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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: 303, 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: 196, 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: 388, 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: 151, 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
  [SJR: 4.289]   [H-I: 64]   [45 followers]  Follow
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 1552-5260 - ISSN (Online) 1552-5279
   Published by Elsevier Homepage  [3031 journals]
  • Predicting the progression of Alzheimer's disease dementia:
           A multidomain health policy model
    • Authors: Colin Green; Shenqiu Zhang
      Pages: 776 - 785
      Abstract: Publication date: July 2016
      Source:Alzheimer's & Dementia, Volume 12, Issue 7
      Author(s): Colin Green, Shenqiu Zhang
      Introduction We develop a multidomain model to predict progression of Alzheimer's disease dementia (AD). Methods Data from the US National Alzheimer's Coordinating Center (n = 3009) are used to examine change in symptom status and to estimate transition probabilities between health states described using cognitive function, functional ability, and behavior. A model is used to predict progression and to assess a hypothetical treatment scenario that slows mild to moderate AD progression. Results More than 70% of participants moved state over 12 months. The majority moved in domains other than cognitive function. Over 5 years, of those alive more than half are in severe AD health states. Assessing an intervention scenario, we see fewer years in more severe health states and a potential impact (life years saved) due to mortality improvements. Discussion The model developed is exploratory and has limitations but illustrates the importance of using a multidomain approach when assessing impacts of AD and interventions.

      PubDate: 2017-04-03T22:09:05Z
      DOI: 10.1016/j.jalz.2016.01.011
  • Crowdsourced estimation of cognitive decline and resilience in Alzheimer's
    • Authors: Genevera Allen; Nicola Amoroso Catalina Anghel Venkat Balagurusamy Christopher Bare
      Abstract: Publication date: June 2016
      Source:Alzheimer's & Dementia, Volume 12, Issue 6
      Author(s): Genevera I. Allen, Nicola Amoroso, Catalina Anghel, Venkat Balagurusamy, Christopher J. Bare, Derek Beaton, Roberto Bellotti, David A. Bennett, Kevin L. Boehme, Paul C. Boutros, Laura Caberlotto, Cristian Caloian, Frederick Campbell, Elias Chaibub Neto, Yu-Chuan Chang, Beibei Chen, Chien-Yu Chen, Ting-Ying Chien, Tim Clark, Sudeshna Das, Christos Davatzikos, Jieyao Deng, Donna Dillenberger, Richard J.B. Dobson, Qilin Dong, Jimit Doshi, Denise Duma, Rosangela Errico, Guray Erus, Evan Everett, David W. Fardo, Stephen H. Friend, Holger Fröhlich, Jessica Gan, Peter St George-Hyslop, Satrajit S. Ghosh, Enrico Glaab, Robert C. Green, Yuanfang Guan, Ming-Yi Hong, Chao Huang, Jinseub Hwang, Joseph Ibrahim, Paolo Inglese, Anandhi Iyappan, Qijia Jiang, Yuriko Katsumata, John S.K. Kauwe, Arno Klein, Dehan Kong, Roland Krause, Emilie Lalonde, Mario Lauria, Eunjee Lee, Xihui Lin, Zhandong Liu, Julie Livingstone, Benjamin A. Logsdon, Simon Lovestone, Tsung-wei Ma, Ashutosh Malhotra, Lara M. Mangravite, Taylor J. Maxwell, Emily Merrill, John Nagorski, Aishwarya Namasivayam, Manjari Narayan, Mufassra Naz, Stephen J. Newhouse, Thea C. Norman, Ramil N. Nurtdinov, Yen-Jen Oyang, Yudi Pawitan, Shengwen Peng, Mette A. Peters, Stephen R. Piccolo, Paurush Praveen, Corrado Priami, Veronica Y. Sabelnykova, Philipp Senger, Xia Shen, Andrew Simmons, Aristeidis Sotiras, Gustavo Stolovitzky, Sabina Tangaro, Andrea Tateo, Yi-An Tung, Nicholas J. Tustison, Erdem Varol, George Vradenburg, Michael W. Weiner, Guanghua Xiao, Lei Xie, Yang Xie, Jia Xu, Hojin Yang, Xiaowei Zhan, Yunyun Zhou, Fan Zhu, Hongtu Zhu, Shanfeng Zhu
      Identifying accurate biomarkers of cognitive decline is essential for advancing early diagnosis and prevention therapies in Alzheimer's disease. The Alzheimer's disease DREAM Challenge was designed as a computational crowdsourced project to benchmark the current state-of-the-art in predicting cognitive outcomes in Alzheimer's disease based on high dimensional, publicly available genetic and structural imaging data. This meta-analysis failed to identify a meaningful predictor developed from either data modality, suggesting that alternate approaches should be considered for prediction of cognitive performance.

      PubDate: 2017-04-03T22:09:05Z
  • Consensus classification of posterior cortical atrophy
    • Authors: Sebastian J. Crutch; Jonathan M. Schott; Gil D. Rabinovici; Melissa Murray; Julie S. Snowden; Wiesje M. van der Flier; Bradford C. Dickerson; Rik Vandenberghe; Samrah Ahmed; Thomas H. Bak; Bradley F. Boeve; Christopher Butler; Stefano F. Cappa; Mathieu Ceccaldi; Leonardo Cruz de Souza; Bruno Dubois; Olivier Felician; Douglas Galasko; Jonathan Graff-Radford; Neill R. Graff-Radford; Patrick R. Hof; Pierre Krolak-Salmon; Manja Lehmann; Eloi Magnin; Mario F. Mendez; Peter J. Nestor; Chiadi U. Onyike; Victoria S. Pelak; Yolande Pijnenburg; Silvia Primativo; Martin N. Rossor; Natalie S. Ryan; Philip Scheltens; Timothy J. Shakespeare; Aida Suárez González; David F. Tang-Wai; Keir X.X. Yong; Maria Carrillo; Nick C. Fox
      Abstract: Publication date: Available online 2 March 2017
      Source:Alzheimer's & Dementia
      Author(s): Sebastian J. Crutch, Jonathan M. Schott, Gil D. Rabinovici, Melissa Murray, Julie S. Snowden, Wiesje M. van der Flier, Bradford C. Dickerson, Rik Vandenberghe, Samrah Ahmed, Thomas H. Bak, Bradley F. Boeve, Christopher Butler, Stefano F. Cappa, Mathieu Ceccaldi, Leonardo Cruz de Souza, Bruno Dubois, Olivier Felician, Douglas Galasko, Jonathan Graff-Radford, Neill R. Graff-Radford, Patrick R. Hof, Pierre Krolak-Salmon, Manja Lehmann, Eloi Magnin, Mario F. Mendez, Peter J. Nestor, Chiadi U. Onyike, Victoria S. Pelak, Yolande Pijnenburg, Silvia Primativo, Martin N. Rossor, Natalie S. Ryan, Philip Scheltens, Timothy J. Shakespeare, Aida Suárez González, David F. Tang-Wai, Keir X.X. Yong, Maria Carrillo, Nick C. Fox
      Introduction A classification framework for posterior cortical atrophy (PCA) is proposed to improve the uniformity of definition of the syndrome in a variety of research settings. Methods Consensus statements about PCA were developed through a detailed literature review, the formation of an international multidisciplinary working party which convened on four occasions, and a Web-based quantitative survey regarding symptom frequency and the conceptualization of PCA. Results A three-level classification framework for PCA is described comprising both syndrome- and disease-level descriptions. Classification level 1 (PCA) defines the core clinical, cognitive, and neuroimaging features and exclusion criteria of the clinico-radiological syndrome. Classification level 2 (PCA-pure, PCA-plus) establishes whether, in addition to the core PCA syndrome, the core features of any other neurodegenerative syndromes are present. Classification level 3 (PCA attributable to AD [PCA-AD], Lewy body disease [PCA-LBD], corticobasal degeneration [PCA-CBD], prion disease [PCA-prion]) provides a more formal determination of the underlying cause of the PCA syndrome, based on available pathophysiological biomarker evidence. The issue of additional syndrome-level descriptors is discussed in relation to the challenges of defining stages of syndrome severity and characterizing phenotypic heterogeneity within the PCA spectrum. Discussion There was strong agreement regarding the definition of the core clinico-radiological syndrome, meaning that the current consensus statement should be regarded as a refinement, development, and extension of previous single-center PCA criteria rather than any wholesale alteration or redescription of the syndrome. The framework and terminology may facilitate the interpretation of research data across studies, be applicable across a broad range of research scenarios (e.g., behavioral interventions, pharmacological trials), and provide a foundation for future collaborative work.

      PubDate: 2017-03-02T15:50:30Z
      DOI: 10.1016/j.jalz.2017.01.014
  • The Alu neurodegeneration hypothesis: A primate-specific mechanism for
           neuronal transcription noise, mitochondrial dysfunction,
           and manifestation of neurodegenerative disease
    • Authors: Peter A. Larsen; Michael W. Lutz; Kelsie E. Hunnicutt; Mirta Mihovilovic; Ann M. Saunders; Anne D. Yoder; Allen D. Roses
      Abstract: Publication date: Available online 24 February 2017
      Source:Alzheimer's & Dementia
      Author(s): Peter A. Larsen, Michael W. Lutz, Kelsie E. Hunnicutt, Mirta Mihovilovic, Ann M. Saunders, Anne D. Yoder, Allen D. Roses
      It is hypothesized that retrotransposons have played a fundamental role in primate evolution and that enhanced neurologic retrotransposon activity in humans may underlie the origin of higher cognitive function. As a potential consequence of this enhanced activity, it is likely that neurons are susceptible to deleterious retrotransposon pathways that can disrupt mitochondrial function. An example is observed in the TOMM40 gene, encoding a β-barrel protein critical for mitochondrial preprotein transport. Primate-specific Alu retrotransposons have repeatedly inserted into TOMM40 introns and at least one variant associated with late-onset Alzheimer's disease originated from an Alu insertion event. We provide evidence of enriched Alu content in mitochondrial genes and postulate that Alus can disrupt mitochondrial populations in neurons, thereby setting the stage for progressive neurologic dysfunction. This Alu neurodegeneration hypothesis is compatible with decades of research and offers a plausible mechanism for the disruption of neuronal mitochondrial homeostasis, ultimately cascading into neurodegenerative disease.

      PubDate: 2017-03-02T15:50:30Z
      DOI: 10.1016/j.jalz.2017.01.017
  • Transethnic genome-wide scan identifies novel Alzheimer's disease loci
    • Authors: Gyungah Jun; Jaeyoon Chung Jesse Mez Robert Barber Gary Beecham
      Abstract: Publication date: Available online 7 February 2017
      Source:Alzheimer's & Dementia
      Author(s): Gyungah R. Jun, Jaeyoon Chung, Jesse Mez, Robert Barber, Gary W. Beecham, David A. Bennett, Joseph D. Buxbaum, Goldie S. Byrd, Minerva M. Carrasquillo, Paul K. Crane, Carlos Cruchaga, Philip De Jager, Nilufer Ertekin-Taner, Denis Evans, M. Danielle Fallin, Tatiana M. Foroud, Robert P. Friedland, Alison M. Goate, Neill R. Graff-Radford, Hugh Hendrie, Kathleen S. Hall, Kara L. Hamilton-Nelson, Rivka Inzelberg, M. Ilyas Kamboh, John S.K. Kauwe, Walter A. Kukull, Brian W. Kunkle, Ryozo Kuwano, Eric B. Larson, Mark W. Logue, Jennifer J. Manly, Eden R. Martin, Thomas J. Montine, Shubhabrata Mukherjee, Adam Naj, Eric M. Reiman, Christiane Reitz, Richard Sherva, Peter H. St. George-Hyslop, Timothy Thornton, Steven G. Younkin, Badri N. Vardarajan, Li-San Wang, Jens R. Wendlund, Ashley R. Winslow, Jonathan Haines, Richard Mayeux, Margaret A. Pericak-Vance, Gerard Schellenberg, Kathryn L. Lunetta, Lindsay A. Farrer
      Background Genetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood. Methods We conducted a transethnic genome-wide association study (GWAS) for late-onset AD in Stage 1 sample including whites of European Ancestry, African-Americans, Japanese, and Israeli-Arabs assembled by the Alzheimer's Disease Genetics Consortium. Suggestive results from Stage 1 from novel loci were followed up using summarized results in the International Genomics Alzheimer's Project GWAS dataset. Results Genome-wide significant (GWS) associations in single-nucleotide polymorphism (SNP)–based tests (P < 5 × 10−8) were identified for SNPs in PFDN1/HBEGF, USP6NL/ECHDC3, and BZRAP1-AS1 and for the interaction of the APOE ɛ4 allele with NFIC SNP. We also obtained GWS evidence (P < 2.7 × 10−6) for gene-based association in the total sample with a novel locus, TPBG (P = 1.8 × 10−6). Discussion Our findings highlight the value of transethnic studies for identifying novel AD susceptibility loci.

