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Publisher: John Wiley and Sons   (Total: 1582 journals)

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Showing 1 - 200 of 1583 Journals sorted alphabetically
Abacus     Hybrid Journal   (Followers: 11, SJR: 0.48, h-index: 22)
About Campus     Hybrid Journal   (Followers: 5)
Academic Emergency Medicine     Hybrid Journal   (Followers: 53, SJR: 1.385, h-index: 91)
Accounting & Finance     Hybrid Journal   (Followers: 43, SJR: 0.547, h-index: 30)
ACEP NOW     Free  
Acta Anaesthesiologica Scandinavica     Hybrid Journal   (Followers: 50, SJR: 1.02, h-index: 88)
Acta Archaeologica     Hybrid Journal   (Followers: 132, 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: 54, SJR: 0.794, h-index: 88)
Acta Physiologica     Hybrid Journal   (Followers: 7, 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: 5, SJR: 0.459, h-index: 29)
Acute Medicine & Surgery     Hybrid Journal   (Followers: 2)
Addiction     Hybrid Journal   (Followers: 32, 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: 25, SJR: 0.81, h-index: 81)
Advanced Functional Materials     Hybrid Journal   (Followers: 47, SJR: 5.21, h-index: 203)
Advanced Healthcare Materials     Hybrid Journal   (Followers: 13, SJR: 0.232, h-index: 7)
Advanced Materials     Hybrid Journal   (Followers: 246, 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: 4, SJR: 2.488, h-index: 21)
Advanced Science     Open Access   (Followers: 4)
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: 33, SJR: 0.275, h-index: 17)
African J. of Ecology     Hybrid Journal   (Followers: 14, SJR: 0.477, h-index: 39)
Aggressive Behavior     Hybrid Journal   (Followers: 15, SJR: 1.391, h-index: 66)
Aging Cell     Open Access   (Followers: 9, 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: 28, 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: 33, 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: 126, 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: 89, SJR: 2.325, h-index: 51)
American J. of Economics and Sociology     Hybrid Journal   (Followers: 28, SJR: 0.211, h-index: 26)
American J. of Hematology     Hybrid Journal   (Followers: 30, 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 Orthopsychiatry     Hybrid Journal   (Followers: 4, SJR: 0.756, h-index: 69)
American J. of Physical Anthropology     Hybrid Journal   (Followers: 35, SJR: 1.41, h-index: 88)
American J. of Political Science     Hybrid Journal   (Followers: 234, SJR: 5.101, h-index: 114)
American J. of Primatology     Hybrid Journal   (Followers: 14, 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: 15, SJR: 2.792, h-index: 140)
American J. on Addictions     Hybrid Journal   (Followers: 9, SJR: 0.843, h-index: 57)
Anaesthesia     Hybrid Journal   (Followers: 115, 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: 15)
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: 152)
Angewandte Chemie Intl. Edition     Hybrid Journal   (Followers: 203, SJR: 6.229, h-index: 397)
Animal Conservation     Hybrid Journal   (Followers: 34, SJR: 1.576, h-index: 62)
Animal Genetics     Hybrid Journal   (Followers: 8, SJR: 0.957, h-index: 67)
Animal Science J.     Hybrid Journal   (Followers: 5, 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: 42, 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: 66, SJR: 0.754, h-index: 69)
Applied Organometallic Chemistry     Hybrid Journal   (Followers: 6, SJR: 0.632, h-index: 58)
Applied Psychology     Hybrid Journal   (Followers: 126, SJR: 1.023, h-index: 64)
Applied Psychology: Health and Well-Being     Hybrid Journal   (Followers: 47, 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: 13, 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: 24, 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: 201, SJR: 0.153, h-index: 13)
Arthritis & Rheumatology     Hybrid Journal   (Followers: 48, SJR: 1.984, h-index: 20)
Arthritis Care & Research     Hybrid Journal   (Followers: 26, 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: 13)
Asia & the Pacific Policy Studies     Open Access   (Followers: 15)
Asia Pacific J. of Human Resources     Hybrid Journal   (Followers: 316, 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: 3, 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: 7, 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: 3, 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: 42, 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: 21, 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: 16, SJR: 0.384, h-index: 30)
Australian J. of Public Administration     Hybrid Journal   (Followers: 380, 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: 64, 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: 9, 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: 3, 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: 7, SJR: 0.297, h-index: 23)
Behavioral Sciences & the Law     Hybrid Journal   (Followers: 21, 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: 2, SJR: 6.469, h-index: 114)
Biologie in Unserer Zeit (Biuz)     Hybrid Journal   (Followers: 44, 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: 37, 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: 134, 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: 17, SJR: 1.374, h-index: 71)
Bipolar Disorders     Hybrid Journal   (Followers: 10, SJR: 2.592, h-index: 100)
Birth     Hybrid Journal   (Followers: 33, 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)

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Journal Cover Annals of Neurology
  [SJR: 5.584]   [H-I: 241]   [42 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  [1582 journals]
  • The repetition of behavioral assessments in diagnosis of disorders of
           consciousness
    • 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
           Individuals
    • 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
           Actions
    • 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
           sclerosis
    • 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
           Review
    • 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 clinicaltrials.gov, 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
           Mutations
    • 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
           sclerosis'
    • 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
           pupillometry
    • 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
           Epilepsy
    • 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
           Patients
    • Authors: Argye E. Hillis; Christopher Rorden, Julius Fridriksson
      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
       
  • Confirmation of absence of GABA-A receptor potentiation in idiopathic
           hypersomnia
    • Authors: Yves Dauvilliers; Pierre Charnet
      PubDate: 2017-04-25T03:51:00.568628-05:
      DOI: 10.1002/ana.24939
       
  • 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
      PubDate: 2017-04-25T03:50:55.280535-05:
      DOI: 10.1002/ana.24940
       
  • 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
      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
       
