confidence interval: 0.54–0.99). Discussion Our study suggests that operating community salons that encourage social interactions, light physical activity, and cognitive activities among older participants may be effective for preventing cognitive decline. In future studies, we need to understand what sorts of activities (e.g., those involving light physical activity vs. purely intellectual activities) are most effective in maintaining cognitive function.

      PubDate: 2016-12-23T00:14:13Z
      DOI: 10.1016/j.trci.2016.11.003
       
  • Combination treatment with leptin and pioglitazone in a mouse model
           of Alzheimer's disease

    • Authors: Carmen M. Fernandez-Martos; Rachel A.K. Atkinson; Meng Inn Chuah; Anna E. King; James C. Vickers
      Abstract: Publication date: Available online 20 December 2016
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Carmen M. Fernandez-Martos, Rachel A.K. Atkinson, Meng Inn Chuah, Anna E. King, James C. Vickers
      Introduction Combination therapy approaches may be necessary to address the many facets of pathologic change in the brain in Alzheimer's disease (AD). The drugs leptin and pioglitazone have previously been shown individually to have neuroprotective and anti-inflammatory actions, respectively, in animal models. Methods We studied the impact of combined leptin and pioglitazone treatment in 6-month-old APP/PS1 (APPswe/PSEN1dE9) transgenic AD mouse model. Results We report that an acute 2-week treatment with combined leptin and pioglitazone resulted in a reduction of spatial memory deficits (Y maze) and brain β-amyloid levels (soluble β-amyloid and amyloid plaque burden) relative to vehicle-treated animals. Combination treatment was also associated with amelioration in plaque-associated neuritic pathology and synapse loss, and also a significantly reduced neocortical glial response. Discussion Combination therapy with leptin and pioglitazone ameliorates pathologic changes in APP/PS1 mice and may represent a potential treatment approach for AD.

      PubDate: 2016-12-23T00:14:13Z
      DOI: 10.1016/j.trci.2016.11.002
       
  • Cyclic AC253, a novel amylin receptor antagonist, improves cognitive
           deficits in a mouse model of Alzheimer's

    • Authors: Rania Soudy; Aarti Patel; Wen Fu; Kamaljit Kaur; David MacTavish; David Westaway; Rachel Davey; Jeffrey Zajac; Jack Jhamandas
      Abstract: Publication date: Available online 10 December 2016
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Rania Soudy, Aarti Patel, Wen Fu, Kamaljit Kaur, David MacTavish, David Westaway, Rachel Davey, Jeffrey Zajac, Jack Jhamandas
      Introduction Amylin receptor serves as a portal for the expression of deleterious effects of amyloid β-protein (Aβ), a key pathologic hallmark of Alzheimer's disease. Previously, we showed that AC253, an amylin receptor antagonist, is neuroprotective against Aβ toxicity in vitro and abrogates Aβ-induced impairment of hippocampal long-term potentiation. Methods Amyloid precursor protein–overexpressing TgCRND8 mice received intracerebroventricularly AC253 for 5 months. New cyclized peptide cAC253 was synthesized and administered intraperitoneally three times a week for 10 weeks in the same mouse model. Cognitive functions were monitored, and pathologic changes were quantified biochemically and immunohistochemically. Results AC253, when administered intracerebroventricularly, improves spatial memory and learning, increases synaptic integrity, reduces microglial activation without discernible adverse effects in TgCRND8 mice. cAC253 demonstrates superior brain permeability, better proteolytic stability, and enhanced binding affinity to brain amylin receptors after a single intraperitoneal injection. Furthermore, cAC253 administered intraperitoneally also demonstrates improvement in spatial memory in TgCRND8 mice. Discussion Amylin receptor is a therapeutic target for Alzheimer's disease and represents a disease-modifying therapy for this condition.

