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Publisher: John Wiley and Sons   (Total: 1589 journals)

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Showing 1 - 200 of 1589 Journals sorted alphabetically
Abacus     Hybrid Journal   (Followers: 12, SJR: 0.48, h-index: 22)
About Campus     Hybrid Journal   (Followers: 5)
Academic Emergency Medicine     Hybrid Journal   (Followers: 65, SJR: 1.385, h-index: 91)
Accounting & Finance     Hybrid Journal   (Followers: 47, SJR: 0.547, h-index: 30)
ACEP NOW     Free   (Followers: 1)
Acta Anaesthesiologica Scandinavica     Hybrid Journal   (Followers: 52, SJR: 1.02, h-index: 88)
Acta Archaeologica     Hybrid Journal   (Followers: 164, 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: 6, SJR: 0.112, h-index: 1)
Acta Paediatrica     Hybrid Journal   (Followers: 56, SJR: 0.794, h-index: 88)
Acta Physiologica     Hybrid Journal   (Followers: 6, SJR: 1.69, h-index: 88)
Acta Polymerica     Hybrid Journal   (Followers: 9)
Acta Psychiatrica Scandinavica     Hybrid Journal   (Followers: 35, SJR: 2.518, h-index: 113)
Acta Zoologica     Hybrid Journal   (Followers: 7, SJR: 0.459, h-index: 29)
Acute Medicine & Surgery     Hybrid Journal   (Followers: 4)
Addiction     Hybrid Journal   (Followers: 35, SJR: 2.086, h-index: 143)
Addiction Biology     Hybrid Journal   (Followers: 14, SJR: 2.091, h-index: 57)
Adultspan J.     Hybrid Journal   (SJR: 0.127, h-index: 4)
Advanced Energy Materials     Hybrid Journal   (Followers: 27, SJR: 6.411, h-index: 86)
Advanced Engineering Materials     Hybrid Journal   (Followers: 26, SJR: 0.81, h-index: 81)
Advanced Functional Materials     Hybrid Journal   (Followers: 51, SJR: 5.21, h-index: 203)
Advanced Healthcare Materials     Hybrid Journal   (Followers: 14, SJR: 0.232, h-index: 7)
Advanced Materials     Hybrid Journal   (Followers: 267, 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: 7, SJR: 2.488, h-index: 21)
Advanced Science     Open Access   (Followers: 5)
Advanced Synthesis & Catalysis     Hybrid Journal   (Followers: 17, SJR: 2.729, h-index: 121)
Advances in Polymer Technology     Hybrid Journal   (Followers: 13, SJR: 0.344, h-index: 31)
Africa Confidential     Hybrid Journal   (Followers: 21)
Africa Research Bulletin: Economic, Financial and Technical Series     Hybrid Journal   (Followers: 13)
Africa Research Bulletin: Political, Social and Cultural Series     Hybrid Journal   (Followers: 10)
African Development Review     Hybrid Journal   (Followers: 33, SJR: 0.275, h-index: 17)
African J. of Ecology     Hybrid Journal   (Followers: 16, SJR: 0.477, h-index: 39)
Aggressive Behavior     Hybrid Journal   (Followers: 15, SJR: 1.391, h-index: 66)
Aging Cell     Open Access   (Followers: 11, SJR: 4.374, h-index: 95)
Agribusiness : an Intl. J.     Hybrid Journal   (Followers: 3, SJR: 0.627, h-index: 14)
Agricultural and Forest Entomology     Hybrid Journal   (Followers: 16, SJR: 0.925, h-index: 43)
Agricultural Economics     Hybrid Journal   (Followers: 45, SJR: 1.099, h-index: 51)
AIChE J.     Hybrid Journal   (Followers: 32, 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: 51, SJR: 3.048, h-index: 129)
Alternatives to the High Cost of Litigation     Hybrid Journal   (Followers: 3)
American Anthropologist     Hybrid Journal   (Followers: 148, 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: 92, SJR: 2.325, h-index: 51)
American J. of Economics and Sociology     Hybrid Journal   (Followers: 29, SJR: 0.211, h-index: 26)
American J. of Hematology     Hybrid Journal   (Followers: 34, 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: 16, SJR: 1.115, h-index: 61)
American J. of Medical Genetics Part B: Neuropsychiatric Genetics     Hybrid Journal   (Followers: 4, SJR: 1.771, h-index: 107)
American J. of Medical Genetics Part C: Seminars in Medical Genetics     Partially Free   (Followers: 6, SJR: 2.315, h-index: 79)
American J. of Physical Anthropology     Hybrid Journal   (Followers: 37, SJR: 1.41, h-index: 88)
American J. of Political Science     Hybrid Journal   (Followers: 278, SJR: 5.101, h-index: 114)
American J. of Primatology     Hybrid Journal   (Followers: 15, SJR: 1.197, h-index: 63)
American J. of Reproductive Immunology     Hybrid Journal   (Followers: 3, SJR: 1.347, h-index: 75)
American J. of Transplantation     Hybrid Journal   (Followers: 17, SJR: 2.792, h-index: 140)
American J. on Addictions     Hybrid Journal   (Followers: 9, SJR: 0.843, h-index: 57)
Anaesthesia     Hybrid Journal   (Followers: 138, SJR: 1.404, h-index: 88)
Analyses of Social Issues and Public Policy     Hybrid Journal   (Followers: 9, SJR: 0.397, h-index: 18)
Analytic Philosophy     Hybrid Journal   (Followers: 18)
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: 219)
Angewandte Chemie Intl. Edition     Hybrid Journal   (Followers: 222, SJR: 6.229, h-index: 397)
Animal Conservation     Hybrid Journal   (Followers: 41, SJR: 1.576, h-index: 62)
Animal Genetics     Hybrid Journal   (Followers: 8, SJR: 0.957, h-index: 67)
Animal Science J.     Hybrid Journal   (Followers: 6, SJR: 0.569, h-index: 24)
Annalen der Physik     Hybrid Journal   (Followers: 5, SJR: 1.46, h-index: 40)
Annals of Anthropological Practice     Partially Free   (Followers: 2, SJR: 0.187, h-index: 5)
Annals of Applied Biology     Hybrid Journal   (Followers: 7, 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: 47, SJR: 5.584, h-index: 241)
Annals of Noninvasive Electrocardiology     Hybrid Journal   (Followers: 1, SJR: 0.531, h-index: 38)
Annals of Public and Cooperative Economics     Hybrid Journal   (Followers: 8, 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: 13)
Annual Review of Information Science and Technology     Hybrid Journal   (Followers: 14)
Anthropology & Education Quarterly     Hybrid Journal   (Followers: 25, SJR: 0.72, h-index: 31)
Anthropology & Humanism     Hybrid Journal   (Followers: 17, SJR: 0.137, h-index: 3)
Anthropology News     Hybrid Journal   (Followers: 15)
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: 89, SJR: 0.545, h-index: 15)
Antipode     Hybrid Journal   (Followers: 49, SJR: 2.212, h-index: 69)
Anz J. of Surgery     Hybrid Journal   (Followers: 8, 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: 70, SJR: 0.754, h-index: 69)
Applied Organometallic Chemistry     Hybrid Journal   (Followers: 7, SJR: 0.632, h-index: 58)
Applied Psychology     Hybrid Journal   (Followers: 207, SJR: 1.023, h-index: 64)
Applied Psychology: Health and Well-Being     Hybrid Journal   (Followers: 49, SJR: 0.868, h-index: 13)
Applied Stochastic Models in Business and Industry     Hybrid Journal   (Followers: 5, SJR: 0.613, h-index: 24)
Aquaculture Nutrition     Hybrid Journal   (Followers: 14, SJR: 1.025, h-index: 55)
Aquaculture Research     Hybrid Journal   (Followers: 31, SJR: 0.807, h-index: 60)
Aquatic Conservation Marine and Freshwater Ecosystems     Hybrid Journal   (Followers: 36, 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: 15, SJR: 0.156, h-index: 2)
Architectural Design     Hybrid Journal   (Followers: 25, SJR: 0.261, h-index: 9)
Archiv der Pharmazie     Hybrid Journal   (Followers: 3, SJR: 0.628, h-index: 43)
Archives of Drug Information     Hybrid Journal   (Followers: 5)
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: 246, SJR: 0.153, h-index: 13)
Arthritis & Rheumatology     Hybrid Journal   (Followers: 52, SJR: 1.984, h-index: 20)
Arthritis Care & Research     Hybrid Journal   (Followers: 27, 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: 15)
Asia & the Pacific Policy Studies     Open Access   (Followers: 16)
Asia Pacific J. of Human Resources     Hybrid Journal   (Followers: 320, SJR: 0.494, h-index: 19)
Asia Pacific Viewpoint     Hybrid Journal   (Followers: 1, SJR: 0.616, h-index: 26)
Asia-Pacific J. of Chemical Engineering     Hybrid Journal   (Followers: 8, 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: 4, SJR: 0.377, h-index: 7)
Asian Economic J.     Hybrid Journal   (Followers: 8, SJR: 0.234, h-index: 21)
Asian Economic Policy Review     Hybrid Journal   (Followers: 4, SJR: 0.196, h-index: 12)
