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Publisher: John Wiley and Sons   (Total: 1577 journals)

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Showing 1 - 200 of 1577 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: 64, SJR: 1.385, h-index: 91)
Accounting & Finance     Hybrid Journal   (Followers: 46, SJR: 0.547, h-index: 30)
ACEP NOW     Free   (Followers: 1)
Acta Anaesthesiologica Scandinavica     Hybrid Journal   (Followers: 49, SJR: 1.02, h-index: 88)
Acta Archaeologica     Hybrid Journal   (Followers: 148, SJR: 0.101, h-index: 9)
Acta Geologica Sinica (English Edition)     Hybrid Journal   (Followers: 3, SJR: 0.552, h-index: 41)
Acta Neurologica Scandinavica     Hybrid Journal   (Followers: 5, SJR: 1.203, h-index: 74)
Acta Obstetricia et Gynecologica Scandinavica     Hybrid Journal   (Followers: 15, SJR: 1.197, h-index: 81)
Acta Ophthalmologica     Hybrid Journal   (Followers: 5, SJR: 0.112, h-index: 1)
Acta Paediatrica     Hybrid Journal   (Followers: 56, SJR: 0.794, h-index: 88)
Acta Physiologica     Hybrid Journal   (Followers: 6, SJR: 1.69, h-index: 88)
Acta Polymerica     Hybrid Journal   (Followers: 9)
Acta Psychiatrica Scandinavica     Hybrid Journal   (Followers: 35, SJR: 2.518, h-index: 113)
Acta Zoologica     Hybrid Journal   (Followers: 6, SJR: 0.459, h-index: 29)
Acute Medicine & Surgery     Hybrid Journal   (Followers: 3)
Addiction     Hybrid Journal   (Followers: 35, SJR: 2.086, h-index: 143)
Addiction Biology     Hybrid Journal   (Followers: 13, SJR: 2.091, h-index: 57)
Adultspan J.     Hybrid Journal   (SJR: 0.127, h-index: 4)
Advanced Energy Materials     Hybrid Journal   (Followers: 26, SJR: 6.411, h-index: 86)
Advanced Engineering Materials     Hybrid Journal   (Followers: 26, SJR: 0.81, h-index: 81)
Advanced Functional Materials     Hybrid Journal   (Followers: 50, SJR: 5.21, h-index: 203)
Advanced Healthcare Materials     Hybrid Journal   (Followers: 13, SJR: 0.232, h-index: 7)
Advanced Materials     Hybrid Journal   (Followers: 256, SJR: 9.021, h-index: 345)
Advanced Materials Interfaces     Hybrid Journal   (Followers: 6, SJR: 1.177, h-index: 10)
Advanced Optical Materials     Hybrid Journal   (Followers: 5, SJR: 2.488, h-index: 21)
Advanced Science     Open Access   (Followers: 5)
Advanced Synthesis & Catalysis     Hybrid Journal   (Followers: 17, SJR: 2.729, h-index: 121)
Advances in Polymer Technology     Hybrid Journal   (Followers: 13, SJR: 0.344, h-index: 31)
Africa Confidential     Hybrid Journal   (Followers: 19)
Africa Research Bulletin: Economic, Financial and Technical Series     Hybrid Journal   (Followers: 12)
Africa Research Bulletin: Political, Social and Cultural Series     Hybrid Journal   (Followers: 9)
African Development Review     Hybrid Journal   (Followers: 35, SJR: 0.275, h-index: 17)
African J. of Ecology     Hybrid Journal   (Followers: 15, SJR: 0.477, h-index: 39)
Aggressive Behavior     Hybrid Journal   (Followers: 15, SJR: 1.391, h-index: 66)
Aging Cell     Open Access   (Followers: 10, SJR: 4.374, h-index: 95)
Agribusiness : an Intl. J.     Hybrid Journal   (Followers: 6, SJR: 0.627, h-index: 14)
Agricultural and Forest Entomology     Hybrid Journal   (Followers: 14, SJR: 0.925, h-index: 43)
Agricultural Economics     Hybrid Journal   (Followers: 45, SJR: 1.099, h-index: 51)
AIChE J.     Hybrid Journal   (Followers: 30, SJR: 1.122, h-index: 120)
Alcoholism and Drug Abuse Weekly     Hybrid Journal   (Followers: 7)
Alcoholism Clinical and Experimental Research     Hybrid Journal   (Followers: 7, SJR: 1.416, h-index: 125)
Alimentary Pharmacology & Therapeutics     Hybrid Journal   (Followers: 34, SJR: 2.833, h-index: 138)
Alimentary Pharmacology & Therapeutics Symposium Series     Hybrid Journal   (Followers: 3)
Allergy     Hybrid Journal   (Followers: 50, SJR: 3.048, h-index: 129)
Alternatives to the High Cost of Litigation     Hybrid Journal   (Followers: 3)
American Anthropologist     Hybrid Journal   (Followers: 135, 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: 27, SJR: 0.211, h-index: 26)
American J. of Hematology     Hybrid Journal   (Followers: 33, 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: 264, 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: 126, SJR: 1.404, h-index: 88)
Analyses of Social Issues and Public Policy     Hybrid Journal   (Followers: 10, SJR: 0.397, h-index: 18)
Analytic Philosophy     Hybrid Journal   (Followers: 16)
Anatomia, Histologia, Embryologia: J. of Veterinary Medicine Series C     Hybrid Journal   (Followers: 3, SJR: 0.295, h-index: 27)
Anatomical Sciences Education     Hybrid Journal   (Followers: 1, SJR: 0.633, h-index: 24)
Andrologia     Hybrid Journal   (Followers: 2, SJR: 0.528, h-index: 45)
Andrology     Hybrid Journal   (Followers: 2, SJR: 0.979, h-index: 14)
Angewandte Chemie     Hybrid Journal   (Followers: 207)
Angewandte Chemie Intl. Edition     Hybrid Journal   (Followers: 213, SJR: 6.229, h-index: 397)
Animal Conservation     Hybrid Journal   (Followers: 37, SJR: 1.576, h-index: 62)
Animal Genetics     Hybrid Journal   (Followers: 9, 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: 48, 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: 13)
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: 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: 91, SJR: 0.545, h-index: 15)
Antipode     Hybrid Journal   (Followers: 47, SJR: 2.212, h-index: 69)
Anz J. of Surgery     Hybrid Journal   (Followers: 7, 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: 68, SJR: 0.754, h-index: 69)
Applied Organometallic Chemistry     Hybrid Journal   (Followers: 7, SJR: 0.632, h-index: 58)
Applied Psychology     Hybrid Journal   (Followers: 152, SJR: 1.023, h-index: 64)
Applied Psychology: Health and Well-Being     Hybrid Journal   (Followers: 48, SJR: 0.868, h-index: 13)
Applied Stochastic Models in Business and Industry     Hybrid Journal   (Followers: 5, SJR: 0.613, h-index: 24)
Aquaculture Nutrition     Hybrid Journal   (Followers: 14, SJR: 1.025, h-index: 55)
Aquaculture Research     Hybrid Journal   (Followers: 31, SJR: 0.807, h-index: 60)
Aquatic Conservation Marine and Freshwater Ecosystems     Hybrid Journal   (Followers: 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: 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: 231, SJR: 0.153, h-index: 13)
Arthritis & Rheumatology     Hybrid Journal   (Followers: 51, 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: 14)
Asia & the Pacific Policy Studies     Open Access   (Followers: 15)
Asia Pacific J. of Human Resources     Hybrid Journal   (Followers: 313, 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: 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: 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: 13, 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: 7, SJR: 0.39, h-index: 22)
Australian & New Zealand J. of Statistics     Hybrid Journal   (Followers: 13, SJR: 0.275, h-index: 28)
Australian Accounting Review     Hybrid Journal   (Followers: 4, SJR: 0.709, h-index: 14)
Australian and New Zealand J. of Family Therapy (ANZJFT)     Hybrid Journal   (Followers: 3, SJR: 0.382, h-index: 12)
Australian and New Zealand J. of Obstetrics and Gynaecology     Hybrid Journal   (Followers: 44, 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: 4, SJR: 0.171, h-index: 12)
Australian Economic Papers     Hybrid Journal   (Followers: 27, 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: 401, 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: 69, SJR: 0.59, h-index: 29)
Australian Psychologist     Hybrid Journal   (Followers: 11, SJR: 0.331, h-index: 31)
Australian Veterinary J.     Hybrid Journal   (Followers: 19, SJR: 0.459, h-index: 45)
Autism Research     Hybrid Journal   (Followers: 31, SJR: 2.126, h-index: 39)
Autonomic & Autacoid Pharmacology     Hybrid Journal   (SJR: 0.371, h-index: 29)
Banks in Insurance Report     Hybrid Journal   (Followers: 1)
Basic & Clinical Pharmacology & Toxicology     Hybrid Journal   (Followers: 10, SJR: 0.539, h-index: 70)
Basic and Applied Pathology     Open Access   (Followers: 2, SJR: 0.113, h-index: 4)
Basin Research     Hybrid Journal   (Followers: 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: 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: 16, SJR: 1.172, h-index: 90)
Biological Reviews     Hybrid Journal   (Followers: 3, SJR: 6.469, h-index: 114)
Biologie in Unserer Zeit (Biuz)     Hybrid Journal   (Followers: 42, SJR: 0.12, h-index: 1)
Biology of the Cell     Full-text available via subscription   (Followers: 9, SJR: 1.812, h-index: 69)
Biomedical Chromatography     Hybrid Journal   (Followers: 6, SJR: 0.572, h-index: 49)
Biometrical J.     Hybrid Journal   (Followers: 5, SJR: 0.784, h-index: 44)
Biometrics     Hybrid Journal   (Followers: 36, SJR: 1.906, h-index: 96)
Biopharmaceutics and Drug Disposition     Hybrid Journal   (Followers: 10, SJR: 0.715, h-index: 44)
Biopolymers     Hybrid Journal   (Followers: 18, SJR: 1.199, h-index: 104)
Biotechnology and Applied Biochemistry     Hybrid Journal   (Followers: 45, SJR: 0.415, h-index: 55)
Biotechnology and Bioengineering     Hybrid Journal   (Followers: 177, 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: 19, SJR: 1.374, h-index: 71)
Bipolar Disorders     Hybrid Journal   (Followers: 9, SJR: 2.592, h-index: 100)
Birth     Hybrid Journal   (Followers: 37, SJR: 0.763, h-index: 64)
Birth Defects Research Part A : Clinical and Molecular Teratology     Hybrid Journal   (Followers: 2, SJR: 0.727, h-index: 77)
Birth Defects Research Part B: Developmental and Reproductive Toxicology     Hybrid Journal   (Followers: 5, SJR: 0.468, h-index: 47)
Birth Defects Research Part C : Embryo Today : Reviews     Hybrid Journal   (SJR: 1.513, h-index: 55)
BJOG : An Intl. J. of Obstetrics and Gynaecology     Partially Free   (Followers: 225, SJR: 2.083, h-index: 125)

