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Publisher: Oxford University Press   (Total: 406 journals)

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Showing 1 - 200 of 406 Journals sorted alphabetically
ACS Symposium Series     Full-text available via subscription   (SJR: 0.189, CiteScore: 0)
Acta Biochimica et Biophysica Sinica     Hybrid Journal   (Followers: 5, SJR: 0.79, CiteScore: 2)
Adaptation     Hybrid Journal   (Followers: 9, SJR: 0.143, CiteScore: 0)
Advances in Nutrition     Hybrid Journal   (Followers: 54, SJR: 2.196, CiteScore: 5)
Aesthetic Surgery J.     Hybrid Journal   (Followers: 6, SJR: 1.434, CiteScore: 1)
Aesthetic Surgery J. Open Forum     Open Access  
African Affairs     Hybrid Journal   (Followers: 66, SJR: 1.869, CiteScore: 2)
Age and Ageing     Hybrid Journal   (Followers: 89, SJR: 1.989, CiteScore: 4)
Alcohol and Alcoholism     Hybrid Journal   (Followers: 19, SJR: 1.376, CiteScore: 3)
American Entomologist     Full-text available via subscription   (Followers: 8)
American Historical Review     Hybrid Journal   (Followers: 174, SJR: 0.467, CiteScore: 1)
American J. of Agricultural Economics     Hybrid Journal   (Followers: 44, SJR: 2.113, CiteScore: 3)
American J. of Clinical Nutrition     Hybrid Journal   (Followers: 179, SJR: 3.438, CiteScore: 6)
American J. of Epidemiology     Hybrid Journal   (Followers: 197, SJR: 2.713, CiteScore: 3)
American J. of Health-System Pharmacy     Full-text available via subscription   (Followers: 54, SJR: 0.595, CiteScore: 1)
American J. of Hypertension     Hybrid Journal   (Followers: 26, SJR: 1.322, CiteScore: 3)
American J. of Jurisprudence     Hybrid Journal   (Followers: 19, SJR: 0.281, CiteScore: 1)
American J. of Legal History     Full-text available via subscription   (Followers: 9, SJR: 0.116, CiteScore: 0)
American Law and Economics Review     Hybrid Journal   (Followers: 28, SJR: 1.053, CiteScore: 1)
American Literary History     Hybrid Journal   (Followers: 17, SJR: 0.391, CiteScore: 0)
Analysis     Hybrid Journal   (Followers: 22, SJR: 1.038, CiteScore: 1)
Animal Frontiers     Hybrid Journal   (Followers: 1)
Annals of Behavioral Medicine     Hybrid Journal   (Followers: 16, SJR: 1.423, CiteScore: 3)
Annals of Botany     Hybrid Journal   (Followers: 38, SJR: 1.721, CiteScore: 4)
Annals of Oncology     Hybrid Journal   (Followers: 56, SJR: 5.599, CiteScore: 9)
Annals of the Entomological Society of America     Full-text available via subscription   (Followers: 10, SJR: 0.722, CiteScore: 1)
Annals of Work Exposures and Health     Hybrid Journal   (Followers: 34, SJR: 0.728, CiteScore: 2)
Antibody Therapeutics     Open Access  
AoB Plants     Open Access   (Followers: 4, SJR: 1.28, CiteScore: 3)
Applied Economic Perspectives and Policy     Hybrid Journal   (Followers: 17, SJR: 0.858, CiteScore: 2)
Applied Linguistics     Hybrid Journal   (Followers: 60, SJR: 2.987, CiteScore: 3)
Applied Mathematics Research eXpress     Hybrid Journal   (Followers: 1, SJR: 1.241, CiteScore: 1)
Arbitration Intl.     Full-text available via subscription   (Followers: 21)
Arbitration Law Reports and Review     Hybrid Journal   (Followers: 14)
Archives of Clinical Neuropsychology     Hybrid Journal   (Followers: 30, SJR: 0.731, CiteScore: 2)
Aristotelian Society Supplementary Volume     Hybrid Journal   (Followers: 3)
Arthropod Management Tests     Hybrid Journal   (Followers: 2)
Astronomy & Geophysics     Hybrid Journal   (Followers: 44, SJR: 0.146, CiteScore: 0)
Behavioral Ecology     Hybrid Journal   (Followers: 53, SJR: 1.871, CiteScore: 3)
Bioinformatics     Hybrid Journal   (Followers: 342, SJR: 6.14, CiteScore: 8)
Biology Methods and Protocols     Hybrid Journal  
Biology of Reproduction     Full-text available via subscription   (Followers: 10, SJR: 1.446, CiteScore: 3)
Biometrika     Hybrid Journal   (Followers: 20, SJR: 3.485, CiteScore: 2)
BioScience     Hybrid Journal   (Followers: 29, SJR: 2.754, CiteScore: 4)
Bioscience Horizons : The National Undergraduate Research J.     Open Access   (Followers: 1, SJR: 0.146, CiteScore: 0)
Biostatistics     Hybrid Journal   (Followers: 17, SJR: 1.553, CiteScore: 2)
BJA : British J. of Anaesthesia     Hybrid Journal   (Followers: 186, SJR: 2.115, CiteScore: 3)
BJA Education     Hybrid Journal   (Followers: 65)
Brain     Hybrid Journal   (Followers: 69, SJR: 5.858, CiteScore: 7)
Briefings in Bioinformatics     Hybrid Journal   (Followers: 49, SJR: 2.505, CiteScore: 5)
Briefings in Functional Genomics     Hybrid Journal   (Followers: 3, SJR: 2.15, CiteScore: 3)
British J. for the Philosophy of Science     Hybrid Journal   (Followers: 37, SJR: 2.161, CiteScore: 2)
British J. of Aesthetics     Hybrid Journal   (Followers: 25, SJR: 0.508, CiteScore: 1)
British J. of Criminology     Hybrid Journal   (Followers: 603, SJR: 1.828, CiteScore: 3)
British J. of Social Work     Hybrid Journal   (Followers: 86, SJR: 1.019, CiteScore: 2)
British Medical Bulletin     Hybrid Journal   (Followers: 6, SJR: 1.355, CiteScore: 3)
British Yearbook of Intl. Law     Hybrid Journal   (Followers: 34)
Bulletin of the London Mathematical Society     Hybrid Journal   (Followers: 4, SJR: 1.376, CiteScore: 1)
Cambridge J. of Economics     Hybrid Journal   (Followers: 71, SJR: 0.764, CiteScore: 2)
Cambridge J. of Regions, Economy and Society     Hybrid Journal   (Followers: 12, SJR: 2.438, CiteScore: 4)
Cambridge Quarterly     Hybrid Journal   (Followers: 10, SJR: 0.104, CiteScore: 0)
Capital Markets Law J.     Hybrid Journal   (Followers: 2, SJR: 0.222, CiteScore: 0)
Carcinogenesis     Hybrid Journal   (Followers: 2, SJR: 2.135, CiteScore: 5)
Cardiovascular Research     Hybrid Journal   (Followers: 14, SJR: 3.002, CiteScore: 5)
Cerebral Cortex     Hybrid Journal   (Followers: 50, SJR: 3.892, CiteScore: 6)
CESifo Economic Studies     Hybrid Journal   (Followers: 22, SJR: 0.483, CiteScore: 1)
Chemical Senses     Hybrid Journal   (Followers: 1, SJR: 1.42, CiteScore: 3)
Children and Schools     Hybrid Journal   (Followers: 6, SJR: 0.246, CiteScore: 0)
Chinese J. of Comparative Law     Hybrid Journal   (Followers: 5, SJR: 0.412, CiteScore: 0)
Chinese J. of Intl. Law     Hybrid Journal   (Followers: 22, SJR: 0.329, CiteScore: 0)
Chinese J. of Intl. Politics     Hybrid Journal   (Followers: 10, SJR: 1.392, CiteScore: 2)
Christian Bioethics: Non-Ecumenical Studies in Medical Morality     Hybrid Journal   (Followers: 10, SJR: 0.183, CiteScore: 0)
Classical Receptions J.     Hybrid Journal   (Followers: 27, SJR: 0.123, CiteScore: 0)
Clean Energy     Open Access   (Followers: 1)
Clinical Infectious Diseases     Hybrid Journal   (Followers: 69, SJR: 5.051, CiteScore: 5)
Communication Theory     Hybrid Journal   (Followers: 25, SJR: 2.424, CiteScore: 3)
Communication, Culture & Critique     Hybrid Journal   (Followers: 28, SJR: 0.222, CiteScore: 1)
Community Development J.     Hybrid Journal   (Followers: 27, SJR: 0.268, CiteScore: 1)
Computer J.     Hybrid Journal   (Followers: 9, SJR: 0.319, CiteScore: 1)
Conservation Physiology     Open Access   (Followers: 3, SJR: 1.818, CiteScore: 3)
Contemporary Women's Writing     Hybrid Journal   (Followers: 9, SJR: 0.121, CiteScore: 0)
Contributions to Political Economy     Hybrid Journal   (Followers: 6, SJR: 0.906, CiteScore: 1)
Critical Values     Full-text available via subscription  
Current Developments in Nutrition     Open Access   (Followers: 2)
Current Legal Problems     Hybrid Journal   (Followers: 29)
Current Zoology     Full-text available via subscription   (Followers: 3, SJR: 1.164, CiteScore: 2)
Database : The J. of Biological Databases and Curation     Open Access   (Followers: 9, SJR: 1.791, CiteScore: 3)
Digital Scholarship in the Humanities     Hybrid Journal   (Followers: 14, SJR: 0.259, CiteScore: 1)
Diplomatic History     Hybrid Journal   (Followers: 21, SJR: 0.45, CiteScore: 1)
DNA Research     Open Access   (Followers: 5, SJR: 2.866, CiteScore: 6)
Dynamics and Statistics of the Climate System     Open Access   (Followers: 4)
Early Music     Hybrid Journal   (Followers: 17, SJR: 0.139, CiteScore: 0)
Econometrics J.     Hybrid Journal   (Followers: 32, SJR: 2.926, CiteScore: 1)
Economic J.     Hybrid Journal   (Followers: 115, SJR: 5.161, CiteScore: 3)
Economic Policy     Hybrid Journal   (Followers: 47, SJR: 3.584, CiteScore: 3)
ELT J.     Hybrid Journal   (Followers: 24, SJR: 0.942, CiteScore: 1)
English Historical Review     Hybrid Journal   (Followers: 56, SJR: 0.612, CiteScore: 1)
English: J. of the English Association     Hybrid Journal   (Followers: 17, SJR: 0.1, CiteScore: 0)
Environmental Entomology     Full-text available via subscription   (Followers: 11, SJR: 0.818, CiteScore: 2)
Environmental Epigenetics     Open Access   (Followers: 2)
Environmental History     Hybrid Journal   (Followers: 26, SJR: 0.408, CiteScore: 1)
