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Publisher: John Wiley and Sons   (Total: 1576 journals)

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Showing 1 - 200 of 1576 Journals sorted alphabetically
Abacus     Hybrid Journal   (Followers: 12, SJR: 0.48, h-index: 22)
About Campus     Hybrid Journal   (Followers: 5)
Academic Emergency Medicine     Hybrid Journal   (Followers: 58, SJR: 1.385, h-index: 91)
Accounting & Finance     Hybrid Journal   (Followers: 46, SJR: 0.547, h-index: 30)
ACEP NOW     Free   (Followers: 1)
Acta Anaesthesiologica Scandinavica     Hybrid Journal   (Followers: 51, SJR: 1.02, h-index: 88)
Acta Archaeologica     Hybrid Journal   (Followers: 138, SJR: 0.101, h-index: 9)
Acta Geologica Sinica (English Edition)     Hybrid Journal   (Followers: 3, SJR: 0.552, h-index: 41)
Acta Neurologica Scandinavica     Hybrid Journal   (Followers: 5, SJR: 1.203, h-index: 74)
Acta Obstetricia et Gynecologica Scandinavica     Hybrid Journal   (Followers: 15, SJR: 1.197, h-index: 81)
Acta Ophthalmologica     Hybrid Journal   (Followers: 5, SJR: 0.112, h-index: 1)
Acta Paediatrica     Hybrid Journal   (Followers: 56, SJR: 0.794, h-index: 88)
Acta Physiologica     Hybrid Journal   (Followers: 6, SJR: 1.69, h-index: 88)
Acta Polymerica     Hybrid Journal   (Followers: 9)
Acta Psychiatrica Scandinavica     Hybrid Journal   (Followers: 35, SJR: 2.518, h-index: 113)
Acta Zoologica     Hybrid Journal   (Followers: 6, SJR: 0.459, h-index: 29)
Acute Medicine & Surgery     Hybrid Journal   (Followers: 2)
Addiction     Hybrid Journal   (Followers: 33, SJR: 2.086, h-index: 143)
Addiction Biology     Hybrid Journal   (Followers: 12, SJR: 2.091, h-index: 57)
Adultspan J.     Hybrid Journal   (SJR: 0.127, h-index: 4)
Advanced Energy Materials     Hybrid Journal   (Followers: 24, SJR: 6.411, h-index: 86)
Advanced Engineering Materials     Hybrid Journal   (Followers: 26, SJR: 0.81, h-index: 81)
Advanced Functional Materials     Hybrid Journal   (Followers: 50, SJR: 5.21, h-index: 203)
Advanced Healthcare Materials     Hybrid Journal   (Followers: 13, SJR: 0.232, h-index: 7)
Advanced Materials     Hybrid Journal   (Followers: 249, SJR: 9.021, h-index: 345)
Advanced Materials Interfaces     Hybrid Journal   (Followers: 6, SJR: 1.177, h-index: 10)
Advanced Optical Materials     Hybrid Journal   (Followers: 5, SJR: 2.488, h-index: 21)
Advanced Science     Open Access   (Followers: 5)
Advanced Synthesis & Catalysis     Hybrid Journal   (Followers: 17, SJR: 2.729, h-index: 121)
Advances in Polymer Technology     Hybrid Journal   (Followers: 13, SJR: 0.344, h-index: 31)
Africa Confidential     Hybrid Journal   (Followers: 19)
Africa Research Bulletin: Economic, Financial and Technical Series     Hybrid Journal   (Followers: 12)
Africa Research Bulletin: Political, Social and Cultural Series     Hybrid Journal   (Followers: 9)
African Development Review     Hybrid Journal   (Followers: 35, SJR: 0.275, h-index: 17)
African J. of Ecology     Hybrid Journal   (Followers: 15, SJR: 0.477, h-index: 39)
Aggressive Behavior     Hybrid Journal   (Followers: 15, SJR: 1.391, h-index: 66)
Aging Cell     Open Access   (Followers: 10, SJR: 4.374, h-index: 95)
Agribusiness : an Intl. J.     Hybrid Journal   (Followers: 6, SJR: 0.627, h-index: 14)
Agricultural and Forest Entomology     Hybrid Journal   (Followers: 14, SJR: 0.925, h-index: 43)
Agricultural Economics     Hybrid Journal   (Followers: 44, SJR: 1.099, h-index: 51)
AIChE J.     Hybrid Journal   (Followers: 29, SJR: 1.122, h-index: 120)
Alcoholism and Drug Abuse Weekly     Hybrid Journal   (Followers: 7)
Alcoholism Clinical and Experimental Research     Hybrid Journal   (Followers: 7, SJR: 1.416, h-index: 125)
Alimentary Pharmacology & Therapeutics     Hybrid Journal   (Followers: 34, SJR: 2.833, h-index: 138)
Alimentary Pharmacology & Therapeutics Symposium Series     Hybrid Journal   (Followers: 3)
Allergy     Hybrid Journal   (Followers: 50, SJR: 3.048, h-index: 129)
Alternatives to the High Cost of Litigation     Hybrid Journal   (Followers: 3)
American Anthropologist     Hybrid Journal   (Followers: 130, SJR: 0.951, h-index: 61)
American Business Law J.     Hybrid Journal   (Followers: 24, SJR: 0.205, h-index: 17)
American Ethnologist     Hybrid Journal   (Followers: 91, SJR: 2.325, h-index: 51)
American J. of Economics and Sociology     Hybrid Journal   (Followers: 27, SJR: 0.211, h-index: 26)
American J. of Hematology     Hybrid Journal   (Followers: 31, SJR: 1.761, h-index: 77)
American J. of Human Biology     Hybrid Journal   (Followers: 12, SJR: 1.018, h-index: 58)
American J. of Industrial Medicine     Hybrid Journal   (Followers: 16, SJR: 0.993, h-index: 85)
American J. of Medical Genetics Part A     Hybrid Journal   (Followers: 15, SJR: 1.115, h-index: 61)
American J. of Medical Genetics Part B: Neuropsychiatric Genetics     Hybrid Journal   (Followers: 3, SJR: 1.771, h-index: 107)
American J. of Medical Genetics Part C: Seminars in Medical Genetics     Partially Free   (Followers: 5, SJR: 2.315, h-index: 79)
American J. of Physical Anthropology     Hybrid Journal   (Followers: 36, SJR: 1.41, h-index: 88)
American J. of Political Science     Hybrid Journal   (Followers: 250, SJR: 5.101, h-index: 114)
American J. of Primatology     Hybrid Journal   (Followers: 15, SJR: 1.197, h-index: 63)
American J. of Reproductive Immunology     Hybrid Journal   (Followers: 3, SJR: 1.347, h-index: 75)
American J. of Transplantation     Hybrid Journal   (Followers: 16, SJR: 2.792, h-index: 140)
American J. on Addictions     Hybrid Journal   (Followers: 9, SJR: 0.843, h-index: 57)
Anaesthesia     Hybrid Journal   (Followers: 120, SJR: 1.404, h-index: 88)
Analyses of Social Issues and Public Policy     Hybrid Journal   (Followers: 11, SJR: 0.397, h-index: 18)
Analytic Philosophy     Hybrid Journal   (Followers: 16)
Anatomia, Histologia, Embryologia: J. of Veterinary Medicine Series C     Hybrid Journal   (Followers: 3, SJR: 0.295, h-index: 27)
Anatomical Sciences Education     Hybrid Journal   (Followers: 1, SJR: 0.633, h-index: 24)
Andrologia     Hybrid Journal   (Followers: 2, SJR: 0.528, h-index: 45)
Andrology     Hybrid Journal   (Followers: 2, SJR: 0.979, h-index: 14)
Angewandte Chemie     Hybrid Journal   (Followers: 161)
Angewandte Chemie Intl. Edition     Hybrid Journal   (Followers: 210, SJR: 6.229, h-index: 397)
Animal Conservation     Hybrid Journal   (Followers: 35, SJR: 1.576, h-index: 62)
Animal Genetics     Hybrid Journal   (Followers: 8, SJR: 0.957, h-index: 67)
Animal Science J.     Hybrid Journal   (Followers: 6, SJR: 0.569, h-index: 24)
Annalen der Physik     Hybrid Journal   (Followers: 5, SJR: 1.46, h-index: 40)
Annals of Anthropological Practice     Partially Free   (Followers: 2, SJR: 0.187, h-index: 5)
Annals of Applied Biology     Hybrid Journal   (Followers: 8, SJR: 0.816, h-index: 56)
Annals of Clinical and Translational Neurology     Open Access   (Followers: 1)
Annals of Human Genetics     Hybrid Journal   (Followers: 9, SJR: 1.191, h-index: 67)
Annals of Neurology     Hybrid Journal   (Followers: 44, SJR: 5.584, h-index: 241)
Annals of Noninvasive Electrocardiology     Hybrid Journal   (Followers: 2, SJR: 0.531, h-index: 38)
Annals of Public and Cooperative Economics     Hybrid Journal   (Followers: 9, SJR: 0.336, h-index: 23)
Annals of the New York Academy of Sciences     Hybrid Journal   (Followers: 5, SJR: 2.389, h-index: 189)
Annual Bulletin of Historical Literature     Hybrid Journal   (Followers: 12)
Annual Review of Information Science and Technology     Hybrid Journal   (Followers: 14)
Anthropology & Education Quarterly     Hybrid Journal   (Followers: 24, SJR: 0.72, h-index: 31)
Anthropology & Humanism     Hybrid Journal   (Followers: 16, SJR: 0.137, h-index: 3)
Anthropology News     Hybrid Journal   (Followers: 14)
Anthropology of Consciousness     Hybrid Journal   (Followers: 11, SJR: 0.172, h-index: 5)
Anthropology of Work Review     Hybrid Journal   (Followers: 11, SJR: 0.256, h-index: 5)
Anthropology Today     Hybrid Journal   (Followers: 93, SJR: 0.545, h-index: 15)
Antipode     Hybrid Journal   (Followers: 45, SJR: 2.212, h-index: 69)
Anz J. of Surgery     Hybrid Journal   (Followers: 6, SJR: 0.432, h-index: 59)
Anzeiger für Schädlingskunde     Hybrid Journal   (Followers: 1)
Apmis     Hybrid Journal   (Followers: 1, SJR: 0.855, h-index: 73)
Applied Cognitive Psychology     Hybrid Journal   (Followers: 67, SJR: 0.754, h-index: 69)
Applied Organometallic Chemistry     Hybrid Journal   (Followers: 7, SJR: 0.632, h-index: 58)
Applied Psychology     Hybrid Journal   (Followers: 135, SJR: 1.023, h-index: 64)
Applied Psychology: Health and Well-Being     Hybrid Journal   (Followers: 48, SJR: 0.868, h-index: 13)
Applied Stochastic Models in Business and Industry     Hybrid Journal   (Followers: 5, SJR: 0.613, h-index: 24)
Aquaculture Nutrition     Hybrid Journal   (Followers: 14, SJR: 1.025, h-index: 55)
Aquaculture Research     Hybrid Journal   (Followers: 31, SJR: 0.807, h-index: 60)
Aquatic Conservation Marine and Freshwater Ecosystems     Hybrid Journal   (Followers: 34, SJR: 1.047, h-index: 57)
