Publisher: Oxford University Press   (Total: 412 journals)

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Showing 1 - 200 of 412 Journals sorted alphabetically
ACS Symposium Series     Full-text available via subscription   (Followers: 3, 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: 58, SJR: 2.196, CiteScore: 5)
Aesthetic Surgery J.     Hybrid Journal   (Followers: 7, SJR: 1.434, CiteScore: 1)
Aesthetic Surgery J. Open Forum     Open Access   (Followers: 1)
African Affairs     Hybrid Journal   (Followers: 73, SJR: 1.869, CiteScore: 2)
Age and Ageing     Hybrid Journal   (Followers: 93, SJR: 1.989, CiteScore: 4)
Alcohol and Alcoholism     Hybrid Journal   (Followers: 20, SJR: 1.376, CiteScore: 3)
American Entomologist     Hybrid Journal   (Followers: 8)
American Historical Review     Hybrid Journal   (Followers: 212, SJR: 0.467, CiteScore: 1)
American J. of Agricultural Economics     Hybrid Journal   (Followers: 54, SJR: 2.113, CiteScore: 3)
American J. of Clinical Nutrition     Hybrid Journal   (Followers: 226, SJR: 3.438, CiteScore: 6)
American J. of Epidemiology     Hybrid Journal   (Followers: 226, SJR: 2.713, CiteScore: 3)
American J. of Health-System Pharmacy     Full-text available via subscription   (Followers: 62, SJR: 0.595, CiteScore: 1)
American J. of Hypertension     Hybrid Journal   (Followers: 28, 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: 11, SJR: 0.116, CiteScore: 0)
American Law and Economics Review     Hybrid Journal   (Followers: 31, SJR: 1.053, CiteScore: 1)
American Literary History     Hybrid Journal   (Followers: 18, SJR: 0.391, CiteScore: 0)
Analysis     Hybrid Journal   (Followers: 25, SJR: 1.038, CiteScore: 1)
Animal Frontiers     Hybrid Journal   (Followers: 2)
Annals of Behavioral Medicine     Hybrid Journal   (Followers: 15, SJR: 1.423, CiteScore: 3)
Annals of Botany     Hybrid Journal   (Followers: 38, SJR: 1.721, CiteScore: 4)
Annals of Oncology     Hybrid Journal   (Followers: 62, SJR: 5.599, CiteScore: 9)
Annals of the Entomological Society of America     Full-text available via subscription   (Followers: 11, SJR: 0.722, CiteScore: 1)
Annals of Work Exposures and Health     Hybrid Journal   (Followers: 10, SJR: 0.728, CiteScore: 2)
Antibody Therapeutics     Open Access   (Followers: 1)
AoB Plants     Open Access   (Followers: 4, SJR: 1.28, CiteScore: 3)
Applied Economic Perspectives and Policy     Hybrid Journal   (Followers: 18, SJR: 0.858, CiteScore: 2)
Applied Linguistics     Hybrid Journal   (Followers: 66, 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: 20)
Arbitration Law Reports and Review     Hybrid Journal   (Followers: 14)
Archives of Clinical Neuropsychology     Hybrid Journal   (Followers: 33, SJR: 0.731, CiteScore: 2)
Aristotelian Society Supplementary Volume     Hybrid Journal   (Followers: 2)
Arthropod Management Tests     Hybrid Journal   (Followers: 2)
Astronomy & Geophysics     Hybrid Journal   (Followers: 47, SJR: 0.146, CiteScore: 0)
Behavioral Ecology     Hybrid Journal   (Followers: 58, SJR: 1.871, CiteScore: 3)
Bioinformatics     Hybrid Journal   (Followers: 391, SJR: 6.14, CiteScore: 8)
Biology Methods and Protocols     Open Access   (Followers: 1)
Biology of Reproduction     Full-text available via subscription   (Followers: 11, SJR: 1.446, CiteScore: 3)
Biometrika     Hybrid Journal   (Followers: 20, SJR: 3.485, CiteScore: 2)
BioScience     Hybrid Journal   (Followers: 30, SJR: 2.754, CiteScore: 4)
