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Publisher: John Wiley and Sons   (Total: 1597 journals)

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Showing 1 - 200 of 1597 Journals sorted alphabetically
Abacus     Hybrid Journal   (Followers: 13, SJR: 0.48, h-index: 22)
About Campus     Hybrid Journal   (Followers: 5)
Academic Emergency Medicine     Hybrid Journal   (Followers: 67, SJR: 1.385, h-index: 91)
Accounting & Finance     Hybrid Journal   (Followers: 49, SJR: 0.547, h-index: 30)
ACEP NOW     Free   (Followers: 1)
Acta Anaesthesiologica Scandinavica     Hybrid Journal   (Followers: 55, SJR: 1.02, h-index: 88)
Acta Archaeologica     Hybrid Journal   (Followers: 177, 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: 14, SJR: 1.197, h-index: 81)
Acta Ophthalmologica     Hybrid Journal   (Followers: 7, 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: 37, SJR: 2.518, h-index: 113)
Acta Zoologica     Hybrid Journal   (Followers: 7, SJR: 0.459, h-index: 29)
Acute Medicine & Surgery     Hybrid Journal   (Followers: 5)
Addiction     Hybrid Journal   (Followers: 36, SJR: 2.086, h-index: 143)
Addiction Biology     Hybrid Journal   (Followers: 15, 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: 28, SJR: 0.81, h-index: 81)
Advanced Functional Materials     Hybrid Journal   (Followers: 51, SJR: 5.21, h-index: 203)
Advanced Healthcare Materials     Hybrid Journal   (Followers: 14, SJR: 0.232, h-index: 7)
Advanced Materials     Hybrid Journal   (Followers: 283, SJR: 9.021, h-index: 345)
Advanced Materials Interfaces     Hybrid Journal   (Followers: 6, SJR: 1.177, h-index: 10)
Advanced Optical Materials     Hybrid Journal   (Followers: 7, SJR: 2.488, h-index: 21)
Advanced Science     Open Access   (Followers: 5)
Advanced Synthesis & Catalysis     Hybrid Journal   (Followers: 18, SJR: 2.729, h-index: 121)
Advances in Polymer Technology     Hybrid Journal   (Followers: 14, SJR: 0.344, h-index: 31)
Africa Confidential     Hybrid Journal   (Followers: 21)
Africa Research Bulletin: Economic, Financial and Technical Series     Hybrid Journal   (Followers: 13)
Africa Research Bulletin: Political, Social and Cultural Series     Hybrid Journal   (Followers: 11)
African Development Review     Hybrid Journal   (Followers: 33, SJR: 0.275, h-index: 17)
African J. of Ecology     Hybrid Journal   (Followers: 16, SJR: 0.477, h-index: 39)
Aggressive Behavior     Hybrid Journal   (Followers: 17, SJR: 1.391, h-index: 66)
Aging Cell     Open Access   (Followers: 11, SJR: 4.374, h-index: 95)
Agribusiness : an Intl. J.     Hybrid Journal   (Followers: 3, SJR: 0.627, h-index: 14)
Agricultural and Forest Entomology     Hybrid Journal   (Followers: 16, SJR: 0.925, h-index: 43)
Agricultural Economics     Hybrid Journal   (Followers: 45, SJR: 1.099, h-index: 51)
AIChE J.     Hybrid Journal   (Followers: 32, SJR: 1.122, h-index: 120)
Alcoholism and Drug Abuse Weekly     Hybrid Journal   (Followers: 7)
Alcoholism Clinical and Experimental Research     Hybrid Journal   (Followers: 7, SJR: 1.416, h-index: 125)
Alimentary Pharmacology & Therapeutics     Hybrid Journal   (Followers: 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: 152, 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: 93, SJR: 2.325, h-index: 51)
American J. of Economics and Sociology     Hybrid Journal   (Followers: 30, SJR: 0.211, h-index: 26)
American J. of Hematology     Hybrid Journal   (Followers: 35, SJR: 1.761, h-index: 77)
American J. of Human Biology     Hybrid Journal   (Followers: 13, 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: 17, 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: 38, SJR: 1.41, h-index: 88)
American J. of Political Science     Hybrid Journal   (Followers: 300, SJR: 5.101, h-index: 114)
American J. of Primatology     Hybrid Journal   (Followers: 14, SJR: 1.197, h-index: 63)
American J. of Reproductive Immunology     Hybrid Journal   (Followers: 4, SJR: 1.347, h-index: 75)
American J. of Transplantation     Hybrid Journal   (Followers: 19, SJR: 2.792, h-index: 140)
American J. on Addictions     Hybrid Journal   (Followers: 10, SJR: 0.843, h-index: 57)
Anaesthesia     Hybrid Journal   (Followers: 146, 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: 20)
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: 175)
Angewandte Chemie Intl. Edition     Hybrid Journal   (Followers: 238, SJR: 6.229, h-index: 397)
Animal Conservation     Hybrid Journal   (Followers: 41, SJR: 1.576, h-index: 62)
Animal Genetics     Hybrid Journal   (Followers: 8, SJR: 0.957, h-index: 67)
Animal Science J.     Hybrid Journal   (Followers: 6, SJR: 0.569, h-index: 24)
Annalen der Physik     Hybrid Journal   (Followers: 5, SJR: 1.46, h-index: 40)
Annals of Anthropological Practice     Partially Free   (Followers: 2, SJR: 0.187, h-index: 5)
Annals of Applied Biology     Hybrid Journal   (Followers: 7, SJR: 0.816, h-index: 56)
Annals of Clinical and Translational Neurology     Open Access   (Followers: 1)
Annals of Gastroenterological Surgery     Open Access  
Annals of Human Genetics     Hybrid Journal   (Followers: 9, SJR: 1.191, h-index: 67)
Annals of Neurology     Hybrid Journal   (Followers: 49, SJR: 5.584, h-index: 241)
Annals of Noninvasive Electrocardiology     Hybrid Journal   (Followers: 1, SJR: 0.531, h-index: 38)
Annals of Public and Cooperative Economics     Hybrid Journal   (Followers: 8, SJR: 0.336, h-index: 23)
Annals of the New York Academy of Sciences     Hybrid Journal   (Followers: 5, SJR: 2.389, h-index: 189)
Annual Bulletin of Historical Literature     Hybrid Journal   (Followers: 12)
Annual Review of Information Science and Technology     Hybrid Journal   (Followers: 14)
Anthropology & Education Quarterly     Hybrid Journal   (Followers: 26, SJR: 0.72, h-index: 31)
Anthropology & Humanism     Hybrid Journal   (Followers: 18, 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: 94, SJR: 0.545, h-index: 15)
Antipode     Hybrid Journal   (Followers: 54, SJR: 2.212, h-index: 69)
Anz J. of Surgery     Hybrid Journal   (Followers: 8, SJR: 0.432, h-index: 59)
Anzeiger für Schädlingskunde     Hybrid Journal   (Followers: 1)
Apmis     Hybrid Journal   (Followers: 1, SJR: 0.855, h-index: 73)
Applied Cognitive Psychology     Hybrid Journal   (Followers: 74, SJR: 0.754, h-index: 69)
Applied Organometallic Chemistry     Hybrid Journal   (Followers: 7, SJR: 0.632, h-index: 58)
Applied Psychology     Hybrid Journal   (Followers: 170, SJR: 1.023, h-index: 64)
Applied Psychology: Health and Well-Being     Hybrid Journal   (Followers: 53, 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: 12, 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: 12, 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: 31, 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: 29, SJR: 0.261, h-index: 9)
Archiv der Pharmazie     Hybrid Journal   (Followers: 3, SJR: 0.628, h-index: 43)
Archives of Drug Information     Hybrid Journal   (Followers: 5)
Archives of Insect Biochemistry and Physiology     Hybrid Journal   (SJR: 0.768, h-index: 54)
Area     Hybrid Journal   (Followers: 13, SJR: 0.938, h-index: 57)
Art History     Hybrid Journal   (Followers: 272, SJR: 0.153, h-index: 13)
Arthritis & Rheumatology     Hybrid Journal   (Followers: 56, SJR: 1.984, h-index: 20)
Arthritis Care & Research     Hybrid Journal   (Followers: 29, SJR: 2.256, h-index: 114)
Artificial Organs     Hybrid Journal   (Followers: 1, SJR: 0.872, h-index: 60)
ASHE Higher Education Reports     Hybrid Journal   (Followers: 15)
Asia & the Pacific Policy Studies     Open Access   (Followers: 17)
Asia Pacific J. of Human Resources     Hybrid Journal   (Followers: 329, 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   (Followers: 1, SJR: 0.394, h-index: 7)
Asian J. of Organic Chemistry     Hybrid Journal   (Followers: 6, SJR: 1.443, h-index: 19)
Asian J. of Social Psychology     Hybrid Journal   (Followers: 6, 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: 3, SJR: 0.701, h-index: 40)
Atmospheric Science Letters     Open Access   (Followers: 29, SJR: 1.332, h-index: 27)
Austral Ecology     Hybrid Journal   (Followers: 15, SJR: 1.095, h-index: 66)
Austral Entomology     Hybrid Journal   (Followers: 9, SJR: 0.524, h-index: 28)
Australasian J. of Dermatology     Hybrid Journal   (Followers: 8, SJR: 0.714, h-index: 40)
Australasian J. On Ageing     Hybrid Journal   (Followers: 6, SJR: 0.39, h-index: 22)
Australian & New Zealand J. of Statistics     Hybrid Journal   (Followers: 14, SJR: 0.275, h-index: 28)
Australian Accounting Review     Hybrid Journal   (Followers: 3, SJR: 0.709, h-index: 14)
Australian and New Zealand J. of Family Therapy (ANZJFT)     Hybrid Journal   (Followers: 3, SJR: 0.382, h-index: 12)
Australian and New Zealand J. of Obstetrics and Gynaecology     Hybrid Journal   (Followers: 46, SJR: 0.814, h-index: 49)
Australian and New Zealand J. of Public Health     Hybrid Journal   (Followers: 13, SJR: 0.82, h-index: 62)
Australian Dental J.     Hybrid Journal   (Followers: 6, SJR: 0.482, h-index: 46)
Australian Economic History Review     Hybrid Journal   (Followers: 6, SJR: 0.171, h-index: 12)
Australian Economic Papers     Hybrid Journal   (Followers: 31, SJR: 0.23, h-index: 9)
Australian Economic Review     Hybrid Journal   (Followers: 6, SJR: 0.357, h-index: 21)
Australian Endodontic J.     Hybrid Journal   (Followers: 3, SJR: 0.513, h-index: 24)
Australian J. of Agricultural and Resource Economics     Hybrid Journal   (Followers: 3, SJR: 0.765, h-index: 36)
Australian J. of Grape and Wine Research     Hybrid Journal   (Followers: 5, SJR: 0.879, h-index: 56)
Australian J. of Politics & History     Hybrid Journal   (Followers: 15, 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: 441, SJR: 0.418, h-index: 29)
Australian J. of Rural Health     Hybrid Journal   (Followers: 6, SJR: 0.43, h-index: 34)
Australian Occupational Therapy J.     Hybrid Journal   (Followers: 75, SJR: 0.59, h-index: 29)
Australian Psychologist     Hybrid Journal   (Followers: 11, SJR: 0.331, h-index: 31)
Australian Veterinary J.     Hybrid Journal   (Followers: 23, SJR: 0.459, h-index: 45)
Autism Research     Hybrid Journal   (Followers: 38, SJR: 2.126, h-index: 39)
Autonomic & Autacoid Pharmacology     Hybrid Journal   (SJR: 0.371, h-index: 29)
Banks in Insurance Report     Hybrid Journal   (Followers: 1)
Basic & Clinical Pharmacology & Toxicology     Hybrid Journal   (Followers: 11, SJR: 0.539, h-index: 70)
Basic and Applied Pathology     Open Access   (Followers: 2, SJR: 0.113, h-index: 4)
Basin Research     Hybrid Journal   (Followers: 5, SJR: 1.54, h-index: 60)
Bauphysik     Hybrid Journal   (Followers: 2, SJR: 0.194, h-index: 5)
Bauregelliste A, Bauregelliste B Und Liste C     Hybrid Journal  
Bautechnik     Hybrid Journal   (Followers: 1, SJR: 0.321, h-index: 11)
Behavioral Interventions     Hybrid Journal   (Followers: 10, SJR: 0.297, h-index: 23)
Behavioral Sciences & the Law     Hybrid Journal   (Followers: 23, SJR: 0.736, h-index: 57)
Berichte Zur Wissenschaftsgeschichte     Hybrid Journal   (Followers: 10, SJR: 0.11, h-index: 5)
Beton- und Stahlbetonbau     Hybrid Journal   (Followers: 2, SJR: 0.493, h-index: 14)
Biochemistry and Molecular Biology Education     Hybrid Journal   (Followers: 6, SJR: 0.311, h-index: 26)
Bioelectromagnetics     Hybrid Journal   (Followers: 1, SJR: 0.568, h-index: 64)
Bioengineering & Translational Medicine     Open Access  
BioEssays     Hybrid Journal   (Followers: 10, SJR: 3.104, h-index: 155)
Bioethics     Hybrid Journal   (Followers: 14, SJR: 0.686, h-index: 39)
Biofuels, Bioproducts and Biorefining     Hybrid Journal   (Followers: 1, SJR: 1.725, h-index: 56)
Biological J. of the Linnean Society     Hybrid Journal   (Followers: 18, SJR: 1.172, h-index: 90)
Biological Reviews     Hybrid Journal   (Followers: 5, SJR: 6.469, h-index: 114)
Biologie in Unserer Zeit (Biuz)     Hybrid Journal   (Followers: 41, SJR: 0.12, h-index: 1)
Biology of the Cell     Full-text available via subscription   (Followers: 9, SJR: 1.812, h-index: 69)
Biomedical Chromatography     Hybrid Journal   (Followers: 7, SJR: 0.572, h-index: 49)
Biometrical J.     Hybrid Journal   (Followers: 5, SJR: 0.784, h-index: 44)
Biometrics     Hybrid Journal   (Followers: 37, SJR: 1.906, h-index: 96)
Biopharmaceutics and Drug Disposition     Hybrid Journal   (Followers: 10, SJR: 0.715, h-index: 44)
Biopolymers     Hybrid Journal   (Followers: 18, SJR: 1.199, h-index: 104)
Biotechnology and Applied Biochemistry     Hybrid Journal   (Followers: 44, SJR: 0.415, h-index: 55)
Biotechnology and Bioengineering     Hybrid Journal   (Followers: 160, SJR: 1.633, h-index: 146)
Biotechnology J.     Hybrid Journal   (Followers: 15, SJR: 1.185, h-index: 51)
Biotechnology Progress     Hybrid Journal   (Followers: 39, SJR: 0.736, h-index: 101)
Biotropica     Hybrid Journal   (Followers: 20, SJR: 1.374, h-index: 71)
Bipolar Disorders     Hybrid Journal   (Followers: 9, SJR: 2.592, h-index: 100)
Birth     Hybrid Journal   (Followers: 38, SJR: 0.763, h-index: 64)
Birth Defects Research Part A : Clinical and Molecular Teratology     Hybrid Journal   (Followers: 2, SJR: 0.727, h-index: 77)
Birth Defects Research Part B: Developmental and Reproductive Toxicology     Hybrid Journal   (Followers: 8, SJR: 0.468, h-index: 47)
Birth Defects Research Part C : Embryo Today : Reviews     Hybrid Journal   (SJR: 1.513, h-index: 55)

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Journal Cover Annals of Neurology
  [SJR: 5.584]   [H-I: 241]   [49 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  [1597 journals]
  • Epileptiform activity in traumatic brain injury predicts post-traumatic
    • Authors: Jennifer A. Kim; Emily Boyle, Alexander C. Wu, Andrew J. Cole, Kevin J Staley, Sahar Zafar, Sydney S. Cash, M. Brandon Westover
      Abstract: We hypothesize that epileptiform abnormalities (EA) in the electroencephalopgram (EEG) during the acute period following traumatic brain injury (TBI) independently predict first-year post-traumatic epilepsy (PTE1). We analyzed PTE1 risk factors in two cohorts matched for TBI severity and age (n=50). EA independently predict risk for PTE1 (OR 3.16[0.99 11.68]); subdural hematoma is another independent risk factor (OR 4.13 [1.18 39.33]). Differences in EA rates are apparent within 5 days following TBI. Our results suggest increased EA prevalence identifies patients at increased risk for PTE1, and that EA acutely post-TBI can identify patients most likely to benefit from anti-epileptogenesis drug trials. This article is protected by copyright. All rights reserved.