EP-Europace     Hybrid Journal   (Followers: 3, SJR: 2.748, CiteScore: 4)
Epidemiologic Reviews     Hybrid Journal   (Followers: 9, SJR: 4.505, CiteScore: 8)
ESHRE Monographs     Hybrid Journal  
Essays in Criticism     Hybrid Journal   (Followers: 19, SJR: 0.113, CiteScore: 0)
European Heart J.     Hybrid Journal   (Followers: 66, SJR: 9.315, CiteScore: 9)
European Heart J. - Cardiovascular Imaging     Hybrid Journal   (Followers: 10, SJR: 3.625, CiteScore: 3)
European Heart J. - Cardiovascular Pharmacotherapy     Full-text available via subscription   (Followers: 2)
European Heart J. - Quality of Care and Clinical Outcomes     Hybrid Journal  
European Heart J. : Case Reports     Open Access  
European Heart J. Supplements     Hybrid Journal   (Followers: 8, SJR: 0.223, CiteScore: 0)
European J. of Cardio-Thoracic Surgery     Hybrid Journal   (Followers: 9, SJR: 1.681, CiteScore: 2)
European J. of Intl. Law     Hybrid Journal   (Followers: 202, SJR: 0.694, CiteScore: 1)
European J. of Orthodontics     Hybrid Journal   (Followers: 5, SJR: 1.279, CiteScore: 2)
European J. of Public Health     Hybrid Journal   (Followers: 19, SJR: 1.36, CiteScore: 2)
European Review of Agricultural Economics     Hybrid Journal   (Followers: 10, SJR: 1.172, CiteScore: 2)
European Review of Economic History     Hybrid Journal   (Followers: 30, SJR: 0.702, CiteScore: 1)
European Sociological Review     Hybrid Journal   (Followers: 43, SJR: 2.728, CiteScore: 3)
Evolution, Medicine, and Public Health     Open Access   (Followers: 12)
Family Practice     Hybrid Journal   (Followers: 15, SJR: 1.018, CiteScore: 2)
Fems Microbiology Ecology     Hybrid Journal   (Followers: 16, SJR: 1.492, CiteScore: 4)
Fems Microbiology Letters     Hybrid Journal   (Followers: 28, SJR: 0.79, CiteScore: 2)
Fems Microbiology Reviews     Hybrid Journal   (Followers: 33, SJR: 7.063, CiteScore: 13)
Fems Yeast Research     Hybrid Journal   (Followers: 14, SJR: 1.308, CiteScore: 3)
Food Quality and Safety     Open Access   (Followers: 1)
Foreign Policy Analysis     Hybrid Journal   (Followers: 24, SJR: 1.425, CiteScore: 1)
Forest Science     Hybrid Journal   (Followers: 8, SJR: 0.89, CiteScore: 2)
Forestry: An Intl. J. of Forest Research     Hybrid Journal   (Followers: 16, SJR: 1.133, CiteScore: 3)
Forum for Modern Language Studies     Hybrid Journal   (Followers: 6, SJR: 0.104, CiteScore: 0)
French History     Hybrid Journal   (Followers: 34, SJR: 0.118, CiteScore: 0)
French Studies     Hybrid Journal   (Followers: 21, SJR: 0.148, CiteScore: 0)
French Studies Bulletin     Hybrid Journal   (Followers: 10, SJR: 0.152, CiteScore: 0)
Gastroenterology Report     Open Access   (Followers: 3)
Genome Biology and Evolution     Open Access   (Followers: 16, SJR: 2.578, CiteScore: 4)
Geophysical J. Intl.     Hybrid Journal   (Followers: 39, SJR: 1.506, CiteScore: 3)
German History     Hybrid Journal   (Followers: 23, SJR: 0.161, CiteScore: 0)
GigaScience     Open Access   (Followers: 6, SJR: 5.022, CiteScore: 7)
Global Summitry     Hybrid Journal   (Followers: 1)
Glycobiology     Hybrid Journal   (Followers: 13, SJR: 1.493, CiteScore: 3)
Health and Social Work     Hybrid Journal   (Followers: 57, SJR: 0.388, CiteScore: 1)
Health Education Research     Hybrid Journal   (Followers: 16, SJR: 0.854, CiteScore: 2)
Health Policy and Planning     Hybrid Journal   (Followers: 24, SJR: 1.512, CiteScore: 2)
Health Promotion Intl.     Hybrid Journal   (Followers: 22, SJR: 0.812, CiteScore: 2)
History Workshop J.     Hybrid Journal   (Followers: 33, SJR: 1.278, CiteScore: 1)
Holocaust and Genocide Studies     Hybrid Journal   (Followers: 28, SJR: 0.105, CiteScore: 0)
Human Communication Research     Hybrid Journal   (Followers: 15, SJR: 2.146, CiteScore: 3)
Human Molecular Genetics     Hybrid Journal   (Followers: 9, SJR: 3.555, CiteScore: 5)
Human Reproduction     Hybrid Journal   (Followers: 74, SJR: 2.643, CiteScore: 5)
Human Reproduction Open     Open Access   (Followers: 1)
Human Reproduction Update     Hybrid Journal   (Followers: 21, SJR: 5.317, CiteScore: 10)
Human Rights Law Review     Hybrid Journal   (Followers: 64, SJR: 0.756, CiteScore: 1)
ICES J. of Marine Science: J. du Conseil     Hybrid Journal   (Followers: 58, SJR: 1.591, CiteScore: 3)
ICSID Review : Foreign Investment Law J.     Hybrid Journal   (Followers: 11)
ILAR J.     Hybrid Journal   (Followers: 2, SJR: 1.732, CiteScore: 4)
IMA J. of Applied Mathematics     Hybrid Journal   (SJR: 0.679, CiteScore: 1)
IMA J. of Management Mathematics     Hybrid Journal   (SJR: 0.538, CiteScore: 1)
IMA J. of Mathematical Control and Information     Hybrid Journal   (Followers: 2, SJR: 0.496, CiteScore: 1)
IMA J. of Numerical Analysis - advance access     Hybrid Journal   (SJR: 1.987, CiteScore: 2)
Industrial and Corporate Change     Hybrid Journal   (Followers: 10, SJR: 1.792, CiteScore: 2)
Industrial Law J.     Hybrid Journal   (Followers: 40, SJR: 0.249, CiteScore: 1)
Inflammatory Bowel Diseases     Hybrid Journal   (Followers: 47, SJR: 2.511, CiteScore: 4)
Information and Inference     Free  
Innovation in Aging     Open Access  
Integrative and Comparative Biology     Hybrid Journal   (Followers: 9, SJR: 1.319, CiteScore: 2)
Integrative Biology     Full-text available via subscription   (Followers: 6, SJR: 1.36, CiteScore: 3)
Integrative Organismal Biology     Open Access  
Interacting with Computers     Hybrid Journal   (Followers: 11, SJR: 0.292, CiteScore: 1)
Interactive CardioVascular and Thoracic Surgery     Hybrid Journal   (Followers: 7, SJR: 0.762, CiteScore: 1)
Intl. Affairs     Hybrid Journal   (Followers: 67, SJR: 1.505, CiteScore: 3)
Intl. Data Privacy Law     Hybrid Journal   (Followers: 26)
Intl. Health     Hybrid Journal   (Followers: 6, SJR: 0.851, CiteScore: 2)
Intl. Immunology     Hybrid Journal   (Followers: 3, SJR: 2.167, CiteScore: 4)
Intl. J. for Quality in Health Care     Hybrid Journal   (Followers: 36, SJR: 1.348, CiteScore: 2)
Intl. J. of Constitutional Law     Hybrid Journal   (Followers: 64, SJR: 0.601, CiteScore: 1)
Intl. J. of Epidemiology     Hybrid Journal   (Followers: 249, SJR: 3.969, CiteScore: 5)
Intl. J. of Law and Information Technology     Hybrid Journal   (Followers: 5, SJR: 0.202, CiteScore: 1)
Intl. J. of Law, Policy and the Family     Hybrid Journal   (Followers: 28, SJR: 0.223, CiteScore: 1)
Intl. J. of Lexicography     Hybrid Journal   (Followers: 10, SJR: 0.285, CiteScore: 1)
Intl. J. of Low-Carbon Technologies     Open Access   (Followers: 1, SJR: 0.403, CiteScore: 1)
Intl. J. of Neuropsychopharmacology     Open Access   (Followers: 3, SJR: 1.808, CiteScore: 4)
Intl. J. of Public Opinion Research     Hybrid Journal   (Followers: 11, SJR: 1.545, CiteScore: 1)
Intl. J. of Refugee Law     Hybrid Journal   (Followers: 38, SJR: 0.389, CiteScore: 1)
Intl. J. of Transitional Justice     Hybrid Journal   (Followers: 11, SJR: 0.724, CiteScore: 2)
Intl. Mathematics Research Notices     Hybrid Journal   (Followers: 1, SJR: 2.168, CiteScore: 1)
Intl. Political Sociology     Hybrid Journal   (Followers: 40, SJR: 1.465, CiteScore: 3)
Intl. Relations of the Asia-Pacific     Hybrid Journal   (Followers: 23, SJR: 0.401, CiteScore: 1)
Intl. Studies Perspectives     Hybrid Journal   (Followers: 9, SJR: 0.983, CiteScore: 1)
Intl. Studies Quarterly     Hybrid Journal   (Followers: 50, SJR: 2.581, CiteScore: 2)
Intl. Studies Review     Hybrid Journal   (Followers: 25, SJR: 1.201, CiteScore: 1)
ISLE: Interdisciplinary Studies in Literature and Environment     Hybrid Journal   (Followers: 2, SJR: 0.15, CiteScore: 0)
ITNOW     Hybrid Journal   (Followers: 1, SJR: 0.103, CiteScore: 0)
J. of African Economies     Hybrid Journal   (Followers: 17, SJR: 0.533, CiteScore: 1)
J. of American History     Hybrid Journal   (Followers: 46, SJR: 0.297, CiteScore: 1)
J. of Analytical Toxicology     Hybrid Journal   (Followers: 14, SJR: 1.065, CiteScore: 2)
J. of Antimicrobial Chemotherapy     Hybrid Journal   (Followers: 15, SJR: 2.419, CiteScore: 4)
J. of Antitrust Enforcement     Hybrid Journal   (Followers: 1)
J. of Applied Poultry Research     Hybrid Journal   (Followers: 5, SJR: 0.585, CiteScore: 1)
J. of Biochemistry     Hybrid Journal   (Followers: 41, SJR: 1.226, CiteScore: 2)
J. of Breast Imaging     Full-text available via subscription   (Followers: 1)
J. of Burn Care & Research     Hybrid Journal   (Followers: 10, SJR: 0.768, CiteScore: 2)

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Similar Journals
Journal Cover
Journal Prestige (SJR): 5.858
Citation Impact (citeScore): 7
Number of Followers: 69  
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0006-8950 - ISSN (Online) 1460-2156
Published by Oxford University Press Homepage  [406 journals]
  • Novel GABRA2 variants in epileptic encephalopathy and intellectual
           disability with seizures
    • Authors: Maljevic S; Keren B, Aung Y, et al.
