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Publisher: Elsevier   (Total: 3184 journals)

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Showing 1 - 200 of 3184 Journals sorted alphabetically
Academic Pediatrics     Hybrid Journal   (Followers: 37, SJR: 1.655, CiteScore: 2)
Academic Radiology     Hybrid Journal   (Followers: 26, SJR: 1.015, CiteScore: 2)
Accident Analysis & Prevention     Partially Free   (Followers: 100, SJR: 1.462, CiteScore: 3)
Accounting Forum     Hybrid Journal   (Followers: 28, SJR: 0.932, CiteScore: 2)
Accounting, Organizations and Society     Hybrid Journal   (Followers: 40, SJR: 1.771, CiteScore: 3)
Achievements in the Life Sciences     Open Access   (Followers: 6)
Acta Anaesthesiologica Taiwanica     Open Access   (Followers: 7)
Acta Astronautica     Hybrid Journal   (Followers: 433, SJR: 0.758, CiteScore: 2)
Acta Automatica Sinica     Full-text available via subscription   (Followers: 2)
Acta Biomaterialia     Hybrid Journal   (Followers: 28, SJR: 1.967, CiteScore: 7)
Acta Colombiana de Cuidado Intensivo     Full-text available via subscription   (Followers: 3)
Acta de Investigación Psicológica     Open Access   (Followers: 3)
Acta Ecologica Sinica     Open Access   (Followers: 11, SJR: 0.18, CiteScore: 1)
Acta Histochemica     Hybrid Journal   (Followers: 3, SJR: 0.661, CiteScore: 2)
Acta Materialia     Hybrid Journal   (Followers: 305, SJR: 3.263, CiteScore: 6)
Acta Mathematica Scientia     Full-text available via subscription   (Followers: 5, SJR: 0.504, CiteScore: 1)
Acta Mechanica Solida Sinica     Full-text available via subscription   (Followers: 9, SJR: 0.542, CiteScore: 1)
Acta Oecologica     Hybrid Journal   (Followers: 12, SJR: 0.834, CiteScore: 2)
Acta Otorrinolaringologica (English Edition)     Full-text available via subscription  
Acta Otorrinolaringológica Española     Full-text available via subscription   (Followers: 2, SJR: 0.307, CiteScore: 0)
Acta Pharmaceutica Sinica B     Open Access   (Followers: 1, SJR: 1.793, CiteScore: 6)
Acta Poética     Open Access   (Followers: 4, SJR: 0.101, CiteScore: 0)
Acta Psychologica     Hybrid Journal   (Followers: 25, SJR: 1.331, CiteScore: 2)
Acta Sociológica     Open Access   (Followers: 1)
Acta Tropica     Hybrid Journal   (Followers: 6, SJR: 1.052, CiteScore: 2)
Acta Urológica Portuguesa     Open Access  
Actas Dermo-Sifiliograficas     Full-text available via subscription   (Followers: 3, SJR: 0.374, CiteScore: 1)
Actas Dermo-Sifiliográficas (English Edition)     Full-text available via subscription   (Followers: 2)
Actas Urológicas Españolas     Full-text available via subscription   (Followers: 3, SJR: 0.344, CiteScore: 1)
Actas Urológicas Españolas (English Edition)     Full-text available via subscription   (Followers: 1)
Actualites Pharmaceutiques     Full-text available via subscription   (Followers: 7, SJR: 0.19, CiteScore: 0)
Actualites Pharmaceutiques Hospitalieres     Full-text available via subscription   (Followers: 3)
Acupuncture and Related Therapies     Hybrid Journal   (Followers: 8)
Acute Pain     Full-text available via subscription   (Followers: 15, SJR: 2.671, CiteScore: 5)
Ad Hoc Networks     Hybrid Journal   (Followers: 11, SJR: 0.53, CiteScore: 4)
Addictive Behaviors     Hybrid Journal   (Followers: 18, SJR: 1.29, CiteScore: 3)
Addictive Behaviors Reports     Open Access   (Followers: 9, SJR: 0.755, CiteScore: 2)
Additive Manufacturing     Hybrid Journal   (Followers: 11, SJR: 2.611, CiteScore: 8)
Additives for Polymers     Full-text available via subscription   (Followers: 23)
Advanced Drug Delivery Reviews     Hybrid Journal   (Followers: 181, SJR: 4.09, CiteScore: 13)
Advanced Engineering Informatics     Hybrid Journal   (Followers: 12, SJR: 1.167, CiteScore: 4)
Advanced Powder Technology     Hybrid Journal   (Followers: 17, SJR: 0.694, CiteScore: 3)
Advances in Accounting     Hybrid Journal   (Followers: 9, SJR: 0.277, CiteScore: 1)
Advances in Agronomy     Full-text available via subscription   (Followers: 17, SJR: 2.384, CiteScore: 5)
Advances in Anesthesia     Full-text available via subscription   (Followers: 29, SJR: 0.126, CiteScore: 0)
Advances in Antiviral Drug Design     Full-text available via subscription   (Followers: 2)
Advances in Applied Mathematics     Full-text available via subscription   (Followers: 11, SJR: 0.992, CiteScore: 1)
Advances in Applied Mechanics     Full-text available via subscription   (Followers: 11, SJR: 1.551, CiteScore: 4)
Advances in Applied Microbiology     Full-text available via subscription   (Followers: 24, SJR: 2.089, CiteScore: 5)
Advances In Atomic, Molecular, and Optical Physics     Full-text available via subscription   (Followers: 15, SJR: 0.572, CiteScore: 2)
Advances in Biological Regulation     Hybrid Journal   (Followers: 4, SJR: 2.61, CiteScore: 7)
Advances in Botanical Research     Full-text available via subscription   (Followers: 2, SJR: 0.686, CiteScore: 2)
Advances in Cancer Research     Full-text available via subscription   (Followers: 33, SJR: 3.043, CiteScore: 6)
Advances in Carbohydrate Chemistry and Biochemistry     Full-text available via subscription   (Followers: 9, SJR: 1.453, CiteScore: 2)
Advances in Catalysis     Full-text available via subscription   (Followers: 5, SJR: 1.992, CiteScore: 5)
Advances in Cell Aging and Gerontology     Full-text available via subscription   (Followers: 5)
Advances in Cellular and Molecular Biology of Membranes and Organelles     Full-text available via subscription   (Followers: 14)
Advances in Chemical Engineering     Full-text available via subscription   (Followers: 29, SJR: 0.156, CiteScore: 1)
Advances in Child Development and Behavior     Full-text available via subscription   (Followers: 10, SJR: 0.713, CiteScore: 1)
Advances in Chronic Kidney Disease     Full-text available via subscription   (Followers: 10, SJR: 1.316, CiteScore: 2)
Advances in Clinical Chemistry     Full-text available via subscription   (Followers: 26, SJR: 1.562, CiteScore: 3)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 20, SJR: 1.977, CiteScore: 8)
Advances in Computers     Full-text available via subscription   (Followers: 14, SJR: 0.205, CiteScore: 1)
Advances in Dermatology     Full-text available via subscription   (Followers: 15)
Advances in Developmental Biology     Full-text available via subscription   (Followers: 13)
Advances in Digestive Medicine     Open Access   (Followers: 12)
Advances in DNA Sequence-Specific Agents     Full-text available via subscription   (Followers: 7)
Advances in Drug Research     Full-text available via subscription   (Followers: 26)
Advances in Ecological Research     Full-text available via subscription   (Followers: 43, SJR: 2.524, CiteScore: 4)
Advances in Engineering Software     Hybrid Journal   (Followers: 29, SJR: 1.159, CiteScore: 4)
Advances in Experimental Biology     Full-text available via subscription   (Followers: 8)
Advances in Experimental Social Psychology     Full-text available via subscription   (Followers: 51, SJR: 5.39, CiteScore: 8)
Advances in Exploration Geophysics     Full-text available via subscription   (Followers: 1)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 9)
Advances in Food and Nutrition Research     Full-text available via subscription   (Followers: 65, SJR: 0.591, CiteScore: 2)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 17)
Advances in Genetics     Full-text available via subscription   (Followers: 21, SJR: 1.354, CiteScore: 4)
Advances in Genome Biology     Full-text available via subscription   (Followers: 10, SJR: 12.74, CiteScore: 13)
Advances in Geophysics     Full-text available via subscription   (Followers: 7, SJR: 1.193, CiteScore: 3)
Advances in Heat Transfer     Full-text available via subscription   (Followers: 26, SJR: 0.368, CiteScore: 1)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 11, SJR: 0.749, CiteScore: 3)
Advances in Human Factors/Ergonomics     Full-text available via subscription   (Followers: 24)
Advances in Imaging and Electron Physics     Full-text available via subscription   (Followers: 3, SJR: 0.193, CiteScore: 0)
Advances in Immunology     Full-text available via subscription   (Followers: 36, SJR: 4.433, CiteScore: 6)
Advances in Inorganic Chemistry     Full-text available via subscription   (Followers: 10, SJR: 1.163, CiteScore: 2)
Advances in Insect Physiology     Full-text available via subscription   (Followers: 2, SJR: 1.938, CiteScore: 3)
Advances in Integrative Medicine     Hybrid Journal   (Followers: 6, SJR: 0.176, CiteScore: 0)
Advances in Intl. Accounting     Full-text available via subscription   (Followers: 3)
Advances in Life Course Research     Hybrid Journal   (Followers: 9, SJR: 0.682, CiteScore: 2)
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: 21, SJR: 0.88, CiteScore: 2)
Advances in Mathematics     Full-text available via subscription   (Followers: 12, SJR: 3.027, CiteScore: 2)
Advances in Medical Sciences     Hybrid Journal   (Followers: 8, SJR: 0.694, CiteScore: 2)
Advances in Medicinal Chemistry     Full-text available via subscription   (Followers: 6)
Advances in Microbial Physiology     Full-text available via subscription   (Followers: 5, SJR: 1.158, CiteScore: 3)
Advances in Molecular and Cell Biology     Full-text available via subscription   (Followers: 24)
Advances in Molecular and Cellular Endocrinology     Full-text available via subscription   (Followers: 8)
Advances in Molecular Toxicology     Full-text available via subscription   (Followers: 7, SJR: 0.182, CiteScore: 0)
Advances in Nanoporous Materials     Full-text available via subscription   (Followers: 5)
Advances in Oncobiology     Full-text available via subscription   (Followers: 2)
Advances in Organ Biology     Full-text available via subscription   (Followers: 2)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 18, SJR: 1.875, CiteScore: 4)
Advances in Parallel Computing     Full-text available via subscription   (Followers: 7, SJR: 0.174, CiteScore: 0)
Advances in Parasitology     Full-text available via subscription   (Followers: 5, SJR: 1.579, CiteScore: 4)
Advances in Pediatrics     Full-text available via subscription   (Followers: 27, SJR: 0.461, CiteScore: 1)
Advances in Pharmaceutical Sciences     Full-text available via subscription   (Followers: 18)
Advances in Pharmacology     Full-text available via subscription   (Followers: 17, SJR: 1.536, CiteScore: 3)
Advances in Physical Organic Chemistry     Full-text available via subscription   (Followers: 9, SJR: 0.574, CiteScore: 1)
Advances in Phytomedicine     Full-text available via subscription  
Advances in Planar Lipid Bilayers and Liposomes     Full-text available via subscription   (Followers: 3, SJR: 0.109, CiteScore: 1)
Advances in Plant Biochemistry and Molecular Biology     Full-text available via subscription   (Followers: 10)
Advances in Plant Pathology     Full-text available via subscription   (Followers: 6)
Advances in Porous Media     Full-text available via subscription   (Followers: 5)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 19)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 20, SJR: 0.791, CiteScore: 2)
Advances in Psychology     Full-text available via subscription   (Followers: 66)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 6, SJR: 0.371, CiteScore: 1)
Advances in Radiation Oncology     Open Access   (Followers: 1, SJR: 0.263, CiteScore: 1)
Advances in Small Animal Medicine and Surgery     Hybrid Journal   (Followers: 3, SJR: 0.101, CiteScore: 0)
Advances in Space Biology and Medicine     Full-text available via subscription   (Followers: 6)
Advances in Space Research     Full-text available via subscription   (Followers: 418, SJR: 0.569, CiteScore: 2)
Advances in Structural Biology     Full-text available via subscription   (Followers: 5)
Advances in Surgery     Full-text available via subscription   (Followers: 13, SJR: 0.555, CiteScore: 2)
Advances in the Study of Behavior     Full-text available via subscription   (Followers: 37, SJR: 2.208, CiteScore: 4)
Advances in Veterinary Medicine     Full-text available via subscription   (Followers: 20)
Advances in Veterinary Science and Comparative Medicine     Full-text available via subscription   (Followers: 15)
Advances in Virus Research     Full-text available via subscription   (Followers: 5, SJR: 2.262, CiteScore: 5)
Advances in Water Resources     Hybrid Journal   (Followers: 53, SJR: 1.551, CiteScore: 3)
Aeolian Research     Hybrid Journal   (Followers: 6, SJR: 1.117, CiteScore: 3)
Aerospace Science and Technology     Hybrid Journal   (Followers: 380, SJR: 0.796, CiteScore: 3)
AEU - Intl. J. of Electronics and Communications     Hybrid Journal   (Followers: 8, SJR: 0.42, CiteScore: 2)
African J. of Emergency Medicine     Open Access   (Followers: 6, SJR: 0.296, CiteScore: 0)
Ageing Research Reviews     Hybrid Journal   (Followers: 12, SJR: 3.671, CiteScore: 9)
Aggression and Violent Behavior     Hybrid Journal   (Followers: 471, SJR: 1.238, CiteScore: 3)
Agri Gene     Hybrid Journal   (Followers: 1, SJR: 0.13, CiteScore: 0)
Agricultural and Forest Meteorology     Hybrid Journal   (Followers: 18, SJR: 1.818, CiteScore: 5)
Agricultural Systems     Hybrid Journal   (Followers: 31, SJR: 1.156, CiteScore: 4)
Agricultural Water Management     Hybrid Journal   (Followers: 45, SJR: 1.272, CiteScore: 3)
Agriculture and Agricultural Science Procedia     Open Access   (Followers: 4)
Agriculture and Natural Resources     Open Access   (Followers: 3)
Agriculture, Ecosystems & Environment     Hybrid Journal   (Followers: 58, SJR: 1.747, CiteScore: 4)
Ain Shams Engineering J.     Open Access   (Followers: 5, SJR: 0.589, CiteScore: 3)
Air Medical J.     Hybrid Journal   (Followers: 7, SJR: 0.26, CiteScore: 0)
AKCE Intl. J. of Graphs and Combinatorics     Open Access   (SJR: 0.19, CiteScore: 0)
Alcohol     Hybrid Journal   (Followers: 12, SJR: 1.153, CiteScore: 3)
Alcoholism and Drug Addiction     Open Access   (Followers: 11)
Alergologia Polska : Polish J. of Allergology     Full-text available via subscription   (Followers: 1)
Alexandria Engineering J.     Open Access   (Followers: 2, SJR: 0.604, CiteScore: 3)
Alexandria J. of Medicine     Open Access   (Followers: 1, SJR: 0.191, CiteScore: 1)
Algal Research     Partially Free   (Followers: 11, SJR: 1.142, CiteScore: 4)
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 2)
Allergologia et Immunopathologia     Full-text available via subscription   (Followers: 1, SJR: 0.504, CiteScore: 1)
Allergology Intl.     Open Access   (Followers: 5, SJR: 1.148, CiteScore: 2)
Alpha Omegan     Full-text available via subscription   (SJR: 3.521, CiteScore: 6)
ALTER - European J. of Disability Research / Revue Européenne de Recherche sur le Handicap     Full-text available via subscription   (Followers: 10, SJR: 0.201, CiteScore: 1)
Alzheimer's & Dementia     Hybrid Journal   (Followers: 54, SJR: 4.66, CiteScore: 10)
Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring     Open Access   (Followers: 6, SJR: 1.796, CiteScore: 4)
Alzheimer's & Dementia: Translational Research & Clinical Interventions     Open Access   (Followers: 6, SJR: 1.108, CiteScore: 3)
Ambulatory Pediatrics     Hybrid Journal   (Followers: 5)
American Heart J.     Hybrid Journal   (Followers: 58, SJR: 3.267, CiteScore: 4)
American J. of Cardiology     Hybrid Journal   (Followers: 63, SJR: 1.93, CiteScore: 3)
American J. of Emergency Medicine     Hybrid Journal   (Followers: 46, SJR: 0.604, CiteScore: 1)
American J. of Geriatric Pharmacotherapy     Full-text available via subscription   (Followers: 12)
American J. of Geriatric Psychiatry     Hybrid Journal   (Followers: 14, SJR: 1.524, CiteScore: 3)
American J. of Human Genetics     Hybrid Journal   (Followers: 37, SJR: 7.45, CiteScore: 8)
American J. of Infection Control     Hybrid Journal   (Followers: 29, SJR: 1.062, CiteScore: 2)
American J. of Kidney Diseases     Hybrid Journal   (Followers: 36, SJR: 2.973, CiteScore: 4)
American J. of Medicine     Hybrid Journal   (Followers: 50)
American J. of Medicine Supplements     Full-text available via subscription   (Followers: 3, SJR: 1.967, CiteScore: 2)
American J. of Obstetrics and Gynecology     Hybrid Journal   (Followers: 247, SJR: 2.7, CiteScore: 4)
American J. of Ophthalmology     Hybrid Journal   (Followers: 66, SJR: 3.184, CiteScore: 4)
American J. of Ophthalmology Case Reports     Open Access   (Followers: 5, SJR: 0.265, CiteScore: 0)
American J. of Orthodontics and Dentofacial Orthopedics     Full-text available via subscription   (Followers: 6, SJR: 1.289, CiteScore: 1)
American J. of Otolaryngology     Hybrid Journal   (Followers: 25, SJR: 0.59, CiteScore: 1)
American J. of Pathology     Hybrid Journal   (Followers: 32, SJR: 2.139, CiteScore: 4)
American J. of Preventive Medicine     Hybrid Journal   (Followers: 28, SJR: 2.164, CiteScore: 4)
American J. of Surgery     Hybrid Journal   (Followers: 39, SJR: 1.141, CiteScore: 2)
American J. of the Medical Sciences     Hybrid Journal   (Followers: 12, SJR: 0.767, CiteScore: 1)
Ampersand : An Intl. J. of General and Applied Linguistics     Open Access   (Followers: 7)
Anaerobe     Hybrid Journal   (Followers: 4, SJR: 1.144, CiteScore: 3)
Anaesthesia & Intensive Care Medicine     Full-text available via subscription   (Followers: 66, SJR: 0.138, CiteScore: 0)
Anaesthesia Critical Care & Pain Medicine     Full-text available via subscription   (Followers: 24, SJR: 0.411, CiteScore: 1)
Anales de Cirugia Vascular     Full-text available via subscription   (Followers: 1)
Anales de Pediatría     Full-text available via subscription   (Followers: 3, SJR: 0.277, CiteScore: 0)
Anales de Pediatría (English Edition)     Full-text available via subscription  
Anales de Pediatría Continuada     Full-text available via subscription  
Analytic Methods in Accident Research     Hybrid Journal   (Followers: 5, SJR: 4.849, CiteScore: 10)
Analytica Chimica Acta     Hybrid Journal   (Followers: 44, SJR: 1.512, CiteScore: 5)
Analytica Chimica Acta : X     Open Access  
Analytical Biochemistry     Hybrid Journal   (Followers: 207, SJR: 0.633, CiteScore: 2)
Analytical Chemistry Research     Open Access   (Followers: 13, SJR: 0.411, CiteScore: 2)
Analytical Spectroscopy Library     Full-text available via subscription   (Followers: 14)
Anesthésie & Réanimation     Full-text available via subscription   (Followers: 2)
Anesthesiology Clinics     Full-text available via subscription   (Followers: 25, SJR: 0.683, CiteScore: 2)
Angiología     Full-text available via subscription   (SJR: 0.121, CiteScore: 0)
Angiologia e Cirurgia Vascular     Open Access   (Followers: 1, SJR: 0.111, CiteScore: 0)
Animal Behaviour     Hybrid Journal   (Followers: 217, SJR: 1.58, CiteScore: 3)
Animal Feed Science and Technology     Hybrid Journal   (Followers: 6, SJR: 0.937, CiteScore: 2)
Animal Reproduction Science     Hybrid Journal   (Followers: 7, SJR: 0.704, CiteScore: 2)