      PubDate: 2016-12-14T23:26:57Z
      DOI: 10.1016/j.trci.2016.11.005
       
  • Tolerability of ORM-12741 and effects on episodic memory in patients with
           Alzheimer disease

    • Authors: J.O. Rinne; K. Wesnes; J.L. Cummings; P. Hakulinen; M. Hallikainen; J. Hänninen; M. Murphy; H. Riordan; M. Scheinin; H. Soininen; J. Rouru
      Abstract: Publication date: Available online 8 December 2016
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): J.O. Rinne, K. Wesnes, J.L. Cummings, P. Hakulinen, M. Hallikainen, J. Hänninen, M. Murphy, H. Riordan, M. Scheinin, H. Soininen, J. Rouru
      Introduction ORM-12741 is a novel selective antagonist of alpha-2C adrenoceptors. This trial evaluated the safety and efficacy of ORM-12741 in patients with Alzheimer disease (AD). Methods A randomized, double-blind, placebo-controlled, exploratory phase 2a trial was conducted in 100 subjects with AD and neuropsychiatric symptoms. Participants were randomized to receive one of two flexible doses of ORM-12741 (30–60 mg or 100–200 mg) or placebo b.i.d. for 12 weeks in addition to standard therapy with cholinesterase inhibitors. Efficacy was assessed primarily with the Cognitive Drug Research (CDR) computerized assessment system and secondarily with the Neuropsychiatric Inventory (NPI). Results A statistically significant treatment effect was seen in one of the four primary CDR system end points, Quality of Episodic Memory (P = .030; not adjusted for multiple comparisons), favoring ORM-12741 over placebo. NPI caregiver distress scores also favored ORM-12741 (P = .034). ORM-12741 was well tolerated. Discussion This is the first clinical trial providing evidence on an acceptable safety profile for ORM-12741 in patients with AD and neuropsychiatric symptoms. In addition, the trial provided hints of potential therapeutic benefit, primarily on episodic memory, in this patient population.

      PubDate: 2016-12-14T23:26:57Z
      DOI: 10.1016/j.trci.2016.11.004
       
  • Multiple neuropathologies and dementia in the aging brain: A key role for
           cerebrovascular disease'

    • Authors: Andreas Charidimou; Anand Viswanathan
      Abstract: Publication date: Available online 29 November 2016
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Andreas Charidimou, Anand Viswanathan
      ▪▪▪.

      PubDate: 2016-12-01T10:46:56Z
      DOI: 10.1016/j.trci.2016.11.001
       
  • SAR110894, a potent histamine H3-receptor antagonist, displays
           disease-modifying activity in a transgenic mouse model of tauopathy

    • Authors: Philippe Delay-Goyet; Véronique Blanchard; Nathalie Schussler; Mati Lopez-Grancha; Jean Ménager; Véronique Mary; Eric Sultan; Armelle Buzy; Jean-Claude Guillemot; Jeanne Stemmelin; Philippe Bertrand; Thomas Rooney; Laurent Pradier; Pascal Barnéoud
      Abstract: Publication date: Available online 3 November 2016
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Philippe Delay-Goyet, Véronique Blanchard, Nathalie Schussler, Mati Lopez-Grancha, Jean Ménager, Véronique Mary, Eric Sultan, Armelle Buzy, Jean-Claude Guillemot, Jeanne Stemmelin, Philippe Bertrand, Thomas Rooney, Laurent Pradier, Pascal Barnéoud
      Introduction Tau hyperphosphorylation and neurofibrillary tangles are histopathologic hallmarks of tauopathies. Histamine H3-receptor antagonists have been proposed to reduce tau hyperphosphorylation in preclinical models. Methods We evaluated the ability of SAR110894, a selective histamine H3-receptor antagonist, to inhibit tau pathology and prevent cognitive deficits in a tau transgenic mouse model (THY-Tau22). Results SAR110894 treatment for 6 months (but not 2 weeks) in THY-Tau22 mice decreased both tau hyperphosphorylation at pSer396-pSer404 (AD2 signal) in the hippocampus and the number of AT8 (pSer199/202-Thr205) positive cells in the cortex and decreased the formation of neurofibrillary tangles in the cortex, hippocampus, and amygdala. MIP-1α messenger RNA expression was decreased in the hippocampus. SAR110894 also prevented episodic memory deficits, and this effect was still detected after treatment washout. Discussion Long-term SAR110894 treatment could have potential disease modifying activity in tauopathies.

