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Publisher: Oxford University Press   (Total: 370 journals)

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Showing 1 - 200 of 370 Journals sorted alphabetically
Acta Biochimica et Biophysica Sinica     Hybrid Journal   (Followers: 6, SJR: 0.881, h-index: 38)
Adaptation     Hybrid Journal   (Followers: 8, SJR: 0.111, h-index: 4)
Aesthetic Surgery J.     Hybrid Journal   (Followers: 6, SJR: 1.538, h-index: 35)
African Affairs     Hybrid Journal   (Followers: 59, SJR: 1.512, h-index: 46)
Age and Ageing     Hybrid Journal   (Followers: 85, SJR: 1.611, h-index: 107)
Alcohol and Alcoholism     Hybrid Journal   (Followers: 16, SJR: 0.935, h-index: 80)
American Entomologist     Full-text available via subscription   (Followers: 6)
American Historical Review     Hybrid Journal   (Followers: 139, SJR: 0.652, h-index: 43)
American J. of Agricultural Economics     Hybrid Journal   (Followers: 40, SJR: 1.441, h-index: 77)
American J. of Epidemiology     Hybrid Journal   (Followers: 171, SJR: 3.047, h-index: 201)
American J. of Hypertension     Hybrid Journal   (Followers: 23, SJR: 1.397, h-index: 111)
American J. of Jurisprudence     Hybrid Journal   (Followers: 17)
American J. of Legal History     Full-text available via subscription   (Followers: 6, SJR: 0.151, h-index: 7)
American Law and Economics Review     Hybrid Journal   (Followers: 25, SJR: 0.824, h-index: 23)
American Literary History     Hybrid Journal   (Followers: 12, SJR: 0.185, h-index: 22)
Analysis     Hybrid Journal   (Followers: 23)
Annals of Botany     Hybrid Journal   (Followers: 36, SJR: 1.912, h-index: 124)
Annals of Occupational Hygiene     Hybrid Journal   (Followers: 28, SJR: 0.837, h-index: 57)
Annals of Oncology     Hybrid Journal   (Followers: 49, SJR: 4.362, h-index: 173)
Annals of the Entomological Society of America     Full-text available via subscription   (Followers: 8, SJR: 0.642, h-index: 53)
Annals of Work Exposures and Health     Hybrid Journal  
AoB Plants     Open Access   (Followers: 4, SJR: 0.78, h-index: 10)
Applied Economic Perspectives and Policy     Hybrid Journal   (Followers: 19, SJR: 0.884, h-index: 31)
Applied Linguistics     Hybrid Journal   (Followers: 51, SJR: 1.749, h-index: 63)
Applied Mathematics Research eXpress     Hybrid Journal   (Followers: 1, SJR: 0.779, h-index: 11)
Arbitration Intl.     Full-text available via subscription   (Followers: 20)
Arbitration Law Reports and Review     Hybrid Journal   (Followers: 13)
Archives of Clinical Neuropsychology     Hybrid Journal   (Followers: 26, SJR: 0.96, h-index: 71)
Aristotelian Society Supplementary Volume     Hybrid Journal   (Followers: 2, SJR: 0.102, h-index: 20)
Arthropod Management Tests     Hybrid Journal   (Followers: 2)
Astronomy & Geophysics     Hybrid Journal   (Followers: 47, SJR: 0.144, h-index: 15)
Behavioral Ecology     Hybrid Journal   (Followers: 49, SJR: 1.698, h-index: 92)
Bioinformatics     Hybrid Journal   (Followers: 304, SJR: 4.643, h-index: 271)
Biology Methods and Protocols     Hybrid Journal  
Biology of Reproduction     Full-text available via subscription   (Followers: 9, SJR: 1.646, h-index: 149)
Biometrika     Hybrid Journal   (Followers: 19, SJR: 2.801, h-index: 90)
BioScience     Hybrid Journal   (Followers: 30, SJR: 2.374, h-index: 154)
Bioscience Horizons : The National Undergraduate Research J.     Open Access   (Followers: 1, SJR: 0.213, h-index: 9)
Biostatistics     Hybrid Journal   (Followers: 16, SJR: 1.955, h-index: 55)
BJA : British J. of Anaesthesia     Hybrid Journal   (Followers: 148, SJR: 2.314, h-index: 133)
BJA Education     Hybrid Journal   (Followers: 64, SJR: 0.272, h-index: 20)
Brain     Hybrid Journal   (Followers: 61, SJR: 6.097, h-index: 264)
Briefings in Bioinformatics     Hybrid Journal   (Followers: 44, SJR: 4.086, h-index: 73)
Briefings in Functional Genomics     Hybrid Journal   (Followers: 4, SJR: 1.771, h-index: 50)
British J. for the Philosophy of Science     Hybrid Journal   (Followers: 34, SJR: 1.267, h-index: 38)
British J. of Aesthetics     Hybrid Journal   (Followers: 26, SJR: 0.217, h-index: 18)
British J. of Criminology     Hybrid Journal   (Followers: 527, SJR: 1.373, h-index: 62)
British J. of Social Work     Hybrid Journal   (Followers: 83, SJR: 0.771, h-index: 53)
British Medical Bulletin     Hybrid Journal   (Followers: 7, SJR: 1.391, h-index: 84)
British Yearbook of Intl. Law     Hybrid Journal   (Followers: 27)
Bulletin of the London Mathematical Society     Hybrid Journal   (Followers: 3, SJR: 1.474, h-index: 31)
Cambridge J. of Economics     Hybrid Journal   (Followers: 58, SJR: 0.957, h-index: 59)
Cambridge J. of Regions, Economy and Society     Hybrid Journal   (Followers: 11, SJR: 1.067, h-index: 22)
Cambridge Quarterly     Hybrid Journal   (Followers: 11, SJR: 0.1, h-index: 7)
Capital Markets Law J.     Hybrid Journal   (Followers: 1)
Carcinogenesis     Hybrid Journal   (Followers: 2, SJR: 2.439, h-index: 167)
Cardiovascular Research     Hybrid Journal   (Followers: 12, SJR: 2.897, h-index: 175)
Cerebral Cortex     Hybrid Journal   (Followers: 41, SJR: 4.827, h-index: 192)
CESifo Economic Studies     Hybrid Journal   (Followers: 16, SJR: 0.501, h-index: 19)
Chemical Senses     Hybrid Journal   (Followers: 1, SJR: 1.436, h-index: 76)
Children and Schools     Hybrid Journal   (Followers: 6, SJR: 0.211, h-index: 18)
Chinese J. of Comparative Law     Hybrid Journal   (Followers: 3)
Chinese J. of Intl. Law     Hybrid Journal   (Followers: 21, SJR: 0.737, h-index: 11)
Chinese J. of Intl. Politics     Hybrid Journal   (Followers: 9, SJR: 1.238, h-index: 15)
Christian Bioethics: Non-Ecumenical Studies in Medical Morality     Hybrid Journal   (Followers: 11, SJR: 0.191, h-index: 8)
Classical Receptions J.     Hybrid Journal   (Followers: 24, SJR: 0.1, h-index: 3)
Clinical Infectious Diseases     Hybrid Journal   (Followers: 59, SJR: 4.742, h-index: 261)
Clinical Kidney J.     Open Access   (Followers: 4, SJR: 0.338, h-index: 19)
Community Development J.     Hybrid Journal   (Followers: 24, SJR: 0.47, h-index: 28)
Computer J.     Hybrid Journal   (Followers: 7, SJR: 0.371, h-index: 47)
Conservation Physiology     Open Access   (Followers: 2)
Contemporary Women's Writing     Hybrid Journal   (Followers: 11, SJR: 0.111, h-index: 3)
Contributions to Political Economy     Hybrid Journal   (Followers: 5, SJR: 0.313, h-index: 10)
Critical Values     Full-text available via subscription  
Current Legal Problems     Hybrid Journal   (Followers: 26)
Current Zoology     Full-text available via subscription   (SJR: 0.999, h-index: 20)
Database : The J. of Biological Databases and Curation     Open Access   (Followers: 11, SJR: 1.068, h-index: 24)
Digital Scholarship in the Humanities     Hybrid Journal   (Followers: 12)
Diplomatic History     Hybrid Journal   (Followers: 19, SJR: 0.296, h-index: 22)
DNA Research     Open Access   (Followers: 4, SJR: 2.42, h-index: 77)
Dynamics and Statistics of the Climate System     Open Access   (Followers: 3)
Early Music     Hybrid Journal   (Followers: 15, SJR: 0.124, h-index: 11)
Economic Policy     Hybrid Journal   (Followers: 63, SJR: 2.052, h-index: 52)
ELT J.     Hybrid Journal   (Followers: 25, SJR: 1.26, h-index: 23)
English Historical Review     Hybrid Journal   (Followers: 51, SJR: 0.311, h-index: 10)
English: J. of the English Association     Hybrid Journal   (Followers: 13, SJR: 0.144, h-index: 3)
Environmental Entomology     Full-text available via subscription   (Followers: 11, SJR: 0.791, h-index: 66)
Environmental Epigenetics     Open Access   (Followers: 1)
Environmental History     Hybrid Journal   (Followers: 26, SJR: 0.197, h-index: 25)
EP-Europace     Hybrid Journal   (Followers: 2, SJR: 2.201, h-index: 71)
Epidemiologic Reviews     Hybrid Journal   (Followers: 10, SJR: 3.917, h-index: 81)
ESHRE Monographs     Hybrid Journal  
Essays in Criticism     Hybrid Journal   (Followers: 16, SJR: 0.1, h-index: 6)
European Heart J.     Hybrid Journal   (Followers: 49, SJR: 6.997, h-index: 227)
European Heart J. - Cardiovascular Imaging     Hybrid Journal   (Followers: 8, SJR: 2.044, h-index: 58)
European Heart J. - Cardiovascular Pharmacotherapy     Full-text available via subscription   (Followers: 1)
European Heart J. - Quality of Care and Clinical Outcomes     Hybrid Journal  
European Heart J. Supplements     Hybrid Journal   (Followers: 7, SJR: 0.152, h-index: 31)
European J. of Cardio-Thoracic Surgery     Hybrid Journal   (Followers: 8, SJR: 1.568, h-index: 104)