Asian J. of Control     Hybrid Journal   (SJR: 0.862, h-index: 34)
Asian J. of Endoscopic Surgery     Hybrid Journal   (SJR: 0.394, h-index: 7)
Asian J. of Organic Chemistry     Hybrid Journal   (Followers: 6, 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: 12, 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: 15, SJR: 1.095, h-index: 66)
Austral Entomology     Hybrid Journal   (Followers: 9, SJR: 0.524, h-index: 28)
Australasian J. of Dermatology     Hybrid Journal   (Followers: 8, SJR: 0.714, h-index: 40)
Australasian J. On Ageing     Hybrid Journal   (Followers: 6, SJR: 0.39, h-index: 22)
Australian & New Zealand J. of Statistics     Hybrid Journal   (Followers: 14, 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: 47, 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: 7, SJR: 0.482, h-index: 46)
Australian Economic History Review     Hybrid Journal   (Followers: 5, SJR: 0.171, h-index: 12)
Australian Economic Papers     Hybrid Journal   (Followers: 31, 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: 14, SJR: 0.203, h-index: 14)
Australian J. of Psychology     Hybrid Journal   (Followers: 18, SJR: 0.384, h-index: 30)
Australian J. of Public Administration     Hybrid Journal   (Followers: 408, SJR: 0.418, h-index: 29)
Australian J. of Rural Health     Hybrid Journal   (Followers: 5, SJR: 0.43, h-index: 34)
Australian Occupational Therapy J.     Hybrid Journal   (Followers: 72, SJR: 0.59, h-index: 29)
Australian Psychologist     Hybrid Journal   (Followers: 12, SJR: 0.331, h-index: 31)
Australian Veterinary J.     Hybrid Journal   (Followers: 21, SJR: 0.459, h-index: 45)
Autism Research     Hybrid Journal   (Followers: 36, 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: 11, 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: 5, SJR: 1.54, h-index: 60)
Bauphysik     Hybrid Journal   (Followers: 2, SJR: 0.194, h-index: 5)
Bauregelliste A, Bauregelliste B Und Liste C     Hybrid Journal  
Bautechnik     Hybrid Journal   (Followers: 1, SJR: 0.321, h-index: 11)
Behavioral Interventions     Hybrid Journal   (Followers: 9, SJR: 0.297, h-index: 23)
Behavioral Sciences & the Law     Hybrid Journal   (Followers: 24, SJR: 0.736, h-index: 57)
Berichte Zur Wissenschaftsgeschichte     Hybrid Journal   (Followers: 10, 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: 16, SJR: 1.172, h-index: 90)
Biological Reviews     Hybrid Journal   (Followers: 4, SJR: 6.469, h-index: 114)
Biologie in Unserer Zeit (Biuz)     Hybrid Journal   (Followers: 41, 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: 44, SJR: 0.415, h-index: 55)
Biotechnology and Bioengineering     Hybrid Journal   (Followers: 141, SJR: 1.633, h-index: 146)
Biotechnology J.     Hybrid Journal   (Followers: 14, SJR: 1.185, h-index: 51)
Biotechnology Progress     Hybrid Journal   (Followers: 39, SJR: 0.736, h-index: 101)
Biotropica     Hybrid Journal   (Followers: 20, SJR: 1.374, h-index: 71)
Bipolar Disorders     Hybrid Journal   (Followers: 9, SJR: 2.592, h-index: 100)
Birth     Hybrid Journal   (Followers: 38, 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: 6, SJR: 0.468, h-index: 47)
Birth Defects Research Part C : Embryo Today : Reviews     Hybrid Journal   (SJR: 1.513, h-index: 55)
BJOG : An Intl. J. of Obstetrics and Gynaecology     Partially Free   (Followers: 243, SJR: 2.083, h-index: 125)

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Journal Cover Annals of Neurology
  [SJR: 5.584]   [H-I: 241]   [47 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  [1589 journals]
  • Antisense suppression of glial fibrillary acidic protein as a treatment
           for Alexander disease
    • Authors: Tracy L. Hagemann; Berit Powers, Curt Mazur, Aneeza Kim, Steven Wheeler, Gene Hung, Eric Swayze, Albee Messing
      Abstract: Objective: Alexander disease is a fatal leukodystrophy caused by autosomal dominant gain-of-function mutations in the gene for glial fibrillary acidic protein (GFAP), an intermediate filament protein primarily expressed in astrocytes of the central nervous system. A key feature of pathogenesis is over-expression and accumulation of GFAP, with formation of characteristic cytoplasmic aggregates known as Rosenthal fibers. Here we investigate whether suppressing GFAP with antisense oligonucleotides could provide a therapeutic strategy for treating Alexander disease.Methods: In this study we use GFAP mutant mouse models of Alexander disease to test the efficacy of antisense suppression and evaluate the effects on molecular and cellular phenotypes and non-cell autonomous toxicity. Antisense oligonucleotides were designed to target the murine Gfap transcript, and screened using primary mouse cortical cultures. Lead oligonucleotides were then tested for their ability to reduce GFAP transcripts and protein, first in wild-type mice with normal levels of GFAP, and then in adult mutant mice with established pathology and elevated levels of GFAP.Results: Nearly complete and long-lasting elimination of GFAP occurred in brain and spinal cord following single bolus intracerebroventricular injections, with a striking reversal of Rosenthal fibers and downstream markers of microglial and other stress related responses. GFAP protein was also cleared from cerebrospinal fluid, demonstrating its potential utility as a biomarker in future clinical applications. Finally, treatment led to improved body condition and rescue of hippocampal neurogenesis.Interpretation: These results demonstrate the efficacy of antisense suppression for an astrocyte target, and provide a compelling therapeutic approach for Alexander disease. This article is protected by copyright. All rights reserved.
      PubDate: 2017-12-11T06:05:39.328931-05:
      DOI: 10.1002/ana.25118
  • Effect of sleep on overnight CSF amyloid-β kinetics
    • Authors: Brendan P. Lucey; Terry J. Hicks, Jennifer S. McLeland, Cristina D. Toedebusch, Jill Boyd, Donald L. Elbert, Bruce W. Patterson, Jack Baty, John C. Morris, Vitaliy Ovod, Kwasi G. Mawuenyega, Randall J. Bateman
      Abstract: Sleep disturbances are associated with future risk of Alzheimer's disease. Disrupted sleep increases soluble amyloid-β, suggesting a mechanism for sleep disturbances to increase Alzheimer's disease risk. We tested this response in humans using indwelling lumbar catheters to serially sample cerebrospinal fluid while participants were sleep-deprived, treated with sodium oxybate, or allowed to sleep normally. All participants were infused with 13C6-leucine to measure amyloid-β kinetics. We found that sleep deprivation increased overnight amyloid-β-38, amyloid-β-40, and amyloid-β-42 levels by 25-30% via increased overnight amyloid-β production relative to sleeping controls. These findings suggest that disrupted sleep increases Alzheimer's disease risk via increased amyloid-β production. This article is protected by copyright. All rights reserved.
      PubDate: 2017-12-08T18:15:55.478228-05:
      DOI: 10.1002/ana.25117
  • Single-unit activities during the transition to seizures in deep mesial
    • Authors: Virginie Lambrecq; Katia Lehongre, Claude Adam, Valério Frazzini, Bertrand Mathon, Stéphane Clemenceau, Dominique Hasboun, Stéphane Charpier, Michel Baulac, Vincent Navarro, Michel Le Van Quyen
      Abstract: Focal seizures are assumed to arise from a hypersynchronous activity affecting a circumscribed brain region. Using microelectrodes in seizure-generating deep mesial regions of 9 patients, we investigated the firing of hundreds of single-neurons before, during and after ictal EEG discharges. Neuronal spiking activity at seizure initiation was highly heterogeneous and not hypersynchronous. Furthermore, groups of neurons showed significant changes in activity minutes before the seizure with no concomitant changes in the corresponding macroscopic EEG recordings. Altogether, our findings suggest that only limitedsubsets of neurons in epileptic depth regions initiate the seizure-onset and that ictogenic mechanisms operate in sub-millimeter-scale microdomains. This article is protected by copyright. All rights reserved.