Bioscience Horizons : The National Undergraduate Research J.     Open Access   (Followers: 3, SJR: 0.146, CiteScore: 0)
Biostatistics     Hybrid Journal   (Followers: 18, SJR: 1.553, CiteScore: 2)
BJA : British J. of Anaesthesia     Hybrid Journal   (Followers: 227, SJR: 2.115, CiteScore: 3)
BJA Education     Hybrid Journal   (Followers: 69)
Brain     Hybrid Journal   (Followers: 76, SJR: 5.858, CiteScore: 7)
Brain Communications     Open Access   (Followers: 1)
Briefings in Bioinformatics     Hybrid Journal   (Followers: 53, 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: 41, SJR: 2.161, CiteScore: 2)
British J. of Aesthetics     Hybrid Journal   (Followers: 24, SJR: 0.508, CiteScore: 1)
British J. of Criminology     Hybrid Journal   (Followers: 619, SJR: 1.828, CiteScore: 3)
British J. of Social Work     Hybrid Journal   (Followers: 98, 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: 35)
Bulletin of the London Mathematical Society     Hybrid Journal   (Followers: 3, SJR: 1.376, CiteScore: 1)
Cambridge J. of Economics     Hybrid Journal   (Followers: 75, 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: 15, SJR: 3.002, CiteScore: 5)
Cerebral Cortex     Hybrid Journal   (Followers: 55, SJR: 3.892, CiteScore: 6)
CESifo Economic Studies     Hybrid Journal   (Followers: 24, SJR: 0.483, CiteScore: 1)
Chemical Senses     Hybrid Journal   (Followers: 1, SJR: 1.42, CiteScore: 3)
Children and Schools     Hybrid Journal   (Followers: 8, 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: 24, SJR: 0.329, CiteScore: 0)
Chinese J. of Intl. Politics     Hybrid Journal   (Followers: 11, 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: 29, SJR: 0.123, CiteScore: 0)
Clean Energy     Open Access   (Followers: 3)
Clinical Infectious Diseases     Hybrid Journal   (Followers: 78, SJR: 5.051, CiteScore: 5)
Communication Theory     Hybrid Journal   (Followers: 29, SJR: 2.424, CiteScore: 3)
Communication, Culture & Critique     Hybrid Journal   (Followers: 29, SJR: 0.222, CiteScore: 1)
Community Development J.     Hybrid Journal   (Followers: 28, 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: 11, SJR: 0.121, CiteScore: 0)
Contributions to Political Economy     Hybrid Journal   (Followers: 8, SJR: 0.906, CiteScore: 1)
Critical Values     Full-text available via subscription  
Current Developments in Nutrition     Open Access   (Followers: 5)
Current Legal Problems     Hybrid Journal   (Followers: 29)
Current Zoology     Full-text available via subscription   (Followers: 6, SJR: 1.164, CiteScore: 2)
Database : The J. of Biological Databases and Curation     Open Access   (Followers: 10, SJR: 1.791, CiteScore: 3)
Digital Scholarship in the Humanities     Hybrid Journal   (Followers: 15, SJR: 0.259, CiteScore: 1)
Diplomatic History     Hybrid Journal   (Followers: 24, SJR: 0.45, CiteScore: 1)
DNA Research     Open Access   (Followers: 6, 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: 34, SJR: 2.926, CiteScore: 1)
Economic J.     Hybrid Journal   (Followers: 124, SJR: 5.161, CiteScore: 3)
Economic Policy     Hybrid Journal   (Followers: 51, SJR: 3.584, CiteScore: 3)
ELT J.     Hybrid Journal   (Followers: 26, SJR: 0.942, CiteScore: 1)
English Historical Review     Hybrid Journal   (Followers: 59, SJR: 0.612, CiteScore: 1)
English: J. of the English Association     Hybrid Journal   (Followers: 22, SJR: 0.1, CiteScore: 0)
Environmental Entomology     Full-text available via subscription   (Followers: 12, 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: 22, SJR: 0.113, CiteScore: 0)