      Abstract: Sir,
      PubDate: Wed, 10 Apr 2019 00:00:00 GMT
      DOI: 10.1093/brain/awz079
      Issue No: Vol. 142, No. 5 (2019)
  • Reply: Novel GABRA2 variants in epileptic encephalopathy and intellectual
           disability with seizures
    • Authors: Jenkins A; Escayg A.
      Abstract: Sir,
      PubDate: Wed, 10 Apr 2019 00:00:00 GMT
      DOI: 10.1093/brain/awz086
      Issue No: Vol. 142, No. 5 (2019)
  • Reply: Heterogeneous neuroimaging findings, damage propagation and
           connectivity: an integrative view
    • Authors: Darby R; Fox M.
      Abstract: Sir,
      PubDate: Mon, 25 Mar 2019 00:00:00 GMT
      DOI: 10.1093/brain/awz081
      Issue No: Vol. 142, No. 5 (2019)
  • Heterogeneous neuroimaging findings, damage propagation and connectivity:
           an integrative view
    • Authors: Cauda F; Mancuso L, Nani A, et al.
      PubDate: Mon, 25 Mar 2019 00:00:00 GMT
      DOI: 10.1093/brain/awz080
      Issue No: Vol. 142, No. 5 (2019)
  • Key role of SMN/SYNCRIP and RNA-Motif 7 in spinal muscular atrophy:
           RNA-Seq and motif analysis of human motor neurons
    • Abstract: Federica Rizzo, Monica Nizzardo, Shikha Vashisht, Erika Molteni, Valentina Melzi, Michela Taiana, Sabrina Salani, Pamela Santonicola, Elia Di Schiavi, Monica Bucchia, Andreina Bordoni, Irene Faravelli, Nereo Bresolin, Giacomo Pietro Comi, Uberto Pozzoli, Stefania Corti. Key role of SMN/SYNCRIP and RNA-Motif 7 in spinal muscular atrophy: RNA-Seq and motif analysis of human motor neurons. Brain 2018; 142: 276–294,
      PubDate: Mon, 18 Feb 2019 00:00:00 GMT
      DOI: 10.1093/brain/awz036
      Issue No: Vol. 142, No. 5 (2019)
  • Early neurophysiological biomarkers and spinal cord pathology in inherited
           prion disease
    • Abstract: Peter Rudge, Zane Jaunmuktane, Harpreet Hyare, Matthew Ellis, Martin Koltzenburg, John Collinge, Sebastian Brandner, Simon Mead. Early neurophysiological biomarkers and spinal cord pathology in inherited prion disease. Brain, awy358,
      PubDate: Mon, 18 Feb 2019 00:00:00 GMT
      DOI: 10.1093/brain/awz040
      Issue No: Vol. 142, No. 5 (2019)
  • Plasma tau/amyloid-β1–42 ratio predicts brain tau deposition and
           neurodegeneration in Alzheimer’s disease
    • Abstract: Jong-Chan Park, Sun-Ho Han, Dahyun Yi, Min Soo Byun, Jun Ho Lee, Sukjin Jang, Kang Ko, So Yeon Jeon, Yun-Sang Lee, Yu Kyeong Kim, Dong Young Lee, Inhee Mook-Jung for the KBASE Research Group. Plasma tau/amyloid-β1–42 ratio predicts brain tau deposition and neurodegeneration in Alzheimer’s disease. Brain 2019; 142: 1–16; doi:10.1093/brain/awy347.
      PubDate: Mon, 11 Feb 2019 00:00:00 GMT
      DOI: 10.1093/brain/awz033
      Issue No: Vol. 142, No. 5 (2019)
  • Editorial
    • Authors: Kullmann D.
      Pages: 1165 - 1165
      Abstract: The cover of this issue relates to an article by Jae-Sik Nam and co-workers, which argues that incidental unruptured intracranial aneurysms are not linked to an increased risk of subarachnoid haemorrhage in patients undergoing cardiovascular surgery. Elsewhere in this issue Elaine Kingwell and colleagues report that beta-interferon treatment was associated with a 32% decrease in mortality in patients with multiple sclerosis in two cohorts from Canada and France. This article has already attracted considerable interest since it appeared online, and the accompanying Scientific Commentary by Gavin Giovannoni rehearses the argument for early and aggressive treatment of multiple sclerosis. Also arguing against therapeutic nihilism, albeit in a different field, Gabriel Brooks and co-workers report that successful recanalization in patients with extensive middle cerebral artery territory ischaemia, as defined by a low initial Alberta Stroke Program Early Computer Tomography Score, resulted in a reduction of oedema formation, fewer malignant infarctions and better clinical outcome. A further article by Daniel Rubin et al. describes the range of neurological complications observed in patients undergoing chimeric antigen receptor (CAR) T cell therapy. A common theme of these papers is that they were based on observational studies. A randomized double-blinded clinical trial is, however, the subject of another paper by Judith Pijpers, Dennis Kies and colleagues, who show that botulinum toxin A offered no additional benefit to patients with chronic migraine and medication overuse undergoing acute withdrawal.
      PubDate: Mon, 29 Apr 2019 00:00:00 GMT
      DOI: 10.1093/brain/awz110
      Issue No: Vol. 142, No. 5 (2019)
  • Survival: the ultimate long-term outcome in multiple sclerosis
    • Authors: Giovannoni G.
      Pages: 1166 - 1167
      Abstract: This scientific commentary refers to ‘Multiple sclerosis: effect of beta interferon treatment on survival’, by Kingwell et al. (doi:10.1093/brain/awz055).
      PubDate: Mon, 29 Apr 2019 00:00:00 GMT
      DOI: 10.1093/brain/awz101
      Issue No: Vol. 142, No. 5 (2019)
  • The structure of amyloid-β dimers in Alzheimer’s disease brain: a step
           forward for oligomers
    • Authors: Bateman R; Mawuenyega K, Wildburger N.
      Pages: 1168 - 1169
      Abstract: This scientific commentary refers to ‘Identification of neurotoxic cross-linked amyloid-β dimers in the Alzheimer’s brain’, by Brinkmalm et al. (doi:10.1093/brain/awz066).
      PubDate: Mon, 29 Apr 2019 00:00:00 GMT
      DOI: 10.1093/brain/awz082
      Issue No: Vol. 142, No. 5 (2019)
  • Thalamus: a key player in alcohol use disorder and Korsakoff’s
    • Authors: Tuladhar A; de Leeuw F.
      Pages: 1170 - 1172
      Abstract: This scientific commentary refers to ‘Dissociating thalamic alterations in alcohol use disorder defines specificity of Korsakoff’s syndrome’, by Segobin et al. (doi:10.1093/brain/awz056).
      PubDate: Mon, 29 Apr 2019 00:00:00 GMT
      DOI: 10.1093/brain/awz096
      Issue No: Vol. 142, No. 5 (2019)
  • Theoretically meaningful models can answer clinically relevant questions
    • Authors: Evans N; Wagenmakers E.
      Pages: 1172 - 1175
      Abstract: This scientific commentary refers to ‘The ease and sureness of a decision: evidence accumulation of conflict and uncertainty’, by Mandali et al. (doi:10.1093/brain/awz013).
      PubDate: Mon, 29 Apr 2019 00:00:00 GMT
      DOI: 10.1093/brain/awz073
      Issue No: Vol. 142, No. 5 (2019)
  • The debated toxic role of aggregated TDP-43 in amyotrophic lateral
           sclerosis: a resolution in sight'
    • Authors: Hergesheimer R; Chami AA, de Assis D, et al.
      Pages: 1176 - 1194
      Abstract: Transactive response DNA-binding protein-43 (TDP-43) is an RNA/DNA binding protein that forms phosphorylated and ubiquitinated aggregates in the cytoplasm of motor neurons in amyotrophic lateral sclerosis, which is a hallmark of this disease. Amyotrophic lateral sclerosis is a neurodegenerative condition affecting the upper and lower motor neurons. Even though the aggregative property of TDP-43 is considered a cornerstone of amyotrophic lateral sclerosis, there has been major controversy regarding the functional link between TDP-43 aggregates and cell death. In this review, we attempt to reconcile the current literature surrounding this debate by discussing the results and limitations of the published data relating TDP-43 aggregates to cytotoxicity, as well as therapeutic perspectives of TDP-43 aggregate clearance. We point out key data suggesting that the formation of TDP-43 aggregates and the capacity to self-template and propagate among cells as a ‘prion-like’ protein, another pathological property of TDP-43 aggregates, are a significant cause of motor neuronal death. We discuss the disparities among the various studies, particularly with respect to the type of models and the different forms of TDP-43 used to evaluate cellular toxicity. We also examine how these disparities can interfere with the interpretation of the results pertaining to a direct toxic effect of TDP-43 aggregates. Furthermore, we present perspectives for improving models in order to better uncover the toxic role of aggregated TDP-43. Finally, we review the recent studies on the enhancement of the cellular clearance mechanisms of autophagy, the ubiquitin proteasome system, and endocytosis in an attempt to counteract TDP-43 aggregation-induced toxicity. Altogether, the data available so far encourage us to suggest that the cytoplasmic aggregation of TDP-43 is key for the neurodegeneration observed in motor neurons in patients with amyotrophic lateral sclerosis. The corresponding findings provide novel avenues toward early therapeutic interventions and clinical outcomes for amyotrophic lateral sclerosis management.