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Journal Cover Annals of Neurology
  [SJR: 5.584]   [H-I: 241]   [48 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  [1577 journals]
  • Dendritic spines provide cognitive resilience against Alzheimer's disease
    • Authors: Benjamin D. Boros; Kelsey M. Greathouse, Erik G. Gentry, Kendall A. Curtis, Elizabeth L. Birchall, Marla Gearing, Jeremy H. Herskowitz
      Abstract: Objective: Neuroimaging and other biomarker assays suggest that the pathological processes of Alzheimer's disease (AD) initiate years prior to clinical dementia onset. However some 30%-50% of older individuals that harbor AD pathology do not become symptomatic in their lifetime. It is hypothesized that such individuals exhibit cognitive resilience that protects against AD dementia. We hypothesized that in cases with AD pathology structural changes in dendritic spines would distinguish individuals that had or did not have clinical dementia.Methods: We compared dendritic spines within layers II and III pyramidal neuron dendrites in Brodmann Area 46 dorsolateral prefrontal cortex using the Golgi-Cox technique in 12 age-matched pathology-free controls, 8 controls with AD pathology (CAD), and 21 AD cases. We used highly optimized methods to trace impregnated dendrites from brightfield microscopy images which enabled accurate three-dimensional digital reconstruction of dendritic structure for morphologic analyses.Results: Spine density was similar among control and CAD cases but reduced significantly in AD. Thin and mushroom spines were reduced significantly in AD compared to CAD brains, whereas stubby spine density was decreased significantly in CAD and AD compared to controls. Increased spine extent distinguished CAD cases from controls and AD. Linear regression analysis of all cases indicated that spine density was not associated with neuritic plaque score but did display negative correlation with Braak staging.Interpretation: These observations provide cellular evidence to support the hypothesis that dendritic spine plasticity is a mechanism of cognitive resilience that protects older individuals with AD pathology from developing dementia. This article is protected by copyright. All rights reserved.
      PubDate: 2017-09-16T11:00:28.864784-05:
      DOI: 10.1002/ana.25049
       
  • DNAJC12 and dopa-responsive non-progressive Parkinsonism
    • Authors: Letizia Straniero; Ilaria Guella, Roberto Cilia, Laura Parkkinen, Valeria Rimoldi, Alexander Young, Rosanna Asselta, Giulia Soldà, Vesna Sossi, A. Jon Stoessl, Alberto Priori, Kenya Nishioka, Nobutaka Hattori, Jordan Follett, Alex Rajput, Nenad Blau, Gianni Pezzoli, Matthew J. Farrer, Stefano Goldwurm, Ali H. Rajput, Stefano Duga
      Abstract: Biallelic DNAJC12 mutations were described in children with hyperphenylalaninemia, neurodevelopmental delay, and dystonia.We identified DNAJC12 homozygous null variants (c.187A>T;p.K63*and c.79-2A>G;p.V27Wfs*14) in two kindreds with early-onset parkinsonism. Both probands had mild intellectual disability, mild non-progressive, motor symptoms, sustained benefit from small dose of levodopa and substantial worsening of symptoms after levodopa discontinuation. Neuropathology (Proband-A) revealed no alpha-synuclein pathology and substantia nigra depigmentation with moderate cell loss DNAJC12 transcripts were reduced in both patients. Our results suggest DNAJC12 mutations (absent in 500 early-onset patients with Parkinson's disease) rarely cause dopa-responsive non-progressive parkinsonism in adulthood, broadening the clinical spectrum of DNAJC12 deficiency. This article is protected by copyright. All rights reserved.
      PubDate: 2017-09-11T11:26:48.037191-05:
      DOI: 10.1002/ana.25048
       
  • Bicycling suppresses abnormal beta synchrony in the Parkinsonian basal
           ganglia
    • Authors: Lena Storzer; Markus Butz, Jan Hirschmann, Omid Abbasi, Maciej Gratkowski, Dietmar Saupe, Jan Vesper, Sarang S. Dalal, Alfons Schnitzler
      Abstract: Objective:Freezing of gait is a poorly understood symptom of Parkinson's disease, and can severely disrupt the locomotion of affected patients. However, bicycling ability remains surprisingly unaffected in most patients suffering from freezing suggesting functional differences in the motor network. The purpose of this study was to characterize and contrast the oscillatory dynamics underlying bicycling and walking in the basal ganglia.Methods:We present the first local field potential recordings directly comparing bicycling and walking in Parkinson's disease patients with electrodes implanted in the subthalamic nuclei for deep brain stimulation. Low (13-22 Hz) and high (23-35 Hz) beta power changes were analyzed in 22 subthalamic nuclei from 13 Parkinson's disease patients (57.5 +/- 5.9 years, four female). The study group consisted of five patients with and eight patients without freezing of gait.Results:In patients without freezing of gait, both bicycling and walking led to a suppression of subthalamic beta power (13-35 Hz), and this suppression was stronger for bicycling. Freezers showed a similar pattern in general. Superimposed on this pattern, however, we observed a movement-induced, narrowband power increase around 18 Hz, which was evident even in the absence of freezing.Interpretation:These results indicate that bicycling facilitates overall suppression of beta power. Furthermore, movement leads to exaggerated synchronization in the low beta band specifically within the basal ganglia of patients susceptible to freezing. Abnormal ∼18 Hz oscillations are implicated in the pathophysiology of freezing of gait, and suppressing them may form a key strategy in developing potential therapies. This article is protected by copyright. All rights reserved.
      PubDate: 2017-09-11T11:21:14.343547-05:
      DOI: 10.1002/ana.25047
       
  • Brain-heart interactions reveal consciousness in non-communicating
           patients
    • Authors: Federico Raimondo; Benjamin Rohaut, Athena Demertzi, Melanie Valente, Denis Engemann, Moti Salti, Diego Fernandez Slezak, Lionel Naccache, Jacobo D. Sitt
      Abstract: ObjectiveWe here aimed at characterizing heart-brain interactions in patients with disorders of consciousness. We tested how this information impacts data-driven classification between unresponsive and minimally conscious patients.MethodsA cohort of 127 patients in vegetative state/unresponsive wakefulness syndrome (VS/UWS, n=70) and minimally conscious state (MCS, n=57) were presented with the ‘Local-Global' auditory oddball paradigm, which distinguishes two levels of processing: short-term deviation of local auditory regularities and global long-term rule violations. In addition to previously validated markers of consciousness extracted from electroencephalograms (EEG), we computed autonomic cardiac markers, such as heart rate and variability (HR, HRV), and cardiac cycle phase-shifts triggered by the processing of the auditory stimuli.ResultsHR and HRV were similar in patients across groups. The cardiac cycle was not sensitive to the processing of local regularities in either the VS/UWS or MCS patients. In contrast, global regularities induced a phase-shift of the cardiac cycle exclusively in the MCS group. The interval between the auditory stimulation and the following R-peak was significantly shortened in MCS when the auditory rule was violated. When the information of the cardiac cycle modulations and other consciousness-related EEG markers were combined, single-patient classification performance was enhanced compared to classification with solely EEG markers.InterpretationOur work shows a link between residual cognitive processing and the modulation of autonomic somatic markers. These results open a new window to evaluate patients with disorders of consciousness via the embodied paradigm, according to which body-brain functions contribute to a holistic approach to conscious processing. This article is protected by copyright. All rights reserved.
      PubDate: 2017-09-11T11:21:07.104682-05:
      DOI: 10.1002/ana.25045
       
  • Mutations of KIF14 Cause Primary Microcephaly by Impairing Cytokinesis
    • Authors: Abubakar Moawia; Ranad Shaheen, Sajida Rasool, Syeda Seema Waseem, Nour Ewida, Birgit Budde, Amit Kawalia, Susanne Motameny, Kamal Khan, Ambrin Fatima, Muhammad Jameel, Farid Ullah, Talia Akram, Zafar Ali, Uzma Abdullah, Saba Irshad, Wolfgang Höhne, Angelika Anna Noegel, Mohammed Al-Owain, Konstanze Hörtnagel, Petra Stöbe, Shahid Mahmood Baig, Peter Nürnberg, Fowzan Sami Alkuraya, Andreas Hahn, Muhammad Sajid Hussain
      Abstract: Objective: Autosomal recessive primary microcephaly (MCPH) is a rare condition characterized by a reduced cerebral cortex accompanied with intellectual disability. Mutations in 17 genes have been shown to cause this phenotype. Recently, mutations in CIT, encoding CRIK (Citron Rho-interacting kinase) — a component of the central spindle matrix, were added. We aimed at identifying novel MCPH-associated genes and exploring their functional role in pathogenesis.Methods: Linkage analysis and whole-exome sequencing were performed in consanguineous and nonconsanguineous MCPH families to identify disease-causing variants. Functional consequences were investigated by RNA studies and on cellular level using immunofluorescence and microscopy.Results: We identified homozygous mutations in KIF14 (NM_014875.2;c.263T>A;pLeu88*, c.2480_2482delTTG;p.Val827del and c.4071G>A;p.Gln1357=) as the likely cause in three MCPH families. Further, in a patient presenting with a severe form of primary microcephaly and short stature, we identified compound heterozygous missense mutations in KIF14 (NM_014875.2;c.2545C>G;p.His849Asp and c.3662G>T;p.Gly1221Val). Three of the five identified mutations impaired splicing and two resulted in a truncated protein. Intriguingly, Kif14 knockout mice also showed primary microcephaly. Human kinesin-like protein KIF14, a microtubule motor protein, localizes at the midbody to finalize cytokinesis by interacting with CRIK. We found impaired localization of both KIF14 and CRIK at the midbody in patient-derived fibroblasts. Further, we observed a large number of binucleated and apoptotic cells — signs of failed cytokinesis that we also observed in experimentally KIF14-depleted cells.Interpretation: Our data corroborate the role of an impaired cytokinesis for the etiology of primary and syndromic microcephaly as has been proposed by recent findings on CIT mutations. This article is protected by copyright. All rights reserved.
      PubDate: 2017-09-11T11:20:49.611043-05:
      DOI: 10.1002/ana.25044
       