Arabian Archaeology and Epigraphy     Hybrid Journal   (Followers: 11, SJR: 0.453, h-index: 11)
Archaeological Prospection     Hybrid Journal   (Followers: 12, SJR: 0.922, h-index: 21)
Archaeology in Oceania     Hybrid Journal   (Followers: 13, SJR: 0.745, h-index: 18)
Archaeometry     Hybrid Journal   (Followers: 27, SJR: 0.809, h-index: 48)
Archeological Papers of The American Anthropological Association     Hybrid Journal   (Followers: 14, SJR: 0.156, h-index: 2)
Architectural Design     Hybrid Journal   (Followers: 25, SJR: 0.261, h-index: 9)
Archiv der Pharmazie     Hybrid Journal   (Followers: 4, SJR: 0.628, h-index: 43)
Archives of Drug Information     Hybrid Journal   (Followers: 4)
Archives of Insect Biochemistry and Physiology     Hybrid Journal   (SJR: 0.768, h-index: 54)
Area     Hybrid Journal   (Followers: 12, SJR: 0.938, h-index: 57)
Art History     Hybrid Journal   (Followers: 216, SJR: 0.153, h-index: 13)
Arthritis & Rheumatology     Hybrid Journal   (Followers: 51, SJR: 1.984, h-index: 20)
Arthritis Care & Research     Hybrid Journal   (Followers: 28, SJR: 2.256, h-index: 114)
Artificial Organs     Hybrid Journal   (Followers: 1, SJR: 0.872, h-index: 60)
ASHE Higher Education Reports     Hybrid Journal   (Followers: 14)
Asia & the Pacific Policy Studies     Open Access   (Followers: 14)
Asia Pacific J. of Human Resources     Hybrid Journal   (Followers: 315, SJR: 0.494, h-index: 19)
Asia Pacific Viewpoint     Hybrid Journal   (SJR: 0.616, h-index: 26)
Asia-Pacific J. of Chemical Engineering     Hybrid Journal   (Followers: 7, SJR: 0.345, h-index: 20)
Asia-pacific J. of Clinical Oncology     Hybrid Journal   (Followers: 6, SJR: 0.554, h-index: 14)
Asia-Pacific J. of Financial Studies     Hybrid Journal   (SJR: 0.241, h-index: 7)
Asia-Pacific Psychiatry     Hybrid Journal   (Followers: 3, SJR: 0.377, h-index: 7)
Asian Economic J.     Hybrid Journal   (Followers: 8, SJR: 0.234, h-index: 21)
Asian Economic Policy Review     Hybrid Journal   (Followers: 4, SJR: 0.196, h-index: 12)
Asian J. of Control     Hybrid Journal   (SJR: 0.862, h-index: 34)
Asian J. of Endoscopic Surgery     Hybrid Journal   (SJR: 0.394, h-index: 7)
Asian J. of Organic Chemistry     Hybrid Journal   (Followers: 4, SJR: 1.443, h-index: 19)
Asian J. of Social Psychology     Hybrid Journal   (Followers: 5, SJR: 0.665, h-index: 37)
Asian Politics and Policy     Hybrid Journal   (Followers: 13, SJR: 0.207, h-index: 7)
Asian Social Work and Policy Review     Hybrid Journal   (Followers: 5, SJR: 0.318, h-index: 5)
Asian-pacific Economic Literature     Hybrid Journal   (Followers: 5, SJR: 0.168, h-index: 15)
Assessment Update     Hybrid Journal   (Followers: 4)
Astronomische Nachrichten     Hybrid Journal   (Followers: 2, SJR: 0.701, h-index: 40)
Atmospheric Science Letters     Open Access   (Followers: 29, SJR: 1.332, h-index: 27)
Austral Ecology     Hybrid Journal   (Followers: 12, SJR: 1.095, h-index: 66)
Austral Entomology     Hybrid Journal   (Followers: 10, SJR: 0.524, h-index: 28)
Australasian J. of Dermatology     Hybrid Journal   (Followers: 8, SJR: 0.714, h-index: 40)
Australasian J. On Ageing     Hybrid Journal   (Followers: 7, SJR: 0.39, h-index: 22)
Australian & New Zealand J. of Statistics     Hybrid Journal   (Followers: 13, SJR: 0.275, h-index: 28)
Australian Accounting Review     Hybrid Journal   (Followers: 4, SJR: 0.709, h-index: 14)
Australian and New Zealand J. of Family Therapy (ANZJFT)     Hybrid Journal   (Followers: 3, SJR: 0.382, h-index: 12)
Australian and New Zealand J. of Obstetrics and Gynaecology     Hybrid Journal   (Followers: 43, SJR: 0.814, h-index: 49)
Australian and New Zealand J. of Public Health     Hybrid Journal   (Followers: 11, SJR: 0.82, h-index: 62)
Australian Dental J.     Hybrid Journal   (Followers: 6, SJR: 0.482, h-index: 46)
Australian Economic History Review     Hybrid Journal   (Followers: 4, SJR: 0.171, h-index: 12)
Australian Economic Papers     Hybrid Journal   (Followers: 23, SJR: 0.23, h-index: 9)
Australian Economic Review     Hybrid Journal   (Followers: 6, SJR: 0.357, h-index: 21)
Australian Endodontic J.     Hybrid Journal   (Followers: 3, SJR: 0.513, h-index: 24)
Australian J. of Agricultural and Resource Economics     Hybrid Journal   (Followers: 3, SJR: 0.765, h-index: 36)
Australian J. of Grape and Wine Research     Hybrid Journal   (Followers: 5, SJR: 0.879, h-index: 56)
Australian J. of Politics & History     Hybrid Journal   (Followers: 13, SJR: 0.203, h-index: 14)
Australian J. of Psychology     Hybrid Journal   (Followers: 17, SJR: 0.384, h-index: 30)
Australian J. of Public Administration     Hybrid Journal   (Followers: 391, SJR: 0.418, h-index: 29)
Australian J. of Rural Health     Hybrid Journal   (Followers: 4, SJR: 0.43, h-index: 34)
Australian Occupational Therapy J.     Hybrid Journal   (Followers: 66, SJR: 0.59, h-index: 29)
Australian Psychologist     Hybrid Journal   (Followers: 11, SJR: 0.331, h-index: 31)
Australian Veterinary J.     Hybrid Journal   (Followers: 19, SJR: 0.459, h-index: 45)
Autism Research     Hybrid Journal   (Followers: 31, SJR: 2.126, h-index: 39)
Autonomic & Autacoid Pharmacology     Hybrid Journal   (SJR: 0.371, h-index: 29)
Banks in Insurance Report     Hybrid Journal   (Followers: 1)
Basic & Clinical Pharmacology & Toxicology     Hybrid Journal   (Followers: 10, SJR: 0.539, h-index: 70)
Basic and Applied Pathology     Open Access   (Followers: 2, SJR: 0.113, h-index: 4)
Basin Research     Hybrid Journal   (Followers: 4, SJR: 1.54, h-index: 60)
Bauphysik     Hybrid Journal   (Followers: 2, SJR: 0.194, h-index: 5)
Bauregelliste A, Bauregelliste B Und Liste C     Hybrid Journal  
Bautechnik     Hybrid Journal   (Followers: 1, SJR: 0.321, h-index: 11)
Behavioral Interventions     Hybrid Journal   (Followers: 9, SJR: 0.297, h-index: 23)
Behavioral Sciences & the Law     Hybrid Journal   (Followers: 23, SJR: 0.736, h-index: 57)
Berichte Zur Wissenschaftsgeschichte     Hybrid Journal   (Followers: 9, SJR: 0.11, h-index: 5)
Beton- und Stahlbetonbau     Hybrid Journal   (Followers: 2, SJR: 0.493, h-index: 14)
Biochemistry and Molecular Biology Education     Hybrid Journal   (Followers: 6, SJR: 0.311, h-index: 26)
Bioelectromagnetics     Hybrid Journal   (Followers: 1, SJR: 0.568, h-index: 64)
Bioengineering & Translational Medicine     Open Access  
BioEssays     Hybrid Journal   (Followers: 10, SJR: 3.104, h-index: 155)
Bioethics     Hybrid Journal   (Followers: 14, SJR: 0.686, h-index: 39)
Biofuels, Bioproducts and Biorefining     Hybrid Journal   (Followers: 1, SJR: 1.725, h-index: 56)
Biological J. of the Linnean Society     Hybrid Journal   (Followers: 14, SJR: 1.172, h-index: 90)
Biological Reviews     Hybrid Journal   (Followers: 3, SJR: 6.469, h-index: 114)
Biologie in Unserer Zeit (Biuz)     Hybrid Journal   (Followers: 42, SJR: 0.12, h-index: 1)
Biology of the Cell     Full-text available via subscription   (Followers: 9, SJR: 1.812, h-index: 69)
Biomedical Chromatography     Hybrid Journal   (Followers: 6, SJR: 0.572, h-index: 49)
Biometrical J.     Hybrid Journal   (Followers: 5, SJR: 0.784, h-index: 44)
Biometrics     Hybrid Journal   (Followers: 36, SJR: 1.906, h-index: 96)
Biopharmaceutics and Drug Disposition     Hybrid Journal   (Followers: 10, SJR: 0.715, h-index: 44)
Biopolymers     Hybrid Journal   (Followers: 18, SJR: 1.199, h-index: 104)
Biotechnology and Applied Biochemistry     Hybrid Journal   (Followers: 45, SJR: 0.415, h-index: 55)
Biotechnology and Bioengineering     Hybrid Journal   (Followers: 135, SJR: 1.633, h-index: 146)
Biotechnology J.     Hybrid Journal   (Followers: 13, SJR: 1.185, h-index: 51)
Biotechnology Progress     Hybrid Journal   (Followers: 39, SJR: 0.736, h-index: 101)
Biotropica     Hybrid Journal   (Followers: 18, SJR: 1.374, h-index: 71)
Bipolar Disorders     Hybrid Journal   (Followers: 10, SJR: 2.592, h-index: 100)
Birth     Hybrid Journal   (Followers: 34, SJR: 0.763, h-index: 64)
Birth Defects Research Part A : Clinical and Molecular Teratology     Hybrid Journal   (Followers: 2, SJR: 0.727, h-index: 77)
Birth Defects Research Part B: Developmental and Reproductive Toxicology     Hybrid Journal   (Followers: 5, SJR: 0.468, h-index: 47)
Birth Defects Research Part C : Embryo Today : Reviews     Hybrid Journal   (SJR: 1.513, h-index: 55)
BJOG : An Intl. J. of Obstetrics and Gynaecology     Partially Free   (Followers: 219, SJR: 2.083, h-index: 125)

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Journal Cover Annals of Neurology
  [SJR: 5.584]   [H-I: 241]   [44 followers]  Follow
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0364-5134 - ISSN (Online) 1531-8249
   Published by John Wiley and Sons Homepage  [1576 journals]
  • Polygenic Risk Score Analysis of Pathologically Confirmed Alzheimer's
    • Authors: Valentina Escott-Price; Amanda J. Myers, Matt Huentelman, John Hardy
      Abstract: Previous estimates of the utility of polygenic risk score analysis for the prediction of Alzheimer's disease have given Area Under the Curve estimates of
      PubDate: 2017-07-20T10:20:36.802296-05:
      DOI: 10.1002/ana.24999
  • Thiamine deficiency in childhood with attention to genetic causes:
           Survival and outcome predictors
    • Authors: Juan Darío Ortigoza-Escobar; Majid Alfadhel, Marta Molero-Luis, Niklas Darin, Ronen Spiegel, Irenaeus F de Coo, Mike Gerards, Robert W Taylor, Rafael Artuch, Marwan Nashabat, Pilar Rodríguez-Pombo, Brahim Tabarki, Belén Pérez-Dueñas,
      Abstract: Primary and secondary conditions leading to thiamine deficiency have overlapping features in children, presenting with acute episodes of encephalopathy, bilateral symmetric brain lesions and high excretion of organic acids that are specific of thiamine-dependent mitochondrial enzymes, mainly lactate, alpha-ketoglutarate and branched chain keto-acids. Undiagnosed and untreated thiamine deficiencies are often fatal or lead to severe sequelae. Herein we describe the clinical and genetic characterization of 79 patients with inherited thiamine defects causing encephalopathy in childhood, identifying outcome predictors in patients with pathogenic SLC19A3 variants, the most common genetic etiology. We propose diagnostic criteria that will aid clinicians to establish a faster and accurate diagnosis so that early vitamin supplementation is considered. This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-18T11:10:43.872677-05:
      DOI: 10.1002/ana.24998
  • Multimodal image analysis of clinical influences on preterm brain
    • Authors: Gareth Ball; Paul Aljabar, Phumza Nongena, Nigel Kennea, Nuria Gonzalez-Cinca, Shona Falconer, Andrew T.M. Chew, Nicholas Harper, Julia Wurie, Mary A. Rutherford, Serena J. Counsell, A. David Edwards
      Abstract: ObjectivePremature birth is associated with numerous complex abnormalities of white and grey matter and a high incidence of long-term neurocognitive impairment. An integrated understanding of these abnormalities and their association with clinical events is lacking. The aim of this study was to identify specific patterns of abnormal cerebral development and their antenatal and postnatal antecedents.MethodsIn a prospective cohort of 449 infants (226 male), we performed a multi-variate and data-driven analysis combining multiple imaging modalities. Using canonical correlation analysis, we sought separable multimodal imaging markers associated with specific clinical and environmental factors and correlated to neurodevelopmental outcome at 2 years.ResultsWe found five independent patterns of neuroanatomical variation that related to clinical factors including age, prematurity, sex, intrauterine complications, and postnatal adversity. We also confirmed the association between imaging markers of neuroanatomical abnormality and poor cognitive and motor outcomes at 2 years.InterpretationThis data-driven approach defined novel and clinically relevant imaging markers of cerebral maldevelopment, which offer new insights into the nature of preterm brain injury. This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-18T10:55:40.210267-05:
      DOI: 10.1002/ana.24995
  • Fibrin(ogen) and neurodegeneration in the progressive multiple sclerosis
    • Authors: Richard L. Yates; Margaret M. Esiri, Jacqueline Palace, Benjamin Jacobs, Rafael Perera, Gabriele C. DeLuca
      Abstract: Objective: Neuronal loss, a key substrate of irreversible disability in multiple sclerosis (MS), is a recognised feature of MS cortical pathology of which the cause remains unknown. Fibrin(ogen) deposition is neurotoxic in animal models of MS, but has not been evaluated in human progressive MS cortex. The aim of this study was to investigate the extent and distribution of fibrin(ogen) in progressive MS cortex and elucidate its relationship with neurodegeneration.Methods: A post-mortem cohort of pathologically confirmed MS (n=47) and control (n=10) cases was used. The extent and distribution of fibrin(ogen) was assessed and related to measures of demyelination, inflammation, and neuronal density. In a subset of cases (MS, n=20; control, n=10), the expression of plasminogen activator inhibitor (PAI-1), a key enzyme in the fibrinolytic cascade, was assessed and related to the extent of fibrin(ogen).Results: Motor cortical fibrin(ogen) deposition was significantly overrepresented in MS compared to control cases in all compartments studied (i.e. extracellular (p=0.001), cell body (p=0.003) and neuritic/glial-processes (p=0.004)). MS cases with high levels of extracellular fibrin(ogen) had significantly up-regulated PAI-1 expression in all cortical layers assessed (p
      PubDate: 2017-07-18T10:55:34.09144-05:0
      DOI: 10.1002/ana.24997
  • Ante mortem CSF tau levels correlate with post mortem tau pathology in
    • Authors: D.J. Irwin; A. Lleó, S.X. Xie, C.T. McMillan, D. Wolk, E.B. Lee, V.M. Van Deerlin, L.M. Shaw, J.Q. Trojanowski, M. Grossman
      Abstract: Objective: To test the hypotheses that 1) antemortem cerebrospinal fluid tau levels correlate with postmortem tau pathology in frontotemporal lobar degeneration and 2) tauopathy patients have higher phosphorylated-tau levels compared to TDP-43 proteinopathy patients while accounting for Alzheimer's disease co-pathology.Methods: Patients had autopsy-confirmed frontotemporal lobar degeneration with tauopathy (n=31), TDP-43 proteinopathy (n=49), or Alzheimer's disease (n=26) with antemortem cerebrospinal fluid. Cerebrospinal fluid tau levels were compared between groups and correlated with digital histology measurement of postmortem tau pathology averaged from three cerebral regions (angular gyrus, mid-frontal cortex, anterior cingulate gyrus). Multivariate linear regression tested the association of ante mortem cerebrospinal fluid tau levels with post mortem tau pathology adjusting for demographics.Results: Multivariate regression found an independent association of ante mortem cerebrospinal fluid phosphorylated tau levels with post mortem cerebral tau pathology in frontotemporal lobar degeneration (Beta=1.3, 95%CI=0.2-2.4, p
      PubDate: 2017-07-18T10:55:23.886245-05:
      DOI: 10.1002/ana.24996
  • Brain microvascular injury and white matter disease provoked by
           diabetes-associated hyperamylinemia
    • Authors: Han Ly; Nirmal Verma, Fengen Wu, Miao Liu, Kathryn E. Saatman, Peter T. Nelson, John T. Slevin, Larry B. Goldstein, Geert Jan Biessels, Florin Despa
      Abstract: Objectives: The brain blood vessels of patients with type-2 diabetes and dementia have deposition of amylin, an amyloidogenic hormone co-secreted with insulin. It is not known whether vascular amylin deposition is a consequence or a trigger of vascular injury. We tested the hypothesis that the vascular amylin deposits cause endothelial dysfunction and microvascular injury and are modulated by the amylin transport in the brain via plasma apolipoproteins.Methods: Rats overexpressing amyloidogenic (human) amylin in the pancreas (HIP rats) and amylin knockout (AKO) rats intravenously infused with aggregated amylin were used for in vivo phenotyping. We also carried out biochemical analyses of human brain tissues and studied the effects of the aggregated amylin on endothelial cells, ex vivo.Results: Amylin deposition in brain blood vessels is associated with vessel wall disruption and abnormal surrounding neuropil in patients with type-2 diabetes and dementia, in HIP rats, and in AKO rats infused with aggregated amylin. HIP rats have brain microhemorrhages, white matter injury and neurologic deficits. Vascular amylin deposition provokes loss of endothelial cell coverage and tight junctions. Intravenous infusion in AKO rats of human amylin, or combined human amylin and apolipoprotein E4, showed that amylin binds to plasma apolipoproteins. The intravenous infusion of apolipoprotein E4 exacerbated the brain accumulation of aggregated amylin and vascular pathology in HIP rats.Interpretation: These data identify vascular amylin deposition as a trigger of brain endothelial dysfunction that is modulated by plasma apolipoproteins and represents a potential therapeutic target in diabetes-associated dementia and stroke. This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-11T10:46:59.6732-05:00
      DOI: 10.1002/ana.24992
  • Neutrophil extracellular traps in ischemic stroke thrombi
    • Authors: Elodie Laridan; Frederik Denorme, Linda Desender, Olivier François, Tommy Andersson, Hans Deckmyn, Karen Vanhoorelbeke, Simon F. De Meyer