      PubDate: 2017-12-05T07:50:40.744639-05:
      DOI: 10.1002/ana.25111
  • Ischemic core thresholds change with time to reperfusion: A case control
    • Authors: Andrew Bivard; Tim Kleinig, Ferdinand Miteff, Kenneth Butcher, Longting Lin, Christopher Levi, Mark Parsons
      Abstract: Introduction: We aimed to identify if acute ischemic stroke patients with known complete reperfusion after thrombectomy had the same baseline CTP ischemic core threshold to predict infarction as thrombolysis patients with complete reperfusion. Methods: Patients who underwent thrombectomy were matched by age, clinical severity, occlusion location, and baseline perfusion lesion volume to patients who were treated with intravenous alteplase alone from the International Stroke Perfusion Imaging Registry. A pixel-based analysis of co-registered pre-treatment CT perfusion (CTP) and 24 hour diffusion-weighted imaging (DWI) was then undertaken to define the optimum CTP thresholds for the ischemic core. Results: There were 132 eligible thrombectomy patients and 132 matched controls treated with alteplase alone. Baseline National Institutes of Health Stroke Score (median 15, IQR 11-19), age (median 65, IQR 59 - 80) and time to IV treatment (median 153min, IQR 82- 315min) were well-matched (all p>0.05). Despite similar baseline CTP ischemic core volumes using the previously validated measure (rCBF
      PubDate: 2017-12-04T10:30:54.306544-05:
      DOI: 10.1002/ana.25109
  • Progressive deafness-dystonia due to SERAC1 mutations – a study of
           67 cases
    • Authors: Saskia B Wortmann; Katarzyna Iwanicka-Pronicka, Sema Kalkan Ucar, Bader Alhaddad, Moeenaldeen AlSayed, Mohammed A Al-Owain, Hamad I Al-Zaidan, Shanti Balasubramaniam, Ivo Barić, Dalal Bubshait, Alberto Burlina, John Christodoulou, Wendy K. Chung, Roberto Colombo, Niklas Darin, Peter Freisinger, Maria Teresa Garcia Silva, Stephanie Grunewald, Tobias B Haack, Peter M van Hasselt, Omar Hikmat, Friederike Hörster, Pirjo Isohanni, Khushnooda Ramzan, Reka Kovacs-Nagy, Zita Krumina, Elena Martin-Hernandez, Johannes A. Mayr, Patricia McClean, Linda De Meirleir, Karin Naess, Lock H Ngu, Magdalena Pajdowska, Shamima Rahman, Gillian Riordan, Lisa Riley, Benjamin Roeben, Frank Rutsch, Rene Santer, Manuel Schiff, Martine Seders, Silvia Sequeira, Wolfgang Sperl, Christian Staufner, Matthis Synofzik, Robert W. Taylor, Joanna Trubicka, Konstantinos Tsiakas, Ozlem Unal, Evangeline Wassmer, Yehani Wedatilake, Toni Wolff, Holger Prokisch, Eva Morava, Ewa Pronicka, Ron A Wevers, Arjan P de Brouwer, Roeltje R Maas
      Abstract: Objective: 3-MEthylGlutaconic aciduria, Dystonia-Deafness, Hepatopathy, Encephalopathy, Leigh-like syndrome (MEGDHEL) syndrome is caused by biallelic variants in SERAC1.Methods: Multi centre study concerning the course of disease for each organ system, together with metabolic, neuroradiological and genetic findings.Results: 67 individuals (39 previously unreported) from 59 families were included (age range 5 days - 33.4 years, median age 9 years). A total of 41 different SERAC1 variants were identified, including 20 that have not been reported before. With exception of two families with a milder phenotype, all affected individuals show a strikingly homogeneous phenotype and time course. Severe, reversible neonatal liver dysfunction and hypoglycemia was seen in more than 40% of all cases. Starting at a median age of six months muscular hypotonia (91%) was seen, followed by progressive spasticity (82%, median onset 15 months) and dystonia (82%, 18 months). The majority of affected individuals never learnt to walk (68%). 79% suffered hearing loss, 58% never learnt to speak, nearly all had significant intellectual disability (88%). MRI features were accordingly homogenous with bilateral basal ganglia involvement (98%), the characteristic “putaminal eye” was seen in 53%. The urinary marker 3-methylglutaconic aciduria is virtually present in all patients (98%). Supportive treatment focused on spasticity and drooling, was effective in individuals treated, hearing aids or cochlear implants did not improve communication skills.Interpretation: MEGDHEL syndrome is as a progressive deafness-dystonia syndrome with frequent and reversible neonatal liver involvement and a strikingly homogenous course of disease. This article is protected by copyright. All rights reserved.
      PubDate: 2017-12-02T10:53:05.22054-05:0
      DOI: 10.1002/ana.25110
  • Mutant huntingtin protein expression and blood-spinal cord barrier
           dysfunction in Huntington's disease
    • Authors: Giacomo Sciacca; Francesca Cicchetti
      Abstract: Objective: The aim of the study was to assess the distribution, frequency and specific location of mutant huntingtin protein (mHTT) aggregates - the pathological hallmark of HD - within the various compartments of the spinal cord and their potential impact on the local vasculature and BSCB.Methods: We performed a series of post-mortem immunohistochemical and immunofluorescent stainings, as well as western blot analyses, on cervical and lumbar sections of the spinal cord in patients diagnosed with HD (n=11 of all grades of disease severity) along with sex and age-matched healthy controls (n=9).Results: We observed that mHTT was preferably expressed within the anterior horn of the grey matter, in both cervical and lumbar sections. At the cellular level, mHTT aggregates were more often encountered in the extracellular matrix but could also be observed within cell bodies, neurites as well as within the endothelium of blood vessels with an increase in the density of small blood vessels in cervical sections of HD cases. These vasculature changes were accompanied with features of BSCB leakage, as assessed by the presence of increased levels of fibrinogen in the surrounding parenchyma and enhanced leukocyte infiltration.Interpretation: This alteration in BSCB integrity may be explained, in part, by the dysregulation we found in some of the main proteins associated with it such as the junctional adhesion molecule-1 (JAM-1) and vascular endothelial cadherin (VE-cadherin). These observations have important implications for our understanding of HD pathology and may also have significant therapeutic implications. This article is protected by copyright. All rights reserved.
      PubDate: 2017-11-24T10:50:49.259294-05:
      DOI: 10.1002/ana.25107
  • Building on NeuroNEXT: “Next Generation” Clinics to Cure
           Chronic Neurological Disability
    • Authors: Rajiv R. Ratan
      Abstract: Chronic disability from neurological conditions is a looming, if not present, epidemic. The combination of an increasingly aged population, and our improved ability to keep patients alive after acute neurological injury, means that the ranks of the chronically disabled are swelling. Indeed, it is estimated that by 2050, the leading causes of motor and cognitive disability in the United States- stroke and Alzheimer's disease-, will cost the country $1.4 trillion per year1-3. If these daunting numbers do not provoke action to accelerate progress on their own, the human suffering wrought by these conditions should. This article is protected by copyright. All rights reserved.
      PubDate: 2017-11-24T10:50:19.563171-05:
      DOI: 10.1002/ana.25108
  • Clinical and genetic findings in children with CNS arteriovenous fistulas
    • Authors: Guillaume Saliou; Mélanie Eyries, Marta Iacobucci, Jean François Knebel, Marie-Christine Waill, Florence Coulet, Augustin Ozanne, Florent Soubrier
      Abstract: Objective:To assess the spectrum of genetic anomalies in a cohort of children presenting at least one cerebral or spinal pial arteriovenous fistula (AVF), and to describe their clinical characteristics.Methods:From 1988 to 2016, all consecutive patients with at least one cerebral or spinal pial AVF were screened for genetic disease. All patients under the age of 18 years were included. Symptoms associated with AVF were recorded: heart failure, neurologic deficit/seizure, hemorrhage. The outcome was assessed using the mRS and school performance in children with cerebral AVF and the ASIA impairment scale in children with spinal AVF.Results:Forty-three children were included. Twenty-five children were male and 18 were female. A germline mutation was identified in 23 probands (53.5%±14.9%): 8 in ENG (34.8%±14.2%), 1 in ACVRL1 (4.3%±6%) leading to a diagnosis of HHT and 14 in RASA1 (60.9%±14.4%) leading to a diagnosis of CM-AVM1. No EphB4 gene mutation was identified. HHT patients presented a significantly lower rate of heart failure at diagnosis (p =0.047). A trend towards an increased bleeding rate at presentation was observed in HHT (p=0.069) and an increased rate of giant venous pouch in children in whom no mutation was identified (p=0.097). Finally, an association with RASA1 mutation was observed in children with associated skin capillary hemangioma (p
      PubDate: 2017-11-24T10:45:35.07039-05:0
      DOI: 10.1002/ana.25106
  • Increasing motor neuron excitability to treat weakness in sepsis
    • Authors: Paul Nardelli; Randall Powers, Tim C. Cope, Mark M. Rich
      Abstract: Objective: Weakness induced by critical illness (intensive care unit acquired weakness) is a major cause of disability in patients and is currently untreatable. We recently identified a defect in repetitive firing of lower motor neurons as a novel contributor to intensive care unit acquired weakness. In order to develop therapy for intensive care unit acquired weakness, it was necessary to determine the mechanism underlying the defect in repetitive firing.Methods: Both computer simulation and in vivo dynamic voltage clamp of spinal motor neurons in septic rats were employed to explore potential mechanisms underlying defective repetitive firing.Results: Our results suggested alteration in subthreshold voltage-activated currents might be the mechanism underlying defective repetitive firing. It has been shown previously that pharmacologic activation of serotonin receptors on motor neurons increases motor neuron excitability, in part by enhancing subthreshold voltage-activated inward currents. Administration of a food and drug administration approved serotonin agonist (lorcaserin) to septic rats greatly improved repetitive firing and motor unit force generation.Interpretation: Our findings suggest activation of serotonin receptors with lorcaserin may provide the first ever therapy for intensive care unit acquired weakness in patients. This article is protected by copyright. All rights reserved.
      PubDate: 2017-11-24T10:45:31.912695-05:
      DOI: 10.1002/ana.25105
  • Targeting Hypersensitive Corticostriatal Terminals in Restless Legs
    • Authors: Gabriel Yepes; Xavier Guitart, William Rea, Amy H. Newman, Richard P. Allen, Christopher J. Earley, César Quiroz, Sergi Ferré
      Abstract: Objective: The first aim was to demonstrate a previously hypothesized increased sensitivity of corticostriatal glutamatergic terminals in the rodent with brain iron deficiency (BID), a pathogenetic model of Restless Legs Syndrome (RLS). The second aim was to determine if these putative hypersensitive terminals could constitute a significant target for drugs effective in RLS, including dopamine agonists (pramipexole and ropinirole) and α2δ ligands (gabapentin).Methods: A recently introduced in vivo optogenetic-microdialysis approach was used, which allows the measurement of the extracellular concentration of glutamate upon local light-induced stimulation of corticostriatal glutamatergic terminals. The method also allows to analyze the effect of local perfusion of compounds within the same area being sampled for glutamate.Results: BID rats showed hypersensitivity of corticostriatal glutamatergic terminals (lower frequency of optogenetic stimulation to induce glutamate release). Both hypersensitive and control glutamatergic terminals were significant targets for locally perfused pramipexole, ropinirole and gabapentin, which significantly counteracted optogenetically-induced glutamate release. The use of selective antagonists demonstrated the involvement of dopamine D4 and D2 receptor subtypes on the effects of pramipexole.Interpretation: Hypersensitivity of corticostriatal glutamatergic terminals can constitute a main pathogenetic mechanism of RLS symptoms. Selective D4 receptor agonists, by specifically targeting these terminals, should provide a new efficient treatment with less secondary effects. This article is protected by copyright. All rights reserved.