  • Deconstructing normal pressure hydrocephalus: Ventriculomegaly as early
           sign of neurodegeneration
    • Authors: Alberto J. Espay; Gustavo A. Da Prat, Alok K. Dwivedi, Federico Rodriguez-Porcel, Jennifer E. Vaughan, Michela Rosso, Johnna L. Devoto, Andrew P. Duker, Mario Masellis, Charles D. Smith, J. George T. Mandybur, Aristide Merola, Anthony E. Lang
      Abstract: Idiopathic normal pressure hydrocephalus (NPH) remains both over-suspected on clinical grounds and under-confirmed when based on immediate and sustained response to cerebrospinal fluid diversion. Poor long-term post-shunt benefits and findings of neurodegenerative pathology in most patients with adequate follow up suggests that hydrocephalic disorders appearing in late adulthood may often result from initially unapparent parenchymal abnormalities. We critically review the NPH literature, highlighting the near universal lack of blinding and controls, the absence of specific clinical, imaging, or pathologic features, and the ongoing dependence for diagnostic confirmation on variable cutoffs of gait response to bedside fluid-drainage testing. We also summarize our long-term institutional experience, in which post-shunt benefits in patients with initial diagnosis of idiopathic NPH persist in only 32% of patients at 36 months, with known revised diagnosis in over 25% (Alzheimer disease, dementia with Lewy bodies, and progressive supranuclear palsy). We postulate that previously reported NPH cases with “dual” pathology (i.e., developing a “second” disorder) more likely represent ventriculomegalic presentations of selected neurodegenerative disorders in which benefits from shunting may be short-lived, with a consequently unfavorable risk-benefit ratio. This article is protected by copyright. All rights reserved.
      PubDate: 2017-09-11T11:20:42.492699-05:
      DOI: 10.1002/ana.25046
       
  • Reply: MMP-9 as a biomarker of PML development in MS patients receiving
           Natalizumab
    • Authors: Nicolas Fissolo; Béatrice Pignolet, David Brassat, Manuel Comabella
      PubDate: 2017-09-04T10:30:49.847295-05:
      DOI: 10.1002/ana.25039
       
  • On establishing a grant pre-review process for new investigators
    • Authors: Seward B. Rutkove
      PubDate: 2017-09-04T10:30:47.732143-05:
      DOI: 10.1002/ana.25038
       
  • Alcohol improves cerebellar-learning deficit in myoclonus-dystonia - a
           clinical and electrophysiological investigation
    • Authors: Anne Weissbach; Elisa Werner, Julien F. Bally, Sinem Tunc, Sebastian Löns, Dagmar Timmann, Kirsten E. Zeuner, Vera Tadic, Norbert Brüggemann, Anthony Lang, Christine Klein, Alexander Münchau, Tobias Bäumer
      Abstract: Objectives: To characterize neurophysiological subcortical abnormalities in myoclonus-dystonia and their modulation by alcohol administration.Methods: Cerebellar associative learning and basal ganglia-brainstem interaction were investigated in 17 myoclonus-dystonia patients with epsilon-sarcoglycan (SGCE) gene mutation and 21 age- and sex-matched healthy controls by means of classical eyeblink conditioning and blink reflex recovery cycle before and after alcohol intake resulting in a breath alcohol concentration of 0.08% (0.8 g/l). The alcohol responsiveness of clinical symptoms was evaluated by three blinded raters with a standardized video protocol and clinical rating scales including the Unified Myoclonus Rating Scale (UMRS) and the Burke Fahn Marsden Dystonia Rating Scale (BFMDRS).Results: Patients showed a significantly reduced number of conditioned eyeblink responses before alcohol administration compared to controls. While the conditioning response rate decreased under alcohol intake in controls, it increased in patients (ANOVA: alcohol state x Group p = 0.004). Blink reflex recovery cycle before and after alcohol intake did not differ between groups. Myoclonus improved significantly after alcohol intake (p = 0.016). The severity of action myoclonus at baseline correlated negatively with the conditioning response in classical eyeblink conditioning in patients.Interpretation: The combination of findings with reduced baseline acquisition of conditioned eyeblink responses and normal blink reflex recovery cycle in patients that improved significantly by alcohol intake suggests a crucial role of cerebellar networks in the generation of symptoms in these patients. This article is protected by copyright. All rights reserved.
      PubDate: 2017-09-04T10:30:46.471723-05:
      DOI: 10.1002/ana.25035
       
  • MMP-9 as a biomarker of PML development in MS patients receiving
           Natalizumab
    • Authors: Hamid Zahednasab; Mohammad Hossein Harirchian, Sajad Karampoor, Hossein Keyvani
      PubDate: 2017-09-04T10:30:42.652287-05:
      DOI: 10.1002/ana.25037
       
  • Internal Grant Review to Increase Grant Funding for Junior Investigators
    • Authors: Heather S. Thomas; Martin B. Brodsky, Joshua B. Ewen, Gregory K. Bergey, Thomas E. Lloyd, Norman J. Haughey, Cherie L. Marvel
      Abstract: Decreasing biomedical research support over the past decade has driven many talented young scientists to seek careers outside academia. In 2011, the Department of Neurology at Johns Hopkins University School of Medicine developed an internal grant review program (IGRP) to systematically review career development awards (CDAs) and research grants (e.g., R01s) for junior investigators prior to NIH submission. With IGRP implementation, we observed significant increases in the number of CDAs and R-grants awarded to junior investigators. Thus, internal grant review is an effective means for supporting junior faculty and help them retain their research roles within academia. This article is protected by copyright. All rights reserved.
      PubDate: 2017-09-04T10:25:34.216618-05:
      DOI: 10.1002/ana.25040
       
  • Concussion in adolescence and risk of multiple sclerosis
    • Authors: Scott Montgomery; Ayako Hiyoshi, Sarah Burkill, Lars Alfredsson, Shahram Bahmanyar, Tomas Olsson
      Abstract: Objective: To assess whether concussion in childhood or adolescence is associated with subsequent multiple sclerosis risk. Previous research suggests an association but methodological limitations included retrospective data collection and small study populations.Methods: The national Swedish Patient (hospital diagnoses) and Multiple Sclerosis registers were used to identify all MS diagnoses up to 2012 among people born from 1964, when the Patient Register was established. The 7292 patients with multiple sclerosis were matched individually with 10 people without MS by sex, year of birth, age/vital status at multiple sclerosis diagnosis, and region of residence (county), resulting in a study population of 80212. Diagnoses of concussion and control diagnoses of broken limb bones were identified using the Patient Register from birth to age 10 years or from ages 11 to 20 years. Conditional logistic regression was used to examine associations with multiple sclerosis.Results: Concussion in adolescence was associated with a raised risk of multiple sclerosis, producing adjusted odds ratios (and 95% confidence intervals) of 1.22 (1.05-1.42, p=0.008) and 2.33 (1.35-4.04, p=0.002) for one diagnosis of concussion, or more than one diagnosis of concussion, respectively, compared with none. No notable association with multiple sclerosis was observed for concussion in childhood, or broken limb bones in childhood and adolescence.Interpretation: Head trauma in adolescence, particularly if repeated, is associated with a raised risk of future multiple sclerosis, possibly due to initiation of an autoimmune process in the central nervous system. This further emphasises the importance of protecting young people from head injuries. This article is protected by copyright. All rights reserved.
      PubDate: 2017-09-04T10:25:32.111146-05:
      DOI: 10.1002/ana.25036
       
  • The Missing, the Short, and the Long: Exploring the borderland between
           psychiatry and neurology
    • Authors: Hamilton Moses
      PubDate: 2017-08-31T10:45:23.704289-05:
      DOI: 10.1002/ana.25034
       
  • Fetal Growth and Premature Delivery in Pregnant Women on Anti-epileptic
           Drugs
    • Authors: Sonia Hernández-Díaz; Thomas F McElrath, Page B. Pennell, W Allen Hauser, Mark Yerby, Lewis B. Holmes,
      Abstract: Objective: To evaluate the effects of epilepsy and antiepileptic drugs (AED) use during pregnancy on fetal growth and preterm delivery.Methods: This study included singleton liveborns born to women enrolled in the North American Antiepileptic Drug Pregnancy Registry between 1997 and 2016. Data were collected prospectively through telephone interviews. The prevalence of preterm birth (
      PubDate: 2017-08-30T03:30:45.090177-05:
      DOI: 10.1002/ana.25031
       
  • Degeneration of serotonin neurons triggers spasticity in amyotrophic
           lateral sclerosis
    • Authors: Hajer El Oussini; Jelena Scekic-Zahirovic, Pauline Vercruysse, Christine Marques, Sylvie Dirrig-Grosch, Stéphane Dieterlé, Gina Picchiarelli, Jérôme Sinniger, Caroline Rouaux, Luc Dupuis
      Abstract: Objective: Spasticity occurs in a wide range of neurological diseases, including neurodegenerative diseases, after trauma or after stroke and is characterized by increased reflexes leading to muscle hypertonia. Spasticity is a painful symptom and can severely restrict everyday life, but might also participate in maintaining a low level of motor function in severely impaired patients. Constitutive activity of the serotonin receptors 5-HT2B/C is required for the development of spasticity after spinal cord injury or during amyotrophic lateral sclerosis (ALS). We sought here to provide direct evidence for a role of brainstem serotonin neurons in spasticity.Methods: SOD1(G37R) mice expressing a conditional allele of an ALS-linked SOD1 mutation were crossed to Tph2-CRE mice expressing CRE in serotonergic neurons. Measurement of long lasting reflex using EMG, behavioural follow up and histological techniques were used to characterize spasticity and motor phenotype.Results: Deleting mutant SOD1 expression selectively in brainstem serotonin neurons was sufficient to rescue loss of TPH2 immunoreactivity and largely preserve serotonin innervation of motor neurons in the spinal cord. Furthermore, this abrogated constitutive activity of 5-HT2B/C receptors and abolished spasticity in end-stage mice. Consistent with spasticity mitigating motor symptoms, selective deletion worsened motor function and accelerated the onset of paralysis.Interpretation: Degeneration of serotonin neurons is necessary to trigger spasticity through the 5-HT2B/C receptor. The wide range of drugs targeting the serotonergic system could be useful to treat spasticity in neurological diseases. This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-30T03:30:41.892418-05:
      DOI: 10.1002/ana.25030
       
  • Reply to “The Missing, the Short, and the Long: Exploring the borderland
           between psychiatry and neurology”
    • Authors: Roger L. Albin; Daniel K. Leventhal
      PubDate: 2017-08-30T03:30:33.073597-05:
      DOI: 10.1002/ana.25033
       