      PubDate: 2017-02-10T13:30:54Z
  • Factors associated with the quality of life of family carers of people
           with dementia: A systematic review
    • Authors: Nicolas Farina; Thomas E. Page; Stephanie Daley; Anna Brown; Ann Bowling; Thurstine Basset; Gill Livingston; Martin Knapp; Joanna Murray; Sube Banerjee
      Abstract: Publication date: Available online 5 February 2017
      Source:Alzheimer's & Dementia
      Author(s): Nicolas Farina, Thomas E. Page, Stephanie Daley, Anna Brown, Ann Bowling, Thurstine Basset, Gill Livingston, Martin Knapp, Joanna Murray, Sube Banerjee
      Introduction Family carers of people with dementia are their most important support in practical, personal, and economic terms. Carers are vital to maintaining the quality of life (QOL) of people with dementia. This review aims to identify factors related to the QOL of family carers of people with dementia. Methods Searches on terms including “carers,” “dementia,” “family,” and “quality of life” in research databases. Findings were synthesized inductively, grouping factors associated with carer QOL into themes. Results A total of 909 abstracts were identified. Following screening, lateral searches, and quality appraisal, 41 studies (n = 5539) were included for synthesis. A total of 10 themes were identified: demographics; carer–patient relationship; dementia characteristics; demands of caring; carer health; carer emotional well-being; support received; carer independence; carer self-efficacy; and future. Discussion The quality and level of evidence supporting each theme varied. We need further research on what factors predict carer QOL in dementia and how to measure it.

      PubDate: 2017-02-10T13:30:54Z
      DOI: 10.1016/j.jalz.2016.12.010
  • The validity of the Memory Alteration Test and the Test Your Memory test
           for community-based identification of amnestic mild cognitive impairment
    • Authors: Seline Ozer; Krist Noonan; Melanie Burke; John Young; Sally Barber; Anne Forster; Roy Jones
      Pages: 987 - 995
      Abstract: Publication date: September 2016
      Source:Alzheimer's & Dementia, Volume 12, Issue 9
      Author(s): Seline Ozer, Krist Noonan, Melanie Burke, John Young, Sally Barber, Anne Forster, Roy Jones
      Introduction This study investigated the validity of two brief cognitive tests (Memory Alteration Test [M@T] and Test Your Memory [TYM] test) for identifying people with aMCI in the community. Methods Older people were invited to participate by their general practitioner practice. Eligible participants were assessed for aMCI using an operationalized approach to the Petersen criteria and the M@T and TYM. Results Both tests demonstrated significant ability in discriminating between people with aMCI and controls (AUC = 0.91 for M@T and 0.80 for TYM [P < .001 for both]). M@T performed with higher sensitivity than TYM (85% vs. 63%) and similar specificity (84% vs. 87%). Both tests demonstrated moderate test-retest reliability (κ = ∼0.5) and took <10 minutes to administer. Discussion M@T and TYM are quick to administer. M@T demonstrated higher diagnostic test accuracy than TYM and could provide an efficient method for identifying aMCI in clinical and research settings.

      PubDate: 2016-10-03T13:45:08Z
      DOI: 10.1016/j.jalz.2016.03.014
  • Big data to smart data in Alzheimer's disease: The brain health modeling
           initiative to foster actionable knowledge
    • Authors: Hugo Geerts; Penny A. Dacks; Viswanath Devanarayan; Magali Haas; Zaven S. Khachaturian; Mark Forrest Gordon; Stuart Maudsley; Klaus Romero; Diane Stephenson
      Pages: 1014 - 1021
      Abstract: Publication date: September 2016
      Source:Alzheimer's & Dementia, Volume 12, Issue 9
      Author(s): Hugo Geerts, Penny A. Dacks, Viswanath Devanarayan, Magali Haas, Zaven S. Khachaturian, Mark Forrest Gordon, Stuart Maudsley, Klaus Romero, Diane Stephenson
      Massive investment and technological advances in the collection of extensive and longitudinal information on thousands of Alzheimer patients results in large amounts of data. These “big-data” databases can potentially advance CNS research and drug development. However, although necessary, they are not sufficient, and we posit that they must be matched with analytical methods that go beyond retrospective data-driven associations with various clinical phenotypes. Although these empirically derived associations can generate novel and useful hypotheses, they need to be organically integrated in a quantitative understanding of the pathology that can be actionable for drug discovery and development. We argue that mechanism-based modeling and simulation approaches, where existing domain knowledge is formally integrated using complexity science and quantitative systems pharmacology can be combined with data-driven analytics to generate predictive actionable knowledge for drug discovery programs, target validation, and optimization of clinical development.

      PubDate: 2016-10-03T13:45:08Z
      DOI: 10.1016/j.jalz.2016.04.008
  • Big data to smart data in Alzheimer's disease: Real-world examples of
           advanced modeling and simulation
    • Authors: Magali Haas; Diane Stephenson; Klaus Romero; Mark Forrest Gordon; Neta Zach; Hugo Geerts
      Pages: 1022 - 1030
      Abstract: Publication date: September 2016
      Source:Alzheimer's & Dementia, Volume 12, Issue 9
      Author(s): Magali Haas, Diane Stephenson, Klaus Romero, Mark Forrest Gordon, Neta Zach, Hugo Geerts
      Many disease-modifying clinical development programs in Alzheimer's disease (AD) have failed to date, and development of new and advanced preclinical models that generate actionable knowledge is desperately needed. This review reports on computer-based modeling and simulation approach as a powerful tool in AD research. Statistical data-analysis techniques can identify associations between certain data and phenotypes, such as diagnosis or disease progression. Other approaches integrate domain expertise in a formalized mathematical way to understand how specific components of pathology integrate into complex brain networks. Private-public partnerships focused on data sharing, causal inference and pathway-based analysis, crowdsourcing, and mechanism-based quantitative systems modeling represent successful real-world modeling examples with substantial impact on CNS diseases. Similar to other disease indications, successful real-world examples of advanced simulation can generate actionable support of drug discovery and development in AD, illustrating the value that can be generated for different stakeholders.

      PubDate: 2016-10-03T13:45:08Z
      DOI: 10.1016/j.jalz.2016.05.005
  • Synergistic interaction between amyloid and tau predicts the
           progression to dementia
    • Authors: Tharick A. Pascoal; Sulantha S. Mathotaarachchi; Monica Shin; Andrea Lessa Benedet; Min Su Kang; Sara Mohades; Thomas Beaudry; Jean-Paul Soucy; Serge Gauthier; Pedro Rosa-Neto
      Abstract: Publication date: Available online 23 December 2016
      Source:Alzheimer's & Dementia
      Author(s): Tharick A. Pascoal, Sulantha Mathotaarachchi, Monica Shin, Andrea L. Benedet, Sara Mohades, Seqian Wang, Tom Beaudry, Min Su Kang, Jean-Paul Soucy, Aurelie Labbe, Serge Gauthier, Pedro Rosa-Neto
      Introduction Recent literature proposes that amyloid-β and phosphorylated tau (p-tau) synergism accelerates biomarker abnormalities in controls. Yet, it remains to be answered whether this synergism is the driving force behind Alzheimer disease (AD) dementia. Methods We stratified 314 mild cognitive impairment individuals using [18F]florbetapir positron emission tomography amyloid-β imaging and cerebrospinal fluid p-tau. Regression and voxel-based logistic regression models with interaction terms evaluated 2-year changes in cognition and clinical status as a function of baseline biomarkers. Results We found that the synergism between [18F]florbetapir and p-tau, rather than their additive effects, was associated with the cognitive decline and progression to AD. Furthermore, voxel-based analysis revealed that temporal and inferior parietal were the regions where the synergism determined an increased likelihood of developing AD. Discussion Together, the present results support that progression to AD dementia is driven by the synergistic rather than a mere additive effect between amyloid-β and p-tau proteins.

      PubDate: 2016-12-28T19:33:07Z
      DOI: 10.1016/j.jalz.2016.06.115
  • Meta-analysis of synaptic pathology in Alzheimer's disease reveals
           selective molecular vesicular machinery vulnerability
    • Authors: Martijn C. de Wilde; Cassia R. Overk; John W. Sijben; Eliezer Masliah
      Pages: 633 - 644
      Abstract: Publication date: June 2016
      Source:Alzheimer's & Dementia, Volume 12, Issue 6
      Author(s): Martijn C. de Wilde, Cassia R. Overk, John W. Sijben, Eliezer Masliah
      Introduction Loss of synapses best correlates to cognitive deficits in Alzheimer's disease (AD) in which oligomeric neurotoxic species of amyloid-β appears to contribute synaptic pathology. Although a number of clinical pathologic studies have been performed with limited sample size, there are no systematic studies encompassing large samples. Therefore, we performed a meta-analysis study. Methods We identified 417 publications reporting postmortem synapse and synaptic marker loss from AD patients. Two meta-analyses were performed using a single database of subselected publications and calculating the standard mean differences. Results Meta-analysis confirmed synaptic loss in selected brain regions is an early event in AD pathogenesis. The second meta-analysis of 57 synaptic markers revealed that presynaptic makers were affected more than postsynaptic markers. Discussion The present meta-analysis study showed a consistent synaptic loss across brain regions and that molecular machinery including endosomal pathways, vesicular assembly mechanisms, glutamate receptors, and axonal transport are often affected.

      PubDate: 2016-10-26T14:48:35Z
      DOI: 10.1016/j.jalz.2015.12.005
  • Understanding the genetics of APOE and TOMM40 and role of mitochondrial
           structure and function in clinical pharmacology of Alzheimer's disease
    • Authors: Allen Roses; Scott Sundseth; Ann Saunders; William Gottschalk; Dan Burns; Michael Lutz
      Pages: 687 - 694
      Abstract: Publication date: June 2016
      Source:Alzheimer's & Dementia, Volume 12, Issue 6
      Author(s): Allen Roses, Scott Sundseth, Ann Saunders, William Gottschalk, Dan Burns, Michael Lutz
      The methodology of Genome-Wide Association Screening (GWAS) has been applied for more than a decade. Translation to clinical utility has been limited, especially in Alzheimer's Disease (AD). It has become standard practice in the analyses of more than two dozen AD GWAS studies to exclude the apolipoprotein E (APOE) region because of its extraordinary statistical support, unique thus far in complex human diseases. New genes associated with AD are proposed frequently based on SNPs associated with odds ratio (OR) < 1.2. Most of these SNPs are not located within the associated gene exons or introns but are located variable distances away. Often pathologic hypotheses for these genes are presented, with little or no experimental support. By eliminating the analyses of the APOE-TOMM40 linkage disequilibrium region, the relationship and data of several genes that are co-located in that LD region have been largely ignored. Early negative interpretations limited the interest of understanding the genetic data derived from GWAS, particularly regarding the TOMM40 gene. This commentary describes the history and problem(s) in interpretation of the genetic interrogation of the “APOE” region and provides insight into a metabolic mitochondrial basis for the etiology of AD using both APOE and TOMM40 genetics.

      PubDate: 2016-10-26T14:48:35Z
      DOI: 10.1016/j.jalz.2016.03.015
  • Information and communication technology solutions for outdoor navigation
           in dementia
    • Authors: Stefan Teipel; Claudio Babiloni; Jesse Hoey; Jeffrey Kaye; Thomas Kirste; Oliver K. Burmeister
      Pages: 695 - 707
      Abstract: Publication date: June 2016
      Source:Alzheimer's & Dementia, Volume 12, Issue 6
      Author(s): Stefan Teipel, Claudio Babiloni, Jesse Hoey, Jeffrey Kaye, Thomas Kirste, Oliver K. Burmeister
      Introduction Information and communication technology (ICT) is potentially mature enough to empower outdoor and social activities in dementia. However, actual ICT-based devices have limited functionality and impact, mainly limited to safety. What is an ideal operational framework to enhance this field to support outdoor and social activities' Methods Review of literature and cross-disciplinary expert discussion. Results A situation-aware ICT requires a flexible fine-tuning by stakeholders of system usability and complexity of function, and of user safety and autonomy. It should operate by artificial intelligence/machine learning and should reflect harmonized stakeholder values, social context, and user residual cognitive functions. ICT services should be proposed at the prodromal stage of dementia and should be carefully validated within the life space of users in terms of quality of life, social activities, and costs. Discussion The operational framework has the potential to produce ICT and services with high clinical impact but requires substantial investment.