European Heart J.     Hybrid Journal   (Followers: 68, 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   (Followers: 1)
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: 234, 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: 22, SJR: 1.36, CiteScore: 2)
European Review of Agricultural Economics     Hybrid Journal   (Followers: 12, SJR: 1.172, CiteScore: 2)
European Review of Economic History     Hybrid Journal   (Followers: 31, SJR: 0.702, CiteScore: 1)
European Sociological Review     Hybrid Journal   (Followers: 46, SJR: 2.728, CiteScore: 3)
Evolution, Medicine, and Public Health     Open Access   (Followers: 12)
Family Practice     Hybrid Journal   (Followers: 16, SJR: 1.018, CiteScore: 2)
Fems Microbiology Ecology     Hybrid Journal   (Followers: 19, SJR: 1.492, CiteScore: 4)
Fems Microbiology Letters     Hybrid Journal   (Followers: 29, SJR: 0.79, CiteScore: 2)
Fems Microbiology Reviews     Hybrid Journal   (Followers: 38, 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: 26, 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: 36, 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: 17, SJR: 2.578, CiteScore: 4)
Geophysical J. Intl.     Hybrid Journal   (Followers: 38, SJR: 1.506, CiteScore: 3)
German History     Hybrid Journal   (Followers: 26, 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: 10, SJR: 1.493, CiteScore: 3)
Health and Social Work     Hybrid Journal   (Followers: 68, SJR: 0.388, CiteScore: 1)
Health Education Research     Hybrid Journal   (Followers: 19, SJR: 0.854, CiteScore: 2)
Health Policy and Planning     Hybrid Journal   (Followers: 26, SJR: 1.512, CiteScore: 2)
Health Promotion Intl.     Hybrid Journal   (Followers: 26, SJR: 0.812, CiteScore: 2)
History Workshop J.     Hybrid Journal   (Followers: 33, SJR: 1.278, CiteScore: 1)
Holocaust and Genocide Studies     Hybrid Journal   (Followers: 30, SJR: 0.105, CiteScore: 0)
Human Communication Research     Hybrid Journal   (Followers: 16, SJR: 2.146, CiteScore: 3)
Human Molecular Genetics     Hybrid Journal   (Followers: 11, SJR: 3.555, CiteScore: 5)
Human Reproduction     Hybrid Journal   (Followers: 77, SJR: 2.643, CiteScore: 5)
Human Reproduction Open     Open Access   (Followers: 1)
Human Reproduction Update     Hybrid Journal   (Followers: 19, SJR: 5.317, CiteScore: 10)
Human Rights Law Review     Hybrid Journal   (Followers: 66, 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: 3, 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: 12, SJR: 1.792, CiteScore: 2)
Industrial Law J.     Hybrid Journal   (Followers: 29, SJR: 0.249, CiteScore: 1)
Inflammatory Bowel Diseases     Hybrid Journal   (Followers: 46, SJR: 2.511, CiteScore: 4)
Information and Inference     Free  
Innovation in Aging     Open Access   (Followers: 1)
Insect Systematics and Diversity     Hybrid Journal  
Integrative and Comparative Biology     Hybrid Journal   (Followers: 10, SJR: 1.319, CiteScore: 2)
Integrative Biology     Full-text available via subscription   (Followers: 5, SJR: 1.36, CiteScore: 3)
Integrative Organismal Biology     Open Access  
Interacting with Computers     Hybrid Journal   (Followers: 10, SJR: 0.292, CiteScore: 1)
Interactive CardioVascular and Thoracic Surgery     Hybrid Journal   (Followers: 7, SJR: 0.762, CiteScore: 1)
Intl. Affairs     Hybrid Journal   (Followers: 71, SJR: 1.505, CiteScore: 3)
Intl. Data Privacy Law     Hybrid Journal   (Followers: 22)