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Similar Journals
Journal Cover
Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring
Journal Prestige (SJR): 1.796
Citation Impact (citeScore): 4
Number of Followers: 6  

  This is an Open Access Journal Open Access journal
ISSN (Online) 2352-8729
Published by Elsevier Homepage  [3184 journals]
  • Breadth and depth of working memory and executive function compromises in
           mild cognitive impairment and their relationships to frontal lobe
           morphometry and functional competence

    • Abstract: Publication date: December 2019Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 11Author(s): Leticia Garcia-Alvarez, Jesus J. Gomar, Amber Sousa, Maria P. Garcia-Portilla, Terry E. GoldbergAbstractIntroductionThe extent of working memory (WM) and executive function (EF) impairment in mild cognitive impairment (MCI) is not well-characterized.MethodsWe compared 48 patients with MCI, 124 noncognitively impaired elderly healthy controls, and 57 patients with Alzheimer's disease (AD) on multiple WM/EF measures, frontal lobe integrity indexes, and functioning.ResultsPatients with MCI demonstrated worse performance on nearly all WM/EF tests. This profile of impairment was refined in a factor analysis that identified three primary WM/EF constructs: WM storage; speed and controlled visual search; and manipulation of information and problem solving. EF impairments were associated with reductions in prefrontal cortical thickness. WM/EF accounted for over 50% of the variance in functional competence.DiscussionIn MCI, WM/EF impairments are far from rare, based on specific compromises to frontal cortex circuitry, and are associated with loss of everyday functioning. WM/EF impairments, even at this potentially prodromal stage of AD, have clinically deleterious consequences.
  • Actual memory as a mediator of the amyloid-subjective cognitive decline

    • Abstract: Publication date: December 2019Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 11Author(s): Xi Chen, Michelle E. Farrell, William Moore, Denise C. ParkABSTRACTIntroductionAmyloid pathology in cognitively normal adults is associated with subjective cognitive decline, potentially reflecting awareness of Alzheimer's-related memory deficits. To clarify the mechanism underlying this relationship, we used mediational analyses to determine the role of depression, anxiety, and actual memory performance.MethodsTo assess amyloid deposition, we imaged 85 cognitively normal adults with florbetapir positron emission tomography imaging. Subjective cognitive decline was measured using a multidimensional instrument that assessed seven subjective memory domains. Mediational measures included assessments of actual memory performance (current and retrospective longitudinal change), depression, and anxiety.ResultsThe relationship between amyloid and subjective cognitive decline was mediated by poorer memory performance and greater retrospective memory decline, not depression or anxiety. The mediational roles were significant for domains associated with memory function and memory-related anxiety.DiscussionIn individuals harboring amyloid, self-reported beliefs of declining memory likely indicate early self-awareness of actual worsening function rather than depression or anxiety.
  • Brain and cognitive correlates of sleep fragmentation in elderly subjects
           with and without cognitive deficits

    • Abstract: Publication date: December 2019Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 11Author(s): Claire André, Clémence Tomadesso, Robin de Flores, Pierre Branger, Stéphane Rehel, Florence Mézenge, Brigitte Landeau, Vincent de la Sayette, Francis Eustache, Gaël Chételat, Géraldine RauchsAbstractIntroductionSleep disturbances are increasingly recognized as a risk factor for Alzheimer's disease. However, no study has assessed the relationships between objective sleep fragmentation (SF) and brain and cognitive integrity across different cognitive stages, from cognitively unimpaired elderly subjects to patients with subjective cognitive decline and/or mild cognitive impairment.Methods30 cognitively unimpaired elderly participants and 36 patients with subjective cognitive decline and/or mild cognitive impairment underwent a neuropsychological evaluation, structural MRI, 18F-fluorodeoxyglucose, and 18F-florbetapir-PET scans, and an actigraphy recording over a minimum of six consecutive nights. Multiple regression and mediation analyses were performed between SF parameters, neuroimaging data, and cognitive scores.ResultsIn cognitively unimpaired elderly participants, SF intensity mediated the association between frontohippocampal hypometabolism and lower executive functioning. Moreover, to a lower extent, increased SF variability was related to thalamic atrophy and ventromedial prefrontal amyloid burden. However, in patients with subjective cognitive decline and/or mild cognitive impairment, SF no longer contributed to the expression of cognitive deficits.DiscussionThese findings suggest that SF may directly contribute to lower cognitive performance in cognitively unimpaired elderly subjects. Therefore, treating sleep disturbances before the onset of cognitive deficits may help to cope with brain alterations and maintain cognitive functioning.
  • Quantifying memory deficits in amnestic mild cognitive impairment

    • Abstract: Publication date: December 2019Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 11Author(s): Pilar Andrés, Helena Vico, Aina Yáñez, Antònia Siquier, Guillermo Amer FerrerAbstractIntroductionIn the present study, we use the item-specific deficit approach (ISDA), a method for characterizing memory deficits in list-learning, to portray the memory deficits in amnestic mild cognitive impairment (aMCI).MethodsWe applied the ISDA to compare memory performance of patients with aMCI and healthy controls in encoding, consolidation, and retrieval using the Free and Cued Selective Reminding Test.ResultsThe results revealed clear differences in recall performance between patients with aMCI and controls. When analyzing the ISDA deficit indices, the results revealed a prominent encoding deficit, followed by a consolidating deficit. A greater sensitivity for the encoding index confirmed that a difficulty with encoding information plays a major role in explaining the episodic memory deficits experienced by patients with aMCI.DiscussionThe present study applying the ISDA reveals great sensitivity and specificity of the encoding deficit index when identifying aMCI. As aMCI constitutes a risk factor to develop Alzheimer's disease, the current findings also confirm the need to concentrate on encoding deficits as an early diagnostic sign of cognitive decline.
  • Measuring longitudinal cognition: Individual tests versus composites

    • Abstract: Publication date: December 2019Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 11Author(s): Erin M. Jonaitis, Rebecca L. Koscik, Lindsay R. Clark, Yue Ma, Tobey J. Betthauser, Sara E. Berman, Samantha L. Allison, Kimberly D. Mueller, Bruce P. Hermann, Carol A. Van Hulle, Bradley T. Christian, Barbara B. Bendlin, Kaj Blennow, Henrik Zetterberg, Cynthia M. Carlsson, Sanjay Asthana, Sterling C. JohnsonAbstractIntroductionLongitudinal cohort studies of cognitive aging must confront several sources of within-person variability in scores. In this article, we compare several neuropsychological measures in terms of longitudinal error variance and relationships with biomarker-assessed brain amyloidosis (Aβ).MethodsAnalyses used data from the Wisconsin Registry for Alzheimer's Prevention. We quantified within-person longitudinal variability and age-related trajectories for several global and domain-specific composites and their constituent scores. For a subset with cerebrospinal fluid or amyloid positron emission tomography measures, we examined how Aβ modified cognitive trajectories.ResultsGlobal and theoretically derived composites exhibited lower intraindividual variability and stronger age × Aβ interactions than did empirically derived composites or raw scores from single tests. For example, the theoretical executive function outperformed other executive function scores on both metrics.DiscussionThese results reinforce the need for careful selection of cognitive outcomes in study design, and support the emerging consensus favoring composites over single-test measures.
  • The social functioning in dementia scale (SF-DEM): Exploratory factor
           analysis and psychometric properties in mild, moderate, and severe

    • Abstract: Publication date: December 2019Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 11Author(s): Jessica Budgett, Anna Brown, Stephanie Daley, Thomas E. Page, Sube Banerjee, Gill Livingston, Andrew SommerladAbstractIntroductionThe psychometric properties of the social functioning in dementia scale over different dementia severities are unknown.MethodsWe interviewed 299 family carers of people with mild, moderate, or severe dementia from two UK research sites; examined acceptability (completion rates); conducted exploratory factor analysis; and tested each factor's internal consistency and construct validity.ResultsOf 299, 285 (95.3%) carers completed questionnaires. Factor analysis indicated three distinct factors with acceptable internal consistency: spending time with other people, correlating with overall social function (r = 0.56, P 
  • Normative data from linear and nonlinear quantile regression in CANTAB:
           Cognition in mid-to-late life in an epidemiological sample

    • Abstract: Publication date: December 2019Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 11Author(s): Rosemary A. Abbott, Caroline Skirrow, Martha Jokisch, Maarten Timmers, Johannes Streffer, Luc van Nueten, Michael Krams, Angela Winkler, Noreen Pundt, Pradeep J. Nathan, Philippa Rock, Francesca K. Cormack, Christian WeimarAbstractIntroductionNormative cognitive data can help to distinguish pathological decline from normal aging. This study presents normative data from the Cambridge Neuropsychological Test Automated Battery, using linear regression and nonlinear quantile regression approaches.MethodsHeinz Nixdorf Recall study participants completed Cambridge Neuropsychological Test Automated Battery tests: paired-associate learning, spatial working memory, and reaction time. Data were available for 1349-1529 healthy adults aged 57-84 years. Linear and nonlinear quantile regression analyses examined age-related changes, adjusting for sex and education. Quantile regression differentiated seven performance bands (percentiles: 97.7, 93.3, 84.1, 50, 15.9, 6.7, and 2.3).ResultsNormative data show age-related cognitive decline across all tests, but with quantile regression revealing heterogeneous trajectories of cognitive aging, particularly for the test of episodic memory function (paired-associate learning).DiscussionThis study presents normative data from Cambridge Neuropsychological Test Automated Battery in mid-to-late life. Quantile regression can model heterogeneity in age-related cognitive trajectories as seen in the paired-associate learning episodic memory measure.
  • Frontotemporal dementia is the leading cause of “true” A−/T+
           profiles defined with Aβ42/40 ratio

    • Abstract: Publication date: December 2019Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 11Author(s): Hélène Pouclet-Courtemanche, Tri-Bao Nguyen, Emilie Skrobala, Claire Boutoleau-Bretonnière, Florence Pasquier, Elodie Bouaziz-Amar, Edith Bigot-Corbel, Susanna Schraen, Julien Dumurgier, Claire Paquet, Thibaud LebouvierAbstractIntroductionPatients with positive tauopathy but negative Aβ42 (A−T+) in the cerebrospinal fluid (CSF) represent a diagnostic challenge. The Aβ42/40 ratio supersedes Aβ42 and reintegrates “false” A−T+ patients into the Alzheimer's disease spectrum. However, the biomarker and clinical characteristics of “true” and “false” A−T+ patients remain elusive.MethodsAmong the 509 T+N+ patients extracted from the databases of three memory clinics, we analyzed T+N+ patients with normal Aβ42 and compared “false” A−T+ with abnormal Aβ42/40 ratio and “true” A−T+ patients with normal Aβ42/40 ratio, before CSF analysis and at follow-up.Results24.9% of T+N+ patients had normal Aβ42 levels. Among them, 42.7% were “true” A−T+. “True” A−T+ had lower CSF tauP181 than “false” A−T+ patients. 48.0% of “true” A−T+ patients were diagnosed with frontotemporal lobar degeneration before CSF analysis and 64.0% at follow-up, as compared with 6% in the “false” A−T+ group (P 
  • Decision tree supports the interpretation of CSF biomarkers in Alzheimer's

    • Abstract: Publication date: December 2019Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 11Author(s): Rosha Babapour Mofrad, Niki S.M. Schoonenboom, Betty M. Tijms, Philip Scheltens, Pieter Jelle Visser, Wiesje M. van der Flier, Charlotte E. TeunissenAbstractIntroductionWe developed and validated a clinically applicable decision tree for the use of cerebrospinal fluid biomarkers in the diagnosis of Alzheimer's disease (AD).MethodsSubjects with probable AD (n = 1004) and controls (n = 442) were included. A decision tree was modeled using Classification And Regression Tree analysis in a training cohort (AD n = 221; controls n = 221) and validated in an independent cohort (AD n = 783; controls n = 221). Diagnostic performance was compared to previously defined cutoffs (amyloid β 1-42 375 pg/ml).ResultsTwo cerebrospinal fluid AD biomarker profiles were revealed: the “classical” AD biomarker profile (amyloid β 1-42: 647-803 pg/ml; tau>374 pg/ml) and an “atypical” AD biomarker profile with strongly decreased amyloid β 1-42 (
  • Harmonizing brain magnetic resonance imaging methods for vascular
           contributions to neurodegeneration

    • Abstract: Publication date: December 2019Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 11Author(s): Eric E. Smith, Geert Jan Biessels, François De Guio, Frank Erik de Leeuw, Simon Duchesne, Marco Düring, Richard Frayne, M. Arfan Ikram, Eric Jouvent, Bradley J. MacIntosh, Michael J. Thrippleton, Meike W. Vernooij, Hieab Adams, Walter H. Backes, Lucia Ballerini, Sandra E. Black, Christopher Chen, Rod Corriveau, Charles DeCarli, Steven M. GreenbergAbstractIntroductionMany consequences of cerebrovascular disease are identifiable by magnetic resonance imaging (MRI), but variation in methods limits multicenter studies and pooling of data. The European Union Joint Program on Neurodegenerative Diseases (EU JPND) funded the HARmoNizing Brain Imaging MEthodS for VaScular Contributions to Neurodegeneration (HARNESS) initiative, with a focus on cerebral small vessel disease.MethodsSurveys, teleconferences, and an in-person workshop were used to identify gaps in knowledge and to develop tools for harmonizing imaging and analysis.ResultsA framework for neuroimaging biomarker development was developed based on validating repeatability and reproducibility, biological principles, and feasibility of implementation. The status of current MRI biomarkers was reviewed. A website was created at with acquisition protocols, a software database, rating scales and case report forms, and a deidentified MRI repository.ConclusionsThe HARNESS initiative provides resources to reduce variability in measurement in MRI studies of cerebral small vessel disease.
  • Harmonization of neuroimaging biomarkers for neurodegenerative diseases: A
           survey in the imaging community of perceived barriers and suggested

    • Abstract: Publication date: December 2019Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 11Author(s): Jorge Jovicich, Frederik Barkhof, Claudio Babiloni, Karl Herholz, Christoph Mulert, Bart N.M. van Berckel, Giovanni B. Frisoni, SRA-NED JPND Working GroupAbstractIntroductionMolecular, functional, and structural neuroimaging biomarkers are largely used to study neurodegenerative diseases, but their benefits to patients/science might be greatly enhanced by improving standardization and cross-validation. In this EU Joint Programme-Neurodegenerative Diseases Research–funded project, we surveyed the neuroimaging community to assess perceived barriers in multicentric neuroimaging harmonization and actions to overcome them.MethodsAn anonymous survey addressed researchers, clinicians, pharma industry, and professional associations, inquiring about both general and modality-specific harmonization barriers.ResultsSurvey participants (459) represented an international (37 countries) multidisciplinary community. We identified two sets of funding actions, one proposing the creation of an updated hub of documents to help researchers plan and execute multicentric neuroimaging studies capitalizing from previous studies, and the other focused on modality-specific harmonization challenges in future neurodegenerative diseases clinical trials.DiscussionThis large survey of priorities and actions may help define harmonization calls launched by worldwide science funding agencies.
  • Brain imaging working group summaries for the European Joint Programme for
           Neurodegenerative Disease Research

    • Abstract: Publication date: December 2019Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 11Author(s): Giovanni B. Frisoni, Jorge Jovicich
  • Comparison of Pittsburgh compound B and florbetapir in cross-sectional and
           longitudinal studies

    • Abstract: Publication date: December 2019Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 11Author(s): Yi Su, Shaney Flores, Guoqiao Wang, Russ C. Hornbeck, Benjamin Speidel, Nelly Joseph-Mathurin, Andrei G. Vlassenko, Brian A. Gordon, Robert A. Koeppe, William E. Klunk, Clifford R. Jack, Martin R. Farlow, Stephen Salloway, Barbara J. Snider, Sarah B. Berman, Erik D. Roberson, Jared Brosch, Ivonne Jimenez-Velazques, Christopher H. van Dyck, Douglas GalaskoAbstractIntroductionQuantitative in vivo measurement of brain amyloid burden is important for both research and clinical purposes. However, the existence of multiple imaging tracers presents challenges to the interpretation of such measurements. This study presents a direct comparison of Pittsburgh compound B–based and florbetapir-based amyloid imaging in the same participants from two independent cohorts using a crossover design.MethodsPittsburgh compound B and florbetapir amyloid PET imaging data from three different cohorts were analyzed using previously established pipelines to obtain global amyloid burden measurements. These measurements were converted to the Centiloid scale to allow fair comparison between the two tracers. The mean and inter-individual variability of the two tracers were compared using multivariate linear models both cross-sectionally and longitudinally.ResultsGlobal amyloid burden measured using the two tracers were strongly correlated in both cohorts. However, higher variability was observed when florbetapir was used as the imaging tracer. The variability may be partially caused by white matter signal as partial volume correction reduces the variability and improves the correlations between the two tracers. Amyloid burden measured using both tracers was found to be in association with clinical and psychometric measurements. Longitudinal comparison of the two tracers was also performed in similar but separate cohorts whose baseline amyloid load was considered elevated (i.e., amyloid positive). No significant difference was detected in the average annualized rate of change measurements made with these two tracers.DiscussionAlthough the amyloid burden measurements were quite similar using these two tracers as expected, difference was observable even after conversion into the Centiloid scale. Further investigation is warranted to identify optimal strategies to harmonize amyloid imaging data acquired using different tracers.
  • Amygdala subnuclei are differentially affected in the different genetic
           and pathological forms of frontotemporal dementia