      PubDate: 2016-10-26T14:48:35Z
      DOI: 10.1016/j.jalz.2015.11.003
  • Molecular genetics of early-onset Alzheimer's disease revisited
    • Authors: Rita Cacace; Kristel Sleegers; Christine Van Broeckhoven
      Pages: 733 - 748
      Abstract: Publication date: June 2016
      Source:Alzheimer's & Dementia, Volume 12, Issue 6
      Author(s): Rita Cacace, Kristel Sleegers, Christine Van Broeckhoven
      As the discovery of the Alzheimer's disease (AD) genes, APP, PSEN1, and PSEN2, in families with autosomal dominant early-onset AD (EOAD), gene discovery in familial EOAD came more or less to a standstill. Only 5% of EOAD patients are carrying a pathogenic mutation in one of the AD genes or a apolipoprotein E (APOE) risk allele ε4, most of EOAD patients remain unexplained. Here, we aimed at summarizing the current knowledge of EOAD genetics and its role in ongoing approaches to understand the biology of AD and disease symptomatology as well as developing new therapeutics. Next, we explored the possible molecular mechanisms that might underlie the missing genetic etiology of EOAD and discussed how the use of massive parallel sequencing technologies triggered novel gene discoveries. To conclude, we commented on the relevance of reinvestigating EOAD patients as a means to explore potential new avenues for translational research and therapeutic discoveries.

      PubDate: 2016-10-26T14:48:35Z
      DOI: 10.1016/j.jalz.2016.01.012
  • Technical performance of a novel, fully automated electrochemiluminescence
           immunoassay for the quantitation of β-amyloid (1–42) in human
           cerebrospinal fluid
    • Authors: Tobias Bittner; Henrik Zetterberg; Charlotte E. Teunissen; Richard E. Ostlund; Michael Militello; Ulf Andreasson; Isabelle Hubeek; David Gibson; David C. Chu; Udo Eichenlaub; Peter Heiss; Uwe Kobold; Andreas Leinenbach; Kairat Madin; Ekaterina Manuilova; Christina Rabe; Kaj Blennow
      Pages: 517 - 526
      Abstract: Publication date: May 2016
      Source:Alzheimer's & Dementia, Volume 12, Issue 5
      Author(s): Tobias Bittner, Henrik Zetterberg, Charlotte E. Teunissen, Richard E. Ostlund, Michael Militello, Ulf Andreasson, Isabelle Hubeek, David Gibson, David C. Chu, Udo Eichenlaub, Peter Heiss, Uwe Kobold, Andreas Leinenbach, Kairat Madin, Ekaterina Manuilova, Christina Rabe, Kaj Blennow
      Introduction Available assays for quantitation of the Alzheimer's disease (AD) biomarker amyloid-beta 1–42 (Aβ [1–42]) in cerebrospinal fluid demonstrate significant variability and lack of standardization to reference measurement procedures (RMPs). We report analytical performance data for the novel Elecsys β-amyloid (1–42) assay (Roche Diagnostics). Methods Lot-to-lot comparability was tested using method comparison. Performance parameters were measured according to Clinical & Laboratory Standards Institute (CLSI) guidelines. The assay was standardized to a Joint Committee for Traceability in Laboratory Medicine (JCTLM) approved RMP. Results Limit of quantitation was <11.28 pg/mL, and the assay was linear throughout the measuring range (200–1700 pg/mL). Excellent lot-to-lot comparability was observed (correlation coefficients [Pearson's r] >0.995; bias in medical decision area <2%). Repeatability coefficients of variation (CVs) were 1.0%–1.6%, intermediate CVs were 1.9%–4.0%, and intermodule CVs were 1.1%–3.9%. Estimated total reproducibility was 2.0%–5.1%. Correlation with the RMP was good (Pearson's r, 0.93). Discussion The Elecsys β-amyloid (1–42) assay has high analytical performance that may improve biomarker-based AD diagnosis.

      PubDate: 2016-10-26T14:48:35Z
      DOI: 10.1016/j.jalz.2015.09.009
  • The pattern of amyloid accumulation in the brains of adults with Down
    • Authors: Tiina Annus; Liam R. Wilson; Young T. Hong; Julio Acosta–Cabronero; Tim D. Fryer; Arturo Cardenas–Blanco; Robert Smith; Istvan Boros; Jonathan P. Coles; Franklin I. Aigbirhio; David K. Menon; Shahid H. Zaman; Peter J. Nestor; Anthony J. Holland
      Pages: 538 - 545
      Abstract: Publication date: May 2016
      Source:Alzheimer's & Dementia, Volume 12, Issue 5
      Author(s): Tiina Annus, Liam R. Wilson, Young T. Hong, Julio Acosta–Cabronero, Tim D. Fryer, Arturo Cardenas–Blanco, Robert Smith, Istvan Boros, Jonathan P. Coles, Franklin I. Aigbirhio, David K. Menon, Shahid H. Zaman, Peter J. Nestor, Anthony J. Holland
      Introduction Adults with Down syndrome (DS) invariably develop Alzheimer's disease (AD) neuropathology. Understanding amyloid deposition in DS can yield crucial information about disease pathogenesis. Methods Forty-nine adults with DS aged 25–65 underwent positron emission tomography with Pittsburgh compound–B (PIB). Regional PIB binding was assessed with respect to age, clinical, and cognitive status. Results Abnormal PIB binding became evident from 39 years, first in striatum followed by rostral prefrontal-cingulo-parietal regions, then caudal frontal, rostral temporal, primary sensorimotor and occipital, and finally parahippocampal cortex, thalamus, and amygdala. PIB binding was related to age, diagnostic status, and cognitive function. Discussion PIB binding in DS, first appearing in striatum, began around age 40 and was strongly associated with dementia and cognitive decline. The absence of a substantial time lag between amyloid accumulation and cognitive decline contrasts to sporadic/familial AD and suggests this population's suitability for an amyloid primary prevention trial.

      PubDate: 2016-10-26T14:48:35Z
      DOI: 10.1016/j.jalz.2015.07.490
  • Ethical challenges in preclinical Alzheimer's disease observational
           studies and trials: Results of the Barcelona summit
    • Authors: José L. Molinuevo; Jordi Cami; Xavier Carné; Maria C. Carrillo; Jean Georges; Maria B. Isaac; Zaven Khachaturian; Scott Y.H. Kim; John C. Morris; Florence Pasquier; Craig Ritchie; Reisa Sperling; Jason Karlawish
      Pages: 614 - 622
      Abstract: Publication date: May 2016
      Source:Alzheimer's & Dementia, Volume 12, Issue 5
      Author(s): José L. Molinuevo, Jordi Cami, Xavier Carné, Maria C. Carrillo, Jean Georges, Maria B. Isaac, Zaven Khachaturian, Scott Y.H. Kim, John C. Morris, Florence Pasquier, Craig Ritchie, Reisa Sperling, Jason Karlawish
      Alzheimer's disease (AD) is among the most significant health care burdens. Disappointing results from clinical trials in late-stage AD persons combined with hopeful results from trials in persons with early-stage suggest that research in the preclinical stage of AD is necessary to define an optimal therapeutic success window. We review the justification for conducting trials in the preclinical stage and highlight novel ethical challenges that arise and are related to determining appropriate risk-benefit ratios and disclosing individuals' biomarker status. We propose that to conduct clinical trials with these participants, we need to improve public understanding of AD using unified vocabulary, resolve the acceptable risk-benefit ratio in asymptomatic participants, and disclose or not biomarker status with attention to study type (observational studies vs clinical trials). Overcoming these challenges will justify clinical trials in preclinical AD at the societal level and aid to the development of societal and legal support for trial participants.

      PubDate: 2016-10-26T14:48:35Z
      DOI: 10.1016/j.jalz.2016.01.009
  • Report on milestones for care and support under the U.S. National Plan to
           Address Alzheimer's Disease
    • Authors: Soo Borson; Malaz A. Boustani; Kathleen C. Buckwalter; Louis D. Burgio; Joshua Chodosh; Richard H. Fortinsky; David R. Gifford; Lisa P. Gwyther; Mary Jane Koren; Joanne Lynn; Cheryl Phillips; Martha Roherty; Judah Ronch; Claudia Stahl; Lauren Rodgers; Hye Kim; Matthew Baumgart; Angela Geiger
      Pages: 334 - 369
      Abstract: Publication date: March 2016
      Source:Alzheimer's & Dementia, Volume 12, Issue 3
      Author(s): Soo Borson, Malaz A. Boustani, Kathleen C. Buckwalter, Louis D. Burgio, Joshua Chodosh, Richard H. Fortinsky, David R. Gifford, Lisa P. Gwyther, Mary Jane Koren, Joanne Lynn, Cheryl Phillips, Martha Roherty, Judah Ronch, Claudia Stahl, Lauren Rodgers, Hye Kim, Matthew Baumgart, Angela Geiger
      Introduction Under the U.S. national Alzheimer's plan, the National Institutes of Health identified milestones required to meet the plan's biomedical research goal (Goal 1). However, similar milestones have not been created for the goals on care (Goal 2) and support (Goal 3). Methods The Alzheimer's Association convened a workgroup with expertise in clinical care, long-term services and supports, dementia care and support research, and public policy. The workgroup reviewed the literature on Alzheimer's care and support; reviewed how other countries are addressing the issue; and identified public policies needed over the next 10 years to achieve a more ideal care and support system. Results The workgroup developed and recommended 73 milestones for Goal 2 and 56 milestones for Goal 3. Discussion To advance the implementation of the U.S. national Alzheimer's plan, the U.S. government should adopt these recommended milestones, or develop similar milestones, to be incorporated into the national plan.

      PubDate: 2016-10-26T14:48:35Z
      DOI: 10.1016/j.jalz.2016.01.005
  • Prudent diet may attenuate the adverse effects of Western diet on
           cognitive decline
    • Authors: Behnaz Shakersain; Giola Santoni; Susanna C. Larsson; Gerd Faxén-Irving; Johan Fastbom; Laura Fratiglioni; Weili Xu
      Pages: 100 - 109
      Abstract: Publication date: February 2016
      Source:Alzheimer's & Dementia, Volume 12, Issue 2
      Author(s): Behnaz Shakersain, Giola Santoni, Susanna C. Larsson, Gerd Faxén-Irving, Johan Fastbom, Laura Fratiglioni, Weili Xu
      Introduction The influence of mixed dietary patterns on cognitive changes is unknown. Methods A total of 2223 dementia-free participants aged ≥60 were followed up for 6 years to examine the impact of dietary patterns on cognitive decline. Mini-mental state examination (MMSE) was administered. Diet was assessed by a food frequency questionnaire. By factor analysis, Western and prudent dietary patterns emerged. Mixed-effect models for longitudinal data with repeated measurements were used. Results Compared with the lowest adherence to each pattern, the highest adherence to prudent pattern was related to less MMSE decline (β = 0.106, P = .011), whereas the highest adherence to Western pattern was associated with more MMSE decline (β = −0.156, P < .001). The decline associated with Western diet was attenuated when accompanied by high adherence to prudent pattern. Discussion High adherence to prudent diet may diminish the adverse effects of high adherence to Western diet on cognitive decline.

      PubDate: 2016-10-26T14:48:35Z
      DOI: 10.1016/j.jalz.2015.08.002
  • Phase 3 solanezumab trials: Secondary outcomes in mild Alzheimer's disease
    • Authors: Eric R. Siemers; Karen L. Sundell; Christopher Carlson; Michael Case; Gopalan Sethuraman; Hong Liu-Seifert; Sherie A. Dowsett; Michael J. Pontecorvo; Robert A. Dean; Ronald Demattos
      Pages: 110 - 120
      Abstract: Publication date: February 2016
      Source:Alzheimer's & Dementia, Volume 12, Issue 2
      Author(s): Eric R. Siemers, Karen L. Sundell, Christopher Carlson, Michael Case, Gopalan Sethuraman, Hong Liu-Seifert, Sherie A. Dowsett, Michael J. Pontecorvo, Robert A. Dean, Ronald Demattos
      Introduction EXPEDITION and EXPEDITION2 were identically designed placebo-controlled phase 3 studies assessing effects of solanezumab, an antiamyloid monoclonal antibody binding soluble amyloid-β peptide, on cognitive and functional decline over 80 weeks in patients with mild-to-moderate Alzheimer's disease (AD). Primary findings for both studies have been published. Methods Secondary analyses of efficacy, biomarker, and safety endpoints in the pooled (EXPEDTION + EXPEDITION2) mild AD population were performed. Results In the mild AD population, less cognitive and functional decline was observed with solanezumab (n = 659) versus placebo (n = 663), measured by Alzheimer's Disease Assessment Scale Cognitive subscale, Mini-Mental State Examination, and Alzheimer's Disease Cooperative Study–Activities of Daily Living functional scale Instrumental ADLs. Baseline-to-endpoint changes did not differ between treatment groups for Alzheimer's Disease Cooperative Study–Activities of Daily Living functional scale, basic items of the ADCS-ADL, and Clinical Dementia Rating Sum of Boxes. Plasma/cerebrospinal fluid biomarker findings indicated target engagement by solanezumab. Solanezumab demonstrated acceptable safety. Efficacy findings for the moderate AD population are also provided. Discussion These findings describe solanezumab effects on efficacy/safety measures in a mild AD population. Another phase 3 study, EXPEDITION3, will investigate solanezumab's effects in a mild AD population.