      Abstract: Objective: Neutrophil extracellular traps (NETs) have been shown to promote thrombus formation. Little is known about the exact composition of thrombi that cause ischemic stroke. In particular no information is yet available on the presence of NETs in cerebral occlusions. Such information is however essential to improve current thrombolytic therapy with t-PA. This study aimed at investigating the presence of neutrophils and more specifically NETs in ischemic stroke thrombi.Methods: Sixty-eight thrombi retrieved from ischemic stroke patients undergoing endovascular treatment were characterized by immunostaining using neutrophil markers (CD66b and neutrophil elastase) and NETs markers (citrullinated histones H3 (H3Cit) and extracellular DNA). Neutrophils and NETs were quantified. In addition, extracellular DNA was targeted by performing ex vivo lysis of retrieved thrombi with DNase 1 and t-PA.Results: Neutrophils were detected extensively throughout all thrombi. Citrullinated histones H3 (H3Cit), a hallmark of NETs, were observed in almost all thrombi. H3Cit-positive area varied up to 13.45% of total thrombus area. Co-localization of H3Cit with extracellular DNA released from neutrophils confirmed the specific presence of NETs. H3Cit was more abundant in thrombi from cardioembolic origin compared to other etiologies. Older thrombi contained significantly more neutrophils and H3Cit compared to fresh thrombi. Interestingly, ex vivo lysis of patient thrombi was more successful when adding DNase 1 to standard t-PA.Interpretation: Neutrophils and NETs form important constituents of cerebral thrombi. Targeting of NETs with DNase 1 might have prothrombolytic potential in treatment of acute ischemic stroke. This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-11T10:40:57.74534-05:0
      DOI: 10.1002/ana.24993
  • Corrigendum
    • PubDate: 2017-07-07T02:05:22.064457-05:
      DOI: 10.1002/ana.24963
  • Timing Is Everything: Where Status Epilepticus Treatment Fails
    • Authors: Chloe E. Hill; Alomi O. Parikh, Colin Ellis, Jennifer S. Myers, Brian Litt
      Abstract: Status epilepticus is an emergency, however prompt treatment of patients with status epilepticus is challenging. Clinical trials, such as the Established Status Epilepticus Treatment Trial (ESETT), compare effectiveness of antiepileptic medications, and rigorous examination of effectiveness of care delivery is similarly warranted. We reviewed the medical literature on observed deviations from guidelines, clinical significance, and initiatives to improve timely treatment. We found pervasive, substantial gaps between recommended and “real world” practice with regard to timing, dosing, and sequence of antiepileptic therapy. Applying quality improvement methodology at the institutional level can increase adherence to guidelines, and may improve patient outcomes. This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-06T00:30:36.794866-05:
      DOI: 10.1002/ana.24986
  • Familial mesial temporal lobe epilepsy and the borderland of
           déjà vu
    • Authors: Piero Perucca; Douglas E. Crompton, Susannah T. Bellows, Anne M. McIntosh, Tomas Kalincik, Mark R. Newton, Frank J.E. Vajda, Ingrid E. Scheffer, Patrick Kwan, Terence J. O'Brien, K. Meng Tan, Samuel F. Berkovic
      Abstract: Objective: The cause of mesial temporal lobe epilepsy (MTLE) is often unknown. We ascertained to what extent newly-diagnosed non-lesional MTLE actually represents familial MTLE (FMTLE).Methods: We identified all consecutive patients presenting to the Austin Heath First Seizure Clinic with MTLE and a normal MRI or MRI-evidence of hippocampal sclerosis over a 10-year period. Patients' first-degree relatives and pairwise age- and sex-matched controls underwent a comprehensive epilepsy interview. Each interview transcript was reviewed independently by two epileptologists, blinded to relative or control status. Reviewers classified each subject as follows: epilepsy, specifying if MTLE; manifestations suspicious of epilepsy; or unaffected. Physiological déjà vu was noted.Results: Forty-four patients were included. At the Clinic, MTLE had been recognized to be familial in 2 patients only. Among 242 subjects interviewed, MTLE was diagnosed in 9/121 relatives vs 0/121 controls (p=0.008). All affected relatives had seizures with intense déjà vu and accompanying features; 6 relatives had not been previously diagnosed. Déjà vu experiences which were suspicious, but not diagnostic, of MTLE occurred in 6 additional relatives vs none of the controls (p=0.04). Physiological déjà vu was common, and did not differ significantly between relatives and controls. After completing the relatives' interviews, FMTLE was diagnosed in 8 of 44 patients (18.2%).Interpretation: FMTLE accounts for almost one-fifth of newly diagnosed non-lesional MTLE, and it is largely unrecognized without direct questioning of relatives. Relatives of patients with MTLE may experience déjà vu phenomena which clinically lie in the ‘borderland' between epileptic seizures and physiological déjà vu. This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-06T00:30:34.635635-05:
      DOI: 10.1002/ana.24984
  • Time-Dependent Risk of Seizures in Critically Ill Patients on Continuous
    • Authors: Aaron F. Struck; Gamaleldin Osman, Nishi Rampal, Siddhartha Biswal, Benjamin Legros, Lawrence Hirsch, M. Brandon Westover, Nicolas Gaspard
      Abstract: OBJECTIVE: Find the optimal Continuous EEG (cEEG) monitoring duration for seizure detection in critically ill patients.METHODS: We analyzed prospective data from 665 consecutive cEEGs, including clinical factors and time-to-event emergence of EEG findings over 72-hours. Clinical factors were selected using logistic regression. EEG risk factors were selected a priori. Clinical factors were used for baseline (pre-EEG) risk. EEG findings were used for creation of multistate survival model with three states (entry, EEG risk, and seizure). EEG Risk state is defined by emergence of epileptiform patterns.RESULTS: Clinical variables of greatest predictive value were coma (31% had seizures; OR 1.8; p
      PubDate: 2017-07-06T00:30:32.827605-05:
      DOI: 10.1002/ana.24985
  • MMP9 is decreased in natalizumab-treated MS patients at risk for PML
    • Authors: Nicolas Fissolo; Béatrice Pignolet, Clara Matute-Blanch, Juan Carlos Triviño, Berta Miró, Miriam Mota, Santiago Perez-Hoyos, Alex Sanchez, Patrick Vermersch, Aurélie Ruet, Jérome de Sèze, Pierre Labauge, Sandra Vukusic, Caroline Papeix, Laurent Almoyna, Ayman Tourbah, Pierre Clavelou, Thibault Moreau, Jean Pelletier, Christine Lebrun-Frenay, Xavier Montalban, David Brassat, Manuel Comabella,
      Abstract: Objective: To identify biomarkers associated with the development of progressive multifocal leukoencephalopathy (PML) in multiple sclerosis (MS) patients treated with natalizumab (NTZ).Methods: Relapsing-remitting MS (RRMS) patients who developed PML under NTZ therapy (pre-PML) and non-PML natalizumab-treated patients (NTZ-ctr) were included in the study. Cryopreserved peripheral blood mononuclear cells (PBMC) and serum samples collected at baseline, at one- and two-year treated time points, and during PML were analyzed for gene expression by RNA-sequencing and for serum protein levels by LUMINEX and ELISA assays respectively.Results: Among top differentially expressed genes in the RNA-sequencing between pre-PML and NTZ-ctr patients, pathway analysis revealed a high representation of genes belonging to the following categories: pro-angiogenic factors (MMP9, VEGFA), chemokines (CXCL1, CXCL5, IL8, CCL2), cytokines (IL1B, IFNG), and plasminogen- and coagulation-related molecules (SERPINB2, PLAU, PLAUR, TFPI, THBD). Serum protein levels for these candidates were measured in a two-step manner in a screening cohort and a validation cohort of pre-PML and NTZ-ctr patients. Only MMP9 was validated and, in pre-PML patients MMP9 protein levels were significantly reduced at baseline compared with NTZ-ctr patients and levels remained lower at later time points during NTZ treatment.Interpretation: The results from this study suggest that the pro-angiogenic factor MMP9 may play a role as biomarker associated with the development of PML in MS patients treated with NTZ. This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-06T00:30:30.804852-05:
      DOI: 10.1002/ana.24987
  • Microbleeds in the SPS3 Trial: Stroke, Mortality and Treatment
    • Authors: Ashkan Shoamanesh; Lesly A. Pearce, Carlos Bazan, Luciana Catanese, Leslie A. McClure, Mukul Sharma, Joan Marti-Fabregas, David C. Anderson, Carlos S. Kase, Robert G. Hart, Oscar R. Benavente,
      Abstract: Objectives: To characterize cerebral microbleeds (CMBs) in lacunar stroke patients in the SPS3 trial and to assess their relationship with recurrent stroke and death, and response to assigned treatment.Methods: SPS3 is a randomized, clinical trial conducted between 2003 and 2011. Patients with recent MRI-documented lacunar infarcts were randomly assigned in a factorial design to target levels of systolic blood pressure (SBP; 130–149 mmHg vs
      PubDate: 2017-07-06T00:30:21.007213-05:
      DOI: 10.1002/ana.24988
  • Issue Information - Masthead
    • PubDate: 2017-06-20T01:00:19.921405-05:
      DOI: 10.1002/ana.24977
  • Annals of Neurology: Volume 81, Number 6, June 2017
    • Abstract: ON THE COVER: A schematic drawing showing the components of the peripheral sensory neuron that are vulnerable to injuries that cause neuropathy in patients being treated with chemotherapy for cancer. These include the dorsal root ganglion cell body (large blue cell with a magenta nucleus), ion channels (blue protein inserted in the axon membrane at myelin nodes), microtubules (coiled yellow and blue protein in the axon), mitochondria (brown intraxonal organelles with blue interior), nerve terminals innervating skin, and attack by inflammatory cells (purple and blue cells with blue arrow). See Staff and colleagues, pages 772–781, for details.