      PubDate: 2016-11-10T01:59:48Z
      DOI: 10.1016/j.trci.2016.10.002
       
  • A multicenter, randomized, placebo-controlled trial for cilostazol in
           patients with mild cognitive impairment: The COMCID study protocol

    • Authors: Satoshi Saito; Shinsuke Kojima; Naoya Oishi; Ryosuke Kakuta; Takakuni Maki; Fumihiko Yasuno; Kazuyuki Nagatsuka; Haruko Yamamoto; Hidenao Fukuyama; Masanori Fukushima; Masafumi Ihara
      Abstract: Publication date: Available online 27 October 2016
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Satoshi Saito, Shinsuke Kojima, Naoya Oishi, Ryosuke Kakuta, Takakuni Maki, Fumihiko Yasuno, Kazuyuki Nagatsuka, Haruko Yamamoto, Hidenao Fukuyama, Masanori Fukushima, Masafumi Ihara
      Introduction There are currently no effective treatments preventing conversion from mild cognitive impairment (MCI) to Alzheimer's disease. Cilostazol is a selective type-3 phosphodiesterase inhibitor that ameliorates accumulation of amyloid-β and has prevented cognitive decline in rodent models. Furthermore, cilostazol is known to suppress platelet aggregation, protect vascular endothelia, dilate vessels, and increase cerebral blood flow. Beneficial effects have also been shown in observational cohort studies, demonstrating the need for a prospective clinical trial. Methods The Cilostazol for Prevention of Conversion From MCI to Dementia (COMCID) study is a double-blind, randomized phase II study of patients with MCI. Participants will receive cilostazol or placebo for 96 weeks. The primary objective is to evaluate whether cilostazol slows down cognitive decline measured by the Mini-Mental State Examination. Secondary objectives are assessing time to conversion from MCI to dementia and assessing incremental changes in several psychological assessment scales. Discussion The COMCID trial will identify the therapeutic potential of cilostazol. This trial, which is based on a drug repositioning strategy, may aid the development of a neurovascular treatment for neurocognitive disorders.

      PubDate: 2016-11-03T01:43:36Z
      DOI: 10.1016/j.trci.2016.10.001
       
  • NGP 555, a γ-secretase modulator, lowers the amyloid biomarker, Aβ42, in
           cerebrospinal fluid while preventing Alzheimer's disease cognitive decline
           in rodents

    • Authors: Maria Z. Kounnas; Courtney Lane-Donovan; Dan W. Nowakowski; Joachim Herz; William T. Comer
      Abstract: Publication date: Available online 15 October 2016
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Maria Z. Kounnas, Courtney Lane-Donovan, Dan W. Nowakowski, Joachim Herz, William T. Comer
      Introduction Alzheimer's disease (AD) is defined by the progressive accumulation of amyloid plaques and neurofibrillary tangles in the brain which precedes cognitive decline by years. Methods Using amyloid biomarkers, chemical modeling, mouse behavioral models, and drug development techniques, we investigate the properties of NGP 555, a clinical-stage γ-secretase modulator. Results NGP 555 shifts amyloid peptide production to the smaller, nonaggregating forms of amyloid. Our preclinical studies show beneficial effects on amyloid biomarkers, pathology, and cognition. NGP 555 has successfully completed chemistry, pharmacology, toxicity, metabolism, and safety studies. Discussion Abundant data support Aβ42 as a target for prophylactic or early-stage intervention therapies in AD. The γ-secretase modulator, NGP 555 is being actively developed in human clinical trials for the prevention of Alzheimer's disease with the overall aim to achieve an appropriate balance of potency/efficacy on reducing the toxic forms of amyloid versus safety.