      PubDate: 2016-10-26T14:48:35Z
      DOI: 10.1016/j.jalz.2015.06.1893
  • Genome-wide linkage analyses of non-Hispanic white families identify novel
           loci for familial late-onset Alzheimer's disease
    • Authors: Brian W. Kunkle; James Jaworski; Sandra Barral; Badri Vardarajan; Gary W. Beecham; Eden R. Martin; Laura S. Cantwell; Amanda Partch; Thomas D. Bird; Wendy H. Raskind; Anita L. DeStefano; Regina M. Carney; Michael Cuccaro; Jeffrey M. Vance; Lindsay A. Farrer; Alison M. Goate; Tatiana Foroud; Richard P. Mayeux; Gerard D. Schellenberg; Jonathan L. Haines; Margaret A. Pericak-Vance
      Pages: 2 - 10
      Abstract: Publication date: January 2016
      Source:Alzheimer's & Dementia, Volume 12, Issue 1
      Author(s): Brian W. Kunkle, James Jaworski, Sandra Barral, Badri Vardarajan, Gary W. Beecham, Eden R. Martin, Laura S. Cantwell, Amanda Partch, Thomas D. Bird, Wendy H. Raskind, Anita L. DeStefano, Regina M. Carney, Michael Cuccaro, Jeffrey M. Vance, Lindsay A. Farrer, Alison M. Goate, Tatiana Foroud, Richard P. Mayeux, Gerard D. Schellenberg, Jonathan L. Haines, Margaret A. Pericak-Vance
      Introduction Few high penetrance variants that explain risk in late-onset Alzheimer's disease (LOAD) families have been found. Methods We performed genome-wide linkage and identity-by-descent (IBD) analyses on 41 non-Hispanic white families exhibiting likely dominant inheritance of LOAD, and having no mutations at known familial Alzheimer's disease (AD) loci, and a low burden of APOE ε4 alleles. Results Two-point parametric linkage analysis identified 14 significantly linked regions, including three novel linkage regions for LOAD (5q32, 11q12.2–11q14.1, and 14q13.3), one of which replicates a genome-wide association LOAD locus, the MS4A6A-MS4A4E gene cluster at 11q12.2. Five of the 14 regions (3q25.31, 4q34.1, 8q22.3, 11q12.2–14.1, and 19q13.41) are supported by strong multipoint results (logarithm of odds [LOD*] ≥1.5). Nonparametric multipoint analyses produced an additional significant locus at 14q32.2 (LOD* = 4.18). The 1-LOD confidence interval for this region contains one gene, C14orf177, and the microRNA Mir_320, whereas IBD analyses implicates an additional gene BCL11B, a regulator of brain-derived neurotrophic signaling, a pathway associated with pathogenesis of several neurodegenerative diseases. Discussion Examination of these regions after whole-genome sequencing may identify highly penetrant variants for familial LOAD.

      PubDate: 2016-10-26T14:48:35Z
      DOI: 10.1016/j.jalz.2015.05.020
  • Could ecosystem management provide a new framework for Alzheimer's
    • Authors: Ellen Hubin; Bram Vanschoenwinkel; Kerensa Broersen; Peter P. De Deyn; Nico Koedam; Nico A. van Nuland; Kris Pauwels
      Pages: 65 - 74.e1
      Abstract: Publication date: January 2016
      Source:Alzheimer's & Dementia, Volume 12, Issue 1
      Author(s): Ellen Hubin, Bram Vanschoenwinkel, Kerensa Broersen, Peter P. De Deyn, Nico Koedam, Nico A. van Nuland, Kris Pauwels
      Alzheimer's disease (AD) is a progressive neurodegenerative brain disorder that involves a plethora of molecular pathways. In the context of therapeutic treatment and biomarker profiling, the amyloid-beta (Aβ) peptide constitutes an interesting research avenue that involves interactions within a complex mixture of Aβ alloforms and other disease-modifying factors. Here, we explore the potential of an ecosystem paradigm as a novel way to consider AD and Aβ dynamics in particular. We discuss the example that the complexity of the Aβ network not only exhibits interesting parallels with the functioning of complex systems such as ecosystems but that this analogy can also provide novel insights into the neurobiological phenomena in AD and serve as a communication tool. We propose that combining network medicine with general ecosystem management principles could be a new and holistic approach to understand AD pathology and design novel therapies.

      PubDate: 2016-10-26T14:48:35Z
      DOI: 10.1016/j.jalz.2015.07.491
  • The influence of biological and technical factors on quantitative analysis
           of amyloid PET: Points to consider and recommendations for controlling
           variability in longitudinal data
    • Authors: Mark E. Schmidt; Ping Chiao; Gregory Klein; Dawn Matthews; Lennart Thurfjell; Patricia E. Cole; Richard Margolin; Susan Landau; Norman L. Foster; N. Scott Mason; Susan De Santi; Joyce Suhy; Robert A. Koeppe; William Jagust
      Pages: 1050 - 1068
      Abstract: Publication date: September 2015
      Source:Alzheimer's & Dementia, Volume 11, Issue 9
      Author(s): Mark E. Schmidt, Ping Chiao, Gregory Klein, Dawn Matthews, Lennart Thurfjell, Patricia E. Cole, Richard Margolin, Susan Landau, Norman L. Foster, N. Scott Mason, Susan De Santi, Joyce Suhy, Robert A. Koeppe, William Jagust
      In vivo imaging of amyloid burden with positron emission tomography (PET) provides a means for studying the pathophysiology of Alzheimer's and related diseases. Measurement of subtle changes in amyloid burden requires quantitative analysis of image data. Reliable quantitative analysis of amyloid PET scans acquired at multiple sites and over time requires rigorous standardization of acquisition protocols, subject management, tracer administration, image quality control, and image processing and analysis methods. We review critical points in the acquisition and analysis of amyloid PET, identify ways in which technical factors can contribute to measurement variability, and suggest methods for mitigating these sources of noise. Improved quantitative accuracy could reduce the sample size necessary to detect intervention effects when amyloid PET is used as a treatment end point and allow more reliable interpretation of change in amyloid burden and its relationship to clinical course.

      PubDate: 2016-10-26T14:48:35Z
      DOI: 10.1016/j.jalz.2014.09.004
  • Self-reported sleep disturbance is associated with Alzheimer's disease
           risk in men
    • Authors: Christian Benedict; Liisa Byberg; Jonathan Cedernaes; Pleunie S. Hogenkamp; Vilmantas Giedratis; Lena Kilander; Lars Lind; Lars Lannfelt; Helgi B. Schiöth
      Pages: 1090 - 1097
      Abstract: Publication date: September 2015
      Source:Alzheimer's & Dementia, Volume 11, Issue 9
      Author(s): Christian Benedict, Liisa Byberg, Jonathan Cedernaes, Pleunie S. Hogenkamp, Vilmantas Giedratis, Lena Kilander, Lars Lind, Lars Lannfelt, Helgi B. Schiöth
      Objective To study the association between self-reported sleep disturbances and dementia risk. Methods Self-reported sleep disturbances and established risk factors for dementia were measured in men at ages 50 (n = 1574) and 70 (n = 1029) years. Dementia incidence was determined by reviewing their patient history between ages 50 and 90 years. In addition, plasma levels of β-amyloid (Aβ) peptides 1–40 and 1–42 were measured at ages 70, 77, and 82 years. Results Cox regression demonstrated that men with self-reported sleep disturbances had a higher risk of developing dementia (+33%) and Alzheimer's disease (AD, +51%) than men without self-reported sleep disturbances (both P < .05). Binary logistic regression showed the increased risk for both dementia (+114%) and AD (+192%) were highest when sleep disturbance was reported at age 70 years (both P < .001). No group differences were found in Aβ levels. Conclusion Improving sleep quality may help reduce the neurodegenerative risk in older men.

      PubDate: 2016-10-26T14:48:35Z
      DOI: 10.1016/j.jalz.2014.08.104
  • Guidelines for reporting methodological challenges and evaluating
           potential bias in dementia research
    • Authors: Jennifer Weuve; Cécile Proust-Lima; Melinda C. Power; Alden L. Gross; Scott M. Hofer; Rodolphe Thiébaut; Geneviève Chêne; M. Maria Glymour; Carole Dufouil
      Pages: 1098 - 1109
      Abstract: Publication date: September 2015
      Source:Alzheimer's & Dementia, Volume 11, Issue 9
      Author(s): Jennifer Weuve, Cécile Proust-Lima, Melinda C. Power, Alden L. Gross, Scott M. Hofer, Rodolphe Thiébaut, Geneviève Chêne, M. Maria Glymour, Carole Dufouil
      Clinical and population research on dementia and related neurologic conditions, including Alzheimer's disease, faces several unique methodological challenges. Progress to identify preventive and therapeutic strategies rests on valid and rigorous analytic approaches, but the research literature reflects little consensus on “best practices.” We present findings from a large scientific working group on research methods for clinical and population studies of dementia, which identified five categories of methodological challenges as follows: (1) attrition/sample selection, including selective survival; (2) measurement, including uncertainty in diagnostic criteria, measurement error in neuropsychological assessments, and practice or retest effects; (3) specification of longitudinal models when participants are followed for months, years, or even decades; (4) time-varying measurements; and (5) high-dimensional data. We explain why each challenge is important in dementia research and how it could compromise the translation of research findings into effective prevention or care strategies. We advance a checklist of potential sources of bias that should be routinely addressed when reporting dementia research.

      PubDate: 2016-10-26T14:48:35Z
      DOI: 10.1016/j.jalz.2015.06.1885
  • Medical costs of Alzheimer's disease misdiagnosis among US
           Medicare beneficiaries
    • Authors: Craig A. Hunter; Noam Y. Kirson; Urvi Desai; Alice Kate G. Cummings; Douglas E. Faries; Howard G. Birnbaum
      Pages: 887 - 895
      Abstract: Publication date: August 2015
      Source:Alzheimer's & Dementia, Volume 11, Issue 8
      Author(s): Craig A. Hunter, Noam Y. Kirson, Urvi Desai, Alice Kate G. Cummings, Douglas E. Faries, Howard G. Birnbaum
      Introduction Recent developments in diagnostic technology can support earlier, more accurate diagnosis of non-Alzheimer's disease (AD) dementias. Methods To evaluate potential economic benefits of early rule-out of AD, annual medical resource use and costs for Medicare beneficiaries potentially misdiagnosed with AD prior to their diagnosis of vascular dementia (VD) or Parkinson's disease (PD) were compared with that of similar patients never diagnosed with AD. Results Patients with prior AD diagnosis used substantially more medical services every year until their VD/PD diagnosis, resulting in incremental annual medical costs of approximately $9,500-$14,000. However, following their corrected diagnosis, medical costs converged with those of patients never diagnosed with AD. Discussion The observed correlation between timing of correct diagnosis and subsequent reversal in excess costs is strongly suggestive of the role of misdiagnosis of AD - rather than AD comorbidity - in this patient population. Our findings suggest potential benefits from earlier, accurate diagnosis.

      PubDate: 2016-10-26T14:48:35Z
      DOI: 10.1016/j.jalz.2015.06.1889
  • Early cost-utility analysis of general and cerebrospinal fluid-specific
           Alzheimer's disease biomarkers for hypothetical disease-modifying
           treatment decision in mild cognitive impairment
    • Authors: Ron L.H. Handels; Manuela A. Joore; An Tran-Duy; Anders Wimo; Claire A.G. Wolfs; Frans R.J. Verhey; Johan L. Severens
      Pages: 896 - 905
      Abstract: Publication date: August 2015
      Source:Alzheimer's & Dementia, Volume 11, Issue 8
      Author(s): Ron L.H. Handels, Manuela A. Joore, An Tran-Duy, Anders Wimo, Claire A.G. Wolfs, Frans R.J. Verhey, Johan L. Severens
      Introduction The study aimed to determine the room for improvement of a perfect cerebrospinal fluid (CSF) biomarker and the societal incremental net monetary benefit of CSF in subjects with mild cognitive impairment (MCI) assuming a hypothetical disease-modifying Alzheimer's disease (AD) treatment. Methods A decision model compared current practice to a perfect biomarker and to two strategies positioning CSF as add-on test when current practice concluded the presence or absence of AD. Results The simulated MCI population was aged on average 68.3 and 49% had AD. The room for improvement by the perfect CSF test was 0.39 quality adjusted life years, €33,622 ($43,372) savings, 2.0 potential beneficial treatment years, and 1.3-year delay in dementia conversion. Discussion The results indicated more potential benefit from a biomarker positioned to verify subjects who are not expected to have AD (i.e., to prevent undertreatment) rather than to verify subjects expected to have AD (prevent overtreatment). Sensitivity analyses explored different CSF positions.