      PubDate: Mon, 01 Apr 2019 00:00:00 GMT
      DOI: 10.1093/brain/awz078
      Issue No: Vol. 142, No. 5 (2019)
  • Absence of iron-responsive element-binding protein 2 causes a novel
           neurodegenerative syndrome
    • Authors: Costain G; Ghosh M, Maio N, et al.
      Pages: 1195 - 1202
      Abstract: Disruption of cellular iron homeostasis can contribute to neurodegeneration. In mammals, two iron-regulatory proteins (IRPs) shape the expression of the iron metabolism proteome. Targeted deletion of Ireb2 in a mouse model causes profoundly disordered iron metabolism, leading to functional iron deficiency, anemia, erythropoietic protoporphyria, and a neurodegenerative movement disorder. Using exome sequencing, we identified the first human with bi-allelic loss-of-function variants in the gene IREB2 leading to an absence of IRP2. This 16-year-old male had neurological and haematological features that emulate those of Ireb2 knockout mice, including neurodegeneration and a treatment-resistant choreoathetoid movement disorder. Cellular phenotyping at the RNA and protein level was performed using patient and control lymphoblastoid cell lines, and established experimental assays. Our studies revealed functional iron deficiency, altered post-transcriptional regulation of iron metabolism genes, and mitochondrial dysfunction, as observed in the mouse model. The patient’s cellular abnormalities were reversed by lentiviral-mediated restoration of IRP2 expression. These results confirm that IRP2 is essential for regulation of iron metabolism in humans, and reveal a previously unrecognized subclass of neurodegenerative disease. Greater understanding of how the IRPs mediate cellular iron distribution may ultimately provide new insights into common and rare neurodegenerative processes, and could result in novel therapies.
      PubDate: Tue, 26 Mar 2019 00:00:00 GMT
      DOI: 10.1093/brain/awz072
      Issue No: Vol. 142, No. 5 (2019)
  • Acute withdrawal and botulinum toxin A in chronic migraine with medication
           overuse: a double-blind randomized controlled trial
    • Authors: Pijpers J; Kies D, Louter M, et al.
      Pages: 1203 - 1214
      Abstract: Botulinum toxin A (BTA) is widely used as treatment of chronic migraine. Efficacy in studies, however, was only modest and likely influenced by unblinding due to BTA-induced removal of forehead wrinkles. Moreover, most study participants were overusing acute headache medications and might have benefitted from withdrawal. We assessed in a double blind, placebo-controlled, randomized clinical trial whether add-on therapy with BTA enhances efficacy of acute withdrawal. Participants were enrolled between December 2012 and February 2015, with follow-up to January 2016, in a single academic hospital in the Netherlands. A total of 179 participants, male and female, aged 18–65, diagnosed with chronic migraine and overuse of acute headache medication were included. All participants were instructed to withdraw acutely from all medication for a 12-week period, in an outpatient setting. In addition, they were randomly assigned (1:1) to 31 injections with BTA (155 units) or placebo (saline); to prevent unblinding, placebo-treated participants received low doses of BTA (17.5 units in total) in the forehead, along with saline injections outside the forehead region. Primary endpoint was percentage change in monthly headache days from baseline to the last 4 weeks of double-blind treatment (Weeks 9–12). Among 179 randomized patients, 90 received BTA and 89 received placebo, and 175 (98%) completed the double-blind phase. All 179 patients were included in the intention-to-treat analyses. BTA did not reduce monthly headache days versus placebo (−26.9% versus −20.5%; difference −6.4%; 95% confidence interval: −15.2 to 2.4; P = 0.15). Absolute changes in migraine days at 12 weeks for BTA versus placebo were −6.2 versus −7.0 (difference: 0.8; 95% confidence interval: −1.0 to 2.7; P = 0.38). Other secondary endpoints, including measures for disability and quality of life, did also not differ. Withdrawal was well tolerated and blinding was successful. Thus, in patients with chronic migraine and medication overuse, BTA does not afford any additional benefit over acute withdrawal alone. Acute withdrawal should be tried first before initiating more expensive treatment with BTA.
      PubDate: Fri, 18 Jan 2019 00:00:00 GMT
      DOI: 10.1093/brain/awz052
      Issue No: Vol. 142, No. 5 (2019)
  • Electrophysiological and transcriptomic correlates of neuropathic pain in
           human dorsal root ganglion neurons
    • Authors: North R; Li Y, Ray P, et al.
      Pages: 1215 - 1226
      Abstract: Neuropathic pain encompasses a diverse array of clinical entities affecting 7–10% of the population, which is challenging to adequately treat. Several promising therapeutics derived from molecular discoveries in animal models of neuropathic pain have failed to translate following unsuccessful clinical trials suggesting the possibility of important cellular-level and molecular differences between animals and humans. Establishing the extent of potential differences between laboratory animals and humans, through direct study of human tissues and/or cells, is likely important in facilitating translation of preclinical discoveries to meaningful treatments. Patch-clamp electrophysiology and RNA-sequencing was performed on dorsal root ganglia taken from patients with variable presence of radicular/neuropathic pain. Findings establish that spontaneous action potential generation in dorsal root ganglion neurons is associated with radicular/neuropathic pain and radiographic nerve root compression. Transcriptome analysis suggests presence of sex-specific differences and reveals gene modules and signalling pathways in immune response and neuronal plasticity related to radicular/neuropathic pain that may suggest therapeutic avenues and that has the potential to predict neuropathic pain in future cohorts.
      PubDate: Tue, 19 Mar 2019 00:00:00 GMT
      DOI: 10.1093/brain/awz063
      Issue No: Vol. 142, No. 5 (2019)
  • Gene replacement therapy in a model of Charcot-Marie-Tooth 4C neuropathy
    • Authors: Schiza N; Georgiou E, Kagiava A, et al.
      Pages: 1227 - 1241
      Abstract: Charcot-Marie-Tooth disease type 4C is the most common recessively inherited demyelinating neuropathy that results from loss of function mutations in the SH3TC2 gene. Sh3tc2−/− mice represent a well characterized disease model developing early onset progressive peripheral neuropathy with hypo- and demyelination, slowing of nerve conduction velocities and disturbed nodal architecture. The aim of this project was to develop a gene replacement therapy for treating Charcot-Marie-Tooth disease type 4C to rescue the phenotype of the Sh3tc2−/− mouse model. We generated a lentiviral vector LV-Mpz.SH3TC2.myc to drive expression of the human SH3TC2 cDNA under the control of the Mpz promoter specifically in myelinating Schwann cells. The vector was delivered into 3-week-old Sh3tc2−/− mice by lumbar intrathecal injection and gene expression was assessed 4–8 weeks after injection. Immunofluorescence analysis showed presence of myc-tagged human SH3TC2 in sciatic nerves and lumbar roots in the perinuclear cytoplasm of a subset of Schwann cells, in a dotted pattern co-localizing with physiologically interacting protein Rab11. Quantitative PCR analysis confirmed SH3TC2 mRNA expression in different peripheral nervous system tissues. A treatment trial was initiated in 3 weeks old randomized Sh3tc2−/− littermate mice which received either the full or mock (LV-Mpz.Egfp) vector. Behavioural analysis 8 weeks after injection showed improved motor performance in rotarod and foot grip tests in treated Sh3tc2−/− mice compared to mock vector-treated animals. Moreover, motor nerve conduction velocities were increased in treated Sh3tc2−/− mice. On a structural level, morphological analysis revealed significant improvement in g-ratios, myelin thickness, and ratios of demyelinated fibres in lumbar roots and sciatic nerves of treated Sh3tc2−/− mice. Finally, treated mice also showed improved nodal molecular architecture and reduction of blood neurofilament light levels, a clinically relevant biomarker for axonal injury/degeneration. This study provides a proof of principle for viral gene replacement therapy targeted to Schwann cells to treat Charcot-Marie-Tooth disease type 4C and potentially other similar demyelinating inherited neuropathies.
      PubDate: Mon, 25 Mar 2019 00:00:00 GMT
      DOI: 10.1093/brain/awz064
      Issue No: Vol. 142, No. 5 (2019)
  • A mutation in the major autophagy gene, WIPI2, associated with global
           developmental abnormalities
    • Authors: Jelani M; Dooley HC, Gubas A, et al.
      Pages: 1242 - 1254
      Abstract: We describe a large consanguineous pedigree from a remote area of Northern Pakistan, with a complex developmental disorder associated with wide-ranging symptoms, including mental retardation, speech and language impairment and other neurological, psychiatric, skeletal and cardiac abnormalities. We initially carried out a genetic study using the HumanCytoSNP-12 v2.1 Illumina gene chip on nine family members and identified a single region of homozygosity shared amongst four affected individuals on chromosome 7p22 (positions 3059377–5478971). We performed whole-exome sequencing on two affected individuals from two separate branches of the extended pedigree and identified a novel nonsynonymous homozygous mutation in exon 9 of the WIPI2 (WD-repeat protein interacting with phosphoinositide 2) gene at position 5265458 (c.G745A;pV249M). WIPI2 plays a critical role in autophagy, an evolutionary conserved cellular pathway implicated in a growing number of medical conditions. The mutation is situated in a highly conserved and critically important region of WIPI2, responsible for binding PI(3)P and PI(3,5)P2, an essential requirement for autophagy to proceed. The mutation is absent in all public databases, is predicted to be damaging and segregates with the disease phenotype. We performed functional studies in vitro to determine the potential effects of the mutation on downstream pathways leading to autophagosome assembly. Binding of the V231M mutant of WIPI2b to ATG16L1 (as well as ATG5–12) is significantly reduced in GFP pull-down experiments, and fibroblasts derived from the patients show reduced WIPI2 puncta, reduced LC3 lipidation and reduced autophagic flux.