      PubDate: 2016-10-16T22:15:23Z
      DOI: 10.1016/j.trci.2016.09.003
       
  • African Americans are less likely to enroll in preclinical Alzheimer's
           disease clinical trials

    • Authors: Yan Zhou; David Elashoff; Sarah Kremen; Edmond Teng; Jason Karlawish; Joshua D. Grill
      Abstract: Publication date: Available online 15 October 2016
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Yan Zhou, David Elashoff, Sarah Kremen, Edmond Teng, Jason Karlawish, Joshua D. Grill
      Introduction Alzheimer's disease (AD) incidence is disproportionately high in African Americans, yet, recruitment of this community to AD clinical trials is challenging. Methods We compared 47 African Americans and 78 whites in their willingness to enroll in a hypothetical preclinical AD trial and examined barriers and facilitators in their decision making. Results African American race (OR = 0.45; 95% CI, 0.22–0.93) and score on the research attitude questionnaire (OR = 1.12; 95% CI, 1.04–1.22) were independently associated with willingness to participate. African Americans rated study risks, the requirement of a study partner, study procedures, the ratio of drug to placebo, and study location as more important factors in the decision whether to enroll than did whites. Discussion These results suggest that researchers will encounter challenges in recruiting African Americans to preclinical AD trials. Future research will be necessary to understand the optimal means to improve recruitment of underrepresented populations.

      PubDate: 2016-10-16T22:15:23Z
      DOI: 10.1016/j.trci.2016.09.004
       
  • Multiple comorbid neuropathologies in the setting of Alzheimer's disease
           neuropathology and implications for drug development

    • Authors: Gil D. Rabinovici; Maria C. Carrillo; Mark Forman; Susan DeSanti; David S. Miller; Nicholas Kozauer; Ronald C. Petersen; Christopher Randolph; David S. Knopman; Eric E. Smith; Maria Isaac; Niklas Mattsson; Lisa J. Bain; James A. Hendrix; John R. Sims
      Abstract: Publication date: Available online 20 September 2016
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Gil D. Rabinovici, Maria C. Carrillo, Mark Forman, Susan DeSanti, David S. Miller, Nicholas Kozauer, Ronald C. Petersen, Christopher Randolph, David S. Knopman, Eric E. Smith, Maria Isaac, Niklas Mattsson, Lisa J. Bain, James A. Hendrix, John R. Sims
      Dementia is often characterized as being caused by one of several major diseases, such as Alzheimer's disease (AD), cerebrovascular disease, Lewy body disease, or a frontotemporal degeneration. Failure to acknowledge that more than one entity may be present precludes attempts to understand interactive relationships. The clinicopathological studies of dementia demonstrate that multiple pathologic processes often coexist. How overlapping pathologic findings affect the diagnosis and treatment of clinical AD and other dementia phenotypes was the topic taken up by the Alzheimer's Association's Research Roundtable in October 2014. This review will cover the neuropathologic basis of dementia, provide clinical perspectives on multiple pathologies, and discuss therapeutics and biomarkers targeting overlapping pathologies and how these issues impact clinical trials.High prevalence of multiple pathologic findings among individuals with clinical diagnosis of AD suggests that new treatment strategies may be needed to effectively treat AD and other dementing illnesses.

      PubDate: 2016-09-22T19:36:26Z
      DOI: 10.1016/j.trci.2016.09.002
       
  • Measuring informed consent capacity in an Alzheimer's disease clinical
           trial

    • Authors: Peter D. Guarino; Julia E. Vertrees; Sanjay Asthana; Mary Sano; Maria Llorente; Muralidhar Pallaki; Susan Love; Gerard D. Schellenberg; Maurice W. Dysken
      Abstract: Publication date: Available online 20 September 2016
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Peter D. Guarino, Julia E. Vertrees, Sanjay Asthana, Mary Sano, Maria Llorente, Muralidhar Pallaki, Susan Love, Gerard D. Schellenberg, Maurice W. Dysken
      Introduction Accurately and efficiently determining a participant's capacity to consent to research is critically important to protect the rights of patients with Alzheimer's disease (AD). Methods Understanding of the informed consent document was assessed in 613 community-dwelling patients with mild-to-moderate AD enrolled in a randomized, placebo-controlled trial. Associations were examined between clinically determined capacity to consent and (1) patient demographics and clinical characteristics and (2) the Informed Consent Questionnaire (ICQ), an objective measurement of a participant's factual understanding and perceived understanding. Results A total of 453 (74%) participants were determined to have capacity to consent by clinical judgment. ICQ perceived understanding, race, measures of cognitive function, and caregiver time were all significantly associated with the determination of capacity in multivariate analyses. Discussion We found a significant association between capacity and disease severity level, caregiver time, race, and ICQ perceived understanding.