European J. of Intl. Law     Hybrid Journal   (Followers: 160, SJR: 0.722, h-index: 38)
European J. of Orthodontics     Hybrid Journal   (Followers: 4, SJR: 1.09, h-index: 60)
European J. of Public Health     Hybrid Journal   (Followers: 22, SJR: 1.284, h-index: 64)
European Review of Agricultural Economics     Hybrid Journal   (Followers: 11, SJR: 1.549, h-index: 42)
European Review of Economic History     Hybrid Journal   (Followers: 28, SJR: 0.628, h-index: 24)
European Sociological Review     Hybrid Journal   (Followers: 41, SJR: 2.061, h-index: 53)
Evolution, Medicine, and Public Health     Open Access   (Followers: 11)
Family Practice     Hybrid Journal   (Followers: 11, SJR: 1.048, h-index: 77)
Fems Microbiology Ecology     Hybrid Journal   (Followers: 9, SJR: 1.687, h-index: 115)
Fems Microbiology Letters     Hybrid Journal   (Followers: 20, SJR: 1.126, h-index: 118)
Fems Microbiology Reviews     Hybrid Journal   (Followers: 25, SJR: 7.587, h-index: 150)
Fems Yeast Research     Hybrid Journal   (Followers: 13, SJR: 1.213, h-index: 66)
Foreign Policy Analysis     Hybrid Journal   (Followers: 22, SJR: 0.859, h-index: 10)
Forestry: An Intl. J. of Forest Research     Hybrid Journal   (Followers: 16, SJR: 0.903, h-index: 44)
Forum for Modern Language Studies     Hybrid Journal   (Followers: 6, SJR: 0.108, h-index: 6)
French History     Hybrid Journal   (Followers: 32, SJR: 0.123, h-index: 10)
French Studies     Hybrid Journal   (Followers: 20, SJR: 0.119, h-index: 7)
French Studies Bulletin     Hybrid Journal   (Followers: 10, SJR: 0.102, h-index: 3)
Gastroenterology Report     Open Access   (Followers: 2)
Genome Biology and Evolution     Open Access   (Followers: 10, SJR: 3.22, h-index: 39)
Geophysical J. Intl.     Hybrid Journal   (Followers: 34, SJR: 1.839, h-index: 119)
German History     Hybrid Journal   (Followers: 25, SJR: 0.437, h-index: 13)
GigaScience     Open Access   (Followers: 3)
Global Summitry     Hybrid Journal  
Glycobiology     Hybrid Journal   (Followers: 14, SJR: 1.692, h-index: 101)
Health and Social Work     Hybrid Journal   (Followers: 49, SJR: 0.505, h-index: 40)
Health Education Research     Hybrid Journal   (Followers: 12, SJR: 0.814, h-index: 80)
Health Policy and Planning     Hybrid Journal   (Followers: 20, SJR: 1.628, h-index: 66)
Health Promotion Intl.     Hybrid Journal   (Followers: 21, SJR: 0.664, h-index: 60)
History Workshop J.     Hybrid Journal   (Followers: 27, SJR: 0.313, h-index: 20)
Holocaust and Genocide Studies     Hybrid Journal   (Followers: 24, SJR: 0.115, h-index: 13)
Human Molecular Genetics     Hybrid Journal   (Followers: 9, SJR: 4.288, h-index: 233)
Human Reproduction     Hybrid Journal   (Followers: 78, SJR: 2.271, h-index: 179)
Human Reproduction Update     Hybrid Journal   (Followers: 17, SJR: 4.678, h-index: 128)
Human Rights Law Review     Hybrid Journal   (Followers: 60, SJR: 0.7, h-index: 21)
ICES J. of Marine Science: J. du Conseil     Hybrid Journal   (Followers: 54, SJR: 1.233, h-index: 88)
ICSID Review     Hybrid Journal   (Followers: 10)
ILAR J.     Hybrid Journal   (Followers: 1, SJR: 1.099, h-index: 51)
IMA J. of Applied Mathematics     Hybrid Journal   (SJR: 0.329, h-index: 26)
IMA J. of Management Mathematics     Hybrid Journal   (Followers: 2, SJR: 0.351, h-index: 20)
IMA J. of Mathematical Control and Information     Hybrid Journal   (Followers: 2, SJR: 0.661, h-index: 28)
IMA J. of Numerical Analysis - advance access     Hybrid Journal   (SJR: 2.032, h-index: 44)
Industrial and Corporate Change     Hybrid Journal   (Followers: 8, SJR: 1.37, h-index: 81)
Industrial Law J.     Hybrid Journal   (Followers: 30, SJR: 0.184, h-index: 15)
Information and Inference     Free  
Integrative and Comparative Biology     Hybrid Journal   (Followers: 8, SJR: 1.911, h-index: 90)
Interacting with Computers     Hybrid Journal   (Followers: 10, SJR: 0.529, h-index: 59)
Interactive CardioVascular and Thoracic Surgery     Hybrid Journal   (Followers: 5, SJR: 0.743, h-index: 35)
Intl. Affairs     Hybrid Journal   (Followers: 52, SJR: 1.264, h-index: 53)
Intl. Data Privacy Law     Hybrid Journal   (Followers: 28)
Intl. Health     Hybrid Journal   (Followers: 5, SJR: 0.835, h-index: 15)
Intl. Immunology     Hybrid Journal   (Followers: 3, SJR: 1.613, h-index: 111)
Intl. J. for Quality in Health Care     Hybrid Journal   (Followers: 33, SJR: 1.593, h-index: 69)
Intl. J. of Constitutional Law     Hybrid Journal   (Followers: 60, SJR: 0.613, h-index: 19)
Intl. J. of Epidemiology     Hybrid Journal   (Followers: 148, SJR: 4.381, h-index: 145)
Intl. J. of Law and Information Technology     Hybrid Journal   (Followers: 4, SJR: 0.247, h-index: 8)
Intl. J. of Law, Policy and the Family     Hybrid Journal   (Followers: 29, SJR: 0.307, h-index: 15)
Intl. J. of Lexicography     Hybrid Journal   (Followers: 8, SJR: 0.404, h-index: 18)
Intl. J. of Low-Carbon Technologies     Open Access   (Followers: 1, SJR: 0.457, h-index: 12)
Intl. J. of Neuropsychopharmacology     Open Access   (Followers: 3, SJR: 1.69, h-index: 79)
Intl. J. of Public Opinion Research     Hybrid Journal   (Followers: 9, SJR: 0.906, h-index: 33)
Intl. J. of Refugee Law     Hybrid Journal   (Followers: 33, SJR: 0.231, h-index: 21)
Intl. J. of Transitional Justice     Hybrid Journal   (Followers: 13, SJR: 0.833, h-index: 12)
Intl. Mathematics Research Notices     Hybrid Journal   (Followers: 1, SJR: 2.052, h-index: 42)
Intl. Political Sociology     Hybrid Journal   (Followers: 31, SJR: 1.339, h-index: 19)
Intl. Relations of the Asia-Pacific     Hybrid Journal   (Followers: 18, SJR: 0.539, h-index: 17)
Intl. Studies Perspectives     Hybrid Journal   (Followers: 7, SJR: 0.998, h-index: 28)
Intl. Studies Quarterly     Hybrid Journal   (Followers: 39, SJR: 2.184, h-index: 68)
Intl. Studies Review     Hybrid Journal   (Followers: 18, SJR: 0.783, h-index: 38)
ISLE: Interdisciplinary Studies in Literature and Environment     Hybrid Journal   (Followers: 1, SJR: 0.155, h-index: 4)
ITNOW     Hybrid Journal   (Followers: 2, SJR: 0.102, h-index: 4)
J. of African Economies     Hybrid Journal   (Followers: 15, SJR: 0.647, h-index: 30)
J. of American History     Hybrid Journal   (Followers: 43, SJR: 0.286, h-index: 34)
J. of Analytical Toxicology     Hybrid Journal   (Followers: 13, SJR: 1.038, h-index: 60)
J. of Antimicrobial Chemotherapy     Hybrid Journal   (Followers: 13, SJR: 2.157, h-index: 149)
J. of Antitrust Enforcement     Hybrid Journal   (Followers: 1)
J. of Applied Poultry Research     Hybrid Journal   (Followers: 3, SJR: 0.563, h-index: 43)
J. of Biochemistry     Hybrid Journal   (Followers: 43, SJR: 1.341, h-index: 96)
J. of Chromatographic Science     Hybrid Journal   (Followers: 16, SJR: 0.448, h-index: 42)
J. of Church and State     Hybrid Journal   (Followers: 11, SJR: 0.167, h-index: 11)
J. of Competition Law and Economics     Hybrid Journal   (Followers: 35, SJR: 0.442, h-index: 16)
J. of Complex Networks     Hybrid Journal   (Followers: 1, SJR: 1.165, h-index: 5)
J. of Conflict and Security Law     Hybrid Journal   (Followers: 13, SJR: 0.196, h-index: 15)
J. of Consumer Research     Full-text available via subscription   (Followers: 43, SJR: 4.896, h-index: 121)
J. of Crohn's and Colitis     Hybrid Journal   (Followers: 10, SJR: 1.543, h-index: 37)
J. of Cybersecurity     Hybrid Journal   (Followers: 3)
J. of Deaf Studies and Deaf Education     Hybrid Journal   (Followers: 9, SJR: 0.69, h-index: 36)
J. of Design History     Hybrid Journal   (Followers: 16, SJR: 0.166, h-index: 14)
J. of Economic Entomology     Full-text available via subscription   (Followers: 6, SJR: 0.894, h-index: 76)
J. of Economic Geography     Hybrid Journal   (Followers: 39, SJR: 2.909, h-index: 69)
J. of Environmental Law     Hybrid Journal   (Followers: 23, SJR: 0.457, h-index: 20)
J. of European Competition Law & Practice     Hybrid Journal   (Followers: 19)
J. of Experimental Botany     Hybrid Journal   (Followers: 14, SJR: 2.798, h-index: 163)
J. of Financial Econometrics     Hybrid Journal   (Followers: 23, SJR: 1.314, h-index: 27)
J. of Global Security Studies     Hybrid Journal   (Followers: 3)
J. of Heredity     Hybrid Journal   (Followers: 4, SJR: 1.024, h-index: 76)
J. of Hindu Studies     Hybrid Journal   (Followers: 7, SJR: 0.186, h-index: 3)
J. of Hip Preservation Surgery     Open Access  
J. of Human Rights Practice     Hybrid Journal   (Followers: 20, SJR: 0.399, h-index: 10)
J. of Infectious Diseases     Hybrid Journal   (Followers: 39, SJR: 4, h-index: 209)
J. of Insect Science     Open Access   (Followers: 8, SJR: 0.388, h-index: 31)