      PubDate: 2017-11-24T10:45:19.926161-05:
      DOI: 10.1002/ana.25104
  • Striatal dopamine in Parkinson's disease: A meta-analysis of imaging
    • Authors: Valtteri Kaasinen; Tero Vahlberg
      Abstract: A meta-analysis of 141 PET and SPECT studies that have investigated striatal presynaptic dopamine function in Parkinson's disease (PD) was performed. Subregional estimates of striatal dopamine metabolism are presented. The aromatic L-amino-acid decarboxylase (AADC) defect appears to be consistently smaller than the dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) defects, suggesting up-regulation of AADC function in PD. The correlation between disease severity and dopamine loss appears linear but the majority of longitudinal studies point to a negative exponential progression pattern of dopamine loss in PD. This article is protected by copyright. All rights reserved.
      PubDate: 2017-11-22T10:40:34.414529-05:
      DOI: 10.1002/ana.25103
  • Sensation, mechanoreceptor and nerve fiber function after nerve
    • Authors: Christian Krarup; Birgitta Rosén, Michel Boeckstyns, Allan Ibsen Sørensen, Göran Lundborg, Mihai Moldovan, Simon J. Archibald
      Abstract: Objective: Sensation is essential for recovery after peripheral nerve injury. However, the relationship between sensory modalities and function of regenerated fibers is uncertain. We have investigated the relationships between touch threshold, tactile gnosis and mechanoreceptor and sensory fiber function after nerve regeneration.Methods: Twenty-one median or ulnar nerve lesions were repaired by a collagen nerve conduit or direct suture. Quantitative sensory hand function and sensory conduction studies by near-nerve technique including tactile stimulation of mechanoreceptors were followed for 2 years, and results were compared to non-injured hands.Results: At both repair methods, touch thresholds at the finger tips recovered to 81±3% and tactile gnosis only to 20±4% (P
      PubDate: 2017-11-20T17:45:57.882573-05:
      DOI: 10.1002/ana.25102
  • Annals of Neurology: Volume 82, Number 5, November 2017
    • Abstract: ON THE COVER: A 3-dimensional z-stack of images taken with a confocal microscope of synapses (stained green for synaptophysin) being phagocytosed by microglia (stained red for CD68), in the spinal cord of a mouse with knockout of the Abcd1 gene. Mutations in this gene in humans cause adrenoleukodystrophy, one component of which is adrenomyeloneuropathy, in which there is loss of spinal cord synapses.
      PubDate: 2017-11-20T01:18:37.715908-05:
      DOI: 10.1002/ana.25093
  • Issue Information - Masthead
    • PubDate: 2017-11-20T01:18:36.212711-05:
      DOI: 10.1002/ana.25091
  • Issue Information - TOC
    • PubDate: 2017-11-20T01:18:35.92765-05:0
      DOI: 10.1002/ana.25092
  • Issue Information - Copyright
    • PubDate: 2017-11-20T01:18:34.423407-05:
      DOI: 10.1002/ana.25090
  • Natural History of Infantile-Onset Spinal Muscular Atrophy
    • Authors: Stephen J. Kolb; Christopher S. Coffey, Jon W. Yankey, Kristin Krosschell, W. David Arnold, Seward B. Rutkove, Kathryn J. Swoboda, Sandra P. Reyna, Ai Sakonju, Basil T. Darras, Richard Shell, Nancy Kuntz, Diana Castro, Julie Parsons, Anne M. Connolly, Claudia A. Chiriboga, Craig McDonald, W. Bryan Burnette, Klaus Werner, Mathula Thangarajh, Perry B. Shieh, Erika Finanger, Merit E. Cudkowicz, Michelle M. McGovern, D. Elizabeth McNeil, Richard Finkel, Susan T. Iannaccone, Edward Kaye, Allison Kingsley, Samantha R. Renusch, Vicki L. McGovern, Xueqian Wang, Phillip G. Zaworski, Thomas W. Prior, Arthur H.M. Burghes, Amy Bartlett, John T. Kissel, ,
      Abstract: Objective: Infantile-onset spinal muscular atrophy (SMA) is the most common genetic cause of infant mortality, typically resulting in death prior to age 2. Clinical trials in this population require an understanding of disease progression and identification of meaningful biomarkers to hasten therapeutic development and predict outcomes.Methods: A longitudinal, multi-center, prospective natural history study enrolled 26 SMA infants, and 27 control infants less than six months of age. Recruitment occurred at 14 centers over 21 months within the NINDS-sponsored NeuroNEXT Network. Infant motor function scales (TIMPSI, CHOP-INTEND and AIMS) and putative physiologic and molecular biomarkers were assessed prior to 6 months of age and at 6, 9, 12, 18 and 24-months with progression, correlations between motor function and biomarkers and hazard ratios were analyzed.Results: Motor function scores (MFS) and CMAP decreased rapidly in SMA infants, whereas MFS in all healthy infants rapidly increased. Correlations were identified between TIMPSI and CMAP in SMA infants. TIMPSI at first study visit was associated with risk of combined endpoint of death or permanent invasive ventilation in SMA infants. Post hoc analysis of survival to combined endpoint in SMA infants with 2 copies of SMN2 indicated a median age of 8 months at death (95%CI: 6,17).Interpretation: These data of SMA and control outcome measures delineates meaningful change in clinical trials in infantile-onset SMA. The power and utility of NeuroNEXT to provide “real world”, prospective natural history data sets to accelerate public and private drug development programs for rare disease is demonstrated. This article is protected by copyright. All rights reserved.
      PubDate: 2017-11-17T18:20:27.188961-05:
      DOI: 10.1002/ana.25101
  • Mitochondrial DNA changes in pedunculopontine cholinergic neurons in
    • Authors: Alexander G. Bury; Angela Pyle, Joanna L. Elson, Laura Greaves, Christopher M. Morris, Gavin Hudson, Ilse S. Pienaar
      Abstract: In Parkinson's disease (PD), mitochondrial dysfunction associates with nigral dopaminergic neuronal loss. Cholinergic neuronal loss co-occurs, particularly within a brainstem structure, the pedunculopontine nucleus (PPN). We isolated single cholinergic neurons from post-mortem PPNs of aged controls and PD patients. Mitochondrial DNA (mtDNA) copy number and mtDNA deletions were increased significantly in PD patients compared to controls. Furthermore, compared to controls the PD patients had significantly more PPN cholinergic neurons containing mtDNA deletion levels exceeding 60%, a level associated with deleterious effects on oxidative phosphorylation. The current results differ from studies reporting mtDNA depletion in nigral dopaminergic neurons of PD patients. This article is protected by copyright. All rights reserved.
      PubDate: 2017-11-17T18:10:41.672899-05:
      DOI: 10.1002/ana.25099
  • NeuroNEXT Is At Your Service
    • Authors: Seward B. Rutkove; Basil T. Darras
      PubDate: 2017-11-17T18:10:37.206121-05:
      DOI: 10.1002/ana.25100
  • Is There Even Such a Thing as “Idiopathic Normal Pressure
    • Authors: Alberto J. Espay; Anthony E. Lang
      PubDate: 2017-11-14T10:55:32.124507-05:
      DOI: 10.1002/ana.25097
  • Reply to Is There Even Such a Thing as “Idiopathic Normal Pressure
    • Authors: Clifford B. Saper
      PubDate: 2017-11-14T10:55:22.41667-05:0
      DOI: 10.1002/ana.25098
  • A variant in PPP4R3A protects against Alzheimer-related metabolic decline
    • Authors: Leigh Christopher; Valerio Napolioni, Raiyan R. Khan, Summer S. Han, Michael D. Greicius,
      Abstract: Objectives: A reduction in glucose metabolism in the posterior cingulate cortex (PCC) predicts conversion to Alzheimer's disease (AD) and tracks disease progression, signifying its importance in AD. We aimed to use decline in PCC glucose metabolism as a proxy for the development and progression of AD to discover common genetic variants associated with disease vulnerability.Methods: We performed a genome-wide association study (GWAS) of decline in PCC [18F] FDG PET measured in Alzheimer's Disease Neuroimaging Initiative (ADNI) participants (n=606). We then performed follow-up analyses to assess the impact of significant single nucleotide polymorphisms (SNPs) on disease risk and longitudinal cognitive performance in a large independent dataset (n=870). Lastly, we assessed whether significant SNPs influence gene expression using two RNA sequencing (RNA-Seq) datasets (n=210 & n=159).Results: We demonstrate a novel genome-wide significant association between rs2273647-T in the gene PPP4R3A and reduced [18F] FDG decline (p= 4.44 x 10−8). In a follow-up analysis using an independent dataset, we demonstrate a protective effect of this variant against risk of conversion to MCI or AD (p=0.038) and against cognitive decline in individuals who develop dementia (p = 3.41 x 10−15). Furthermore, this variant is associated with altered gene expression in peripheral blood and altered PPPP4R3A transcript expression in temporal cortex, suggesting a role at the molecular level.Interpretations: PPP4R3A is a gene involved in AD risk and progression. Given the protective effect of this variant PPP4R3A should be further investigated as a gene of interest in neurodegenerative diseases and as a potential target for AD therapies. This article is protected by copyright. All rights reserved.