    • Abstract: Publication date: December 2019Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 11Author(s): Martina Bocchetta, Juan Eugenio Iglesias, David M. Cash, Jason D. Warren, Jonathan D. RohrerAbstractIntroductionFrontotemporal dementia (FTD) is a heterogeneous neurodegenerative disorder with multiple genetic and pathological causes. It is characterized by both cortical and subcortical atrophies, with previous studies showing early involvement of the amygdala. However, no prior study has specifically investigated the atrophy of different subnuclei of the amygdala.MethodsUsing an automated segmentation tool for T1-weighted volumetric magnetic resonance imaging, we investigated amygdalar subnuclei (AS) involvement in a cohort of 132 patients with genetic or pathologically confirmed FTD (age: mean = 61 years (standard deviation = 8); disease duration: 5 (3) years) compared with 107 age-matched controls.ResultsAS were affected in all genetic and pathological forms of FTD. MAPT mutations/FTDP-17, Pick's disease, and transactive response DNA binding protein 43 kDa type C were the forms with the smallest amygdala (35%–50% smaller than controls in the most affected hemisphere, P 
  • Structural connectivity centrality changes mark the path toward
           Alzheimer's disease

    • Abstract: Publication date: December 2019Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 11Author(s): Luis R. Peraza, Antonio Díaz-Parra, Oliver Kennion, David Moratal, John-Paul Taylor, Marcus Kaiser, Roman Bauer, Alzheimer's Disease Neuroimaging InitiativeAbstractIntroductionThe pathophysiological process of Alzheimer's disease is thought to begin years before clinical decline, with evidence suggesting prion-like spreading processes of neurofibrillary tangles and amyloid plaques.MethodsUsing diffusion magnetic resonance imaging data from the Alzheimer's Disease Neuroimaging Initiative database, we first identified relevant features for dementia diagnosis. We then created dynamic models with the Nathan Kline Institute-Rockland Sample database to estimate the earliest detectable stage associated with dementia in the simulated disease progression.ResultsA classifier based on centrality measures provides informative predictions. Strength and closeness centralities are the most discriminative features, which are associated with the medial temporal lobe and subcortical regions, together with posterior and occipital brain regions. Our model simulations suggest that changes associated with dementia begin to manifest structurally at early stages.DiscussionOur analyses suggest that diffusion magnetic resonance imaging–based centrality measures can offer a tool for early disease detection before clinical dementia onset.
  • White matter and its relationship with cognition in subjective cognitive

    • Abstract: Publication date: December 2019Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 11Author(s): Lisa Ohlhauser, Ashleigh F. Parker, Colette M. Smart, Jodie R. Gawryluk, Alzheimer's Disease Neuroimaging InitiativeAbstractIntroductionSubjective cognitive decline (SCD) is the earliest stage on the continuum toward Alzheimer's disease. This study examined (1) differences in white matter integrity between individuals with SCD and healthy control subjects and (2) how white matter integrity related to memory and executive function.MethodsDiffusion tensor imaging and neuropsychological assessment data were retrieved from the Alzheimer's Disease Neuroimaging Initiative database for 30 individuals with SCD and 44 control subjects.ResultsResults revealed significantly lower white matter integrity in individuals with SCD relative to control subjects in widespread regions, including the bilateral corticospinal tracts, superior and inferior longitudinal fasciculi, fronto-occipital fasciculi, corpus callosum, forceps major and minor, hippocampi, anterior thalamic radiations, and the cerebellum. There was a widespread relationship between diffusion tensor imaging metrics and executive function in SCD, but not healthy control subjects, and no relationship with memory for either group.DiscussionRelatively lower white matter integrity in SCD may be a useful early biomarker for risk of future cognitive decline. Future research should better characterize the SCD group longitudinally and in individuals at risk for Alzheimer's disease.
  • A proteomic signature for dementia with Lewy bodies

    • Abstract: Publication date: December 2019Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 11Author(s): Sid E. O'Bryant, Tanis J. Ferman, Fan Zhang, James Hall, Otto Pedraza, Zbigniew K. Wszolek, Tori Como, David Julovich, Sravan Mattevada, Leigh A. Johnson, Melissa Edwards, James Hall, Neill R. Graff-RadfordAbstractIntroductionWe sought to determine if a proteomic profile approach developed to detect Alzheimer's disease would distinguish patients with Lewy body disease from normal controls, and if it would distinguish dementia with Lewy bodies (DLB) from Parkinson's disease (PD).MethodsStored plasma samples were obtained from 145 patients (DLB n = 57, PD without dementia n = 32, normal controls n = 56) enrolled from patients seen in the Behavioral Neurology or Movement Disorders clinics at the Mayo Clinic, Florida. Proteomic assays were conducted and analyzed as per our previously published protocols.ResultsIn the first step, the proteomic profile distinguished the DLB-PD group from controls with a diagnostic accuracy of 0.97, sensitivity of 0.91, and specificity of 0.86. In the second step, the proteomic profile distinguished the DLB from PD groups with a diagnostic accuracy of 0.92, sensitivity of 0.94, and specificity of 0.88.DiscussionThese data provide evidence of the potential utility of a multitiered blood-based proteomic screening method for detecting DLB and distinguishing DLB from PD.
  • Aβ and tau structure-based biomarkers for a blood- and CSF-based two-step
           recruitment strategy to identify patients with dementia due to Alzheimer's

    • Abstract: Publication date: December 2019Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 11Author(s): Andreas Nabers, Henning Hafermann, Jens Wiltfang, Klaus GerwertAbstractIntroductionAlzheimer's disease (AD) diagnosis requires invasive CSF analysis or expensive brain imaging. Therefore, a minimal-invasive reliable and cost-effective blood test is requested to power large clinical AD trials at reduced screening failure.MethodsWe applied an immuno-infrared sensor to measure the amyloid-β (Aβ) and tau secondary structure distribution in plasma and CSF as structure-based biomarkers for AD (61 disease controls, 39 AD cases).ResultsWithin a first diagnostic screening step, the structure-based Aβ blood biomarker supports AD identification with a sensitivity of 90%. In a second diagnostic validation step, the combined use of the structure-based CSF biomarkers Aβ and tau excluded false-positive cases which offers an overall specificity of 97%.DiscussionThe primary Aβ-based blood biomarker funnels individuals with suspected AD for subsequent validation of the diagnosis by structure-based combined analysis of the CSF biomarkers Aβ and tau. Our novel two-step recruitment strategy substantiates the diagnosis of AD with a likelihood of 29.
  • Posttraumatic stress disorder and total amyloid burden and amyloid-β
           42/40 ratios in plasma: Results from a pilot study of World Trade Center

    • Abstract: Publication date: December 2019Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 11Author(s): Sean A.P. Clouston, Yael Deri, Erica Diminich, Richard Kew, Roman Kotov, Candace Stewart, Xiaohua Yang, Sam Gandy, Mary Sano, Evelyn J. Bromet, Benjamin J. LuftAbstractIntroductionChronic posttraumatic stress disorder (PTSD) is associated with poor memory and increased burden of various degenerative cerebral neuropathologies. The goal of this pilot study was to determine whether PTSD was associated with changes in plasma-based neuropathological biomarkers of neurodegeneration among World Trade Center (WTC) responders.MethodsThirty-four WTC responders had blood drawn and flash-frozen within 15 minutes of retrieval. PTSD symptoms were assessed at that time. Age, sex, and WTC exposure duration were obtained from medical records. Plasma was assayed in duplicate using an ultra-sensitive single-molecule enzyme-linked immunosorbent assay to examine the distribution of amyloid-β (Aβ) 42/40 ratios, total Aβ, total tau, and neurofilament light (NfL). The comparison group was drawn from a bank of healthy controls collected and assayed at the same facility.ResultsThe average age of WTC responders at blood draw was 53 years. Half were PTSD positive (PTSD+) as indicated by symptom severity. WTC responders had lower Aβ42/Aβ40 ratios but higher total tau and NfL levels in the plasma than healthy controls. PTSD+ status was associated with lower plasma Aβ load and higher Aβ42/Aβ40 ratios.DiscussionFindings suggest that PTSD may be associated with alterations in plasma markers related to Aβ, tau, and NfL, highlighting the potential association between PTSD status and neurodegenerative neuropathology in WTC responders.
  • Serum levels of proteins involved in amyloid-β clearance are related to
           cognitive decline and neuroimaging changes in mild cognitive impairment

    • Abstract: Publication date: December 2019Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 11Author(s): Shan Liu, Hideaki Suzuki, Hitomi Ito, Tatsumi Korenaga, Hiroyasu Akatsu, Kohji Meno, Kazuhiko UchidaAbstractIntroductionAmyloid-β (Aβ) clearance is important for damage prevention in Alzheimer's disease. We investigated the utility of Aβ clearance proteins as biomarkers for mild cognitive impairment (MCI).MethodsSerum apolipoprotein (apo) A-I, compliment protein C3 (C3), transthyretin, and cholesterol levels were measured in 273 subjects, and we analyzed the relationship between these levels and brain atrophy and cerebral blood flow in 63 clinically diagnosed mild cognitive impairment, Alzheimer's disease, and nondemented disease control subjects.ResultsApoA-I and transthyretin levels and the active form of C3:native form of C3 ratio achieved an area under the curve of 0.89 (sensitivity: 83%, specificity: 90%) for detecting late mild cognitive impairment. Atrophy was associated with decreased apoA-I and high-density lipoprotein levels. Subjects with reduced cerebral blood flow had lower levels of native form of C3, apoA-I, high-density lipoprotein, and total cholesterol. Low native form of C3 and high active form of C3 levels were found in the hippocampi of patients with Alzheimer's disease.DiscussionAβ clearance proteins in the serum are potential biomarkers for mild cognitive impairment evaluation.
  • Complement protein levels in plasma astrocyte-derived exosomes are
           abnormal in conversion from mild cognitive impairment to Alzheimer's
           disease dementia

    • Abstract: Publication date: December 2019Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 11Author(s): Charisse N. Winston, Edward J. Goetzl, Janice B. Schwartz, Fanny M. Elahi, Robert A. RissmanAbstractIntroductionLevels of complement proteins (CPs) in plasma astrocyte-derived exosomes (ADEs) that are abnormal in Alzheimer's disease (AD) have not been assessed in mild cognitive impairment (MCI).MethodsParticipants (n = 20 per group) had either MCI converting to dementia within 3 years (MCIC), MCI remaining stable over 3 years (MCIS), Alzheimer's disease, or were controls. CPs of ADEs isolated from plasmas by anti-human glutamine aspartate transporter antibody absorption were quantified by ELISAs.ResultsADE levels of C1q and C4b of the classical pathway, factor D and fragment Bb of the alternative pathway, and C5b, C3b, and C5b-C9 of both pathways were significantly higher in patients with MCIC than those with MCIS. ADE levels of inhibitory CPs decay-accelerating factor, CD46, CD59, and type 1 complement receptor were significantly lower in patients with MCIC than those with MCIS.DiscussionADE CPs are components of neurotoxic neuroinflammation that may be predictive biomarkers of MCI conversion to Alzheimer's disease.
  • Retinal ganglion cell–inner plexiform layer thickness is nonlinearly
           associated with cognitive impairment in the community-dwelling elderly

    • Abstract: Publication date: December 2019Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 11Author(s): Yao-Lin Liu, Yi-Ting Hsieh, Ta-Fu Chen, Jeng-Min Chiou, Min-Kuang Tsai, Jen-Hau Chen, Yen-Ching ChenAbstractIntroductionThinning of optical coherence tomography–measured retinal nerve fiber layer thickness and ganglion cell–inner plexiform layer (GC-IPL) thickness has been found in patients with Alzheimer's disease. However, the association of these retinal markers and cognition in nondemented elders may not be linear.MethodsThis cross-sectional study included 227 community-dwelling elders (age 65+ years). Multivariable regression analyses were performed to investigate the association between retinal nerve fiber layer/GC-IPL and global/domain-specific cognition.ResultsThe performance of global cognition decreased as mean GC-IPL of bilateral eyes deviated from the sample mean (77.5 μm) (quadratic GC-IPL: β = –0.49 × 10−2; 95% confidence interval: −0.74 × 10−2 to −0.23 × 10−2). Similar associations were also found for logical memory. No significant association was observed between retinal nerve fiber layer and cognition.DiscussionEither thinning or thickening of GC-IPL was associated with poor cognition in nondemented elderly (a U-shaped association). GC-IPL may serve as a noninvasive preclinical predictor of Alzheimer's disease.
  • ApoE4 lowers age at onset in patients with frontotemporal dementia and
           tauopathy independent of amyloid-β copathology

    • Abstract: Publication date: December 2019Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 11Author(s): Carolin Koriath, Tammaryn Lashley, William Taylor, Ronald Druyeh, Athanasios Dimitriadis, Nicola Denning, Julie Williams, Jason D. Warren, Nick C. Fox, Jonathan M. Schott, James B. Rowe, John Collinge, Jonathan D. Rohrer, Simon MeadAbstractIntroductionApolipoprotein E (ApoE) is the most important genetic risk factor for Alzheimer's disease (AD), with ApoE4 thought to enhance and accelerate amyloid-β (Aβ) pathology. ApoE4 has recently been described to increase neurodegeneration in a mouse model of frontotemporal dementia (FTD), in vitro, and in patients, demonstrating that ApoE4 modifies tauopathy independently of Aβ. This raises the question whether ApoE genotype also modifies the clinical phenotype in patients with FTD with tau pathology.MethodsWe analyzed 704 patients with FTD, including a genetically and neuropathologically confirmed subset, and 452 healthy elderly controls. We compared ApoE4 genotype frequency and age at onset in tau+ or TDP43+ FTD patients with or without Aβ copathology.ResultsThe ApoE4 genotype lowered age at onset in patients with FTD and tau pathology, particularly once accounting for confounding effects of Aβ pathology.DiscussionWe conclude that ApoE4 accelerates neurodegeneration in FTD patients with MAPT mutations or FTLD-tau pathology, independent of Aβ.
  • APOE ε4, the door to insulin-resistant dyslipidemia and
           brain fog' A case study

    • Abstract: Publication date: December 2019Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 11Author(s): Seth Stoykovich, Kelly GibasAbstractFor decades, scientists have known that carriers of the apolipoprotein E ε4 (APOE ε4) allele (homozygous/heterozygous) are at respectively higher risk for developing Alzheimer's disease (AD). Although previous research reveals that the APOE ε4 variant impacts the clearance capacity and degradation of β-amyloid from the brain, as compared with APOE ε3 (wild type with normal risk) and APOE ε2 (variant with accelerated clearance and reduced risk), little has been documented about APOE ε4's dual role in cholesterol transport, both peripheral and cerebral, and the effects of sluggish APOE ε4 cholesterol transport on cerebral metabolic rate. An understanding of the connection between brain metabolism and brain fat/cholesterol transport may unlock new prevention strategies for treating patients with a comorbidity of metabolic syndrome (MetS) with cognitive impairment. Recent findings suggest that the APOE ε4 carrier impedes the shuttling of lipids from neurons and circumvents the storage of fat within the glia lipid droplets. This sluggish transport of lipids to triglyceride droplets in the glia cells can lead to dangerous reactive oxygen species and hydroxyl-free radicals as lipids are prematurely oxidized.This case study evaluates the effects of a 10-week clinically prescribed ketogenic diet (KD) with a 68-year-old male, heterozygous APOE ε4 carrier, with a dual diagnosis of mild AD and type 2 diabetes (T2DM). The patient was administering both long- and short-acting injectable insulin to mediate his T2DM for 15+ years. Clinical goals of the intervention included increased hypothalamic and peripheral insulin sensitivity as measured via blood ketones with the Abbott Precision Xtra Blood Ketone Meter to confirm metabolic flexibility; controlled plasma glucose as measured via Abbott Precision Xtra Blood Glucose Meter and HgA1c via venous draw; normalization of lipid panel via venous draw and improved memory with restoration of cognitive functionality measured via the Montreal Cognitive Assessment. The Montreal Cognitive Assessment is considered to be a gold standard assessment in the diagnosis of early AD. Physiological biomarkers for T2DM/MetS and cognitive functionality were assessed before/during/after intervention. These measures included HOMA-IR, triglycerides/HDL ratio, HgA1c, fasting glucose, fasting insulin, complete fasting lipid panel and the PEAK mobile application for real-time measurement of cognitive improvement. The results were statistically significant. The patient's baseline Montreal Cognitive Assessment improved from 23/30 (mild AD) to 29/30 (normal ≥ 26). His T2DM was reversed. Pre-intervention HgA1c was 7.8% (T2DM); post intervention HgA1c measured 5.5% (normal). Likewise, the patient achieved statistically significant improvements in the other aforementioned biomarkers of MetS. The results of this case study suggest that a clinically prescribed ketogenic diet has strong potential to restore systemic insulin sensitivity and metabolic flexibility in diabetic, APOE ε4 heterozygous carriers. Mechanisms of action point to normalization of homeostatic negative feedback loops resetting/restoring lipid synthesis/utilization and glucose (insulin)/fatty acid (glucagon) utilization/production in both the body and brain, resulting in increased cerebral metabolism, improved cognition, and reversal of T2DM via renewed cellular insulin sensitivity.
  • Heritability in frontotemporal tauopathies