  • GABBR2 mutations determine phenotype in Rett syndrome and epileptic
           encephalopathy
    • Authors: Yongjin Yoo; Jane Jung, Yoo-Na Lee, Youngha Lee, Hyosuk Cho, Eunjung Na, JeaYeok Hong, Eunjin Kim, Jin Sook Lee, Je Sang Lee, Chansik Hong, Sang-Yoon Park, Jinhong Wie, Kathryn Miller, Natasha Shur, Cheryl Clow, Roseànne S. Ebel, Suzanne D. DeBrosse, Lindsay B. Henderson, Rebecca Willaert, Christopher Castaldi, Irina Tikhonova, Kaya Bilgüvar, Shrikant Mane, Ki Joong Kim, Yong Seung Hwang, Seok-Geun Lee, Insuk So, Byung Chan Lim, Hee-Jung Choi, Jae Young Seong, Yong Beom Shin, Hosung Jung, Jong-Hee Chae, Murim Choi
      Abstract: Objective: Rett syndrome (RTT) and epileptic encephalopathy (EE) are devastating neurodevelopmental disorders with distinct diagnostic criteria. However, highly heterogeneous and overlapping clinical features often allocate patients into the boundary of the two conditions, complicating accurate diagnosis and appropriate medical interventions. Therefore, we investigated the specific molecular mechanism that allows an understanding of the pathogenesis and relationship of these two conditions.Methods: We screened novel genetic factors from 34 RTT-like patients without MECP2 mutations, which account for ∼90% of RTT cases, by whole exome sequencing. The biological function of the discovered variants was assessed in cell culture and Xenopus tropicalis models.Results: We identified a recurring de novo variant in GABAB receptor R2 (GABBR2) that reduces the receptor function, whereas different GABBR2 variants in EE patients possess a more profound effect in reducing receptor activity and are more responsive to agonist rescue in an animal model.Interpretation: GABBR2 is a genetic factor that determines RTT- or EE-like phenotype expression depending on the variant positions. GABBR2-mediated GABA signaling is a crucial factor in determining the severity and nature of neurodevelopmental phenotypes. This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-30T03:30:28.200258-05:
      DOI: 10.1002/ana.25032
       
  • Dysregulation of LIMK-1/Cofilin-1 pathway: A possible basis for alteration
           of neuronal morphology in experimental cerebral malaria
    • Authors: Praveen Kumar Simhadri; Ruchi Malwade, Ravisankar Vanka, Venkata Prasuja Nakka, Gowthamarajan Kuppusamy, Prakash Babu Phanithi
      Abstract: Objective: Loss of cognition even after survival is the salient feature of cerebral malaria (CM). Currently, the fate of neuronal morphology is not studied at the ultra-structural level in CM. Recent studies suggest that maintenance of neuronal morphology and dendritic spine density (actin dynamics in particular) are essential for proper cognitive functions. LIMK-1/Cofilin-1signaling pathway is known to involve in the maintenance of actin dynamics through regulation of cofilin-1, in executing learning and memory functions.Methods: Using experimental mouse model, we analyzed the behavioural parameters of CM, asymptomatic mice by performing Rapid Murine Coma Behaviour Scale experiment (RMCBS). We performed Golgi-Cox staining to assess neuronal morphology, dendritic spine density and arborization in the brain cortex subjected to Plasmodium berghei ANKA infection compared to asymptomatic, anemic and control groups. We studied the neural gene expression pattern of LIMK-1, cofilin-1 and β-actin in all the experimental groups by semi-quantitative, quantitative PCR followed by immunoblotting and immunofluorescence.Results: We observed significant loss of dendritic spine density, abnormal spine morphology, reduced dendritic arborization; extensive dendritic varicosities in the cortical neurons of CM infected brain. Further, these observations correlated with diminished protein levels of LIMK-1, cofilin-1, phospho-cofilin-1 and β-actin in the whole brain lysates as well as formation of actin-cofilin rods in the brain sections of mice symptomatic to CM.Interpretation: Overall, our findings suggest that the altered neuronal morphology and dysregulation of LIMK-1/cofilin-1 pathway could affect the cognitive outcome after experimental CM. Therefore, this study could help to establish newer therapeutic strategies aiming long-term cognitive impairment after CM. This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-26T09:45:12.220007-05:
      DOI: 10.1002/ana.25028
       
  • Converse well-being of locked-in patients and caregivers
    • Authors: Simone Renault; Amar Dhand
      PubDate: 2017-08-22T10:43:02.709369-05:
      DOI: 10.1002/ana.25027
       
  • Dopamine transporter imaging deficit predicts early transition to
           synucleinopathy in idiopathic REM sleep behavior disorder
    • Authors: Alex Iranzo; Joan Santamaría, Francesc Valldeoriola, Monica Serradell, Manel Salamero, Carles Gaig, Aida Niñerola-Baizan, Raquel Sánchez-Valle, Albert Lladó, Roberto De Marzi, Ambra Stefani, Klaus Seppi, Javier Pavia, Birgit Högl, Werner Poewe, Eduard Tolosa, Francesc Lomeña
      Abstract: Objective: To determine the usefulness of dopamine transporter (DAT) imaging to identify idiopathic REM sleep behavior disorder (IRBD) patients at risk for short-term development of clinically-defined synucleinopathy.Methods: Eighty-seven patients with polysomnography-confirmed IRBD underwent 123I-FP-CIT DAT-SPECT. Results were compared with 20 matched controls without RBD who underwent DAT-SPECT. In patients, FP-CIT uptake was considered abnormal when values were two standard deviations below controls' mean uptake. After DAT-SPECT, patients were followed-up during 5.7 ± 2.2 (range, 2.6-9.9) years.Results: Baseline DAT deficit was found in 51 (58.6%) patients. During follow-up 25 (28.7%) subjects developed clinically-defined synucleinopathy (Parkinson disease in 11, dementia with Lewy bodies in 13, multiple system atrophy in one) with mean latency of 3.2 ± 1.9 years from imaging.Kaplan-Meier survival analysis showed increased risk of incident synucleinopathy in patients with abnormal DAT-SPECT than with normal DAT-SPECT (20% vs. 6% at three years, 33% vs. 18% at five years; log rank test, p=0.006).Receiver operating characteristics curve revealed that reduction of FP-CIT uptake in putamen greater than 25% discriminated patients with DAT deficit who developed synucleinopathy from patients with DAT deficit that remained disease-free after three years of follow-up.At 5-year follow-up, DAT-SPECT had 75% sensitivity, 51% specificity, 44% positive predictive value, 80% negative predictive value, and like-hood ratio 1.54 to predict synucleinopathy.Interpretation: DAT-SPECT identifies IRBD patients at short-term risk for synucleinopathy. Decreased FP-CIT putamen uptake greater than 25% predicts synucleinopathy after three years follow-up. These observations may be useful to select candidates for disease-modification trials in IRBD. This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-22T10:42:56.120346-05:
      DOI: 10.1002/ana.25026
       
  • Reply to Letter to the Editor: “Converse well-being of locked in
           patients and caregivers” by S. Renault and A. Dhand.
    • Authors: Elisa Aust; Katharina Linse, Wolfgang Rüger, Markus Joos, Henning Schmitz-Peiffer, Alexander Storch, Andreas Hermann
      PubDate: 2017-08-22T10:35:20.284011-05:
      DOI: 10.1002/ana.25025
       
  • Issue Information - Masthead
    • PubDate: 2017-08-22T01:06:28.79032-05:0
      DOI: 10.1002/ana.25013
       
  • Issue Information - Copyright
    • PubDate: 2017-08-22T01:06:27.961531-05:
      DOI: 10.1002/ana.25014
       
  • Issue Information - TOC
    • PubDate: 2017-08-22T01:06:26.677486-05:
      DOI: 10.1002/ana.25012
       
  • Annals of Neurology: Volume 82, Number 2, August 2017
    • Abstract: ON THE COVER: A section through the brain of a patient with type-2 diabetes showing vascular deposition of amylin (brown) and astroglial reaction (green stain for glial fibrillary acidic protein). See Ly et al, pages 208–222, in this issue for details.
      PubDate: 2017-08-22T01:06:26.268019-05:
      DOI: 10.1002/ana.25011
       
  • Insufficient sleep: Enhanced risk-seeking relates to low local sleep
           intensity
    • Authors: Angelina Maric; Eszter Montvai, Esther Werth, Matthias Storz, Janina Leemann, Sebastian Weissengruber, Christian C. Ruff, Reto Huber, Rositsa Poryazova, Christian R. Baumann
      Abstract: Objectives: Chronic sleep restriction is highly prevalent in modern society and is in its clinical form, insufficient sleep syndrome, one of the most prevalent diagnoses in clinical sleep laboratories, with substantial negative impact on health and community burden. It reflects every-day sleep loss better than acute sleep deprivation, but its effects and particularly the underlying mechanisms remain largely unknown for a variety of critical cognitive domains, as for example risky decision-making.Methods: We assessed financial risk-taking behavior after 7 consecutive nights of sleep restriction and after one night of acute sleep deprivation compared to a regular sleep condition in a within-subject design. We further investigated potential underlying mechanisms of sleep loss induced changes in behavior by high-density electroencephalography recordings during restricted sleep.Results: We show that chronic sleep restriction increases risk-seeking, while this was not observed after acute sleep deprivation. This increase was subjectively not noticed and was related to locally lower values of slow wave energy during preceding sleep, an electrophysiological marker of sleep intensity and restoration, in electrodes over the right prefrontal cortex.Interpretation: This study provides for the first time evidence that insufficient sleep restoration over circumscribed cortical areas leads to aberrant behavior. In chronically sleep restricted subjects, low slow wave sleep intensity over the right prefrontal cortex - which has been shown to be linked to risk behavior – may lead to increased and subjectively unnoticed risk-seeking. This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-21T10:20:25.147117-05:
      DOI: 10.1002/ana.25023
       
  • T1-/T2-weighted ratio differs in demyelinated cortex of multiple sclerosis
    • Authors: Kunio Nakamura; Jacqueline T. Chen, Daniel Ontaneda, Robert J. Fox, Bruce D. Trapp
      Abstract: Detecting cortical demyelination in patients with multiple sclerosis (MS) is difficult. Using magnetic resonance imaging (MRI), ratio maps of T1-weighted and T2-weighted images (T1w/T2w) may be sensitive to cortical myelin levels. In this MRI-histological study, postmortem in situ scans were acquired from six cadavers with MS on a 3 Tesla MRI. Immunocytochemistry was used to correlate myelin status and cortical T1w/T2w measures. The results showed that the T1w/T2w values significantly differed between demyelinated and myelinated cortex (p 
      PubDate: 2017-08-18T12:29:59.607611-05:
      DOI: 10.1002/ana.25019
       