      PubDate: 2017-11-11T09:55:34.818265-05:
      DOI: 10.1002/ana.25094
  • Heterogenous migraine aura symptoms correlate with visual cortex fMRI
    • Authors: Nanna Arngrim; Anders Hougaard, Khazar Ahmadi, Mark Bitsch Vestergaard, Henrik Winther Schytz, Faisal Mohammad Amin, Henrik Bo Wiberg Larsson, Jes Olesen, Michael B. Hoffmann, Messoud Ashina
      Abstract: Objective: Migraine aura is sparsely studied due to the highly challenging task of capturing patients during aura. Cortical spreading depression (CSD) is likely the underlying phenomenon of aura. The possible correlation between the multifaceted phenomenology of aura symptoms and the effects of CSD on the brain has not been ascertained.Methods: Five migraine patients were studied during various forms of aura symptoms induced by hypoxia, sham or physical exercise and photostimulation. The blood oxygenation level-dependent (BOLD) functional MRI (fMRI) signal response to visual stimulation was measured in retinotopic mapping defined visual cortex area V1 - V4.Results: We found reduced BOLD response in patients reporting scotoma and increased response in patients who only experienced positive symptoms. Furthermore, patients with bilateral visual symptoms had corresponding bi-hemispherical changes in BOLD response.Interpretation: These findings suggest that different aura symptoms reflect different types of cerebral dysfunction, which correspond to specific changes in BOLD signal reactivity. Furthermore, we provide evidence of bilateral CSD recorded by fMRI during bilateral aura symptoms. This article is protected by copyright. All rights reserved.
      PubDate: 2017-11-11T09:55:32.350265-05:
      DOI: 10.1002/ana.25096
  • A localized pallidal physiomarker in cervical dystonia
    • Authors: Wolf-Julian Neumann; Andreas Horn, Siobhan Ewert, Julius Huebl, Christof Brücke, Colleen Slentz, Gerd-Helge Schneider, Andrea A. Kühn
      Abstract: Objective: Deep brain stimulation (DBS) allows for direct recordings of neuronal activity from the human basal ganglia. In Parkinson's disease, a disease-specific physiomarker was identified that is now used to investigate adaptive closed-loop stimulation in first studies. In dystonia such a physiomarker is missing.Methods: Pallidal oscillations were recorded from 153 contact pairs in 27 patients. We investigated whether power amplitudes in theta and beta bands correlate with dystonic symptom severity across patients. We then projected theta power from each contact pair onto standard subcortical anatomy. This way, we defined a theta hot spot on a group level and investigated whether proximity of the active DBS contacts to it correlates with clinical improvement.Results: Dystonic symptom severity significantly correlated with theta, but not beta oscillatory amplitudes (ρ=0.4; P=0.009) and interhemispheric coherence (ρ=0.5; P=0.002). The sweet spot of theta activity localized to the posterior third of the internal pallidum and theta power correlated with proximity to this location (ρ=0.23; P=0.002), which coincided with three previously published coordinates describing optimal stimulation targets. Finally, motor improvement through pallidal long term DBS correlated with theta peak amplitude (ρ=0.38; P=0.018).Interpretation: Our findings suggest that theta oscillations in the internal pallidum are robustly associated with dystonic symptoms in cervical dystonia and may be a useful biomarker for adaptive closed-loop stimulation. Furthermore, theta oscillatory activity may have a predictive value for the clinical benefit after chronic DBS that could be used to improve intraoperative neurophysiological target mapping during electrode implantation. This article is protected by copyright. All rights reserved.
      PubDate: 2017-11-11T09:55:21.319545-05:
      DOI: 10.1002/ana.25095
  • Nosologic Considerations in Disorders of Consciousness
    • Authors: James L. Bernat
      PubDate: 2017-11-01T11:00:20.314433-05:
      DOI: 10.1002/ana.25089
  • Reforming the Taxonomy in Disorders of Consciousness
    • Authors: Tim Bayne; Jakob Hohwy, Adrian M. Owen
      Abstract: This paper examines the serious shortcomings that characterize the current taxonomy of post-comatose disorders of consciousness (DoC), and it provides guidelines for how an improved DoC taxonomy might be developed. In particular, it is argued that behavioural criteria for the application of DoC categories should be supplemented with brain-based criteria (e.g., information derived from EEG and fMRI), and that the categorical framework that currently characterizes DoC should be replaced by a more complex framework that better captures the performance of patients across a range of cognitive and behavioural tasks. This article is protected by copyright. All rights reserved.
      PubDate: 2017-11-01T10:55:22.542437-05:
      DOI: 10.1002/ana.25088
  • A clinical predictive score for postoperative myasthenic crisis
    • Authors: Tetsuya Kanai; Akiyuki Uzawa, Yasunori Sato, Shigeaki Suzuki, Naoki Kawaguchi, Keiichi Himuro, Fumiko Oda, Yukiko Ozawa, Jin Nakahara, Norihiro Suzuki, Yuko K Takahashi, Satoru Ishibashi, Takanori Yokota, Takashi Ogawa, Kazumasa Yokoyama, Nobutaka Hattori, Shoko Izaki, Satoru Oji, Kyoichi Nomura, Juntaro Kaneko, Kazutoshi Nishiyama, Ichiro Yoshino, Satoshi Kuwabara
      Abstract: Objective: Myasthenia gravis (MG) is an autoimmune disease mostly caused by autoantibodies against acetylcholine receptor (AChR) associated with thymus abnormalities. Thymectomy has been proven to be an efficacious treatment for patients with MG, but postoperative myasthenic crisis often occurs and is a major complication. We aimed to develop and validate a simple scoring system based on clinical characteristics in the preoperative status to predict the risk of postoperative myasthenic crisis.Methods: We studied 393 patients with MG who underwent thymectomy at six tertiary centers in Japan (275 patients for derivation and 118 for validation). Clinical characteristics, such as gender, age at onset and operation, body mass index, disease duration, MG subtype, severity, symptoms, preoperative therapy, operative data, and laboratory data, were reviewed retrospectively. A multivariate logistic regression with LASSO penalties was used to determine the factors associated with postoperative myasthenic crisis and score was assigned. Finally, the predictive score was evaluated using bootstrapping technique in the derivation and validation group.Results: Multivariate logistic regression identified three clinical factors for predicting postoperative myasthenic crisis risk: (1) vital capacity 
      PubDate: 2017-10-30T10:37:25.174693-05:
      DOI: 10.1002/ana.25087
  • Microglial dysfunction as a key pathologic change in adrenomyeloneuropathy
    • Authors: Yi Gong; Nikhil Sasidharan, Fiza Laheji, Matthew Frosch, Patricia Musolino, Rudy Tanzi, Doo Yeon Kim, Alessandra Biffi, Joseph El Khoury, Florian Eichler
      Abstract: Objective: Mutations in ABCD1 cause the neurodegenerative disease adrenoleukodystrophy, which manifests as the spinal cord axonopathy adrenomyeloneuropathy (AMN) in nearly all males surviving into adulthood. Microglial dysfunction has long been implicated in pathogenesis of brain disease but its role in the spinal cord is unclear.Methods: We assessed spinal cord microglia in humans and mice with AMN and investigated the role of ABCD1 in microglial activity toward neuronal phagocytosis in cell culture. As mutations in ABCD1 lead to incorporation of very long chain fatty acids into phospholipids, we separately examined the effects of lysophosphatidylcholine (LPC) upon microglia.Results: Within the spinal cord of humans and mice with AMN, upregulation of several phagocytosis-related markers such as MFGE8 and TREM2 precedes complement activation and synapse loss. Unexpectedly, this occurs in the absence of overt inflammation. LPC C26:0 added to ABCD1-deficient microglia in culture further enhances MFGE8 expression, aggravates phagocytosis and leads to neuronal injury. Furthermore, exposure to a MFGE8 blocking antibody reduces phagocytic activity.Interpretation: Spinal cord microglia lacking ABCD1 are primed for phagocytosis, affecting neurons within an altered metabolic milieu. Blocking phagocytosis or specific phagocytic receptors may alleviate synapse loss and axonal degeneration. This article is protected by copyright. All rights reserved.