    • Abstract: Publication date: December 2019Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 11Author(s): Shelley L. Forrest, Glenda M. Halliday, Heather McCann, Andrew B. McGeachie, Ciara V. McGinley, John R. Hodges, Olivier Piguet, John B. Kwok, Maria G. Spillantini, Jillian J. KrilAbstractIntroductionExploring the degree of heritability in a large cohort of frontotemporal lobar degeneration with tau-immunopositive inclusions (FTLD-tau) and determining if different FTLD-tau subtypes are associated with stronger heritability will provide important insight into disease pathogenesis.MethodsUsing modified Goldman pedigree classifications, heritability was examined in pathologically proven FTLD-tau cases with dementia at any time (n = 124) from the Sydney-Cambridge collection.ResultsThirteen percent of the FTLD-tau cohort have a suggested autosomal dominant pattern of inheritance, 25% have some family history, and 62% apparently sporadic. MAPT mutations were found in 9% of cases. Globular glial tauopathy was associated with the strongest heritability with 40% having a suggested autosomal dominant pattern of inheritance followed by corticobasal degeneration (19%), Pick's disease (8%), and progressive supranuclear palsy (6%).DiscussionSimilar to clinical frontotemporal dementia syndromes, heritability varies between pathological subtypes. Further identification of a genetic link in cases with strong heritability await discovery.
  • Apolipoprotein E particle size is increased in Alzheimer's disease

    • Abstract: Publication date: December 2019Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 11Author(s): Thomas J. Nelson, Abhik SenAbstractIntroductionApolipoprotein E4 (apoE4) is the predominant risk factor for late-onset Alzheimer's disease (AD), but the question of which structural differences might explain its effect remains unclear.MethodsWe compared high-density lipoprotein–like apoE particles from 12 AD and 10 control patients using size-exclusion chromatography.ResultsApoE particles from patients genotyped as ε4/ε4 were 2.2 ± 0.3 times as massive as particles from ε3/ε3 control subjects and 1.4 ± 0.1 times as massive as particles from ε3/ε3 AD patients. The increased particle size was not because of incorporation of amyloid β or apoE proteolysis products. Particles from AD patients genotyped as ε3/ε3 were 1.59 ± 0.27 times as massive as ε3/ε3 control subjects.DiscussionIncreased particle size in AD is affected by APOE genotype and by disease-related differences in assembly or stability. These differences suggest that lipoprotein assembly or stability in AD brain plays an important role in determining apoE4 pathogenicity.
  • The incidence of mild cognitive impairment: A systematic review and data

    • Abstract: Publication date: December 2019Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 11Author(s): Cai Gillis, Fariba Mirzaei, Michele Potashman, M. Arfan Ikram, Nancy MaserejianAbstractIntroductionIncidence estimates of mild cognitive impairment (MCI) range widely. We obtained contemporary age-specific MCI incidence rates and examined sources of heterogeneity.MethodsWe conducted a systematic review of population-based studies from the Americas, Europe, and Australia using restrictive inclusion criteria to limit heterogeneity. Incidence was examined using 5-year age categories for MCI and amnestic/nonamnestic subtypes. Data were synthesized using quantitative and qualitative descriptive analyses and quantitative meta-analyses.ResultsMeta-analysis estimates (95% CI) of MCI incidence per 1000 person-years were 22.5 (5.1–51.4) for ages 75–79y, 40.9 (7.7–97.5) for ages 80–84y, and 60.1 (6.7–159.0) for ages 85+y. Despite restrictive inclusion criteria, considerable heterogeneity (measured by I2) remained. Meta-analysis findings and simple descriptive statistics were consistent and supported by qualitative review.DiscussionHeterogeneity in MCI incidence estimates persisted across age-specific estimates from population samples, likely reflecting differences in populations and methods. Incidence rate ranges are important to consider with summary point estimates.
  • Subjective cognitive decline, APOE ε4, and incident mild cognitive
           impairment in men and women

    • Abstract: Publication date: December 2019Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 11Author(s): Diana Müller-Gerards, Christian Weimar, Jessica Abramowski, Sarah Tebrügge, Martha Jokisch, Nico Dragano, Raimund Erbel, Karl-Heinz Jöckel, Susanne Moebus, Angela Winkler, Heinz Nixdorf Recall Study Investigative GroupAbstractIntroductionPossible joint effects of subjective cognitive decline (SCD) and apolipoprotein E (APOE) ε4 genotype on incident mild cognitive impairment (MCI) were examined for men and women separately.MethodsCognitively normal participants with and without SCD were included from the first follow-up examination of the population-based Heinz Nixdorf Recall study. Sex-stratified logistic regression models estimated main effects and interactions (additive, multiplicative) of SCD at the first follow-up (yes+/no−) and APOE ε4 (positive+/negative−) groups for MCI 5 years later.ResultsOdds for MCI 5 years later were higher in SCD/APOE ε4 group +/+ than the sum of groups +/− and −/+ in women, with a trend for positive interaction. Odds for incident MCI in men was highest in group +/−, with no interaction effect.DiscussionOur findings indicate that APOE ε4 may play an important role in the association of SCD and incident MCI, especially considering sex. Further studies need to examine these associations with larger sample sizes.
  • Predicting time to dementia using a quantitative template of disease

    • Abstract: Publication date: December 2019Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 11Author(s): Murat Bilgel, Bruno M. Jedynak, Alzheimer's Disease Neuroimaging InitiativeAbstractIntroductionCharacterization of longitudinal trajectories of biomarkers implicated in sporadic Alzheimer's disease (AD) in decades before clinical diagnosis is important for disease prevention and monitoring.MethodsWe used a multivariate Bayesian model to temporally align 1369 Alzheimer's disease Neuroimaging Initiative participants based on the similarity of their longitudinal biomarker measures and estimated a quantitative template of the temporal evolution of cerebrospinal fluid Aβ1−42, p-tau181p, and t-tau and hippocampal volume, brain glucose metabolism, and cognitive measurements. We computed biomarker trajectories as a function of time to AD dementia and predicted AD dementia onset age in a disjoint sample.ResultsQuantitative template showed early changes in verbal memory, cerebrospinal fluid Aβ1–42 and p-tau181p, and hippocampal volume. Mean error in predicted AD dementia onset age was
  • Development and validation of a salivary tau biomarker in Alzheimer's

    • Abstract: Publication date: December 2019Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 11Author(s): Heather Pekeles, Hamid Y. Qureshi, Hemant K. Paudel, Hyman M. Schipper, Mervyn Gornistky, Howard ChertkowAbstractIntroductionTotal tau (t-tau) and phosphorylated tau (p-tau) are abnormally elevated in the brain and cerebrospinal fluid of individuals with Alzheimer's disease (AD). Tau is also present in the salivary gland tissue and saliva, and salivary measures might produce an accurate, accessible, and inexpensive biomarker.MethodsUsing unstimulated saliva and Western blot analysis, we quantified the p-tau/t-tau ratio at different phosphorylation sites.ResultsWe found that for one phosphorylation site, S396, p-tau/t-tau ratio was significantly elevated in patients with AD compared with normal elderly control subjects. The elevation in saliva, however, did not correlate with cerebrospinal fluid tau or with brain measures such as hippocampal volume.DiscussionThere is significant elevation of p-tau/t-tau ratio for the S396 phosphorylation site. Large variation in the AD salivary tau levels, however, limits the utility of this test as a clinical biomarker.
  • Free and Cued Selective Reminding Test sensitivity

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Raphael M. Castilhos, Marcia L. Chaves
  • Optimal cutoffs for the Montreal Cognitive Assessment vary by race and

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Sadaf Arefi Milani, Michael Marsiske, Linda B. Cottler, Xinguang Chen, Catherine W. StrileyAbstractIntroductionThe Montreal Cognitive Assessment (MoCA), scored from 0 to 30, is used as a screening tool for mild cognitive impairment (MCI). The current cutoff (26) may not be optimal among minorities.MethodsData from the National Alzheimer's Coordinating Center Uniform Data Set March 2018 data freeze was used to calculate optimal cutoffs for detection of MCI and dementia by race/ethnic group and education.ResultsOf the 3895 individuals included, 80.7% were non-Hispanic White, 15.0% were non-Hispanic Black, and 4.2% were Hispanic. Optimal cutoffs for detection of MCI were 25 among non-Hispanic Whites, 24 among Hispanics, and 23 among non-Hispanic Blacks. Optimal cutoffs for detection of dementia were 19 among non-Hispanic Whites and 16 for both non-Hispanic Blacks and Hispanics. Lower educational attainment produced lower optimal cutoffs.DiscussionOur findings suggest cutoffs may need to be stratified by race/ethnicity and education to ensure detecting MCI from normal and MCI from dementia.
  • Utility of the NIH Toolbox for assessment of prodromal Alzheimer's disease
           and dementia

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Katherine Hackett, Robert Krikorian, Tania Giovannetti, Josefina Melendez-Cabrero, Aneela Rahman, Emily E. Caesar, Jaclyn L. Chen, Hollie Hristov, Alon Seifan, Lisa Mosconi, Richard S. IsaacsonAbstractIntroductionThe NIH Toolbox Cognition Battery (NIHTB-CB) is a computer-based protocol not yet validated for clinical assessment.MethodsWe administered the NIHTB-CB and traditional neuropsychological tests to 247 Memory Disorders and Alzheimer's Prevention Clinic patients with subjective cognitive decline, mild cognitive impairment, mild dementia due to Alzheimer's disease, and normal cognition. Principal component analysis, partial correlations, and univariate general linear model tests were performed to assess construct validity. Discriminant function analyses compared classification accuracy.ResultsPrincipal component analysis identified three conceptually coherent factors: memory (MEMNIH), executive function (EFNIH), and crystallized intelligence (CINIH). These factors were strongly associated with corresponding traditional tests and differed across diagnostic groups as expected. Both NIHTB and traditional batteries yielded strong overall discriminative ability (>80%).DiscussionThe NIHTB-CB is a valid method to assess neurocognitive domains pertinent to aging and dementia and has utility for applications in a memory clinic setting.
  • A very light lunch: Interoceptive deficits and food aversion at onset in a
           case of behavioral variant frontotemporal dementia

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Gerardo Salvato, Matteo Mercurio, Maurizio Sberna, Eraldo Paulesu, Gabriella BottiniAbstractIntroductionPatients affected by the behavioral variant frontotemporal dementia (bvFTD) frequently experience, at a delayed onset, abnormal eating behavior involving increased food intake. Although delusional food-related symptoms have attracted much attention, the behavioral and neural features of food aversion manifestations in bvFTD remain poorly documented.MethodsWe describe the rare case of a patient with bvFTD presenting with lack of interoception for swallowing and digestion, coupled with a dramatic food aversion at onset. We also compared his MRI scan to 84 healthy individuals using a voxel-based morphometry approach.ResultsWe found gray matter density reductions involving the postcentral gyrus bilaterally, insulae, and right medial orbitofrontal cortex.DiscussionOur results shed new light on the behavioral and neuroanatomical features of food aversion and interoception deficits in bvFTD, suggesting that besides orbitofrontal cortex, also a distributed system associated with interoception might play a role in such behavioral manifestation.
  • Computer-assisted prediction of clinical progression in the earliest
           stages of AD

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Hanneke F.M. Rhodius-Meester, Hilkka Liedes, Juha Koikkalainen, Steffen Wolfsgruber, Nina Coll-Padros, Johannes Kornhuber, Oliver Peters, Frank Jessen, Luca Kleineidam, José Luis Molinuevo, Lorena Rami, Charlotte E. Teunissen, Frederik Barkhof, Sietske A.M. Sikkes, Linda M.P. Wesselman, Rosalinde E.R. Slot, Sander C.J. Verfaillie, Philip Scheltens, Betty M. Tijms, Jyrki LötjönenAbstractIntroductionIndividuals with subjective cognitive decline (SCD) are at increased risk for clinical progression. We studied how combining different diagnostic tests can help to identify individuals who are likely to show clinical progression.MethodsWe included 674 patients with SCD (46% female, 64 ± 9 years, Mini–Mental State Examination 28 ± 2) from three memory clinic cohorts. A multivariate model based on the Disease State Index classifier incorporated the available baseline tests to predict progression to MCI or dementia over time. We developed and internally validated the model in one cohort and externally validated it in the other cohorts.ResultsAfter 2.9 ± 2.0 years, 151(22%) patients showed clinical progression. Overall performance of the classifier when combining cognitive tests, magnetic resonance imagining, and cerebrospinal fluid showed a balanced accuracy of 74.0 ± 5.5, with high negative predictive value (93.3 ± 2.8).DiscussionWe found that a combination of diagnostic tests helps to identify individuals at risk of progression. The classifier had particularly good accuracy in identifying patients who remained stable.
  • A computerized, self-administered test of verbal episodic memory in
           elderly patients with mild cognitive impairment and healthy participants:
           A randomized, crossover, validation study

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Randall L. Morrison, Huiling Pei, Gerald Novak, Daniel I. Kaufer, Kathleen A. Welsh-Bohmer, Stephen Ruhmel, Vaibhav A. NarayanAbstractIntroductionPerformance of “Revere”, a novel iPad-administered word-list recall (WLR) test, in quantifying deficits in verbal episodic memory, was evaluated versus examiner-administered Rey Auditory Verbal Learning Test (RAVLT) in patients with mild cognitive impairment and cognitively normal participants.MethodsElderly patients with clinically diagnosed mild cognitive impairment (Montreal Cognitive Assessment score 24–27) and cognitively normal (Montreal Cognitive Assessment score ≥28) were administered RAVLT or Revere in a randomized crossover design.ResultsA total of 153/161 participants (Revere/RAVLT n = 75; RAVLT/Revere n = 78) were randomized; 148 (97%) completed study; 121 patients (mean [standard deviation] age: 70.4 [7.84] years) were included for analysis. Word-list recall scores (8 trials) were comparable between Revere and RAVLT (Pearson's correlation coefficients: 0.12–0.70; least square mean difference [Revere-RAVLT]: −0.84 [90% CI, −1.15; −0.54]). Model factor estimates indicated trial (P 
  • Neuropsychological comparison of incident MCI and prevalent MCI

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Allison Hansen, Richard J. Caselli, Gretchen Schlosser-Covell, Michael A. Golafshar, Amylou C. Dueck, Bryan K. Woodruff, Cynthia M. Stonnington, Yonas E. Geda, Dona E.C. LockeAbstractIntroductionLittle empirical work has been done to examine differences between mild cognitive impairment (MCI) diagnosed in research settings with longitudinal data (incident MCI) and MCI diagnosed in clinical settings (prevalent MCI). Because Alzheimer's disease progresses over a clinicopathological continuum, we examined the cognitive differences between these two different sources of MCI patients.MethodsWe compared 52 consecutively identified patients with prevalent amnestic MCI with 53 incident amnestic MCI participants from the Arizona APOE study. Neuropsychological data from common tests were compared encompassing four cognitive domains and one global indicator.ResultsPrevalent MCI cases performed significantly worse than incident MCI cases on global as well as domain-specific measures.DiscussionBy the time patients seek evaluation for memory loss, they have more severe single domain, amnestic MCI than research subjects with incident MCI. Studies of MCI should distinguish incident and prevalent not just single- and multiple-domain MCI.
  • Unsupervised online neuropsychological test performance for individuals
           with mild cognitive impairment and dementia: Results from the Brain Health

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): R. Scott Mackin, Philip S. Insel, Diana Truran, Shannon Finley, Derek Flenniken, Rachel Nosheny, Aaron Ulbright, Monica Comacho, David Bickford, Brian Harel, Paul Maruff, Michael W. WeinerAbstractIntroductionThe purpose of this study is to compare online neuropsychological test performance of older adults across self-reported diagnoses of being cognitively normal, mild cognitive impairment, and dementia due to Alzheimer's disease and to determine the association of memory concerns and family history of dementia on cognitive performance.MethodsParticipants completed the Cogstate Brief Battery unsupervised at home.ResultsData from 6463 participants over the age of 55 years were analyzed. Adults with the diagnosis of mild cognitive impairment and Alzheimer's disease were associated with poorer performance on all cognitive tests than cognitively normal adults (P 
  • Factor structure and measurement invariance of a neuropsychological test
           battery designed for assessment of cognitive functioning in older Mexican

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Brandon E. Gavett, Katie Stypulkowski, Leigh Johnson, James Hall, Sid E. O'BryantAbstractIntroductionThe present study sought to investigate the measurement invariance of commonly used neuropsychological tests in an ethnically (Hispanic vs. non-Hispanic) and linguistically (Spanish vs. English) diverse sample.MethodsParticipants were 736 middle-aged and older adults (MAge = 62.1, SD = 9.1) assessed at baseline. Measurement invariance testing was performed using multiple-group confirmatory factor analysis.ResultsA five-factor model (memory, attention/executive functioning/processing speed, language, visuospatial, and motor) fit the data well (CFI = 0.979, RMSEA = 0.047) and the composite reliability of the factors ranged from .76 (visuospatial) to .97 (motor). The five-factor model was found to possess strict measurement invariance for ethnicity and language without a decrement in fit compared to a strong (scalar) invariance model (ΔCFI = .000, ΔRMSEA = .002).DiscussionThese results indicate that a five-factor model is suitable for estimating cognitive functioning in Mexican Americans and non-Hispanic whites without bias by ethnicity or language.
  • The conceptual relevance of assessment measures in patients with
           mild/mild-moderate Alzheimer's disease

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Ann Hartry, Natalie V.J. Aldhouse, Tamara Al-Zubeidi, Myrlene Sanon, Richard G. Stefanacci, Sarah L. KnightAbstractIntroductionThis study aims to evaluate the conceptual relevance of four measures of disease activity in patients with mild/mild-moderate Alzheimer's disease (AD): (1) the Alzheimer's Disease Assessment Scale–Cognitive Subscale; (2) the Alzheimer's Disease Cooperative Study–Activities of Daily Living Inventory; (3) the Neuropsychiatry Inventory; and (4) the Dependence Scale.MethodsA conceptual model depicting patient experience of mild AD was developed via literature review; concepts were compared with the items of the four measures. Relevance of the concepts included in the four measures was evaluated by patients with mild AD in a survey and follow-up interviews.ResultsThe four measures assessed few of the symptoms/impacts of mild AD identified within the literature. Measured items addressing emotional impacts were deemed most relevant by participants but were included in the measures only superficially.DiscussionThe four assessment measures do not appear to capture the concepts most relevant to/important to patients with mild/mild-moderate AD.
  • Apraxia profiles—A single cognitive marker to discriminate all variants
           of frontotemporal lobar degeneration and Alzheimer's disease