Intl. Health     Hybrid Journal   (Followers: 7, SJR: 0.851, CiteScore: 2)
Intl. Immunology     Hybrid Journal   (Followers: 4, SJR: 2.167, CiteScore: 4)
Intl. J. for Quality in Health Care     Hybrid Journal   (Followers: 40, SJR: 1.348, CiteScore: 2)
Intl. J. of Constitutional Law     Hybrid Journal   (Followers: 56, SJR: 0.601, CiteScore: 1)
Intl. J. of Epidemiology     Hybrid Journal   (Followers: 289, 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: 20, SJR: 0.223, CiteScore: 1)
Intl. J. of Lexicography     Hybrid Journal   (Followers: 9, 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: 14, SJR: 0.724, CiteScore: 2)
Intl. Mathematics Research Notices     Hybrid Journal   (Followers: 1, SJR: 2.168, CiteScore: 1)
Intl. Political Sociology     Hybrid Journal   (Followers: 41, SJR: 1.465, CiteScore: 3)
Intl. Relations of the Asia-Pacific     Hybrid Journal   (Followers: 26, SJR: 0.401, CiteScore: 1)
Intl. Studies Perspectives     Hybrid Journal   (Followers: 9, SJR: 0.983, CiteScore: 1)
Intl. Studies Quarterly     Hybrid Journal   (Followers: 55, SJR: 2.581, CiteScore: 2)
Intl. Studies Review     Hybrid Journal   (Followers: 24, 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: 18, SJR: 0.533, CiteScore: 1)
J. of American History     Hybrid Journal   (Followers: 53, 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: 16, 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: 46, SJR: 1.226, CiteScore: 2)

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Similar Journals
Journal Cover
Journal Prestige (SJR): 5.858
Citation Impact (citeScore): 7
Number of Followers: 76  
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0006-8950 - ISSN (Online) 1460-2156
Published by Oxford University Press Homepage  [412 journals]
  • Inhibition between human brain areas or methodological artefact'
    • Authors: Sperber C; Karnath H.
      PubDate: Fri, 15 May 2020 00:00:00 GMT
      DOI: 10.1093/brain/awaa092
      Issue No: Vol. 143, No. 5 (2020)
  • Reply: Inhibition between human brain areas or methodological
    • Authors: Toba M; Malherbe C, Godefroy O, et al.
      Abstract: Sir,
      PubDate: Fri, 15 May 2020 00:00:00 GMT
      DOI: 10.1093/brain/awaa093
      Issue No: Vol. 143, No. 5 (2020)
  • Reply: The influence of sample size and arbitrary statistical thresholds
           in lesion-network mapping
    • Authors: Cohen A; Fox M.
      Abstract: Sir,
      PubDate: Mon, 04 May 2020 00:00:00 GMT
      DOI: 10.1093/brain/awaa095
      Issue No: Vol. 143, No. 5 (2020)
  • The influence of sample size and arbitrary statistical thresholds in
           lesion-network mapping
    • Authors: Sperber C; Dadashi A.
      PubDate: Mon, 04 May 2020 00:00:00 GMT
      DOI: 10.1093/brain/awaa094
      Issue No: Vol. 143, No. 5 (2020)
  • Primary brain calcification due to a homozygous MYORG mutation causing
           isolated paroxysmal kinesigenic dyskinesia
    • Authors: Saranza G; Grütz K, Klein C, et al.
      PubDate: Fri, 17 Apr 2020 00:00:00 GMT
      DOI: 10.1093/brain/awaa086
      Issue No: Vol. 143, No. 5 (2020)
  • Reply: Primary brain calcification due to a homozygous MYORG mutation
           causing isolated paroxysmal kinesigenic dyskinesia
    • Authors: Nicolas G; Grangeon L, Wallon D.
      PubDate: Thu, 16 Apr 2020 00:00:00 GMT
      DOI: 10.1093/brain/awaa087
      Issue No: Vol. 143, No. 5 (2020)
  • How to define migraine with brainstem aura'
    • Authors: Lempert T; Seemungal B.