      PubDate: 2017-10-23T17:30:37.690275-05:
      DOI: 10.1002/ana.25085
  • Stimulation of the mesencephalic locomotor region for gait recovery after
    • Authors: Felix Fluri; Uwe Malzahn, György A. Homola, Michael K. Schuhmann, Christoph Kleinschnitz, Jens Volkmann
      Abstract: Objective: One-third of all stroke survivors are unable to walk, even after intensive physiotherapy. Thus, other concepts to restore walking are needed. Since electrical stimulation of the mesencephalic locomotor region (MLR) is known to elicit gait movements, this area might be a promising target for restorative neurostimulation in stroke patients with gait disability. The present study aims to delineate the effect of high-frequency stimulation of the MLR (MLR-HFS) on gait impairment in a rodent stroke model.Methods: Male Wistar rats underwent photothrombotic stroke of the right sensorimotor cortex and chronic implantation of a stimulating electrode into the right MLR. Gait was assessed using clinical scoring of the beam walking test and videokinematic analysis (CatWalk™) at baseline and on days 3 and 4 after experimental stroke with and without MLR-HFS.Results: Kinematic analysis revealed significant changes in several dynamic and static gait parameters resulting in overall reduced gait velocity. All rats exhibited major coordination deficits during the beam walking challenge and were unable to cross the beam. Simultaneous to the onset of MLR-HFS, a significantly higher walking speed and improvements in several dynamic gait parameters were detected by the Catwalk™-system. Rats regained the ability to cross the beam unassisted showing a reduced number of paw slips and misses.Interpretation: MLR-HFS can improve disordered locomotor function in a rodent stroke model. It may act by shielding brainstem and spinal locomotor centers from abnormal cortical input after stroke, thus allowing for compensatory and independent action of these circuits. This article is protected by copyright. All rights reserved.
      PubDate: 2017-10-23T17:26:13.753602-05:
      DOI: 10.1002/ana.25086
  • Stereo-electroencephalography and surgical outcome in
           polymicrogyria-related epilepsy: A multi-centric study
    • Authors: Louis Georges Maillard; Laura Tassi, Fabrice Bartolomei, Hélène Catenoix, François Dubeau, William Szurhaj, Philippe Kahane, Anca Nica, Petr Marusic, Ioana Mindruta, Francine Chassoux, Georgia Ramantani
      Abstract: Objective: We aimed to 1) assess the concordance between various PMG types and the associated epileptogenic zone (EZ), as defined by stereo-electroencephalography (SEEG), and 2) determine the postsurgical seizure outcome in PMG-related drug-resistant epilepsy. Methods: We retrospectively analyzed 58 cases: 49 had SEEG and 39 corticectomy or hemispherotomy. Results: Mean age at SEEG or surgery was 28.3 years (range 2-50). PMG was bilateral in 9 (16%) patients and unilateral in 49, including 17 (29%) unilobar, 12 (21%) multilobar, 15 (26%) perisylvian, and only 5 (9%) hemispheric. Twenty-eight (48%) patients additionally had schizencephaly, heterotopia or focal cortical dysplasia. The SEEG-determined EZ was fully concordant with the PMG in only 8 (16%) cases, partially concordant in 74% and discordant in 10%. The EZ included remote cortical areas in 21 (43%) cases and was primarily localized in those in 5 (10%), all related to the mesial temporal structures. All but one PMG patients with corticectomy or hemispherotomy had a unilateral PMG. At last follow-up (mean 4.6 years, range 1-16), 28 (72%) patients remained seizure free. Shorter epilepsy duration to surgery was an independent predictor of seizure freedom. Interpretation: PMG-related drug-resistant epilepsy warrants a comprehensive presurgical evaluation, including SEEG investigations in most cases, since the EZ may only partially overlap with the PMG or include solely remote cortical areas. Seizure freedom is feasible in a large proportion of patients. PMG extent should not deter from exploring the possibility of epilepsy surgery. Our data support the early consideration of epilepsy surgery in this patient group. This article is protected by copyright. All rights reserved.
      PubDate: 2017-10-23T13:15:23.317319-05:
      DOI: 10.1002/ana.25081
  • A recessive ataxia diagnosis algorithm for the next-generation sequencing
    • Authors: Mathilde Renaud; Christine Tranchant, Juan Vicente Torres Martin, Fanny Mochel, Matthis Synofzik, Bart van de Warrenburg, Massimo Pandolfo, Michel Koenig, Stefan A. Kolb, Mathieu Anheim,
      Abstract: Objective: Differential diagnosis of autosomal recessive cerebellar ataxias can be challenging. A ranking algorithm that predicts the molecular diagnosis based on the clinical phenotype of a patient has been developed to guide genetic testing and to align genetic findings with the clinical context.Methods: An algorithm that follows clinical practice, including patient history, clinical, MRI, electromyography and biomarker features, was developed following a review of the literature on 67 autosomal recessive cerebellar ataxias and personal clinical experience. Frequency and specificity of each feature were defined for each autosomal recessive cerebellar ataxia, and corresponding prediction scores assigned. Clinical and paraclinical features of patients are entered into the algorithm, and a patient's total score for each autosomal recessive cerebellar ataxia is calculated, producing a ranking of possible diagnoses. Sensitivity and specificity of the algorithm were assessed by blinded analysis of a multinational cohort of 834 patients with molecularly confirmed autosomal recessive cerebellar ataxia. The performance of the algorithm was assessed versus a blinded panel of autosomal recessive cerebellar ataxia experts.Results: The correct diagnosis was ranked within the top 3 highest-scoring diagnoses at a sensitivity or specificity of>90% for 84% and 91% of the evaluated genes, respectively. Mean sensitivity and specificity of the top 3 highest-scoring diagnoses were 92% and 95%, respectively. The algorithm outperformed the panel of ataxia experts (P=0.001).Interpretation: Our algorithm is highly sensitive and specific, accurately predicting the underlying molecular diagnoses of autosomal recessive cerebellar ataxias, thereby guiding targeted sequencing or facilitating interpretation of next-generation sequencing data. This article is protected by copyright. All rights reserved.
      PubDate: 2017-10-23T13:15:20.122894-05:
      DOI: 10.1002/ana.25084
  • Molecular-based diagnosis of Multiple Sclerosis and its progressive stage
    • Authors: Christopher Barbour; Peter Kosa, Mika Komori, Makoto Tanigawa, Ruturaj Masvekar, Tianxia Wu, Kory Johnson, Panagiotis Douvaras, Valentina Fossati, Ronald Herbst, Yue Wang, Keith Tan, Mark Greenwood, Bibiana Bielekova
      Abstract: Objective: Biomarkers aid diagnosis, allow inexpensive screening of therapies and guide selection of patient-specific therapeutic regimens in most internal medicine disciplines. In contrast, neurology lacks validated measurements of the physiological status, or dysfunction(s) of cells of the central nervous system (CNS). Accordingly, patients with chronic neurological diseases are often treated with a single disease-modifying therapy without understanding patient-specific drivers of disability.Therefore, using multiple sclerosis (MS) as an example of a complex polygenic neurological disease, we sought to determine if cerebrospinal fluid (CSF) biomarkers are intra-individually stable, cell type-, disease- and/or process-specific and responsive to therapeutic intervention.Methods: We used statistical learning in a modeling cohort (n=225) to develop diagnostic classifiers from DNA-aptamer-based measurements of 1128 CSF proteins. An independent validation cohort (n=85) assessed the reliability of derived classifiers. The biological interpretation resulted from in-vitro modeling of primary or stem cell-derived human CNS cells and cell lines.Results: The classifier that differentiates MS from CNS diseases that mimic MS clinically, pathophysiologically and on imaging, achieved a validated area under receiver-operator characteristic curve (AUROC) of 0.98, while the classifier that differentiates relapsing-remitting from progressive MS achieved a validated AUROC of 0.91. No classifiers could differentiate primary- from secondary-progressive MS better than random guessing. Treatment-induced changes in biomarkers greatly exceeded intra-individual- and technical variabilities of the assay.Interpretation: CNS biological processes reflected by CSF biomarkers are robust, stable, and disease- or even disease-stage specific. This opens opportunities for broad utilization of CSF biomarkers in drug development and precision medicine for CNS disorders. This article is protected by copyright. All rights reserved.
      PubDate: 2017-10-23T13:10:25.511742-05:
      DOI: 10.1002/ana.25083
  • Does Smoking Impact Dopamine Neuronal Loss in de novo Parkinson's
    • Authors: Yoonju Lee; Jungsu S. Oh, Seok Jong Chung, Su Jin Chung, Soo-Jong Kim, Chung Mo Nam, Phil Hyu Lee, Jae Seung Kim, Young H. Sohn
      PubDate: 2017-10-23T13:10:18.936446-05:
      DOI: 10.1002/ana.25082
  • Effect of sensory and motor connectivity on hand function in pediatric
    • Authors: Disha Gupta; Alexandre Barachant, Andrew M. Gordon, Claudio Ferre, Hsing-Ching Kuo, Jason B. Carmel, Kathleen M. Friel
      Abstract: Objective: We tested the hypothesis that somatosensory system injury would more strongly affect movement than motor system injury in children with unilateral cerebral palsy (USCP). This hypothesis was based on how somatosensory and corticospinal circuits adapt to injury during development: while the motor system can maintain connections to the impaired hand from the uninjured hemisphere, this doesn't occur in the somatosensory system. As a corollary, cortical injury strongly impairs sensory function, so we hypothesized that cortical lesions would impair hand function more than subcortical lesions.Methods: Twenty-four children with unilateral CP had physiological and anatomical measures of the motor and somatosensory systems and lesion classification. Motor physiology was performed with transcranial magnetic stimulation and somatosensory physiology with vibration-evoked EEG potentials. Tractography of the corticospinal tract and the medial lemniscus were performed with diffusion tensor imaging, and lesions were classified by MRI. Anatomical and physiological results were correlated with measures of hand function using two independent statistical methods.Results: Children with disruptions in the somatosensory connectivity, and cortical lesions had the most severe upper extremity impairments, particularly somatosensory function. Motor system connectivity was significantly correlated with bimanual function, but not unimanual function or somatosensory function.Interpretation: Both sensory and motor connectivity impact hand function in children with USCP. Somatosensory connectivity could be an important target for recovery of hand function in children with USCP. This article is protected by copyright. All rights reserved.