      PubDate: 2016-10-26T14:48:35Z
      DOI: 10.1016/j.jalz.2015.02.009
  • Florbetaben PET imaging to detect amyloid beta plaques in Alzheimer's
           disease: Phase 3 study
    • Authors: Osama Sabri; Marwan N. Sabbagh; John Seibyl; Henryk Barthel; Hiroyasu Akatsu; Yasuomi Ouchi; Kohei Senda; Shigeo Murayama; Kenji Ishii; Masaki Takao; Thomas G. Beach; Christopher C. Rowe; James B. Leverenz; Bernardino Ghetti; James W. Ironside; Ana M. Catafau; Andrew W. Stephens; Andre Mueller; Norman Koglin; Anja Hoffmann; Katrin Roth; Cornelia Reininger; Walter J. Schulz-Schaeffer
      Pages: 964 - 974
      Abstract: Publication date: August 2015
      Source:Alzheimer's & Dementia, Volume 11, Issue 8
      Author(s): Osama Sabri, Marwan N. Sabbagh, John Seibyl, Henryk Barthel, Hiroyasu Akatsu, Yasuomi Ouchi, Kohei Senda, Shigeo Murayama, Kenji Ishii, Masaki Takao, Thomas G. Beach, Christopher C. Rowe, James B. Leverenz, Bernardino Ghetti, James W. Ironside, Ana M. Catafau, Andrew W. Stephens, Andre Mueller, Norman Koglin, Anja Hoffmann, Katrin Roth, Cornelia Reininger, Walter J. Schulz-Schaeffer
      Background Evaluation of brain β-amyloid by positron emission tomography (PET) imaging can assist in the diagnosis of Alzheimer disease (AD) and other dementias. Methods Open-label, nonrandomized, multicenter, phase 3 study to validate the 18F-labeled β-amyloid tracer florbetaben by comparing in vivo PET imaging with post-mortem histopathology. Results Brain images and tissue from 74 deceased subjects (of 216 trial participants) were analyzed. Forty-six of 47 neuritic β-amyloid-positive cases were read as PET positive, and 24 of 27 neuritic β-amyloid plaque-negative cases were read as PET negative (sensitivity 97.9% [95% confidence interval or CI 93.8–100%], specificity 88.9% [95% CI 77.0–100%]). In a subgroup, a regional tissue-scan matched analysis was performed. In areas known to strongly accumulate β-amyloid plaques, sensitivity and specificity were 82% to 90%, and 86% to 95%, respectively. Conclusions Florbetaben PET shows high sensitivity and specificity for the detection of histopathology-confirmed neuritic β-amyloid plaques and may thus be a valuable adjunct to clinical diagnosis, particularly for the exclusion of AD. Trial registration NCT01020838.

      PubDate: 2016-10-26T14:48:35Z
      DOI: 10.1016/j.jalz.2015.02.004
  • [18F]flutemetamol amyloid positron emission tomography in preclinical and
           symptomatic Alzheimer's disease: Specific detection of advanced phases of
           amyloid-β pathology
    • Authors: Dietmar Rudolf Thal; Thomas G. Beach; Michelle Zanette; Kerstin Heurling; Aruna Chakrabarty; Azzam Ismail; Adrian P.L. Smith; Christopher Buckley
      Pages: 975 - 985
      Abstract: Publication date: August 2015
      Source:Alzheimer's & Dementia, Volume 11, Issue 8
      Author(s): Dietmar Rudolf Thal, Thomas G. Beach, Michelle Zanette, Kerstin Heurling, Aruna Chakrabarty, Azzam Ismail, Adrian P.L. Smith, Christopher Buckley
      Background Amyloid positron emission tomography (PET) has become an important tool to identify amyloid-β (Aβ) pathology in Alzheimer's disease (AD) patients. Here, we determined the diagnostic value of the amyloid PET tracer [18F]flutemetamol in relation to Aβ pathology at autopsy. Methods [18F]flutemetamol PET was carried out in a cohort of 68 patients included in a [18F]flutemetamol amyloid PET imaging end-of-life study (GE067-007). At autopsy, AD pathology was determined and Aβ plaque pathology was classified into phases of its regional distribution (0–5). Results [18F]flutemetamol PET was universally positive in cases with advanced stage postmortem Aβ pathology (Aβ phases 4 and 5). Negative amyloid PET was universally observed in nondemented or non-AD dementia cases with initial Aβ phases 1 and 2, whereas 33.3% of the phase 3 cases were positive. Conclusions [18F]flutemetamol amyloid PET detects primarily advanced stages of Aβ pathology in preclinical and symptomatic AD cases.

      PubDate: 2016-10-26T14:48:35Z
      DOI: 10.1016/j.jalz.2015.05.018
  • Genetic studies of quantitative MCI and AD phenotypes in ADNI: Progress,
           opportunities, and plans
    • Authors: Andrew J. Saykin; Li Shen; Xiaohui Yao; Sungeun Kim; Kwangsik Nho; Shannon L. Risacher; Vijay K. Ramanan; Tatiana M. Foroud; Kelley M. Faber; Nadeem Sarwar; Leanne M. Munsie; Xiaolan Hu; Holly D. Soares; Steven G. Potkin; Paul M. Thompson; John S.K. Kauwe; Rima Kaddurah-Daouk; Robert C. Green; Arthur W. Toga; Michael W. Weiner
      Pages: 792 - 814
      Abstract: Publication date: July 2015
      Source:Alzheimer's & Dementia, Volume 11, Issue 7
      Author(s): Andrew J. Saykin, Li Shen, Xiaohui Yao, Sungeun Kim, Kwangsik Nho, Shannon L. Risacher, Vijay K. Ramanan, Tatiana M. Foroud, Kelley M. Faber, Nadeem Sarwar, Leanne M. Munsie, Xiaolan Hu, Holly D. Soares, Steven G. Potkin, Paul M. Thompson, John S.K. Kauwe, Rima Kaddurah-Daouk, Robert C. Green, Arthur W. Toga, Michael W. Weiner
      Introduction Genetic data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) have been crucial in advancing the understanding of Alzheimer's disease (AD) pathophysiology. Here, we provide an update on sample collection, scientific progress and opportunities, conceptual issues, and future plans. Methods Lymphoblastoid cell lines and DNA and RNA samples from blood have been collected and banked, and data and biosamples have been widely disseminated. To date, APOE genotyping, genome-wide association study (GWAS), and whole exome and whole genome sequencing data have been obtained and disseminated. Results ADNI genetic data have been downloaded thousands of times, and >300 publications have resulted, including reports of large-scale GWAS by consortia to which ADNI contributed. Many of the first applications of quantitative endophenotype association studies used ADNI data, including some of the earliest GWAS and pathway-based studies of biospecimen and imaging biomarkers, as well as memory and other clinical/cognitive variables. Other contributions include some of the first whole exome and whole genome sequencing data sets and reports in healthy controls, mild cognitive impairment, and AD. Discussion Numerous genetic susceptibility and protective markers for AD and disease biomarkers have been identified and replicated using ADNI data and have heavily implicated immune, mitochondrial, cell cycle/fate, and other biological processes. Early sequencing studies suggest that rare and structural variants are likely to account for significant additional phenotypic variation. Longitudinal analyses of transcriptomic, proteomic, metabolomic, and epigenomic changes will also further elucidate dynamic processes underlying preclinical and prodromal stages of disease. Integration of this unique collection of multiomics data within a systems biology framework will help to separate truly informative markers of early disease mechanisms and potential novel therapeutic targets from the vast background of less relevant biological processes. Fortunately, a broad swath of the scientific community has accepted this grand challenge.

      PubDate: 2016-10-26T14:48:35Z
      DOI: 10.1016/j.jalz.2015.05.009
  • Atherosclerotic calcification is related to a higher risk of dementia and
           cognitive decline
    • Authors: Daniel Bos; Meike W. Vernooij; Renée F.A.G. de Bruijn; Peter J. Koudstaal; Albert Hofman; Oscar H. Franco; Aad van der Lugt; M. Arfan Ikram
      Pages: 639 - 647.e1
      Abstract: Publication date: June 2015
      Source:Alzheimer's & Dementia, Volume 11, Issue 6
      Author(s): Daniel Bos, Meike W. Vernooij, Renée F.A.G. de Bruijn, Peter J. Koudstaal, Albert Hofman, Oscar H. Franco, Aad van der Lugt, M. Arfan Ikram
      Background Longitudinal data on the role of atherosclerosis in different vessel beds in the etiology of cognitive impairment and dementia are scarce and inconsistent. Methods Between 2003–2006, 2364 nondemented persons underwent computed tomography of the coronaries, aortic arch, extracranial, and intracranial carotid arteries to quantify atherosclerotic calcification. Participants were followed for incident dementia (n = 90) until April 2012. At baseline and follow-up participants also underwent a cognitive test battery. Results Larger calcification volume in all vessels, except in the coronaries, was associated with a higher risk of dementia. After adjustment for relevant confounders, extracranial carotid artery calcification remained significantly associated with a higher risk of dementia [hazard ratio per standard deviation increase in calcification volume: 1.37 (1.05, 1.79)]. Additional analyses for Alzheimer's disease only or censoring for stroke showed similar results. Larger calcification volumes were also associated with cognitive decline. Conclusions Atherosclerosis, in particular in the extracranial carotid arteries, is related to a higher risk of dementia and cognitive decline.

      PubDate: 2016-10-26T14:48:35Z
      DOI: 10.1016/j.jalz.2014.05.1758
  • Frequent use of opioids in patients with dementia and nursing home
           residents: A study of the entire elderly population of Denmark
    • Authors: Christina Jensen-Dahm; Christiane Gasse; Aske Astrup; Preben Bo Mortensen; Gunhild Waldemar
      Pages: 691 - 699
      Abstract: Publication date: June 2015
      Source:Alzheimer's & Dementia, Volume 11, Issue 6
      Author(s): Christina Jensen-Dahm, Christiane Gasse, Aske Astrup, Preben Bo Mortensen, Gunhild Waldemar
      Background Pain is believed to be undertreated in patients with dementia; however, no larger studies have been conducted. The aim was to investigate prevalent use of opioids in elderly with and without dementia in the entire elderly population of Denmark. Method A register-based cross-sectional study in the entire elderly (≥65 years) population in 2010 was conducted. Opioid use among elderly with dementia (N = 35,455) was compared with elderly without (N = 870,645), taking age, sex, comorbidity, and living status into account. Results Nursing home residents (NHRs) used opioids most frequently (41%), followed by home-living patients with dementia (27.5%) and home-living patients without dementia (16.9%). Buprenorphine and fentanyl (primarily patches) were commonly used among NHRs (18.7%) and home-living patients with dementia (10.7%) but less often by home-living patients without dementia (2.4%). Conclusions Opioid use in the elderly Danish population was frequent but particularly in patients with dementia and NHR, which may challenge patient safety and needs further investigation.

      PubDate: 2016-10-26T14:48:35Z
      DOI: 10.1016/j.jalz.2014.06.013
  • Summary of the evidence on modifiable risk factors for cognitive decline
           and dementia: A population-based perspective
    • Authors: Matthew Baumgart; Heather M. Snyder; Maria C. Carrillo; Sam Fazio; Hye Kim; Harry Johns
      Pages: 718 - 726
      Abstract: Publication date: June 2015
      Source:Alzheimer's & Dementia, Volume 11, Issue 6
      Author(s): Matthew Baumgart, Heather M. Snyder, Maria C. Carrillo, Sam Fazio, Hye Kim, Harry Johns
      An estimated 47 million people worldwide are living with dementia in 2015, and this number is projected to triple by 2050. In the absence of a disease-modifying treatment or cure, reducing the risk of developing dementia takes on added importance. In 2014, the World Dementia Council (WDC) requested the Alzheimer's Association evaluate and report on the state of the evidence on modifiable risk factors for cognitive decline and dementia. This report is a summary of the Association's evaluation, which was presented at the October 2014 WDC meeting. The Association believes there is sufficient evidence to support the link between several modifiable risk factors and a reduced risk for cognitive decline, and sufficient evidence to suggest that some modifiable risk factors may be associated with reduced risk of dementia. Specifically, the Association believes there is sufficiently strong evidence, from a population-based perspective, to conclude that regular physical activity and management of cardiovascular risk factors (diabetes, obesity, smoking, and hypertension) reduce the risk of cognitive decline and may reduce the risk of dementia. The Association also believes there is sufficiently strong evidence to conclude that a healthy diet and lifelong learning/cognitive training may also reduce the risk of cognitive decline.