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Journal Cover Brain
  [SJR: 6.097]   [H-I: 264]   [61 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0006-8950 - ISSN (Online) 1460-2156
   Published by Oxford University Press Homepage  [370 journals]
  • Biallelic MCM3AP mutations cause Charcot-Marie-Tooth neuropathy with
           variable clinical presentation
    • Authors: Karakaya M; Mazaheri N, Polat I, et al.
      Abstract: Sir,
      PubDate: 2017-09-13
      DOI: 10.1093/brain/awx222
      Issue No: Vol. 140, No. 10 (2017)
       
  • On assessing neurofeedback effects: should double-blind replace
           neurophysiological mechanisms'
    • Authors: Fovet T; Micoulaud-Franchi J, Vialatte F, et al.
      Abstract: Sir,
      PubDate: 2017-08-24
      DOI: 10.1093/brain/awx211
      Issue No: Vol. 140, No. 10 (2017)
       
  • Reply: On assessing neurofeedback effects: should double-blind replace
           neurophysiological mechanisms'
    • Authors: Schabus M.
      Abstract: Sir,
      PubDate: 2017-08-24
      DOI: 10.1093/brain/awx212
      Issue No: Vol. 140, No. 10 (2017)
       
  • PRUNE1 : a disease-causing gene for secondary microcephaly
    • Authors: Karakaya M; Yilmaz S, Storbeck M, et al.
      Abstract: Sir,
      PubDate: 2017-08-23
      DOI: 10.1093/brain/awx197
      Issue No: Vol. 140, No. 10 (2017)
       
  • Reply: PRUNE1 : a disease-causing gene for secondary microcephaly
    • Authors: Baple EL; Houlden H, Zollo M, et al.
      Abstract: Sir,
      PubDate: 2017-08-23
      DOI: 10.1093/brain/awx199
      Issue No: Vol. 140, No. 10 (2017)
       
  • Editorial
    • Authors: Kullmann DM.
      Pages: 2521 - 2521
      Abstract: The cover of this issue relates to an article by Greg Weir and colleagues who describe a chemogenetic strategy to treat experimental neuropathic pain. Chemogenetics refers to the expression of an exogenous receptor, most commonly using a viral vector, which can subsequently be activated by a chemical ligand to trigger a biological action. Weir et al. targeted a mutated glutamate-gated chloride channel from C. elegans, modified to render it insensitive to glutamate, to dorsal root ganglia neurons of mice that had received a peripheral nerve injury to model neuropathic pain. Upon treatment with the anthelmintic drug ivermectin to activate the channel, treated mice exhibited less pain-related hypersensitivity behaviour, as expected from chloride-channel mediated inhibition of nociceptors. In an accompanying Scientific Commentary Allan Basbaum considers some of the challenges to bring such a strategy to the clinic.
      PubDate: 2017-09-27
      DOI: 10.1093/brain/awx238
      Issue No: Vol. 140, No. 10 (2017)
       