  • Neuromyelitis optica broke my heart too
    • Authors: Pauline Prin; Yorick Rodriguez, Jean-Marc Le Goff, Chérif Héroum, Christelle Molinero, Eric Thouvenot
      PubDate: 2017-08-18T11:55:31.389769-05:
      DOI: 10.1002/ana.25016
       
  • Cortical pathology in MS detected by the T1/T2-weighted ratio from routine
           MRI
    • Authors: Ruthger Righart; Viola Biberacher, Laura E Jonkman, Roel Klaver, Paul Schmidt, Dorothea Buck, Achim Berthele, Jan S Kirschke, Claus Zimmer, Bernhard Hemmer, Jeroen JG Geurts, Mark Mühlau
      Abstract: ObjectiveIn multiple sclerosis, neuropathological studies have shown widespread changes in the cerebral cortex. In vivo imaging is critical since the histopathological substrate of most measurements is unknown.MethodUsing a novel MRI analysis technique, based on the ratio of T1- and T2-weighted signal intensities, we studied the cerebral cortex of a large cohort of patients in early stages of multiple sclerosis. 168 patients with clinically isolated syndrome or relapsing-remitting multiple sclerosis (Expanded Disability Status Scale: median, 1; range, 0-3.5) and 80 age- and sex-matched healthy controls were investigated. We also searched for the histopathological substrate of the T1/T2-weighted ratio by combining post mortem imaging and histopathology in 9 multiple sclerosis brain donors.ResultsPatients showed lower T1/T2-weighted ratio values in parietal and occipital areas. The four most significant clusters appeared in the medial occipital and posterior cingulate cortex (each left and right). The decrease of the T1/T2-weighted ratio in the posterior cingulate was related to performance in attention. Analysis of the T1/T2-weighted ratio values of post mortem imaging yielded a strong correlation with dendrite density but none of the other parameters including myelin.InterpretationThe T1/T2-weighted ratio decreases in early stages of multiple sclerosis in a widespread manner with a preponderance of posterior areas and with a contribution to attentional performance; it seems to reflect dendrite pathology. As the method is broadly available and applicable to (available) clinical scans, we believe that it is a promising candidate for studying and monitoring cortical pathology or therapeutic effects in multiple sclerosis. This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-18T11:55:29.739087-05:
      DOI: 10.1002/ana.25020
       
  • Axonal components of nerves innervating the human arm
    • Authors: Bernhard Gesslbauer; Laura A. Hruby, Aidan D. Roche, Dario Farina, Roland Blumer, Oskar C. Aszmann
      Abstract: Objective: Axons travelling within the brachial plexus are responsible for the dexterous control of human arm and hand movements. Despite comprehensive knowledge on the topographical anatomy of nerves innervating the human upper limb, the definite quantity of sensory and motor axons within this neural network remains elusive. Our aim was to perform a quantitative analysis of the axonal components of human upper limb nerves based on highly specific molecular features from spinal cord level to the terminal nerves at wrist level.Methods: Nerve specimen harvest at pre-defined harvesting sites (plexus roots and cords as well as major nerves originating from the brachial plexus innervating the arm and hand) was performed in nine human heart-beating organ donors. Double immunofluorescence staining using antibodies against choline-acetyltransferase and neurofilament was performed to differentiate motor and sensory axons on nerve cross sections.Results: 350.000 axons emerge from the spinal cord to innervate the human upper limb of which 10% are motor neurons. In all nerves studied sensory axons outnumber motor axons by a ratio of at least 9:1. The sensory axon contribution increases when moving distally while only 1.700 motor axons reach the hand to innervate the intrinsic musculature.Interpretation: Our results suggest that upper limb motor execution, and particularly dexterous coordination of hand movement require an unexpectedly low number of motor neurons, with a large convergence of afferent input for feedback control. This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-18T11:55:26.951941-05:
      DOI: 10.1002/ana.25018
       
  • Persistent seizure control in epileptic mice transplanted with GABA
           progenitors
    • Authors: Mariana L. Casalia; MacKenzie A. Howard, Scott C. Baraban
      Abstract: ObjectiveA significant proportion of the more than 50 million people world-wide currently suffering with epilepsy are resistant to antiepileptic drugs (AEDs). As an alternative to AEDs, novel therapies based on cell transplantation offer an opportunity for long-lasting modification of epileptic circuits. To develop such a treatment requires careful preclinical studies in a chronic epilepsy model featuring unprovoked seizures, hippocampal histopathology, and behavioral comorbidities.MethodsTransplantation of progenitor cells from embryonic medial or caudal ganglionic eminence (MGE, CGE) were made in a well-characterized mouse model of status epilepticus-induced epilepsy (systemic pilocarpine). Behavioral testing (handling and open field), continuous video-electroencephalographic (vEEG) monitoring and slice electrophysiology outcomes were obtained up to 270 days after transplantation (DAT). Post hoc immunohistochemistry was used to confirm cell identity.ResultsMGE progenitors transplanted into the hippocampus of epileptic mice rescued handling and open field deficits starting at 60 DAT. In these same mice, an 84-88% reduction in seizure activity was observed between 180 and 210 DAT. Inhibitory postsynaptic current frequency, measured on pyramidal neurons in acute hippocampal slices at 270 DAT, was reduced in epileptic mice but restored to naïve levels in epileptic mice receiving MGE transplants. No reduction in seizure activity was observed in epileptic mice receiving intra-hippocampal CGE progenitors.InterpretationOur findings demonstrate that transplanted MGE progenitors enhance functional GABA-mediated inhibition, reduce spontaneous seizure frequency and rescue behavioral deficits in a chronic epileptic animal model more than six months after treatment. This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-18T11:55:24.103268-05:
      DOI: 10.1002/ana.25021
       
  • Inhibiting persistent inward sodium currents prevents myotonia
    • Authors: Ahmed A. Hawash; Andrew A. Voss, Mark M. Rich
      Abstract: Objective: Patients with myotonia congenita have muscle hyperexcitability due to loss-of-function mutations in the ClC-1 chloride channel in skeletal muscle, which causes involuntary firing of muscle action potentials (myotonia), producing muscle stiffness. The excitatory events that trigger myotonic action potentials in the absence of stabilizing ClC-1 current are not fully understood. Our goal was to identify currents that trigger spontaneous firing of muscle in the setting of reduced ClC-1 current.Methods: In vitro intracellular current clamp and voltage clamp recordings were performed in muscle from a mouse model of myotonia congenita.Results: Intracellular recordings revealed a slow after-depolarization (AfD) that triggers myotonic action potentials. The after depolarization is well-explained by a tetrododoxin-sensitive and voltage-dependent Na+ persistent inward current (NaPIC). Notably, this NaPIC undergoes slow inactivation over seconds, suggesting this may contribute to the end of myotonic runs. Highlighting the significance of this mechanism, we found that ranolazine and elevated serum divalent cations eliminate myotonia by inhibiting AfD and NaPIC.Interpretation: This work significantly changes our understanding of the mechanisms triggering myotonia. Our work suggests that the current focus of treating myotonia, blocking the transient Na+ current underlying action potentials, is an inefficient approach. We show that inhibiting NaPIC is paralleled by elimination of myotonia. We suggest the ideal myotonia therapy would selectively block NaPIC and spare the transient Na+ current. This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-18T11:55:21.447503-05:
      DOI: 10.1002/ana.25017
       
  • MicroRNA-137 and -195* inhibit vasculogenesis in brain arteriovenous
           malformations
    • Authors: Jun Huang; Jianping Song, Meijie Qu, Yang Wang, Qinzhu An, Yaying Song, Wei Yan, Bingshun Wang, Xiaojin Wang, Song Zhang, Xi Chen, Bing Zhao, Peixi Liu, Tongyi Xu, Zhijun Zhang, David A. Greenberg, Yongting Wang, Pingjin Gao, Wei Zhu, Guo-Yuan Yang
      Abstract: Objectives: Brain arteriovenous malformations (AVMs) are the most common cause of non-traumatic intracerebral hemorrhage in young adults. The genesis of brain AVM remains enigmatic. We investigated microRNA (miRNA) expression and its contribution to the pathogenesis of brain AVMs.Methods: We used a large-scale miRNA analysis on 16 samples including AVMs, hemangioblastoma, and controls to identify a distinct AVM miRNA signature. AVM smooth muscle cells (AVMSMCs) were isolated and identified by flow cytometry and immunohistochemistry and candidate miRNAs were then tested in these cells. Migration, tube formation, and CCK-8-induced proliferation assays were used to test the miRNAs effect on phenotypic properties of AVMSMCs. A quantitative proteomics approach was used to identify protein expression changes in AVMSMCs treated with miRNA mimics.Results: A distinct AVM miRNA signature comprising a large portion of lowly expressed miRNAs was identified. Among these miRNAs, miR-137 and miR-195* levels were significantly decreased in AVMs and constituent AVMSMCs. Experimentally elevating the level of these microRNAs inhibited AVMSMC migration, tube formation and survival in vitro and the formation of vascular rings in vivo. Proteomics showed the protein expression signature of AVMSMCs and identified downstream proteins regulated by miR-137 and miR-195* which were key signaling proteins involved in vessel development.Interpretation: Our results indicate that miR-137 and miR-195* act as vasculogenic suppressors in AVMs by altering phenotypic properties of AVMSMCs, and that the absence of miR-137 and miR-195* expression leads to abnormal vasculogenesis. This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-12T10:30:21.497519-05:
      DOI: 10.1002/ana.25015
       
  • Natural history of Charcot-Marie-Tooth disease during childhood
    • Authors: Kayla MD Cornett; Manoj P Menezes, Rosemary R Shy, Isabella Moroni, Emanuela Pagliano, Davide Pareyson, Timothy Estilow, Sabrina W Yum, Trupti Bhandari, Francesco Muntoni, Matilde Laura, Mary M Reilly, Richard S Finkel, Kate J Eichinger, David N Herrmann, Paula Bray, Mark Halaki, Michael E Shy, Joshua Burns,
      Abstract: Objective: To determine the rate of disease progression in a longitudinal natural history study of children with Charcot-Marie-Tooth disease (CMT).Methods: 206 (103 female) participants aged 3-20 years enrolled in the Inherited Neuropathies Consortium were assessed at baseline and 2-years. Demographic, anthropometric, and diagnostic information were collected. Disease progression was assessed with the CMT Pediatric Scale (CMTPedS), a reliable Rasch-built linearly weighted disability scale evaluating fine and gross motor function, strength, sensation, and balance.Results: On average CMTPedS Total scores progressed at a rate of 2.4±4.9 over 2-years (14% change from baseline, p
      PubDate: 2017-08-10T06:30:19.923479-05:
      DOI: 10.1002/ana.25009
       