      PubDate: 2016-10-26T14:48:35Z
      DOI: 10.1016/j.jalz.2015.05.016
  • A 22-single nucleotide polymorphism Alzheimer's disease risk score
           correlates with family history, onset age, and cerebrospinal fluid Aβ42
    • Authors: Kristel Sleegers; Karolien Bettens; Arne De Roeck; Caroline Van Cauwenberghe; Elise Cuyvers; Jan Verheijen; Hanne Struyfs; Jasper Van Dongen; Steven Vermeulen; Sebastiaan Engelborghs; Mathieu Vandenbulcke; Rik Vandenberghe; Peter Paul De Deyn; Christine Van Broeckhoven
      Pages: 1452 - 1460
      Abstract: Publication date: December 2015
      Source:Alzheimer's & Dementia, Volume 11, Issue 12
      Author(s): Kristel Sleegers, Karolien Bettens, Arne De Roeck, Caroline Van Cauwenberghe, Elise Cuyvers, Jan Verheijen, Hanne Struyfs, Jasper Van Dongen, Steven Vermeulen, Sebastiaan Engelborghs, Mathieu Vandenbulcke, Rik Vandenberghe, Peter Paul De Deyn, Christine Van Broeckhoven
      Introduction The ability to identify individuals at increased genetic risk for Alzheimer's disease (AD) may streamline biomarker and drug trials and aid clinical and personal decision making. Methods We evaluated the discriminative ability of a genetic risk score (GRS) covering 22 published genetic risk loci for AD in 1162 Flanders-Belgian AD patients and 1019 controls and assessed correlations with family history, onset age, and cerebrospinal fluid (CSF) biomarkers (Aβ1–42, T-Tau, P-Tau181P). Results A GRS including all single nucleotide polymorphisms (SNPs) and age-specific APOE ε4 weights reached area under the curve (AUC) 0.70, which increased to AUC 0.78 for patients with familial predisposition. Risk of AD increased with GRS (odds ratio, 2.32 (95% confidence interval 2.08–2.58 per unit; P < 1.0e−15). Onset age and CSF Aβ1–42 decreased with increasing GRS (P onset_age  = 9.0e−11; P Aβ  = 8.9e−7). Discussion The discriminative ability of this 22-SNP GRS is still limited, but these data illustrate that incorporation of age-specific weights improves discriminative ability. GRS-phenotype correlations highlight the feasibility of identifying individuals at highest susceptibility.

      PubDate: 2016-10-26T14:48:35Z
      DOI: 10.1016/j.jalz.2015.02.013
  • C-terminal neurogranin is increased in cerebrospinal fluid but unchanged
           in plasma in Alzheimer's disease
    • Authors: Ann De Vos; Dirk Jacobs; Hanne Struyfs; Erik Fransen; Kerstin Andersson; Erik Portelius; Ulf Andreasson; Didier De Surgeloose; Daniëlle Hernalsteen; Kristel Sleegers; Caroline Robberecht; Christine Van Broeckhoven; Henrik Zetterberg; Kaj Blennow; Sebastiaan Engelborghs; Eugeen Vanmechelen
      Pages: 1461 - 1469
      Abstract: Publication date: December 2015
      Source:Alzheimer's & Dementia, Volume 11, Issue 12
      Author(s): Ann De Vos, Dirk Jacobs, Hanne Struyfs, Erik Fransen, Kerstin Andersson, Erik Portelius, Ulf Andreasson, Didier De Surgeloose, Daniëlle Hernalsteen, Kristel Sleegers, Caroline Robberecht, Christine Van Broeckhoven, Henrik Zetterberg, Kaj Blennow, Sebastiaan Engelborghs, Eugeen Vanmechelen
      Introduction Biomarkers monitoring synaptic degeneration/loss would be valuable for Alzheimer's disease (AD) diagnosis. Postsynaptic protein neurogranin may be a promising cerebrospinal fluid (CSF) biomarker but has not yet been evaluated as a plasma biomarker. Methods Using an in-house designed prototype enzyme-linked immunosorbent assay (ELISA) targeting neurogranin C-terminally, we studied neurogranin in paired CSF/plasma samples of controls (n = 29) versus patients experiencing MCI, or dementia, due to AD (in total n = 59). Results CSF neurogranin was increased in AD and positively correlated with CSF tau, whereas there was a negative relationship between CSF neurogranin (and tau) and CSF Aβ1–42/Aβ1–40. No differences were detected in plasma neurogranin between controls and AD. Also, there was no correlation between CSF and plasma neurogranin, excluding confounding effects of the latter. Discussion This study strengthens the potential of neurogranin as an AD CSF biomarker, which now needs validation in larger studies. As tools, straightforward immunoassays can be used, as demonstrated by the described ELISA.

      PubDate: 2016-10-26T14:48:35Z
      DOI: 10.1016/j.jalz.2015.05.012
  • Genetic risk of neurodegenerative diseases is associated with mild
           cognitive impairment and conversion to dementia
    • Authors: Hieab H.H. Adams; Renée F.A.G. de Bruijn; Albert Hofman; André G. Uitterlinden; Cornelia M. van Duijn; Meike W. Vernooij; Peter J. Koudstaal; M. Arfan Ikram
      Pages: 1277 - 1285
      Abstract: Publication date: November 2015
      Source:Alzheimer's & Dementia, Volume 11, Issue 11
      Author(s): Hieab H.H. Adams, Renée F.A.G. de Bruijn, Albert Hofman, André G. Uitterlinden, Cornelia M. van Duijn, Meike W. Vernooij, Peter J. Koudstaal, M. Arfan Ikram
      Introduction Neurodegenerative diseases are a major cause of cognitive impairment and can ultimately lead to dementia. Genome-wide association studies have uncovered many genetic variants conferring risk of neurodegenerative diseases, but their role in cognitive impairment remains unexplored. Methods In the prospective, population-based Rotterdam Study, 3605 nondemented persons aged ≥55 years were genotyped, screened for mild cognitive impairment (MCI) in 2002 to 2005 and underwent continuous follow-up for dementia until 2012. Weighted polygenic risk scores of genetic variants for Alzheimer's disease (AD), Parkinson's disease (PD), and the frontotemporal lobar degeneration/amyotrophic lateral sclerosis disease spectrum (FTLD/ALS) were constructed and investigated for association with MCI and the subsequent conversion to dementia. Results In total, 360 (10.0%) persons had MCI, of whom 147 (4.1%) were amnestic and 213 (5.9%) nonamnestic. The AD risk score was associated with both MCI subtypes (odds ratio for all MCI 1.15 [95% CI, 1.03–1.28]), whereas PD and FTLD/ALS risk scores were associated only with nonamnestic MCI (odds ratios 1.15 [1.00–1.32] and 1.19 [1.03–1.37], respectively). The AD risk score, but not PD and FTLD/ALS risk scores, was associated with an increased risk of dementia (hazard ratio 1.55 [1.37–1.77]). Discussion Genetic evidence supports the view that multiple neurodegenerative pathways lead to MCI and that the subsequent conversion to dementia, primarily of the AD subtype, is mainly due to the AD pathway(s).

      PubDate: 2016-11-22T21:52:47Z
      DOI: 10.1016/j.jalz.2014.12.008
  • Computable cause-and-effect models of healthy and Alzheimer's disease
           states and their mechanistic differential analysis
    • Authors: Alpha Tom Kodamullil; Erfan Younesi; Mufassra Naz; Shweta Bagewadi; Martin Hofmann-Apitius
      Pages: 1329 - 1339
      Abstract: Publication date: November 2015
      Source:Alzheimer's & Dementia, Volume 11, Issue 11
      Author(s): Alpha Tom Kodamullil, Erfan Younesi, Mufassra Naz, Shweta Bagewadi, Martin Hofmann-Apitius
      Introduction The discovery and development of new treatments for Alzheimer's disease (AD) requires a profound mechanistic understanding of the disease. Here, we propose a model-driven approach supporting the systematic identification of putative disease mechanisms. Methods We have created a model for AD and a corresponding model for the normal physiology of neurons using biological expression language to systematically model causal and correlative relationships between biomolecules, pathways, and clinical readouts. Through model-model comparison we identify “chains of causal relationships” that lead to new insights into putative disease mechanisms. Results Using differential analysis of our models we identified a new mechanism explaining the effect of amyloid-beta on apoptosis via both the neurotrophic tyrosine kinase receptor, type 2 and nerve growth factor receptor branches of the neurotrophin signaling pathway. We also provide the example of a model-guided interpretation of genetic variation data for a comorbidity analysis between AD and type 2 diabetes mellitus. Discussion The two computable, literature-based models introduced here provide a powerful framework for the generation and validation of rational, testable hypotheses across disease areas.

      PubDate: 2016-10-26T14:48:35Z
      DOI: 10.1016/j.jalz.2015.02.006
  • The sensitivity to change over time of the Amsterdam IADL
    • Authors: Naomi Koster; Dirk L. Knol; Bernard M.J. Uitdehaag; Philip Scheltens; Sietske A.M. Sikkes
      Pages: 1231 - 1240
      Abstract: Publication date: October 2015
      Source:Alzheimer's & Dementia, Volume 11, Issue 10
      Author(s): Naomi Koster, Dirk L. Knol, Bernard M.J. Uitdehaag, Philip Scheltens, Sietske A.M. Sikkes
      Introduction This study aimed to investigate the sensitivity to change over time of a new informant-based instrument to assess instrumental activities of daily living (IADL) during the course of dementia: the Amsterdam IADL Questionnaire© (A-IADL-Q). Methods Participants (n = 102) were patients and their informants who visited the Alzheimer Center of the VU University Medical Center. Linear mixed models with random effects were used to relate longitudinal change on the A-IADL-Q to diagnosis and to longitudinal change in cognitive measures. Results We found longitudinal change on the A-IADL-Q to differ between diagnosis (P = .003), with dementia patients showing the fastest rate of decline (P < .001). In addition, we found longitudinal change on the A-IADL-Q to be related to longitudinal change in cognitive measures (global cognition: P < .001; memory: P = .024; executive functioning: P = .028). Discussion Findings indicate the A-IADL-Q is sensitive to change over time in IADL functioning and can be used in evaluating treatment effects and assessing individual disease progress.

      PubDate: 2016-10-26T14:48:35Z
      DOI: 10.1016/j.jalz.2014.10.006
  • Recommendations for CSF AD biomarkers in the diagnostic evaluation of MCI
    • Authors: Sanna-Kaisa Herukka; Anja Hviid Simonsen; Niels Andreasen; Ines Baldeiras; Maria Bjerke; Kaj Blennow; Sebastiaan Engelborghs; Giovanni B. Frisoni; Tomasz Gabryelewicz; Samantha Galluzzi; Ron Handels; Milica G. Kramberger; Agnieszka Kulczyńska; Jose Luis Molinuevo; Barbara Mroczko; Agneta Nordberg; Catarina Resende Oliveira; Markus Otto; Juha O. Rinne; Uroš Rot; Esen Saka; Hilkka Soininen; Hanne Struyfs; Silvia Suardi; Pieter Jelle Visser; Bengt Winblad; Henrik Zetterberg; Gunhild Waldemar
      Abstract: Publication date: Available online 27 October 2016
      Source:Alzheimer's & Dementia
      Author(s): Sanna-Kaisa Herukka, Anja Hviid Simonsen, Niels Andreasen, Ines Baldeiras, Maria Bjerke, Kaj Blennow, Sebastiaan Engelborghs, Giovanni B. Frisoni, Tomasz Gabryelewicz, Samantha Galluzzi, Ron Handels, Milica G. Kramberger, Agnieszka Kulczyńska, Jose Luis Molinuevo, Barbara Mroczko, Agneta Nordberg, Catarina Resende Oliveira, Markus Otto, Juha O. Rinne, Uroš Rot, Esen Saka, Hilkka Soininen, Hanne Struyfs, Silvia Suardi, Pieter Jelle Visser, Bengt Winblad, Henrik Zetterberg, Gunhild Waldemar
      This article presents recommendations, based on the Grading of Recommendations, Assessment, Development, and Evaluation method, for the clinical application of cerebrospinal fluid (CSF) amyloid-β1–42, tau, and phosphorylated tau in the diagnostic evaluation of patients with mild cognitive impairment (MCI). The recommendations were developed by a multidisciplinary working group and based on the available evidence and consensus from focused group discussions for 1) prediction of clinical progression to Alzheimer's disease (AD) dementia, 2) cost-effectiveness, 3) interpretation of results, and 4) patient counseling. The working group recommended using CSF AD biomarkers in the diagnostic workup of MCI patients, after prebiomarker counseling, as an add-on to clinical evaluation to predict functional decline or conversion to AD dementia and to guide disease management. Because of insufficient evidence, it was uncertain whether CSF AD biomarkers outperform imaging biomarkers. Furthermore, the working group provided recommendations for interpretation of ambiguous CSF biomarker results and for pre- and post-biomarker counseling.