      PubDate: 2017-06-20T01:00:16.347589-05:
      DOI: 10.1002/ana.24978
  • Issue Information - Copyright
    • PubDate: 2017-06-20T01:00:16.265856-05:
      DOI: 10.1002/ana.24975
  • Issue Information - TOC
    • PubDate: 2017-06-20T01:00:15.412359-05:
      DOI: 10.1002/ana.24976
  • A Novel Cause of Chronic Viral Meningoencephalitis: Cache Valley Virus
    • Authors: Michael R. Wilson; Dan Suan, Andrew Duggins, Ryan D. Schubert, Lillian M. Khan, Hannah A. Sample, Kelsey C. Zorn, Aline Rodrigues Hoffman, Anna Blick, Meena Shingde, Joseph L. DeRisi
      Abstract: Objective: Immunodeficient patients are particularly vulnerable to neuroinvasive infections that can be challenging to diagnose. Metagenomic next-generation sequencing can identify unusual or novel microbes and is therefore well suited for investigating the etiology of chronic meningoencephalitis in immunodeficient patients.Methods: We present the case of a 34 year-old man with X-linked agammaglobulinemia from Australia suffering from three years of meningoencephalitis that defied an etiologic diagnosis despite extensive conventional testing, including a brain biopsy. Metagenomic next-generation sequencing of his cerebrospinal fluid and brain biopsy tissue was performed to identify a causative pathogen.Results: Sequences aligning to multiple Cache Valley virus genes were identified via metagenomic next-generation sequencing. Reverse transcription polymerase chain reaction and immunohistochemistry subsequently confirmed the presence of Cache Valley virus in the brain biopsy tissue.Interpretation: Cache Valley virus, a mosquito-borne orthobunyavirus, has only been identified in three immunocompetent North American patients with acute neuroinvasive disease. The reported severity ranges from a self-limiting meningitis to a rapidly fatal meningoencephalitis with multi-organ failure. The virus has never been known to cause a chronic systemic or neurologic infection in humans. Cache Valley virus has also never previously been detected on the Australian continent. Indeed, our research subject traveled to North and South Carolina and Michigan in the weeks prior to the onset of his illness. This report demonstrates that metagenomic next-generation sequencing allows for unbiased pathogen identification, the early detection of emerging viruses as they spread to new locales, and the discovery of novel disease phenotypes. This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-19T18:23:24.381762-05:
      DOI: 10.1002/ana.24982
  • Structural plasticity of the ventral stream and aphasia recovery
    • Authors: Emilie T. McKinnon; Julius Fridriksson, G. Russell Glenn, Jens H. Jensen, Joseph A. Helpern, Alexandra Basilakos, Christopher Rorden, Andy Y. Shih, M. Vittoria Spampinato, Leonardo Bonilha
      Abstract: Re-strengthening of the residual language network is likely crucial for speech recovery in post-stroke aphasia. Eight participants with chronic aphasia received intensive speech therapy for three weeks, with standardized naming tests and brain MRIs before and after therapy. Kurtosis-based diffusion tensor tractography was used to measure mean kurtosis (MK) along a segment of the inferior longitudinal fasciculus (ILF). Therapy related reduction in the number of semantic but not phonemic errors was associated with strengthening (renormalization) of ILF MK (r=-0.90, P
      PubDate: 2017-06-19T18:23:20.438918-05:
      DOI: 10.1002/ana.24983
  • Phosphorylated neurofilament heavy chain: A biomarker of survival for
           C9ORF72-associated amyotrophic lateral sclerosis
    • Authors: Tania F. Gendron; Lillian M. Daughrity, Michael G. Heckman, Nancy N. Diehl, Joanne Wuu, Timothy M. Miller, Pau Pastor, John Q. Trojanowski, Murray Grossman, James D. Berry, William T. Hu, Antonia Ratti, Michael Benatar, Vincenzo Silani, Jonathan D. Glass, Mary Kay Floeter, Andreas Jeromin, Kevin B. Boylan, Leonard Petrucelli,
      Abstract: As potential treatments for C9ORF72-associated amyotrophic lateral sclerosis (c9ALS) approach clinical trials, the identification of prognostic biomarkers for c9ALS becomes a priority. We show that levels of phosphorylated neurofilament heavy chain (pNFH) in cerebrospinal fluid (CSF) predict disease status and survival in c9ALS patients, and are largely stable over time. Moreover, c9ALS patients exhibit higher pNFH levels, more rapid disease progression, and shorter survival after disease onset than ALS patients without C9ORF72 expansions. These data support the use of CSF pNFH as a prognostic biomarker for clinical trials, which will increase the likelihood of successfully developing a treatment for c9ALS. This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-19T10:30:57.753078-05:
      DOI: 10.1002/ana.24980
  • Gene Therapy Decreases Seizures in a Model of Incontinentia Pigmenti
    • Authors: Godwin K. Dogbevia; Kathrin Töllner, Jakob Körbelin, Sonja Bröer, Dirk A. Ridder, Hanna Grasshoff, Claudia Brandt, Jan Wenzel, Beate K. Straub, Martin Trepel, Wolfgang Löscher, Markus Schwaninger
      Abstract: Objective: Incontinentia pigmenti (IP) is a genetic disease leading to severe neurological symptoms, such as epileptic seizures, but no specific treatment is available. IP is caused by pathogenic variants that inactivate the Nemo gene. Replacing Nemo through gene therapy might provide therapeutic benefits.Methods: In a mouse model of IP we administered a single intravenous dose of the AAV vector AAV-BR1-CAG-NEMO delivering the Nemo gene to the brain endothelium. Spontaneous epileptic seizures and the integrity of the BBB were monitored.Results: The endothelium-targeted gene therapy improved the integrity of the blood-brain barrier. In parallel, it reduced the incidence of seizures and delayed their occurrence. Neonate mice intravenously injected with the AAV-BR1-CAG-NEMO vector developed no hepatocellular carcinoma or other major adverse effects 11 months after vector injection, demonstrating that the vector has a favorable safety profile.Interpretation: The data show that the blood-brain barrier is a target of antiepileptic treatment and more specifically provide evidence for the therapeutic benefit of a brain endothelial-targeted gene therapy in IP. This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-19T10:30:55.924313-05:
      DOI: 10.1002/ana.24981
  • Expanded phenotypes and outcomes among 256 LGI1/CASPR2-IgG positive
    • Authors: Avi Gadoth; Sean J. Pittock, Divyanshu Dubey, Andrew McKeon, Jeff W. Britton, John E. Schmeling, Aurelia Smith, Amy L. Kotsenas, Robert E. Watson, Daniel H. Lachance, Eoin P. Flanagan, Vanda A. Lennon, Christopher J. Klein
      Abstract: Objective: To describe an expanded phenotypic spectrum and longitudinal outcome in 256 LGI1-IgG or CASPR2-IgG seropositive patients. Methods: Patients were identified through service neural autoantibody evaluation. Ninety-five had longitudinal follow-up (7-456 months; median 35). Results: Among 3,910 patients tested, 196 were LGI1-IgG-positive; 51 were CASPR2-IgG-positive and 9 were dual-positive. CSF-testing was less sensitive than serum-testing, detecting only 24/38 LGI1-IgG-positive (63%) and 5/6 CASPR2-IgG-positive (83%). LGI1-IgG-positive specimens had higher VGKC-IgG immunoprecipitation values [0.33 nmol/L (0.02-5.14)] than CASPR2-IgG-positives [0.10 nmol/L (0.00-0.45; p50 years; OR 15, p
      PubDate: 2017-06-19T10:30:21.588473-05:
      DOI: 10.1002/ana.24979
  • Connectivity predicts deep brain stimulation outcome in Parkinson's
    • Authors: Andreas Horn; Martin Reich, Johannes Vorwerk, Ningfei Li, Gregor Wenzel, Qianqian Fang, Tanja Schmitz-Hübsch, Robert Nickl, Andreas Kupsch, Jens Volkmann, Andrea A. Kühn, Michael D. Fox
      Abstract: Objective: The benefit of deep brain stimulation (DBS) for Parkinson's disease (PD) may depend on connectivity between the stimulation site and other brain regions, but which regions and whether connectivity can predict outcome in patients remains unknown. Here, we identify the structural and functional connectivity profile of effective DBS to the subthalamic nucleus (STN) and test its ability to predict outcome in an independent cohort.Methods: A training dataset of 51 PD patients with STN DBS was combined with publicly available human connectome data (diffusion tractography and resting state functional connectivity) to identify connections reliably associated with clinical improvement (motor score of Unified Parkinson's Disease Rating Scale). This connectivity profile was then used to predict outcome in an independent cohort of 44 patients from a different center.Results: In the training dataset, connectivity between the DBS electrode and a distributed network of brain regions correlated with clinical response including structural connectivity to supplementary motor area and functional anticorrelation to primary motor cortex (p 
      PubDate: 2017-06-06T09:50:25.134114-05:
      DOI: 10.1002/ana.24974
  • Epileptic networks in action: Synchrony between distant hemodynamic
    • Authors: Hui Ming Khoo; Nicolás von Ellenrieder, Natalja Zazubovits, François Dubeau, Jean Gotman
      Abstract: Objective: Structural and functional imaging studies in focal epilepsy often reveal distributed regions of abnormality. These are interpreted as representing the existence of epileptic networks but the presence of actual neuronal interactions between these regions has not been demonstrated. We sought to determine if the distributed hemodynamic responses often seen in fMRI studies of scalp interictal epileptic discharges (IEDs) actually correspond to synchronized neuronal activities when examining the intracerebral EEG (iEEG) at distant nodes of the network.Methods: We studied 28 patients who underwent first EEG-fMRI and then iEEG, and had significant hemodynamic responses in the gray matter. We co-registered the hemodynamic responses to the iEEG electrode contacts positions and analyzed synchrony, measured by correlation, between IEDs recorded by iEEG in regions with and without hemodynamic responses.Results: The synchrony of intracerebral IED activity between pairs of regions showing a hemodynamic response was higher compared to that between pairs of regions without (p
      PubDate: 2017-06-06T09:50:20.232178-05:
      DOI: 10.1002/ana.24973
  • Serum IGF-I levels are associated with improved white matter recovery
           after TBI
    • Authors: Claire Feeney; David J. Sharp, Peter J. Hellyer, Amy E. Jolly, James H. Cole, Gregory Scott, David Baxter, Sagar Jilka, Ewan Ross, Timothy E. Ham, Peter O. Jenkins, Lucia M. Li, Nikos Gorgoraptis, Mark Midwinter, Anthony P. Goldstone