  • Chemogenetic management of neuropathic pain
    • Authors: Basbaum A.
      Pages: 2522 - 2525
      Abstract: This scientific commentary refers to ‘Using an engineered glutamate-gated chloride channel to silence sensory neurons and treat neuropathic pain at the source’, by Weir et al. (doi:10.1093/brain/awx201).
      PubDate: 2017-09-27
      DOI: 10.1093/brain/awx227
      Issue No: Vol. 140, No. 10 (2017)
       
  • Connectome-based models of the epileptogenic network: a step towards
           epileptomics'
    • Authors: Bernasconi A.
      Pages: 2525 - 2527
      Abstract: This scientific commentary refers to ‘Anatomic consistencies across epilepsies: a stereotactic-EEG informed high-resolution structural connectivity study’, by Besson et al. (doi:10.1093/brain/awx181).
      PubDate: 2017-09-27
      DOI: 10.1093/brain/awx229
      Issue No: Vol. 140, No. 10 (2017)
       
  • Spreading depolarization and acute ischaemia in subarachnoid haemorrhage:
           the role of mass depolarization waves
    • Authors: Ghoshal S; Claassen J.
      Pages: 2527 - 2529
      Abstract: This scientific commentary refers to ‘Subarachnoid blood acutely induces spreading depolarizations and early cortical infarction’, by Hartings et al. (doi:10.1093/brain/awx214).
      PubDate: 2017-09-27
      DOI: 10.1093/brain/awx226
      Issue No: Vol. 140, No. 10 (2017)
       
  • Monitoring clinical progression with mitochondrial disease biomarkers
    • Authors: Steele HE; Horvath R, Lyon JJ, et al.
      Pages: 2530 - 2540
      Abstract: AbstractMitochondrial disorders are genetically determined metabolic diseases due to a biochemical deficiency of the respiratory chain. Given that multi-system involvement and disease progression are common features of mitochondrial disorders they carry substantial morbidity and mortality. Despite this, no disease-modifying treatments exist with clear clinical benefits, and the current best management of mitochondrial disease is supportive. Several therapeutic strategies for mitochondrial disorders are now at a mature preclinical stage. Some are making the transition into early-phase patient trials, but the lack of validated biomarkers of disease progression presents a challenge when developing new therapies for patients. This update discusses current biomarkers of mitochondrial disease progression including metabolomics, circulating serum markers, exercise physiology, and both structural and functional imaging. We discuss the advantages and disadvantages of each approach, and consider emerging techniques with a potential role in trials of new therapies.
      PubDate: 2017-08-03
      DOI: 10.1093/brain/awx168
      Issue No: Vol. 140, No. 10 (2017)
       
  • Novel insights in the disease biology of mutant small heat shock proteins
           in neuromuscular diseases
    • Authors: Adriaenssens E; Geuens T, Baets J, et al.
      Pages: 2541 - 2549
      Abstract: AbstractSmall heat shock proteins are molecular chaperones that exert diverse cellular functions. To date, mutations in the coding regions of HSPB1 (Hsp27) and HSPB8 (Hsp22) were reported to cause distal hereditary motor neuropathy and Charcot-Marie-Tooth disease. Recently, the clinical spectrum of HSPB1 and HSPB8 mutations was expanded to also include myopathies. Here we provide an update on the molecular genetics and biology of small heat shock protein mutations in neuromuscular diseases.
      PubDate: 2017-08-14
      DOI: 10.1093/brain/awx187
      Issue No: Vol. 140, No. 10 (2017)
       
  • Biallelic mutations in the homeodomain of NKX6-2 underlie a severe
           hypomyelinating leukodystrophy
    • Authors: Dorboz I; Aiello C, Simons C, et al.
      Pages: 2550 - 2556
      Abstract: AbstractHypomyelinating leukodystrophies are genetically heterogeneous disorders with overlapping clinical and neuroimaging features reflecting variable abnormalities in myelin formation. We report on the identification of biallelic inactivating mutations in NKX6-2, a gene encoding a transcription factor regulating multiple developmental processes with a main role in oligodendrocyte differentiation and regulation of myelin-specific gene expression, as the cause underlying a previously unrecognized severe variant of hypomyelinating leukodystrophy. Five affected subjects (three unrelated families) were documented to share biallelic inactivating mutations affecting the NKX6-2 homeobox domain. A trio-based whole exome sequencing analysis in the first family detected a homozygous frameshift change [c.606delinsTA; p.(Lys202Asnfs*')]. In the second family, homozygosity mapping coupled to whole exome sequencing identified a homozygous nucleotide substitution (c.565G>T) introducing a premature stop codon (p.Glu189*). In the third family, whole exome sequencing established compound heterozygosity for a non-conservative missense change affecting a key residue participating in DNA binding (c.599G>A; p.Arg200Gln) and a nonsense substitution (c.589C>T; p.Gln197*), in both affected siblings. The clinical presentation was homogeneous, with four subjects having severe motor delays, nystagmus and absent head control, and one individual showing gross motor delay at the age of 6 months. All exhibited neuroimaging that was consistent with hypomyelination. These findings define a novel, severe form of leukodystrophy caused by impaired NKX6-2 function.
      PubDate: 2017-08-18
      DOI: 10.1093/brain/awx207
      Issue No: Vol. 140, No. 10 (2017)
       
  • Chronic non-freezing cold injury results in neuropathic pain due to a
           sensory neuropathy
    • Authors: Vale TA; Symmonds M, Polydefkis M, et al.
      Pages: 2557 - 2569
      Abstract: AbstractNon-freezing cold injury develops after sustained exposure to cold temperatures, resulting in tissue cooling but not freezing. This can result in persistent sensory disturbance of the hands and feet including numbness, paraesthesia and chronic pain. Both vascular and neurological aetiologies of this pain have been suggested but remain unproven. We prospectively approached patients referred for clinical assessment of chronic pain following non-freezing cold injury between 12 February 2014 and 30 November 2016. Of 47 patients approached, 42 consented to undergo detailed neurological evaluations including: questionnaires to detail pain location and characteristics, structured neurological examination, quantitative sensory testing, nerve conduction studies and skin biopsy for intraepidermal nerve fibre assessment. Of the 42 study participants, all had experienced non-freezing cold injury while serving in the UK armed services and the majority were of African descent (76.2%) and male (95.2%). Many participants reported multiple exposures to cold. The median time between initial injury and referral was 3.72 years. Pain was principally localized to the hands and the feet, neuropathic in nature and in all study participants associated with cold hypersensitivity. Clinical examination and quantitative sensory testing were consistent with a sensory neuropathy. In all cases, large fibre nerve conduction studies were normal. The intraepidermal nerve fibre density was markedly reduced with 90.5% of participants having a count at or below the 0.05 centile of published normative controls. Using the Neuropathic Pain Special Interest Group of the International Association for the Study of Pain grading for neuropathic pain, 100% had probable and 95.2% definite neuropathic pain. Chronic non-freezing cold injury is a disabling neuropathic pain disorder due to a sensory neuropathy. Why some individuals develop an acute painful sensory neuropathy on sustained cold exposure is not yet known, but individuals of African descent appear vulnerable. Screening tools, such as the DN4 questionnaire, and treatment algorithms for neuropathic pain should now be used in the management of these patients.
      PubDate: 2017-08-31
      DOI: 10.1093/brain/awx215
      Issue No: Vol. 140, No. 10 (2017)
       