      PubDate: 2016-11-02T00:02:54Z
      DOI: 10.1016/j.jalz.2016.09.009
  • Blood-brain barrier failure as a core mechanism in cerebral small vessel
           disease and dementia: evidence from a cohort study
    • Authors: Joanna M. Wardlaw; Stephen Makin; Maria C. Valdés Hernández; Paul Armitage; Anna K. Heye; Francesca M. Chappell; Susana Muñoz-Maniega; Eleni Sakka; Kirsten Shuler; Martin S. Dennis; Michael J. Thrippleton
      Abstract: Publication date: Available online 27 October 2016
      Source:Alzheimer's & Dementia
      Author(s): Joanna M. Wardlaw, Stephen Makin, Maria C. Valdés Hernández, Paul Armitage, Anna K. Heye, Francesca M. Chappell, Susana Muñoz-Maniega, Eleni Sakka, Kirsten Shuler, Martin S. Dennis, Michael J. Thrippleton
      Introduction Small vessel disease (SVD) is a common contributor to dementia. Subtle blood-brain barrier (BBB) leakage may be important in SVD-induced brain damage. Methods We assessed imaging, clinical variables, and cognition in patients with mild (i.e., nondisabling) ischemic lacunar or cortical stroke. We analyzed BBB leakage, interstitial fluid, and white matter integrity using multimodal tissue-specific spatial analysis around white matter hyperintensities (WMH). We assessed predictors of 1 year cognition, recurrent stroke, and dependency. Results In 201 patients, median age 67 (range 34–97), BBB leakage, and interstitial fluid were higher in WMH than normal-appearing white matter; leakage in normal-appearing white matter increased with proximity to WMH (P < .0001), with WMH severity (P = .033), age (P = .03), and hypertension (P < .0001). BBB leakage in WMH predicted declining cognition at 1 year. Discussion BBB leakage increases in normal-appearing white matter with WMH and predicts worsening cognition. Interventions to reduce BBB leakage may prevent SVD-associated dementia.

      PubDate: 2016-11-02T00:02:54Z
      DOI: 10.1016/j.jalz.2016.09.006
  • Recommendations for CSF AD biomarkers in the diagnostic evaluation of
    • Authors: Anja Hviid Simonsen; Sanna-Kaisa Herukka; Niels Andreasen; Ines Baldeiras; Maria Bjerke; Kaj Blennow; Sebastiaan Engelborghs; Giovanni B. Frisoni; Tomasz Gabryelewicz; Samantha Galluzzi; Ron Handels; Milica G. Kramberger; Agnieszka Kulczyńska; Jose Luis Molinuevo; Barbara Mroczko; Agneta Nordberg; Catarina Resende Oliveira; Markus Otto; Juha O. Rinne; Uroš Rot; Esen Saka; Hilkka Soininen; Hanne Struyfs; Silvia Suardi; Pieter Jelle Visser; Bengt Winblad; Henrik Zetterberg; Gunhild Waldemar
      Abstract: Publication date: Available online 27 October 2016
      Source:Alzheimer's & Dementia
      Author(s): Anja Hviid Simonsen, Sanna-Kaisa Herukka, Niels Andreasen, Ines Baldeiras, Maria Bjerke, Kaj Blennow, Sebastiaan Engelborghs, Giovanni B. Frisoni, Tomasz Gabryelewicz, Samantha Galluzzi, Ron Handels, Milica G. Kramberger, Agnieszka Kulczyńska, Jose Luis Molinuevo, Barbara Mroczko, Agneta Nordberg, Catarina Resende Oliveira, Markus Otto, Juha O. Rinne, Uroš Rot, Esen Saka, Hilkka Soininen, Hanne Struyfs, Silvia Suardi, Pieter Jelle Visser, Bengt Winblad, Henrik Zetterberg, Gunhild Waldemar
      This article presents recommendations, based on the Grading of Recommendations, Assessment, Development, and Evaluation method, for the clinical application of cerebrospinal fluid (CSF) amyloid-β1–42, tau, and phosphorylated tau in the diagnostic evaluation of patients with dementia. The recommendations were developed by a multidisciplinary working group based on the available evidence and consensus from focused discussions for (i) identification of Alzheimer's disease (AD) as the cause of dementia, (ii) prediction of rate of decline, (iii) cost-effectiveness, and (iv) interpretation of results. The working group found sufficient evidence to support a recommendation to use CSF AD biomarkers as a supplement to clinical evaluation, particularly in uncertain and atypical cases, to identify or exclude AD as the cause of dementia. Because of insufficient evidence, it was uncertain whether CSF AD biomarkers outperform imaging biomarkers. Operational recommendations for the interpretation of ambiguous CSF biomarker results were also provided.

      PubDate: 2016-11-02T00:02:54Z
      DOI: 10.1016/j.jalz.2016.09.008
  • An investigation of cerebrovascular lesions in dementia with Lewy bodies
           compared to Alzheimer's disease
    • Authors: Lidia Sarro; Nirubol Tosakulwong; Christopher G. Schwarz; Jonathan Graff-Radford; Scott A. Przybelski; Timothy G. Lesnick; Samantha M. Zuk; Robert I. Reid; Mekala R. Raman; Bradley F. Boeve; Tanis J. Ferman; David S. Knopman; Giancarlo Comi; Massimo Filippi; Melissa E. Murray; Joseph E. Parisi; Dennis W. Dickson; Ronald C. Petersen; Clifford R. Jack; Kejal Kantarci
      Abstract: Publication date: Available online 10 August 2016
      Source:Alzheimer's & Dementia
      Author(s): Lidia Sarro, Nirubol Tosakulwong, Christopher G. Schwarz, Jonathan Graff-Radford, Scott A. Przybelski, Timothy G. Lesnick, Samantha M. Zuk, Robert I. Reid, Mekala R. Raman, Bradley F. Boeve, Tanis J. Ferman, David S. Knopman, Giancarlo Comi, Massimo Filippi, Melissa E. Murray, Joseph E. Parisi, Dennis W. Dickson, Ronald C. Petersen, Clifford R. Jack, Kejal Kantarci
      Introduction Cerebrovascular lesions on MRI are common in Alzheimer's disease (AD) dementia, but less is known about their frequency and impact on dementia with Lewy bodies (DLB). Methods White-matter hyperintensities (WMHs) and infarcts on MRI were assessed in consecutive DLB (n = 81) and AD dementia (n = 240) patients and compared to age-matched and sex-matched cognitively normal subjects (CN) from a population-based cohort. Results DLB had higher WMH volume compared to CN, and WMH volume was higher in the occipital and posterior periventricular regions in DLB compared to AD. Higher WMH volume was associated with history of cardiovascular disease and diabetes but not with clinical disease severity in DLB. Frequency of infarcts in DLB was not different from CN and AD dementia. Discussion In DLB, WMH volume is higher than AD and CN and appears to be primarily associated with history of vascular disease.

      PubDate: 2016-10-26T14:48:35Z
      DOI: 10.1016/j.jalz.2016.07.003
  • Genetic risk factors for the posterior cortical atrophy variant of
           Alzheimer's disease
    • Authors: Jonathan Schott; Sebastian Crutch Minerva Carrasquillo James Uphill Tim Shakespeare
      Abstract: Publication date: August 2016
      Source:Alzheimer's & Dementia, Volume 12, Issue 8
      Author(s): Jonathan M. Schott, Sebastian J. Crutch, Minerva M. Carrasquillo, James Uphill, Tim J. Shakespeare, Natalie S. Ryan, Keir X. Yong, Manja Lehmann, Nilufer Ertekin-Taner, Neill R. Graff-Radford, Bradley F. Boeve, Melissa E. Murray, Qurat ul Ain Khan, Ronald C. Petersen, Dennis W. Dickson, David S. Knopman, Gil D. Rabinovici, Bruce L. Miller, Aida Suárez González, Eulogio Gil-Néciga, Julie S. Snowden, Jenny Harris, Stuart M. Pickering-Brown, Eva Louwersheimer, Wiesje M. van der Flier, Philip Scheltens, Yolande A. Pijnenburg, Douglas Galasko, Marie Sarazin, Bruno Dubois, Eloi Magnin, Daniela Galimberti, Elio Scarpini, Stefano F. Cappa, John R. Hodges, Glenda M. Halliday, Lauren Bartley, Maria C. Carrillo, Jose T. Bras, John Hardy, Martin N. Rossor, John Collinge, Nick C. Fox, Simon Mead
      Introduction The genetics underlying posterior cortical atrophy (PCA), typically a rare variant of Alzheimer's disease (AD), remain uncertain. Methods We genotyped 302 PCA patients from 11 centers, calculated risk at 24 loci for AD/DLB and performed an exploratory genome-wide association study. Results We confirm that variation in/near APOE/TOMM40 (P = 6 × 10−14) alters PCA risk, but with smaller effect than for typical AD (PCA: odds ratio [OR] = 2.03, typical AD: OR = 2.83, P = .0007). We found evidence for risk in/near CR1 (P = 7 × 10−4), ABCA7 (P = .02) and BIN1 (P = .04). ORs at variants near INPP5D and NME8 did not overlap between PCA and typical AD. Exploratory genome-wide association studies confirmed APOE and identified three novel loci: rs76854344 near CNTNAP5 (P = 8 × 10−10 OR = 1.9 [1.5–2.3]); rs72907046 near FAM46A (P = 1 × 10−9 OR = 3.2 [2.1–4.9]); and rs2525776 near SEMA3C (P = 1 × 10−8, OR = 3.3 [2.1–5.1]). Discussion We provide evidence for genetic risk factors specifically related to PCA. We identify three candidate loci that, if replicated, may provide insights into selective vulnerability and phenotypic diversity in AD.

      PubDate: 2016-10-26T14:48:35Z
  • METACOHORTS for the study of vascular disease and its contribution to
           cognitive decline and neurodegeneration: An initiative of the Joint
           Programme for Neurodegenerative Disease Research
    • Authors: Martin Dichgans; Joanna Wardlaw Eric Smith Vera Zietemann Sudha Seshadri
      Abstract: Publication date: Available online 1 August 2016
      Source:Alzheimer's & Dementia
      Author(s): Martin Dichgans, Joanna Wardlaw, Eric Smith, Vera Zietemann, Sudha Seshadri, Perminder Sachdev, Geert Jan Biessels, Franz Fazekas, Oscar Benavente, Leonardo Pantoni, Frank-Erik De Leeuw, Bo Norrving, Paul Matthews, Christopher Chen, Vincent Mok, Marco Düring, Will Whiteley, Kirsten Shuler, Alvaro Alonso, Sandra E. Black, Carol Brayne, Hugues Chabriat, Charlotte Cordonnier, Fergus Doubal, Emrah Duzel, Michael Ewers, Richard Frayne, Vladimir Hachinski, Mohammad Arfan Ikram, Frank Jessen, Eric Jouvent, Jennifer Linn, John O'Brien, Robert van Oostenbrugge, Rainer Malik, Bernard Mazoyer, Reinhold Schmidt, Luciano A. Sposato, Blossom Stephan, Richard H. Swartz, Meike Vernooij, Anand Viswanathan, David Werring, Koji Abe, Louise Allan, Francesco Arba, H.-C. Diener, S. Davis, G. Hankey, K.R. Lees, B. Ovbiagele, C. Weir, Hee-Joon Bae, Philip MW. Bath, Regis Bordet, Monique Breteler, Seong Choi, Ian Deary, Charles DeCarli, Klaus Ebmeier, Lei Feng, Steven M. Greenberg, Masafumi Ihara, Rajesh Kalaria, SanYun Kim, Jae-Sung Lim, Richard I. Lindley, Gillian Mead, Alison Murray, Terry Quinn, Craig Ritchie, Ralph Sacco, Rustam Al-Shahi Salman, Nikola Sprigg, Cathie Sudlow, Alan Thomas, Martin van Boxtel, Jeroen van der Grond, Aad van der Lugt, Yuan-Han Yang
      Dementia is a global problem and major target for health care providers. Although up to 45% of cases are primarily or partly due to cerebrovascular disease, little is known of these mechanisms or treatments because most dementia research still focuses on pure Alzheimer's disease. An improved understanding of the vascular contributions to neurodegeneration and dementia, particularly by small vessel disease, is hampered by imprecise data, including the incidence and prevalence of symptomatic and clinically “silent” cerebrovascular disease, long-term outcomes (cognitive, stroke, or functional), and risk factors. New large collaborative studies with long follow-up are expensive and time consuming, yet substantial data to advance the field are available. In an initiative funded by the Joint Programme for Neurodegenerative Disease Research, 55 international experts surveyed and assessed available data, starting with European cohorts, to promote data sharing to advance understanding of how vascular disease affects brain structure and function, optimize methods for cerebrovascular disease in neurodegeneration research, and focus future research on gaps in knowledge. Here, we summarize the results and recommendations from this initiative. We identified data from over 90 studies, including over 660,000 participants, many being additional to neurodegeneration data initiatives. The enthusiastic response means that cohorts from North America, Australasia, and the Asia Pacific Region are included, creating a truly global, collaborative, data sharing platform, linked to major national dementia initiatives. Furthermore, the revised World Health Organization International Classification of Diseases version 11 should facilitate recognition of vascular-related brain damage by creating one category for all cerebrovascular disease presentations and thus accelerate identification of targets for dementia prevention.