  • Prognostic indicators in pediatric clinically isolated syndrome
    • Authors: Pietro Iaffaldano; Marta Simone, Giuseppe Lucisano, Angelo Ghezzi, Gabriella Coniglio, Vincenzo Brescia Morra, Giuseppe Salemi, Francesco Patti, Alessandra Lugaresi, Guillermo Izquierdo, Roberto Bergamaschi, Jose Antonio Cabrera-Gomez, Carlo Pozzilli, Enrico Millefiorini, Raed Alroughani, Cavit Boz, Eugenio Pucci, Giovanni Bosco Zimatore, Patrizia Sola, Giacomo Lus, Davide Maimone, Carlo Avolio, Eleonora Cocco, Seyed Aidin Sajedi, Gianfranco Costantino, Pierre Duquette, Vahid Shaygannejad, Thor Petersen, Ricardo Fernández Bolaños, Damiano Paolicelli, Carla Tortorella, Tim Spelman, Lucia Margari, Maria Pia Amato, Giancarlo Comi, Helmut Butzkueven, Maria Trojano, ,
      Abstract: Objective: To assess prognostic factors for a second clinical attack and a first disability worsening event in pediatric clinically isolated syndrome (pCIS) suggestive of Multiple Sclerosis (MS) patients.Methods: A cohort of 770 pCIS patients was followed-up for at least 10 years. Cox proportional hazard models and RECursive Partitioning and AMalgamation (RECPAM) tree-regression were used to analyze data.Results: In pCIS, female sex and a multifocal onset were risk factors for a second clinical attack (HR, 95% CI: 1.28, 1.06-1.55; 1.42, 1.10-1.84, respectively), whereas disease modifying drugs (DMDs) exposure reduced this risk (HR, 95% CI: 0.75, 0.60-0.95). After pediatric onset MS (POMS) diagnosis, age at onset younger than 15 years and DMDs exposure decreased the risk of a first EDSS worsening event (HR, 95% CI: 0.59, 0.42-0.83; 0.75, 0.71-0.80, respectively), whereas the occurrence of relapse/s increased this risk (HR, 95% CI: 5.08, 3.46-7.46).An exploratory RECPAM analysis highlighted a significant higher incidence of a first EDSS worsening event in patients with multifocal or isolated spinal-cord or optic neuritis involvement at onset in comparison to those with an isolated supratentorial or brainstem syndrome. A Cox regression model including RECPAM classes confirmed DMDs exposure as the most protective factor against EDSS worsening events and relapses as the most important risk factor for attaining EDSS worsening.Interpretation: This work represents an important step forward in identifying predictors of unfavorable course in pCIS and POMS and supports a protective effect of early DMDs treatment in preventing MS development and disability accumulation in this population. This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-25T03:50:31.180637-05:
      DOI: 10.1002/ana.24938
       
  • Lewis P. Rowland, MD 1925 - 2017
    • Authors: Timothy A. Pedley; Richard Mayeux
      PubDate: 2017-04-24T18:15:55.859434-05:
      DOI: 10.1002/ana.24934
       
  • Multiple sclerosis broke my heart
    • Authors: Géraldine Androdias; Emilien Bernard, Damien Biotti, Nicolas Collongues, Françoise Durand-Dubief, Julie Pique, Ingrid Sanchez, Clément Delmas, Jacques Ninet, Romain Marignier, Sandra Vukusic
      Abstract: We report 5 cases of acute heart failure (AHF) related to multiple sclerosis (MS) relapses. AHF was inaugural in 3 patients, always preceded or accompanied by signs of brainstem dysfunction; it was severe, requiring intensive care management. Echocardiography showed left ventricular hypokinesis. No other cause of AHF has been found. All patients showed a new medullary lesion on brain MRI. All had rapid and complete recovery of ventricular function after intravenous corticosteroids. We concluded to a takotsubo phenomenon. Physicians should be aware of rare cases of takotsubo cardiomyopathy in MS relapses. This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-24T18:15:53.581448-05:
      DOI: 10.1002/ana.24935
       
  • Blood biomarkers of carbohydrate, lipid and apolipoprotein metabolisms and
           risk of amyotrophic lateral sclerosis: A more than 20 year follow-up of
           the Swedish AMORIS cohort
    • Authors: Daniela Mariosa; Niklas Hammar, Håkan Malmström, Caroline Ingre, Ingmar Jungner, Weimin Ye, Fang Fang, Göran Walldius
      Abstract: Objective To assess the associations of blood biomarkers of carbohydrate, lipid and apolipoprotein metabolisms with the future risk of ALS.Methods In the Apolipoprotein-related MOrtality RISk (AMORIS) study, we enrolled 636,132 men and women during 1985-1996 in Stockholm, Sweden with measurements of serum glucose, total cholesterol, triglycerides, apolipoprotein B (apoB), and apolipoprotein A-I (apoA-I). Serum LDL-C and HDL-C were either directly measured or calculated from total cholesterol, triglycerides and apoA-I. The cohort was followed until end of 2011. We used Cox models and mixed-effects models to first estimate the associations between these biomarkers and ALS incidence, and secondly to assess the changes of these biomarkers during the 20 years before ALS diagnosis.Results One-unit increase of LDL-C (HR=1.14, 95%CI=1.02-1.27), apoB (HR=1.68, 95%CI=1.17-2.42) and apoB/apoA-I ratio (HR=1.90, 95%CI=1.29-2.78) was associated with a higher incidence of ALS. High glucose level (≥6.11 mmol/L) was associated with a lower incidence (HR=0.62, 95%CI=0.42-0.93), whereas high LDL-C/HDL-C (≥3.50; HR=1.50, 95%CI 1.15-1.96) and high apoB/apoA-I (≥0.90 for men, ≥0.8 for women; HR=1.41, 95%CI 1.04-1.90) ratios were associated with a higher incidence. During the 10 years before diagnosis, ALS patients had increasing levels of LDL-C, HDL-C, apoB and apoA-I, whereas gradually decreasing levels of LDL-C/HDL-C and apoB/apoA-I ratios.Interpretation Alterations in the carbohydrate, lipid and apolipoprotein metabolisms are associated with ALS risk and may serve as prodromal symptoms decades before ALS diagnosis. The imbalance between apoB and apoA-I as well as between LDL-C and HDL-C may be an etiologic mechanism for ALS and needs to be further studied. This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-24T18:15:47.92454-05:0
      DOI: 10.1002/ana.24936
       
  • Issue Information - Masthead
    • PubDate: 2017-04-22T02:07:36.686154-05:
      DOI: 10.1002/ana.24926
       
  • Issue Information - TOC
    • PubDate: 2017-04-22T02:07:36.619607-05:
      DOI: 10.1002/ana.24925
       
  • Annals of Neurology: Volume 81, Number 4, April 2017
    • Abstract: ON THE COVER: A photomicrograph of neuromuscular junctions in a normal control mouse triangular sterni muscle. Acetylcholine receptors on the postsynaptic membrane are stained red with alphabungarotoxin, and the motor axons are stained green with neurofilament NF150 and synaptotagmin-2 antibodies. In mice with mutations of the Vamp1 (vesicle associated membrane protein 1), which causes a congenital myasthenic syndrome similar to humans, the neuromuscular junctions are smaller. See Salpietro et al, pp. 597-603, this issue. Ann Neurol 2017;81:1–1
      PubDate: 2017-04-22T02:07:36.179297-05:
      DOI: 10.1002/ana.24923
       
  • Issue Information - Copyright
    • PubDate: 2017-04-22T02:07:35.318106-05:
      DOI: 10.1002/ana.24924
       