      PubDate: 2018-03-14T11:06:18.88436-05:0
      DOI: 10.1002/ana.25211
  • Bilateral taste disorders in patients with Ramsay Hunt Syndrome and Bell's
    • Authors: Pavlos Pavlidis; Rafael J. A. Cámara, Georgios Kekes, Haralampos Gouveris
      Abstract: Objective: Ramsay Hunt syndrome (RHS) and Bell's palsy (BP) are typically known as facial nerve motor syndromes and are primarily unilateral. The aim of this study was to challenge this assertion because both conditions are also known to be associated with viruses that typically affect several nerves.Methods: Ten participants with RHS, 12 with BP, all clinically unilateral, and 12 healthy controls were prospectively enrolled. Electrogustometric thresholds were measured bilaterally in the areas of the chorda tympani, the glossopharyngeal, and the major petrosal nerve. Also bilaterally, the taste function was tested using chemogustometry with different tastant concentrations. Again bilaterally, the morphology of the mucosa and the vessels of the anterior fungiform papillae were examined by contact endoscopy. Statistically, RHS and BP participants were compared with the healthy controls, and the paretic sides of RHS and BP were compared pairwise with their mobile sides.Results: Electrogustometrically, the perception was reduced bilaterally in RHS (10-19 dB, p 
      PubDate: 2018-03-14T11:06:11.64892-05:0
      DOI: 10.1002/ana.25210
  • The Nerve Conditioning Lesion – a Strategy to Enhance Nerve
    • Authors: Jenna-Lynn B. Senger; Valerie M.K. Verge, K. Ming Chan, Christine A. Webber
      Abstract: By altering the intrinsic metabolism of the cell, including the upregulation of regeneration-associated genes (RAGs) and the production of structural proteins for axonal outgrowth, the conditioning lesion sets up an environment highly conducive to regeneration. In this review, we assess forty years of research to provide a comprehensive overview of the conditioning lesion literature, directed at: a) discussing the mechanisms of, and barriers to nerve regeneration that can be mitigated by the conditioning lesion; b) describing the cellular and molecular pathways implicated in the conditioning lesion effect; and c) deliberating on how these insights might be applied clinically. The consequential impact on regeneration is profound, with a conditioned nerve demonstrating longer neurite extensions in vitro, enhanced expression of RAGs within the dorsal root ganglia, early assembly and transportation of cytoskeletal elements, accelerated axonal growth, and improved functional recovery in vivo. Although this promising technique is not yet feasible to be performed in humans, there are potential strategies, such as conditioning electrical stimulation that may be explored to allow nerve conditioning in a clinically safe and well-tolerated manner. This article is protected by copyright. All rights reserved.
      PubDate: 2018-03-14T11:01:48.040104-05:
      DOI: 10.1002/ana.25209
  • Bone marrow transplantation stimulates neural repair in Friedreich's
           ataxia mice
    • Authors: Kevin C Kemp; Kelly Hares, Juliana Redondo, Amelia J Cook, Harry R Haynes, Bronwen R Burton, Mark A Pook, Claire M Rice, Neil J Scolding, Alastair Wilkins
      Abstract: Objectives: Friedreich's ataxia is an incurable inherited neurological disease caused by frataxin deficiency. Here we report the neuro-reparative effects of myeloablative allogeneic bone marrow transplantation in a humanised murine model of the disease.Methods: Mice received a transplant of fluorescently-tagged sex mis-matched bone marrow cells expressing wild-type frataxin and were assessed at monthly intervals using a range of behavioural motor performance tests. At six months post-transplant, mice were sacrificed for protein and histological analysis. In an attempt to augment numbers of bone marrow-derived cells integrating within the nervous system and improve therapeutic efficacy, a sub-group of transplanted mice also received monthly subcutaneous infusions of cytokines granulocyte-colony stimulating factor and stem cell factor.Results: Transplantation caused improvements in several indicators of motor coordination and locomotor activity. Elevations in frataxin levels and anti-oxidant defences were detected. Abrogation of disease pathology throughout the nervous system was apparent, together with extensive integration of bone marrow-derived cells in areas of nervous tissue injury that contributed genetic material to mature neurons, satellite-like cells and myelinating Schwann cells by processes including cell fusion. Elevations in circulating bone marrow-derived cell numbers were detected post-cytokine administration and were associated with increased frequencies of Purkinje cell fusion and bone marrow-derived dorsal root ganglion satellite-like cells. Further improvements in motor coordination and activity were evident.Interpretation: Our data provide proof-of-concept of gene replacement therapy, via allogeneic bone marrow transplantation, that reverses neurological features of Friedreich's ataxia with the potential for rapid clinical translation. This article is protected by copyright. All rights reserved.
      PubDate: 2018-03-13T11:25:53.137256-05:
      DOI: 10.1002/ana.25207
  • Getting the best outcomes from epilepsy surgery
    • Authors: VN Vakharia; JS Duncan, J-A Witt, CE Elger, R Staba, J Engel
      Abstract: Neurosurgery is an under-utilised treatment that can potentially cure drug-refractory epilepsy. Careful, multidisciplinary pre-surgical evaluation is vital for selecting patients and ensure optimal outcomes. Advances in neuroimaging have improved diagnosis and guide surgical intervention. Invasive electroencephalography allows the evaluation of complex patients who would otherwise not be candidates for neurosurgery. We review the current state of the assessment and selection of patients and consider established and novel surgical procedures, and associated outcome data. We aim to dispel myths that may inhibit physicians from referring and patients from considering neurosurgical intervention for drug-refractory focal epilepsies. This article is protected by copyright. All rights reserved.
      PubDate: 2018-03-13T11:25:33.791194-05:
      DOI: 10.1002/ana.25205
  • The reality of “ghosts” in authorship of clinical trials in
           multiple sclerosis
    • Authors: Jack Antel
      PubDate: 2018-03-13T11:20:35.170902-05:
      DOI: 10.1002/ana.25199
  • De Novo Hotspot Variants in CYFIP2 Cause Early-Onset Epileptic
    • Authors: Mitsuko Nakashima; Mitsuhiro Kato, Kazushi Aoto, Masaaki Shiina, Hazrat Belal, Souichi Mukaida, Satoko Kumada, Atsushi Sato, Ayelet Zerem, Tally Lerman-Sagie, Dorit Lev, Huey Yin Leong, Yoshinori Tsurusaki, Takeshi Mizuguchi, Satoko Miyatake, Noriko Miyake, Kazuhiro Ogata, Hirotomo Saitsu, Naomichi Matsumoto
      Abstract: Objective: The cytoplasmic fragile X mental retardation 1 interacting proteins 2 (CYFIP2) is a component of the WAVE regulatory complex, which is involved in actin dynamics. An obvious association of CYFIP2 variants with human neurological disorders has never been reported. Here, we identified de novo hotspot CYFIP2 variants in neurodevelopmental disorders and explore the possible involvement of the CYFIP2 mutants in the WAVE signaling pathway.Methods: We performed trio-based whole exome sequencing (WES) in 210 families and case-only WES in 489 individuals with epileptic encephalopathies. The functional effect of CYFIP2 variants on WAVE signaling was evaluated by computational structural analysis and in vitro transfection experiments.Results: We identified three de novo CYFIP2 variants at the Arg87 residue in four unrelated individuals with early-onset epileptic encephalopathy. Structural analysis indicated that the Arg87 residue is buried at an interface between CYFIP2 and WAVE1, and the Arg87 variant may disrupt hydrogen bonding, leading to structural instability and aberrant activation of the WAVE regulatory complex. All mutant CYFIP2 showed comparatively weaker interactions to the VCA domain than wild type CYFIP2. Immunofluorescence revealed that ectopic speckled accumulation of actin and CYFIP2 was significantly increased in cells transfected with mutant CYFIP2.Interpretation: Our findings suggest that de novo Arg87 variants in CYFIP2 have gain-of-function effects on the WAVE signaling pathway, and are associated with severe neurological disorders. This article is protected by copyright. All rights reserved.
      PubDate: 2018-03-13T11:20:22.847633-05:
      DOI: 10.1002/ana.25208
  • Are spikes non-inferior to high-frequency oscillations'
    • Authors: Shennan Aibel Weiss
      PubDate: 2018-03-10T11:30:34.164316-05:
      DOI: 10.1002/ana.25201
  • PET-guided MR Spectroscopy in Alzheimer's disease
    • Authors: Nasim Sheikh-Bahaei; S. Ahmad Sajjadi, Roido Manavaki, Mary McLean, John T. O'Brien, Jonathan H. Gillard
      Abstract: Objectives: To determine if the level of metabolites in MR Spectroscopy (MRS) is a representative marker of underlying pathological changes identified in PET images in Alzheimer's disease (AD).Methods: We performed PET-guided MRS in cases of probable AD, Mild Cognitive Impairment (MCI) and healthy controls (HC). All participants were imaged by 11 C-Pittsburgh Compound B (11C-PiB) and 18 F-fluorodeoxy-glucose (18F-FDG)-PET followed by 3T MRS. PET images were assessed both visually and using standardized uptake value ratios (SUVR). MRS voxels were placed in regions with maximum abnormality on amyloid (Aβ+s) and FDG (hypometabolic) areas on PET scans. Corresponding normal areas were selected in controls. The ratios of total N-acetyl group (tNA), myoinositol(mI), choline(Chol), glutamate+glutamine (Glx) over Creatine (Cr) were compared between these regions.Results: Aβ+ regions had significantly higher (p=0.02) mI/Cr and lower tNA/Cr (p=0.02), while in hypometabolic areas only tNA/Cr was reduced (p=0.003). Multiple regression analysis adjusting for sex, age and education showed mI/Cr was only associated with 11C-PiB SUVR (p
      PubDate: 2018-03-08T12:29:59.627696-05:
      DOI: 10.1002/ana.25202
  • Reduced contrast sensitivity among older women is associated with
           increased risk of cognitive impairment
    • Authors: Michael E. Ward; Jeffrey M. Gelfand, Li-Yung Lui, Yvonne Ou, Ari J. Green, Katie Stone, Kathryn L. Pedula, Steven R. Cummings, Kristine Yaffe
      Abstract: Objective: Several cross-sectional studies have reported an association between visual contrast sensitivity (a functional measure of low contrast vision) and poor cognitive performance or dementia, but no studies have investigated this association prospectively in a population based cohort with final adjudication of mild cognitive impairment (MCI)/dementia.Methods: In a prospective, community-based study of aging women (Study of Osteoporotic Fractures), we analyzed whether visual contrast sensitivity was associated with increased risk of MCI or dementia and/or worse performance on various cognitive tests assessed 10 years later. Contrast sensitivity was assessed at baseline in each eye using a VISTECH VCTS 6500 wall chart. MCI/dementia was adjudicated by an expert panel. Multivariable logistic and linear regression models were analyzed.Results: Of 1,352 White (88.2%) and African-American (11.8%) women with a mean age of 77.7 years (SD 3.3), 536 (39.6%) went on to develop MCI/dementia over 10 years. MCI/Dementia risk was more than doubled (OR 2.16, 95% CI 1.58 to 2.96) in women with the lowest quartile of contrast sensitivity compared to highest (p
      PubDate: 2018-03-08T12:29:53.058459-05:
      DOI: 10.1002/ana.25196
  • Myelin Abnormality in CMT4J Recapitulates Features of Acquired
    • Authors: Bo Hu; Megan Mccollum, Vignesh Ravi, Sezgi Arpag, Daniel Moiseev, Ryan Castoro, Bret C. Mobley, Bryan W. Burnette, Carly Siskind, John W. Day, Robin Yawn, Shawna Feely, Yuebing Li, Qing Yan, Michael E. Shy, Jun Li
      Abstract: Objective: Charcot-Marie-Tooth type 4J (CMT4J) is a rare autosomal recessive neuropathy caused by mutations in FIG4 that result in loss of FIG4 protein. This study investigates the natural history and mechanisms of segmental demyelination in CMT4J. Methods: Over the past 9 years, we have enrolled and studied a cohort of 12 CMT4J patients, including 6 novel FIG4 mutations. We evaluated these patients and related mouse models using morphological, electrophysiological and biochemical approaches. Results: We found sensory motor demyelinating polyneuropathy consistently in all patients. This underlying myelin pathology was associated with non-uniform slowing of conduction velocities, conduction block, and temporal dispersion on nerve conduction studies (NCS), which resemble those features in acquired demyelinating peripheral nerve diseases. Segmental demyelination was also confirmed in mice without Fig4 (Fig4-/-). The demyelination was associated with an increase of Schwann cell dedifferentiation and macrophages in spinal roots where nerve blood barriers are weak. Schwann cell dedifferentiation was induced by the increasing intracellular Ca2+. Suppression of Ca2+ level by a chelator reduced dedifferentiation and demyelination of Schwann cells in vitro and in vivo. Interestingly, cell-specific knockout of Fig4 in mouse Schwann cells or neurons failed to cause segmental demyelination. Interpretation: Myelin change in CMT4J recapitulates the features of acquired demyelinating neuropathies. This pathology is not Schwann cell autonomous. Instead, it relates to systemic processes involving interactions of multiple cell types and abnormally elevated intracellular Ca2+. Injection of a Ca2+ chelator in Fig4-/- mice improved segmental demyelination, thereby providing a therapeutic strategy against demyelination. This article is protected by copyright. All rights reserved.