      PubDate: Wed, 10 Apr 2019 00:00:00 GMT
      DOI: 10.1093/brain/awz075
      Issue No: Vol. 142, No. 5 (2019)
  • Aberrant gyrification contributes to the link between gestational age and
           adult IQ after premature birth
    • Authors: Hedderich D; Bäuml J, Berndt M, et al.
      Pages: 1255 - 1269
      Abstract: Gyrification is a hallmark of human brain development, starting in the second half of gestation in primary cortices, followed by unimodal and then transmodal associative cortices. Alterations in gyrification have been noted in premature-born newborns and children, suggesting abnormal cortical folding to be a permanent feature of prematurity. Furthermore, both gyrification and prematurity are tightly linked with cognitive performance, indicating a link between prematurity, gyrification, and cognitive performance. To investigate this triangular relation, we tested the following two hypotheses: (i) gyrification is aberrant in premature-born adults; and (ii) aberrant gyrification contributes to the impact of prematurity on adult cognitive performance. One hundred and one very premature-born adults (i.e. adults born before 32 weeks of gestation, and/or with birth weight <1500 g) and 111 mature-born adults were assessed by structural MRI and cognitive testing at 27 years of age. Gyrification was measured by local cortical absolute mean curvature (AMC), evaluated through structural MRI. Cognitive performance was assessed by the Wechsler Adult Intelligence Scale, full-scale IQ test. Two-sample t-tests, regression and mediation analyses were used to assess AMC group differences and the relation between AMC, birth-related variables, and full-scale IQ. Three key findings were identified. First, local AMC was widely increased in fronto-temporo-parietal primary and associative cortices of very premature-born adults. Increase of AMC was inversely associated with gestational age and birth weight and positively associated with medical complications at birth, respectively. Second, increased AMC of temporal associative cortices specifically contributed to the association between prematurity and reduced adult IQ (two-path mediation), indicating that aberrant gyrification of temporal associative cortices is critical for impaired cognitive performance after premature birth. Finally, further investigation of the relationship of gyrification between the early folding postcentral cortices and associative temporal cortices, folding later during neurodevelopment, revealed that the effect of gyrification abnormalities in associative temporal cortices on adult IQ is influenced itself by gyrification abnormalities occurring in the early folding postcentral cortices (three-path mediation). These results indicate that gyrification development across cortical areas in the brain conveys prematurity effects on adult IQ. Overall, these results provide evidence that premature birth leads to permanently aberrant gyrification patterns suggesting an altered neurodevelopmental trajectory. Statistical mediation modelling suggests that both aberrant gyrification itself as well as its propagation across the cortex express aspects of impaired neurodevelopment after premature birth and lead to reduced cognitive performance in adulthood. Thus, markers of gyrification appear as potential candidates for prognosis and treatment of prematurity effects.
      PubDate: Wed, 10 Apr 2019 00:00:00 GMT
      DOI: 10.1093/brain/awz071
      Issue No: Vol. 142, No. 5 (2019)
  • Left temporal plane growth predicts language development in newborns with
           congenital heart disease
    • Authors: Jakab A; Meuwly E, Feldmann M, et al.
      Pages: 1270 - 1281
      Abstract: Congenital heart defects are the most common congenital anomalies, accounting for a third of all congenital anomaly cases. While surgical correction dramatically improved survival rates, the lag behind normal neurodevelopment appears to persist. Deficits in higher cognitive functions are particularly common, including developmental delay in communication and oral-motor apraxia. It remains unclear whether the varying degree of cognitive developmental delay is reflected in variability in brain growth patterns. To answer this question, we aimed to investigate whether the rate of regional brain growth is correlated with later life neurodevelopment. Forty-four newborns were included in our study, of whom 33 were diagnosed with dextro-transposition of the great arteries and 11 with other forms of severe congenital heart defects. During the first month of life, neonates underwent corrective or palliative cardiovascular bypass surgery, pre- and postoperative cerebral MRI were performed 18.7 ± 7.03 days apart. MRI was performed in natural sleep on a 3.0 T scanner using an 8-channel head coil, fast spin-echo T2-weighted anatomical sequences were acquired in three planes. Based on the principles of deformation-based morphometry, we calculated brain growth rate maps reflecting average daily growth occurring between pre- and postoperative brain images. An explorative, whole-brain, threshold-free cluster enhancement analysis revealed strong correlation between the growth rate of the Heschl’s gyrus, anterior planum temporale and language score at 12 months of age, corrected for demographic variables (P = 0.018, t = 5.656). No significant correlation was found between brain growth rates and motor or cognitive scores. Post hoc analysis showed that the length of hospitalization interacted with this correlation, longer hospitalization resulted in faster enlargement of the internal CSF spaces. Our longitudinal cohort study provides evidence for the early importance of left-dominant perisylvian regions in auditory and language development before direct postnatal exposure to native language. In congenital heart disease patients, the perioperative period results in a critical variability of brain growth rate in this region, which is a reliable neural correlate of language development at 1 year of age.
      PubDate: Mon, 08 Apr 2019 00:00:00 GMT
      DOI: 10.1093/brain/awz067
      Issue No: Vol. 142, No. 5 (2019)
  • Cortico-striatal synchronization in human focal seizures
    • Authors: Aupy J; Wendling F, Taylor K, et al.
      Pages: 1282 - 1295
      Abstract: Although a number of experimental and clinical studies have pointed out participation or an even more prominent role of basal ganglia in focal seizures, the mode of interaction between cortical and striatal signals remains unclear. In the present study, we took stereoelectroencephalographic (SEEG) recordings in drug-resistant epilepsy patients, to qualitatively and quantitatively analyse the ictal striatum activity as well as its synchronization with cerebral cortex. Eleven patients who underwent SEEG evaluation were prospectively included if they fulfilled two inclusion criteria: (i) at least one orthogonal intracerebral electrode contact explored the basal ganglia, in either their putaminal or caudate part; and (ii) at least two SEEG seizures were recorded. Cortical and subcortical regions of interest were defined and different periods of interest were analysed. SEEG was visually inspected and h2 non-linear correlation analysis performed to study functional connectivity between cortical region of interest and striatum. Six correlation indices were calculated. Two main patterns of striatal activation were recorded: the most frequent was characterized by an early alpha/beta activity that started within the first 5 s after seizure onset, sometimes concomitant with it. The second one was characterized by late, slower, theta/delta activity. A significant difference in h2 correlation indices was observed during the preictal and seizure onset period compared to background for global striatal index, mesio-temporal/striatal index, latero-temporal/striatal index, insular/striatal index, prefrontal/striatal index. In addition, a significant difference in h2 correlation indices was observed during the seizure termination period compared to all the other periods of interest for the six indices calculated. These results indicate that cortico-striatal synchronization can arise from the start of focal seizures. Depending on the ictal frequency pattern, desynchronization can occur later, but a late and terminal hypersynchronization progressively takes over. These changes in synchronization level between cortical and striatal activity might be part of an endogenous mechanism controlling the duration of abnormal oscillations within the striato-thalamo-cortical loop and thereby their termination. Pathophysiology of basal ganglia in focal seizures appears to be much more interlinked with the cortex than expected. Beyond the stereotypical features they could imprint to seizure semiology, their role in strengthening mechanisms underlying cessation of ictal propagation should inspire new rationales for deep brain stimulation in patients with intractable focal epilepsies.
      PubDate: Mon, 01 Apr 2019 00:00:00 GMT
      DOI: 10.1093/brain/awz062
      Issue No: Vol. 142, No. 5 (2019)
  • Scalp recorded spike ripples predict seizure risk in childhood epilepsy
           better than spikes
    • Authors: Kramer M; Ostrowski L, Song D, et al.
      Pages: 1296 - 1309
      Abstract: In the past decade, brief bursts of fast oscillations in the ripple range have been identified in the scalp EEG as a promising non-invasive biomarker for epilepsy. However, investigation and clinical application of this biomarker have been limited because standard approaches to identify these brief, low amplitude events are difficult, time consuming, and subjective. Recent studies have demonstrated that ripples co-occurring with epileptiform discharges (‘spike ripple events’) are easier to detect than ripples alone and have greater pathological significance. Here, we used objective techniques to quantify spike ripples and test whether this biomarker predicts seizure risk in childhood epilepsy. We evaluated spike ripples in scalp EEG recordings from a prospective cohort of children with a self-limited epilepsy syndrome, benign epilepsy with centrotemporal spikes, and healthy control children. We compared the rate of spike ripples between children with epilepsy and healthy controls, and between children with epilepsy during periods of active disease (active, within 1 year of seizure) and after a period of sustained seizure-freedom (seizure-free, >1 year without seizure), using semi-automated and automated detection techniques. Spike ripple rate was higher in subjects with active epilepsy compared to healthy controls (P = 0.0018) or subjects with epilepsy who were seizure-free ON or OFF medication (P = 0.0018). Among epilepsy subjects with spike ripples, each month seizure-free decreased the odds of a spike ripple by a factor of 0.66 [95% confidence interval (0.47, 0.91), P = 0.021]. Comparing the diagnostic accuracy of the presence of at least one spike ripple versus a classic spike event to identify group, we found comparable sensitivity and negative predictive value, but greater specificity and positive predictive value of spike ripples compared to spikes (P = 0.016 and P = 0.006, respectively). We found qualitatively consistent results using a fully automated spike ripple detector, including comparison with an automated spike detector. We conclude that scalp spike ripple events identify disease and track with seizure risk in this epilepsy population, using both semi-automated and fully automated detection methods, and that this biomarker outperforms analysis of spikes alone in categorizing seizure risk. These data provide evidence that spike ripples are a specific non-invasive biomarker for seizure risk in benign epilepsy with centrotemporal spikes and support future work to evaluate the utility of this biomarker to guide medication trials and tapers in these children and predict seizure risk in other at-risk populations.
      PubDate: Mon, 25 Mar 2019 00:00:00 GMT
      DOI: 10.1093/brain/awz059
      Issue No: Vol. 142, No. 5 (2019)
  • Outcome prediction models in AQP4-IgG positive neuromyelitis optica
           spectrum disorders
    • Authors: Palace J; Lin D, Zeng D, et al.