  • Global Exosome Transcriptome Profiling Reveals Biomarkers for Multiple
           Sclerosis
    • Authors: Igor Selmaj; Maria Cichalewska, Magdalena Namiecinska, Grazyna Galazka, Wojciech Horzelski, Krzysztof W. Selmaj, Marcin P. Mycko
      Abstract: Objective: Accumulating evidence supports a role for exosomes in immune regulation. In this study, we investigated the total circulating exosome transcriptome in relapsing-remitting multiple sclerosis patients (RRMS) and healthy controls (HC).Methods: Next generation sequencing (NGS) was used to define the global RNA profile of serum exosomes in 19 RRMS patients (9 in relapse, 10 in remission) and 10 HC. We analyzed 5 million reads and over 50,000 transcripts per sample, including a detailed analysis of microRNA (miRNA) differentially expressed in RRMS. The discovery set data were validated by quantification using digital quantitative PCR with an independent cohort of 63 RRMS patients (33 in relapse, 30 in remission) and 32 HC.Results: Exosomal RNA NGS revealed that of 15 different classes of transcripts detected 4 circulating exosomal sequences within the miRNA category were differentially expressed in RRMS patients vs HC: hsa-miR-122-5p, hsa-miR-196b-5p, hsa-miR-301a-3p and hsa-miR-532-5p. Serum exosomal expression of these miRNA was significantly decreased during relapse in RRMS. These miRNA were also decreased in patients with a gadolinium enhancement on brain magnetic resonance imaging. In vitro secretion of these miRNA by peripheral blood mononuclear cells was also significantly impaired in RRMS.Interpretation: These data show that circulating exosomes have a distinct RNA profile in RRMS. Since putative targets for these miRNA include the signal transducer and activator of transcription 3 and the cell cycle regulator aryl hydrocarbon receptor the data suggest a disturbed cell-to-cell communication in this disease. Thus exosomal miRNA might represent a useful biomarker to distinguish MS relapse. This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-15T03:30:39.175319-05:
      DOI: 10.1002/ana.24931
       
  • Focused ultrasound as a novel strategy for Alzheimer's disease
           therapeutics
    • Authors: Ying Meng; Matthew Volpini, Sandra Black, Andres M. Lozano, Kullervo Hynynen, Nir Lipsman
      Abstract: Despite decades of advances in the pathology, genetics and imaging of Alzheimer's disease (AD), there remain no effective treatments that significantly alter its natural history. Several late phase clinical trials, focused largely on amyloid beta metabolism and clearance, have unfortunately demonstrated no significant benefit in early AD patients. Recent work investigating blood-brain barrier opening using focused ultrasound in transgenic animal models has shown that repeated ultrasound administration coupled with microbubble-containing contrast can reduce plaque burden and reverse memory deficits. While the mechanisms underlying plaque clearance are under investigation, this image-guided, noninvasive technique appears promising. This article describes the rationale and underlying principles of focused ultrasound as applied to Alzheimer's disease and suggests that based on promising pre-clinical results, this technology, whether alone or in conjunction with targeted therapies, can be of potential benefit. This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-10T11:31:54.917213-05:
      DOI: 10.1002/ana.24933
       
  • Are midsagittal tissue bridges predictive of outcome after cervical spinal
           cord injury'
    • Authors: Eveline Huber; Patrice Lachappelle, Reto Sutter, Armin Curt, Patrick Freund
      Abstract: T2-weighted scans provided data on the extent and dynamics of neuronal tissue damage and midsagittal tissue bridges at the epicenter of traumatic cervical spinal cord lesions in 24 subacute tetraplegic patients. At one month post-injury, smaller lesion area and midsagittal tissue bridges identified those patients with lower extremity evoked potentials and better clinical recovery. Wider midsagittal tissue bridges and smaller lesions at one month post-injury were associated with neurological and functional recovery at 1 year follow-up. Neuroimaging biomarkers of lesion area and midsagittal tissue bridges are potential outcome predictors and patient stratifiers in both subacute and chronic clinical trials. This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-10T03:40:47.557886-05:
      DOI: 10.1002/ana.24932
       
  • A mutation in the Tubb4a gene leads to microtubule accumulation with
           hypomyelination and demyelination
    • Authors: Ian D. Duncan; Marianna Bugiani, Abigail B. Radcliff, John J. Moran, Camila Lopez-Anido, Phu Duong, Benjamin K. August, Nicole I. Wolf, Marjo S. van der Knaap, John Svaren
      Abstract: Objective: Our goal was to define the genetic cause of the profound hypomyelination in the taiep rat model and determine its relevance to human white matter disease.Methods: Based on previous localization of the taiep mutation to rat chromosome 9, we tested if the mutation resided within the Tubb4a (β-tubulin 4A) gene, since mutations in the TUBB4A gene have been described in patients with CNS hypomyelination. To determine whether accumulation of microtubules led to progressive demyelination we analyzed the spinal cord and optic nerves of 2 year old rats by light and electron microscopy. Cerebral white matter from a patient with TUBB4A Asn414Lys mutation and MRI evidence of severe hypomyelination was studied similarly.Results: As the taiep rat ages there is progressive loss of myelin in the brain and dorsal column of the spinal cord associated with increased oligodendrocyte numbers with accumulation of microtubules. This accumulation involved the entire cell body and distal processes of oligodendrocytes but there was no accumulation of microtubules in axons. A single point mutation in Tubb4a (p.Ala302Thr) was found in homozygous taiep samples. A similar hypomyelination associated with increased oligodendrocyte numbers and arrays of microtubules in oligodendrocytes was demonstrated in the human patient sample.Interpretation: The taiep rat is the first animal model of TUBB4 mutations in humans and a novel system in which to test the mechanism of microtubule accumulation. The finding of microtubule accumulation in a patient with a TUBB4A mutation and leukodystrophy confirms the usefulness of taiep as a model of the human disease. This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-10T03:40:43.076059-05:
      DOI: 10.1002/ana.24930
       
  • Myoclonus epilepsy and ataxia due to KCNC1 mutation: Analysis of 20 cases
           and K+ channel properties
    • Authors: Karen L. Oliver; Silvana Franceschetti, Carol J. Milligan, Mikko Muona, Simone A. Mandelstam, Laura Canafoglia, Anna M. Boguszewska-Chachulska, Amos Korczyn, Francesca Bisulli, Carlo Di Bonaventura, Francesca Ragona, Roberto Michelucci, Bruria Ben-Zeev, Rachel Straussberg, Ferruccio Panzica, João Massano, Daniel Friedman, Arielle Crespel, Bernt A. Engelsen, Frederick Andermann, Eva Andermann, Krystyna Spodar, Anetta Lasek-Bal, Patrizia Riguzzi, Elena Pasini, Paolo Tinuper, Laura Licchetta, Elena Gardella, Matthias Lindenau, Annette Wulf, Rikke S. Møller, Felix Benninger, Zaid Afawi, Guido Rubboli, Christopher A. Reid, Snezana Maljevic, Holger Lerche, Anna-Elina Lehesjoki, Steven Petrou, Samuel F. Berkovic
      Abstract: Objective:To comprehensively describe the new syndrome of myoclonus epilepsy and ataxia due to potassium (K+) channel mutation (MEAK), including cellular electrophysiological characterization of observed clinical improvement with fever.Methods:We analysed clinical, electroclinical and neuroimaging data for twenty patients with MEAK due to recurrent KCNC1 p.R320H mutation. In vitro electrophysiological studies were conducted using whole cell patch clamp to explore biophysical properties of wild-type and mutant KV3.1 channels.Results:Symptoms began between 3-15 years (median 9.5) with progressively severe myoclonus and rare tonic-clonic seizures. Ataxia was present early but quickly became overshadowed by myoclonus; ten patients were wheelchair-bound by late teenage. Mild cognitive decline occurred in half. Early death was not observed. EEG showed generalized spike and polyspike wave discharges with documented photosensitivity in most. Polygraphic EEG-EMG studies demonstrated a cortical origin for myoclonus and striking co-activation of agonist and antagonist muscles. MRI revealed symmetrical cerebellar atrophy, that appeared progressive, and a prominent corpus callosum. Unexpectedly, transient clinical improvement with fever was noted in six patients. To explore this, we performed high temperature in vitro recordings. At elevated temperatures there was a robust left-shift in activation of wild-type KV3.1 increasing channel availability.Interpretation:MEAK has a relatively homogeneous presentation resembling Unverricht-Lundborg disease, despite the genetic and biological basis being quite different. A remarkable improvement with fever may be explained by the temperature-dependent left-shift in activation of wild-type KV3.1 subunit containing channels that would counter the loss-of-function observed for mutant channels, highlighting KCNC1 as a potential target for precision therapeutics. This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-05T18:32:01.606886-05:
      DOI: 10.1002/ana.24929
       