  • Using an engineered glutamate-gated chloride channel to silence sensory
           neurons and treat neuropathic pain at the source
    • Authors: Weir GA; Middleton SJ, Clark AJ, et al.
      Pages: 2570 - 2585
      Abstract: AbstractSee Basbaum (doi:10.1093/brain/awx227) for a scientific commentary on this article.Peripheral neuropathic pain arises as a consequence of injury to sensory neurons; the development of ectopic activity in these neurons is thought to be critical for the induction and maintenance of such pain. Local anaesthetics and anti-epileptic drugs can suppress hyperexcitability; however, these drugs are complicated by unwanted effects on motor, central nervous system and cardiac function, and alternative more selective treatments to suppress hyperexcitability are therefore required. Here we show that a glutamate-gated chloride channel modified to be activated by low doses of ivermectin (but not glutamate) is highly effective in silencing sensory neurons and reversing neuropathic pain-related hypersensitivity. Activation of the glutamate-gated chloride channel expressed in either rodent or human induced pluripotent stem cell-derived sensory neurons in vitro potently inhibited their response to both electrical and algogenic stimuli. We have shown that silencing is achieved both at nerve terminals and the soma and is independent of membrane hyperpolarization and instead likely mediated by lowering of the membrane resistance. Using intrathecal adeno-associated virus serotype 9-based delivery, the glutamate-gated chloride channel was successfully targeted to mouse sensory neurons in vivo, resulting in high level and long-lasting expression of the channel selectively in sensory neurons. This enabled reproducible and reversible modulation of thermal and mechanical pain thresholds in vivo; analgesia was observed for 3 days after a single systemic dose of ivermectin. We did not observe any motor or proprioceptive deficits and noted no reduction in cutaneous afferent innervation or upregulation of the injury marker ATF3 following prolonged glutamate-gated chloride channel expression. Established mechanical and cold pain-related hypersensitivity generated by the spared nerve injury model of neuropathic pain was reversed by ivermectin treatment. The efficacy of ivermectin in ameliorating behavioural hypersensitivity was mirrored at the cellular level by a cessation of ectopic activity in sensory neurons. These findings demonstrate the importance of aberrant afferent input in the maintenance of neuropathic pain and the potential for targeted chemogenetic silencing as a new treatment modality in neuropathic pain.
      PubDate: 2017-08-19
      DOI: 10.1093/brain/awx201
      Issue No: Vol. 140, No. 10 (2017)
       
  • Mutations in DNM1L , as in OPA1 , result indominant optic atrophy despite
           opposite effectson mitochondrial fusion and fission
    • Authors: Gerber S; Charif M, Chevrollier A, et al.
      Pages: 2586 - 2596
      Abstract: AbstractDominant optic atrophy is a blinding disease due to the degeneration of the retinal ganglion cells, the axons of which form the optic nerves. In most cases, the disease is caused by mutations in OPA1, a gene encoding a mitochondrial large GTPase involved in cristae structure and mitochondrial network fusion. Using exome sequencing, we identified dominant mutations in DNM1L on chromosome 12p11.21 in three large families with isolated optic atrophy, including the two families that defined the OPA5 locus on chromosome 19q12.1-13.1, the existence of which is denied by the present study. Analyses of patient fibroblasts revealed physiological abundance and homo-polymerization of DNM1L, forming aggregates in the cytoplasm and on highly tubulated mitochondrial network, whereas neither structural difference of the peroxisome network, nor alteration of the respiratory machinery was noticed. Fluorescence microscopy of wild-type mouse retina disclosed a strong DNM1L expression in the ganglion cell layer and axons, and comparison between 3-month-old wild-type and Dnm1l+/− mice revealed increased mitochondrial length in retinal ganglion cell soma and axon, but no degeneration. Thus, our results disclose that in addition to OPA1, OPA3, MFN2, AFG3L2 and SPG7, dominant mutations in DNM1L jeopardize the integrity of the optic nerve, suggesting that alterations of the opposing forces governing mitochondrial fusion and fission, similarly affect retinal ganglion cell survival.
      PubDate: 2017-09-23
      DOI: 10.1093/brain/awx219
      Issue No: Vol. 140, No. 10 (2017)
       
  • WDR81 mutations cause extreme microcephaly and impair mitotic progression
           in human fibroblasts and Drosophila neural stem cells
    • Authors: Cavallin M; Rujano MA, Bednarek N, et al.
      Pages: 2597 - 2609
      Abstract: AbstractMicrolissencephaly is a rare brain malformation characterized by congenital microcephaly and lissencephaly. Microlissencephaly is suspected to result from abnormalities in the proliferation or survival of neural progenitors. Despite the recent identification of six genes involved in microlissencephaly, the pathophysiological basis of this condition remains poorly understood. We performed trio-based whole exome sequencing in seven subjects from five non-consanguineous families who presented with either microcephaly or microlissencephaly. This led to the identification of compound heterozygous mutations in WDR81, a gene previously associated with cerebellar ataxia, intellectual disability and quadrupedal locomotion. Patient phenotypes ranged from severe microcephaly with extremely reduced gyration with pontocerebellar hypoplasia to moderate microcephaly with cerebellar atrophy. In patient fibroblast cells, WDR81 mutations were associated with increased mitotic index and delayed prometaphase/metaphase transition. Similarly, in vivo, we showed that knockdown of the WDR81 orthologue in Drosophila led to increased mitotic index of neural stem cells with delayed mitotic progression. In summary, we highlight the broad phenotypic spectrum of WDR81-related brain malformations, which include microcephaly with moderate to extremely reduced gyration and cerebellar anomalies. Our results suggest that WDR81 might have a role in mitosis that is conserved between Drosophila and humans.
      PubDate: 2017-09-13
      DOI: 10.1093/brain/awx218
      Issue No: Vol. 140, No. 10 (2017)
       
  • Mutations of AKT3 are associated with a wide spectrum of developmental
           disorders including extreme megalencephaly
    • Authors: Alcantara D; Timms AE, Gripp K, et al.
      Pages: 2610 - 2622
      Abstract: AbstractMutations of genes within the phosphatidylinositol-3-kinase (PI3K)-AKT-MTOR pathway are well known causes of brain overgrowth (megalencephaly) as well as segmental cortical dysplasia (such as hemimegalencephaly, focal cortical dysplasia and polymicrogyria). Mutations of the AKT3 gene have been reported in a few individuals with brain malformations, to date. Therefore, our understanding regarding the clinical and molecular spectrum associated with mutations of this critical gene is limited, with no clear genotype–phenotype correlations. We sought to further delineate this spectrum, study levels of mosaicism and identify genotype–phenotype correlations of AKT3-related disorders. We performed targeted sequencing of AKT3 on individuals with these phenotypes by molecular inversion probes and/or Sanger sequencing to determine the type and level of mosaicism of mutations. We analysed all clinical and brain imaging data of mutation-positive individuals including neuropathological analysis in one instance. We performed ex vivo kinase assays on AKT3 engineered with the patient mutations and examined the phospholipid binding profile of pleckstrin homology domain localizing mutations. We identified 14 new individuals with AKT3 mutations with several phenotypes dependent on the type of mutation and level of mosaicism. Our comprehensive clinical characterization, and review of all previously published patients, broadly segregates individuals with AKT3 mutations into two groups: patients with highly asymmetric cortical dysplasia caused by the common p.E17K mutation, and patients with constitutional AKT3 mutations exhibiting more variable phenotypes including bilateral cortical malformations, polymicrogyria, periventricular nodular heterotopia and diffuse megalencephaly without cortical dysplasia. All mutations increased kinase activity, and pleckstrin homology domain mutants exhibited enhanced phospholipid binding. Overall, our study shows that activating mutations of the critical AKT3 gene are associated with a wide spectrum of brain involvement ranging from focal or segmental brain malformations (such as hemimegalencephaly and polymicrogyria) predominantly due to mosaic AKT3 mutations, to diffuse bilateral cortical malformations, megalencephaly and heterotopia due to constitutional AKT3 mutations. We also provide the first detailed neuropathological examination of a child with extreme megalencephaly due to a constitutional AKT3 mutation. This child has one of the largest documented paediatric brain sizes, to our knowledge. Finally, our data show that constitutional AKT3 mutations are associated with megalencephaly, with or without autism, similar to PTEN-related disorders. Recognition of this broad clinical and molecular spectrum of AKT3 mutations is important for providing early diagnosis and appropriate management of affected individuals, and will facilitate targeted design of future human clinical trials using PI3K-AKT pathway inhibitors.
      PubDate: 2017-09-07
      DOI: 10.1093/brain/awx203
      Issue No: Vol. 140, No. 10 (2017)
       