      Pages: 1310 - 1323
      Abstract: Pathogenic antibodies targeting the aquaporin-4 water channel on astrocytes are associated with relapsing inflammatory neuromyelitis optica spectrum disorders. The clinical phenotype is characterized by recurrent episodes of optic neuritis, longitudinally extensive transverse myelitis, area postrema attacks and less common brainstem and cerebral events. Patients often develop major residual disability from these attacks, so early diagnosis and initiation of attackpreventing medications is important. Accurate prediction of relapse would assist physicians in counselling patients, planning treatment and designing clinical trials. We used a large multicentre dataset of 441 patients from the UK, USA, Japan and Martinique who collectively experienced 1976 attacks, and applied sophisticated mathematical modelling to predict likelihood of relapse and disability at different time points. We found that Japanese patients had a lower risk of subsequent attacks except for brainstem and cerebral events, with an overall relative relapse risk of 0.681 (P = 0.001) compared to Caucasians and African patients, who had a higher likelihood of cerebral attacks, with a relative relapse risk of 3.309 (P = 0.009) compared to Caucasians. Female patients had a higher chance of relapse than male patients (P = 0.009), and patients with younger age of onset were more likely to have optic neuritis relapses (P < 0.001). Immunosuppressant drugs reduced and multiple sclerosis disease-modifying agents increased the likelihood of relapse (P < 0.001). Patients with optic neuritis at onset were more likely to develop blindness (P < 0.001), and those with older age of onset were more likely to develop ambulatory disability. Only 25% of long-term disability was related to initial onset attack, indicating the importance of early attack prevention. With respect to selection of patients for clinical trial design, there would be no gain in power by selecting recent onset patients and only a small gain by selecting patients with recent high disease activity. We provide risk estimates of relapse and disability for patients diagnosed and treated with immunosuppressive treatments over the subsequent 2, 3, 5 and 10 years according to type of attack at onset or the first 2-year course, ethnicity, sex and onset age. This study supports significant effects of onset age, onset phenotype and ethnicity on neuromyelitis optica spectrum disorders outcomes. Our results suggest that powering clinical treatment trials based upon relapse activity in the preceding 2 years may offer little benefit in the way of attack risk yet severely hamper clinical trial success.
      PubDate: Mon, 01 Apr 2019 00:00:00 GMT
      DOI: 10.1093/brain/awz054
      Issue No: Vol. 142, No. 5 (2019)
  • Multiple sclerosis: effect of beta interferon treatment on survival
    • Authors: Kingwell E; Leray E, Zhu F, et al.
      Pages: 1324 - 1333
      Abstract: Worldwide, the beta interferons remain the most commonly prescribed disease-modifying drugs for multiple sclerosis. However, it is unclear if they alter survival. We investigated the association between beta interferon and mortality in the ‘real-world’ setting. This was a multi-centre population-based observational study of patients with relapsing-onset multiple sclerosis who were initially registered at a clinic in British Columbia, Canada (1980–2004) or Rennes, France (1976–2013). Data on this cohort were accessed from the clinical multiple sclerosis databases and from individually linked health administrative data; all data were collected prospectively. Participants were followed from the latter of their first multiple sclerosis clinic visit, 18th birthday or 1 January 1996; until death, emigration or 31 December 2013. Only those who were naïve to disease-modifying therapy and immunosuppressant treatment of multiple sclerosis at the start of their follow-up were included in the analysis. A nested case-control approach was used. Up to 20 controls, matched to cases (deaths) by country, sex, age ± 5 years, year and disability level at study entry, were randomly selected from the cohort by incidence density sampling. The associations between all-cause mortality and at least 6 months beta interferon exposure, and also cumulative exposure (‘low’, 6 months to 3 years; and ‘high’, >3 years), were estimated by conditional logistic regression adjusting for treatment with other disease-modifying therapies and age in years. Further analyses included separate analyses by sex and country, additional adjustment for comorbidity burden in the Canadian cohort, and estimation of the association between beta interferon and multiple sclerosis-related death in both countries. Among 5989 participants (75% female) with a mean age of 42 (standard deviation, SD 11) years at study entry, there were 742 deaths (70% female) and the mean age at death was 61 (SD 13) years. Of these cases, 649 were matched to between one and 20 controls. Results of the conditional logistic regression analyses are expressed as adjusted odds ratios with 95% confidence intervals. The odds of beta interferon exposure were 32% lower among cases than controls (0.68; 0.53–0.89). Increased survival was associated with >3 years beta interferon exposure (0.44; 0.30–0.66), but not between 6 months and 3 years exposure (1.00; 0.73–1.38). Findings were similar within sex and country, and for multiple sclerosis-related death. Beta interferon treatment was associated with a lower mortality risk among people with relapsing-onset multiple sclerosis. Findings were consistent between two geographically distinct regions in North America and Europe.
      PubDate: Mon, 18 Mar 2019 00:00:00 GMT
      DOI: 10.1093/brain/awz055
      Issue No: Vol. 142, No. 5 (2019)
  • Neurological toxicities associated with chimeric antigen receptor T-cell
    • Authors: Rubin D; Danish H, Ali A, et al.
      Pages: 1334 - 1348
      Abstract: Chimeric antigen receptor T cell therapy has become an important tool in the treatment of relapsed and refractory malignancy; however, it is associated with significant neurological toxicity. We characterized the neurological toxicity associated with chimeric antigen receptor T-cell therapy in a consecutive series of 100 patients up to 2 months post transfusion, 28 of whom were obtained from chart review and the others by prospective observation. The underlying neoplasms were lymphoma (74%), myeloma (14%), leukaemia (10%), and sarcoma (2%). The median age of the cohort was 64.5 years old and 39% of patients were female. The most commonly occurring neurological symptoms were encephalopathy (57%), headache (42%), tremor (38%), aphasia (35%) and focal weakness (11%). Focal neurological deficits are frequently observed after chimeric antigen receptor T-cell therapy and are associated with regional EEG abnormalities, FDG-PET hypometabolism, and elevated velocities on transcranial Doppler ultrasound. In contrast, structural imaging was typically normal. As this form of treatment is more widely adopted, recognition of the frequently encountered symptoms will be of increasing importance for the neurologists and oncologists caring for this growing patient population.
      PubDate: Tue, 19 Mar 2019 00:00:00 GMT
      DOI: 10.1093/brain/awz053
      Issue No: Vol. 142, No. 5 (2019)
  • Reactivation of nonsense-mediated mRNA decay protects against C9orf72
           dipeptide-repeat neurotoxicity
    • Authors: Xu W; Bao P, Jiang X, et al.
      Pages: 1349 - 1364
      Abstract: Amyotrophic lateral sclerosis is a deleterious neurodegenerative disease without effective treatment options. Recent studies have indicated the involvement of the dysregulation of RNA metabolism in the pathogenesis of amyotrophic lateral sclerosis. Among the various RNA regulatory machineries, nonsense-mediated mRNA decay (NMD) is a stress responsive cellular surveillance system that degrades selected mRNA substrates to prevent the translation of defective or harmful proteins. Whether this pathway is affected in neurodegenerative diseases is unclear. Here we report the inhibition of NMD by arginine-rich dipeptide repeats derived from C9orf72 hexanucleotide repeat expansion, the most common cause of familial amyotrophic lateral sclerosis. Bioinformatic analysis of multiple transcriptome profiles revealed significant overlap of upregulated genes in NMD-defective cells with those in the brain tissues, micro-dissected motor neurons, or induced pluripotent stem cell-derived motor neurons specifically from amyotrophic lateral sclerosis patients carrying C9orf72 hexanucleotide repeat expansion, suggesting the suppression of NMD pathway in these patients. Using Drosophila as a model, we have validated that the C9orf72 hexanucleotide repeat expansion products could lead to the accumulation of the NMD substrates and identified arginine-rich dipeptide repeats, including poly glycine-arginine and poly proline-arginine, as the main culprits of NMD inhibition. Furthermore, in human SH-SY5Y neuroblastoma cells and in mouse brains, expression of glycine-arginine with 36 repeats (GR36) was sufficient to cause NMD inhibition. In cells expressing GR36, stress granule accumulation was accompanied by decreased processing body formation, which contributed to the inhibition of NMD. Remarkably, expression of UPF1, a core gene in the NMD pathway, efficiently blocked neurotoxicity caused by arginine-rich dipeptide repeats in both cellular and Drosophila models. Although not as effective as UPF1, expression of another NMD gene UPF2 also ameliorated the degenerative phenotypes in dipeptide repeat-expressing flies, indicating that genetically reactivating the NMD pathway could suppress dipeptide repeat toxicity. Finally, after validating tranilast as an NMD-activating drug, we demonstrated the therapeutic potential of this asthma drug in cellular and Drosophila models of C9orf72 dipeptide repeat neurotoxicity. Therefore, our study has revealed a cellular mechanism whereby arginine-rich C9orf72 dipeptide repeats could inhibit NMD activities by reducing the abundance of processing bodies. Furthermore, our results suggested that activation of the NMD pathway could be a potential therapeutic strategy for amyotrophic lateral sclerosis with defective RNA metabolism.
      PubDate: Mon, 01 Apr 2019 00:00:00 GMT
      DOI: 10.1093/brain/awz070
      Issue No: Vol. 142, No. 5 (2019)
  • Alpha-synuclein targets GluN2A NMDA receptor subunit causing striatal
           synaptic dysfunction and visuospatial memory alteration
    • Authors: Durante V; de Iure A, Loffredo V, et al.
      Pages: 1365 - 1385
      Abstract: Parkinson’s disease is a progressive neurodegenerative disorder characterized by altered striatal dopaminergic signalling that leads to motor and cognitive deficits. Parkinson’s disease is also characterized by abnormal presence of soluble toxic forms of α-synuclein that, when clustered into Lewy bodies, represents one of the pathological hallmarks of the disease. However, α-synuclein oligomers might also directly affect synaptic transmission and plasticity in Parkinson’s disease models. Accordingly, by combining electrophysiological, optogenetic, immunofluorescence, molecular and behavioural analyses, here we report that α-synuclein reduces N-methyl-d-aspartate (NMDA) receptor-mediated synaptic currents and impairs corticostriatal long-term potentiation of striatal spiny projection neurons, of both direct (D1-positive) and indirect (putative D2-positive) pathways. Intrastriatal injections of α-synuclein produce deficits in visuospatial learning associated with reduced function of GluN2A NMDA receptor subunit indicating that this protein selectively targets this subunit both in vitro and ex vivo. Interestingly, this effect is observed in spiny projection neurons activated by optical stimulation of either cortical or thalamic glutamatergic afferents. We also found that treatment of striatal slices with antibodies targeting α-synuclein prevents the α-synuclein-induced loss of long-term potentiation and the reduced synaptic localization of GluN2A NMDA receptor subunit suggesting that this strategy might counteract synaptic dysfunction occurring in Parkinson’s disease.