  • Randomized clinical trial of deep brain stimulation for post-stroke pain
    • Authors: Scott F. Lempka; Donald A. Malone, Bo Hu, Kenneth B. Baker, Alexandria Wyant, John Ozinga, Ela B. Plow, Mayur Pandya, Cynthia S. Kubu, Paul J. Ford, Andre G. Machado
      Abstract: Objective: The experience with deep brain stimulation (DBS) for pain is largely based on uncontrolled studies targeting the somatosensory pathways, with mixed results. We hypothesized that targeting limbic neural pathways would modulate the affective sphere of pain and alleviate suffering.Methods: We conducted a prospective, double-blinded, randomized, placebo-controlled, crossover study of DBS targeting the ventral striatum/anterior limb of the internal capsule (VS/ALIC) in 10 patients with post-stroke pain syndrome. One month after bilateral DBS, patients were randomized to active DBS or sham for 3 months, followed by cross-over for another 3-month period. The primary endpoint was a ≥ 50% improvement in the Pain Disability Index in 50% of patients with active DBS compared to sham. This 6-month blinded phase was followed by an 18-month open-stimulation phase.Results: Nine participants completed randomization. Although this trial was negative for its primary and secondary endpoints, we did observe significant differences in multiple outcome measures related to the affective sphere of pain (e.g. Montgomery-Åsberg Depression Rating Scale, Beck Depression Inventory, Affective Pain Rating Index of the Short-form McGill Pain Questionnaire). 14 serious adverse events were recorded and resolved.Interpretation: VS/ALIC DBS to modulate the affective sphere of pain represents a paradigm shift in chronic pain management. While this exploratory study was negative for its primary endpoint, VS/ALIC DBS demonstrated an acceptable safety profile and statistically-significant improvements in multiple outcome measures related to the affective sphere of pain. Therefore, we believe these results justify further work in neuromodulation therapies targeting the affective sphere of pain. This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-05T18:30:26.729914-05:
      DOI: 10.1002/ana.24927
       
  • Tailoring epilepsy surgery with fast ripples in the intra-operative
           electrocorticogram
    • Authors: M.A. van 't Klooster; N.E.C. van Klink, W.J.E.M. Zweiphenning, F.S.S. Leijten, R. Zelmann, C.H. Ferrier, P.C. van Rijen, W.M. Otte, K.P.J. Braun, G.J.M. Huiskamp, M. Zijlmans
      Abstract: Objective: Intra-operative electrocorticography (ECoG) can be used to delineate the resection area in epilepsy surgery. High frequency oscillations (HFOs, 80-500Hz) seem better biomarkers for epileptogenic tissue than spikes. We studied how HFOs and spikes in combined pre- and post-resection ECoG predict surgical outcome in different tailoring approaches.Methods: We, retrospectively, marked HFOs, divided into fast ripples (FRs, 250-500Hz) and ripples (80-250Hz), and spikes in pre- and post-resection ECoG sampled at 2048 Hz in people with refractory focal epilepsy. We defined four groups of EEG-event occurrence: pre+post- (+/-), pre+post+ (+/+), pre-post+ (-/+) and pre-post- (-/-). We subcategorized three tailoring approaches: hippocampectomy with tailoring for neocortical involvement, lesionectomy of temporal lesions with tailoring for mesiotemporal involvement and lesionectomy with tailoring for surrounding neocortical involvement. We compared the percentage of resected pre-EEG-events, the time to recurrence and the different tailoring approaches to outcome (seizure-free versus recurrence).Results: We included 54 patients (median age 15.5y, 25 months follow-up, 30 seizure-free). The percentage of resected FRs, ripples or spikes in pre-ECoG did not predict outcome. The occurrence of FRs in post-ECoG, given FRs in pre-ECoG (+/-,+/+), predicted outcome (hazard ratio: 3.13 (CI=1.22-6.25); p=0.01). Seven out of eight patients without spikes in pre-ECoG were seizure-free. The highest predictive value for seizure recurrence was the presence of FRs in post-ECoG for all tailoring approaches.Interpretation: FRs which persists before and after resection predict poor post-surgical outcome. These findings hold for different tailoring approaches. FRs can thus be used for tailoring epilepsy surgery with repeated intra-operative ECoG measurements. This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-05T18:30:22.807094-05:
      DOI: 10.1002/ana.24928
       
  • Low normal CSF Aβ42 levels predict clinical progression in
           non-demented subjects
    • Authors: Betty M. Tijms; Daniela Bertens, Rosalinde E. Slot, Alida A. Gouw, Charlotte E. Teunissen, Philip Scheltens, Wiesje M. van der Flier, Pieter Jelle Visser
      Abstract: We studied whether continuous lower normal cerebrospinal fluid (CSF) amyloid β 1-42 (≥640 pg/ml) levels related with rate of clinical progression in a sample of 393 non-demented memory clinic patients. Lower normal levels were associated with faster clinical progression and this depended on baseline cognitive status (subjective cognitive decline: HR = 0.59, p
      PubDate: 2017-03-20T04:02:25.640996-05:
      DOI: 10.1002/ana.24921
       