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Andreas Johnen, Sophia Reul, Heinz Wiendl, Sven G. Meuth, Thomas DuningAbstractIntroductionApraxia is common in neurodegenerative dementias but underrepresented in clinical workup for differential diagnoses.MethodsPraxis-profiles were assessed with the Dementia Apraxia Test in 93 patients with early stages of biologically supported Alzheimer's disease or frontotemporal lobar degeneration: semantic primary-progressive aphasia, nonfluent primary-progressive aphasia, and behavioral variant frontotemporal dementia. Associations with core cognitive deficits of the dementia subtypes (i.e., visuospatial, sociocognitive, and semantic-linguistic) were explored.ResultsPatients showed significant apraxia compared with healthy controls but also disease-specific praxis-profiles. Using only the Dementia Apraxia Test, all four dementia subtypes could be correctly discriminated in 64.4% of cases, and in 78.2% when only distinguishing Alzheimer's disease versus frontotemporal lobar degeneration. Praxis-profiles showed consistent associations with core cognitive impairments of the different dementia subtypes.DiscussionThe Dementia Apraxia Test is a valid, time-efficient and versatile cognitive marker to delineate variants of frontotemporal lobar degeneration and Alzheimer's disease in clinical routine, facilitating differential diagnoses of dementia subtypes in early disease stages.
  • Understanding hallucinations in probable Alzheimer's disease: Very low
           prevalence rates in a tertiary memory clinic

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Mascha M.J. Linszen, Afina W. Lemstra, Meenakshi Dauwan, Rachel M. Brouwer, Philip Scheltens, Iris E.C. SommerAbstractIntroductionAveraging at 13.4%, current literature reports widely varying prevalence rates of hallucinations in patients with probable Alzheimer's disease (AD), and is still inconclusive on contributive factors to hallucinations in AD.MethodsThis study assessed prevalence, associated factors and clinical characteristics of hallucinations in 1227 patients with probable AD, derived from a tertiary memory clinic specialized in early diagnosis of dementia. Hallucinations were assessed with the Neuropsychiatric Inventory.ResultsHallucination prevalence was very low, with only 4.5% (n = 55/1227) affected patients. Hallucinations were mostly visual (n = 40/55) or auditory (n = 12/55). Comorbid delusions were present in over one-third of cases (n = 23/55).Hallucinations were associated with increased dementia severity, neuropsychiatric symptoms, and a lifetime history of hallucination-evoking disease (such as depression and sensory impairment), but not with age or gender.DiscussionIn the largest sample thus far, we report a low prevalence of hallucinations in probable AD patients, comparable to rates in non-demented elderly. Our results suggest that hallucinations are uncommon in early stage AD. Clinicians that encounter hallucinations in patients with early AD should be sensitive to hallucination-evoking comorbidity.
  • Computer-based evaluation of Alzheimer’s disease and mild cognitive
           impairment patients during a picture description task

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Laura Hernández-Domínguez, Sylvie Ratté, Gerardo Sierra-Martínez, Andrés Roche-BerguaAbstractIntroductionWe present a methodology to automatically evaluate the performance of patients during picture description tasks.MethodsTranscriptions and audio recordings of the Cookie Theft picture description task were used. With 25 healthy elderly control (HC) samples and an information coverage measure, we automatically generated a population-specific referent. We then assessed 517 transcriptions (257 Alzheimer's disease [AD], 217 HC, and 43 mild cognitively impaired samples) according to their informativeness and pertinence against this referent. We extracted linguistic and phonetic metrics which previous literature correlated to early-stage AD. We trained two learners to distinguish HCs from cognitively impaired individuals.ResultsOur measures significantly (P 
  • Computer simulations for assessing cognitively intensive instrumental
           activities of daily living in older adults

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Stephen R. Rapp, Ryan T. Barnard, Kaycee M. Sink, Dana G. Chamberlain, Valerie Wilson, Lingyi Lu, Edward H. IpAbstractIntroductionAim is to evaluate validity, reliability, diagnostic precision, and user acceptability of computer simulations of cognitively demanding tasks when administered to older adults with and without cognitive impairment.MethodsFive simulation modules were administered to 161 individuals aged ≥60 years with no cognitive impairment (N = 81), mild cognitive impairment (N = 52), or dementia (N = 28). Groups were compared on total accuracy and time to complete the tasks (seconds). Receiver operating characteristics were evaluated. Reliability was assessed over one month. Participants rated face validity and acceptability.ResultsTotal accuracy (P 
  • Improving the quality of cognitive screening assessments: ACEmobile, an
           iPad-based version of the Addenbrooke's Cognitive Examination-III

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Craig G.J. Newman, Adam D. Bevins, John P. Zajicek, John R. Hodges, Emil Vuillermoz, Jennifer M. Dickenson, Denise S. Kelly, Simona Brown, Rupert F. NoadAbstractIntroductionEnsuring reliable administration and reporting of cognitive screening tests are fundamental in establishing good clinical practice and research. This study captured the rate and type of errors in clinical practice, using the Addenbrooke's Cognitive Examination-III (ACE-III), and then the reduction in error rate using a computerized alternative, the ACEmobile app.MethodsIn study 1, we evaluated ACE-III assessments completed in National Health Service (NHS) clinics (n = 87) for administrator error. In study 2, ACEmobile and ACE-III were then evaluated for their ability to capture accurate measurement.ResultsIn study 1, 78% of clinically administered ACE-IIIs were either scored incorrectly or had arithmetical errors. In study 2, error rates seen in the ACE-III were reduced by 85%–93% using ACEmobile.DiscussionError rates are ubiquitous in routine clinical use of cognitive screening tests and the ACE-III. ACEmobile provides a framework for supporting reduced administration, scoring, and arithmetical error during cognitive screening.
  • Temporal unfolding of declining episodic memory on the Free and Cued
           Selective Reminding Test in the predementia phase of Alzheimer's disease:
           Implications for clinical trials

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Ellen Grober, Amy E. Veroff, Richard B. LiptonAbstractIntroductionFree and Cued Selective Reminding Test (FCSRT) performance identifies patients with preclinical disease at elevated risk for developing Alzheimer’s dementia, predicting diagnosis better than other memory tests.MethodsBased on literature mapping FCSRT performance to clinical outcomes and biological markers, and on longitudinal preclinical data from the Baltimore Longitudinal Study of Aging, we developed the Stages of Objective Memory Impairment (SOMI) model. Five sequential stages of episodic memory decline are defined by Free Recall (FR) and Total Recall (TR) score ranges and years prior to dementia diagnosis. We sought to replicate the SOMI model using longitudinal assessments of 142 Einstein Aging Study participants who developed AD over 10 years.ResultsAverage time to diagnosis was seven years if FR was intact, four years if TR was intact, and two years if TR was impaired, consistent with SOMI model predictions. The SOMI identified incipient dementia with excellent sensitivity and specificity.DiscussionThe SOMI model provides an efficient approach for clinical trial cognitive screening in advance of more costly biomarker studies and ultimately in clinical practice, and provides a vocabulary for understanding AD biomarker patterns and for re-analysis of existing clinical trial data.
  • A novel cognitive-functional composite measure to detect changes in early
           Alzheimer's disease: Test–retest reliability and feasibility

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Roos J. Jutten, John Harrison, Philippe R. Lee Meeuw Kjoe, Esther M. Opmeer, Niki S.M. Schoonenboom, Frank Jan de Jong, Craig W. Ritchie, Philip Scheltens, Sietske A.M. SikkesAbstractIntroductionTo improve the detection of changes in Alzheimer's disease (AD), we designed the cognitive-functional composite (CFC). As a first validation step, we investigated its test–retest reliability and feasibility of use.MethodsWe performed a test–retest study with 2–3 weeks between assessments, including patients with mild cognitive impairment (MCI) or mild AD dementia and cognitively healthy participants. We calculated intraclass correlation coefficients (ICCs) type absolute agreement for all CFC measures and compared baseline and retest scores using paired-samples t-tests. We evaluated feasibility by interviewing participants.ResultsForty-three patients (40% female, mean age = 69.9) and 30 controls (50% female, mean age = 65) were included. Subtest intraclass correlation coefficients ranged from .70 to .96. We found negligible improvements after retesting on only two subtests. Overall, patients perceived the administration of the CFC as feasible.DiscussionThe CFC is a stable and feasible measure in MCI and mild AD dementia, and thereby meets important quality metrics for clinically meaningful outcome measures.
  • The relationship between recall of recently versus remotely encoded famous
           faces and amyloidosis in clinically normal older adults

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Irina Orlovsky, Willem Huijbers, Bernard J. Hanseeuw, Elizabeth C. Mormino, Trey Hedden, Rachel F. Buckley, Molly LaPoint, Jennifer S. Rabin, Dorene M. Rentz, Keith A. Johnson, Reisa A. Sperling, Kathryn V. PappAbstractIntroductionAlzheimer's disease (AD) patients exhibit temporally graded memory loss with remote memories remaining more intact than recent memories. It is unclear whether this temporal pattern is observable in clinically normal adults with amyloid pathology (i.e. preclinical AD).MethodsParticipants were asked to recall the names of famous figures most prominent recently (famous after 1990) and remotely (famous from 1960–1980) and were provided with a phonemic cue to ensure that memory failure was not purely due to verbal retrieval weaknesses. In addition, participants identified line drawings of objects. Clinically normal older adults (n = 125) were identified as amyloid β positive or negative (Aβ+/−) using Pittsburgh compound B positron emission tomography. The relationship between Aβ+/− and recall of remote and recent famous face-names and objects was examined using repeated measures analyses and general linear models controlling for demographics and media usage.ResultsWhen provided with a phonemic cue, Aβ+ participants recalled the names of fewer recent famous faces compared with Aβ− participants. However, recall of remote famous face-names and objects did not differ by Aβ group.DiscussionRelative sparing of remotely learned information compared with recently learned information is (1) detectable in the preclinical stages of AD and (2) related to amyloid pathology. Both this temporal gradient and assessment of person-centered rather than object-centered semantic information may be particularly meaningful for tracking early memory changes in the AD trajectory.
  • Continuous measurement of object location memory is sensitive to effects
           of age and mild cognitive impairment and related to medial temporal lobe

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Benjamin M. Hampstead, Stephen Towler, Anthony Y. Stringer, Krishnankutty SathianAbstractIntroductionWe present findings of a novel and ecologically relevant associative memory test, the Object Location Touchscreen Test (OLTT), which was posited as sensitive to early medial temporal lobe compromise associated with mild cognitive impairment (MCI).MethodsA total of 114 participants, including healthy young and older controls and patients with MCI, completed the OLTT and standard neuropsychological testing. The OLTT required participants to recall the location of objects under free and cued recall conditions, with accuracy evaluated using distance measures (i.e., a continuous error score), and a standard recognition format. Correlations between performance and volumetric data were evaluated from a subset of 77 participants.ResultsSignificant age effects were dwarfed by MCI effects across all test conditions. OLTT Cued Recall was strongly and specifically related to the volume of disease-relevant medial temporal lobe regions, generally more than traditional memory tests.DiscussionThe OLTT may be sensitive to early structural compromise in regions affected by Alzheimer's disease.
  • Long-term impact of intensive lifestyle intervention on cognitive function
           assessed with the National Institutes of Health Toolbox: The Look AHEAD

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Kathleen M. Hayden, Laura D. Baker, George Bray, Raymond Carvajal, Kathryn Demos-McDermott, Andrea L. Hergenroeder, James O. Hill, Edward Horton, John M. Jakicic, Karen C. Johnson, Rebecca H. Neiberg, Stephen R. Rapp, Thomas A. Wadden, Michael E. Miller, Look AHEAD Movement and Memory and Look AHEAD Brain MRI Ancillary Study GroupsAbstractIntroductionThis study sought to determine whether 10 years of assignment to intensive lifestyle intervention (ILI) relative to diabetes support and education leads to better cognition. We examine intervention effects overall and among clinical subgroups, and report correlations between computer-administered and interviewer-administered cognitive batteries.MethodsThe Action for Health in Diabetes (Look AHEAD) was a 16-site randomized controlled trial with overweight/obese individuals (aged 45–76) who had type 2 diabetes. The NIH Toolbox Cognition Battery tests developed to measure cognition across the lifespan were used to evaluate cognition. Results were compared with standard paper-and-pencil tests. The Toolbox and paper-and-pencil tests were administered an average of 10.9 years after randomization to 1002 participants.ResultsToolbox measures significantly correlated with interviewer-administered measures, with the strongest correlations between the Toolbox Fluid Cognition Composite and Trails B (r = −0.64, P 
  • Analysis of macrolinguistic aspects of narratives from individuals with
           Alzheimer's disease, mild cognitive impairment, and no cognitive

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Cíntia Matsuda Toledo, Sandra Maria Aluísio, Leandro Borges dos Santos, Sonia Maria Dozzi Brucki, Eduardo Sturzeneker Trés, Maira Okada de Oliveira, Letícia Lessa MansurAbstractIntroductionThe depiction of features in discourse production promotes accurate diagnosis and helps to establish the therapeutic intervention in cognitive impairment and dementia. We aimed to identify alterations in the macrolinguistic aspects of discourse using a new computational tool.MethodsSixty individuals, aged 60 years and older, were distributed in three different groups: mild Alzheimer's disease (mAD), amnestic mild cognitive impairment, and healthy controls. A narrative created by individuals was analyzed through the Coh-Metrix-Dementia program, extracting the features of interest automatically.ResultsmAD showed worse overall performance compared to the other groups: less informative discourse, greater impairment in global coherence, greater modalization, and inferior narrative structure. It was not possible to discriminate between amnestic mild cognitive impairment and healthy controls.DiscussionOur results are in line with the literature, verifying a pathological change in the macrostructure of discourse in mAD.
  • Further education improves cognitive reserve and triggers improvement in
           selective cognitive functions in older adults: The Tasmanian Healthy Brain

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Megan E. Thow, Mathew J. Summers, Nichole L. Saunders, Jeffery J. Summers, Karen Ritchie, James C. VickersAbstractIntroductionThe strong link between early-life education and subsequent reduced risk of dementia suggests that education in later life could enhance cognitive function and may reduce age-related cognitive decline and protect against dementia.MethodsEpisodic memory, working memory, executive function, and language processing performances were assessed annually over 4 years in 359 healthy older adults who attended university for a minimum of 12 months (intervention) and were compared against 100 healthy adult controls.ResultsMultiple group latent growth curve modeling revealed a significant improvement in language processing capacity over time in the intervention group. No changes were detected for episodic memory, working memory, or executive function.DiscussionThese results suggest that complex mental stimulation resulting from late-life further education results in improved crystallized knowledge but no changes to fluid cognitive functions.
  • Temporospatial components of brain ERPs as biomarkers for Alzheimer's

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Robert M. Chapman, Margaret N. Gardner, Rafael Klorman, Mark Mapstone, Anton P. Porsteinsson, Inga M. Antonsdottir, Lily KamalyanAbstractIntroductionDeveloping biomarkers that distinguish individuals with Alzheimer's disease (AD) from those with normal cognition remains a crucial goal for improving the health of older adults. We investigated adding brain spatial information to temporal event-related potentials (ERPs) to increase AD identification accuracy over temporal ERPs alone.MethodsWith two-step principal components analysis, we applied multivariate analyses that incorporated temporal and spatial ERP information from a cognitive task. Discriminant analysis used temporospatial ERP scores to classify participants as belonging to either the AD or healthy control group.ResultsTemporospatial ERPs produced a cross-validated area under the curve of 0.84. Adding spatial information through a formal procedure significantly improves classification accuracy.DiscussionA weighted combination of temporospatial ERP markers performs well in detecting AD. Because ERPs are noninvasive and inexpensive, they may be promising biomarkers for AD that can add functional information to other biomarker systems while providing the individual's probability of correct classification.
  • Event-related potentials during sustained attention and memory tasks:
           Utility as biomarkers for mild cognitive impairment

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Shani Waninger, Chris Berka, Amir Meghdadi, Marija S. Karic, Kimberly Stevens, Cinthya Aguero, Tatiana Sitnikova, David H. Salat, Ajay VermaAbstractIntroductionThe objective of the study is to validate attention and memory tasks that elicit event-related potentials (ERPs) for utility as sensitive biomarkers for early dementia.MethodsA 3-choice vigilance task designed to evaluate sustained attention and standard image recognition memory task designed to evaluate attention, encoding, and image recognition memory were administered with concurrent electroencephalography acquisition to elicit ERPs in mild cognitive impairment (MCI) and healthy cohorts. ERPs were averaged, and mean or maximum amplitude of components was measured and compared between and within cohorts.ResultsThere was significant suppression of the amplitude of the late positive potential in the MCI cohort compared with the healthy controls during 3-choice vigilance task, predominantly over occipital and right temporal-parietal region, and standard image recognition memory task over all regions. During standard image recognition memory task, diminished performance showed strong correlation with electroencephalography measurements. The old/new effects observed in the healthy controls cohort correlated with performance and were lost in MCI.DiscussionERPs obtained during cognitive tasks may provide a powerful tool for assessing MCI and have strong potential as sensitive and robust biomarkers for tracking disease progression and evaluating response to investigative therapeutics.
  • Genetically elevated high-density lipoprotein cholesterol through the
           cholesteryl ester transfer protein gene does not associate with risk of
           Alzheimer's disease

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Gina M. Peloso, Sven J. van der Lee, R. Sims, S.J. van der Lee, A.C. Naj, C. Bellenguez, N. Badarinarayan, J. Jakobsdottir, B.W. Kunkle, A. Boland, R. Raybould, J.C. Bis, E.R. Martin, B. Grenier-Boley, S. Heilmann-Heimbach, V. Chouraki, A.B. Kuzma, K. Sleegers, M. Vronskaya, A. RuizAbstractIntroductionThere is conflicting evidence whether high-density lipoprotein cholesterol (HDL-C) is a risk factor for Alzheimer's disease (AD) and dementia. Genetic variation in the cholesteryl ester transfer protein (CETP) locus is associated with altered HDL-C. We aimed to assess AD risk by genetically predicted HDL-C.MethodsTen single nucleotide polymorphisms within the CETP locus predicting HDL-C were applied to the International Genomics of Alzheimer's Project (IGAP) exome chip stage 1 results in up 16,097 late onset AD cases and 18,077 cognitively normal elderly controls. We performed instrumental variables analysis using inverse variance weighting, weighted median, and MR-Egger.ResultsBased on 10 single nucleotide polymorphisms distinctly predicting HDL-C in the CETP locus, we found that HDL-C was not associated with risk of AD (P > .7).DiscussionOur study does not support the role of HDL-C on risk of AD through HDL-C altered by CETP. This study does not rule out other mechanisms by which HDL-C affects risk of AD.
  • Apolipoproteins and Alzheimer's pathophysiology