      PubDate: 2018-03-08T12:29:48.145546-05:
      DOI: 10.1002/ana.25198
  • Inflammatory intrathecal profiles and cortical damage in multiple
    • Authors: R. Magliozzi; O.W. Howell, R. Nicholas, C. Cruciani, M. Castellaro, C. Romualdi, S. Rossi, M. Pitteri, M.D. Benedetti, A. Gajofatto, F.B. Pizzini, S. Montemezzi, S. Rasia, R. Capra, A. Bertoldo, F. Facchiano, S. Monaco, R. Reynolds, M. Calabrese
      Abstract: Objective: Grey matter (GM) damage and meningeal inflammation have been associated with early disease onset and a more aggressive disease course in Multiple Sclerosis (MS), but can these changes be identified in the patient early in the disease course'Methods: To identify possible biomarkers linking meningeal inflammation, GM damage and disease severity, gene and protein expression were analysed in meninges and CSF from 27 post-mortem secondary progressive MS (SPMS) and 14 control cases. Combined cytokine/chemokine CSF profiling and 3T-MRI were performed at diagnosis in two independent cohorts of MS patients (35 and 38 subjects) and in 26 non-MS patients.Results: Increased expression of pro-inflammatory cytokines (IFNγ, TNF, IL2 and IL22) and molecules related to sustained B-cell activity and lymphoid-neogenesis (CXCL13, CXCL10, LTα, IL6, IL10) was detected in the meninges and CSF of post-mortem MS cases with high levels of meningeal inflammation and GM demyelination. Similar pro-inflammatory patterns, including increased levels of CXCL13, TNF, IFNγ, CXCL12, IL6, IL8 and IL10, together with high levels of BAFF, APRIL, LIGHT, TWEAK, sTNFR1, sCD163, MMP2 and pentraxin III, were detected in the CSF of MS patients with higher levels of GM damage at diagnosis.Interpretation: A common pattern of intrathecal (meninges and CSF) inflammatory profile strongly correlates with increased cortical pathology, both at time of the diagnosis and of death. These results suggest a role for detailed CSF analysis combined with MRI, as a prognostic marker for more aggressive MS. This article is protected by copyright. All rights reserved.
      PubDate: 2018-03-08T12:29:21.006384-05:
      DOI: 10.1002/ana.25197
  • Recessive mutations in VPS13D cause childhood-onset movement disorders
    • Authors: Julie Gauthier; Inge A. Meijer, Davor Lessel, Niccolò E. Mencacci, Dimitri Krainc, Maja Hempel, Konstantinos Tsiakas, Holger Prokisch, Elsa Rossignol, Margaret H. Helm, Lance H. Rodan, Jason Karamchandani, Miryam Carecchio, Steven J. Lubbe, Aida Telegrafi, Lindsay B. Henderson, Kerry Lorenzo, Stephanie E Wallace, Ian A Glass, Fadi F. Hamdan, Jacques L. Michaud, Guy A. Rouleau, Philippe M. Campeau
      Abstract: VPS13 protein family members, VPS13A through VPS13C, have been associated with various recessive movement disorders. We describe the first disease association of rare recessive VPS13D variants including a frameshift, missense and a partial duplication with a novel complex, hyperkinetic neurological disorder. The clinical features include developmental delay, a childhood onset movement disorder (chorea, dystonia or tremor) and progressive spastic ataxia or paraparesis. Characteristic brain MRI shows basal ganglia or diffuse white matter T2 hyperintensities as seen in Leigh syndrome and chorea-acanthocytosis. Muscle biopsy in one case showed mitochondrial aggregates and lipidosis, suggesting mitochondrial dysfunction. These findings underline the importance of the VPS13 complex in neurological disease and a possible role in mitochondrial function. This article is protected by copyright. All rights reserved.
      PubDate: 2018-03-08T12:27:47.767152-05:
      DOI: 10.1002/ana.25204
  • Authorship of phase 3 trials in multiple sclerosis
    • Authors: Alasdair Coles
      PubDate: 2018-03-08T12:27:40.739307-05:
      DOI: 10.1002/ana.25203
  • Reply to “Are spikes non-inferior to high-frequency oscillations'”
           by S. Weiss and M. Sperling
    • Authors: Nicolas Roehri; Francesca Pizzo, Aileen McGonigal, Inserm Systèmes, Fabrice Bartolomei, Christian George Bénar
      PubDate: 2018-03-08T12:27:31.85004-05:0
      DOI: 10.1002/ana.25200
  • Dorsal root ganglia volume differentiate schwannomatosis and
           neurofibromatosis 2
    • Authors: Tim Godel; Victor-Felix Mautner, Said Farschtschi, Mirko Pham, Daniel Schwarz, Moritz Kronlage, Isabel Gugel, Sabine Heiland, Martin Bendszus, Philipp Bäumer
      Abstract: Schwannomatosis and neurofibromatosis type 2 are hereditary tumor syndromes and peripheral neuropathy has been reported in both. We prospectively applied in-vivo morphometric measurement of dorsal root ganglia volume in 16 schwannomatosis, 14 neurofibromatosis type 2 patients, and 26 healthy controls by MR-Neurography. Compared to healthy controls, dorsal root ganglia hypertrophy was a consistent finding in neurofibromatosis type 2 (L3: +267%, L4: +235%, L5: +241%, S1: +300% and S2: +242%, Bonferroni-adjusted p
      PubDate: 2018-02-22T11:10:22.257292-05:
      DOI: 10.1002/ana.25191
  • Seizures and disturbed brain potassium dynamics in the leukodystrophy MLC
    • Authors: Mohit Dubey; Eelke Brouwers, Eline M.C. Hamilton, Oliver Stiedl, Marianna Bugiani, Henner Koch, Maarten H.P. Kole, Ursula Boschert, Robert C. Wykes, Huibert D. Mansvelder, Marjo S. van der Knaap, Rogier Min
      Abstract: Objective: Loss of function of the astrocyte-specific protein MLC1 leads to the childhood onset leukodystrophy “megalencephalic leukoencephalopathy with subcortical cysts” (MLC). Studies on isolated cells show a role for MLC1 in astrocyte volume regulation and suggest that disturbed brain ion and water homeostasis is central to the disease. Excitability of neuronal networks is particularly sensitive to ion and water homeostasis. In line with this, reports of seizures and epilepsy in MLC patients exist. However, systematic assessment and mechanistic understanding of seizures in MLC are lacking.Methods: We analyzed an MLC patient inventory to study occurrence of seizures in MLC. We used two distinct genetic mouse models of MLC to further study epileptiform activity and seizure threshold through wireless extracellular field potential recordings. Whole cell patch-clamp recordings and K+-sensitive electrode recordings in mouse brain slices were used to explore the underlying mechanisms of epilepsy in MLC.Results: An early onset of seizures is common in MLC. Similarly, in MLC mice we uncovered spontaneous epileptiform brain activity and a lowered threshold for induced seizures. At the cellular level, we found that although passive and active properties of individual pyramidal neurons are unchanged, extracellular K+ dynamics and neuronal network activity are abnormal in MLC mice.Interpretation: Disturbed astrocyte regulation of ion and water homeostasis in MLC causes hyperexcitability of neuronal networks and seizures. These findings suggest a role for defective astrocyte volume regulation in epilepsy. This article is protected by copyright. All rights reserved.
      PubDate: 2018-02-21T18:00:49.712983-05:
      DOI: 10.1002/ana.25190
  • Mutations in SCN3A cause early infantile epileptic encephalopathy
    • Authors: Tariq Zaman; Ingo Helbig, Ivana Babić Božović, Suzanne D. DeBrosse, A. Christina Bergqvist, Kimberly Wallis, Livija Medne, Aleš Maver, Borut Peterlin, Katherine L. Helbig, Xiaohong Zhang, Ethan M. Goldberg
      Abstract: Objective: Voltage-gated sodium (Na+) channels underlie action potential generation and propagation and hence are central to the regulation of excitability in the nervous system. Mutations in the genes SCN1A, SCN2A, and SCN8A, encoding the Na+ channel pore-forming (α) subunits Nav1.1, 1.2, and 1.6, respectively, and SCN1B, encoding the accessory subunit β1, are established causes of genetic epilepsies. SCN3A, encoding Nav1.3, is known to be highly expressed in brain, but has not previously been linked to early infantile epileptic encephalopathy. Here, we describe a cohort of four patients with epileptic encephalopathy and heterozygous de novo missense variants in SCN3A (p.Ile875Thr in two cases, p.Pro1333Leu, and p.Val1769Ala).Methods: All patients presented with treatment-resistant epilepsy in the first year of life, severe to profound intellectual disability, and, in two cases (both with the variant p.Ile875Thr), diffuse polymicrogyria.Results: Electrophysiological recordings of mutant channels revealed prominent gain of channel function, with a markedly increased amplitude of the slowly inactivating current component, and, for two of three mutants (p.Ile875Thr and p.Pro1333Leu), a left-shift in the voltage dependence of activation to more hyperpolarized potentials. Gain of function was not observed for Nav1.3 variants known or presumed to be inherited (p.Arg1642Cys and p.Lys1799Gln). The anti-seizure medications phenytoin and lacosamide selectively blocked slowly inactivating over transient current in wild-type and mutant Nav1.3 channels.Interpretation: These findings establish SCN3A as a new gene for infantile epileptic encephalopathy and suggest a potential pharmacologic intervention. These findings also reinforce the role of Nav1.3 as an important regulator of neuronal excitability in the developing brain while providing additional insight into mechanisms of slow inactivation of Nav1.3. This article is protected by copyright. All rights reserved.