  • Deoxycytidine and deoxythymidine treatment for thymidine kinase 2
           deficiency
    • Authors: Carlos Lopez-Gomez; Rebecca J Levy, Maria J Sanchez-Quintero, Marti Juanola-Falgarona, Emanuele Barca, Beatriz Garcia-Diaz, Saba Tadesse, Caterina Garone, Michio Hirano
      Abstract: Objective: Thymidine kinase 2 (TK2), a critical enzyme in the mitochondrial pyrimidine salvage pathway, is essential for mitochondrial DNA (mtDNA) maintenance. Mutations in the nuclear gene TK2 cause TK2 deficiency, which manifests predominantly in children as myopathy with mtDNA depletion. Molecular bypass therapy with the TK2 products, dCMP and dTMP, prolongs the lifespan of Tk2-deficient (Tk2-/-) mice by 2-3 fold. Because we observed rapid catabolism of the deoxynucleoside monophosphates to deoxythymidine (dT) and deoxycytidine (dC), we hypothesized that: 1) deoxynucleosides might be the major active agents and 2) inhibition of deoxycytidine deamination might enhance dTMP+dCMP therapy.Methods: To test these hypotheses, we assessed two therapies in Tk2-/- mice: 1) dT+dC and 2) co-administration of the deaminase inhibitor, tetrahydrouridine (THU), with dTMP+dCMP.Results: We observed that dC+dT delayed disease onset, prolonged lifespan of Tk2-deficient mice, and restored mtDNA copy number as well as respiratory chain enzyme activities and levels. In contrast, dCMP+dTMP+THU therapy decreased lifespan of Tk2-/- animals compared to dCMP+dTMP.Interpretation: Our studies demonstrate that deoxynucleoside substrate enhancement is a novel therapy, which may ameliorate TK2 deficiency in patients. This article is protected by copyright. All rights reserved.
      PubDate: 2017-03-20T04:02:15.130624-05:
      DOI: 10.1002/ana.24922
       
  • Novel screening for transthyretin amyloidosis by using fat ultrasonography
    • Authors: Yohei Misumi; Mitsuharu Ueda, Taro Yamashita, Teruaki Masuda, Yumiko Kinoshita, Masayoshi Tasaki, Terumasa Nagase, Yukio Ando
      Abstract: We aimed to assess the possibility of using a noninvasive screening method for hereditary transthyretin amyloidosis by means of abdominal fat ultrasonography. Quantitative analysis of ultrasound B-mode images demonstrated a significant increase in mean echogenicity and a loss of the normal structure of the layers of fat tissue in patients with hereditary transthyretin amyloidosis (n = 19). The ultrasound features of the fat tissue and the degree of amyloid deposition seen histopathologically showed a significant correlation. These results suggest that abdominal fat ultrasonography may be a valuable method for screening for hereditary transthyretin amyloidosis. This article is protected by copyright. All rights reserved.
      PubDate: 2017-03-08T03:31:27.21652-05:0
      DOI: 10.1002/ana.24914
       
  • Reply to a Letter to the Editor, related article “Computed tomography
           based quantification of lesion water uptake identifies patients within 4.5
           hours of stroke onset: A multicenter observational study”, observational
           study” ANN
    • Authors: André Kemmling; Jens Minnerup
      PubDate: 2017-03-02T18:15:56.679971-05:
      DOI: 10.1002/ana.24912
       
  • Computed tomography-based acute stroke lesion timing and patient
           stratification
    • Authors: Risto A. Kauppinen; Michael J Knight
      PubDate: 2017-03-02T18:15:54.010249-05:
      DOI: 10.1002/ana.24913
       
  • Wounded Brain, Ailing Heart: Central autonomic network disruption in acute
           stroke
    • Authors: Peter Sörös; Vladimir Hachinski
      PubDate: 2017-03-02T18:15:51.687435-05:
      DOI: 10.1002/ana.24911
       
  • Stroke in right dorsal anterior insular cortex is related to myocardial
           injury
    • Authors: Thomas Krause; Kathrin Werner, Jochen B. Fiebach, Kersten Villringer, Sophie K. Piper, Karl Georg Haeusler, Matthias Endres, Jan F. Scheitz, Christian H. Nolte
      Abstract: Objective: Elevated levels of cardiac troponin and especially their relative changes over time indicate acute myocardial injury. They are also frequently observed after acute ischemic stroke (AIS), indicating poor functional outcome and increased mortality. However, recent evidence showed that in most AIS patients myocardial injury is not caused by coronary ischemia. Instead, stroke lesion location has been suggested to precipitate myocardial injury. Methods: Voxel-based lesion-symptom mapping (VLSM) was employed in 299 patients who had an MRI-confirmed acute ischemic stroke within the anterior circulation and a high-sensitivity cardiac Troponin T (hs-cTnT) acquired on the day of admission. Out of these, 228 had a second troponin measurement during the acute phase. The absolute hs-cTnT levels above the 99th percentile of a healthy reference population (≥14 ng/L) as well as their relative temporal changes were used as continuous variables of interest in the VLSM model, including a multiple regression analysis adjusted for confounding variables. Results: The anterior insular cortex of the right hemisphere, in particular its dorsal sub-region, was significantly associated with the relative temporal changes of hs-cTnT (p
      PubDate: 2017-03-02T18:15:48.818286-05:
      DOI: 10.1002/ana.24906
       
  • The neurology of acutely failing respiratory mechanics
    • Authors: Eelco F. M. Wijdicks
      Abstract: Forces involved in breathing—which effectively pull in air—are the diaphragmatic, intercostal, spine, and neck muscles. Equally important are the bulbar musculature maintaining the architecture of a patent airway conduit and abdominal wall and internal intercostal muscles providing cough. Acute injury along a neural trajectory from brainstem to muscle will impair the coordinated interaction between these muscle groups. Acutely failing respiratory mechanics can be caused by central and peripheral lesions. In central lesions, the key lesion is in the nucleus ambiguus innervating the dilator muscles of the soft palate, pharynx, and larynx, but abnormal respiratory mechanics rarely coincide with abnormalities of the respiratory pattern generator. In peripheral lesions, diaphragmatic weakness is a main element, but in many neuromuscular disorders mechanical upper airway obstruction from oropharyngeal weakness contributes equally to an increased respiratory load. The neurology of breathing involves changes in respiratory drive, rhythm, mechanics and dynamics. This review focuses on the fundamentals of abnormal respiratory mechanics in acute neurologic conditions, bedside judgment, interpretation of additional laboratory tests, and initial stabilization with practical solutions provided. Many of these respiratory signs are relevant to neurologists, who, in acute situations, may see these patients first. This article is protected by copyright. All rights reserved.
      PubDate: 2017-03-02T18:15:45.003322-05:
      DOI: 10.1002/ana.24908
       
  • The immune response of the human brain to abdominal surgery
    • Authors: Anton Forsberg; Simon Cervenka, Malin Jonsson Fagerlund, Lars S. Rasmussen, Henrik Zetterberg, Helena Erlandsson Harris, Pernilla Stridh, Eva Christensson, Anna Granström, Anna Schening, Karin Dymmel, Nina Knave, Niccolò Terrando, Mervyn Maze, Jacqueline Borg, Andrea Varrone, Christer Halldin, Kaj Blennow, Lars Farde, Lars I Eriksson
      Abstract: Objective: Surgery launches a systemic inflammatory reaction that reaches the brain and associates with immune activation and cognitive decline. While preclinical studies have in part described this systemic-to-brain signaling pathway, we lack information on how these changes appear in humans. This study examines the short- and long-term impact of abdominal surgery on the human brain immune system by Positron Emission Tomography (PET) in relation to blood immune reactivity, plasma inflammatory biomarkers and cognitive function.Methods: Eight males undergoing prostatectomy under general anesthesia were included. Prior to surgery (baseline), at postoperative day 3-4 and after 3 months, patients were examined using [11C]PBR28 brain PET imaging to assess brain immune cell activation. Concurrently, systemic inflammatory biomarkers, ex vivo blood tests on immunoreactivity to lipopolysaccharide (LPS) stimulation and cognitive function were assessed.Results: Patients showed a global down-regulation of GM [11C]PBR28 binding of 26±26% (mean±SD) at 3-4 days postoperatively compared to baseline (p=0.023), recovering or even increasing after 3 months. LPS-induced release of the pro-inflammatory marker TNF-α in blood displayed a reduction (41±39%) on the 3-4th postoperative day, corresponding to changes in [11C]PBR28 VT. Change in Stroop color word cognitive test performance between postoperative day 3-4 and 3 months correlated to change in [11C]PBR28 binding (p=0.027).Interpretation: This study translates preclinical data on changes in the brain immune system after surgery to humans, and suggests an interplay between the human brain and the inflammatory response of the peripheral innate immune system. These findings may be related to post-surgical impairments of cognitive function. This article is protected by copyright. All rights reserved.
      PubDate: 2017-03-02T18:15:41.31896-05:0
      DOI: 10.1002/ana.24909
       