      PubDate: Fri, 29 Mar 2019 00:00:00 GMT
      DOI: 10.1093/brain/awz065
      Issue No: Vol. 142, No. 5 (2019)
  • Probabilistic mapping of the antidystonic effect of pallidal
           neurostimulation: a multicentre imaging study
    • Authors: Reich M; Horn A, Lange F, et al.
      Pages: 1386 - 1398
      Abstract: Deep brain stimulation of the internal globus pallidus is a highly effective and established therapy for primary generalized and cervical dystonia, but therapeutic success is compromised by a non-responder rate of up to 25%, even in carefully-selected groups. Variability in electrode placement and inappropriate stimulation settings may account for a large proportion of this outcome variability. Here, we present probabilistic mapping data on a large cohort of patients collected from several European centres to resolve the optimal stimulation volume within the pallidal region. A total of 105 dystonia patients with pallidal deep brain stimulation were enrolled and 87 datasets (43 with cervical dystonia and 44 with generalized dystonia) were included into the subsequent ‘normative brain’ analysis. The average improvement of dystonia motor score was 50.5 ± 30.9% in cervical and 58.2 ± 48.8% in generalized dystonia, while 19.5% of patients did not respond to treatment (<25% benefit). We defined probabilistic maps of anti-dystonic effects by aggregating individual electrode locations and volumes of tissue activated (VTA) in normative atlas space and ranking voxel-wise for outcome distribution. We found a significant relation between motor outcome and the stimulation volume, but not the electrode location per se. The highest probability of stimulation induced motor benefit was found in a small volume covering the ventroposterior globus pallidus internus and adjacent subpallidal white matter. We then used the aggregated VTA-based outcome maps to rate patient individual VTAs and trained a linear regression model to predict individual outcomes. The prediction model showed robustness between the predicted and observed clinical improvement, with an r2 of 0.294 (P < 0.0001). The predictions deviated on average by 16.9 ± 11.6 % from observed dystonia improvements. For example, if a patient improved by 65%, the model would predict an improvement between 49% and 81%. Results were validated in an independent cohort of 10 dystonia patients, where prediction and observed benefit had a correlation of r2 = 0.52 (P = 0.02) and a mean prediction error of 10.3% (±8.9). These results emphasize the potential of probabilistic outcome brain mapping in refining the optimal therapeutic volume for pallidal neurostimulation and advancing computer-assisted planning and programming of deep brain stimulation.
      PubDate: Fri, 08 Mar 2019 00:00:00 GMT
      DOI: 10.1093/brain/awz046
      Issue No: Vol. 142, No. 5 (2019)
  • Clinical benefit of thrombectomy in stroke patients with low ASPECTS is
           mediated by oedema reduction
    • Authors: Broocks G; Hanning U, Flottmann F, et al.
      Pages: 1399 - 1407
      Abstract: The impact of endovascular vessel recanalization on patients with a low initial Alberta Stroke Program Early Computer Tomography Score (ASPECTS) is still uncertain. We hypothesized that vessel recanalization leads to an improvement in mortality and degree of disability by reducing brain oedema and malignant mass effect. In this multicentre observational study, patients with acute ischaemic stroke due to large vessel occlusion in the anterior circulation and an ASPECTS of ≤ 5 were analysed. Patients were assembled into two groups: successful vessel recanalization (thrombolysis in cerebral infarctions, TICI scale 2b/3) or persistent vessel occlusion (no endovascular procedure or TICI scale 0–2a). Observers were blinded to clinical data. Net water uptake within brain infarct, a quantitative biomarker based on CT densitometry, was used to quantify oedema in admission and follow-up CT and Δ-water uptake was calculated as difference between water uptake at both time points. Occurrence of malignant infarctions and secondary parenchymal haemorrhage was documented. Furthermore, modified Rankin scale score at 90 days was used for functional outcome. We included 117 patients admitted between March 2015 and August 2017 in three German stroke centres: 71 with persistent vessel occlusion and 46 with successful recanalization. The mean water uptake in the admission imaging was not different between both groups: 10.0% (±4.8) in patients with persistent vessel occlusion and 9.0% (±4.8) in patients with vessel recanalization (P = 0.4). After follow-up CT, the mean Δ-water uptake was 16.0% (±7.5) in patients with persistent vessel occlusion and 8.0% (±5.7) in patients with vessel recanalization (P < 0.001). Successful reperfusion was independently associated with a lowered Δ-water uptake of 8.0% (95% confidence interval, CI: −10.5 to −5.3%; P < 0.001) and lowered modifed Rankin scale score after 90 days of 1.5 (95% CI: −2.2 to −0.8; P < 0.001). The prevalence of malignant infarctions was 44.3% in patients with persistent vessel occlusion and 26.1% in patients with vessel recanalization. There was no significant difference for secondary haemorrhage in both groups (P = 0.7). In conclusion, successful recanalization in patients with low initial ASPECTS resulted in a significant reduction of oedema formation and was associated with a decreased prevalence of malignant infarctions and an improvement of clinical outcome.
      PubDate: Mon, 11 Mar 2019 00:00:00 GMT
      DOI: 10.1093/brain/awz057
      Issue No: Vol. 142, No. 5 (2019)
  • Perioperative rupture risk of unruptured intracranial aneurysms in
           cardiovascular surgery
    • Authors: Nam J; Jeon S, Jo J, et al.
      Pages: 1408 - 1415
      Abstract: Although unruptured intracranial aneurysms are increasingly being diagnosed incidentally, perioperative rupture risk of unruptured intracranial aneurysm in patients undergoing cardiovascular surgery remains unclear. Therefore, we conducted an observational study to assess the prevalence and perioperative rupture risk of unruptured intracranial aneurysm in patients undergoing cardiovascular surgery. Adult patients (n = 4864) who underwent cardiovascular surgery between January 2010 and December 2016 were included. We assessed the prevalence of unruptured intracranial aneurysms in these patients using preoperative neurovascular imaging. The incidence of postoperative 30-day subarachnoid haemorrhage from aneurysmal rupture was investigated in patients undergoing cardiovascular surgery with unruptured intracranial aneurysm. Postoperative outcomes were compared between patients with unruptured intracranial aneurysm and those without unruptured intracranial aneurysm. Of the 4864 patients (39.6% females; mean ± standard deviation age, 62.3 ± 11.3 years), 353 patients had unruptured intracranial aneurysms (prevalence rate, 7.26%; 95% confidence interval, 6.52–8.06%). Of these, eight patients received surgical or endovascular treatment before surgery and 345 patients underwent cardiovascular surgery with unruptured intracranial aneurysms. Within 30 days postoperatively, subarachnoid haemorrhage occurred only in one patient, and the cumulative postoperative 30-day subarachnoid haemorrhage incidence was 0.29% (95% confidence interval, 0.01% to 1.61%). The Kaplan–Meier estimated subarachnoid haemorrhage probabilities according to the unruptured intracranial aneurysm rupture risk scores were not higher than the previously reported risk in the general population. There were no significant differences in postoperative subarachnoid haemorrhage-free survival, haemorrhagic stroke-free survival, in-hospital mortality, and hospital length of stay between patients with unruptured intracranial aneurysm and those without unruptured intracranial aneurysm. In conclusion, the prevalence of unruptured intracranial aneurysm in patients undergoing cardiovascular surgery is higher than in the general population. However, incidentally detected unruptured intracranial aneurysms are not linked to an increased risk of subarachnoid haemorrhage or adverse postoperative outcomes. These findings may help determine the optimal management of unruptured intracranial aneurysms before cardiovascular surgery.
      PubDate: Fri, 08 Mar 2019 00:00:00 GMT
      DOI: 10.1093/brain/awz058
      Issue No: Vol. 142, No. 5 (2019)
  • Variant Creutzfeldt-Jakob disease strain is identical in individuals of
           two PRNP codon 129 genotypes
    • Authors: Diack A; Boyle A, Plinston C, et al.
      Pages: 1416 - 1428
      Abstract: In 2004, a subclinical case of variant Creutzfeldt-Jakob disease in a PRNP 129 methionine/valine heterozygous individual infected via blood transfusion was reported, and we established that the spleen from this individual was infectious. Since host genetics is an important factor in strain modification, the identification of variant Creutzfeldt-Jakob disease infection in a PRNP 129 methionine/valine heterozygous individual has raised the possibility that the properties of the variant Creutzfeldt-Jakob disease agent could change after transmission to this different genetic background and concerns that this could lead to a more virulent strain of variant Creutzfeldt-Jakob disease. The variant Creutzfeldt-Jakob disease strain has to date been characterized only in methionine homozygous individuals, therefore to establish whether the strain characteristics of variant Creutzfeldt-Jakob disease had been modified by the host genotype, spleen material with prion protein deposition from a PRNP 129 methionine/valine individual was inoculated into a panel of wild-type mice. Three passages in mice were undertaken to allow stabilization of the strain characteristics following its passage into mice. In each passage, a combination of clinical signs, neuropathology (transmissible spongiform encephalopathy vacuolation and prion protein deposition) were analysed and biochemical analysis carried out. While some differences were observed at primary and first subpassage, following the second subpassage, strain characteristics in the methionine/valine individual were totally consistent with those of variant Creutzfeldt-Jakob disease transmitted to 129 methionine/methionine individuals thus demonstrated no alteration in strain properties were imposed by passage through the different host genotype. Thus we have demonstrated variant Creutzfeldt-Jakob disease strain properties are not affected by transmission through an individual with the PRNP methionine/valine codon 129 genotype and thus no alteration in virulence should be associated with the different host genotype.
      PubDate: Mon, 01 Apr 2019 00:00:00 GMT
      DOI: 10.1093/brain/awz076
      Issue No: Vol. 142, No. 5 (2019)
  • Clinical, pathophysiological and genetic features of motor symptoms in
           autosomal dominant Alzheimer’s disease
    • Authors: Vöglein J; Paumier K, Jucker M, et al.