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Manja Koch, Steven T. DeKosky, Annette L. Fitzpatrick, Jeremy D. Furtado, Oscar L. Lopez, Lewis H. Kuller, Rachel H. Mackey, Timothy M. Hughes, Kenneth J. Mukamal, Majken K. JensenAbstractIntroductionApolipoproteins of demonstrated importance to brain cholesterol and ß-amyloid metabolism may serve as novel risk markers for Alzheimer's pathology.MethodsWe measured apolipoproteins (apoE, apoJ, apoA-I, and apoC-III and their uniquely defined subspecies) by enzyme-linked immunosorbent assay in plasma collected in 2000 and 2008 from 176 dementia-free participants of the Ginkgo Evaluation of Memory Study and related these to ß-amyloid on positron emission tomography scans, hippocampal volume, and white matter lesion volume in 2009.ResultsHigher apoE was associated with lower ß-amyloid deposition. Despite apoA-I being unrelated to hippocampal volume, subspecies of apoA-I containing or lacking apoJ or apoC-III showed opposite associations with hippocampal volume. Higher apoJ and apoE lacking apoJ were associated with higher hippocampal volume and higher white matter lesion volume, respectively. Associations were similar in participants without cognitive impairment or APOE ε4 noncarrier and when analyzing apolipoproteins in 2000–2002.DiscussionApolipoproteins may be important minimally invasive biomarkers indicative of Alzheimer's pathology.
  • A novel detection method of cleaved plasma high-molecular-weight kininogen
           reveals its correlation with Alzheimer's pathology and cognitive

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Hitomi Yamamoto-Imoto, Daria Zamolodchikov, Zu-Lin Chen, S. Lloyd Bourne, Syeda Rizvi, Pradeep Singh, Erin H. Norris, Frances Weis-Garcia, Sidney StricklandAbstractIntroductionAccumulation of β-amyloid is a pathological hallmark of Alzheimer's disease (AD). β-Amyloid activates the plasma contact system leading to kallikrein-mediated cleavage of intact high-molecular-weight kininogen (HKi) to cleaved high-molecular-weight kininogen (HKc). Increased HKi cleavage is observed in plasma of AD patients and mouse models by Western blot. For potential diagnostic purposes, a more quantitative method that can measure HKc levels in plasma with high sensitivity and specificity is needed.MethodsHKi/c, HKi, and HKc monoclonal antibodies were screened from hybridomas using direct ELISA with a fluorescent substrate.ResultsWe generated monoclonal antibodies recognizing HKi or HKc specifically and developed sandwich ELISAs that can quantitatively detect HKi and HKc levels in human. These new assays show that decreased HKi and increased HKc levels in AD plasma correlate with dementia and neuritic plaque scores.DiscussionHigh levels of plasma HKc could be used as an innovative biomarker for AD.
  • Stability of blood-based biomarkers of Alzheimer's disease over multiple
           freeze-thaw cycles

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Ashvini Keshavan, Amanda Heslegrave, Henrik Zetterberg, Jonathan M. SchottAbstractIntroductionFreeze-thaw instability may contribute to preanalytical variation in blood-based biomarker studies. We investigated the effects of up to four freeze-thaw cycles on single molecule array immunoassays of serum neurofilament light chain and plasma total tau, amyloid β 1–40 (Aß40), and Aβ 1–42 (Aβ42).MethodsIndividuals who had peripheral venepuncture during investigation of suspected neurodegenerative disease were recruited. After standardized preprocessing, 200 μL of plasma and serum aliquots were stored at −80°C within 60 minutes. Aliquots underwent one to four freeze-thaw cycles.ResultsThere was no significant difference across four freeze-thaw cycles for serum neurofilament light chain (n = 12), plasma total tau (n = 11), or plasma Aβ42 (n = 12). For plasma Aβ40 (n = 14), there were significant median reductions by ratios of .96 and .92 at the third and fourth cycles, respectively.DiscussionUp to four freeze-thaw cycles do not influence single molecule array blood biomarkers of neurofilament light chain, total tau, or Aβ42, with at most minor reductions in Aβ40.
  • Cerebrospinal fluid and serum MHPG improve Alzheimer's disease versus
           dementia with Lewy bodies differential diagnosis

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Jana Janssens, Yannick Vermeiren, Erik Fransen, Tony Aerts, Debby Van Dam, Sebastiaan Engelborghs, Peter P. De DeynAbstractIntroductionGiven the challenges concerning the differential diagnosis of dementia, we investigated the possible added value of monoaminergic compounds to the standard cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers. Particularly, regarding the AD versus dementia with Lewy bodies (DLB) comparison, monoamines or their metabolites might have added discriminative value as there is a more severe neuropathological burden in the locus coeruleus of DLB patients, the principal site of noradrenaline synthesis.MethodsWe applied enzyme-linked immunosorbent assay (ELISA) to analyze CSF amyloid β peptide of 42 amino acids, total tau, and tau phosphorylated at threonine 181, in patients with AD, frontotemporal dementia, DLB/Parkinson's disease dementia, and controls. Reversed-phase high-performance liquid chromatography with electrochemical detection was implemented to study monoamine and metabolite levels in CSF and serum. Stepwise forward conditional logistic regression and receiver operating characteristic (ROC) curve analyses were performed to assess the diagnostic accuracy of these newly fitted models containing the most discriminative indicators of disease status.ResultsMost significant differences in CSF and serum were confined to the noradrenergic system. More specifically, CSF 3-methoxy-4-hydroxyphenylglycol (MHPG) levels were higher, whereas serum MHPG levels were lower, in DLB patients compared with all other groups. Addition of CSF and serum MHPG levels to the CSF AD biomarker panel significantly increased diagnostic accuracy between DLB/Parkinson's disease dementia and AD. Interestingly, a model only including CSF and serum MHPG without the classic AD biomarker panel reached similar area under the curve values.DiscussionWe hypothesize that varying degrees of neuronal loss in the locus coeruleus of DLB/Parkinson's disease dementia versus AD patients result in differentially altered MHPG levels, making this metabolite a valuable biomarker.
  • Retinal oxygen metabolism in patients with mild cognitive impairment

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Olof Birna Olafsdottir, Hrafnhildur Sif Saevarsdottir, Sveinn Hakon Hardarson, Kristin Hanna Hannesdottir, Valgerdur Dora Traustadottir, Robert Arnar Karlsson, Anna Bryndis Einarsdottir, Katrin Dilja Jonsdottir, Einar Stefansson, Jon SnaedalAbstractIntroductionWe have previously reported that retinal vessel oxygen saturation is increased in mild-to-moderate dementia of Alzheimer's type when compared with healthy individuals. Mild cognitive impairment (MCI) is the predementia stage of the disease. The main purpose was to investigate if these changes are seen in MCI.MethodsRetinal vessel oxygen saturation was measured in 42 patients with MCI and 42 healthy individuals with a noninvasive retinal oximeter, Oxymap T1. The groups were paired according to age.ResultsArteriolar and venular oxygen saturation was increased in MCI patients compared to healthy individuals (arterioles: 93.1 ± 3.7% vs. 91.1 ± 3.4%, P = .01; venules: 59.6 ± 6.1% vs. 54.9 ± 6.4%, P = .001). Arteriovenous difference was decreased in MCI compared to healthy individuals (33.5 ± 4.5% vs. 36.2 ± 5.2%, P = .01).DiscussionIncreased retinal vessel oxygen saturation and decreased arteriovenous difference in MCI could reflect less oxygen extraction by retinal tissue. This indicates that retinal oxygen metabolism may be affected in patients with MCI.
  • Change in retinal structural anatomy during the preclinical stage of
           Alzheimer's disease

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Cláudia Y. Santos, Lenworth N. Johnson, Stuart E. Sinoff, Elena K. Festa, William C. Heindel, Peter J. SnyderAbstractIntroductionWe conducted a 27-month longitudinal study of mid-life adults with preclinical Alzheimer's disease (AD), using spectral domain optical coherence tomography to compare changes in volume and thickness in all retinal neuronal layers to those of age-matched healthy control subjects.MethodsFifty-six older adults (mean age = 65.36 years) with multiple risk factors for AD completed spectral domain optical coherence tomography retinal imaging and cognitive testing at baseline. Twenty-seven months later, they completed the same examinations and an 18F-florbetapir positron emission tomography imaging study.ResultsCompared to healthy control subjects, those in the preclinical stage of AD showed a significant decrease in macular retinal nerve fiber layer (mRNFL) volume, over a 27-month follow-up interval period, as well as a decrease in outer nuclear layer and inner plexiform layer volumes and thickness in the inferior quadrant. However, only the mRNFL volume was linearly related to neocortical positron emission tomography amyloid standardized uptake value ratio after controlling for any main effects of age (R2 = 0.103; ρ = 0.017). Furthermore, the magnitude of mRNFL volume reduction was significantly correlated with performance on a task of participants' abilities to efficiently integrate visual and auditory speech information (McGurk effect).DiscussionWe observed a decrease in mRNFL, outer nuclear layer, and inner plexiform layer volumes, in preclinical AD relative to controls. Moreover, the largely myelinated axonal loss in the RNFL is related to increased neocortical amyloid-β accumulation after controlling for age. Volume loss in the RNFL, during the preclinical stage, is not related to performance on measures of episodic memory or problem solving. However, this retinal change does appear to be modestly related to relative decrements in performance on a measure of audiovisual integration efficiency that has been recently advanced as a possible early cognitive marker of mild cognitive impairment.
  • Retinal thickness correlates with parietal cortical atrophy in early-onset
           Alzheimer's disease and controls

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Jurre den Haan, Sarah F. Janssen, Jacoba A. van de Kreeke, Philip Scheltens, Frank D. Verbraak, Femke H. BouwmanAbstractIntroductionThe retina may reflect Alzheimer's disease (AD) neuropathological changes and is easily visualized with optical coherence tomography (OCT). Retinal thickness decrease has been correlated to AD, however, without information on amyloid status. We correlated retinal (layer) thickness to AD biomarkers in amyloid-positive early-onset AD (EOAD) patients and amyloid-negative controls.MethodsWe measured macular thickness and peripapillary retinal nerve fiber layer thickness with OCT in 15 EOAD patients and 15 controls and correlated retinal thickness to visual rating scores for atrophy on magnetic resonance imaging.ResultsTotal macular thickness correlated to parietal cortical atrophy in both groups (Spearman ρ −0.603, P = .001). Macular and peripapillary retinal nerve fiber layer thicknesses were not significantly decreased in EOAD compared to controls.DiscussionRetinal thickness does not discriminate EOAD from controls but is correlated to parietal cortical atrophy in both groups. These findings may suggest reflection of cerebral cortical changes in the retina, independent of amyloid.
  • CSF total tau levels are associated with hippocampal novelty irrespective
           of hippocampal volume

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Emrah Düzel, David Berron, Hartmut Schütze, Arturo Cardenas-Blanco, Coraline Metzger, Matthew Betts, Gabriel Ziegler, Yi Chen, Laura Dobisch, Daniel Bittner, Wenzel Glanz, Martin Reuter, Annika Spottke, Janna Rudolph, Frederic Brosseron, Katharina Buerger, Daniel Janowitz, Klaus Fliessbach, Michael Heneka, Christoph LaskeAbstractIntroductionWe examined the association between cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease, neural novelty responses, and brain volume in predementia old age.MethodsWe conducted a cross-sectional analysis of the observational, multicentric DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE) study. Seventy-six participants completed task functional magnetic resonance imaging and provided CSF (40 cognitively unimpaired, 21 experiencing subjective cognitive decline, and 15 with mild cognitive impairment). We assessed the correlation between CSF biomarkers and whole-brain functional magnetic resonance imaging novelty responses to scene images.ResultsTotal tau levels were specifically and negatively associated with novelty responses in the right amygdala and right hippocampus. Mediation analyses showed no evidence that these associations were dependent on the volume of hippocampus/amygdala. No relationship was found between phosphorylated-tau or Aβ42 levels and novelty responses.DiscussionOur data show that CSF levels of total tau are associated with anatomically specific reductions in novelty processing, which cannot be fully explained by atrophy.
  • Derivation of cutoffs for the Elecsys® amyloid β (1–42) assay in
           Alzheimer's disease

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Leslie M. Shaw, Teresa Waligorska, Leona Fields, Magdalena Korecka, Michal Figurski, John Q. Trojanowski, Udo Eichenlaub, Simone Wahl, Marian Quan, Michael J. Pontecorvo, D. Richard Lachno, Jayne A. Talbot, Scott W. Andersen, Eric R. Siemers, Robert A. DeanAbstractIntroductionAn Elecsys® Amyloid β (Aβ [1–42]) immunoassay cutoff for classification of patients with Alzheimer's disease was investigated.MethodsCerebrospinal fluid samples collected from patients with mild-to-moderate Alzheimer's disease were analyzed by Elecsys® immunoassays: (1) Aβ (1–42), (2) total tau, and (3) phosphorylated tau. Cutoffs (Aβ [1–42] and ratios with tau) were estimated by method comparison between AlzBio3 (n = 206), mixture modeling (n = 216), and concordance with florbetapir F 18 imaging-based classification (n = 75).ResultsA 1065-pg/mL (95% confidence interval: 985–1153) Elecsys® Aβ (1–42) cutoff provided 94% overall percentage agreement with AlzBio3. Comparable cutoff estimates (95% confidence interval) were derived from mixture modeling (equally weighted: 1017 [949–1205] pg/mL; prevalence weighted: 1172 [1081–1344] pg/mL) and concordance with florbetapir F 18 imaging (visual read: 1198 [998–1591] pg/mL; automated: 1198 [1051–1638] pg/mL).DiscussionBased on three approaches, a 1100-pg/mL Elecsys® Aβ (1–42) cutoff is suitable for clinical trials with similar populations and preanalytical handling.
  • Diagnostic performance of Elecsys immunoassays for cerebrospinal fluid
           Alzheimer's disease biomarkers in a nonacademic, multicenter memory clinic
           cohort: The ABIDE project

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Eline A.J. Willemse, Ingrid S. van Maurik, Betty M. Tijms, Femke H. Bouwman, Andreas Franke, Isabelle Hubeek, Leo Boelaarts, Jules J. Claus, Esther S.C. Korf, Rob J. van Marum, Gerwin Roks, Niki Schoonenboom, Nicolaas Verwey, Marissa D. Zwan, Simone Wahl, Wiesje M. van der Flier, Charlotte E. TeunissenAbstractIntroductionWe compared the automated Elecsys and manual Innotest immunoassays for cerebrospinal fluid (CSF) Alzheimer's disease biomarkers in a multicenter diagnostic setting.MethodsWe collected CSF samples from 137 participants in eight local memory clinics. Amyloid β(1–42) (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau) were centrally analyzed with Innotest and Elecsys assays. Concordances between methods were assessed.ResultsBiomarker results strongly correlated between assays with Spearman's ρ 0.94 for Aβ42, 0.98 for t-tau, and 0.98 for p-tau. Using Gaussian mixture modeling, cohort-specific cut-points were estimated at 1092 pg/mL for Aβ42, 235 pg/mL for t-tau, and 24 pg/mL for p-tau. We found an excellent concordance of biomarker abnormality between assays of 97% for Aβ42 and 96% for both t-tau and p-tau.DiscussionThe high concordances between Elecsys and Innotest in this nonacademic, multicenter cohort support the use of Elecsys for CSF Alzheimer's disease diagnostics and allow conversion of results between methods.
  • Interlaboratory validation of cerebrospinal fluid α-synuclein
           quantification in the diagnosis of sporadic Creutzfeldt-Jakob disease

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Niels Kruse, Amanda Heslegrave, Vandana Gupta, Martha Foiani, Anna Villar-Piqué, Matthias Schmitz, Sylvain Lehmann, Charlotte Teunissen, Kaj Blennow, Henrik Zetterberg, Brit Mollenhauer, Inga Zerr, Franc LlorensAbstractIntroductionCerebrospinal fluid α-synuclein level is increased in sporadic Creutzfeldt-Jakob disease cases. However, the clinical value of this biomarker remains to be established. In this study, we have addressed the clinical validation parameters and the interlaboratory reproducibility by using an electrochemiluminescent assay.MethodsCerebrospinal fluid α-synuclein was quantified in a total of 188 sporadic Creutzfeldt-Jakob disease and non–Creutzfeldt-Jakob-disease cases to determine sensitivity and specificity values and lot-to-lot variability. Two round robin tests with 70 additional cases were performed in six independent laboratories.ResultsA sensitivity of 93% and a specificity of 96% were achieved in discriminating sporadic Creutzfeldt-Jakob disease. No differences were detected between lots. The mean interlaboratory coefficient of variation was 23%, and the intralaboratory coefficient of variations ranged 2.70%–11.39%. Overall, 97% of samples were correctly diagnosed.DiscussionThe herein validated α-synuclein assay is robust, accurate, and reproducible in identifying Creutzfeldt-Jakob disease cases. Thus, it is ready for implementation in the clinical practice to support the diagnosis of Creutzfeldt-Jakob disease.
  • Amyloid β peptides are differentially vulnerable to preanalytical surface
           exposure, an effect incompletely mitigated by the use of ratios

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Jamie Toombs, Martha S. Foiani, Henrietta Wellington, Ross W. Paterson, Charles Arber, Amanda Heslegrave, Michael P. Lunn, Jonathan M. Schott, Selina Wray, Henrik ZetterbergAbstractIntroductionWe tested the hypothesis that the amyloid β (Aβ) peptide ratios are more stable than Aβ42 alone when biofluids are exposed to two preanalytical conditions known to modify measurable Aβ concentration.MethodsHuman cerebrospinal fluid (CSF) and culture media (CM) from human cortical neurons were exposed to a series of volumes and polypropylene surfaces. Aβ42, Aβ40, and Aβ38 peptide concentrations were measured using a multiplexed electrochemiluminescence immunoassay. Data were analyzed using mixed models in R.ResultsDecrease of measurable Aβ peptide concentrations was exaggerated in longer peptides, affecting the Aβ42:Aβ40 and Aβ42:Aβ38 ratios. However, the effect size of surface treatment was reduced in Aβ peptide ratios versus Aβ42 alone. For Aβ42:Aβ40, the effect was reduced by approximately 50% (volume) and 75% (transfer) as compared to Aβ42 alone.DiscussionUse of Aβ ratios, in conjunction with concentrations, may mitigate confounding factors and assist the clinical diagnostic process for Alzheimer's disease.
  • Monoaminergic impairment in Down syndrome with Alzheimer's disease
           compared to early-onset Alzheimer's disease