      PubDate: 2018-02-21T17:50:32.651751-05:
      DOI: 10.1002/ana.25188
  • Memory Complaints, Dementia, and Neuropathology in Older Blacks and Whites
    • Authors: Zoe Arvanitakis; Sue E. Leurgans, Debra A. Fleischman, Julie A. Schneider, Kumar B. Rajan, Jeremy J. Pruzin, Raj C. Shah, Denis A. Evans, Lisa L. Barnes, David A. Bennett
      Abstract: Objective: To determine relationships of memory complaints to cognitive function and decline, incident dementia, and neurodegenerative and other neuropathologies, as well as the population-attributable risk for dementia in older black and white persons.Methods: 4015 community-based persons (28% black; 74% women; mean baseline age 78 years), were enrolled in one of four longitudinal cohort studies, and another 2937 in a population-based cohort. Memory scores, assessed using two questions (5-point Likert scales) were categorized as complaints present or absent. Global cognition and five cognitive domains were derived from annual neuropsychological tests. Dementia was assessed from these tests and additional data. Neuropathologic data were available for 1350 deceased with brain autopsies. Regression and mixed effects models were used to examine relationships of memory complaints to cognition and neuropathology.Results: Baseline memory complaints (n=1310; 33% of 4015) were associated with lower cognition and faster decline in all domains (global score estimate = -0.032 [SE=0.004], p
      PubDate: 2018-02-21T17:50:24.265262-05:
      DOI: 10.1002/ana.25189
  • Issue Information - Copyright
    • PubDate: 2018-02-20T23:18:03.400686-05:
      DOI: 10.1002/ana.25174
  • Issue Information - Masthead
    • PubDate: 2018-02-20T23:18:03.347367-05:
      DOI: 10.1002/ana.25176
  • Annals of Neurology: Volume 83, Number 2, February 2018
    • Abstract: A raster display of repeated motor cortical evoked potentials with single pulses of deep brain stimulation in the globus pallidus, pars interna in a patient with cervical dystonia. Each line represents a single trial, with stimulation beginning at the left margin, and the length of each line equivalent to 50 msec of recording. Dark blue = 0 mV, lighter blue-green colors = negative voltage, purple-red colors = positive voltage. Note that the evoked potential is negative at about 10 msec, positive at about 25 msec, and then near zero again at 50 msec. See Ni et al., pp 352–362, this issue. Ann Neurol 2018;83:1–1
      PubDate: 2018-02-20T23:17:59.106756-05:
      DOI: 10.1002/ana.25181
  • Issue Information - TOC
    • PubDate: 2018-02-20T23:17:58.151084-05:
      DOI: 10.1002/ana.25175
  • Dysregulation of NEUROG2 plays a key role in focal cortical dysplasia
    • Authors: Simoni H. Avansini; Fábio R. Torres, André S. Vieira, Danyella B. Dogini, Fabio Rogerio, Ana C. Coan, Marcia E. Morita, Marilisa M. Guerreiro, Clarissa L. Yasuda, Rodrigo Secolin, Benilton S. Carvalho, Murilo G. Borges, Vanessa S. Almeida, Patrícia A.O. R. Araújo, Luciano Queiroz, Fernando Cendes, Iscia Lopes-Cendes
      Abstract: Objective: Focal cortical dysplasias (FCDs) are an important cause of drug-resistant epilepsy. In this work we aimed to investigate whether abnormal gene regulation, mediated by microRNA, could be involved in FCD type II.Methods: We used total RNA from the brain tissue of 16 patients with FCD type II and 28 controls. MicroRNA expression was initially assessed by microarray. Quantitative PCR (qPCR), in situ hybridization, luciferase reporter assays and deep sequencing for genes in the mTOR pathway were performed to validate and further explore our initial study.Results: hsa-let-7f (p=0.039), hsa-miR-31 (p=0.0078) and hsa-miR34a (p=0.021) were downregulated in FCD type II, whereas a transcription factor involved in neuronal and glial fate specification, NEUROG2 (p
      PubDate: 2018-02-20T10:45:39.059829-05:
      DOI: 10.1002/ana.25187
  • Excess Amyloid beta can be degraded in healthy humans
    • Authors: Arash Sadri
      PubDate: 2018-02-20T03:51:08.76041-05:0
      DOI: 10.1002/ana.25186
  • Reply to “Excess amyloid beta can be degraded in healthy
    • Authors: Brendan P. Lucey; Terry J. Hicks, Donald L. Elbert, Vitaliy Ovod, Kwasi G. Mawuenyega, John C. Morris, Randall J. Bateman
      PubDate: 2018-02-19T11:02:13.611551-05:
      DOI: 10.1002/ana.25185
  • Predicting Recovery in Acute Post-stroke Aphasia
    • Authors: Argye E. Hillis; Yuan Ye Beh, Rajani Sebastian, Bonnie Breining, Donna C. Tippett, Amy Wright, Sadhvi Saxena, Chris Rorden, Leonardo Bonilha, Alexandra Basilakos, Grigori Yourganov, Julius Fridriksson
      Abstract: Objective: Many stroke patients show remarkable recovery of language after initial severe impairment, but it is difficult to predict which patients will show good recovery. We aimed to identify patient and lesion characteristics that together predict the best naming outcome in four studies.Methods: We report two longitudinal studies that identified two variables at onset that were strongly associated with good recovery of naming (the most common residual deficit in aphasia) in the first six months after stroke: damage to left posterior superior temporal gyrus (pSTG) and/or superior longitudinal fasciculus/arcuate fasciculus (SLF/AF) and selective serotonin reuptake inhibitor (SSRI) use. We then tested these variables in two independent cohorts of chronic left hemisphere stroke patients, using chi squared tests and multivariable logistic regression for dichotomous outcomes and t-tests for continuous outcomes.Results: Lesion load in left pSTG and SLF/AF was associated with poorer naming outcome. Preservation of these areas and use of SSRIs were associated with naming recovery, independent of lesion volume, time since stroke, and depression. Patients with damage to these critical areas showed better naming outcome if they took SSRIs for three months after stroke. Those with preservation of these critical areas achieved good recovery of naming regardless of SSRI use.Interpretation: Lesion load in left pSTG and SLF/AF at onset predicts later naming performance. Although based on a small number of patients, our preliminary results suggest outcome might be modulated by SSRIs, but these associations need to be confirmed in a larger randomized controlled trial. This article is protected by copyright. All rights reserved.
      PubDate: 2018-02-16T07:40:27.097328-05:
      DOI: 10.1002/ana.25184
  • [18F]AV-1451 tau-PET and primary progressive aphasia
    • Authors: Keith A. Josephs; Peter R. Martin, Hugo Botha, Christopher G. Schwarz, Joseph R. Duffy, Heather M. Clark, Mary M. Machulda, Jonathan Graff-Radford, Stephen D. Weigand, Matthew L. Senjem, Rene L. Utianski, Daniel A. Drubach, Bradley F. Boeve, David T. Jones, David S. Knopman, Ronald C. Petersen, Clifford R. Jack Jr, Val J. Lowe, Jennifer L. Whitwell
      Abstract: Objectives: To assess [18F]AV-1451 tau-PET uptake patterns across the primary progressive aphasia (PPA) variants (logopenic, semantic and agrammatic), examine regional uptake patterns of [18F]AV-1451 independent of clinical diagnosis, and compare the diagnostic utility of [18F]AV-1451, [18F]-fluorodeoxygluclose (FDG)-PET and MRI to differentiate the PPA variants.Methods: We performed statistical parametric mapping of [18F]AV-1451 across 40 PPA patients (logopenic-PPA=14, semantic-PPA=13 and agrammatic-PPA=13) compared to 80 cognitively normal, PiB-negative controls, age and gender matched 2:1. Principal component analysis of regional [18F]AV-1451 tau-PET SUVR was performed to understand underlying patterns of [18F]AV-1451 uptake independent of clinical diagnosis. Penalized multinomial regression analyses were utilized to assess diagnostic utility.Results: Logopenic-PPA showed striking uptake throughout neocortex, particularly temporoparietal, compared to controls, semantic-PPA and agrammatic-PPA. Semantic-PPA and agrammatic-PPA showed milder patterns of focal [18F]AV-1451 uptake. Semantic-PPA showed elevated uptake (left>right) in anteromedial temporal lobes, compared to controls and agrammatic-PPA. Agrammatic-PPA showed elevated uptake (left>right) throughout prefrontal white matter and in subcortical grey matter structures, compared to controls and semantic-PPA. The principal component analysis of regional [18F]AV-1451 indicated two primary dimensions, a severity dimension that distinguished logopenic-PPA from agrammatic-PPA and semantic-PPA, and a frontal-versus-temporal contrast that distinguishes agrammatic-PPA and semantic-PPA cases. Diagnostic utility of [18F]AV-1451was superior to MRI and at least equal to FDG-PET.Interpretation: [18F]AV-1451binding characteristics differ across the PPA variants, and were excellent at distinguishing between the variants. [18F]AV-1451binding characteristics were as good or better than other brain imaging modalities utilized in clinical practice, suggesting that [18F]AV-1451 may have clinical diagnostic utility in PPA. This article is protected by copyright. All rights reserved.
      PubDate: 2018-02-16T05:50:29.428662-05:
      DOI: 10.1002/ana.25183
  • Diabetic neuropathy differs between type 1 and type 2 diabetes Insights
           from magnetic resonance neurography
    • Authors: Johann M. E. Jende; Jan B. Groener, Dimitrios Oikonomou, Sabine Heiland, Stefan Kopf, Mirko Pham, Peter Nawroth, Martin Bendszus, Felix T. Kurz
      Abstract: Objective: To visualize and quantify differences of microstructural nerve damage in distal symmetric diabetic neuropathy (DPN) between type 1 diabetes (T1D) and type 2 diabetes (T2D), and to detect correlations between neuropathic symptoms and serological risk factors.Methods: 3T magnetic resonance neurography of the sciatic nerve was performed in 120 patients (T1D n=35; T2D n=85) with either DPN (n=84) or no DPN (NDPN; n=36). Results were subsequently correlated with clinical, serological, and electrophysiological patient data.Results: T2-weighted (T2w) hyperintense lesions correlated negatively with tibial compound motor action potential (r=-0.58; p
      PubDate: 2018-02-14T11:30:27.260182-05:
      DOI: 10.1002/ana.25182
  • Conscious control of breathing: A key to SUDEP prevention'
    • Authors: Tobias Loddenkemper
      PubDate: 2018-02-08T16:10:27.547202-05:
      DOI: 10.1002/ana.25177
  • Amygdala stimulation-induced apnea is attention and nasal-breathing
    • Authors: William P Nobis; Stephen Schuele, Jessica W Templer, Guangyu Zhou, Gregory Lane, Joshua M Rosenow, Christina Zelano
      Abstract: Objective:Evidence suggests disordered breathing is critically involved in Sudden unexplained death in epilepsy (SUDEP). To that end, evaluating structures that are activated by seizures and can activate brain regions that produce cardiorespiratory changes can further our understanding of the pathophysiology of SUDEP. Prior preclinical studies have shown that electrical stimulation of the human amygdala induces apnea, suggesting a role for the amygdala in controlling respiration. In this study, we aimed to both confirm these findings in a larger group of patients with intractable temporal lobe epilepsy (TLE) and also further explore the anatomical and cognitive properties of this effect.Methods:Seven surgical TLE patients had depth electrodes implanted in the amygdala that were used to deliver electrical stimulation during functional mapping prior to resection. Real-time respiratory monitoring was performed in each patient to confirm apnea.Results:Our data confirm that amygdala stimulation reliably induces apnea (occurring in all seven patients) and further suggest that apnea can be overcome by instructing the patient to inhale, and can be prevented entirely by breathing through the mouth prior to electrical stimulation. Finally, stimulation induced apnea occurred only when stimulating the medial most amygdalar contacts located in the central nucleus.Interpretation:These findings confirm a functional connection between the amygdala and respiratory control in humans. Moreover, they suggest specific amygdalar nuclei may be critical in mediating this effect and that attentional state is critical to apnea mediated by amygdala activation - perhaps alluding to future development of strategies for the prevention of SUDEP. This article is protected by copyright. All rights reserved.
      PubDate: 2018-02-08T16:10:22.459585-05:
      DOI: 10.1002/ana.25178
  • Do subjects with minimal motor features have prodromal PD'
    • Authors: Yaping Chu; Aron S Buchman, C.W. Olanow, Jeffrey H. Kordower
      Abstract: Background: Understanding the pathological changes underlying mild motor features of the eldery and defining a patient population with prodromal Parkinson's disease (PD) are of great clinical importance. It remains unclear, however, how to accurately and specifically diagnose prodromal PD. We examined whether older adults with minimal parkinsonian motor features have nigrostriatal degeneration and α-synuclein pathology consistent with prodromal PD.Methods: Brain sections were obtained from older adults with a clinical diagnosis of PD (N=21) and without a clinical diagnosis of PD (N=27) who underwent motor examination proximate to death. Cases without PD were further dichotomized into no motor deficit (n=9) or minimal motor features (n-18) groups using a modified Unified Parkinson's Disease Rating Scale. We performed quantitative unbiased stereological analyses of dopaminergic neurons/terminals and α-synuclein accumulation in the nigrostriatal system.Results: In all subjects with minimal motor features, there were significant reductions in dopaminergic neurons and terminals in the substantia nigra and putamen that was intermediate between subjects with no motor deficit and PD. Phosphorylated α-synuclein inclusions were observed in the substantia nigra that were of similar density to what was seen in PD. Furthermore, there was greater Lewy neuritic pathology in the putamen relative to PD patients. Lastly, neurons with α-synuclein inclusions displayed reductions in tyrosine hydroxylase expression that was comparable in subjects with both minimal motor features and PD.Interpretation: Minimal motor features in older adults may represent prodromal PD and identify at risk individuals for testing putative neuroprotective interventions that could slow or prevent PD progression. This article is protected by copyright. All rights reserved.
      PubDate: 2018-02-08T16:06:07.286055-05:
      DOI: 10.1002/ana.25179
  • Stereotactic Laser Amygdalohippocampotomy for Mesial Temporal Lobe
    • Authors: Robert E. Gross; Matthew A. Stern, Jon T. Willie, Rebecca E. Fasano, Amit M. Saindane, Bruno P. Soares, Nigel P. Pedersen, Daniel L. Drane
      Abstract: Objective: To evaluate the outcomes one-year and longer following stereotactic laser amygdalohippocampotomy for mesial temporal lobe epilepsy in a large series of patients treated over a five-year period since introduction of this novel technique.Methods: Surgical outcomes of a consecutive series of fifty-eight patients with mesial temporal lobe epilepsy who underwent the surgery at our institution with at least 12-months follow-up were retrospectively evaluated. A subgroup analysis was performed comparing patients with and without mesial temporal sclerosis.Results: One-year following stereotactic laser amygdalohippocampotomy 53.4% (95% confidence interval: 40.8%-65.7%) of all patients were free of disabling seizures (Engel 1). Three of nine patients became seizure free following repeat ablation. Subgroup analysis showed that 60.5% (95% confidence interval: 45.6%-73.7%) of patients with mesial temporal sclerosis were free of disabling seizures as compared to 33.3% (95% confidence interval: 15.0%-58.5%) of patients without mesial temporal sclerosis. Quality of Life in Epilepsy-31 scores significantly improved at the group level, few procedure-related complications were observed, and verbal memory outcome was better than historical open resection data.Interpretation: In an unselected consecutive series of patients, stereotactic laser amygdalohippocampotomy yielded seizure-free rates for patients with mesial temporal lobe epilepsy lower than, but comparable to, the outcomes typically associated with open temporal lobe surgery. Analogous to results from open surgery, patients without mesial temporal sclerosis fared less well. This novel procedure is an effective minimally invasive alternative to resective surgery. In the minority of patients not free of disabling seizures, laser ablation presents no barrier to additional open surgery. This article is protected by copyright. All rights reserved.