  • FDG metabolism associated with tau-amyloid interaction predicts memory
           decline
    • Authors: Bernard J. Hanseeuw; Rebecca A. Betensky, Aaron P. Schultz, Kate V. Papp, Elizabeth C. Mormino, Jorge Sepulcre, John S. Bark, Danielle M. Cosio, Molly LaPoint, Jasmeer P. Chhatwal, Dorene M. Rentz, Reisa A. Sperling, Keith Johnson
      Abstract: Objective:To evaluate in normal older adults and preclinical Alzheimer's disease (AD) the impact of amyloid and regional tauopathy on cerebral glucose metabolism and subsequent memory decline.Methods:We acquired positron emission tomography using F18 Flortaucipir (tau), C11 Pittsburgh Compound B (amyloid) and F18 Fluorodeoxyglucose in 90 clinically normal elderly of the Harvard Aging Brain Study.Results:Posterior cingulate metabolism decreased when both amyloid and neocortical tau were high and predicted subsequent memory decline in a larger sample of normal elderly. In contrast, frontal hypometabolism related to the common age-related entorhinal tauopathy, but this dysfunction was independent of amyloid, and did not predict significant memory decline. Neocortical tauopathy was positively associated with metabolism in individuals with sub-threshold amyloid, suggesting that glucose metabolism increases before decreasing in the course of preclinical AD.Interpretation:Our study identified a synergistic effect of amyloid and tau deposits and demonstrated for the first time in normal elderly its link to AD-like hypometabolism and to AD-like memory decline. The amyloid effect was seen with tau in neocortex, but not with tau in entorhinal cortex, which is the common site of age-related tauopathy. Entorhinal tau was associated with frontal hypometabolism, but this dysfunction was not associated with memory loss. This article is protected by copyright. All rights reserved.
      PubDate: 2017-03-02T18:15:38.10882-05:0
      DOI: 10.1002/ana.24910
       
  • Olig1 is required for Noggin-induced neonatal myelin repair
    • Authors: Jennifer K. Sabo; Vivi Heine, John C. Silbereis, Lucas Schirmer, Steven W. Levison, David H. Rowitch
      Abstract: Objective – Neonatal white matter injury (NWMI) is a lesion found in preterm infants that can lead to cerebral palsy. Although antagonists of bone morphogenetic protein (BMP) signaling, such as Noggin, promote oligodendrocyte precursor cell (OPC) production after hypoxic-ischemic injury, the downstream functional targets are poorly understood. The bHLH protein Olig1 promotes oligodendrocyte (OL) development and is essential during remyelination in adult mice. Here, we investigated whether Olig1 function is required downstream of BMP antagonism for the response to injury in the neonatal brain.Methods – We used wild type and Olig1 mutant mice subjected to neonatal stroke and postnatal neural progenitor cultures, and we analyzed Olig1 expression in human postmortem samples from neonates that suffered hypoxic-ischemic encephalopathy (HIE).Results - Olig1-null neonatal mice showed significant hypomyelination after moderate neonatal stroke. Surprisingly, damaged white matter tracts in Olig1-/- mice lacked Olig2+ OPCs and instead proliferating neuronal precursors and GABAergic interneurons were present. We demonstrate that Noggin-induced OPC production requires Olig1 function. In postnatal neural progenitors, Noggin governs production of OLs versus interneurons through Olig1-mediated repression of Dlx1/2 transcription factors. Additionally, we observed that Olig1 and the BMP signaling effector pSMAD1/5/8 are elevated in the subventricular zone (SVZ) of human infants with HIE compared to controls.Interpretation - These findings indicate that Olig1 has a critical function in the regulation of the postnatal neural progenitor cell production in response to Noggin. This article is protected by copyright. All rights reserved.
      PubDate: 2017-03-02T18:15:33.356899-05:
      DOI: 10.1002/ana.24907
       
  • Homozygous mutations in VAMP1 cause a presynaptic congenital myasthenic
           syndrome
    • Authors: Vincenzo Salpietro; Weichun Lin, Andrea Delle Vedove, Markus Storbeck, Yun Liu, Stephanie Efthymiou, Andreea Manole, Sarah Wiethoff, Qiaohong Ye, Anand Saggar, Kenneth McElreavey, Shyam Krishnakumar, Matthew Pitt, Oscar Bello, James E. Rothman, Lina Basel-Vanagaite, Monika Weisz Hubshman, Sharon Aharoni, Adnan Y. Manzur, Brunhilde Wirth, Henry Houlden
      Abstract: We report 2 families with undiagnosed recessive presynaptic congenital myasthenic syndrome (CMS). Whole exome or genome sequencing identified segregating homozygous variants in VAMP1: c.51_64delAGGTGGGGGTCCCC in a Kuwaiti family and c.146G>C in an Israeli family. VAMP1 is required for vesicle fusion at presynaptic neuromuscular junction (NMJ). Electrodiagnostic examination showed severely low compound muscle action potentials and presynaptic impairment. We assessed the effect of the nonsense mutation on mRNA levels and evaluated the NMJ transmission in VAMP1lew/lew mice, observing neurophysiological features of presynaptic impairment, similar to the patients. Taken together, our findings highlight VAMP1 homozygous mutations as a cause of presynaptic CMS. This article is protected by copyright. All rights reserved.
      PubDate: 2017-03-02T18:15:29.651306-05:
      DOI: 10.1002/ana.24905
       