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Alain D. Dekker, Yannick Vermeiren, Maria Carmona-Iragui, Bessy Benejam, Laura Videla, Ellen Gelpi, Tony Aerts, Debby Van Dam, Susana Fernández, Alberto Lleó, Sebastian Videla, Anne Sieben, Jean-Jacques Martin, Netherlands Brain Bank, Rafael Blesa, Juan Fortea, Peter P. De DeynAbstractIntroductionPeople with Down syndrome (DS) are at high risk for Alzheimer's disease (AD). Defects in monoamine neurotransmitter systems are implicated in DS and AD but have not been comprehensively studied in DS.MethodsNoradrenaline, adrenaline, and their metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG); dopamine and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid; and serotonin and its metabolite 5-hydroxyindoleacetic acid were quantified in 15 brain regions of DS without AD (DS, n = 4), DS with AD (DS+AD, n = 17), early-onset AD (EOAD, n = 11) patients, and healthy non-DS controls (n = 10) in the general population. Moreover, monoaminergic concentrations were determined in cerebrospinal fluid (CSF)/plasma samples of DS (n = 37/149), DS with prodromal AD (DS+pAD, n = 13/36), and DS+AD (n = 18/40).ResultsIn brain, noradrenergic and serotonergic compounds were overall reduced in DS+AD versus EOAD, while the dopaminergic system showed a bidirectional change. For DS versus non-DS controls, significantly decreased MHPG levels were noted in various brain regions, though to a lesser extent than for DS+AD versus EOAD. Apart from DOPAC, CSF/plasma concentrations were not altered between groups.DiscussionMonoamine neurotransmitters and metabolites were evidently impacted in DS, DS+AD, and EOAD. DS and DS+AD presented a remarkably similar monoaminergic profile, possibly related to early deposition of amyloid pathology in DS. To confirm whether monoaminergic alterations are indeed due to early amyloid β accumulation, future avenues include positron emission tomography studies of monoaminergic neurotransmission in relation to amyloid deposition, as well as relating monoaminergic concentrations to CSF/plasma levels of amyloid β and tau within individuals.
  • Type 2 diabetes mellitus and cerebrospinal fluid Alzheimer's disease
           biomarker amyloid β1-42 in Alzheimer's Disease Neuroimaging Initiative

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Wei Li, Shannon L. Risacher, Sujuan Gao, Stephen L. Boehm, Jeffrey S. Elmendorf, Andrew J. Saykin, Alzheimer's Disease Neuroimaging InitiativeAbstractIntroductionType 2 diabetes mellitus (T2DM) is a risk factor for Alzheimer's disease. Cerebrospinal fluid (CSF) amyloid β (Aβ) 1-42 is an important Alzheimer's disease biomarker. However, it is inconclusive on how T2DM is related to CSF Aβ1-42.MethodsParticipants with T2DM were selected from the Alzheimer's Disease Neuroimaging Initiative by searching keywords from the medical history database. A two-way analysis of covariance model was used to analyze how T2DM associates with CSF Aβ1-42 or cerebral cortical Aβ.ResultsCSF Aβ1-42 was higher in the T2DM group than the nondiabetic group. The inverse relation between CSF Aβ1-42 and cerebral cortical Aβ was independent of T2DM status. Participants with T2DM had a lower cerebral cortical Aβ in anterior cingulate, precuneus, and temporal lobe than controls.DiscussionT2DM is positively associated with CSF Aβ1-42 but negatively with cerebral cortical Aβ. The decreased cerebral cortical Aβ associated with T2DM is preferentially located in certain brain regions.
  • The personalized Alzheimer's disease cortical thickness index predicts
           likely pathology and clinical progression in mild cognitive impairment

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Annie M. Racine, Michael Brickhouse, David A. Wolk, Bradford C. Dickerson, Alzheimer's Disease Neuroimaging InitiativeAbstractIntroductionAn Alzheimer's disease (AD) biomarker adjusted for age-related brain changes should improve specificity for AD-related pathological burden.MethodsWe calculated a brain-age-adjusted “personalized AD cortical thickness index” (pADi) in mild cognitive impairment patients from the Alzheimer's Disease Neuroimaging Initiative. We performed receiver operating characteristic analysis for discrimination between patients with and without cerebrospinal fluid evidence of AD and logistic regression in an independent sample to determine if a dichotomized pADi predicted conversion to AD dementia.ResultsReceiver operating characteristic area under the curve was 0.69 and 0.72 in the two samples. Three empirical methods identified the same cut-point for pADi in the discovery sample. In the validation sample, 83% of pADi+ mild cognitive impairment patients were cerebrospinal fluid AD biomarker positive. pADi+ mild cognitive impairment patients (n = 63, 38%) were more likely to progress to AD dementia after 1 (odds ratio = 2.9) and 3 (odds ratio = 2.6) years.DiscussionThe pADi is a personalized, magnetic resonance imaging–derived AD biomarker that predicts progression to dementia.
  • Advances in Alzheimer's imaging are changing the experience of Alzheimer's

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Shana D. Stites, Richard Milne, Jason KarlawishAbstractNeuroimaging is advancing a new definition of Alzheimer's disease (AD). Using imaging biomarkers, clinicians may begin to diagnose the disease by identifying pathology and neurodegeneration in either cognitively impaired or unimpaired adults. This “biomarker-based” diagnosis may allow clinicians novel opportunities to use interventions that either delay the onset or slow the progression of cognitive decline, but it will also bring novel challenges. How will changing the definition of AD from a clinical to a biomarker construct change the experience of living with the disease' Knowledge of AD biomarker status can affect how individuals feel about themselves (internalized stigma) and how others judge them (public stigma). Following a review of AD stigma, we appraise how advances in diagnosis may enable or interrupt its transfer from clinical to preclinical stages and then explore conceptual and pragmatic challenges to addressing stigma in routine care.
  • Regional tract-specific white matter hyperintensities are associated
           with patterns of aging-related brain atrophy via vascular risk factors,
           but also independently

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Mohamad Habes, Guray Erus, Jon B. Toledo, Nick Bryan, Deborah Janowitz, Jimit Doshi, Henry Völzke, Ulf Schminke, Wolfgang Hoffmann, Hans J. Grabe, David A. Wolk, Christos DavatzikosAbstractIntroductionWe sought to investigate associations of regional white matter hyperintensities (WMHs) within white matter (WM) tracts with cardiovascular risk and brain aging-related atrophy throughout adulthood in the general population, leveraging state of the art pattern analysis methods.MethodsWe analyzed a large sample (n = 2367) from the Study of Health in Pomerania, Germany (range 20–90 years). WMHs were automatically segmented on T1-weighted and fluid-attenuated inversion recovery magnetic resonance images, and WMH volumes were calculated in WM regions defined using the John Hopkins University WM tractography atlas. Regions with the highest average WMH volume were selected. We calculated a subject-specific index, Spatial Pattern of Alteration for Recognition of Brain Aging, to measure age-related atrophy patterns. The Framingham cardiovascular disease risk score summarized the individual cardiovascular risk profile. We used structural equation models, independently for each region, using Spatial Pattern of Alteration for Recognition of Brain Aging as a dependent variable, age as an independent variable, and cardiovascular disease risk score and regional WMH volumes as mediators.ResultsSelected 12 WM regions included 75% of the total WMH burden in average. Structural equation models showed that the age effect on Spatial Pattern of Alteration for Recognition of Brain Aging was mediated by WMHs to a different extent in the superior frontal WM, anterior corona radiata, inferior frontal WM, superior corona radiata, superior longitudinal fasciculus, middle temporal WM, posterior corona radiata, superior parietal WM, splenium of corpus callosum, posterior thalamic radiation, and middle occipital WM (variance explained between 2.8% and 10.3%, P 
  • Neuropsychology and neuroimaging profiles of amyloid-positive versus
           amyloid-negative amnestic mild cognitive impairment patients

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Clémence Tomadesso, Vincent de La Sayette, Robin de Flores, Pierrick Bourgeat, Victor L. Villemagne, Stéphanie Egret, Francis Eustache, Gaël ChételatAbstractIntroductionPatients with amnestic mild cognitive impairment (aMCI) are heterogeneous as regard to their amyloid status. The present study aimed at highlighting the neuropsychological, brain atrophy, and hypometabolism profiles of amyloid-positive (Aβpos) versus amyloid-negative (Aβneg) aMCI patients.MethodsForty-four aMCI patients and 24 Aβneg healthy controls underwent neuropsychological, structural magnetic resonance imaging and 18F-fluorodeoxyglucose positron emission tomography scans. Data were compared between groups in specific regions of interest and voxelwise with statistical parametric mapping.ResultsWhen directly comparing Aβpos to Aβneg aMCI, the former had lower performances in episodic memory tests (P = .02 to P 
  • Similar pattern of atrophy in early- and late-onset Alzheimer's disease

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Carl Eckerström, Niklas Klasson, Erik Olsson, Per Selnes, Sindre Rolstad, Anders WallinAbstractIntroductionPrevious research on structural changes in early-onset Alzheimer's disease (EOAD) and late-onset Alzheimer's disease (LOAD) have reported inconsistent findings.MethodsIn the present substudy of the Gothenburg MCI study, 1.5 T scans were used to estimate lobar and hippocampal volumes using FreeSurfer. Study participants (N = 145) included 63 patients with AD, (24 patients with EOAD [aged ≤65 years], 39 patients with LOAD [aged>65 years]), 25 healthy controls aged ≤65 years, and 57 healthy controls aged>65 years.ResultsHippocampal atrophy is the most prominent feature of both EOAD and LOAD compared with controls. Direct comparison between EOAD and LOAD showed that the differences between the groups did not remain after correcting for age.DiscussionStructurally, EOAD and LOAD does not seem to be different nosological entities. The difference in brain volumes between the groups compared with controls is likely due to age-related atrophy.
  • Cross-sectional and longitudinal atrophy is preferentially associated with
           tau rather than amyloid β positron emission tomography pathology

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Brian A. Gordon, Austin McCullough, Shruti Mishra, Tyler M. Blazey, Yi Su, John Christensen, Aylin Dincer, Kelley Jackson, Russ C. Hornbeck, John C. Morris, Beau M. Ances, Tammie L.S. BenzingerAbstractIntroductionStructural magnetic resonance imaging is a marker of gray matter health and decline that is sensitive to impaired cognition and Alzheimer's disease pathology. Prior work has shown that both amyloid β (Aβ) and tau biomarkers are related to cortical thinning, but it is unclear what unique influences they have on the brain.MethodsAβ pathology was measured with [18F] AV-45 (florbetapir) positron emission tomography (PET) and tau was assessed with [18F] AV-1451 (flortaucipir) PET in a population of 178 older adults, of which 123 had longitudinal magnetic resonance imaging assessments (average of 5.7 years) that preceded the PET acquisitions.ResultsIn cross-sectional analyses, greater tau PET pathology was associated with thinner cortices. When examined independently in longitudinal models, both Aβ and tau were associated with greater antecedent loss of gray matter. However, when examined in a combined model, levels of tau, but not Aβ, were still highly related to change in cortical thickness.DiscussionMeasures of tau PET are strongly related to gray matter atrophy and likely mediate relationships between Aβ and gray matter.
  • Tau positron emission tomography imaging in tauopathies: The added hurdle
           of off-target binding

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Laetitia Lemoine, Antoine Leuzy, Konstantinos Chiotis, Elena Rodriguez-Vieitez, Agneta NordbergAbstractLigands targeting tau for use with positron emission tomography have rapidly been developed during the past several years, enabling the in vivo study of tau pathology in patients with Alzheimer's disease and related non-Alzheimer's disease tauopathies. Several candidate compounds have been developed, showing good in vitro characteristics with respect to their ability to bind tau deposits; off-target binding, however, has also been observed. In this short commentary, we briefly summarize the available in vivo and in vitro evidence pertaining to their off-target binding and discuss the different approaches that are needed for the future development of tau positron emission tomography tracers.
  • Topographic staging of tau positron emission tomography images

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Adam J. Schwarz, Sergey Shcherbinin, Lawrence J. Slieker, Shannon L. Risacher, Arnaud Charil, Michael C. Irizarry, Adam S. Fleisher, Sudeepti Southekal, Abhinay D. Joshi, Michael D. Devous, Bradley B. Miller, Andrew J. Saykin, Alzheimer's Disease Neuroimaging InitiativeAbstractIntroductionIt has been proposed that the signal distribution on tau positron emission tomography (PET) images could be used to define pathologic stages similar to those seen in neuropathology.MethodsThree topographic staging schemes for tau PET, two sampling the temporal and occipital subregions only and one sampling cortical gray matter across the major brain lobes, were evaluated on flortaucipir F 18 PET images in a test-retest scenario and from Alzheimer's Disease Neuroimaging Initiative 2.ResultsAll three schemes estimated stages that were significantly associated with amyloid status and when dichotomized to tau positive or negative were 90% to 94% concordant in the populations identified. However, the schemes with fewer regions and simpler decision rules yielded more robust performance in terms of fewer unclassified scans and increased test-retest reproducibility of assigned stage.DiscussionTau PET staging schemes could be useful tools to concisely index the regional involvement of tau pathology in living subjects. Simpler schemes may be more robust.
  • Molecular imaging: What is right and what is an illusion'

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): William E. KlunkAbstractOver the past 40 years, brain molecular imaging has evolved from measuring cerebral metabolism with fluorodeoxyglucose, to neuroreceptor imaging, to imaging pathological protein deposits. In the early going, the characteristics of successful molecular imaging radiotracers were defined, and a detailed “Process” was developed for the collection of basic pharmacodynamic and pharmacokinetic data. These data are essential for the interpretation of in vivo imaging data and for defining the strengths, weaknesses, and limitations of new tracers. This perspective discusses the use of this “Process” in the development of the amyloid β positron emission tomography radiotracer, Pittsburgh Compound-B, and discusses some of the current controversies and difficulties in the field of tau positron emission tomography in the context of human data that preceded completion of this radiotracer characterization process—which still remains to be completed. As a field, we must decide which data are valid and which are artifacts and determine that when the artifacts are so overwhelming, the data are merely an illusion.
  • Elevated medial temporal lobe and pervasive brain tau-PET signal in normal

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Val J. Lowe, Tyler J. Bruinsma, Hoon-Ki Min, Emily S. Lundt, Ping Fang, Matthew L. Senjem, Bradley F. Boeve, Keith A. Josephs, Mukesh K. Pandey, Melissa E. Murray, Kejal Kantarci, David T. Jones, Christopher G. Schwarz, David S. Knopman, Ronald C. Petersen, Clifford R. JackAbstractIntroductionMedial temporal lobe (MTL) uptake on tau–positron emission tomography (PET) is seen not only in Alzheimer's disease (AD) dementia but also in the aging population. The relationship of these findings to the development of AD dementia needs to be better understood.MethodsTau-PET with AV-1451 was performed on 576 cognitively unimpaired (CU) participants aged 50–94 years. The number of CUs with and without abnormal MTL regions and those with or without extra-MTL abnormalities was determined. Left and right regions were compared within each subject.ResultsOf CUs, 58% (334/576) had abnormal tau-PET findings. MTL abnormalities were present in 41% (238/576) of subjects.DiscussionMTL tau-PET signal is often associated with abnormal extra-MTL tau-PET signal in CU participants and may represent neurofibrillary tangle development that could identify participants most likely to develop AD dementia. Tau-PET signal exclusively outside of the MTL is seen in 17% of CU participants and could be the initial findings in participants in different AD dementia pathways. Significant (P 
  • Alzheimer's disease: 3-Dimensional MRI texture for prediction of
           conversion from mild cognitive impairment

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Collin C. Luk, Abdullah Ishaque, Muhammad Khan, Daniel Ta, Sneha Chenji, Yee-Hong Yang, Dean Eurich, Sanjay Kalra, the Alzheimer's Disease Neuroimaging InitiativeAbstractIntroductionCurrently, there are no tools that can accurately predict which patients with mild cognitive impairment (MCI) will progress to Alzheimer's disease (AD). Texture analysis uses image processing and statistical methods to identify patterns in voxel intensities that cannot be appreciated by visual inspection. Our main objective was to determine whether MRI texture could be used to predict conversion of MCI to AD.MethodsA method of 3-dimensional, whole-brain texture analysis was used to compute texture features from T1-weighted MR images. To assess predictive value, texture changes were compared between MCI converters and nonconverters over a 3-year observation period. A predictive model using texture and clinical factors was used to predict conversion of patients with MCI to AD. This model was then tested on ten randomly selected test groups from the data set.ResultsTexture features were found to be significantly different between normal controls (n = 225), patients with MCI (n = 382), and patients with AD (n = 183). A subset of the patients with MCI were used to compare between MCI converters (n = 98) and nonconverters (n = 106). A composite model including texture features, APOE-ε4 genotype, Mini-Mental Status Examination score, sex, and hippocampal occupancy resulted in an area under curve of 0.905. Application of the composite model to ten randomly selected test groups (nonconverters = 26, converters = 24) predicted MCI conversion with a mean accuracy of 76.2%.DiscussionEarly texture changes are detected in patients with MCI who eventually progress to AD dementia. Therefore, whole-brain 3D texture analysis has the potential to predict progression of patients with MCI to AD.
  • Amnestic mild cognitive impairment individuals with dissimilar pathologic
           origins show common regional vulnerability in the default mode network

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Swati Rane, Manus J. Donahue, Daniel O. ClaassenAbstractIntroductionAlzheimer's and Parkinson's disease (AD and PD) are distinct disorders but share similar biomarker profiles. The regions of the default mode network are implicated in these diseases and are associated with amnestic symptoms. The role of apolipoprotein-ε4 (APOE-ε4), which is associated with cognitive function, is unclear in PD.MethodsIn this work, we evaluated cortical thickness of default mode network regions that are likely affected in both early AD and PD individuals, that is, with amnestic mild cognitive impairment. We identified the prevalence of APOE-ε4 and evaluated its association with cortical atrophy.ResultsWe observed significant parahippocampal atrophy and hippocampal atrophy rates in amnestic mild cognitive impairment subjects, regardless of disease origins (AD or PD). Similarly, mild cognitive impairment ε4 carriers showed significant precuneal atrophy compared with noncarriers.DiscussionThis work supports that converging changes to default mode network regions, especially the temporal lobe and precuneus, are shared in AD and PD.
  • Do 2-year changes in superior frontal gyrus and global brain atrophy
           affect cognition'

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Maria del C. Valdés Hernández, Stuart Reid, Shadia Mikhael, Cyril Pernet, The Alzheimer's Disease Neuroimaging InitiativeAbstractIntroductionMetabolic alterations to the superior frontal gyrus (SFG) have been linked to cognitive decline. Whether these indicate structural atrophy, which could be screened for at a larger scale using noninvasive structural imaging, is unknown.MethodsWe assessed annual structural magnetic resonance imaging scans and cognitive data from 3 consecutive years from 204 participants from the AD Neuroimaging Initiative database (mean age 72.24 [8.175] years). We evaluated associations between brain structural changes and performance in the Montreal Cognitive Assessment, Everyday Cognition Visuospatial subtest (ECog Visuospatial), and Functional Assessment Questionnaire.ResultsChanges in the surface area of the SFG were associated with changes in the outcome of the ECog Visuospatial test (P
  • Altered functional connectivity strength in informant-reported subjective
           cognitive decline: A resting-state functional magnetic resonance imaging