  • Gustatory and olfactory responses to stimulation of the human insula
    • Authors: Laure Mazzola; Jean-Pierre Royet, Hélène Catenoix, Alexandra Montavont, Jean Isnard, François Mauguière
      Abstract: Objective: Despite numerous studies suggesting the role of insular cortex in the processing of gustatory and olfactory inputs, the exact location of olfacto-gustatory representation in the insula remains controversial. Here we provide a functional mapping of olfactory-gustatory responses to stimulation of the human insular cortex.Methods: We reviewed 651 electrical stimulations of the insula that were performed in 221 patients, using stereotactically implanted depth electrodes, during the pre-surgical evaluation of drug refractory epilepsy.Results: Gustatory sensations were evoked in 15 (2.7%) of the 550 stimulations that elicited a clinical response. They were exclusively obtained after stimulation of a relatively delimited zone of insula, located in its mid-dorsal part (posterior short gyrus). Six olfactory sensations (1.1%) could be obtained during stimulations of an insular region that partially overlapped with the gustatory representation.Interpretation: Our study provides a functional mapping of gustatory representation in the insular posterior short gyrus and the first detailed description of olfactory sensations obtained by direct stimulation of mid-dorsal insula. Our data also show a spatial overlap between gustatory, olfactory and oral somatosensory representation in the mid-dorsal insula, and suggest that this part of the insula may be an integrated oral sensory region that plays a key role in flavor perception. It also indicates that dysfunction in this region should be considered during the evaluation of gustatory and olfactory epileptic seizures. This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-10T06:15:55.913204-05:
      DOI: 10.1002/ana.25010
       
  • Brexanolone as Adjunctive Therapy in Super-Refractory Status Epilepticus
    • Authors: Eric S. Rosenthal; Jan Claassen, Mark S. Wainwright, Aatif M. Husain, Henrikas Vaitkevicius, Shane Raines, Ethan Hoffmann, Helen Colquhoun, James J. Doherty, Stephen J. Kanes
      Abstract: Objective: Super-refractory status epilepticus (SRSE) is a life-threatening form of status epilepticus that continues or recurs despite 24 hours or more of anesthetic treatment. We conducted a multi-center, phase 1/2 study in SRSE patients to evaluate the safety and tolerability of brexanolone (USAN; formerly SAGE-547 Injection), a proprietary, aqueous formulation of the neuroactive steroid allopregnanolone. Secondary objectives included pharmacokinetic assessment and open-label evaluation of brexanolone response during and after anesthetic third-line agent (TLA) weaning.Methods: Patients receiving TLAs for SRSE control were eligible for open-label, one-hour brexanolone loading infusions, followed by maintenance infusion. After 48 hours of brexanolone infusion, TLAs were weaned during brexanolone maintenance. After four days, the brexanolone dose was tapered. Safety and functional status were assessed over 3-weeks of follow-up.Results: Twenty-five patients received open-label study drug. No serious adverse events (SAEs) were attributable to study drug, as determined by the Safety Review Committee. Sixteen patients (64%) experienced ≥1 SAE. Six patient deaths occurred, all deemed related to underlying medical conditions. Twenty-two patients underwent ≥1 TLA wean attempt. Seventeen (77%) met the response endpoint of weaning successfully off TLAs before tapering brexanolone. Sixteen (73%) were successfully weaned off TLAs within five days of initiating brexanolone infusion without anesthetic agent reinstatement in the following 24-hours.Interpretation: In an open-label cohort of limited size, brexanolone demonstrated tolerability among SRSE patients of heterogeneous etiologies and was associated with a high rate of successful TLA weaning. The results suggest the possible development of brexanolone as an adjunctive therapy for SRSE requiring pharmacologic coma for seizure control. This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-05T10:05:22.625689-05:
      DOI: 10.1002/ana.25008
       
  • Very high frequency oscillations: Novel biomarkers of the epileptogenic
           zone
    • Authors: Milan Brázdil; Martin Pail, Josef Halámek, Filip Plešinger, Jan Cimbálník, Robert Roman, Petr Klimeš, Pavel Daniel, Jan Chrastina, Eva Brichtová, Ivan Rektor, Gregory A. Worrell, Pavel Jurák
      Abstract: Objective: In the present study, we aimed to investigate depth EEG recordings in a large cohort of patients with drug resistant epilepsy and to focus on interictal very high frequency oscillations (VHFOs) between 500 Hz and 2 kHz. We hypothesized that interictal VHFOs are more specific biomarkers for epileptogenic zone compared to traditional HFOs.Methods: Forty patients with focal epilepsy who underwent presurgical stereo-electroencephalography (SEEG) were included in the study. SEEG data have been recorded with sampling rate of 25 kHz and 30 minutes of resting period was analyzed for each patient. Ten patients met selected criteria for analyses of correlations with surgical outcome - detection of interictal ripples (R), fast ripples (FR) and VHFOs, resective surgery, and at least one-year post-operative follow-up. Using power envelope computation and visual inspection of power distribution matrixes, electrode contacts with HFOs and VHFOs were detected and analyzed.Results: Interictal very fast ripples (VFR; 500-1000 Hz) were detected in 23 out of 40 patients and ultra fast ripples (UFR; 1000-2000 Hz) in almost half of investigated subjects (N=19). VFR and UFR were observed only in patients with temporal lobe epilepsy and were recorded exclusively from mesiotemporal structures. The UFR were more spatially restricted in the brain then lower frequency HFOs. When compared to R oscillations, significantly better outcomes were observed in patients with higher percentage of removed contacts containing FR, VFR, and UFR.Interpretation:Interictal VHFOs are relatively frequent abnormal phenomena in patients with epilepsy, and appear to be more specific biomarkers for epileptogenic zone when compared to traditional HFOs. This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-05T10:00:25.777404-05:
      DOI: 10.1002/ana.25006
       
  • Body weight is a robust predictor of clinical progression in Huntington
           disease
    • Authors: Jorien M.M. van der Burg; Sarah L. Gardiner, Albert C. Ludolph, G. Bernhard Landwehrmeyer, Raymund A.C. Roos, N. Ahmad Aziz
      Abstract: Unintended weight loss is a hallmark of Huntington disease (HD), but it is unknown to what extent weight loss impacts the rate of disease progression. Therefore, using longitudinal data from the Enroll-HD study, we assessed the association between baseline body mass index (BMI) and the rate of clinical progression in 5821 HD mutation carriers. We found that high baseline BMI was associated with a significantly slower rate of functional, motor and cognitive deterioration (all p 
      PubDate: 2017-08-05T10:00:20.516288-05:
      DOI: 10.1002/ana.25007
       
  • Response to Gooch et al.
    • Authors: Roger L. Albin
      PubDate: 2017-07-28T06:50:26.706599-05:
      DOI: 10.1002/ana.25001
       
  • Reply from the Author: Letter to the Editor by Roger Albin MD
    • Authors: Clifton L. Gooch
      PubDate: 2017-07-28T06:50:20.382179-05:
      DOI: 10.1002/ana.25000
       
  • Myelopathy in Behçet's Disease: The Bagel Sign
    • Authors: Ugur Uygunoglu; Burcu Zeydan, Yesim Ozguler, Serdal Ugurlu, Emire Seyahi, Naci Kocer, Civan Islak, Kejal Kantarci, Sabahattin Saip, Aksel Siva, Orhun H. Kantarci
      Abstract: Objective: To describe the clinical and distinctive imaging features of myelopathy associated with Behçet's disease.Methods: We evaluated the records of patients meeting the following criteria: a) fulfillment of the International Study Group criteria for Behçet's disease; b) clinically suggestive of myelopathy; c) simultaneous spinal cord and brain MRIs within 1 month of acute worsening of myelopathy; d) follow-up duration ≥1 year after initial MRI evaluation. Patients not fulfilling all inclusion criteria and having MRIs with poor quality or missing sequences were excluded.Results: In 11 patients (9 men, 2 women), we studied 14 MRIs during distinct myelopathy episodes and 9 follow-up MRIs. Two distinct MRI patterns of spinal cord involvement were described according to T2W axial images: 1) “Bagel Sign” pattern: A central lesion with hypo-intense core and hyper-intense rim with or without contrast enhancement; 2) “Motor Neuron” pattern: A symmetric involvement of the anterior horn cells. “Bagel Sign” was present in 13 of 14 myelopathy episodes whereas “Motor Neuron” pattern was observed in 1 of 14 MRIs. Of the 13 MRIs with “Bagel Sign” long myelopathy (n=9), both long and short myelopathy (n=2), and short myelopathy (n=2) was observed. All patterns cleared with some residual lesions after steroid use and immunomodulation with associated clinical recovery in patients.Interpretation: The signal characteristics of the “Bagel Sign” potentially represent venous engorgement and/or acute blood products within the spinal cord. To our knowledge, “Bagel Sign” has not been observed in other forms of longitudinal myelopathy outside of BD including neuromyelitis optica. This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-27T10:25:42.68414-05:0
      DOI: 10.1002/ana.25004
       
  • Seizure activity per se does not induce tissue damage markers in human
           neocortical focal epilepsy
    • Authors: Laura Rossini; Rita Garbelli, Vadym Gnatkovsky, Giuseppe Didato, Flavio Villani, Roberto Spreafico, Francesco Deleo, Giorgio Lo Russo, Giovanni Tringali, Francesca Gozzo, Laura Tassi, Marco de Curtis
      Abstract: Objective The contribute of recurring seizures to the progression of epileptogenesis is debated. Seizure-induced brain damage is not conclusively demonstrated both in humans and in animal models of epilepsy. We evaluated the expression of brain injury biomarkers on post-surgical brain tissue obtained from 20 patients with frequent seizures and a long history of drug-resistant focal epilepsy.Methods The expression patterns of specific glial, neuronal and inflammatory molecules was evaluated by immunohistochemistry in the core of type II focal cortical dysplasias (FCD-II), at the FCD boundary (perilesion) and in the adjacent normal-appearing area included in the epileptogenic region. We also analysed surgical specimens from cryptogenic patients not presenting structural alterations at imaging.Results Astroglial and microglial activation, reduced neuronal density, peri-vascular CD3-positive T lymphocytes clustering and fibrinogen extravasation were demonstrated in the core of FCD-II lesions. No pathological immunoreactivity was observed outside the FCD-II and in cryptogenetic specimens, where the occurrence of interictal and ictal epileptiform activity was confirmed by either stereo-EEG or intraoperative electrocorticography.Interpretation Recurrent seizures do not induce the expression of brain damage markers in non-lesional epileptogenic cortex studied on post-surgical tissue from cryptogenic and FCD patients. This evidence argues against the hypothesis that epileptiform activity per se contributes to focal brain injury, at least in the neocortical epilepsies here considered. This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-27T10:25:35.035606-05:
      DOI: 10.1002/ana.25005
       