      PubDate: 2017-10-16T01:05:26.403892-05:
      DOI: 10.1002/ana.25080
  • Oral Anticoagulation and Functional Outcome after Intracerebral Hemorrhage
    • Authors: Alessandro Biffi; Joji B. Kuramatsu, Audrey Leasure, Hooman Kamel, Christina Kourkoulis, Kristin Schwab, Alison M. Ayres, Jordan Elm, M. Edip Gurol, Steven M. Greenberg, Anand Viswanathan, Christopher D. Anderson, Stefan Schwab, Jonathan Rosand, Fernando D. Testai, Daniel Woo, Hagen B. Huttner, Kevin N Sheth
      Abstract: Objective: Oral Anticoagulation Treatment (OAT) resumption is a therapeutic dilemma in Intracerebral Hemorrhage (ICH) care, particularly for lobar hemorrhages related to amyloid angiopathy. We sought to determine whether OAT resumption after ICH is associated with long-term outcome, accounting for ICH location (i.e. lobar vs. non-lobar).Methods: We meta-analyzed individual patient data from: 1) the multi-center RETRACE study (n=542); 2) a US-based single-center ICH study (n=261); 3) the Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study (n=209). We determined whether, within one year from ICH, OAT resumption was associated with: 1) mortality; 2) favorable functional outcome (modified Rankin Scale [mRS] 0-3); stroke incidence. We separately analyzed non-lobar and lobar ICH cases using propensity score matching and Cox regression models.Results: We included 1012 OAT-related ICH survivors (633 non-lobar and 379 lobar). Among non-lobar ICH survivors 178/633 (28%) resumed OAT, while 86/379 (23%) lobar ICH survivors did. In multivariable analyses OAT resumption after non-lobar ICH was associated with decreased mortality (Hazard Ratio [HR]=0.25, 95% Confidence Interval [CI]=0.14-0.44, p
      PubDate: 2017-10-13T10:55:21.661657-05:
      DOI: 10.1002/ana.25079
  • To do or not to do' Plasma exchange and timing of steroid
           administration in PML
    • Authors: Cristina Scarpazza; Luca Prosperini, Nicola De Rossi, Lucia Moiola, Maria Pia Sormani, Simonetta Gerevini, Ruggero Capra,
      Abstract: Objective: To retrospectively analyze the effect of plasma exchange (PLEX, yes=PLEX+, no=PLEX-) and steroids administration timing (prophylactically –proST- or therapeutically –therST-) on the longitudinal clinical course of patients with natalizumab related progressive multifocal leukoencephalopathy (PML) and full blown immune reconstitution inflammatory syndrome (PML-IRIS).Methods: Clinical and radiological data of 42 Italian patients with PML were analyzed. Patient's data are available until 12 months after PML diagnosis. PLEX and steroids treatment as time-dependent covariates were entered in: i) a Cox model to investigate their impact on full blown PML-IRIS latency; ii) an ANOVA to investigate their impact on IRIS duration; iii) a linear mixed model to assess their impact on the longitudinal clinical course (measured by means of EDSS).Results: Treatment with PLEX was not associated to PML-IRIS latency (HR=1.05, p=0.92), but once IRIS emerged, its duration was significantly longer in patients who underwent PLEX (101 vs 54 days in PLEX+ and PLEX- patients, p=0.028). Receiving proST vs therST was not associated to IRIS latency (HR=0.67, p=0.39) or duration (p=0.95). Patients who underwent proST had a significant higher EDSS increase during PML (0.09 EDSS points per month, p=0.04) as compared to those who had therST.Interpretation: this study highlights that: i) caution on the use of PLEX should be considered as the current data do not support a beneficial effect of PLEX; ii) caution on the early use of steroids is suggested since their prophylactic use to prevent full blown PML-IRIS seems to negatively impact on the longitudinal disability course. This article is protected by copyright. All rights reserved.
      PubDate: 2017-10-10T23:55:28.859233-05:
      DOI: 10.1002/ana.25070
  • Peripheral nerve involvement in multiple sclerosis Demonstration by
           magnetic resonance neurography
    • Authors: Johann M.E. Jende; Gesa H. Hauck, Ricarda Diem, Markus Weiler, Sabine Heiland, Brigitte Wildemann, Mirjam Korporal-Kuhnke, Wolfgang Wick, John M. Hayes, Johannes Pfaff, Mirko Pham, Martin Bendszus, Jennifer Kollmer
      Abstract: Objective:To detect and quantify peripheral nerve lesions in multiple sclerosis (MS) by magnetic resonance neurography (MRN).Methods: 36 patients diagnosed with MS based on the 2010 McDonald criteria (34 with the relapsing-remitting form, 2 with clinically isolated syndrome) with and without disease modifying treatment were compared to 35 healthy age/sex-matched volunteers. All patients underwent detailed neurological and electrophysiological examinations. 3T MRN with large anatomical coverage of both legs and the lumbosacral plexus was performed by using 2D fat-saturated, T2-weighted and dual echo turbo-spin-echo sequences as well as a 3D T2-weighted, fat-saturated SPACE sequence. Besides qualitative visual nerve assessment, a T2w-signal quantification was performed by calculation of proton-spin-density and T2-relaxation time. Nerve diameter was measured as a morphometric criterion.Results:T2w-hyperintense nerve lesions were detectable in all MS patients with a mean lesion number at thigh level of 151.5±5.7 vs. 19.1±2.4 in controls (p
      PubDate: 2017-10-10T18:45:22.406938-05:
      DOI: 10.1002/ana.25068
  • Imaging Spinal Cord Atrophy in Progressive Myelopathies: HTLV-I Associated
           Neurologic Disease (HAM/TSP) and Multiple Sclerosis (MS)
    • Authors: Shila Azodi; Govind Nair, Yoshimi Enose-Akahata, Emily Charlip, Ashley Vellucci, Irene Cortese, Jennifer Dwyer, B. Jeanne Billioux, Chevaz Thomas, Joan Ohayon, Daniel S Reich, Steven Jacobson
      Abstract: Objective: Previous work measures spinal cord thinning in chronic progressive myelopathies, including HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) and multiple sclerosis (MS). Quantitative measurements of spinal cord atrophy are important in fully characterizing these and other spinal cord diseases. We aimed to investigate patterns of spinal cord atrophy and correlations with clinical markers.Methods: Spinal cord cross sectional area was measured in individuals (24 healthy controls (HC), 17 asymptomatic carriers of HTLV-1 (AC), 47 HAM/TSP, 74 RRMS, 17 SPMS, and 40 PPMS) from C1 to T10. Clinical disability scores, viral markers, and immunological parameters were obtained for patients and correlated with representative spinal cord cross sectional area regions at the C2-C3, C4-C5, and T4-T9 levels. In two HAM/TSP patients, spinal cord cross sectional area was measured over three years.Results: All spinal cord regions are thinner in HAM/TSP (56 mm2 [SD 10], 59 [10], 23 [5]) than in HC (76 [7], 83 [8], 38 [4]) and AC (71 [7], 78 [9], 36 [7]). SPMS (62 [9], 66 [9], 32 [6]) and PPMS (65 [11], 68 [10], 35 [7]) have thinner cervical cords than HC and RRMS (73 [9], 77 [10], 37 [6]). Clinical disability scores (EDSS (p=0.009) and IPEC(p=0.03)) and CD8+ T cell frequency (p=0.04) correlate with T4-T9 spinal cord cross sectional area in HAM/TSP. Higher CSF HTLV-1 proviral load (p=0.01) was associated with thinner spinal cord cross sectional area. Both HAM/TSP patients followed longitudinally showed thoracic thinning followed by cervical thinning.Interpretation: Group average spinal cord cross sectional area in HAM/TSP and progressive MS show spinal cord atrophy. We further hypothesize that is possible that neuroglial loss from a thoracic inflammatory process results in anterograde and retrograde degeneration of axons, leading to the temporal progression of thoracic to cervical atrophy described here. This article is protected by copyright. All rights reserved.
      PubDate: 2017-10-10T13:40:30.335148-05:
      DOI: 10.1002/ana.25072
  • Stroke-Induced Chronic Systolic Dysfunction Driven by Sympathetic
    • Authors: Michael Bieber; Rudolf A. Werner, Edit Tanai, Ulrich Hofmann, Takahiro Higuchi, Kai Schuh, Peter U. Heuschmann, Stefan Frantz, Oliver Ritter, Peter Kraft, Christoph Kleinschnitz
      Abstract: Objective: Cardiac diseases are established risk factors for ischemic stroke incidence and severity. Conversely, there is increasing evidence that brain ischemia can cause cardiac dysfunction. The mechanisms underlying this neurogenic heart disease are incompletely understood. While it is established that ischemic stroke is associated with cardiac arrhythmias, myocardial damage, elevated cardiac enzymes and plasma catecholamines in the acute phase, nothing is known about the delayed consequences of ischemic stroke on cardiovascular function.Methods: To determine the long-term cardiac consequences of a focal cerebral ischemia, we subjected young and aged mice to a 30-minute transient middle cerebral artery occlusion and analyzed cardiac function by serial transthoracic echocardiography and hemodynamic measurements up to week 8 after surgery. Finally, animals were treated with metoprolol to evaluate a pharmacologic treatment option to prevent the development of heart failure.Results: Focal cerebral ischemia induced a long-term cardiac dysfunction with a reduction in left ventricular ejection fraction and an increase in left ventricular volumes; this development was associated with higher peripheral sympathetic activity. Metoprolol treatment prevented the development of chronic cardiac dysfunction by decelerating extracellular cardiac remodeling and inhibiting sympathetic signaling relevant to chronic autonomic dysfunction.Interpretation: Focal cerebral ischemia in mice leads to the development of chronic systolic dysfunction driven by increased sympathetic activity. If these results can be confirmed in a clinical setting, treating physicians should be attentive to clinical signs of heart failure in every patient after ischemic stroke. Therapeutically, the successful β-blockade with metoprolol in mice could also have future clinical implications. This article is protected by copyright. All rights reserved.