      PubDate: Mon, 13 Apr 2020 00:00:00 GMT
      DOI: 10.1093/brain/awaa077
      Issue No: Vol. 143, No. 5 (2020)
  • Corrigendum
    • Abstract: Je-Yeon Yun, Premika S.W. Boedhoe, Chris Vriend, Neda Jahanshad, Yoshinari Abe, Stephanie H. Ameis, Alan Anticevic, Paul D. Arnold, Marcelo C. Batistuzzo, Francesco Benedetti, Jan C. Beucke, Irene Bollettini, Anushree Bose, Silvia Brem, Anna Calvo, Yuqi Cheng, Kang Ik K. Cho, Valentina Ciullo, Sara Dallaspezia, Damiaan Denys, Jamie D. Feusner, Jean-Paul Fouche, Mònica Giménez, Patricia Gruner, Derrek P. Hibar, Marcelo Q. Hoexter, Hao Hu, Chaim Huyser, Keisuke Ikari, Norbert Kathmann, Christian Kaufmann, Kathrin Koch, Luisa Lazaro, Christine Lochner, Paulo Marques, Rachel Marsh, Ignacio Martínez-Zalacaín, David Mataix-Cols, José M. Menchón, Luciano Minuzzi, Pedro Morgado, Pedro Moreira, Takashi Nakamae, Tomohiro Nakao, Janardhanan C. Narayanaswamy, Erika L. Nurmi, Joseph O’Neill, John Piacentini, Fabrizio Piras, Federica Piras, Y.C. Janardhan Reddy, Joao R. Sato, H. Blair Simpson, Noam Soreni, Carles Soriano-Mas, Gianfranco Spalletta, Michael C. Stevens, Philip R. Szeszko, David F. Tolin, Ganesan Venkatasubramanian, Susanne Walitza, Zhen Wang, Guido A. van Wingen, Jian Xu, Xiufeng Xu, Qing Zhao, ENIGMA-OCD working group, Paul M. Thompson, Dan J. Stein, Odile A. van den Heuvel, Jun Soo Kwon. Brain structural covariance networks in obsessive-compulsive disorder: a graph analysis from the ENIGMA Consortium. Brain 2020; 143: 684–700. doi:10.1093/brain/awaa001.
      PubDate: Thu, 12 Mar 2020 00:00:00 GMT
      DOI: 10.1093/brain/awaa061
      Issue No: Vol. 143, No. 5 (2020)
  • Corrigendum
    • Abstract: Valentina Perosa, Anastasia Priester, Gabriel Ziegler, Arturo Cardenas-Blanco, Laura Dobisch, Marco Spallazzi, Anne Assmann, Anne Maass, Oliver Speck, Jan Oltmer, Hans-Jochen Heinze, Stefanie Schreiber, Emrah Düzel. Hippocampal vascular reserve associated with cognitive performance and hippocampal volume. Brain 2020; 143: 622–634. doi:10.1093/brain/awz383.
      PubDate: Wed, 04 Mar 2020 00:00:00 GMT
      DOI: 10.1093/brain/awaa059
      Issue No: Vol. 143, No. 5 (2020)
  • Corrigendum
    • Abstract: Jonathan O’Muircheartaigh, Emma C. Robinson, Maximillian Pietsch, Thomas Wolfers, Paul Aljabar, Lucilio Cordero Grande, Rui P.A.G. Teixeira, Jelena Bozek, Andreas Schuh, Antonios Makropoulos, Dafnis Batalle, Jana Hutter, Katy Vecchiato, Johannes K. Steinweg, Sean Fitzgibbon, Emer Hughes, Anthony N. Price, Andre Marquand, Daniel Reuckert, Mary Rutherford, Joseph V. Hajnal, Serena J. Counsell, A. David Edwards. Modelling brain development to detect white matter injury in term and preterm born neonates. Brain 2020; 143: 467–479. doi:10.1093/brain/awz412.
      PubDate: Fri, 21 Feb 2020 00:00:00 GMT
      DOI: 10.1093/brain/awaa048
      Issue No: Vol. 143, No. 5 (2020)
  • Editorial
    • Authors: Kullmann D.
      Pages: 1285 - 1285
      Abstract: This month marks a year since Brain’s sister journal Brain Communications was launched. At the time of writing (late March 2020), Brain Communications has already published 59 original articles and two reviews, as well as two editorials by Tara Spires-Jones. This is by all accounts an impressive start for a new journal, not least because of the quality of the articles and their anticipated impact on the field. For instance, a paper by Dervis Salih and co-workers (2019), which argues that genetic variability in the microglial response to amyloid deposition is a major determinant for Alzheimer’s disease risk, has already accumulated five citations within 5 months of publication.