      PubDate: 2016-10-26T14:48:35Z
  • Tract-specific white matter hyperintensities disrupt neural network
           function in Alzheimer's disease
    • Authors: Alexander N.W. Taylor; Lana Kambeitz-Ilankovic; Benno Gesierich; Lee Simon-Vermot; Nicolai Franzmeier; Miguel Á. Araque Caballero; Sophia Müller; Liu Hesheng; Birgit Ertl-Wagner; Katharina Bürger; Michael W. Weiner; Martin Dichgans; Marco Duering; Michael Ewers
      Abstract: Publication date: Available online 16 July 2016
      Source:Alzheimer's & Dementia
      Author(s): Alexander N.W. Taylor, Lana Kambeitz-Ilankovic, Benno Gesierich, Lee Simon-Vermot, Nicolai Franzmeier, Miguel Á. Araque Caballero, Sophia Müller, Liu Hesheng, Birgit Ertl-Wagner, Katharina Bürger, Michael W. Weiner, Martin Dichgans, Marco Duering, Michael Ewers
      Introduction White matter hyperintensities (WMHs) increase the risk of Alzheimer's disease (AD). Whether WMHs are associated with the decline of functional neural networks in AD is debated. Method Resting-state functional magnetic resonance imaging and WMH were assessed in 78 subjects with increased amyloid levels on AV-45 positron emission tomography (PET) in different clinical stages of AD. We tested the association between WMH volume in major atlas-based fiber tract regions of interest (ROIs) and changes in functional connectivity (FC) between the tracts' projection areas within the default mode network (DMN). Results WMH volume within the inferior fronto-occipital fasciculus (IFOF) was the highest among all tract ROIs and associated with reduced FC in IFOF-connected DMN areas, independently of global AV-45 PET. Higher AV-45 PET contributed to reduced FC in IFOF-connected, temporal, and parietal DMN areas. Conclusions High fiber tract WMH burden is associated with reduced FC in connected areas, thus adding to the effects of amyloid pathology on neuronal network function.

      PubDate: 2016-10-26T14:48:35Z
      DOI: 10.1016/j.jalz.2016.06.2358
  • Kallikrein-8 inhibition attenuates Alzheimer's pathology in mice
    • Authors: Arne Herring; Yvonne Münster; Tamer Akkaya; Sahar Moghaddam; Katharina Deinsberger; Jakob Meyer; Julia Zahel; Eduardo Sanchez-Mendoza; Yachao Wang; Dirk M. Hermann; Thomas Arzberger; Sarah Teuber-Hanselmann; Kathy Keyvani
      Abstract: Publication date: Available online 18 June 2016
      Source:Alzheimer's & Dementia
      Author(s): Arne Herring, Yvonne Münster, Tamer Akkaya, Sahar Moghaddam, Katharina Deinsberger, Jakob Meyer, Julia Zahel, Eduardo Sanchez-Mendoza, Yachao Wang, Dirk M. Hermann, Thomas Arzberger, Sarah Teuber-Hanselmann, Kathy Keyvani
      Introduction Memory loss and increased anxiety are clinical hallmarks of Alzheimer's disease (AD). Kallikrein-8 is a protease implicated in memory acquisition and anxiety, and its mRNA is known to be up-regulated in AD-affected human hippocampus. Therefore, an involvement of Kallikrein-8 in Alzheimer's pathogenesis is conceivable but remains to be proved. Methods We determined the cerebral expression of Kallikrein-8 mRNA and protein during the course of AD in patients and in transgenic mice and tested the impact of Kallikrein-8 inhibition on AD-related pathology in mice and in primary glial cells. Results Kallikrein-8 mRNA and protein were up-regulated in both species at incipient stages of AD. Kallikrein-8 inhibition impeded amyloidogenic amyloid-precursor-protein processing, facilitated amyloid β (Aβ) clearance across the blood-brain-barrier, boosted autophagy, reduced Aβ load and tau pathology, enhanced neuroplasticity, reversed molecular signatures of anxiety, and ultimately improved memory and reduced fear. Discussion Kallikrein-8 is a promising new therapeutic target against AD.

      PubDate: 2016-10-26T14:48:35Z
      DOI: 10.1016/j.jalz.2016.05.006
  • Magnetic resonance imaging in Alzheimer's Disease Neuroimaging Initiative
    • Authors: Clifford Jack; Josephine Barnes Matt Bernstein Bret Borowski James Brewer
      Abstract: Publication date: July 2015
      Source:Alzheimer's & Dementia, Volume 11, Issue 7
      Author(s): Clifford R. Jack, Josephine Barnes, Matt A. Bernstein, Bret J. Borowski, James Brewer, Shona Clegg, Anders M. Dale, Owen Carmichael, Christopher Ching, Charles DeCarli, Rahul S. Desikan, Christine Fennema-Notestine, Anders M. Fjell, Evan Fletcher, Nick C. Fox, Jeff Gunter, Boris A. Gutman, Dominic Holland, Xue Hua, Philip Insel, Kejal Kantarci, Ron J. Killiany, Gunnar Krueger, Kelvin K. Leung, Scott Mackin, Pauline Maillard, Ian B. Malone, Niklas Mattsson, Linda McEvoy, Marc Modat, Susanne Mueller, Rachel Nosheny, Sebastien Ourselin, Norbert Schuff, Matthew L. Senjem, Alix Simonson, Paul M. Thompson, Dan Rettmann, Prashanthi Vemuri, Kristine Walhovd, Yansong Zhao, Samantha Zuk, Michael Weiner
      Introduction Alzheimer's Disease Neuroimaging Initiative (ADNI) is now in its 10th year. The primary objective of the magnetic resonance imaging (MRI) core of ADNI has been to improve methods for clinical trials in Alzheimer's disease (AD) and related disorders. Methods We review the contributions of the MRI core from present and past cycles of ADNI (ADNI-1, -Grand Opportunity and -2). We also review plans for the future-ADNI-3. Results Contributions of the MRI core include creating standardized acquisition protocols and quality control methods; examining the effect of technical features of image acquisition and analysis on outcome metrics; deriving sample size estimates for future trials based on those outcomes; and piloting the potential utility of MR perfusion, diffusion, and functional connectivity measures in multicenter clinical trials. Discussion Over the past decade the MRI core of ADNI has fulfilled its mandate of improving methods for clinical trials in AD and will continue to do so in the future.

      PubDate: 2016-10-26T14:48:35Z
  • Defining imaging biomarker cut points for brain aging and
           Alzheimer's disease
    • Authors: Clifford R. Jack; Heather J. Wiste; Stephen D. Weigand; Terry M. Therneau; Val J. Lowe; David S. Knopman; Jeffrey L. Gunter; Matthew L. Senjem; David T. Jones; Kejal Kantarci; Mary M. Machulda; Michelle M. Mielke; Rosebud O. Roberts; Prashanthi Vemuri; Denise Reyes; Ronald C. Petersen
      Abstract: Publication date: Available online 30 September 2016
      Source:Alzheimer's & Dementia
      Author(s): Clifford R. Jack, Heather J. Wiste, Stephen D. Weigand, Terry M. Therneau, Val J. Lowe, David S. Knopman, Jeffrey L. Gunter, Matthew L. Senjem, David T. Jones, Kejal Kantarci, Mary M. Machulda, Michelle M. Mielke, Rosebud O. Roberts, Prashanthi Vemuri, Denise Reyes, Ronald C. Petersen
      Introduction Our goal was to develop cut points for amyloid positron emission tomography (PET), tau PET, FDG PET, and MRI cortical thickness. Methods We examined five methods for determining cut points. Results The reliable worsening method produced a cut point only for amyloid PET. The specificity, sensitivity, and accuracy of clinically impaired versus young clinically normal (CN) methods labeled the most people positive and all gave similar cut points for tau PET, FDG PET, and cortical thickness. Cut points defined using the accuracy of clinically impaired versus age-matched CN method labeled fewer people positive. Discussion In the future, we will use a single cut point for amyloid PET (standardized uptake value ratio, 1.42; centiloid, 19) based on the reliable worsening cut-point method. We will base lenient cut points for tau PET, FDG PET, and cortical thickness on the accuracy of clinically impaired versus young CN method and base conservative cut points on the accuracy of clinically impaired versus age-matched CN method.

      PubDate: 2016-10-03T13:45:08Z
      DOI: 10.1016/j.jalz.2016.08.005
  • Association of blood lipids with Alzheimer's disease:
           A comprehensive lipidomics analysis
    • Authors: P. Proitsi; M. Kim; L. Whiley; A. Simmons; M. Sattlecker; L. Velayudhan; M.K. Lupton; H. Soininen; I. Kloszewska; P. Mecocci; M. Tsolaki; B. Vellas; S. Lovestone; J.F. Powell; R.J.B. Dobson; C. Legido-Quigley
      Abstract: Publication date: Available online 28 September 2016
      Source:Alzheimer's & Dementia
      Author(s): P. Proitsi, M. Kim, L. Whiley, A. Simmons, M. Sattlecker, L. Velayudhan, M.K. Lupton, H. Soininen, I. Kloszewska, P. Mecocci, M. Tsolaki, B. Vellas, S. Lovestone, J.F. Powell, R.J.B. Dobson, C. Legido-Quigley
      Introduction The aim of this study was to (1) replicate previous associations between six blood lipids and Alzheimer's disease (AD) (Proitsi et al 2015) and (2) identify novel associations between lipids, clinical AD diagnosis, disease progression and brain atrophy (left/right hippocampus/entorhinal cortex). Methods We performed untargeted lipidomic analysis on 148 AD and 152 elderly control plasma samples and used univariate and multivariate analysis methods. Results We replicated our previous lipids associations and reported novel associations between lipids molecules and all phenotypes. A combination of 24 molecules classified AD patients with >70% accuracy in a test and a validation data set, and we identified lipid signatures that predicted disease progression (R2 = 0.10, test data set) and brain atrophy (R2 ≥ 0.14, all test data sets except left entorhinal cortex). We putatively identified a number of metabolic features including cholesteryl esters/triglycerides and phosphatidylcholines. Discussion Blood lipids are promising AD biomarkers that may lead to new treatment strategies.

      PubDate: 2016-10-03T13:45:08Z
      DOI: 10.1016/j.jalz.2016.08.003
  • The worldwide costs of dementia 2015 and comparisons with 2010
    • Authors: Anders Wimo; Maëlenn Guerchet; Gemma-Claire Ali; Yu-Tzu Wu; A. Matthew Prina; Bengt Winblad; Linus Jönsson; Zhaorui Liu; Martin Prince
      Abstract: Publication date: Available online 29 August 2016
      Source:Alzheimer's & Dementia
      Author(s): Anders Wimo, Maëlenn Guerchet, Gemma-Claire Ali, Yu-Tzu Wu, A. Matthew Prina, Bengt Winblad, Linus Jönsson, Zhaorui Liu, Martin Prince
      Introduction In 2010, Alzheimer's Disease International presented estimates of the global cost of illness (COI) of dementia. Since then, new studies have been conducted, and the number of people with dementia has increased. Here, we present an update of the global cost estimates. Methods This is a societal, prevalence-based global COI study. Results The worldwide costs of dementia were estimated at United States (US) $818 billion in 2015, an increase of 35% since 2010; 86% of the costs occur in high-income countries. Costs of informal care and the direct costs of social care still contribute similar proportions of total costs, whereas the costs in the medical sector are much lower. The threshold of US $1 trillion will be crossed by 2018. Discussion Worldwide costs of dementia are enormous and still inequitably distributed. The increase in costs arises from increases in numbers of people with dementia and in increases in per person costs.

      PubDate: 2016-09-02T01:40:15Z
      DOI: 10.1016/j.jalz.2016.07.150
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