      PubDate: 2016-09-22T19:36:26Z
      DOI: 10.1016/j.trci.2016.09.001
       
  • Mnemonic strategy training of the elderly at risk for dementia enhances
           integration of information processing via cross-frequency coupling

    • Authors: Stavros I. Dimitriadis; Ioannis Tarnanas; Mark Wiederhold; Brenda Wiederhold; Magda Tsolaki; Elgar Fleish
      Abstract: Publication date: Available online 15 September 2016
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Stavros I. Dimitriadis, Ioannis Tarnanas, Mark Wiederhold, Brenda Wiederhold, Magda Tsolaki, Elgar Fleish
      Introduction We sought to identify whether intensive 10-week mobile health mnemonic strategy training (MST) could shift the resting-state brain network more toward cortical-level integration, which has recently been proven to reflect the reorganization of the brain networks compensating the cognitive decline. Methods One hundred fifty-eight patients with mild cognitive impairment (MCI) were selected and participated in 10-week training lasting 90 min/d of memory training. They benefited from an initial and a follow-up neuropsychological evaluation and resting-state electroencephalography (EEG). Results At follow-up, MST revealed an extensive significant training effect that changed the network with an increase of synchronization between parietotemporal and frontal areas; frontalθ-parietalα2 causal strengthening as part of top-down inhibitory control; enhancement of sensorimotor connections in β band; and a general increase of cortical-level integration. More precisely, MST induced gain as an increase of the global cost efficiency (GCE) of the whole cortical network and a neuropsychological performance improvement, which was correlated with it (r = 0.32, P = .0001). The present study unfolded intervention changes based on EEG source activity via novel neuroinformatic tools for revealing intrinsic coupling modes in both amplitude-phase representations and in the mixed spectrospatiotemporal domain. Discussion Further work should identify whether the GCE enhancement of the functional cortical brain networks is a compensation mechanism to the brain network dysfunction or a more permanent neuroplasticity effect.

      PubDate: 2016-09-17T18:48:52Z
      DOI: 10.1016/j.trci.2016.08.004
       
  • Communication Bridge: A pilot feasibility study of Internet-based
           speech–language therapy for individuals with progressive aphasia

    • Authors: Emily J. Rogalski; Marie Saxon; Hannah McKenna; Christina Wieneke; Alfred Rademaker; Marya E. Corden; Kathryn Borio; M.-Marsel Mesulam; Becky Khayum
      Abstract: Publication date: Available online 13 September 2016
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Emily J. Rogalski, Marie Saxon, Hannah McKenna, Christina Wieneke, Alfred Rademaker, Marya E. Corden, Kathryn Borio, M.-Marsel Mesulam, Becky Khayum
      Introduction Individuals with aphasia symptoms because of neurodegenerative dementia are under-referred for speech–language therapy (SLT) services. We sought to determine the feasibility of utilizing telepractice, via Internet videoconferencing, to connect an individual with progressive aphasia because of dementia to a speech–language pathologist (SLP) for treatment. Methods Participants received an initial evaluation, 8 person-centered Internet-based SLT sessions, and 2 post-therapy evaluations. The feasibility of providing Web-based SLT, strategies used and their compliance, functional gains, and the duration of benefit were assessed. Results Thirty-four participants from 21 states and Canada were enrolled. Thirty-one participants completed the 6-month evaluation. SLP-assessed and self-reported functional gains and increased confidence in communication were documented at 2 months and maintained at 6 months postenrollment. Discussion Internet-based SLT using person-centered interventions provides a feasible model for delivering care to individuals with dementia and mild and/or moderate aphasia symptoms who have an engaged care-partner and prior familiarity with a computer.