      PubDate: 2018-02-08T16:06:03.630038-05:
      DOI: 10.1002/ana.25180
  • High complement levels in astrocyte-derived exosomes of Alzheimer's
    • Authors: Edward J. Goetzl; Janice B. Schwartz, Erin L. Abner, Gregory A. Jicha, Dimitrios Kapogiannis
      Abstract: Objective: Astrocytes fulfill neuronal trophic roles normally, but are transformed in Alzheimer's disease (AD) into A1-type reactive astrocytes that may destroy neurons through unknown mechanisms. Methods: To investigate astrocyte inflammatory mechanisms, astrocyte-derived exosomes (ADEs) were isolated immunochemically from plasmas of AD patients and matched controls for ELISA quantification of complement proteins. Results: ADE levels of C1q, C4b, C3d, factor B, factor D, Bb, C3b and C5b-C9 terminal complement complex (TCC), but not mannose-binding lectin (MBL), normalized by the CD81 exosome marker were significantly higher for AD patients (n=28) than age- and gender-matched controls (all p
      PubDate: 2018-02-06T10:50:31.471229-05:
      DOI: 10.1002/ana.25172
  • N-methyl-D-aspartate receptor antibody production from germinal center
           reactions: therapeutic implications
    • Authors: Mateusz Makuch; Robert Wilson, Adam Al-Diwani, James Varley, Anne-Katrin Kienzler, Jennifer Taylor, Antonio Berretta, Darren Fowler, Belinda Lennox, M Isabel Leite, Patrick Waters, Sarosh R Irani
      Abstract: IntroductionN-methyl-D-aspartate receptor (NMDAR)-antibody encephalitis is mediated by IgG-autoantibodies directed against the NR1-subunit of the NMDAR. Around 20% of patients have an underlying ovarian teratoma, and the condition responds to early immunotherapies and ovarian teratoma removal. However, despite clear therapeutic relevance, mechanisms of NR1-IgG production and the contribution of germinal center B cells to NR1-IgG levels are unknown.MethodsClinical data and longitudinal paired serum NR1-reactive IgM and IgG levels from ten patients with NMDAR-antibody encephalitis were determined. Peripheral blood mononuclear cells from these ten patients, and two available ovarian teratomas, were stimulated with combinations of immune factors, and tested for secretion of total IgG and NR1-antibodies.ResultsIn addition to disease-defining NR1-IgG, serum NR1-IgM were found in 6/10 patients. NR1-IgM levels were typically highest around disease onset, and detected for several months into the disease course. Moreover, circulating patient B cells were differentiated into CD19+CD27++CD38++ antibody-secreting cells in vitro and, in 90% of patients, secreted NR1-IgM and NR1-IgG. Secreted levels of NR1-IgG correlated with serum NR1-IgG (p
      PubDate: 2018-02-06T10:50:21.926682-05:
      DOI: 10.1002/ana.25173
  • Predicting clinical diagnosis in Huntington's disease: An imaging
    • Authors: Sarah L Mason; Richard E Daws, Eyal Soreq, Eileanoir B Johnson, Rachael I Scahill, Sarah J Tabrizi, Roger A Barker, Adam Hampshire
      Abstract: Objective: Huntington's disease (HD) gene-carriers can be identified prior to clinical diagnosis; however, statistical models for predicting when overt motor symptoms will manifest are too imprecise to be useful at the level of the individual. Perfecting this prediction is integral to the search for disease modifying therapies. This study aimed to identify an imaging marker capable of reliably predicting real-life clinical diagnosis in HD.Method: A multivariate machine learning approach was applied to resting-state and structural MRI scans from 19 pre-manifest HD gene carriers (preHD, 8 of whom developed clinical disease in the 5 years post-scanning) and 21 healthy controls. A classification model was developed using cross-group comparisons between preHD and controls, and within the preHD group in relation to “estimated” and “actual” proximity to disease onset. Imaging measures were modelled individually, and combined, and permutation modelling robustly tested classification accuracy.Results: Classification performance for preHDs vs. controls was greatest when all measures were combined. The resulting polymarker predicted converters with high accuracy including those who were not expected to manifest in that timescale based on the currently adopted statistical models.Interpretation: We propose that a holistic multivariate machine learning treatment of brain abnormalities in the premanifest phase can be used to accurately identify those patients within 5 years of developing motor features of Huntington's disease, with implications for prognostication and preclinical trials. This article is protected by copyright. All rights reserved.
      PubDate: 2018-02-05T11:30:25.23507-05:0
      DOI: 10.1002/ana.25171
  • Orthostatic Heart Rate Changes in Patients with Autonomic Failure caused
           by Neurodegenerative Synucleinopathies
    • Authors: Lucy Norcliffe-Kaufmann; Horacio Kaufmann, Jose-Alberto Palma, Cyndya A. Shibao, Italo Biaggioni, Amanda C. Peltier, Wolfgang Singer, Phillip A. Low, David S. Goldstein, Christopher H. Gibbons, Roy Freeman, David Robertson,
      Abstract: Objective: Blunted tachycardia during hypotension is a characteristic feature of patients with autonomic failure, but the range has not been defined. This study reports the range of orthostatic heart rate (HR) changes in patients with autonomic failure caused by neurodegenerative synucleinopathies.Methods: Patients evaluated at sites of the U.S. Autonomic Consortium (NCT01799915) underwent standardized autonomic function tests and full neurological evaluation.Results: We identified 402 patients with orthostatic hypotension (OH) who had normal sinus rhythm. Of these, 378 had impaired sympathetic activation, i.e., neurogenic OH, and based on their neurological examination were diagnosed with Parkinson disease, dementia with Lewy bodies, pure autonomic failure or multiple system atrophy. The remaining 24 patients had preserved sympathetic activation and their OH was classified as non-neurogenic, due to volume depletion, anemia or polypharmacy. Patients with neurogenic OH had twice the fall in systolic blood pressure (SBP) [-44±25 vs. -21±14 mmHg (mean±SD), p
      PubDate: 2018-02-05T10:50:27.819931-05:
      DOI: 10.1002/ana.25170
  • Activation of pial and dural macrophages and dendritic cells by CSD (67
    • Authors: Aaron J. Schain; Agustin Melo-Carrillo, David Borsook, Jaime Grutzendler, Andrew M. Strassman, Rami Burstein
      Abstract: Objective:Cortical spreading depression (CSD) has long been implicated in migraine attacks with aura. The process by which CSD, a cortical event that occurs within the blood brain barrier (BBB), results in nociceptor activation outside the BBB is likely mediated by multiple molecules and cells. The objective of this study was to determine whether CSD activates immune cells inside the BBB (pia), outside the BBB (dura), or in both, and if so, when.Methods:Investigating cellular events in the meninges shortly after CSD, we used in-vivo 2-photon imaging to identify changes in macrophages and dendritic cells (DC) that reside in the pia, arachnoid, and dura, and their anatomical relationship to TRPV1 axons.Results:We found that activated meningeal macrophages retract their processes and become circular, and that activated meningeal DC stop migrating. We found that CSD activates pial macrophages instantaneously, pial, subarachnoid and dural DC 6-12 minutes later, and dural macrophages 20 minutes later. Dural macrophages and DC can appear in close proximity to TRPV1-positive axons.Interpretation:The findings suggest that activation of pial macrophages may be more relevant to cases where aura and migraine begin simultaneously, that activation of dural macrophages may be more relevant to cases where headache begins 20-30 minutes after aura, and that activation of dural macrophages may be mediated by activation of migratory DC in the SAS and dura. The anatomical relationship between TRPV1-positive meningeal nociceptors, and dural macrophages and dendritic cells support a role for these immune cells in the modulation of head pain. This article is protected by copyright. All rights reserved.
      PubDate: 2018-02-02T18:00:30.371023-05:
      DOI: 10.1002/ana.25169
  • Rivaroxaban plasma levels in acute ischemic stroke and intracerebral
    • Authors: David J. Seiffge; Georg Kägi, Patrik Michel, Urs Fischer, Yannick Béjot, Susanne Wegener, Marialuisa Zedde, Guillaume Turc, Charlotte Cordonnier, Peter S. Sandor, Gilles Rodier, Andrea Zini, Manuel Cappellari, Sabine Schädelin, Alexandros A. Polymeris, David Werring, Sebastian Thilemann, Ilaria Maestrini, Eivind Berge, Christopher Traenka, Jochen Vehoff, Gian Marco De Marchis, Monika Kapauer, Nils Peters, Gaia Sirimarco, Leo H. Bonati, Marcel Arnold, Philippe A. Lyrer, Emmanuel De Maistre, Andreas Luft, Dimtrios A. Tsakiris, Stefan T. Engelter,
      Abstract: Objective:Information about Rivaroxaban plasma levels (RivLev) may guide treatment decisions in patients with acute ischemic stroke (AIS) and intracerebral hemorrhage (ICH) taking rivaroxaban.Methods:In a multicenter registry-based study (Novel-Oral-Anticoagulants-In-Stroke-Patients collaboration;NOACISP; of patients with stroke while taking rivaroxaban, we compared RivLev in patients with AIS and ICH. We determined how many AIS-patients had RivLev≤100ng/ml, indicating possible eligibility for thrombolysis and how many ICH-patients had RivLev≥75ng/ml, possibly eligible for the use of specific reversal agents. We explored factors associated with RivLev (Spearman correlation; regression models) and studied the sensitivity and specificity of INR-thresholds to substitute RivLevs using cross tables and ROC curves.Results:Among 241 patients (median age 80 years[IQR73-84], median time-from-onset-to-admission 2 hours[IQR1-4.5hours], median RivLev 89ng/ml[31-194]), 190 had AIS and 51 had ICH. RivLev were similar in AIS-patients (82ng/ml[IQR30-202] and ICH-patients (102ng/ml[IQR 51-165]; p=0.24). Trough RivLev(≤137ng/ml) occurred in 126/190 (66.3%) AIS- and 34/51 (66.7%) ICH-patients. Among AIS-patients, 108/190 (56.8%) had RivLev≤100ng/ml. In ICH-patients 33/51(64.7%) had RivLev≥75ng/ml. RivLev were associated with rivaroxaban dosage, inversely with renal function and time-since-last-intake (each p
      PubDate: 2018-02-02T17:57:20.321495-05:
      DOI: 10.1002/ana.25165
  • Sleep and Cognitive Decline: A Prospective Non-demented Elderly Cohort
    • Authors: Seung Wan Suh; Ji Won Han, Ju Ri Lee, Seonjeong Byun, Soon Jai Kwon, Sang Hoon Oh, Kyoung Hwan Lee, Guehee Han, Jong Woo Hong, Kyung Phil Kwak, Bong-Jo Kim, Shin Gyeom Kim, Jeong Lan Kim, Tae Hui Kim, Seung-Ho Ryu, Seok Woo Moon, Joon Hyuk Park, Jiyeong Seo, Jong Chul Youn, Dong Young Lee, Dong Woo Lee, Seok Bum Lee, Jung Jae Lee, Jin Hyeong Jhoo, Ki Woong Kim
      Abstract: Objective: To investigate sleep disturbances that induce cognitive changes over four years in non-demented elderlies.Methods: Data were acquired from a nationwide, population-based, prospective cohort of Korean elderlies (2,238 normal cognition [NC] and 655 mild cognitive impairment [MCI]). At baseline and 4-year follow up assessments, sleep-related parameters (mid-sleep time, sleep duration, latency, subjective quality, efficiency and daytime dysfunction) and cognitive status were measured using Pittsburgh Sleep Quality Index and Consortium to Establish a Registry for Alzheimer's Disease Assessment, respectively. We used logistic regression models adjusted for covariates including age, sex, education, apolipoprotein E genotype, Geriatric Depression Scale, Cumulative Illness Rating Scale, and physical activity.Results: In participants with NC, long sleep latency (> 30 min), long sleep duration (≥ 7.95 hr), and late mid-sleep time (after 3:00AM) at baseline were related to the risk of cognitive decline at 4-year follow-up assessment; odds ratio (OR) was 1.40 for long sleep latency, 1.67 for long sleep duration, and 0.61 for late mid-sleep time. These relationships remained significant when these variables maintained their status throughout the follow-up period. Newly developed long sleep latency also doubled the risk of cognitive decline. In those with MCI, however, only long sleep latency reduced the chance of reversion to NC (OR = 0.69).Interpretation: As early markers of cognitive decline, long sleep latency can be used for elderlies with NC or MCI, while long sleep duration and relatively early sleep time might be used for cognitively normal elderlies only. This article is protected by copyright. All rights reserved.