      Abstract: Objective: Traumatic brain injury (TBI) is a common disabling condition with limited treatment options. Diffusion tensor imaging (DTI) measures recovery of axonal injury in white matter (WM) tracts after TBI. Growth hormone deficiency (GHD) after TBI may impair axonal and neuropsychological recovery, and serum IGF-I may mediate this effect. We conducted a longitudinal study to determine the effects of baseline serum IGF-I concentrations on WM tract and neuropsychological recovery after TBI.Methods: Thirty-nine adults after TBI (84.6% male; age median 30.5y; 87.2% moderate-severe; time since TBI median 16.3 months, n=4 with GHD) were scanned twice, 13.3 months (12.1-14.9) apart, and 35 healthy controls scanned once. Symptom and quality of life questionnaires and cognitive assessments were completed at both visits (n=33). Our main outcome measure was fractional anisotropy (FA), a measure of WM tract integrity, in a priori regions of interest: splenium of corpus callosum (SPCC), and posterior limb of internal capsule (PLIC).Results: At baseline, FA was reduced in many WM tracts including SPCC and PLIC following TBI compared to controls, indicating axonal injury, with longitudinal increases indicating axonal recovery. There was a significantly greater increase in SPCC FA over time in patients with serum IGF-I above vs. below the median-for-age. Only the higher IGF-I group had significant improvements in immediate verbal memory recall over time.Interpretation: WM recovery and memory improvements after TBI were greater in patients with higher serum IGF-I at baseline. These findings suggest that GH/IGF-I system may be a potential therapeutic target following TBI. This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-02T06:45:30.502207-05:
      DOI: 10.1002/ana.24971
  • Sodium intake and multiple sclerosis activity and progression in BENEFIT
    • Authors: Kathryn C Fitzgerald; Kassandra L Munger, Hans P Hartung, Mark S Freedman, Xavier Montalbán, Gilles Edan, Eva-Maria Wicklein, Ernst-Wilhelm Radue, Ludwig Kappos, Christoph Pohl, Alberto Ascherio
      Abstract: Objective: To assess whether a high-salt diet, as measured by urinary sodium concentration, is associated with faster conversion from clinically isolated syndrome (CIS) to multiple sclerosis (MS) and MS activity and disability.Methods: BENEFIT was a randomized clinical trial comparing early versus delayed interferon beta-1b treatment in 465 patients with a CIS. Each patient provided a median of 14 (IQR: 13 to 16) spot urine samples throughout the 5-year follow-up. We estimated 24-hour urine sodium excretion level at each time point using the Tanaka equations, and assessed whether sodium levels estimated from the cumulative average of the repeated measures were associated with clinical (conversion to MS, EDSS) and magnetic resonance imaging (MRI) outcomes.Results: Average 24-hour urine sodium levels were not associated with conversion to clinically-definite MS over the 5-year follow-up (hazard ratio [HR]=0.91; 95% CI: 0.67-1.24 per 1g increase in estimated daily sodium intake); nor were they associated with clinical or MRI outcomes (new active lesions after 6 months HR: 1.05; 95% CI 0.97-1.13; relative change in T2 lesion volume: -0.11; 95% CI -0.25-0.04; change in EDSS: -0.01; 95% CI: -0.09-0.08; relapse rate HR: 0.78; 95% CI: 0.56-1.07). Results were similar in categorical analyses using quintiles.Interpretation: Our results, based on multiple assessments of urine sodium excretion over 5 years and standardized clinical and MRI follow-up, suggest that salt intake does not influence MS disease course or activity. This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-26T19:45:28.492604-05:
      DOI: 10.1002/ana.24965
  • A simple blood test expedites the diagnosis of GLUT1 deficiency syndrome
    • Authors: Domitille Gras; Christelle Cousin, Caroline Kappeler, Cheuk-Wing Fung, Stéphane Auvin, Nouha Essid, Brian Hy Chung, Lydie Da Costa, Elodie Hainque, Marie-Pierre Luton, Vincent Petit, Sandrine Vuillaumier-Barrot, Odile Boespflug-Tanguy, Emmanuel Roze, Fanny Mochel
      Abstract: GLUT1 deficiency syndrome (GLUT1-DS) leads to a wide range of neurological symptoms. Ketogenic diets are very efficient to control epilepsy and movement disorders. We tested a novel simple and rapid blood test in 30 patients with GLUT1-DS with predominant movement disorders, 18 patients with movement disorders due to other genetic defects and 346 healthy controls. We detected significantly reduced GLUT1 expression only on red blood cells from patients with GLUT1-DS (23 patients, 78%), including patients with inconclusive genetic analysis. This test opens perspectives for the screening of GLUT1-DS in children and adults with cognitive impairment, movement disorder or epilepsy. This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-26T19:45:25.848323-05:
      DOI: 10.1002/ana.24970
  • Decreased plasma β-amyloid in the Alzheimer's disease APP A673T
           variant carriers
    • Authors: Henna Martiskainen; Sanna-Kaisa Herukka, Alena Stančáková, Jussi Paananen, Hilkka Soininen, Johanna Kuusisto, Markku Laakso, Mikko Hiltunen
      Abstract: We investigated the association of Alzheimer's disease-related rare variants APP A673T and ABCA7 rs200538373-C with the levels of β-amyloid (Aβ) and parameters of metabolic and cardiovascular health in a population-based cohort of healthy middle-aged and elderly men. Carriers of protective APP A673T variant had on average 28% lower levels of Aβ40 and Aβ42 in plasma as compared to the controls and the carriers of ABCA7 rs200538373-C. This is the first report to show decreased Aβ levels in plasma in APP A673T carriers and thus provides evidence that lower Aβ levels throughout the life may be protective against Alzheimer's disease. This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-26T19:45:24.384588-05:
      DOI: 10.1002/ana.24969
  • The genetic landscape of familial congenital hydrocephalus
    • Authors: Ranad Shaheen; Mohammed Adeeb Sebai, Nisha Patel, Nour Ewida, Wesam Kurdi, Ikhlass Altweijri, Sameera Sogaty, Elham Almardawi, Mohammed Zain Seidahmed, Abdulrahman Alnemri, Sateesh Madirevula, Niema Ibrahim, Firdous Abdulwahab, Mais Hashem, Tarfa Al-Sheddi, Rana Alomar, Eman Alobeid, Bahauddin Sallout, Badi AlBaqawi, Wajeih AlAali, Nouf Ajaji, Harry Lesmana, Robert J Hopkin, Lucie Dupuis, Roberto Mendoza-Londono, Hadeel Al Rukban, Grace Yoon, Eissa Faqeih, Fowzan S Alkuraya
      Abstract: Objective: Congenital hydrocephalus is an important birth defect, the genetics of which remains incompletely understood. To date, only four genes are known to cause Mendelian diseases in which congenital hydrocephalus is the main or sole clinical feature, two X-linked (L1CAM and AP1S2) and two autosomal recessive (CCDC88C and MPDZ). In this study, we aimed to determine the genetic etiology of familial congenital hydrocephalus with the assumption that these cases represent Mendelian forms of the disease.Methods: Exome sequencing combined, where applicable, with positional mapping.Results: We identified a likely causal mutation in the majority of these families (21/27, 78%), spanning 16 genes, none of which is X-linked. Ciliopathies and dystroglycanopathies were the most common etiologies of congenital hydrocephalus in our cohort (19% and 26%, respectively). In one family with four affected members, we identified a homozygous truncating variant in EML1, which we propose as a novel cause of congenital hydrocephalus in addition to its suggested role in cortical malformation. Similarly, we show that recessive mutations in WDR81, previously linked to cerebellar ataxia, mental retardation, and dysequilibrium syndrome 2, cause severe congenital hydrocephalus. Furthermore, we confirm the previously reported candidacy of MPDZ by presenting a phenotypic spectrum of congenital hydrocephalus associated with five recessive alleles.Interpretation: Our study highlights the importance of recessive mutations in familial congenital hydrocephalus and expands the locus heterogeneity of this condition. This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-26T19:40:30.835484-05:
      DOI: 10.1002/ana.24964
  • Differential Neuronal Susceptibility and Apoptosis in Congenital ZIKV
    • Authors: Cheng-Ying Ho; Heather M. Ames, Ashley Tipton, Gilbert Vezina, Judy S. Liu, Joseph Scafidi, Masaaki Torii, Fausto J. Rodriguez, Adre du Plessis, Roberta L. DeBiasi
      Abstract: To characterize the mechanism of ZIKV-associated microcephaly, we perform immunolabeling on brain tissue from a 20-week fetus with intrauterine ZIKV infection. While ZIKV demonstrated a wide range of neuronal and non-neuronal tropism, the infection rate was highest in intermediate progenitor cells and immature neurons. Apoptosis was observed in both infected and uninfected bystander cortical neurons, suggesting a role for paracrine factors in induction of neuronal apoptosis. Our results highlight differential neuronal susceptibility and neuronal apoptosis as potential mechanisms in the development of ZIKV-associated microcephaly, and may provide insights into the design and best timing of future therapy. This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-26T19:40:28.325311-05:
      DOI: 10.1002/ana.24968
  • Phenobarbital and Midazolam Increase Neonatal Seizure-Associated Neuronal
    • Authors: Daniel Torolira; Lucie Suchomelova, Claude G. Wasterlain, Jerome Niquet
      Abstract: Status Epilepticus is common in neonates and infants, and is associated with neuronal injury and adverse developmental outcomes. GABAergic drugs, the standard treatment for neonatal seizures, can have excitatory effects in the neonatal brain, which may worsen the seizures and their effects. Using a recently developed model of status epilepticus in P7 rat pups that results in widespread neuronal injury, we found that the GABAA agonists phenobarbital and midazolam significantly increased Status Epilepticus-associated neuronal injury in various brain regions. Our results suggest that more research is needed into the possible deleterious effects of GABAergic drugs on neonatal seizures and on excitotoxic neuronal injury in the immature brain. This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-26T19:40:26.887823-05:
      DOI: 10.1002/ana.24967
  • Reduced glial activity after surgery: A sign of immunoparalysis of the
    • Authors: Annemieke M. Peters van Ton; Matthijs Kox, Peter Pickkers, Wilson F. Abdo
      PubDate: 2017-05-26T19:40:25.765858-05:
      DOI: 10.1002/ana.24966
  • The repetition of behavioral assessments in diagnosis of disorders of
    • Authors: Sarah Wannez; Lizette Heine, Marie Thonnard, Olivia Gosseries, Steven Laureys,
      Abstract: Objective: To determine whether repeated examinations using the Coma Recovery Scale-Revised have an impact on diagnostic accuracy of patients with disorders of consciousness and to provide guidelines regarding the number of assessments required for obtaining a reliable diagnosis.Methods: 123 adult patients with chronic disorders of consciousness were referred to our tertiary center. They were assessed at least 6 times with the Coma Recovery Scale-Revised within a 10-day period. Clinical diagnoses based on 1, 2, 3, 4, and 5 Coma Recovery Scale-Revised assessments were compared with a reference diagnosis (i.e., the highest behavioral diagnosis obtained after 6 evaluations) using non-parametric statistics. Results were considered significant at P