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Chao Dong, Tao Liu, Wei Wen, Nicole A. Kochan, Jiyang Jiang, Qiongge Li, Hao Liu, Haijun Niu, Wei Zhang, Yilong Wang, Henry Brodaty, Perminder S. SachdevAbstractIntroductionInformant-reported subjective cognitive decline (iSCD) has been associated with a higher risk of conversion to dementia, but the findings of whole brain functional connectivity strength (FCS) changes in iSCD are limited.MethodsThe sample comprised 39 participants with iSCD and 39 age- and sex- matched healthy controls. The global absolute (aFCS) and relative functional connectivity strengths were estimated using weighted degree centrality and the z-scores of the weighted degree centrality respectively. FreeSurfer was used for measuring cortical thickness.ResultsThe aFCS was lower in iSCD primarily in left medial superior frontal, left precuneus, left parietal, right cuneus, and bilateral calcarine; while relative functional connectivity strength was higher in posterior cingulate cortex/precuneus compared with healthy controls. No significant differences in cortical thickness were observed.DiscussionThere are detectable changes of FCS in iSCD, with the precuneus possibly playing a compensatory role. FCS could therefore have a potential role to serve as one of the earliest neuroimaging markers of neurodegenerative disease.
  • In vivo coupling of tau pathology and cortical thinning in
           Alzheimer's disease

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Elijah Mak, Richard A.I. Bethlehem, Rafael Romero-Garcia, Simon Cervenka, Timothy Rittman, Silvy Gabel, Ajenthan Surendranathan, Richard W. Bevan-Jones, Luca Passamonti, Patricia Vázquez Rodríguez, Li Su, Robert Arnold, Guy B. Williams, Young T. Hong, Tim D. Fryer, Franklin I. Aigbirhio, James B. Rowe, John T. O'BrienAbstractIntroductionThe deposition of neurofibrillary tangles in neurodegenerative disorders is associated with neuronal loss on autopsy; however, their in vivo associations with atrophy across the continuum of Alzheimer's disease (AD) remain unclear.MethodsWe estimated cortical thickness, tau ([18F]-AV-1451), and amyloid β (Aβ) status ([11C]-PiB) in 47 subjects who were stratified into Aβ− (14 healthy controls and six mild cognitive impairment–Aβ−) and Aβ+ (14 mild cognitive impairment–Aβ+ and 13 AD) groups.ResultsCompared with the Aβ− group, tau was increased in widespread regions whereas cortical thinning was restricted to the temporal cortices. Increased tau binding was associated with cortical thinning in each Aβ group. Locally, regional tau was associated with temporoparietal atrophy.DiscussionThese findings position tau as a promising therapeutic target. Further studies are needed to elucidate the casual relationships between tau pathology and trajectories of atrophy in AD.
  • Utility of perfusion PET measures to assess neuronal injury in Alzheimer's

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Nelly Joseph-Mathurin, Yi Su, Tyler M. Blazey, Mateusz Jasielec, Andrei Vlassenko, Karl Friedrichsen, Brian A. Gordon, Russ C. Hornbeck, Lisa Cash, Beau M. Ances, Thomas Veale, David M. Cash, Adam M. Brickman, Virginia Buckles, Nigel J. Cairns, Carlos Cruchaga, Alison Goate, Clifford R. Jack, Celeste Karch, William KlunkAbstractIntroduction18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) is commonly used to estimate neuronal injury in Alzheimer's disease (AD). Here, we evaluate the utility of dynamic PET measures of perfusion using 11C-Pittsburgh compound B (PiB) to estimate neuronal injury in comparison to FDG PET.MethodsFDG, early frames of PiB images, and relative PiB delivery rate constants (PiB-R1) were obtained from 110 participants from the Dominantly Inherited Alzheimer Network. Voxelwise, regional cross-sectional, and longitudinal analyses were done to evaluate the correlation between images and estimate the relationship of the imaging biomarkers with estimated time to disease progression based on family history.ResultsMetabolism and perfusion images were spatially correlated. Regional PiB-R1 values and FDG, but not early frames of PiB images, significantly decreased in the mutation carriers with estimated year to onset and with increasing dementia severity.DiscussionHypometabolism estimated by PiB-R1 may provide a measure of brain perfusion without increasing radiation exposure.
  • Multimodal neuroimaging study of cerebrovascular disease, amyloid
           deposition, and neurodegeneration in Alzheimer's disease progression

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Patrick J. Lao, Adam M. Brickman, Alzheimer's Disease Neuroimaging InitiativeAbstractIntroductionCerebrovascular disease (CVD) is not currently considered a core pathological feature of Alzheimer's disease (AD), but mounting evidence suggests that concurrent CVD may exacerbate AD progression. The purpose of this study was first to examine the relationship among amyloid, CVD, and neurodegeneration and second to examine the extent to which amyloid and CVD pathology drive subsequent neurodegeneration over time.MethodsSix hundred eight (224 normal controls, 291 mild cognitive impairment, 93 AD) subjects from the Alzheimer's Disease Neuroimaging Initiative with longitudinal AV45 positron emission tomography imaging and MR imaging were investigated.ResultsAmyloid and white matter hyperintensity (WMH) burden increased across clinical diagnosis groups (normal control 
  • A multivariate metabolic imaging marker for behavioral variant
           frontotemporal dementia

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Amir Nazem, Chris C. Tang, Phoebe Spetsieris, Christian Dresel, Marc L. Gordon, Janine Diehl-Schmid, Timo Grimmer, Igor Yakushev, Paul J. Mattis, Yilong Ma, Vijay Dhawan, David Eidelberg, Alzheimer's Disease Neuroimaging InitiativeAbstractIntroductionThe heterogeneity of behavioral variant frontotemporal dementia (bvFTD) calls for multivariate imaging biomarkers.MethodsWe studied a total of 148 dementia patients from the Feinstein Institute (Center-A: 25 bvFTD and 10 Alzheimer's disease), Technical University of Munich (Center-B: 44 bvFTD and 29 FTD language variants), and Alzheimer's Disease Neuroimaging Initiative (40 Alzheimer's disease subjects). To identify the covariance pattern of bvFTD (behavioral variant frontotemporal dementia–related pattern [bFDRP]), we applied principal component analysis to combined 18F-fluorodeoxyglucose–positron emission tomography scans from bvFTD and healthy subjects. The phenotypic specificity and clinical correlates of bFDRP expression were assessed in independent testing sets.ResultsThe bFDRP was identified in Center-A data (24.1% of subject × voxel variance; P 
  • Early affective changes and increased connectivity in preclinical
           Alzheimer's disease

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Carolyn A. Fredericks, Virginia E. Sturm, Jesse A. Brown, Alice Y. Hua, Murat Bilgel, Dean F. Wong, Susan M. Resnick, William W. SeeleyAbstractIntroductionAffective changes precede cognitive decline in mild Alzheimer's disease and may relate to increased connectivity in a “salience network” attuned to emotionally significant stimuli. The trajectory of affective changes in preclinical Alzheimer's disease, and its relationship to this network, is unknown.MethodsOne hundred one cognitively normal older adults received longitudinal assessments of affective symptoms, then amyloid-PET. We hypothesized amyloid-positive individuals would show enhanced emotional reactivity associated with salience network connectivity. We tested whether increased global connectivity in key regions significantly related to affective changes.ResultsIn participants later found to be amyloid positive, emotional reactivity increased with age, and interpersonal warmth declined in women. These individuals showed higher global connectivity within the right insula and superior temporal sulcus; higher superior temporal sulcus connectivity predicted increasing emotional reactivity and decreasing interpersonal warmth.ConclusionsAffective changes should be considered an early preclinical feature of Alzheimer's disease. These changes may relate to higher functional connectivity in regions critical for social-emotional processing.
  • Staging of amyloid β, t-tau, regional atrophy rates, and cognitive change
           in a nondemented cohort: Results of serial mediation analyses

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Evan Fletcher, Teresa Jenica Filshtein, Danielle Harvey, Alice Renaud, Dan Mungas, Charles DeCarli, Alzheimer's Disease Neuroimaging InitiativeAbstractIntroductionCurrent models posit a sequence of amyloid β (Aβ), tau, atrophy, and cognitive change leading to Alzheimer's disease, but ambiguities remain. We examined these sequences via serial mediations.MethodsWe studied normal controls, early mild cognitive impairment, and late mild cognitive impairment individuals from the Alzheimer's Disease Neuroimaging Initiative 2 database for the mediation of baseline cerebrospinal fluid Aβ effects on 2-year cognitive change via regional longitudinal atrophy rate (AR) alone or AR and tau.ResultsIn normal controls, Aβ correlated directly with regional ARs and memory loss, with no mediations. In early mild cognitive impairment, tau and lateral temporal ARs serially mediated the influence of Aβ on memory while Aβ affected memory via hippocampal AR. Late mild cognitive impairment consistently showed serial mediations of tau followed by atrophy. However, Aβ effects on memory also continued to be specifically mediated by medial temporal ARs without intermediate tau.DiscussionBiomarker sequences vary by region and disease state, suggesting the need to refine current cascade models.
  • The use of Centiloids for applying [11C]PiB classification cutoffs across
           region-of-interest delineation methods

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Dana L. Tudorascu, Davneet S. Minhas, Patrick J. Lao, Tobey J. Betthauser, Zheming Yu, Charles M. Laymon, Brian J. Lopresti, Chet A. Mathis, William E. Klunk, Benjamin L. Handen, Bradley T. Christian, Ann D. CohenAbstractIntroductionCentiloid standardization was developed to establish a quantitative outcome measure of amyloid burden that could accommodate the integration of different amyloid positron emission tomography radiotracers or different methods of quantifying the same tracer. The goal of this study was to examine the use of Centiloids for establishing amyloid classification cutoffs for differing region-of-interest (ROI) delineation schemes.MethodsUsing ROIs from hand-drawn delineation in native space as the gold standard, we compared standard uptake value ratios obtained from the 6 hand-drawn ROIs that determine amyloid-positivity classification with standard uptake value ratio obtained from 3 different automated techniques (FreeSurfer, Statistical Parametric Mapping, and superimposed hand-drawn ROIs in Pittsburgh Compound B template space). We tested between-methods reliability using repeated measures models and intraclass correlation coefficients.ResultsWe found high reliability between the hand-drawn standard method and other methods for almost all the regions considered. However, small differences in standard uptake value ratio were found to lead to unreliable classifications when the hand-drawn native space-derived cutoffs were used across other ROI delineation methods.DiscussionThe use of Centiloid standardization greatly improved the agreement of Pittsburgh Compound B classification across methods and may serve as an alternative method for applying cutoffs across methodologically different outcomes.
  • Memory concerns in the early Alzheimer's disease prodrome: Regional
           association with tau deposition

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Cecily G. Swinford, Shannon L. Risacher, Arnaud Charil, Adam J. Schwarz, Andrew J. Saykin, Alzheimer's Disease Neuroimaging InitiativeAbstractIntroductionRelationship between self– and informant memory concerns and tau aggregation was assessed in adults at risk for Alzheimer's disease (AD).MethodsRegional mean standardized uptake value ratios were extracted from [18F]flortaucipir positron emission tomography (PET) scans of 82 at-risk adults in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. Associations between self– and informant ECog memory scores and tau aggregation were analyzed on both regional and voxelwise bases. Analyses were completed both on the whole sample and restricted to amyloid-positive individuals only.ResultsMemory concerns were associated with tau aggregation. Self-perception was more associated with frontal tau. In contrast, informant scores were more associated with parietal tau. This source-by-region interaction was more prominent in amyloid-positive participants and observed in both regional and voxelwise analyses.DiscussionQuantitative assessment of perceived memory functioning may be useful for screening older adults at risk for Alzheimer's disease. Individuals and their informants may provide complementary information relating to the anatomical distribution of tau.
  • Microbleeds are associated with depressive symptoms in Alzheimer's disease

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Anna E. Leeuwis, Niels D. Prins, Astrid M. Hooghiemstra, Marije R. Benedictus, Philip Scheltens, Frederik Barkhof, Wiesje M. van der FlierAbstractIntroductionCo-occurrence of cerebrovascular disease and depression led to the “vascular depression hypothesis”. White matter hyperintensities (WMHs) have been associated with depressive symptoms in population-based studies. We studied the association between small vessel disease and depressive symptoms in a memory clinic population.MethodsWe included>2000 patients with subjective cognitive decline (SCD), mild cognitive impairment, and Alzheimer's disease (AD). Magnetic resonance imaging was rated for WMHs, lacunes, and microbleeds. Depressive symptoms were assessed using the Geriatric Depression Scale. We performed logistic regression analysis.ResultsDepressive symptoms were present in AD: 17%; mild cognitive impairment: 25%; and SCD: 23%. SCD patients with WMHs showed higher propensity of depressive symptoms than AD patients with WMHs. AD patients with microbleeds were more likely to have depressive symptoms compared with AD patients without microbleeds (odds ratio = 1.70; 95% confidence interval: 1.08–2.68).DiscussionMicrobleeds are associated with depressive symptoms in AD, supporting a potential role of cerebral amyloid angiopathy in the occurrence of depressive symptoms in AD.
  • White matter signal abnormalities in former National Football League

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Michael L. Alosco, Inga K. Koerte, Yorghos Tripodis, Megan Mariani, Alicia S. Chua, Johnny Jarnagin, Yashar Rahimpour, Christian Puzo, Rose C. Healy, Brett Martin, Christine E. Chaisson, Robert C. Cantu, Rhoda Au, Michael McClean, Ann C. McKee, Alexander P. Lin, Martha E. Shenton, Ronald J. Killiany, Robert A. SternAbstractIntroductionLater-life brain alterations in former tackle football players are poorly understood, particularly regarding their relationship with repetitive head impacts (RHIs) and clinical function. We examined white matter signal abnormalities (WMSAs) and their association with RHIs and clinical function in former National Football League (NFL) players.MethodsEighty-six clinically symptomatic former NFL players and 23 same-age reportedly asymptomatic controls without head trauma exposure underwent magnetic resonance imaging and neuropsychological testing. FreeSurfer calculated WMSAs. A cumulative head impact index quantified RHIs.ResultsIn former NFL players, increased volume of WMSAs was associated with higher cumulative head impact index scores (P = .043) and worse psychomotor speed and executive function (P = .015). Although former NFL players had greater WMSA volume than controls (P = .046), these findings are inconclusive due to recruitment of controls based on lack of clinical symptoms and head trauma exposure.DiscussionIn former NFL players, WMSAs may reflect long-term microvascular and nonmicrovascular pathologies from RHIs that negatively impact cognition.
  • Characterizing biomarker features of cognitively normal individuals with

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Xiaofeng Li, Maowen Ba, Kok Pin Ng, Sulantha Mathotaarachchi, Tharick A. Pascoal, Pedro Rosa-Neto, Serge Gauthier, Alzheimer's Disease Neuroimaging InitiativeAbstractIntroductionThe clinical significance of ventriculomegaly in cognitively normal elderly individuals remains unclear.MethodsWe selected cognitively normal individuals (n = 425) from the Alzheimer's Disease Neuroimaging Initiative database and calculated Evans index (EI) based on the ratio of the frontal horn and skull diameter. We defined ventriculomegaly as EI ≥ 0.30, and the participants were stratified into EI ≥ 0.30 group and EI 
  • Linkage analysis of multiplex Caribbean Hispanic families loaded for
           unexplained early-onset cases identifies novel Alzheimer's disease loci

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Rong Cheng, Min Tang, Izri Martinez, Temitope Ayodele, Penelope Baez, Dolly Reyes-Dumeyer, Rafael Lantigua, Martin Medrano, Ivonne Jimenez-Velazquez, Joseph H. Lee, Gary W. Beecham, Christiane ReitzAbstractIntroductionLess than 10% of early-onset Alzheimer's disease (EOAD) is explained by known mutations.MethodsWe conducted genetic linkage analysis of 68 well-phenotyped Caribbean Hispanic families without clear inheritance patterns or mutations in APP, PSEN1, and PSEN2 and with two or more individuals with EOAD.ResultsWe identified 16 (logarithm of odds > 3.6) linked regions, including eight novel loci for EOAD (2p15, 5q14.1, 11p15.1, 13q21.22, 13q33.1, 16p12.1, 20p12.1, and 20q11.21) and eight regions previously associated with late-onset Alzheimer's disease. The strongest signal was observed at 16p12.1 (25 cM, 33 Mb; heterogeneity logarithm of odds = 5.3), ∼3 Mb upstream of the ceroid lipofuscinosis 3 (CLN3) gene associated with juvenile neuronal ceroid lipofuscinosis (JNCL), which functions in retromer trafficking and has been reported to alter intracellular processing of the amyloid precursor protein.DiscussionThis study supports the notion that the genetic architectures of unexplained EOAD and late-onset AD overlap partially, but not fully.
  • Sex differences in the association between apolipoprotein E ε4 allele and
           Alzheimer's disease markers

    • Abstract: Publication date: 2018Source: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 10Author(s): Erin E. Sundermann, My Tran, Pauline M. Maki, Mark W. Bondi, Alzheimer's Disease Neuroimaging InitiativeAbstractIntroductionWe determined whether the effect of apolipoprotein E (APOE)-ε4 genotype on Alzheimer's disease (AD) markers differs in men and women across AD stages.MethodsAmong normal control (NC) participants (N = 702) and participants with mild cognitive impairment (N = 576) and AD (N = 305), we examined the associations of sex and APOE-ε4 carrier status with cortical amyloid-β (Aβ) burden, hippocampal volume ratio (HpVR; hippocampal volume/intracranial volume × 103), brain glucose metabolism, and verbal memory.ResultsIn NC, APOE-ε4 related to greater Aβ burden and poorer verbal memory across sex but to smaller HpVR and hypometabolism in men only. In mild cognitive impairment, APOE-ε4 related to smaller HpVR, hypometabolism, greater Aβ burden, and poorer verbal memory across sex. In AD, APOE-ε4 related to greater Aβ burden in men only and smaller HpVR across sex and showed no association with hypometabolism or verbal memory.DiscussionSex differences in the association between APOE-ε4 and AD markers vary by disease stage.
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