      PubDate: 2017-10-10T13:40:27.731759-05:
      DOI: 10.1002/ana.25073
  • Traumatic Brain Injury in the Prodromal Period of Parkinson Disease: A
           Large Epidemiological Study Using Medicare Data
    • Authors: Alejandra Camacho-Soto; Mark N. Warden, Susan Searles Nielsen, Amber Salter, David L. Brody, Heidi Prather, Brad A. Racette
      Abstract: Objective: Studies suggest a greater risk of Parkinson disease (PD) after traumatic brain injury (TBI), but it is possible that the risk of TBI is greater in the prodromal period of PD. We aimed to examine the time-to-TBI in PD patients in their prodromal period compared to population-based controls.Methods: We identified 89,790 incident PD cases and 118,095 comparable controls > 65 years of age in 2009 using Medicare claims data. Using data from the preceding five years, we compared time-to-TBI in PD patients in their prodromal period to controls. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for TBI in a Cox regression, while adjusting for age, sex, race/ethnicity, modified Charlson comorbidity index, smoking, and alcohol use.Results: Risk of TBI was greater in PD patients in their prodromal period across all age and sex groups, with HRs consistently increasing with proximity to PD diagnosis. HRs ranged from 1.64 (95% CI 1.52, 1.77) five years prior to diagnosis to 3.93 (95% CI 3.74, 4.13) in the year prior. The interaction between PD, TBI, and time was primarily observed for TBI attributed to falls. Motor dysfunction and cognitive impairment, suggested by corresponding ICD-9 codes, partially mediated the PD-TBI association.Interpretation: There is a strong association between PD and a recent TBI in the prodromal period of PD. This association strengthens as PD diagnosis approaches and may be a result of undetected non-motor and motor symptoms, but confirmation will be required. This article is protected by copyright. All rights reserved.
      PubDate: 2017-10-10T13:40:22.69508-05:0
      DOI: 10.1002/ana.25074
  • Age, Vascular Health, and Alzheimer's disease Biomarkers in an Elderly
    • Authors: Prashanthi Vemuri; Timothy G. Lesnick, Scott A. Przybelski, David S. Knopman, Val J. Lowe, Jonathan Graff-Radford, Rosebud O. Roberts, Michelle M. Mielke, Mary M. Machulda, Ronald C. Petersen, Clifford R. Jack
      Abstract: OBJECTIVE: To investigate the associations between age, vascular health, and Alzheimer's disease (AD) imaging biomarkers in an elderly sample.METHODS: We identified 430 individuals along the cognitive continuum aged>60 years with amyloid-PET, Tau-PET, and MRI scans from the population-based Mayo Clinic Study of Aging. A subset of 329 individuals had FDG-PET. We ascertained presently existing cardiovascular and metabolic conditions (CMC) from healthcare records and used the summation of presence/absence of hypertension, hyperlipidemia, cardiac-arrhythmias, coronary artery disease, congestive heart failure, diabetes mellitus, and stroke as a surrogate for vascular health. We used global amyloid from PiB-PET, entorhinal cortex tau uptake (ERC-tau) from Tau-PET, and neurodegeneration in AD signature regions from MRI and FDG-PET as surrogates for AD pathophysiology. We dichotomized participants into CMC=0 (CMC-) vs. CMC>0 (CMC+) and tested for age-adjusted group differences in AD biomarkers. Using structural equation models (SEM), we assessed the impact of vascular health on AD biomarker cascade (amyloid leads to tau leads to neurodegeneration) after considering the direct and indirect age, sex, and APOE effects.RESULTS: CMC+ participants had significantly greater neurodegeneration than CMC- participants but did not differ by amyloid or ERC-tau. The SEM models showed that i) vascular health had a significant direct and indirect impact on neurodegeneration but not on amyloid; and ii) vascular health specifically the presence of hyperlipidemia had a significant direct impact on ERC-tau.INTERPRETATION: Vascular health had quantifiably greater impact on neurodegeneration in AD regions than on amyloid deposition. Longitudinal studies are warranted to clarify the relationship between tau deposition and vascular health. This article is protected by copyright. All rights reserved.
      PubDate: 2017-10-10T13:35:26.977736-05:
      DOI: 10.1002/ana.25071
  • Prediction of phenotypic severity in mucopolysaccharidosis type IIIA
    • Authors: Suzan J.G. Knottnerus; Stephanie C.M. Nijmeijer, Lodewijk IJlst, Heleen te Brinke, Naomi van Vlies, Frits A Wijburg
      Abstract: Objective: Mucopolysaccharidosis IIIA or Sanfilippo disease type A is a progressive neurodegenerative disorder presenting in early childhood, caused by an inherited deficiency of the lysosomal hydrolase sulfamidase. New missense mutations, for which genotype-phenotype correlations are currently unknown, are frequently reported, hampering early prediction of phenotypic severity and efficacy assessment of new disease-modifying treatments. We aimed to design a method to determine phenotypic severity early in the disease course. Methods: Fifty-three patients were included of whom skin fibroblasts and data on disease course and mutation analysis were available. Patients were phenotypically characterized on clinical data as ‘rapidly progressing' or ‘slowly progressing'. Sulfamidase activity was measured in fibroblasts cultured at 37°C and at 30°C. Results: Sulfamidase activity in fibroblasts from patients homozygous or compound heterozygous for a combination of known severe mutations remained below the limit of quantification under both culture conditions. In contrast, sulfamidase activity in fibroblasts from patients homozygous or compound heterozygous for a known mild mutation increased above the limit of quantification when cultured at 30°C. With division on the basis of the patients phenotype, fibroblasts from ‘slowly progressing' patients could be separated from ‘rapid progressing' patients by increase in sulfamidase activity when cultured at 30°C (p
      PubDate: 2017-10-10T13:35:24.673836-05:
      DOI: 10.1002/ana.25069
  • Can STN DBS protect both nigral somata and innervation of the
    • Authors: D. Luke Fischer; Fredric P. Manfredsson, Caryl E. Sortwell
      PubDate: 2017-10-06T17:30:23.95211-05:0
      DOI: 10.1002/ana.25064
  • Reply to Can STN DBS protect both nigral somata and innervation of the
    • Authors: James B Koprich; Jonathan M Brotchie, Thomas Musacchio, Jens Volkmann, Chi Wang Ip
      PubDate: 2017-10-06T17:30:22.193471-05:
      DOI: 10.1002/ana.25066
  • Serum tau and neurological outcome in cardiac arrest
    • Authors: Niklas Mattsson; Henrik Zetterberg, Niklas Nielsen, Kaj Blennow, Josef Dankiewicz, Hans Friberg, Gisela Lilja, Philip S. Insel, Christian Rylander, Pascal Stammet, Anders Aneman, Christian Hassager, Jesper Kjaergaard, Michael Kuiper, Tommaso Pellis, Jørn Wetterslev, Matthew Wise, Tobias Cronberg
      Abstract: Objective: To test serum tau as a predictor of neurological outcome after cardiac arrest.Methods: We measured the neuronal protein tau in serum at 24, 48, and 72 h after cardiac arrest in 689 patients in the prospective international Target Temperature Management trial. The main outcome was poor neurological outcome, defined as Cerebral Performance Category 3-5 at 6 months.Results: Increased tau was associated with poor outcome at 6 months after cardiac arrest (median 38.5 [IQR 5.7-245] ng/L in poor versus 1.5 [0.7-2.4] ng/L in good outcome, for tau at 72 h, p
      PubDate: 2017-10-05T11:00:36.153206-05:
      DOI: 10.1002/ana.25067
  • Pooled analysis of the HLA-DRB1 by smoking interaction in Parkinson's
    • Authors: Yu-Hsuan Chuang; Pei-Chen Lee, Tim Vlaar, Claire Mulot, Marie-Anne Loriot, Johnni Hansen, Christina M. Lill, Beate Ritz, Alexis Elbaz
      Abstract: Objective: Inflammatory response plays an important role in Parkinson's disease (PD). Previous studies have reported an association between human leukocyte antigen (HLA)-DRB1 and the risk of PD. There has also been growing interest in investigating whether inflammation-related genes interact with environmental factors such as smoking to influence PD risk. We performed a pooled analysis of the interaction between HLA-DRB1 and smoking in PD in three population-based case-control studies from Denmark and France.Methods: We included 2,056 cases and 2,723 controls from three PD studies (Denmark, France) that obtained information on smoking through interviews. Genotyping of the rs660895 polymorphism in the HLA-DRB1 region was based on saliva or blood DNA samples. To assess interactions, we used logistic regression with product terms between rs660895 and smoking. We performed random-effects meta-analysis of marginal associations and interactions.Results: Both carrying rs660895-G (AG vs. AA: OR= 0.81; GG vs. AA: OR= 0.56; p-trend=0.003) and ever smoking (OR=0.56, p
      PubDate: 2017-10-05T11:00:26.51601-05:0
      DOI: 10.1002/ana.25065
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