      PubDate: 2017-05-22T18:40:28.900111-05:
      DOI: 10.1002/ana.24962
  • Neuroimaging Biomarkers and Impaired Olfaction in Cognitively Normal
    • Authors: Maria Vassilaki; Teresa J. Christianson, Michelle M. Mielke, Yonas E. Geda, Walter K. Kremers, Mary M. Machulda, David S. Knopman, Ronald C. Petersen, Val J. Lowe, Clifford R. Jack, Rosebud O. Roberts
      Abstract: Objective: There is a need for inexpensive non-invasive tests to identify older healthy persons at risk for Alzheimer's disease (AD) for enrollment in AD prevention trials. Our objective was to examine whether abnormalities in neuroimaging measures of amyloid and neurodegeneration are correlated with odor identification (OI) in the population-based Mayo Clinic Study of Aging (MCSA).Methods: Cognitively normal (CN) participants had olfactory function assessed using the Brief Smell Identification Test (B-SIT), underwent magnetic resonance imaging (MRI; n=829) to assess a composite Alzheimer's disease (AD) signature cortical thickness and hippocampal volume (HVa), and, 11C-Pittsburgh compound B (11C-PiB; n=306) and 18fluorodeoxyglucose (18F-FDG; n=305) positron emission tomography (PET) scanning to assess amyloid accumulation and brain hypometabolism, respectively. The association of neuroimaging biomarkers with OI was examined using multinomial logistic regression and simple linear regression models adjusted for potential confounders.Results: Among 829 CN participants (mean age 79.2 years; 51.5% men), 248 (29.9%) were normosmic and 78 (9.4%) had anosmia (B-SIT score
      PubDate: 2017-05-22T18:40:27.940631-05:
      DOI: 10.1002/ana.24960
  • The Missing, The Short, and The Long: L-Dopa Responses and Dopamine
    • Authors: Roger L. Albin; Daniel K. Leventhal
      Abstract: We attempt to correlate the clinical pharmacology of dopamine replacement therapy (DRT) in Parkinson Disease with known features of striatal dopamine actions. Despite its obvious impact, DRT does not normalize motor function, likely due to disrupted phasic dopaminergic signaling. The DRT Short Duration Response is likely a permissive-paracrine effect, possibly resulting from dopaminergic support of corticostriate synaptic plasticity. The DRT Long Duration Response may result from mimicry of tonic dopamine signaling regulation of movement vigor. Our understanding of dopamine actions does not explain important aspects of DRT clinical pharmacology. Reducing these knowledge gaps provides opportunities to improve understanding of dopamine actions and symptomatic treatment of Parkinson disease. This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-22T18:40:24.676883-05:
      DOI: 10.1002/ana.24961
  • Fletcher H. McDowell MD 1923-2017
    • Authors: Jesse M. Cedarbaum; Mindy Aisen, Bruce T. Volpe
      PubDate: 2017-05-22T18:40:23.328855-05:
      DOI: 10.1002/ana.24959
  • Serum neurofilament light: A biomarker of neuronal damage in multiple
    • Authors: Giulio Disanto; Christian Barro, Pascal Benkert, Yvonne Naegelin, Sabine Schädelin, Antonella Giardiello, Chiara Zecca, Kaj Blennow, Henrik Zetterberg, David Leppert, Ludwig Kappos, Claudio Gobbi, Jens Kuhle,
      Abstract: Objective: Neurofilament light chains (NfL) are unique to neuronal cells, are shed to the CSF and are detectable at low concentrations in peripheral blood. Various diseases causing neuronal damage have resulted in elevated CSF concentrations. We explored the value of an ultrasensitive single-molecule array (Simoa) serum NfL (sNfL) assay in MS.Methods: sNfL levels were measured in healthy controls (HC, n=254) and two independent MS cohorts: (1) cross-sectional with paired serum and CSF samples (n=142); (2) longitudinal with repeated serum sampling (n=246, median (IQR) follow-up 3.1 (2.0-4.0) years). We assessed their relation to concurrent clinical, imaging and treatment parameters and to future clinical outcomes.Results: sNfL levels were higher in both MS cohorts than in HC (p
      PubDate: 2017-05-16T21:00:34.447001-05:
      DOI: 10.1002/ana.24954
  • Erratum
    • PubDate: 2017-05-16T02:30:25.23738-05:0
      DOI: 10.1002/ana.24942
  • CT Perfusion to Predict Response to Recanalization in Ischemic Stroke
    • Authors: Maarten G. Lansberg; Soren Christensen, Stephanie Kemp, Michael Mlynash, Nishant Mishra, Christian Federau, Jenny P Tsai, Sun Kim, Raul G Nogueria, Tudor Jovin, Thomas G Devlin, Naveed Akhtar, Dileep R Yavagal, Diogo Haussen, Seena Dehkharghani, Roland Bammer, Matus Straka, Greg Zaharchuk, Michael P. Marks, Gregory W. Albers,
      Abstract: Objective: To assess the utility of CT perfusion for selection of patients for endovascular therapy up to 18 hours after symptom onset.Methods: We conducted a multicenter cohort study of consecutive acute stroke patients scheduled to undergo endovascular therapy within 90 min after a baseline CTP. Patients were classified as ‘target mismatch' if they had a small ischemic core and a large penumbra on their baseline CT perfusion. Reperfusion was defined as>50% reduction in critical hypoperfusion between the baseline CT perfusion and the 36-hour follow-up MRI.Results: Of the 201 patients enrolled, 190 patients with an adequate baseline CT perfusion study who underwent angiography were included; mean age 66 years, median NIHSS 16, median time from symptom onset to endovascular therapy 5.2 hours. Rate of reperfusion was 89%. In patients with target mismatch (n=131), reperfusion was associated with higher odds of favorable clinical response, defined as an improvement of ≥8 points on the NIH Stroke Scale (83% vs 44%, p=0.002; adjusted OR=6.6; 95% CI 2.1-20.9). This association did not differ between patients treated within 6 hrs (OR = 6.4; 95% CI 1.5-27.8) and those treated beyond 6 hrs after symptom onset (OR = 13.7; 95% CI 1.4-140).Interpretation: The robust association between endovascular reperfusion and good outcome among patients with the CT perfusion target mismatch profile treated up to 18 hours after symptom onset supports a randomized trial of endovascular therapy in this patient population. This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-09T17:35:43.970751-05:
      DOI: 10.1002/ana.24953
  • Nonpublication of Trial Results for New Neurological Drugs: A Systematic
    • Authors: Amanda K Hakala; Dean Fergusson, Jonathan Kimmelman
      Abstract: Objective: To evaluate nonpublication rates among trials of new successful and unsuccessful neurological drugs.Methods: ‘Licensed' drugs consisted of all novel agents receiving FDA licensure 2005 to 2012 inclusive in seven neurological disorders. ‘Stalled' drugs included all experimental agents tested in the same domains that had at least one completed phase III trial in the same timeframe but failed to receive FDA approval. Trials of these drugs were included in our sample if their primary outcome collection occurred before October 1, 2010. We determined the publication status of eligible trials using searches of, Google Scholar, PubMed, Embase, sponsor websites, and direct electronic query of trial contacts and sponsors. The primary outcome was time to journal publication (or results reporting in other media) after study completion.Results: The adjusted hazard ratio for publication was 1.79 (95% confidence interval 1.20 to 2.67) in favour of licensed drugs. Based on the criteria for nonpublication in this report, 14,092 and 33,882 volunteers participated in unpublished trials of licensed and stalled neurological drugs, respectively. Result data were not publicly available in any form for 10% (16/163) and 46% (94/203) of trials of licensed and stalled drugs, respectively.Interpretation: Results of trials for stalled drugs are heavily underreported. This deprives research and care communities of evidence about pathophysiology, drug class effects, and the value of surrogate endpoints in trials. This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-09T17:35:36.56347-05:0
      DOI: 10.1002/ana.24952
  • Chemotherapy-Induced Peripheral Neuropathy: A Current Review
    • Authors: Nathan P. Staff; Anna Grisold, Wolfgang Grisold, Anthony J. Windebank
      Abstract: Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting side effect experienced by patients receiving treatment for cancer. Approximately 30-40% of patients treated with neurotoxic chemotherapy will develop CIPN and there is considerable variability in its severity between patients. It is often sensory-predominant with pain and can lead to long-term morbidity in survivors. The prevalence and burden of CIPN late effects will likely increase as cancer survival rates continue to improve. In this review, we discuss the approach to peripheral neuropathy in patients with cancer and address the clinical phenotypes and pathomechanisms of specific neurotoxic chemotherapeutic agents. This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-09T17:35:31.286728-05:
      DOI: 10.1002/ana.24951
  • Pyrimethamine Significantly Lowers CSF/SOD1 in ALS Patients With SOD1
    • Authors: Dale J. Lange; Mona Shahbazi, Vincenzo Silani, Albert C. Ludolph, Jochen H. Weishaupt, Senda Ajroud-Driss, Kara G. Fields, Rahul Remanan, Stanley H. Appel, Claudia Morelli, Alberto Doretti, Luca Maderna, Stefano Messina, Ulrike Weiland, Stefan L. Marklund, Peter M. Andersen
      Abstract: Background: Cu/Zn superoxide dismutase (SOD1) reduction prolongs survival in SOD1-transgenic animal models. Pyrimethamine produces dose dependent SOD1 reduction in cell culture systems. A previous phase-1 trial showed pyrimethamine lowers SOD1 levels in leucocytes in patients with SOD1 mutations. This study investigated whether pyrimethamine lowered SOD1 levels in the cerebrospinal fluid (CSF) in patients carrying SOD1 mutations linked to ALS (fALS/SOD1).Methods and Study Design: Multicenter (5 sites), open-label, 9-month duration, dose-ranging, to determine safety and efficacy of pyrimethamine to lower SOD1 levels in the CSF of FALS/SOD1. All participants underwent 3 lumbar punctures, blood draw, clinical assessment of strength, motor function, quality of life, and adverse effects assessments. SOD1 levels were measured in erythrocytes and CSF. Pyrimethamine was measured in plasma and CSF. Appel ALS, ALSFRS-R and single item McGill Quality of Life (SIS-MQoL) were measured at screening, visit 6 and 9.Results: We enrolled 32 patients; 24 completed 6 visits (18 weeks) and 21 completed all study visits. A linear mixed effects model showed a significant reduction in CSF SOD1 at visit 6 (p
      PubDate: 2017-05-08T03:33:33.542739-05:
      DOI: 10.1002/ana.24950
  • Letter on “Natural history of pure autonomic failure: A United States
           prospective cohort.”