  • Combined EEG-fMRI and ESI improves localisation of paediatric focal
           epilepsy
    • Authors: Maria Centeno; Tim M. Tierney, Suejen Perani, Elhum A. Shamshiri, Kelly StPier, Charlotte Wilkinson, Daniel Konn, Serge Vulliemoz, Frédéric Grouiller, Louis Lemieux, Ronit M. Pressler, Christopher A. Clark, J. Helen Cross, David W Carmichael
      Abstract: ObjectiveSurgical treatment in epilepsy is effective if the epileptogenic zone (EZ) can be correctly localized and characterized. Here we use simultaneous Electroencephalography-functional MRI (EEG-fMRI) data to derive EEG-fMRI and Electrical Source Imaging (ESI) maps. Their yield and their individual and combined ability to 1) localize the epileptogenic zone and 2) predict seizure outcome was then evaluated.MethodsFifty-three children with drug-resistant epilepsy underwent EEG-fMRI. Interictal discharges were mapped using both EEG-fMRI haemodynamic responses and Electrical Source Imaging (ESI). A single localization was derived from each individual test (EEG-fMRI global maxima (GM)/ESI maxima) and from the combination of both maps (EEG-fMRI/ESI spatial intersection). To determine the localisation accuracy and its predictive performance the individual and combined test localisations were compared to the presumed EZ and to the postsurgical outcome.ResultsFifty-two/53 patients had significant maps; 47/53 for EEG-fMRI; 44/53 for ESI; 34/53 had both. The epileptogenic zone was well characterised in 29 patients; 26 had an EEG-fMRI GM localisation which was correct in 11; 22 patients had ESI localisation which was correct in 17; 12 patients had combined EEG-fMRI and ESI which was correct in 11.Seizure outcome following resection was correctly predicted by EEG-fMRI GM in 8/20 patients, by the ESI maxima in 13/16. The combined EEG-fMRI/ESI region entirely predicted outcome in 9/9 patients including 3 with no lesion visible on MRI.InterpretationEEG-fMRI combined with ESI provides a simple unbiased localisation that may predict surgery better than each individual test including in MRI-negative patients. This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-27T10:25:30.57525-05:0
      DOI: 10.1002/ana.25003
       
  • A double blind, placebo-controlled study of rituximab in patients with
           stiff person syndrome
    • Authors: Marinos C. Dalakas; Goran Rakocevic, James M. Dambrosia, Harry Alexopoulos, Beverly McElroy
      Abstract: ObjectiveIn Stiff-Person Syndrome (SPS), an antibody-mediated impaired GABAergic neurotransmission is believed to cause muscle stiffness and spasms. Patients improve with GABA-enhancing drugs and IVIg, but several respond poorly and remain disabled. The need for more effective therapy prompted a trial with the anti-CD20 monoclonal antibody rituximab.MethodsThis was a placebo-controlled randomized trial of rituximab (two bi-weekly infusions of 1gr each). The primary outcome was a change in stiffness scores at 6 months. Secondary outcomes were changes in heightened-sensitivity and quality of life scores. Enrolling 24 patients was calculated to detect 50% change in stiffness scores.ResultsRandomization was balanced for age, sex, disease duration and GAD autoantibody titers. No significant changes were noted at 6 months after treatment in all outcomes. Specifically, no differences were noted in the stiffness index, the primary outcome, or sensitivity scores, the secondary outcome, at 3 or 6 months. Quality of life scores improved significantly (p
      PubDate: 2017-07-27T10:25:26.770027-05:
      DOI: 10.1002/ana.25002
       
  • Polygenic Risk Score Analysis of Pathologically Confirmed Alzheimer's
           Disease
    • Authors: Valentina Escott-Price; Amanda J. Myers, Matt Huentelman, John Hardy
      Abstract: Previous estimates of the utility of polygenic risk score analysis for the prediction of Alzheimer's disease have given Area Under the Curve estimates of
      PubDate: 2017-07-20T10:20:36.802296-05:
      DOI: 10.1002/ana.24999
       
  • Thiamine deficiency in childhood with attention to genetic causes:
           Survival and outcome predictors
    • Authors: Juan Darío Ortigoza-Escobar; Majid Alfadhel, Marta Molero-Luis, Niklas Darin, Ronen Spiegel, Irenaeus F de Coo, Mike Gerards, Robert W Taylor, Rafael Artuch, Marwan Nashabat, Pilar Rodríguez-Pombo, Brahim Tabarki, Belén Pérez-Dueñas,
      Abstract: Primary and secondary conditions leading to thiamine deficiency have overlapping features in children, presenting with acute episodes of encephalopathy, bilateral symmetric brain lesions and high excretion of organic acids that are specific of thiamine-dependent mitochondrial enzymes, mainly lactate, alpha-ketoglutarate and branched chain keto-acids. Undiagnosed and untreated thiamine deficiencies are often fatal or lead to severe sequelae. Herein we describe the clinical and genetic characterization of 79 patients with inherited thiamine defects causing encephalopathy in childhood, identifying outcome predictors in patients with pathogenic SLC19A3 variants, the most common genetic etiology. We propose diagnostic criteria that will aid clinicians to establish a faster and accurate diagnosis so that early vitamin supplementation is considered. This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-18T11:10:43.872677-05:
      DOI: 10.1002/ana.24998
       
  • Multimodal image analysis of clinical influences on preterm brain
           development
    • Authors: Gareth Ball; Paul Aljabar, Phumza Nongena, Nigel Kennea, Nuria Gonzalez-Cinca, Shona Falconer, Andrew T.M. Chew, Nicholas Harper, Julia Wurie, Mary A. Rutherford, Serena J. Counsell, A. David Edwards
      Abstract: ObjectivePremature birth is associated with numerous complex abnormalities of white and grey matter and a high incidence of long-term neurocognitive impairment. An integrated understanding of these abnormalities and their association with clinical events is lacking. The aim of this study was to identify specific patterns of abnormal cerebral development and their antenatal and postnatal antecedents.MethodsIn a prospective cohort of 449 infants (226 male), we performed a multi-variate and data-driven analysis combining multiple imaging modalities. Using canonical correlation analysis, we sought separable multimodal imaging markers associated with specific clinical and environmental factors and correlated to neurodevelopmental outcome at 2 years.ResultsWe found five independent patterns of neuroanatomical variation that related to clinical factors including age, prematurity, sex, intrauterine complications, and postnatal adversity. We also confirmed the association between imaging markers of neuroanatomical abnormality and poor cognitive and motor outcomes at 2 years.InterpretationThis data-driven approach defined novel and clinically relevant imaging markers of cerebral maldevelopment, which offer new insights into the nature of preterm brain injury. This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-18T10:55:40.210267-05:
      DOI: 10.1002/ana.24995
       
  • Fibrin(ogen) and neurodegeneration in the progressive multiple sclerosis
           cortex
    • Authors: Richard L. Yates; Margaret M. Esiri, Jacqueline Palace, Benjamin Jacobs, Rafael Perera, Gabriele C. DeLuca
      Abstract: Objective: Neuronal loss, a key substrate of irreversible disability in multiple sclerosis (MS), is a recognised feature of MS cortical pathology of which the cause remains unknown. Fibrin(ogen) deposition is neurotoxic in animal models of MS, but has not been evaluated in human progressive MS cortex. The aim of this study was to investigate the extent and distribution of fibrin(ogen) in progressive MS cortex and elucidate its relationship with neurodegeneration.Methods: A post-mortem cohort of pathologically confirmed MS (n=47) and control (n=10) cases was used. The extent and distribution of fibrin(ogen) was assessed and related to measures of demyelination, inflammation, and neuronal density. In a subset of cases (MS, n=20; control, n=10), the expression of plasminogen activator inhibitor (PAI-1), a key enzyme in the fibrinolytic cascade, was assessed and related to the extent of fibrin(ogen).Results: Motor cortical fibrin(ogen) deposition was significantly overrepresented in MS compared to control cases in all compartments studied (i.e. extracellular (p=0.001), cell body (p=0.003) and neuritic/glial-processes (p=0.004)). MS cases with high levels of extracellular fibrin(ogen) had significantly up-regulated PAI-1 expression in all cortical layers assessed (p
      PubDate: 2017-07-18T10:55:34.09144-05:0
      DOI: 10.1002/ana.24997
       
  • Ante mortem CSF tau levels correlate with post mortem tau pathology in
           FTLD
    • Authors: D.J. Irwin; A. Lleó, S.X. Xie, C.T. McMillan, D. Wolk, E.B. Lee, V.M. Van Deerlin, L.M. Shaw, J.Q. Trojanowski, M. Grossman
      Abstract: Objective: To test the hypotheses that 1) antemortem cerebrospinal fluid tau levels correlate with postmortem tau pathology in frontotemporal lobar degeneration and 2) tauopathy patients have higher phosphorylated-tau levels compared to TDP-43 proteinopathy patients while accounting for Alzheimer's disease co-pathology.Methods: Patients had autopsy-confirmed frontotemporal lobar degeneration with tauopathy (n=31), TDP-43 proteinopathy (n=49), or Alzheimer's disease (n=26) with antemortem cerebrospinal fluid. Cerebrospinal fluid tau levels were compared between groups and correlated with digital histology measurement of postmortem tau pathology averaged from three cerebral regions (angular gyrus, mid-frontal cortex, anterior cingulate gyrus). Multivariate linear regression tested the association of ante mortem cerebrospinal fluid tau levels with post mortem tau pathology adjusting for demographics.Results: Multivariate regression found an independent association of ante mortem cerebrospinal fluid phosphorylated tau levels with post mortem cerebral tau pathology in frontotemporal lobar degeneration (Beta=1.3, 95%CI=0.2-2.4, p
      PubDate: 2017-07-18T10:55:23.886245-05:
      DOI: 10.1002/ana.24996
       