  • Quantitative muscle ultrasound detects disease progression in Duchenne
           muscular dystrophy
    • Authors: Craig M. Zaidman; Jim S. Wu, Kush Kapur, Amy Pasternak, Lavanya Madabusi, Sung Yim, Adam Pacheck, Heather Szelag, Tim Harrington, Basil T. Darras, Seward B. Rutkove
      Abstract: Objective: We assessed changes in quantitative muscle ultrasound data in boys with Duchenne muscular dystrophy (DMD) and healthy controls to determine if ultrasound can serve as a biomarker of disease progression. Two approaches were used: grey scale level (GSL), measured from the ultrasound image, and quantitative backscatter analysis (QBA) measured directly from the received echoes.Methods: GSL and QBA were obtained from six unilateral arm/leg muscles in 36 boys with DMD and 28 healthy boys (age 2-14 years) for up to 2 years. We used a linear mixed-effects model with random intercept and slope terms to compare trajectories of GSL, QBA, and functional assessments. We analyzed separately a subset of boys who initiated corticosteroids.Results: Compared to healthy boys, increasing GSL in DMD boys>7.0 years was first identified at 6 months (e.g., anterior forearm slope difference of 1.16 arbitrary units/month p=0.004, 95% confidence interval (CI) [0.38,1.94]); in boys ≤7 years, differences in GSL first appeared at 12 months (0.82 arbitrary units/month, p=0.04 95%CI [0.075,1.565] in rectus femoris). QBA performed similarly to GSL (e.g., DMD boys>7 years of 0.41dB/month, p=0.01, 95%CI [0.096,0.72] in anterior forearm at 6 months). US identified differences earlier than functional measures including 6-minute walk and supine-to-stand tests. However, neither QBA nor GSL showed an effect of corticosteroid initiation.Interpretation: QBA performs similarly to GSL and both appear more sensitive than functional assessments for detecting muscle deterioration in DMD. Additional studies will be required to determine if quantitative muscle ultrasound can detect therapeutic efficacy. This article is protected by copyright. All rights reserved.
      PubDate: 2017-02-27T18:30:35.120209-05:
      DOI: 10.1002/ana.24904
       
  • Outcomes after diagnosis of mild cognitive impairment in a large autopsy
           series
    • Authors: Erin L. Abner; Richard J. Kryscio, Frederick A. Schmitt, David W. Fardo, Daniela C. Moga, Eseosa T. Ighodaro, Gregory A. Jicha, Lei Yu, Hiroko H. Dodge, Chengjie Xiong, Randall L. Woltjer, Julie A. Schneider, Nigel J. Cairns, David A. Bennett, Peter T. Nelson
      Abstract: Objective: Determine clinical and neuropathological outcomes following a clinical diagnosis of mild cognitive impairment (MCI).Methods: Data were drawn from a large autopsy series (N=1,337) of individuals followed longitudinally from normal or MCI status to death, derived from four Alzheimer's Disease (AD) Centers in the United States.Results: Mean follow-up was 7.9 years. Of the 874 individuals ever diagnosed with MCI, final clinical diagnoses were varied: 39.2% died with an MCI diagnosis, 46.8% with a dementia diagnosis, and 13.9% died with a diagnosis of intact cognition. The latter group had pathological features resembling those with a final clinical diagnosis of MCI. In terms of non-AD pathologies, both primary age-related tauopathy (p
      PubDate: 2017-02-22T03:45:27.780607-05:
      DOI: 10.1002/ana.24903
       
  • Pathogenic role of anti-SRP and anti-HMGCR antibodies in necrotizing
           myopathies: Myofiber atrophy and impairment of muscle regeneration in
           necrotizing autoimmune myopathies
    • Authors: Louiza Arouche-Delaperche; Yves Allenbach, Damien Amelin, Corinna Preusse, Vincent Mouly, Wladimir Mauhin, Gaelle Dzangue Tchoupou, Laurent Drouot, Olivier Boyer, Werner Stenzel, Gillian Butler-Browne, Olivier Benveniste
      Abstract: Objective. Immune mediated necrotizing myopathies (IMNM) may be associated with either anti-SRP or anti-HMGCR antibodies (Abs) and the titer of these Abs is correlated with the disease activity. We investigated if anti-SRP and anti-HMGCR Abs could be involved in muscle damages.Methods. Muscle biopsies of patients were analyzed for atrophy and regeneration, by measuring the fibers size and by performing immunostaining of neonatal myosin heavy chain. To further understand the role of the Abs in the pathology, we performed muscle cell co-culture with the Abs. Atrophy and regeneration were evaluated based on the myotube surface area as well as gene and cytokine profiles.Results. In muscle biopsies of patients with anti-SRP+ and anti-HMGCR+ Abs, a large number of small fibers corresponding to both atrophic and regenerating fibers were observed.In vitro, anti-SRP and anti-HMGCR Abs induced muscle fiber atrophy and increased the transcription of MAFbx and Trim63. In addition, the muscle fiber atrophy was associated with high levels of inflammatory cytokines: TNF, IL-6 and reactive oxygen species.In the presence of anti-SRP or anti-HMGCR Abs, mechanisms involved in muscle regeneration were also impaired due to a defect of myoblast fusion. This defect was associated with a decreased production of IL-4 and IL-13. The addition of IL-4 and/or IL-13 totally rescued fusion capacity.Interpretation. These data show that molecular mechanisms of atrophy and regeneration are affected and contribute to loss of muscle function occurring in IMNM. This emphasizes the potential interest of targeted therapies addressing these mechanisms. This article is protected by copyright. All rights reserved.
      PubDate: 2017-02-22T03:45:24.559275-05:
      DOI: 10.1002/ana.24902
       
  • Language fMRI and Direct Cortical Stimulation in Epilepsy Preoperative
           Planning
    • Authors: Alison Austermuehle; John Cocjin, Richard Reynolds, Shubhi Agrawal, Leigh Sepeta, William D. Gaillard, Kareem Zaghloul, Sara Inati, William H. Theodore
      Abstract: Objective:Presurgical language assessment can help minimize damage to eloquent cortex during resective epilepsy surgery. Two methods for presurgical language mapping are functional MRI (fMRI) and direct cortical stimulation (DCS) of implanted subdural electrodes. We compared fMRI results to DCS to help optimize non-invasive language localization and assess its validity.Methods:We studied 19 patients referred for presurgical evaluation of drug-resistant epilepsy. Patients completed 4 language tasks during preoperative fMRI. After subdural electrode implantation, we used DCS to localize language areas. For each stimulation site, we determined whether language positive electrode pairs intersected with significant fMRI activity clusters for language tasks.Results:Sensitivity and specificity depended on electrode ROI radii and statistical thresholding. For patients with at least one language positive stimulation site, an auditory description decision task provided the best tradeoff between sensitivity and specificity. For patients with no language positive stimulation sites, fMRI was a dependable method of excluding eloquent language processing.Interpretation:Language fMRI is an effective tool for determining language lateralization prior to electrode implantation, and is especially useful for excluding unexpected critical language areas. It can help guide subdural electrode implantation and narrow the search for eloquent cortical areas via DCS. This article is protected by copyright. All rights reserved.
      PubDate: 2017-02-21T03:30:34.863398-05:
      DOI: 10.1002/ana.24899
       