      PubDate: 2018-02-02T17:56:48.678496-05:
      DOI: 10.1002/ana.25166
  • Mutations in MICAL-1 cause autosomal dominant lateral temporal epilepsy
    • Authors: Emanuela Dazzo; Kati Rehberg, Roberto Michelucci, Daniela Passarelli, Clementina Boniver, Valeria Vianello Dri, Pasquale Striano, Salvatore Striano, R. Jeroen Pasterkamp, Carlo Nobile
      Abstract: Objective: Autosomal dominant lateral temporal epilepsy (ADLTE) is a genetic focal epilepsy characterized by auditory symptoms. Two genes, LGI1 and RELN, encoding secreted proteins, are implicated in the etiology of ADLTE, but half of the affected families remain genetically unsolved, and the underlying molecular mechanisms are yet to be clarified. We aimed to identify additional genes causing ADLTE to better understand the genetic basis and molecular pathway underlying this epileptic disorder.Methods: A cohort of Italian ADLTE families was examined by whole exome sequencing combined with genome-wide single nucleotide polymorphism-array linkage analysis.Results: We identified two ADLTE-causing variants in the MICAL-1 gene: a p.Gly150Ser substitution occurring in the enzymatically active monooxygenase (MO) domain, and a p.Ala1065fs frameshift indel in the C-terminal domain, which inhibits the oxidoreductase activity of the MO domain. Each variant segregated with ADLTE in a single family. Examination of candidate variants in additional genes excluded their implication in ADLTE. In cell-based assays, both variants significantly increased MICAL-1 oxidoreductase activity and induced cell contraction in COS7 cells, which likely resulted from deregulation of F-actin dynamics.Interpretation: MICAL-1 oxidoreductase activity induces disassembly of actin filaments, thereby regulating the organization of the actin cytoskeleton in developing and adult neurons and in other cell types. This suggests that dysregulation of the actin cytoskeleton dynamics is a likely mechanism by which MICAL-1 pathogenic variants lead to ADLTE. This article is protected by copyright. All rights reserved.
      PubDate: 2018-02-02T17:56:15.582253-05:
      DOI: 10.1002/ana.25167
  • Increase of HCN current in the aberrant excitability of spinal muscular
    • Authors: Hsing-Jung Lai; Chien-Lin Chen, Li-Kai Tsai
      Abstract: ObjectiveThe pathophysiology of spinal muscular atrophy (SMA) is still unclear.MethodsThe nerve excitability test in SMA patients and a mouse model of SMA was carried out to explore the pathophysiology of nodal and internodal currents, and quantitative PCR, Western blotting and whole-cell patch-clamp recording were used for the identified hypothesis.ResultsThe nerve excitability test in SMA patients showed increased inward rectification in the current-threshold relationship and increased overshoot after hyperpolarizing threshold electrotonus, which indicates increased hyperpolarization-activated cyclic nucleotide-gated (HCN) current; these findings correlated with disease severity. Increased inward rectification in the current-threshold relationship was reproducible in a mouse model of mild SMA and the abnormality preceded the decline of compound motor action potential amplitudes. Furthermore, quantitative PCR of spinal cord tissues and Western blotting of the spinal cord and sciatic nerves showed increased HCN1 and HCN2 expression in the SMA mice, and voltage-clamp recording in dissociated spinal motor neurons from SMA mice also showed increased HCN current density. Treatment with ZD7288, an HCN channel blocker, also reduced early mortality, improved motor function, and restored neuromuscular junction architecture in a mouse model of severe SMA.InterpretationThis study shows that increased HCN current underlies the pathophysiology of SMA and can be a novel non-SMN-target for SMA therapy. This article is protected by copyright. All rights reserved.
      PubDate: 2018-02-02T17:56:04.869285-05:
      DOI: 10.1002/ana.25168
  • When less is more (brain)—Comment on “Rivaroxaban plasma levels in
           acute ischemic stroke and intracerebral hemorrhage”
    • Authors: Patrick D. Lyden
      PubDate: 2018-02-02T17:56:02.06386-05:0
      DOI: 10.1002/ana.25163
  • Cortical Perception
    • Authors: David B. Rosenfield
      PubDate: 2018-02-02T17:55:59.676382-05:
      DOI: 10.1002/ana.25162
  • Interpreting Alzheimer's disease polygenic scores
    • Authors: Chin Hong Tan; Rahul S. Desikan
      PubDate: 2018-02-02T17:55:51.041556-05:
      DOI: 10.1002/ana.25164
  • Reply to “A novel mutation in the TM6 domain of GABBR2 leads to a
           Rett-like phenotype”
    • Authors: Yongjin Yoo; Jaeso Cho, Murim Choi
      PubDate: 2018-01-29T10:50:51.771917-05:
      DOI: 10.1002/ana.25154
  • A novel mutation in the TM6 domain of GABBR2 leads to a Rett-like
    • Authors: M.L. Vuillaume; M. Jeanne, L. Xue, S. Blesson, A.S. Denommé-Pichon, S. Alirol, C. Brulard, E. Colin, B. Isidor, B. Gilbert-Dussardier, S. Odent, P. Parent, A. Donnart, R. Redon, S. Bézieau, P. Rondard, F. Laumonnier, A. Toutain
      PubDate: 2018-01-25T11:20:28.668514-05:
      DOI: 10.1002/ana.25155
  • Gamma-glutamyl transferase predicts future stroke: a Korean nationwide
    • Authors: Wookjin Yang; Chi Kyung Kim, Do Yeon Kim, Han-Gil Jeong, Seung-Hoon Lee
      Abstract: Objective: Although gamma-glutamyl transferase (GGT) is generally regarded as an alternative biomarker for alcohol consumption, its independent role in vascular diseases emerged recently. However, its role in stroke remains unknown. The aim of this study is to clarify the impact of GGT on stroke in a large-sized, national, standardized population cohort in Korea.Methods: In Korea, the National Health Insurance Service (NHIS) provides full-coverage health insurance service for all citizens. Using data from the NHIS, the NHIS-National Sample Cohort (NHIS-NSC) was designed by randomly selecting 2% of Koreans, carefully considering demographic characteristics. We analyzed eligible individuals from this standardized cohort. The Cox proportional hazards model was used for the longitudinal study investigating the relationship between GGT and stroke.Results: Among the 456,100 eligible participants, 7,459 patients (1.64%) developed stroke as follows: 5,789 ischemic strokes, 1,046 intracerebral hemorrhages (ICHs), and 624 subarachnoid hemorrhages. GGT was independently correlated with increased risk of stroke after adjustment for alcohol consumption and stroke risk factors (hazard ratio (HR), 1.39; 95% confidence interval (CI), 1.29–1.51). The risks of both ischemic stroke (HR, 1.45; 95% CI, 1.32–1.58) and ICH (HR, 1.46; 95% CI, 1.18–1.80) were significantly elevated with increasing GGT. Despite some effect modifications by sex, age and alcohol, the risk of total stroke and ischemic stroke in association with GGT remained significant in all subgroups.Interpretation: In a standard Korean population, GGT was a novel biomarker predicting stroke risk, independently from alcohol consumption and other risk factors. This article is protected by copyright. All rights reserved.
      PubDate: 2018-01-25T11:20:23.876175-05:
      DOI: 10.1002/ana.25158
  • Pallidal deep brain stimulation modulates cortical excitability and
    • Authors: Zhen Ni; Sang Jin Kim, Nicolas Phielipp, Soumya Ghosh, Kaviraja Udupa, Carolyn A. Gunraj, Utpal Saha, Mojgan Hodaie, Suneil K. Kalia, Andres M. Lozano, Darrin J. Lee, Elena Moro, Alfonso Fasano, Mark Hallett, Anthony E. Lang, Robert Chen
      Abstract: Objective: Internal globus pallidus (GPi) deep brain stimulation (DBS) relieves symptoms in dystonia patients. However, the physiological effects produced by GPi DBS are not fully understood. In particular, how a single-pulse GPi DBS changes cortical circuits has never been investigated. We studied the modulation of motor cortical excitability and plasticity with single-pulse GPi DBS in dystonia patients with bilateral implantation of GPi DBS.Methods: The cortical evoked potentials from DBS were recorded with electroencephalography. Transcranial magnetic stimulation with a conditioning-test paired-pulse paradigm was used to investigate the effect of GPi DBS on the primary motor cortex. How GPi DBS might modulate the motor cortical plasticity was tested using a paired associative stimulation paradigm with repetitive pairs of GPi DBS and motor cortical stimulation at specific time intervals.Results: GPi stimulation produced two peaks of cortical evoked potentials with latencies of ∼10 and ∼25 ms in the motor cortical area. Cortical facilitation was observed at ∼10 ms after single-pulse GPi DBS and cortical inhibition was observed at ∼25 ms interval. Repetitive pairs of GPi stimulation with cortical stimulation at these two time intervals produced long term potentiation-like effects in the motor cortex.Interpretation: Single-pulse DBS modulates cortical excitability and plasticity at specific time intervals. These effects may be related to the mechanism of action of DBS. Combination of DBS with cortical stimulation at appropriate timing has therapeutic potential and could be explored in the future as a method to enhance the effects of neuromodulation for neurological and psychiatric diseases. This article is protected by copyright. All rights reserved.
      PubDate: 2018-01-25T11:15:49.619536-05:
      DOI: 10.1002/ana.25156
  • Parkinson's disease and the risk of epileptic seizures
    • Authors: Katharina Gruntz; Marlene Bloechliger, Claudia Becker, Susan S Jick, Peter Fuhr, Christoph R Meier, Stephan Rüegg
      Abstract: ObjectiveTo assess the association between incident Parkinson's disease (PD) and subsequent incident epileptic seizures.MethodsWe conducted a retrospective cohort study with a nested case-control analysis using data from the UK Clinical Practice Research Datalink. We identified patients aged ≥40 years with an incident diagnosis of PD between 1995 and 2016 and a matched comparison group of PD-free individuals. We calculated crude incidence rates (IRs) with 95% confidence intervals (CIs) of epileptic seizures in PD patients and the PD-free comparison group, and corresponding crude incidence rate ratios (IRRs). In the nested case-control analysis, we calculated adjusted odds ratios (adj. ORs) of incident PD among cases with incident epileptic seizures and seizure-free controls overall and stratified by various, seizure-provoking comorbidities.ResultsAmong 23,086 incident PD patients and 92,343 PD-free individuals, we identified 898 patients with incident epileptic seizures. The crude IR of epileptic seizures in PD patients was 266.7/100,000 person years (95% CI 235.6-297.7), and in PD-free individuals 112.4/100,000 person years (95% CI 103.5-121.3) [IRR: 2.37, 95% CI 2.06-2.37]. The adj. OR of epileptic seizures was 1.68 [95% CI 1.43-1.98]) in PD patients compared with PD-free individuals. PD patients with comorbid brain disorders (adj. OR 12.36 [95% CI 8.74-17.48]) or with>1 seizure-provoking comorbidity (adj. OR 13.24 [95% CI 10.15-17.25]) were at the highest risk of epileptic seizures compared with PD-free individuals with no seizure-provoking comorbidities.InterpretationThis study suggests that incident PD is associated with an increased risk of incident epileptic seizures. This article is protected by copyright. All rights reserved.
      PubDate: 2018-01-25T11:15:44.906384-05:
      DOI: 10.1002/ana.25157
  • Neutrophil hyperactivation correlates with Alzheimer's disease progression
    • Authors: Yuan Dong; Julien Lagarde, Laura Xicota, Hélène Corne, Yannick Chantran, Thomas Chaigneau, Bruno Crestani, Michel Bottlaender, Marie-Claude Potier, Pierre Aucouturier, Guillaume Dorothée, Marie Sarazin, Carole Elbim
      Abstract: Objective: Recent studies have underlined the effect of systemic inflammation on the pathophysiology of Alzheimer's disease. Neutrophils are key components of early innate immunity and contribute to uncontrolled systemic inflammation if not tightly regulated. The aim of our study was to fully characterize human circulating neutrophils at different disease stages in Alzheimer's disease.Methods: We analyzed neutrophil phenotypes and functions in forty-two patients with Alzheimer's disease (sixteen with mild cognitive impairment and twenty-six with dementia), and compared them with twenty-two age-matched healthy subjects. This study was performed directly in whole blood to avoid issues with data interpretation related to cell isolation procedures.Results: Blood samples from Alzheimer's diseases patients with dementia revealed neutrophil hyperactivation associated with increased reactive oxygen species production and increased levels of intravascular neutrophil extravascular traps. The homeostasis of circulating neutrophils in these patients also changed: the ratio between the harmful hyperreactive CXCR4high/CD62Llow senescent and the CD16bright/CD62Ldim immunosuppressive neutrophil subsets rose in the later stage of the disease. These abnormalities were greater in fast-decliner than in slow-decliner patients.Interpretation: Our results indicate that the inflammatory properties of circulating neutrophils shift as the percentage of aged neutrophils expands in patients with Alzheimer's disease — changes that may play an instrumental role in establishing systemic chronic inflammation. Most important, our data strongly suggest that the neutrophil phenotype may be associated with the rate of cognitive decline and may thus constitute an innovative and prognostic blood biomarker in patients with Alzheimer's disease. This article is protected by copyright. All rights reserved.