  • Mammalian target of rapamycin complex 1 activation sensitizes human glioma
           cells to hypoxia-induced cell death
    • Authors: Thiepold A; Lorenz NI, Foltyn M, et al.
      Pages: 2623 - 2638
      Abstract: AbstractGlioblastomas are characterized by fast uncontrolled growth leading to hypoxic areas and necrosis. Signalling from EGFR via mammalian target of rapamycin complex 1 (mTORC1) is a major driver of cell growth and proliferation and one of the most commonly altered signalling pathways in glioblastomas. Therefore, epidermal growth factor receptor and mTORC1 signalling are plausible therapeutic targets and clinical trials with inhibitors are in progress. However, we have previously shown that epidermal growth factor receptor and mTORC1 inhibition triggers metabolic changes leading to adverse effects under the conditions of the tumour microenvironment by protecting from hypoxia-induced cell death. We hypothesized that conversely mTORC1 activation sensitizes glioma cells to hypoxia-induced cell death. As a model for mTORC1 activation we used gene suppression of its physiological inhibitor TSC2 (TSC2sh). TSC2sh glioma cells showed increased sensitivity to hypoxia-induced cell death that was accompanied by an earlier ATP depletion and an increase in reactive oxygen species. There was no difference in extracellular glucose consumption but an altered intracellular metabolic profile with an increase of intermediates of the pentose phosphate pathway. Mechanistically, mTORC1 upregulated the first and rate limiting enzyme of the pentose phosphate pathway, G6PD. Furthermore, an increase in oxygen consumption in TSC2sh cells was detected. This appeared to be due to higher transcription rates of genes involved in mitochondrial respiratory function including PPARGC1A and PPARGC1B (also known as PGC-1α and -β). The finding that mTORC1 activation causes an increase in oxygen consumption and renders malignant glioma cells susceptible to hypoxia and nutrient deprivation could help identify glioblastoma patient cohorts more likely to benefit from hypoxia-inducing therapies such as the VEGFA-targeting antibody bevacizumab in future clinical evaluations.
      PubDate: 2017-08-11
      DOI: 10.1093/brain/awx196
      Issue No: Vol. 140, No. 10 (2017)
       
  • Anatomic consistencies across epilepsies: a stereotactic-EEG informed
           high-resolution structural connectivity study
    • Authors: Besson P; Bandt S, Proix T, et al.
      Pages: 2639 - 2652
      Abstract: AbstractSee Bernasconi (doi:10.1093/brain/awx229) for a scientific commentary on this article.Drug-resistant localization-related epilepsies are now recognized as network diseases. However, the exact relationship between the organization of the epileptogenic network and brain anatomy overall remains incompletely understood. To better understand this relationship, we studied structural connectivity obtained from diffusion weighted imaging in patients with epilepsy using both stereo-electroencephalography (SEEG)-determined epileptic brain regions and whole-brain analysis. High resolution structural connectivity analysis was applied in 15 patients with drug-resistant localization-related epilepsies and 36 healthy control subjects to study structural connectivity changes in epilepsy. Two different methods of structural connectivity analysis were carried out using diffusion weighted imaging, one focusing on the relationship between epileptic regions determined by SEEG investigations and one blinded to epileptic regions looking at whole-brain connectivity. First, we performed zone-based analysis comparing structural connectivity findings in patients and controls within and between SEEG-defined zones of interest. Next, we performed whole-brain structural connectivity analysis in all subjects and compared findings to the same SEEG-defined zones of interest. Finally, structural connectivity findings were correlated against clinical features. Zone-based analysis revealed no significant decreased structural connectivity within nodes of the epilepsy network at the group level, but did demonstrate significant structural connectivity differences between nodes of the epileptogenic network (regions involved in seizures generation and propagation) and the remaining of the brain in patients compared to controls. Whole-brain analyses showed a total of 133 clusters of significantly decreased structural connectivity across all patients. One cluster of significantly increased structural connectivity was identified in a single patient. Clusters of decreased structural connectivity showed topographical preference for both the salience and default mode networks despite clinical heterogeneity within our patient sample. Correlation analysis did not reveal any significant findings regarding either the effect of age at disease onset, disease duration or post-surgical outcome on structural connectivity. Taken together, this work demonstrates that structural connectivity disintegration targets distributed functional networks while sparing the epilepsy network.
      PubDate: 2017-08-02
      DOI: 10.1093/brain/awx181
      Issue No: Vol. 140, No. 10 (2017)
       
  • Migraine and risk of stroke: a national population-based twin study
    • Authors: Lantz M; Sieurin J, Sjölander A, et al.
      Pages: 2653 - 2662
      Abstract: AbstractNumerous studies have indicated an increased risk for stroke in patients with migraine, especially migraine with aura; however, many studies used self-reported migraine and only a few controlled for familial factors. We aimed to investigate migraine as a risk factor for stroke in a Swedish population-based twin cohort, and whether familial factors contribute to an increased risk. The study population included twins without prior cerebrovascular disease who answered a headache questionnaire during 1998 and 2002 for twins born 1935–58 and during 2005–06 for twins born between 1959 and 1985. Migraine with and without aura and probable migraine was defined by an algorithm mapping on to clinical diagnostic criteria according to the International Classification of Headache Disorders. Stroke diagnoses were obtained from the national patient and cause of death registers. Twins were followed longitudinally, by linkage of national registers, from date of interview until date of first stroke, death, or end of study on 31 Dec 2014. In total, 8635 twins had any migraineous headache, whereof 3553 had migraine with aura and 5082 had non-aura migraineous headache (including migraine without aura and probable migraine), and 44 769 twins had no migraine. During a mean follow-up time of 11.9 years we observed 1297 incident cases of stroke. The Cox proportional hazards model with attained age as underlying time scale was used to estimate hazard ratios with 95% confidence intervals for stroke including ischaemic and haemorrhagic subtypes related to migraine with aura, non-aura migraineous headache, and any migraineous headache. Analyses were adjusted for gender and cardiovascular risk factors. Where appropriate; within-pair analyses were performed to control for confounding by familial factors. The age- and gender-adjusted hazard ratio for stroke related to migraine with aura was 1.27 (95% confidence interval 1.00–1.62), P = 0.05, and 1.07 (95% confidence interval 0.91–1.26), P = 0.39 related to any migraineous headache. Multivariable adjusted analyses showed similar results. When stratified by gender and attained age of ≤50 or >50 years, the estimated hazard ratio for stroke was higher in twins younger than 50 years and in females; however, non-significant. In the within-pair analysis, the hazard ratio for stroke related to migraine with aura was attenuated [hazard ratio 1.09 (95% confidence interval 0.81–1.46), P = 0.59]. In conclusion, we observed no increased stroke risk related to migraine overall but there was a modestly increased risk for stroke related to migraine with aura, and within-pair analyses suggested that familial factors might contribute to this association.
      PubDate: 2017-09-26
      DOI: 10.1093/brain/awx223
      Issue No: Vol. 140, No. 10 (2017)
       