  • The Burden of Neurological Disease in the United States: A Summary Report
           and Call to Action
    • Authors: Clifton L. Gooch; Etienne Pracht, Amy R. Borenstein
      Abstract: The United States carries a substantial fiscal burden resulting from the nearly 100 million Americans with neurological disease. The combined annual costs of Alzheimer's and other dementias, low back pain, stroke, traumatic brain injury, migraine, epilepsy, multiple sclerosis, spinal cord injury and Parkinson's disease totals nearly 800 billion dollars and is rapidly rising due to the aging of the U.S. population. We provide a summary overview of the substantial current and future economic impact of neurological disease, and provide an action plan for reducing this burden through neurological research and enhanced clinical management of neurological disorders in the United States. This article is protected by copyright. All rights reserved.
      PubDate: 2017-02-15T03:25:30.981272-05:
      DOI: 10.1002/ana.24897
       
  • Identity of the Purkinje cell cytoplasmic antibody type 2 autoantibody
           antigen is finally revealed
    • Authors: Christian Gonzalez-Billault
      PubDate: 2017-02-14T09:10:31.385919-05:
      DOI: 10.1002/ana.24884
       
  • Electrical impedance myography for assessment of Duchenne muscular
           dystrophy
    • Authors: Seward B. Rutkove; Kush Kapur, Craig Zaidman, Jim S. Wu, Amy Pasternak, Lavanya Madabusi, Sung Yim, Adam Pacheck, Heather Szelag, Tim Harrington, Basil T. Darras
      Abstract: Objective: Sensitive, objective and easily applied methods for evaluating disease progression and response to therapy are needed for clinical trials in Duchenne muscular dystrophy (DMD). In this study, we evaluated whether electrical impedance myography (EIM) could serve this purpose.Methods: In this non-blinded study, 36 boys with DMD and 29 age-similar healthy boys underwent multifrequency EIM measurements for up to 2 years on 6 muscles unilaterally along with functional assessments. A linear mixed-effects model with random intercept and slope terms was used for the analysis of multifrequency EIM values and functional measures. Seven DMD boys were initiated on corticosteroids; these data were analyzed using a piecewise linear mixed-effects model.Results: In boys>7.0 years, a significant difference in the slope of EIM phase-ratio trajectories in the upper extremity was observed by 6 months of -0.074/month, p=0.023, 95% confidence interval (CI)[-0.013,-0.14]); at two years, this difference was -0.048/month, p
      PubDate: 2017-01-11T18:10:31.851118-05:
      DOI: 10.1002/ana.24874
       
  • Inclusion Body Myositis Pathogenesis: Steady Progress
    • Authors: Steven A. Greenberg
      First page: 498
      PubDate: 2017-04-03T09:35:50.144799-05:
      DOI: 10.1002/ana.24920
       
  • Pathomechanisms of anti-cN1A autoantibodies in sporadic inclusion body
           myositis
    • Authors: Nozomu Tawara; Satoshi Yamashita, Xiao Zhang, Mai Korogi, Ziwei Zhang, Tsukasa Doki, Yoshimasa Matsuo, Shunya Nakane, Yasushi Maeda, Kazuma Sugie, Naoki Suzuki, Masashi Aoki, Yukio Ando
      First page: 512
      Abstract: Objective: Sporadic inclusion body myositis (sIBM), an intractable progressive muscle disease, frequently occurs in older persons. sIBM pathogenesis may involve protein degradation dysfunction and immune abnormalities. Autoantibodies recognizing cytosolic 5'-nucleotidase 1A (cN1A) were found in plasma and serum from sIBM patients. Whether anti-cN1A autoantibodies play a pathogenic role in sIBM is controversial, however. This study investigated the pathogenic properties of anti-cN1A autoantibodies in sIBM pathogenesis.Methods: We developed a cell-based assay to detect anti-cN1A autoantibodies, which we found in serum from patients with neuromuscular diseases including sIBM. We also investigated the clinicopathological differences between sIBM patients with and without the autoantibodies. We used passive in vitro and in vivo immunization models to evaluate the pathogenic role of the autoantibodies.Results: Of 67 patients with sIBM, 24 (35.8%) possessed anti-cN1A autoantibodies as determined via our cell-based assay. In the anti-cN1A-positive group, the percentage of patients with hepatitis C virus antibodies was significantly lower and the mean area of type 2 myofibers was significantly smaller compared with the antibody-negative group. In the in vitro passive immunization model, p62/SQSTM1 significantly increased in anti-cN1A-positive sIBM immunoglobulin G (IgG)-supplemented cells. In the in vivo passive immunization model, anti-cN1A-positive sIBM IgG-injected mice demonstrated p62/SQSTM1-positive sarcoplasmic aggregates in myofibers, associated with macrophage infiltration.Interpretation: Our cell-based assay is useful for anti-cN1A autoantibodies detection. Patients with anti-cN1A autoantibodies demonstrated unique clinicopathological features. In vitro and in vivo passive immunization model results suggest that anti-cN1A autoantibodies may affect protein degradation in myofibers. This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-03T09:36:01.833557-05:
      DOI: 10.1002/ana.24919
       
  • Retraction: ‘DNAJC6 variants in Parkinson's disease and amyotrophic
           lateral sclerosis’ by Jiang, T., Zhang, Y-D., Tan, L., and Yu, J-T.
    • Abstract: The above Letter to the Editor from Annals of Neurology, published online as an Accepted Article on 4th April 2016 on Wiley Online Library (wileyonlinelibrary.com), has been withdrawn at the request of the authors with agreement from the journal editor, Clifford B. Saper, and Wiley Periodicals, Inc. The withdrawal has been agreed due to an acknowledgement from the authors that they inappropriately implied that material from the PD Gene and ALS Gene public databases and a figure from the Max Planck Society for the Advancement of Science was their own work.ReferenceJiang, T., Zhang, Y-D., Tan, L., and Yu, J-T (2016) DNAJC6 variants in Parkinson's disease and amyotrophic lateral sclerosis. Ann Neurol. doi: 10.1002/ana.24658.
      PubDate: 2016-05-25T02:39:40.478086-05:
      DOI: 10.1002/ana.24676
       
  • Retraction: DNAJC6 variants in Parkinson's disease and amyotrophic lateral
           sclerosis
    • Authors: Teng Jiang; Ying-Dong Zhang, Lan Tan, Jin-Tai Yu
      Abstract: The above Letter to the Editor from Annals of Neurology, published online as an Accepted Article on 4th April 2016 on Wiley Online Library (wileyonlinelibrary.com), has been withdrawn at the request of the authors with agreement from the journal editor, Clifford B. Saper, and Wiley Periodicals, Inc. The withdrawal has been agreed due to an acknowledgement from the authors that they inappropriately implied that material from the PD Gene and ALS Gene public databases and a figure from the Max Planck Society for the Advancement of Science was their own work.ReferenceJiang, T., Zhang, Y-D., Tan, L., and Yu, J-T (2016) DNAJC6 variants in Parkinson's disease and amyotrophic lateral sclerosis. Ann Neurol. doi: 10.1002/ana.24658.
      PubDate: 2016-04-04T10:40:38.566548-05:
      DOI: 10.1002/ana.24658
       
  • How to Determine if You Have Succeeded at Neurology Residency
    • Authors: Allan Ropper
      PubDate: 2016-02-12T20:49:27.001432-05:
      DOI: 10.1002/ana.24613
       
 
 
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