      PubDate: 2018-01-25T11:15:42.986187-05:
      DOI: 10.1002/ana.25159
  • Metallothioneins are Neuroprotective Agents in Lysosomal Storage Disorders
    • Authors: Eleonora Cavalca; Martina Cesani, Jennifer Gifford, Miguel Sena Esteves, Maria Rosa Terreni, Giuseppe Leoncini, Marco Peviani, Alessandra Biffi
      Abstract: Objective: Lysosomal Storage Disorders (LSDs) are a broad class of inherited metabolic diseases caused by the defective activity of lysosomal enzymes. Central nervous system (CNS) manifestations are present in roughly 50% of LSD patients and represent an unmet medical need for them. We explored the therapeutic potential of Metallothioneins (MTs), a newly identified family of proteins with reported neuroprotective roles, in the murine models of two LSDs with CNS involvement.Methods: MT-1 over-expressing transgenic mice (MTtg) were crossed with the murine models of Batten and Krabbe diseases. Changes in the survival and in the manifestations of the disease in the MTtg setting were assessed. In addition, we analyzed the therapeutic effects of MT-1 CNS gene delivery in one of these LSD models.Results: Constitutive expression of MT-1 exerted favorable phenotypic effects in both LSD models. MT-LSD mice showed a 5-10% increase in survival and slower disease progression as compared to not-transgenic LSD mice. Rescue of Purkinje cells from degeneration and apoptosis was also observed in the MT- LSD models. This phenotypic amelioration was accompanied by a modulation of the disease-associated activated inflammatory microglia phenotype, and by a reduction of oxidative stress. Importantly for the clinical translation of our findings, the very same effects were obtained when MTs were delivered to the brains by systemic AAV gene transfer.Interpretation: MTs can be considered novel therapeutic agents (and targets) in LSDs and potentiate the effects of approaches aiming at correction of the disease-causing enzyme deficiency in the CNS. This article is protected by copyright. All rights reserved.
      PubDate: 2018-01-25T11:15:36.513889-05:
      DOI: 10.1002/ana.25161
  • Expression profiling suggests microglial impairment in HIV
    • Authors: Stephen D. Ginsberg; Melissa J. Alldred, Satya M. Gunnam, Consuelo Schiroli, Sang Han Lee, Susan Morgello, Tracy Fischer
      Abstract: Objective: CD16+/CD163+ macrophages (MΦ)s and microglia accumulate in the brains of patients with HIV encephalitis (HIVE), a neuropathological correlate of the most severe form of HIV-associated neurocognitive disorders (HAND), HIV-associated dementia (HIV-D). Recently, we found that some parenchymal microglia in brain of HIV+ subjects without encephalitis (HIV/noE) but with varying degrees of neurocognitive impairment express CD16 and CD163, even in the absence of detectable virus production. To further our understanding of microglial activation in HIV, we investigated expression of specific genes by profiling parenchymal microglia from archival brain tissue of patients with HIVE, HIV/noE, and HIV- controls.Methods: Single-population microarray analyses were performed on ∼2,500 laser capture microdissected CD163+, CD16+ or CD68+ MΦs/microglia per case, using terminal continuation (TC) RNA amplification and a custom-designed array platform.Results: Several classes of microglial transcripts in HIVE and HIV/noE, were altered, relative to HIV- subjects, including factors related to cell stress, immune activation, and apoptosis. Additionally, several neurotrophic factors are reduced in HIV infection, suggesting an additional mechanism of neuropathogenesis. The majority of transcripts altered in HIVE displayed intermediate changes in HIV/noE.Interpretation: Our results support the notion that microglia contribute to the maintenance of brain homeostasis and their potential loss of function in the context of chronic inflammation contributes to neuropathogenesis. Furthermore, they indicate the utility of profiling MΦs/microglia to increase our understanding of microglia function, as well as ascertain alterations in specific pathways, genes, and, ostensibly, encoded proteins that may be amenable to targeted treatment modalities in diseases affecting the brain. This article is protected by copyright. All rights reserved.
      PubDate: 2018-01-25T11:15:22.595566-05:
      DOI: 10.1002/ana.25160
  • Diagnostic criteria for disorders of arousal: A video-polysomnography
    • Authors: Régis Lopez; Yun Shen, Sofiene Chenini, Anna Laura Rassu, Elisa Evangelista, Lucie Barateau, Isabelle Jaussent, Yves Dauvilliers
      Abstract: Study objectives:To assess video-polysomnographic (vPSG) criteria and their cut-off values for the diagnosis of disorders of arousal (DOA; sleepwalking, sleep terror).Methods:One hundred and sixty adult patients with DOA and 50 sex- and age-matched healthy participants underwent a clinical evaluation and vPSG assessment to quantify slow wave sleep (SWS) interruptions (SWS fragmentation index; slow/mixed and fast arousal ratios and indexes per hour) and the associated behaviors. First, a case-control analysis was performed in 100 patients and the 50 controls to define the optimal cut-off values using receiver operating characteristic curves. Their sensitivity was then assessed in the other 60 patients with DOA.Results:The SWS fragmentation index and the mixed, slow, slow/mixed arousal indexes and ratios were higher in patients with DOA than controls. The highest area under the curve (AUC) values were obtained for the SWS fragmentation and slow/mixed arousal indexes (AUC = 0.88 and 0.90, respectively). The SWS fragmentation index cut-off value of 6.8/h reached a sensitivity of 79% and a specificity of 82%. The slow/mixed arousal index had a sensitivity of 94% for the 2.5/h cut-off, and 100% specificity for 6/h. Both parameters showed good inter-rater agreement, and their sensitivities were confirmed in the second group of patients. Combining EEG parameters and video-based behavioral analyses increased the correct classification rate up to 91.3%.Conclusion:Frequent slow/mixed arousals in SWS and complex behaviors during vPSG are strongly associated with DOA, and could be promising biomarkers for the diagnosis of non-REM parasomnias. This article is protected by copyright. All rights reserved.
      PubDate: 2018-01-23T11:41:14.728189-05:
      DOI: 10.1002/ana.25153
  • A Mendelian form of neural tube defect caused by a de novo null variant in
           SMARCC1 in an identical twin
    • Authors: Fuad Al Mutairi; Fatema Alzahrani, Farouq Ababneh, Amna A Kashgari, Fowzan S Alkuraya
      Abstract: Neural tube defects (NTD) are among the most common birth defects in humans and yet their molecular etiology remains poorly understood. NTD are believed to result from the complex interaction of environmental factors with a multitude of genetic risk factors in a classical multifactorial disease model. Mendelian forms of NTD in which single variants are sufficient to cause the disease are extremely rare. We report a monozygotic twin with severe NTD (occipital encephalocele and myelomeningocele) and a shared de novo likely truncating variant in SMARCC1. RTPCR analysis suggests the potential null nature of the variant due to NMD. SMARCC1 is extremely constrained in humans and encodes a highly conserved core chromatin remodeler BAF155. Mice that are heterozygous for a null allele or homozygous for a hypomorphic allele develop severe NTD in the form of exencephaly. This is the first report of SMARCC1 mutation in humans and it shows a critical and conserved requirement for intact BAF chromatin remodeling complex in neurulation. This article is protected by copyright. All rights reserved.
      PubDate: 2018-01-23T11:40:31.8075-05:00
      DOI: 10.1002/ana.25152
  • Randomized trial of transcranial DC stimulation for post-stroke dysphagia
    • Authors: Sonja Suntrup-Krueger; Corinna Ringmaier, Paul Muhle, Andreas Wollbrink, Andre Kemmling, Uta Hanning, Inga Claus, Tobias Warnecke, Inga Teismann, Christo Pantev, Rainer Dziewas
      Abstract: Objective: We evaluated whether transcranial direct current stimulation (tDCS) is able to enhance dysphagia rehabilitation following stroke. Besides relating clinical effects with neuroplastic changes in cortical swallowing processing we aimed to identify factors influencing treatment success.Methods: In this double-blind, randomized study 60 acute dysphagic stroke patients received contralesional anodal (1 mA, 20 min) or sham tDCS on four consecutive days. Swallowing function was thoroughly assessed before and after the intervention using the validated Fiberoptic Endoscopic Dysphagia Severity Scale (FEDSS) and clinical assessment. In 10 patients, swallowing-related brain activation was recorded applying magnetoencephalography (MEG) before and after the intervention. Voxel-based statistical lesion pattern analysis was also performed.Results: Study groups did not differ according to demographic data, stroke characteristics, or baseline dysphagia severity. Patients treated with tDCS showed greater improvement in FEDSS than the sham group (1.3 vs 0.4 points, mean difference: 0.9 [95%CI 0.4–1.4], p
      PubDate: 2018-01-19T11:40:30.378543-05:
      DOI: 10.1002/ana.25151
  • Deep grey matter volume loss drives disability worsening in multiple
    • Authors: Arman Eshaghi; Ferran Prados, Wallace Brownlee, Daniel R. Altmann, Carmen Tur, M. Jorge Cardoso, Floriana De Angelis, Steven H. van de Pavert, Niamh Cawley, Nicola De Stefano, M. Laura Stromillo, Marco Battaglini, Serena Ruggieri, Claudio Gasperini, Massimo Filippi, Maria A. Rocca, Alex Rovira, Jaume Sastre-Garriga, Hugo Vrenken, Cyra E Leurs, Joep Killestein, Lukas Pirpamer, Christian Enzinger, Sebastien Ourselin, Claudia A.M. Gandini Wheeler-Kingshott, Declan Chard, Alan J. Thompson, Daniel C. Alexander, Frederik Barkhof, Olga Ciccarelli,
      Abstract: Objective: Grey matter (GM) atrophy occurs in all multiple sclerosis (MS) phenotypes. We investigated whether there is a spatiotemporal pattern of GM atrophy that is associated with faster disability accumulation in MS.Methods: We analysed 3,604 brain high-resolution T1-weighted MRI scans from 1,417 participants: 1,214 MS patients (253 clinically-isolated syndrome[CIS], 708 relapsing-remitting[RRMS], 128 secondary-progressive[SPMS], 125 primary-progressive[PPMS]), over an average follow-up of 2.41 years (standard deviation[SD]=1.97), and 203 healthy controls (HCs) [average follow-up=1.83 year, SD=1.77], attending 7 European centres. Disability was assessed with the Expanded-Disability Status Scale (EDSS). We obtained volumes of the deep GM (DGM), temporal, frontal, parietal, occipital and cerebellar GM, brainstem and cerebral white matter. Hierarchical mixed-models assessed annual percentage rate of regional tissue loss and identified regional volumes associated with time-to-EDSS progression.Results: SPMS showed the lowest baseline volumes of cortical GM and DGM. Of all baseline regional volumes, only that of the DGM predicted time-to-EDSS progression (hazard ratio=0.73, 95% CIs 0.65, 0.82; p
      PubDate: 2018-01-13T10:45:52.701432-05:
      DOI: 10.1002/ana.25145
  • Mechanistic target of rapamycin complex 1 and 2 in human temporal lobe
    • Authors: Delia M. Talos; Leah M. Jacobs, Sarah Gourmaud, Carlos A Coto, Hongyu Sun, Kuei-Cheng Lim, Timothy H. Lucas, Kathryn A. Davis, Maria Martinez-Lage, Frances E. Jensen
      Abstract: Objective: Temporal lobe epilepsy (TLE) is a chronic epilepsy syndrome defined by seizures and progressive neurological disabilities, including cognitive impairments, anxiety and depression. Here, human TLE specimens were investigated focusing on the mechanistic target of rapamycin (mTOR) Complex 1 (mTORC1) and Complex 2 (mTORC2) activities in the brain, as both pathways may represent unique targets for treatment.Methods: Surgically resected hippocampal and temporal lobe samples from therapy-resistant TLE patients were analyzed by Western blotting to quantify the expression of established mTORC1 and mTORC2 activity markers and upstream or downstream signaling pathways involving the two complexes. Histological and immunohistochemical techniques were used to assess hippocampal and neocortical structural abnormalities and cell-specific expression of individual biomarkers. Samples from patients with focal cortical dysplasia (FCD) type II served as positive controls.Results: We found significantly increased expression of phospho-mTOR (Ser2448), phospho-S6 (Ser235/236), phospho-S6 (Ser240/244) and phospho-Akt (Ser473) in TLE samples compared to controls, consistent with activation of both mTORC1 and mTORC2. Our work identified the PI3K and Ras/ERK signaling pathways as potential mTORC1 and mTORC2 upstream activators. In addition, we found that overactive mTORC2 signaling was accompanied by induction of two Akt-dependent pro-survival pathways, as evidenced by increased inhibitory phosphorylation of FoxO3a (Ser253) and GSK-β (Ser9).Interpretation: Our data demonstrate that mTOR signaling is significantly dysregulated in human TLE, offering new targets for pharmacologic interventions. Specifically, clinically available drugs that suppress mTORC1 without compromising mTOR2 signaling, such as rapamycin and its analogs, may represent a new group of antiepileptogenic agents in TLE patients. This article is protected by copyright. All rights reserved.