  • Brain microvascular injury and white matter disease provoked by
           diabetes-associated hyperamylinemia
    • Authors: Han Ly; Nirmal Verma, Fengen Wu, Miao Liu, Kathryn E. Saatman, Peter T. Nelson, John T. Slevin, Larry B. Goldstein, Geert Jan Biessels, Florin Despa
      Abstract: Objectives: The brain blood vessels of patients with type-2 diabetes and dementia have deposition of amylin, an amyloidogenic hormone co-secreted with insulin. It is not known whether vascular amylin deposition is a consequence or a trigger of vascular injury. We tested the hypothesis that the vascular amylin deposits cause endothelial dysfunction and microvascular injury and are modulated by the amylin transport in the brain via plasma apolipoproteins.Methods: Rats overexpressing amyloidogenic (human) amylin in the pancreas (HIP rats) and amylin knockout (AKO) rats intravenously infused with aggregated amylin were used for in vivo phenotyping. We also carried out biochemical analyses of human brain tissues and studied the effects of the aggregated amylin on endothelial cells, ex vivo.Results: Amylin deposition in brain blood vessels is associated with vessel wall disruption and abnormal surrounding neuropil in patients with type-2 diabetes and dementia, in HIP rats, and in AKO rats infused with aggregated amylin. HIP rats have brain microhemorrhages, white matter injury and neurologic deficits. Vascular amylin deposition provokes loss of endothelial cell coverage and tight junctions. Intravenous infusion in AKO rats of human amylin, or combined human amylin and apolipoprotein E4, showed that amylin binds to plasma apolipoproteins. The intravenous infusion of apolipoprotein E4 exacerbated the brain accumulation of aggregated amylin and vascular pathology in HIP rats.Interpretation: These data identify vascular amylin deposition as a trigger of brain endothelial dysfunction that is modulated by plasma apolipoproteins and represents a potential therapeutic target in diabetes-associated dementia and stroke. This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-11T10:46:59.6732-05:00
      DOI: 10.1002/ana.24992
       
  • Neutrophil extracellular traps in ischemic stroke thrombi
    • Authors: Elodie Laridan; Frederik Denorme, Linda Desender, Olivier François, Tommy Andersson, Hans Deckmyn, Karen Vanhoorelbeke, Simon F. De Meyer
      Abstract: Objective: Neutrophil extracellular traps (NETs) have been shown to promote thrombus formation. Little is known about the exact composition of thrombi that cause ischemic stroke. In particular no information is yet available on the presence of NETs in cerebral occlusions. Such information is however essential to improve current thrombolytic therapy with t-PA. This study aimed at investigating the presence of neutrophils and more specifically NETs in ischemic stroke thrombi.Methods: Sixty-eight thrombi retrieved from ischemic stroke patients undergoing endovascular treatment were characterized by immunostaining using neutrophil markers (CD66b and neutrophil elastase) and NETs markers (citrullinated histones H3 (H3Cit) and extracellular DNA). Neutrophils and NETs were quantified. In addition, extracellular DNA was targeted by performing ex vivo lysis of retrieved thrombi with DNase 1 and t-PA.Results: Neutrophils were detected extensively throughout all thrombi. Citrullinated histones H3 (H3Cit), a hallmark of NETs, were observed in almost all thrombi. H3Cit-positive area varied up to 13.45% of total thrombus area. Co-localization of H3Cit with extracellular DNA released from neutrophils confirmed the specific presence of NETs. H3Cit was more abundant in thrombi from cardioembolic origin compared to other etiologies. Older thrombi contained significantly more neutrophils and H3Cit compared to fresh thrombi. Interestingly, ex vivo lysis of patient thrombi was more successful when adding DNase 1 to standard t-PA.Interpretation: Neutrophils and NETs form important constituents of cerebral thrombi. Targeting of NETs with DNase 1 might have prothrombolytic potential in treatment of acute ischemic stroke. This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-11T10:40:57.74534-05:0
      DOI: 10.1002/ana.24993
       
  • Timing Is Everything: Where Status Epilepticus Treatment Fails
    • Authors: Chloe E. Hill; Alomi O. Parikh, Colin Ellis, Jennifer S. Myers, Brian Litt
      Abstract: Status epilepticus is an emergency, however prompt treatment of patients with status epilepticus is challenging. Clinical trials, such as the Established Status Epilepticus Treatment Trial (ESETT), compare effectiveness of antiepileptic medications, and rigorous examination of effectiveness of care delivery is similarly warranted. We reviewed the medical literature on observed deviations from guidelines, clinical significance, and initiatives to improve timely treatment. We found pervasive, substantial gaps between recommended and “real world” practice with regard to timing, dosing, and sequence of antiepileptic therapy. Applying quality improvement methodology at the institutional level can increase adherence to guidelines, and may improve patient outcomes. This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-06T00:30:36.794866-05:
      DOI: 10.1002/ana.24986
       
  • Familial mesial temporal lobe epilepsy and the borderland of
           déjà vu
    • Authors: Piero Perucca; Douglas E. Crompton, Susannah T. Bellows, Anne M. McIntosh, Tomas Kalincik, Mark R. Newton, Frank J.E. Vajda, Ingrid E. Scheffer, Patrick Kwan, Terence J. O'Brien, K. Meng Tan, Samuel F. Berkovic
      Abstract: Objective: The cause of mesial temporal lobe epilepsy (MTLE) is often unknown. We ascertained to what extent newly-diagnosed non-lesional MTLE actually represents familial MTLE (FMTLE).Methods: We identified all consecutive patients presenting to the Austin Heath First Seizure Clinic with MTLE and a normal MRI or MRI-evidence of hippocampal sclerosis over a 10-year period. Patients' first-degree relatives and pairwise age- and sex-matched controls underwent a comprehensive epilepsy interview. Each interview transcript was reviewed independently by two epileptologists, blinded to relative or control status. Reviewers classified each subject as follows: epilepsy, specifying if MTLE; manifestations suspicious of epilepsy; or unaffected. Physiological déjà vu was noted.Results: Forty-four patients were included. At the Clinic, MTLE had been recognized to be familial in 2 patients only. Among 242 subjects interviewed, MTLE was diagnosed in 9/121 relatives vs 0/121 controls (p=0.008). All affected relatives had seizures with intense déjà vu and accompanying features; 6 relatives had not been previously diagnosed. Déjà vu experiences which were suspicious, but not diagnostic, of MTLE occurred in 6 additional relatives vs none of the controls (p=0.04). Physiological déjà vu was common, and did not differ significantly between relatives and controls. After completing the relatives' interviews, FMTLE was diagnosed in 8 of 44 patients (18.2%).Interpretation: FMTLE accounts for almost one-fifth of newly diagnosed non-lesional MTLE, and it is largely unrecognized without direct questioning of relatives. Relatives of patients with MTLE may experience déjà vu phenomena which clinically lie in the ‘borderland' between epileptic seizures and physiological déjà vu. This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-06T00:30:34.635635-05:
      DOI: 10.1002/ana.24984
       
  • Time-Dependent Risk of Seizures in Critically Ill Patients on Continuous
           EEG
    • Authors: Aaron F. Struck; Gamaleldin Osman, Nishi Rampal, Siddhartha Biswal, Benjamin Legros, Lawrence Hirsch, M. Brandon Westover, Nicolas Gaspard
      Abstract: OBJECTIVE: Find the optimal Continuous EEG (cEEG) monitoring duration for seizure detection in critically ill patients.METHODS: We analyzed prospective data from 665 consecutive cEEGs, including clinical factors and time-to-event emergence of EEG findings over 72-hours. Clinical factors were selected using logistic regression. EEG risk factors were selected a priori. Clinical factors were used for baseline (pre-EEG) risk. EEG findings were used for creation of multistate survival model with three states (entry, EEG risk, and seizure). EEG Risk state is defined by emergence of epileptiform patterns.RESULTS: Clinical variables of greatest predictive value were coma (31% had seizures; OR 1.8; p
      PubDate: 2017-07-06T00:30:32.827605-05:
      DOI: 10.1002/ana.24985
       
  • MMP9 is decreased in natalizumab-treated MS patients at risk for PML
    • Authors: Nicolas Fissolo; Béatrice Pignolet, Clara Matute-Blanch, Juan Carlos Triviño, Berta Miró, Miriam Mota, Santiago Perez-Hoyos, Alex Sanchez, Patrick Vermersch, Aurélie Ruet, Jérome de Sèze, Pierre Labauge, Sandra Vukusic, Caroline Papeix, Laurent Almoyna, Ayman Tourbah, Pierre Clavelou, Thibault Moreau, Jean Pelletier, Christine Lebrun-Frenay, Xavier Montalban, David Brassat, Manuel Comabella,
      Abstract: Objective: To identify biomarkers associated with the development of progressive multifocal leukoencephalopathy (PML) in multiple sclerosis (MS) patients treated with natalizumab (NTZ).Methods: Relapsing-remitting MS (RRMS) patients who developed PML under NTZ therapy (pre-PML) and non-PML natalizumab-treated patients (NTZ-ctr) were included in the study. Cryopreserved peripheral blood mononuclear cells (PBMC) and serum samples collected at baseline, at one- and two-year treated time points, and during PML were analyzed for gene expression by RNA-sequencing and for serum protein levels by LUMINEX and ELISA assays respectively.Results: Among top differentially expressed genes in the RNA-sequencing between pre-PML and NTZ-ctr patients, pathway analysis revealed a high representation of genes belonging to the following categories: pro-angiogenic factors (MMP9, VEGFA), chemokines (CXCL1, CXCL5, IL8, CCL2), cytokines (IL1B, IFNG), and plasminogen- and coagulation-related molecules (SERPINB2, PLAU, PLAUR, TFPI, THBD). Serum protein levels for these candidates were measured in a two-step manner in a screening cohort and a validation cohort of pre-PML and NTZ-ctr patients. Only MMP9 was validated and, in pre-PML patients MMP9 protein levels were significantly reduced at baseline compared with NTZ-ctr patients and levels remained lower at later time points during NTZ treatment.Interpretation: The results from this study suggest that the pro-angiogenic factor MMP9 may play a role as biomarker associated with the development of PML in MS patients treated with NTZ. This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-06T00:30:30.804852-05:
      DOI: 10.1002/ana.24987
       
  • Microbleeds in the SPS3 Trial: Stroke, Mortality and Treatment
           Interactions
    • Authors: Ashkan Shoamanesh; Lesly A. Pearce, Carlos Bazan, Luciana Catanese, Leslie A. McClure, Mukul Sharma, Joan Marti-Fabregas, David C. Anderson, Carlos S. Kase, Robert G. Hart, Oscar R. Benavente,
      Abstract: Objectives: To characterize cerebral microbleeds (CMBs) in lacunar stroke patients in the SPS3 trial and to assess their relationship with recurrent stroke and death, and response to assigned treatment.Methods: SPS3 is a randomized, clinical trial conducted between 2003 and 2011. Patients with recent MRI-documented lacunar infarcts were randomly assigned in a factorial design to target levels of systolic blood pressure (SBP; 130–149 mmHg vs
      PubDate: 2017-07-06T00:30:21.007213-05:
      DOI: 10.1002/ana.24988
       
 
 
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