      PubDate: 2016-09-17T18:48:52Z
      DOI: 10.1016/j.trci.2016.08.005
       
  • Design of the NL-ENIGMA study: Exploring the effect of Souvenaid on
           cerebral glucose metabolism in early Alzheimer's disease

    • Authors: Nienke M.E. Scheltens; Ingrid S. Kuyper; Ronald Boellaard; Frederik Barkhof; Charlotte E. Teunissen; Laus M. Broersen; Marieke M. Lansbergen; Wiesje M. van der Flier; Bart N.M. van Berckel; Philip Scheltens
      Abstract: Publication date: Available online 1 September 2016
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Nienke M.E. Scheltens, Ingrid S. Kuyper, Ronald Boellaard, Frederik Barkhof, Charlotte E. Teunissen, Laus M. Broersen, Marieke M. Lansbergen, Wiesje M. van der Flier, Bart N.M. van Berckel, Philip Scheltens
      Introduction Alzheimer's disease is associated with early synaptic loss. Specific nutrients are known to be rate limiting for synapse formation. Studies have shown that administering specific nutrients may improve memory function, possibly by increasing synapse formation. The Dutch Effect of a specific Nutritional Intervention on cerebral Glucose Metabolism in early Alzheimer's disease (NL-ENIGMA) study (Dutch Trial Register NTR4718, http://www.trialregister.nl/trialreg/admin/rctview.asp'TC=4718) is designed to test whether the specific multinutrient combination Fortasyn Connect present in the medical food Souvenaid influences cerebral glucose metabolism as a marker for improved synapse function. Methods This study is a double-blind, randomized controlled parallel-group single-center trial. Forty drug-naive patients with mild cognitive impairment or mild dementia with evidence of amyloid deposition are 1:1 randomized to receive either the multinutrient combination or placebo once daily. Main exploratory outcome parameters include absolute quantitative positron emission tomography with 18F-fluorodeoxyglucose (including arterial sampling) and standard uptake value ratios normalized for the cerebellum or pons after 24 weeks. Discussion We expect the NL-ENIGMA study to provide further insight in the potential of this multinutrient combination to improve synapse function.

      PubDate: 2016-09-06T17:44:41Z
      DOI: 10.1016/j.trci.2016.07.004
       
  • Insufficient evidence for vitamin E in Alzheimer's disease

    • Authors: Dirk Hermann
      Abstract: Publication date: Available online 29 August 2016
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Dirk M. Hermann
      ▪▪▪

      PubDate: 2016-09-01T11:23:00Z
       
  • Alzheimer's drug-development pipeline: 2016

    • Authors: Jeffrey Cummings; Travis Morstorf; Garam Lee
      Abstract: Publication date: Available online 17 August 2016
      Source:Alzheimer's & Dementia: Translational Research & Clinical Interventions
      Author(s): Jeffrey Cummings, Travis Morstorf, Garam Lee
      Background Alzheimer's disease (AD) is growing in frequency and new therapies are urgently needed. Methods We assessed clinicaltrials.gov (accessed 1-4-2016) to determine the number and characteristics of trials in phase I, phase II, and phase III for treatment of AD. Results There are currently 24 agents in 36 trials in phase III of AD drug development. Seven of these 24 agents are symptomatic cognitive-enhancing compounds, and 17 are disease-modifying treatments (DMTs). Most DMTs are currently targeting amyloid-related targets (76%). There are 45 agents in phase II being assessed in 52 clinical trials. Phase II trials include 30 DMTs, including 26 small molecules and 4 immunotherapies. There are 24 agents in the first phase of AD drug development. Discussion There are relatively few agents in clinical trials for AD suggesting a need to amplify the drug discovery ecosystem.

      PubDate: 2016-08-22T09:59:14Z
      DOI: 10.1016/j.trci.2016.07.001
       
 
 
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