  • Genetic variants influencing elevated myeloperoxidase levels increase risk
           of stroke
    • Authors: Phuah C; Dave T, Malik R, et al.
      Pages: 2663 - 2672
      Abstract: AbstractPrimary intracerebral haemorrhage and lacunar ischaemic stroke are acute manifestations of progressive cerebral microvascular disease. Current paradigms suggest atherosclerosis is a chronic, dynamic, inflammatory condition precipitated in response to endothelial injury from various environmental challenges. Myeloperoxidase plays a central role in initiation and progression of vascular inflammation, but prior studies linking myeloperoxidase with stroke risk have been inconclusive. We hypothesized that genetic determinants of myeloperoxidase levels influence the development of vascular instability, leading to increased primary intracerebral haemorrhage and lacunar stroke risk. We used a discovery cohort of 1409 primary intracerebral haemorrhage cases and 1624 controls from three studies, an extension cohort of 12 577 ischaemic stroke cases and 25 643 controls from NINDS-SiGN, and a validation cohort of 10 307 ischaemic stroke cases and 29 326 controls from METASTROKE Consortium with genome-wide genotyping to test this hypothesis. A genetic risk score reflecting elevated myeloperoxidase levels was constructed from 15 common single nucleotide polymorphisms identified from prior genome-wide studies of circulating myeloperoxidase levels (P < 5 × 10−6). This genetic risk score was used as the independent variable in multivariable regression models for association with primary intracerebral haemorrhage and ischaemic stroke subtypes. We used fixed effects meta-analyses to pool estimates across studies. We also used Cox regression models in a prospective cohort of 174 primary intracerebral haemorrhage survivors for association with intracerebral haemorrhage recurrence. We present effects of myeloperoxidase elevating single nucleotide polymorphisms on stroke risk per risk allele, corresponding to a one allele increase in the myeloperoxidase increasing genetic risk score. Genetic determinants of elevated circulating myeloperoxidase levels were associated with both primary intracerebral haemorrhage risk (odds ratio, 1.07, P = 0.04) and recurrent intracerebral haemorrhage risk (hazards ratio, 1.45, P = 0.006). In analysis of ischaemic stroke subtypes, the myeloperoxidase increasing genetic risk score was strongly associated with lacunar subtype only (odds ratio, 1.05, P = 0.0012). These results, demonstrating that common genetic variants that increase myeloperoxidase levels increase risk of primary intracerebral haemorrhage and lacunar stroke, directly implicate the myeloperoxidase pathway in the pathogenesis of cerebral small vessel disease. Because genetic variants are not influenced by environmental exposures, these results provide new support for a causal rather than bystander role for myeloperoxidase in the progression of cerebrovascular disease. Furthermore, these results support a rationale for chronic inflammation as a potential modifiable stroke risk mechanism, and suggest that immune-targeted therapies could be useful for treatment and prevention of cerebrovascular disease.
      PubDate: 2017-09-12
      DOI: 10.1093/brain/awx220
      Issue No: Vol. 140, No. 10 (2017)
       
  • Subarachnoid blood acutely induces spreading depolarizations and early
           cortical infarction
    • Authors: Hartings JA; York J, Carroll CP, et al.
      Pages: 2673 - 2690
      Abstract: AbstractSee Ghoshal and Claassen (doi:10.1093/brain/awx226) for a scientific commentary on this article.Early cortical infarcts are common in poor-grade patients after aneurysmal subarachnoid haemorrhage. There are no animal models of these lesions and mechanisms are unknown, although mass cortical spreading depolarizations are hypothesized as a requisite mechanism and clinical marker of infarct development. Here we studied acute sequelae of subarachnoid haemorrhage in the gyrencephalic brain of propofol-anaesthetized juvenile swine using subdural electrode strips (electrocorticography) and intraparenchymal neuromonitoring probes. Subarachnoid infusion of 1–2 ml of fresh blood at 200 µl/min over cortical sulci caused clusters of spreading depolarizations (count range: 12–34) in 7/17 animals in the ipsilateral but not contralateral hemisphere in 6 h of monitoring, without meaningful changes in other variables. Spreading depolarization clusters were associated with formation of sulcal clots (P < 0.01), a high likelihood of adjacent cortical infarcts (5/7 versus 2/10, P < 0.06), and upregulation of cyclooxygenase-2 in ipsilateral cortex remote from clots/infarcts. In a second cohort, infusion of 1 ml of clotted blood into a sulcus caused spreading depolarizations in 5/6 animals (count range: 4–20 in 6 h) and persistent thick clots with patchy or extensive infarction of circumscribed cortex in all animals. Infarcts were significantly larger after blood clot infusion compared to mass effect controls using fibrin clots of equal volume. Haematoxylin and eosin staining of infarcts showed well demarcated zones of oedema and hypoxic-ischaemic neuronal injury, consistent with acute infarction. The association of spreading depolarizations with early brain injury was then investigated in 23 patients [14 female; age (median, quartiles): 57 years (47, 63)] after repair of ruptured anterior communicating artery aneurysms by clip ligation (n = 14) or coiling (n = 9). Frontal electrocorticography [duration: 54 h (34, 66)] from subdural electrode strips was analysed over Days 0–3 after initial haemorrhage and magnetic resonance imaging studies were performed at ∼ 24–48 h after aneurysm treatment. Patients with frontal infarcts only and those with frontal infarcts and/or intracerebral haemorrhage were both significantly more likely to have spreading depolarizations (6/7 and 10/12, respectively) than those without frontal brain lesions (1/11, P’s < 0.05). These results suggest that subarachnoid clots in sulci/fissures are sufficient to induce spreading depolarizations and acute infarction in adjacent cortex. We hypothesize that the cellular toxicity and vasoconstrictive effects of depolarizations act in synergy with direct ischaemic effects of haemorrhage as mechanisms of infarct development. Results further validate spreading depolarizations as a clinical marker of early brain injury and establish a clinically relevant model to investigate causal pathologic sequences and potential therapeutic interventions.
      PubDate: 2017-09-06
      DOI: 10.1093/brain/awx214
      Issue No: Vol. 140, No. 10 (2017)
       
  • Glymphatic MRI in idiopathic normal pressure hydrocephalus
    • Authors: Ringstad G; Vatnehol S, Eide P.
      Pages: 2691 - 2705
      Abstract: AbstractThe glymphatic system has in previous studies been shown as fundamental to clearance of waste metabolites from the brain interstitial space, and is proposed to be instrumental in normal ageing and brain pathology such as Alzheimer’s disease and brain trauma. Assessment of glymphatic function using magnetic resonance imaging with intrathecal contrast agent as a cerebrospinal fluid tracer has so far been limited to rodents. We aimed to image cerebrospinal fluid flow characteristics and glymphatic function in humans, and applied the methodology in a prospective study of 15 idiopathic normal pressure hydrocephalus patients (mean age 71.3 ± 8.1 years, three female and 12 male) and eight reference subjects (mean age 41.1 + 13.0 years, six female and two male) with suspected cerebrospinal fluid leakage (seven) and intracranial cyst (one). The imaging protocol included T1-weighted magnetic resonance imaging with equal sequence parameters before and at multiple time points through 24 h after intrathecal injection of the contrast agent gadobutrol at the lumbar level. All study subjects were kept in the supine position between examinations during the first day. Gadobutrol enhancement was measured at all imaging time points from regions of interest placed at predefined locations in brain parenchyma, the subarachnoid and intraventricular space, and inside the sagittal sinus. Parameters demonstrating gadobutrol enhancement and clearance in different locations were compared between idiopathic normal pressure hydrocephalus and reference subjects. A characteristic flow pattern in idiopathic normal hydrocephalus was ventricular reflux of gadobutrol from the subarachnoid space followed by transependymal gadobutrol migration. At the brain surfaces, gadobutrol propagated antegradely along large leptomeningeal arteries in all study subjects, and preceded glymphatic enhancement in adjacent brain tissue, indicating a pivotal role of intracranial pulsations for glymphatic function. In idiopathic normal pressure hydrocephalus, we found delayed enhancement (P < 0.05) and decreased clearance of gadobutrol (P < 0.05) at the Sylvian fissure. Parenchymal (glymphatic) enhancement peaked overnight in both study groups, possibly indicating a crucial role of sleep, and was larger in normal pressure hydrocephalus patients (P < 0.05 at inferior frontal gyrus). We interpret decreased gadobutrol clearance from the subarachnoid space, along with persisting enhancement in brain parenchyma, as signs of reduced glymphatic clearance in idiopathic normal hydrocephalus, and hypothesize that reduced glymphatic function is instrumental for dementia in this disease. The study shows promise for glymphatic magnetic resonance imaging as a method to assess human brain metabolic function and renders a potential for contrast enhanced brain extravascular space imaging.
      PubDate: 2017-08-18
      DOI: 10.1093/brain/awx191
      Issue No: Vol. 140, No. 10 (2017)
       