      PubDate: 2018-01-13T10:45:50.159072-05:
      DOI: 10.1002/ana.25149
  • Cerebrospinal fluid macrophage biomarkers in amyotrophic lateral sclerosis
    • Authors: A.G. Thompson; E. Gray, M-L. Thézénas, P.D. Charles, S. Evetts, M.T. Hu, K. Talbot, R. Fischer, B.M. Kessler, M.R. Turner
      Abstract: ObjectiveThe neurodegenerative disease amyotrophic lateral sclerosis (ALS) is a heterogeneous clinical syndrome involving multiple molecular pathways. The development of biomarkers for use in therapeutic trials is a priority. We sought to use a high-throughput proteomic method to identify novel biomarkers in individual cerebrospinal fluid samples.MethodsLiquid chromatography-tandem mass spectrometry with label-free quantification was used to identify cerebrospinal fluid proteins using samples from a well-characterised longitudinal cohort comprising patients with ALS (n=43), the upper motor neuron variant primary lateral sclerosis (PLS, n=6), cross-sectional healthy (n=20) and disease controls (Parkinsons's n=20, ALS mimic disorders n=12).ResultsThree macrophage-derived chitinases showed increased abundance in ALS: chitotriosidase (CHIT1), chitinase-3-like protein 1 (CHI3L1) and chitinase-3-like protein 2 (CHI3L2). Elevated CHI3L1 was common to ALS and PLS, whereas CHIT1 and CHI3L2 levels differed. Chitinase levels correlated with disease progression rate (CHIT1 r=0.56, p
      PubDate: 2018-01-13T10:45:47.073355-05:
      DOI: 10.1002/ana.25143
  • Terminal spreading depolarization and electric silence in death of human
    • Authors: Jens P. Dreier; Sebastian Major, Brandon Foreman, Maren K. L. Winkler, Eun-Jeung Kang, Denny Milakara, Coline L. Lemale, Vince DiNapoli, Jason M. Hinzman, Johannes Woitzik, Norberto Andaluz, Andrew Carlson, Jed A. Hartings
      Abstract: Objective: Restoring the circulation is the primary goal in emergency treatment of cerebral ischemia. However, better understanding of how the brain responds to energy depletion could inform the time available for resuscitation until irreversible damage and advance development of interventions that prolong this span. Experimentally, injury to central neurons begins only with anoxic depolarization. This potentially reversible, spreading wave typically starts 2-5 min after the onset of severe ischemia, marking the onset of a toxic intraneuronal change that eventually results in irreversible injury.Methods: To investigate this in the human brain, we performed recordings with either subdural electrode strips (n=4) or intraparenchymal electrode arrays (n=5) in patients with devastating brain injury that resulted in activation of a Do Not Resuscitate-Comfort Care order followed by terminal extubation.Results: Withdrawal of life-sustaining therapies produced a decline in brain tissue partial pressure of oxygen (ptiO2) and circulatory arrest. Silencing of spontaneous electrical activity developed simultaneously across regional electrode arrays in eight patients. This silencing, termed ‘nonspreading depression', developed during the steep falling phase of ptiO2 (intraparenchymal sensor, n=6) at 11 (7, 14) mmHg. Terminal spreading depolarizations started to propagate between electrodes 3.9 (2.6, 6.3) min after onset of the final drop in perfusion and 13 to 266s after nonspreading depression. In one patient, terminal spreading depolarization induced the initial electrocerebral silence in a spreading depression pattern; circulatory arrest developed thereafter.Interpretation: These results provide fundamental insight into the neurobiology of dying and have important implications for survivable cerebral ischemic insults. This article is protected by copyright. All rights reserved.
      PubDate: 2018-01-13T10:45:23.286801-05:
      DOI: 10.1002/ana.25147
  • Brain atrophy in MS: how deep must we go'
    • Authors: Erin S Beck; Daniel S Reich
      PubDate: 2018-01-12T10:55:40.489251-05:
      DOI: 10.1002/ana.25148
  • The central vein sign differentiates MS from CNS inflammatory
    • Authors: Pietro Maggi; Martina Absinta, Matteo Grammatico, Luisa Vuolo, Giacomo Emmi, Giovanna Carlucci, Gregorio Spagni, Alessandro Barilaro, Anna Maria Repice, Lorenzo Emmi, Domenico Prisco, Vittorio Martinelli, Roberta Scotti, Niloufar Sadeghi, Gaetano Perrotta, Pascal Sati, Bernard Dachy, Daniel S. Reich, Massimo Filippi, Luca Massacesi
      Abstract: Objectives. In multiple sclerosis (MS), MRI is a sensitive tool for detecting white matter lesions, but its diagnostic specificity is still suboptimal; ambiguous cases are frequent in clinical practice. Detection of perivenular lesions in the brain (the “central vein sign”) improves the pathological specificity of MS diagnosis, but comprehensive evaluation of this MRI biomarker in MS-mimicking inflammatory and/or autoimmune diseases, such as CNS inflammatory vasculopathies, is missing. In a multicenter study, we assessed the frequency of perivenular lesions in MS vs. systemic autoimmune diseases with CNS involvement and primary angiitis of the CNS (PACNS).Methods. In 31 patients with inflammatory CNS vasculopathies and 52 with relapsing-remitting MS, 3D-T2*-weighted and T2-FLAIR images were obtained during a single MRI acquisition after gadolinium injection. For each lesion, the “central vein sign” was evaluated according to consensus guidelines. For each patient, lesion count, volume, and brain location, as well as fulfillment of dissemination in space MRI criteria, were assessed.Results. MS showed higher frequency of perivenular lesions (median 88%) than did inflammatory CNS vasculopathies (14%), without overlap between groups or differences between 3T and 1.5T MRI. Among inflammatory vasculopathies, Behçet disease showed the highest median frequency of perivenular lesions (34%), followed by PACNS (14%), antiphospholipid syndromes (12%), Sjögren's syndrome (11%), and systemic lupus erythematosus (0%). When a threshold of 50% perivenular lesions was applied, CVS discriminated MS from inflammatory vasculopathies with diagnostic accuracy of 100%.Interpretation. The “central vein sign” differentiates inflammatory CNS vasculopathies from MS at standard clinical magnetic field strengths. This article is protected by copyright. All rights reserved.
      PubDate: 2018-01-12T10:55:39.139904-05:
      DOI: 10.1002/ana.25146
  • Dysfunctional sarcomere contractility contributes to muscle weakness in
           ACTA1-related nemaline myopathy (NEM3)
    • Authors: B. Joureau; J.M. de Winter, S. Conijn, S.J.P. Bogaards, I. Kovacevic, A. Kalganov, M. Persson, J. Lindqvist, G.J.M. Stienen, T.C. Irving, W. Ma, M. Yuen, N.F. Clarke, D.E. Rassier, E. Malfatti, N.B. Romero, A.H. Beggs, C.A.C Ottenheijm
      Abstract: OBJECTIVE: Nemaline myopathy (NM) is one of the most common congenital non-dystrophic myopathies and is characterized by muscle weakness, often from birth. Mutations in ACTA1 are a frequent cause of NM (i.e. NEM3). ACTA1 encodes alpha-actin 1, the main constituent of the sarcomeric thin filament. The mechanisms by which mutations in ACTA1 contribute to muscle weakness in NEM3 are incompletely understood. We hypothesized that sarcomeric dysfunction contributes to muscle weakness in NEM3 patients.METHODS: To test this hypothesis, we performed contractility measurements in individual muscle fibers and myofibrils obtained from muscle biopsies of fourteen NEM3 patients with different ACTA1 mutations. To identify the structural basis for impaired contractility, low angle x-ray diffraction and stimulated emission-depletion microscopy were applied.RESULTS: Our findings reveal that muscle fibers of NEM3 patients display a reduced maximal force generating capacity, which is caused by dysfunctional sarcomere contractility in the majority of patients, as revealed by contractility measurements in myofibrils. Low angle x-ray diffraction and stimulated emission-depletion microscopy indicate that dysfunctional sarcomere contractility in NEM3 patients involves a lower number of myosin heads binding to actin during muscle activation. This lower number is not the result of reduced thin filament length. Interestingly, the calcium sensitivity of force is unaffected in some patients, but decreased in others.INTERPRETATION: Thus, dysfunctional sarcomere contractility is an important contributor to muscle weakness in the majority of NEM3 patients, information which is crucial for patient stratification in future clinical trials. This article is protected by copyright. All rights reserved.
      PubDate: 2018-01-12T10:55:36.32545-05:0
      DOI: 10.1002/ana.25144
  • Thalamic Atrophy in MS: An MRI Marker of Neurodegeneration Throughout
    • Authors: Christina J. Azevedo; Steven Y. Cen, Sankalpa Khadka, Shuang Liu, John Kornak, Yonggang Shi, Ling Zheng, Stephen L. Hauser, Daniel Pelletier
      Abstract: Objective: Thalamic volume is a candidate MRI-based marker associated with neurodegeneration to hasten development of neuroprotective treatments. Our objective is to describe the longitudinal evolution of thalamic atrophy in MS and normal aging, and to estimate sample sizes for study design.Methods: 601 subjects (2632 MRI scans) were analyzed. 520 subjects with relapse-onset MS [CIS(90); RR(392); SP(38)] underwent annual standardized 3T MRI scans for an average of 4.1 years, including a 1mm3 3D T1-weighted sequence (3DT1; 2485 MRI scans). 81 healthy controls (HC) were scanned longitudinally on the same scanner using the same protocol (147 MRI scans). 3DT1s were processed using FreeSurfer's longitudinal pipeline after lesion inpainting. Rates of normalized thalamic volume loss in MS and HC were compared in linear mixed effects models. Simulation-based sample size calculations were performed incorporating the rate of atrophy in HC.Results: Thalamic volume declined significantly faster in MS subjects compared to HC, with an estimated decline of -0.71% per year (95% CI -0.77%, -0.64%) in MS subjects and -0.28% per year (95% CI -0.58%, 0.02%) in HC (p-value for difference=0.007). The rate of decline was consistent throughout the MS disease duration and across MS clinical subtypes. 80 or 100 subjects per arm (α=0.1 or 0.05, respectively) would be needed to detect the ‘maximal effect size' with 80% power in a 24-month study.Interpretation: Thalamic atrophy occurs early and consistently throughout MS. Preliminary sample size calculations appear feasible, adding to its appeal as an MRI marker associated with neurodegeneration. This article is protected by copyright. All rights reserved.
      PubDate: 2018-01-12T10:55:30.31164-05:0
      DOI: 10.1002/ana.25150
  • Alternative diagnostic criteria for idiopathic hypersomnia: A 32-hour
    • Authors: Elisa Evangelista; Régis Lopez, Lucie Barateau, Sofiene Chenini, Adriana Bosco, Isabelle Jaussent, Yves Dauvilliers
      Abstract: Objective: To assess the diagnostic value of extended sleep duration on a controlled 32-hour bed-rest protocol in idiopathic hypersomnia (IH).Methods: 116 patients with high suspicion of IH (37 clear-cut-IH according to multiple sleep latency test criteria and 79 probable-IH), 32 with hypersomnolence associated with a comorbid disorder (non-IH) and 21 controls underwent a polysomnography, modified-sleep latency tests and a 32-h bed-rest protocol. Receiver operating characteristic curves were used to find optimal total sleep time (TST) cut-off values on various periods that discriminate patients to controls.Results: TST was longer in patients with clear-cut-IH than other groups (probable-IH, non-IH and controls) and in patients with probable-IH than non-IH and controls. TST cut-off best discriminating clear-cut-IH and controls was 19h for the 32-h recording (sensitivity 91.9%, specificity 85.7%) and 12h (100%, 85.7%) for the first 24h. The 19-h cut-off displayed a specificity and sensitivity of 91.9% and 81.2% between IH and non-IH patients. Patients with IH above the 19h cut-off were overweight, had more sleep inertia and higher TST on all periods compared to patients below 19h, while no differences were found for the 12h cut-off. An inverse correlation was found between the mean sleep latency and TST during 32-h recording in IH patients.Interpretation: In standardized and controlled stringent conditions, the optimal cut-off best discriminating patients to controls was 19h over 32-h that allows a clear-cut phenotypical characterization of major interest for research purposes. Sleepier patients on MSLT were also the more severe in terms of extended sleep. This article is protected by copyright. All rights reserved.
      PubDate: 2018-01-11T11:21:11.975256-05:
      DOI: 10.1002/ana.25141
  • [18F]AV-1451 clustering of entorhinal and cortical uptake in Alzheimer's
    • Authors: Jennifer L. Whitwell; Jonathan Graff-Radford, Nirubol Tosakulwong, Stephen D. Weigand, Mary Machulda, Matthew L. Senjem, Christopher G. Schwarz, Anthony J. Spychalla, David T. Jones, Daniel A. Drubach, David S. Knopman, Bradley F. Boeve, Nilüfer Ertekin-Taner, Ronald C. Petersen, Val J. Lowe, Clifford R. Jack, Keith A. Josephs
      Abstract: Objective: To use a cluster analysis of [18F]AV-1451 tau-PET data to determine how subjects with Alzheimer's disease vary in the relative involvement of the entorhinal cortex and neocortex, and determine whether relative involvement of these two regions can help explain variability in age and clinical phenotype in Alzheimer's disease.METHODS: We calculated [18F]AV-1451 uptake in entorhinal cortex and neocortex in 62 amyloid-positive Alzheimer's disease patients (39 typical and 23 atypical presentation). Tau-PET values were normalized to the cerebellum to create SUVRs. Tau-PET SUVRs were log-transformed and clustered blinded to clinical information into three groups using K-median cluster analysis. Demographics, clinical phenotype, cognitive performance, and apolipoprotein e4 frequency were compared across clusters.RESULTS: The cluster analysis identified a cluster with low entorhinal and cortical uptake (ELo/CLo), one with low entorhinal but high cortical uptake (ELo/CHi), and one with high cortical and entorhinal uptake (EHi/CHi). Clinical phenotype differed across clusters, with typical AD most commonly observed in the ELo/CLo and EHi/CHi clusters, and atypical AD most commonly observed in the ELo/CHi cluster. The ELo/CLo cluster had an older age at PET and onset than the other clusters. The apolipoprotein e4 frequency was lower in the ELo/CHi cluster. The EHi/CHi cluster had the worst memory impairment, while the ELo/CHi cluster had the worst impairment in non-memory domains.INTERPRETATION: This study demonstrates considerable variability in [18F]AV-1451 tau-PET uptake in AD, but shows that a straight-forward clustering based on entorhinal and cortical uptake maps well onto age and clinical presentation in AD. This article is protected by copyright. All rights reserved.
      PubDate: 2018-01-11T11:21:03.560795-05:
      DOI: 10.1002/ana.25142
  • In Memoriam
    • Authors: William M. Landau; David M. Holtzman, Clifford B. Saper
      PubDate: 2018-01-09T10:20:44.755715-05:
      DOI: 10.1002/ana.25136
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Heriot-Watt University
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