      Pages: 1429 - 1440
      Abstract: Owing to an early and marked deposition of amyloid-β in the basal ganglia, autosomal dominant Alzheimer’s disease could distinctly involve motor symptoms. Therefore, we aimed to assess the prevalence and characteristics of motor signs in autosomal dominant Alzheimer’s disease. Baseline Unified Parkinson Disease Rating Scale part three scores (UPDRS-III) from 433 participants of the Dominantly Inherited Alzheimer’s Network observational study were analysed. Motor symptoms were scrutinized with respect to associations with mutation carrier status, mutation site within PSEN1, basal ganglia amyloid-β as measured by Pittsburgh compound B PET, estimated years to symptom onset and Clinical Dementia Rating Scale-Sum of Boxes. Motor findings in mutation carriers were compared to patients with sporadic Alzheimer’s disease using data of the National Alzheimer’s Coordination Center. Mutation carriers showed motor findings at a higher frequency (28.4% versus 12.8%; P < 0.001) and severity (mean UPDRS-III scores 2.0 versus 0.4; P < 0.001) compared to non-carriers. Eleven of the 27 UPDRS-III items were statistically more frequently affected in mutation carriers after adjustment for multiple comparisons. Ten of these 11 items were subscale components of bradykinesia. In cognitively asymptomatic mutation carriers, dysdiadochokinesia was more frequent compared to non-carriers (right hand: 3.8% versus 0%; adjusted P = 0.023; left: 4.4% versus 0.6%; adjusted P = 0.031). In this cohort, the positive predictive value for mutation carrier status in cognitively asymptomatic participants (50% a priori risk) of dysdiadochokinesia was 100% for the right and 87.5% for the left side. Mutation carriers with motor findings more frequently were basal ganglia amyloid-β positive (84% versus 63.3%; P = 0.006) and showed more basal ganglia amyloid-β deposition (Pittsburgh compound B-standardized uptake value ratio 2.472 versus 1.928; P = 0.002) than those without. Frequency and severity of motor findings were greater in post-codon 200 PSEN1 mutations (36%; mean UPDRS-III score 3.03) compared to mutations pre-codon 200 PSEN1 (19.3%, P = 0.022; 0.91, P = 0.013). In mutation carriers, motor symptom severity was significantly positively correlated with basal ganglia amyloid-β deposition, Clinical Dementia Rating scores and estimated years to symptom onset. Mutation carriers with a Clinical Dementia Rating global score of 2 exhibited more pronounced motor symptoms than sporadic Alzheimer’s disease patients with the same Clinical Dementia Rating global score (mean UPDRS-III scores 20.71 versus 5.96; P < 0.001). With a prevalence of approximately 30% and increasing severity with progression of dementia, motor symptoms are proven as a clinically relevant finding in autosomal dominant Alzheimer’s disease, in particular in advanced dementia stages, that correlates with deposition of amyloid-β in the basal ganglia. In a very small per cent of cognitively asymptomatic members of families with autosomal dominant Alzheimer’s disease, dysdiadochokinesia may increase the chance of an individual’s status as mutation carrier.
      PubDate: Wed, 20 Mar 2019 00:00:00 GMT
      DOI: 10.1093/brain/awz050
      Issue No: Vol. 142, No. 5 (2019)
  • Identification of neurotoxic cross-linked amyloid-β dimers in the
           Alzheimer’s brain
    • Authors: Brinkmalm G; Hong W, Wang Z, et al.
      Pages: 1441 - 1457
      Abstract: The primary structure of canonical amyloid-β-protein was elucidated more than 30 years ago, yet the forms of amyloid-β that play a role in Alzheimer’s disease pathogenesis remain poorly defined. Studies of Alzheimer’s disease brain extracts suggest that amyloid-β, which migrates on sodium dodecyl sulphate polyacrylamide gel electrophoresis with a molecular weight of ∼7 kDa (7kDa-Aβ), is particularly toxic; however, the nature of this species has been controversial. Using sophisticated mass spectrometry and sensitive assays of disease-relevant toxicity we show that brain-derived bioactive 7kDa-Aβ contains a heterogeneous mixture of covalently cross-linked dimers in the absence of any other detectable proteins. The identification of amyloid-β dimers may open a new phase of Alzheimer’s research and allow a better understanding of Alzheimer’s disease, and how to monitor and treat this devastating disorder. Future studies investigating the bioactivity of individual dimers cross-linked at known sites will be critical to this effort.
      PubDate: Mon, 29 Apr 2019 00:00:00 GMT
      DOI: 10.1093/brain/awz066
      Issue No: Vol. 142, No. 5 (2019)
  • Dissociating thalamic alterations in alcohol use disorder defines
           specificity of Korsakoff's syndrome
    • Authors: Segobin S; Laniepce A, Ritz L, et al.
      Pages: 1458 - 1470
      Abstract: The thalamus, a relay organ consisting of several nuclei, is shared between the frontocerebellar circuit and the Papez circuit, both particularly affected in alcohol use disorder. Shrinkage of the thalamus is known to be more severe in alcoholics with Korsakoff’s syndrome than in those without neurological complications (uncomplicated alcoholics). While thalamic atrophy could thus be a key factor explaining amnesia in Korsakoff’s syndrome, the loci and nature of alterations within the thalamic nuclei in uncomplicated alcoholics and alcoholics with Korsakoff’s syndrome remains unclear. Indeed, the literature from animal and human models is disparate regarding whether the anterior thalamic nuclei, or the mediodorsal nuclei are particularly affected and would be responsible for amnesia. Sixty-two participants (20 healthy controls, 26 uncomplicated alcoholics and 16 patients with Korsakoff’s syndrome) underwent a diffusion tensor imaging sequence and T1-weighted MRI. State-of-the-art probabilistic tractography was used to segment the thalamus according to its connections to the prefrontal cortex and cerebellar Cruses I and II for the frontocerebellar circuit’s executive loop, the precentral gyrus and cerebellar lobes IV–VI for the frontocerebellar circuit’s motor loop, and hippocampus for the Papez circuit. The connectivity and volumes of these parcellations were calculated. Tractography showed that the hippocampus was principally connected to the anterior thalamic nuclei while the prefrontal cortex was principally connected to the mediodorsal nuclei. The fibre pathways connecting these brain regions and their respective thalamic nuclei have also been validated. ANCOVA, with age and gender as covariates, on connectivity measures showed abnormalities in both patient groups for thalamic parcellations connected to the hippocampus only [F(2,57) = 12.1; P < 0.0001; η2 = 0.2964; with graded effects of the number of connections from controls to uncomplicated alcoholics to Korsakoff’s syndrome]. Atrophy, on the other hand, was observed for the prefrontal parcellation in both patient groups and to the same extent compared to controls [F(2,56) = 18.7; P < 0.0001; η2 = 0.40]. For the hippocampus parcellation, atrophy was found in the Korsakoff’s syndrome group only [F(2,56) = 5.5; P = 0.006; η2 = 0.170, corrected for multiple comparisons using Bonferroni, P < 0.01]. Post hoc Tukey’s test for unequal sample sizes, healthy controls > patients with Korsakoff’s syndrome (P = 0.0036). Two different mechanisms seem to affect the thalamus. In the frontocerebellar circuit, atrophy of the mediodorsal nuclei may lead to the alterations, whereas in the Papez circuit, disconnection between the anterior nuclei and hippocampus may be the leading factor. Shrinkage of the anterior nuclei could be specific to patients with Korsakoff’s syndrome, hence a potential neuroimaging marker of its pathophysiology, or more generally of thalamic amnesia for which Korsakoff’s syndrome has historically been used as a model.
      PubDate: Fri, 15 Mar 2019 00:00:00 GMT
      DOI: 10.1093/brain/awz056
      Issue No: Vol. 142, No. 5 (2019)
  • The ease and sureness of a decision: evidence accumulation of conflict and
    • Authors: Mandali A; Weidacker K, Kim S, et al.
      Pages: 1471 - 1482
      Abstract: The likelihood of an outcome (uncertainty or sureness) and the similarity between choices (conflict or ease of a decision) are often critical to decision-making. We often ask ourselves: how likely are we to win or lose' And how different is this option’s likelihood from the other' Uncertainty is a characteristic of the stimulus and conflict between stimuli, but these dissociable processes are often confounded. Here, applying a novel hierarchical drift diffusion approach, we study their interaction using a sequential learning task in healthy volunteers and pathological groups characterized by compulsive behaviours, by posing it as an evidence accumulation problem. The variables, Conflict (difficult or easy; difference between reward probabilities of the stimuli) and Uncertainty (low, medium or high; inverse U-shaped probability-uncertainty function) were then used to extract threshold (‘a’, amount of evidence accumulated before making a decision) and drift rate (‘v’, information processing speed) parameters. Critically, when a decision was both difficult (high conflict) and uncertain, relative to other conditions, healthy volunteers unexpectedly accumulated less evidence with lower decision thresholds and accuracy rates at chance levels. In contrast, patients with obsessive-compulsive disorder had slower processing speeds during these difficult uncertain decisions; yet, despite this more cautious approach, performed suboptimally with poorer accuracy relative to healthy volunteers below that of chance level. Thus, faced with a difficult uncertain decision, healthy controls are capable of rapid possibly random decisions, displaying almost a willingness to ‘walk away’, whereas those with obsessive compulsive disorder become more deliberative and cautious but despite appearing to learn the differential contingencies, still perform poorly. These observations might underlie disordered behaviours characterized by pathological uncertainty or doubt despite compulsive checking with impaired performance. In contrast, alcohol-dependent subjects show a different pattern relative to healthy controls with difficulties in adjusting their behavioural patterns with slower drift rates or processing speed despite decisions being easy or low conflict. We emphasize the multidimensional nature of compulsive behaviours and the utility of computational models in detecting subtle underlying processes relative to behavioural measures. These observations have implications for targeted behavioural interventions for specific cognitive impairments across psychiatric disorders.
      PubDate: Tue, 05 Feb 2019 00:00:00 GMT
      DOI: 10.1093/brain/awz013
      Issue No: Vol. 142, No. 5 (2019)
  • Inheriting madness'
    • Authors: Scull A.
      Pages: 1483 - 1487
      Abstract: Figure 1
      PubDate: Tue, 09 Apr 2019 00:00:00 GMT
      DOI: 10.1093/brain/awz083
      Issue No: Vol. 142, No. 5 (2019)
School of Mathematical and Computer Sciences
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