  • The L444P Gba1 mutation enhances alpha-synuclein induced loss of nigral
           dopaminergic neurons in mice
    • Authors: Migdalska-Richards A; Wegrzynowicz M, Rusconi R, et al.
      Pages: 2706 - 2721
      Abstract: AbstractMutations in glucocerebrosidase 1 (GBA1) represent the most prevalent risk factor for Parkinson’s disease. The molecular mechanisms underlying the link between GBA1 mutations and Parkinson’s disease are incompletely understood. We analysed two aged (24-month-old) Gba1 mouse models, one carrying a knock-out mutation and the other a L444P knock-in mutation. A significant reduction of glucocerebrosidase activity was associated with increased total alpha-synuclein accumulation in both these models. Gba1 mutations alone did not alter the number of nigral dopaminergic neurons nor striatal dopamine levels. We then investigated the effect of overexpression of human alpha-synuclein in the substantia nigra of aged (18 to 21-month-old) L444P Gba1 mice. Following intraparenchymal injections of human alpha-synuclein carrying viral vectors, pathological accumulation of phosphorylated alpha-synuclein occurred within the transduced neurons. Stereological counts of nigral dopaminergic neurons revealed a significantly greater cell loss in Gba1-mutant than wild-type mice. These results indicate that Gba1 deficiency enhances neuronal vulnerability to neurodegenerative processes triggered by increased alpha-synuclein expression.
      PubDate: 2017-09-06
      DOI: 10.1093/brain/awx221
      Issue No: Vol. 140, No. 10 (2017)
       
  • A ventral glomerular deficit in Parkinson’s disease revealed by whole
           olfactory bulb reconstruction
    • Authors: Zapiec B; Dieriks BV, Tan S, et al.
      Pages: 2722 - 2736
      Abstract: AbstractOlfactory dysfunction is common in Parkinson’s disease and is an early symptom, but its pathogenesis remains poorly understood. Hindering progress in our mechanistic understanding of olfactory dysfunction in Parkinson’s disease is the paucity of literature about the human olfactory bulb, both from normal and Parkinson’s disease cases. Qualitatively it is well established that the neat arrangement of the glomerular array seen in the mouse olfactory bulb is missing in humans. But rigorous quantitative approaches to describe and compare the thousands of glomeruli in the human olfactory bulb are not available. Here we report a quantitative approach to describe the glomerular component of the human olfactory bulb, and its application to draw statistical comparisons between olfactory bulbs from normal and Parkinson’s disease cases. We subjected horizontal 10 µm sections of olfactory bulbs from six normal and five Parkinson’s disease cases to fluorescence immunohistochemistry with antibodies against vesicular glutamate transporter-2 and neural cell adhesion molecule. We scanned the immunostained sections with a fluorescence slide scanner, segmented the glomeruli, and generated 3D reconstructions of whole olfactory bulbs. We document the occurrence of atypical glomerular morphologies and glomerular-like structures deep in the olfactory bulb, both in normal and Parkinson’s disease cases. We define a novel and objective parameter: the global glomerular voxel volume, which is the total volume of all voxels that are classified immunohistochemically as glomerular. We find that the global glomerular voxel volume in Parkinson’s disease cases is half that of normal cases. The distribution of glomerular voxels along the dorsal-ventral dimension of the olfactory bulb in these series of horizontal sections is significantly altered in Parkinson’s disease cases: whereas most glomerular voxels reside within the ventral half of olfactory bulbs from normal cases, glomerular voxels are more evenly spread among the ventral and dorsal halves of olfactory bulbs from Parkinson’s disease cases. These quantitative whole-olfactory bulb analyses indicate a predominantly ventral deficit in the glomerular component in Parkinson’s disease, consistent with the olfactory vector hypothesis for the pathogenesis of this neurodegenerative disease. The distribution of serine 129-phosphorylated α-synuclein immunoreactive voxels correlates with that of glomerular voxels. The higher the serine 129-phosphorylated α-synuclein load of an olfactory bulb from a Parkinson’s disease case, the lower the global glomerular voxel volume. Our rigorous quantitative approach to the whole olfactory bulb will help understand the anatomy and histology of the normal human olfactory bulb and its pathological alterations in Parkinson’s disease.
      PubDate: 2017-09-03
      DOI: 10.1093/brain/awx208
      Issue No: Vol. 140, No. 10 (2017)
       
  • Distinct spatiotemporal patterns of neuronal functional connectivity in
           primary progressive aphasia variants
    • Authors: Ranasinghe KG; Hinkley LB, Beagle AJ, et al.
      Pages: 2737 - 2751
      Abstract: AbstractPrimary progressive aphasia is a syndrome characterized by progressive loss of language abilities with three main phenotypic clinical presentations, including logopenic, non-fluent/agrammatic, and semantic variants. Previous imaging studies have shown unique anatomic impacts within language networks in each variant. However, direct measures of spontaneous neuronal activity and functional integrity of these impacted neural networks in primary progressive aphasia are lacking. The aim of this study was to characterize the spatial and temporal patterns of resting state neuronal synchronizations in primary progressive aphasia syndromes. We hypothesized that resting state brain oscillations will show unique deficits within language network in each variant of primary progressive aphasia. We examined 39 patients with primary progressive aphasia including logopenic variant (n = 14, age = 61 ± 9 years), non-fluent/agrammatic variant (n = 12, age = 71 ± 8 years) and semantic variant (n = 13, age = 65 ± 7 years) using magnetoencephalographic imaging, compared to a control group that was matched in age and gender to each primary progressive aphasia subgroup (n = 20, age = 65 ± 5 years). Each patient underwent a complete clinical evaluation including a comprehensive battery of language tests. We examined the whole-brain resting state functional connectivity as measured by imaginary coherence in each patient group compared to the control cohort, in three frequency oscillation bands—delta-theta (2–8 Hz); alpha (8–12 Hz); beta (12–30 Hz). Each variant showed a distinct spatiotemporal pattern of altered functional connectivity compared to age-matched controls. Specifically, we found significant hyposynchrony of alpha and beta frequency within the left posterior temporal and occipital cortices in patients with the logopenic variant, within the left inferior frontal cortex in patients with the non-fluent/agrammatic variant, and within the left temporo-parietal junction in patients with the semantic variant. Patients with logopenic variant primary progressive aphasia also showed significant hypersynchrony of delta-theta frequency within bilateral medial frontal and posterior parietal cortices. Furthermore, region of interest-based analyses comparing the spatiotemporal patterns of variant-specific regions of interest identified in comparison to age-matched controls showed significant differences between primary progressive aphasia variants themselves. We also found distinct patterns of regional spectral power changes in each primary progressive aphasia variant, compared to age-matched controls. Our results demonstrate neurophysiological signatures of network-specific neuronal dysfunction in primary progressive aphasia variants. The unique spatiotemporal patterns of neuronal synchrony signify diverse neurophysiological disruptions and pathological underpinnings of the language network in each variant.
      PubDate: 2017-08-31
      DOI: 10.1093/brain/awx217
      Issue No: Vol. 140, No. 10 (2017)
       
  • Reconnecting with Joseph and Augusta Dejerine: 100 years on
    • Authors: Bajada CJ; Banks B, Lambon Ralph MA, et al.
      Pages: 2752 - 2759
      Abstract: Bajada et al. mark the centenary of Joseph Dejerine’s death by demonstrating the continuing relevance of his research with his long-standing collaborator, Augusta Dejerine-Klumpke, on the white matter pathways of the brain to modern-day connectional anatomy. A first English translation of the original work is provided in the Supplementary Materials.
      PubDate: 2017-09-15
      DOI: 10.1093/brain/awx225
      Issue No: Vol. 140, No. 10 (2017)
       
  • A singular person with multiple interests
    • Authors: Gardner-Thorpe C.
      Pages: 2760 - 2762
      PubDate: 2017-08-29
      DOI: 10.1093/brain/awx216
      Issue No: Vol. 140, No. 10 (2017)
       
 
 
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