    • Authors: Michael H. Silber; Bradley F. Boeve, Erik K. St. Louis
      PubDate: 2017-05-04T17:20:35.247215-05:
      DOI: 10.1002/ana.24948
  • Pure autonomic failure vs. manifest CNS synucleinopathy: Relevance of
           stridor and autonomic biomarkers
    • Authors: Horacio Kaufmann; Lucy Norcliffe-Kaufmann, Jose-Alberto Palma,
      PubDate: 2017-05-04T17:20:33.127602-05:
      DOI: 10.1002/ana.24949
  • Viral Tracing of Presynaptic Inputs to Newly Born Dentate Granule Cells in
           a Rodent Model of mesial Temporal Lobe Epilepsy
    • Authors: Scott C. Baraban
      PubDate: 2017-05-03T18:25:56.033591-05:
      DOI: 10.1002/ana.24945
  • Sublethal oligodendrocyte injury: A reversible condition in multiple
    • Authors: Qiao-Ling Cui; Damla Khan, Malena Rone, Vijayaraghava Rao, Radia Marie Johnson, Yun Hsuan Lin, Philippe-Antoine Bilodeau, Jeffery A. Hall, Moses Rodriguez, Timothy E. Kennedy, Samuel K. Ludwin, Jack P. Antel
      Abstract: Objective: Degeneration of oligodendroglial distal processes has been identified as an early event in MS lesion development. Our objective was to further define the development of the “dying-back” oligodendrocyte lesion in situ and to model the development and potential reversibility of such responses using dissociated cultures of adult human brain-derived oligodendrocytes.Methods In situ analyses were performed on glutaraldehyde-fixed thin sections of clinically acute and pathologically active cases of MS. In vitro studies were conducted using adult human brain-derived oligodendrocytes challenged by metabolic stress conditions (low nutrient/glucose).Results: In situ analyses indicated a spectrum of myelin changes in the presence of morphologically intact oligodendrocytes; these included degeneration of the inner cytoplasmic tongue with increasing sizes of intramyelinic bleb formation that could result in radial fractures of the myelin sheath. Macrophages with ingested myelin fragments were identified only once the fragmentation was established.In vitro studies indicated that oligodendrocyte process retraction that was linked to reduced glycolytic respiratory activity is reversible until a critical time point. Subsequent cell death was not linked to caspase-3 dependent programs. Gene expression studies conducted at the latest reversible time point revealed reduced expression of pathways associated with cell process outgrowth and myelination, as well as with metabolic activity.Interpretation: Our findings reveal the potential to protect and possibly restore myelin elaborated by existent oligodendrocytes in early and evolving MS lesions, and suggest the necessity of ongoing studies on the mechanisms underlying subsequent adult human oligodendrocyte cell death. This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-03T18:25:53.464436-05:
      DOI: 10.1002/ana.24944
  • STN-DBS is neuroprotective in the A53T α-synuclein Parkinson's
           disease rat model
    • Authors: Thomas Musacchio; Maike Rebenstorff, Felix Fluri, Jonathan M. Brotchie, Jens Volkmann, James B. Koprich, Chi Wang Ip
      Abstract: Objective: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a highly effective symptomatic therapy for motor deficits in Parkinson's disease (PD). An additional, disease-modifying effect has been suspected from studies in toxin-based PD animal models, but these models do not reflect the molecular pathology and progressive nature of PD, that would be required to evaluate a disease-modifying action. Defining a disease-modifying effect, could radically change the way in which DBS is used in PD.Methods: We applied STN-DBS in an AAV1/2-driven human mutated A53T α-synuclein (aSyn)-overexpressing PD rat model (AAV1/2-A53T-aSyn). Rats were injected unilaterally, in the substantia nigra (SN), with AAV1/2-A53T-aSyn or control vector. Three weeks later, after behavioural and nigrostriatal dopaminergic deficits had developed, rats underwent STN-DBS electrode implantation ipsilateral to the vector-injected SN. Stimulation lasted for three weeks. Control groups remained OFF stimulation. Animals were sacrificed at six weeks.Results: Motor performance in the single pellet reaching task was impaired in the AAV1/2-A53T-aSyn injected stim-OFF group, six weeks after AAV1/2-A53T-aSyn injection, compared to pre-operative levels (-82%, P
      PubDate: 2017-05-03T18:25:34.283852-05:
      DOI: 10.1002/ana.24947
  • Early prediction of coma recovery after cardiac arrest with blinded
    • Authors: Daria Solari; Andrea O. Rossetti, Laurent Carteron, John-Paul Miroz, Jan Novy, Philippe Eckert, Mauro Oddo
      Abstract: ObjectivesPrognostication studies on comatose cardiac arrest (CA) patients are limited by lack of blinding, potentially causing overestimation of outcome predictors and self-fulfilling prophecy. Using a blinded approach, we analysed the value of quantitative automated pupillometry to predict neurological recovery after CA.MethodsWe examined a prospective cohort of 103 comatose adult patients who were unconscious 48 hours after CA and underwent repeated measurements of quantitative pupillary light reflex (PLR) using the Neurolight-Algiscan® device. Clinical examination, electroencephalography (EEG), somatosensory evoked potentials (SSEP) and serum neuron specific enolase (NSE) were performed in parallel, as part of standard multimodal assessment. Automated pupillometry results were blinded to clinicians involved in patient care. Cerebral Performance Categories (CPC) at 1 year was the outcome endpoint.ResultsSurvivors (n=50 patients; 32 CPC 1, 16 CPC 2, 2 CPC 3) had higher quantitative PLR (median 20 [range 13-41] vs. 11 [0-55] %, p
      PubDate: 2017-05-03T18:20:56.594268-05:
      DOI: 10.1002/ana.24943
  • Rabies Tracing of Birthdated Dentate Granule Cells in Rat Temporal Lobe
    • Authors: Xi Du; Helen Zhang, Jack M. Parent
      Abstract: Objective: To understand how monosynaptic inputs onto adult-born dentate granule cells (DGCs) are altered in experimental mesial temporal lobe epilepsy (mTLE) and whether their integration differs from early-born DGCs that are mature at the time of epileptogenesis.Methods: A dual-virus tracing strategy combining retroviral birthdating with rabies virus-mediated putative retrograde trans-synaptic tracing was used to identify and compare presynaptic inputs onto adult- and early-born DGCs in the rat pilocarpine model of mTLE.Results: Our results demonstrate that hilar ectopic DGCs preferentially synapse onto adult-born DGCs after pilocarpine-induced status epilepticus (SE) while normotopic DGCs synapse onto both adult- and early-born DGCs. We also find that parvalbumin+ and somatostatin+ interneuron inputs are greatly diminished onto early-born DGCs after SE. However, somatostatin+ interneuron inputs onto adult-born DGCs are maintained, likely due to preferential sprouting. Intriguingly, CA3 pyramidal cell backprojections that specifically target adult-born DGCs arise in the epileptic brain, while axons of interneurons and pyramidal cells in CA1 appear to sprout across the hippocampal fissure to preferentially synapse onto early-born DGCs.Interpretation: These data support the presence of substantial hippocampal circuit remodeling after an epileptogenic insult that generates prominent excitatory monosynaptic inputs, both local recurrent and widespread feedback loops, involving DGCs. Both adult- and early-born DGCs are targets of new inputs from other DGCs as well as from CA3 and CA1 pyramidal cells after pilocarpine-treatment, changes that likely contribute to epileptogenesis in experimental mTLE. This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-03T18:20:48.996103-05:
      DOI: 10.1002/ana.24946
  • Brain Regions Essential for Word Comprehension: Drawing Inferences from
    • Authors: Argye E. Hillis; Christopher Rorden, Julius Fridriksson
      First page: 759
      Abstract: Lesion-deficit association studies are important as they can reveal brain regions essential for specific functions, but sometimes appear to yield conflicting results. We aimed to show how pitfalls of lesions studies can be avoided, and converging results obtained, illustrating from studies of the role of posterior superior temporal gyrus in auditory word comprehension. We review published lesion studies on auditory comprehension and present new data from both acute and chronic stroke that address weaknesses in some previous studies. Results demonstrate how convergence of positive results from diverse lesion studies provides strong evidence for the role of a particular region in a given behavior. This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-26T18:55:31.552415-05:
      DOI: 10.1002/ana.24941
  • Involvement of the cerebellum in Parkinson's disease and Dementia with
           Lewy bodies
    • Authors: K Seidel; M Bouzrou, N Heidemann, R Krüger, L Schöls, WFA den Dunnen, H-W Korf, U Rüb
      First page: 898
      Abstract: Patient brains with Parkinson's disease or Dementia with Lewy bodies show aggregation of alpha-synuclein in pre-cerebellar brainstem structures. Furthermore, patients exhibit resting tremor, unstable gait and impaired balance which may be associated with cerebellar dysfunction. Therefore, we screened the cerebella of 12 patients with alpha-synucleinopathies for neuropathological changes. Cerebellar nuclei and neighboring white matter displayed numerous aggregates, while lobules were mildly affected. Cerebellar aggregation pathology may suggest a prion-like spread originating from affected precerebellar structures and the high homogeneity between patients with Dementia with Lewy bodies and Parkinson's disease shows that both diseases likely belong to the same neuropathological spectrum. This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-25T03:50:51.956341-05:
      DOI: 10.1002/ana.24937
  • Rigor, Reproducibility and in vitro CSF assays: The Devil in the Details
    • Authors: Olivia A. Moody; Sahil Talwar, Meagan A. Jenkins, Amanda A. Freeman, Lynn Marie Trotti, Paul S. García, Donald Bliwise, Joseph W. Lynch, Brad Cherson, Eric M Hernandez, Neil Feldman, Prabhjyot Saini, David B. Rye, Andrew Jenkins
      First page: 904
      PubDate: 2017-04-25T03:50:55.280535-05:
      DOI: 10.1002/ana.24940
  • Confirmation of absence of GABA-A receptor potentiation in idiopathic
    • Authors: Yves Dauvilliers; Pierre Charnet
      First page: 907
      PubDate: 2017-04-25T03:51:00.568628-05:
      DOI: 10.1002/ana.24939
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