      PubDate: Thu, 21 May 2020 00:00:00 GMT
      DOI: 10.1093/brain/awaa118
      Issue No: Vol. 143, No. 5 (2020)
  • The NLRP3 inflammasome in progressive multiple sclerosis
    • Authors: Kadowaki A; Quintana F.
      Pages: 1286 - 1288
      Abstract: This scientific commentary refers to ‘NLRP3 inflammasome as prognostic factor and therapeutic target in primary progressive multiple sclerosis patients’, by Malhotra etal. (doi:10.1093/brain/awaa084).
      PubDate: Thu, 21 May 2020 00:00:00 GMT
      DOI: 10.1093/brain/awaa135
      Issue No: Vol. 143, No. 5 (2020)
  • Shaking with fear: the role of noradrenaline in modulating resting tremor
    • Authors: Taylor N; Müller E, Shine J.
      Pages: 1288 - 1291
      Abstract: This scientific commentary refers to ‘Cognitive load amplifies Parkinson’s tremor through excitatory network influences onto the thalamus’, by Dirkx etal. (doi: 10.1093/brain/awaa083).
      PubDate: Thu, 21 May 2020 00:00:00 GMT
      DOI: 10.1093/brain/awaa109
      Issue No: Vol. 143, No. 5 (2020)
  • Neither white nor black: embracing clinical variability in dementia
    • Authors: Piguet O.
      Pages: 1291 - 1293
      Abstract: This scientific commentary refers to ‘Redefining the multidimensional clinical phenotypes of frontotemporal lobar degeneration syndromes’, by Murley etal. (doi:10.1093/brain/awaa097).
      PubDate: Thu, 21 May 2020 00:00:00 GMT
      DOI: 10.1093/brain/awaa119
      Issue No: Vol. 143, No. 5 (2020)
  • Elucidating neural network changes induced by deep brain stimulation for
    • Authors: Kuhn J; Baldermann J.
      Pages: 1293 - 1296
      Abstract: This scientific commentary refers to ‘Deep brain stimulation modulates directional limbic connectivity in obsessive-compulsive disorder’, by Fridgeirsson etal. (doi:10.1093/brain/awaa100).
      PubDate: Thu, 21 May 2020 00:00:00 GMT
      DOI: 10.1093/brain/awaa108
      Issue No: Vol. 143, No. 5 (2020)
  • Microglia and macrophage phenotypes in intracerebral haemorrhage injury:
           therapeutic opportunities
    • Authors: Bai Q; Xue M, Yong V.
      Pages: 1297 - 1314
      Abstract: AbstractThe prognosis of intracerebral haemorrhage continues to be devastating despite much research into this condition. A prominent feature of intracerebral haemorrhage is neuroinflammation, particularly the excessive representation of pro-inflammatory CNS-intrinsic microglia and monocyte-derived macrophages that infiltrate from the circulation. The pro-inflammatory microglia/macrophages produce injury-enhancing factors, including inflammatory cytokines, matrix metalloproteinases and reactive oxygen species. Conversely, the regulatory microglia/macrophages with potential reparative and anti-inflammatory roles are outcompeted in the early stages after intracerebral haemorrhage, and their beneficial roles appear to be overwhelmed by pro-inflammatory microglia/macrophages. In this review, we describe the activation of microglia/macrophages following intracerebral haemorrhage in animal models and clinical subjects, and consider their multiple mechanisms of cellular injury after haemorrhage. We review strategies and medications aimed at suppressing the pro-inflammatory activities of microglia/macrophages, and those directed at elevating the regulatory properties of these myeloid cells after intracerebral haemorrhage. We consider the translational potential of these medications from preclinical models to clinical use after intracerebral haemorrhage injury, and suggest that several approaches still lack the experimental support necessary for use in humans. Nonetheless, the preclinical data support the use of deactivator or inhibitor of pro-inflammatory microglia/macrophages, whilst enhancing the regulatory phenotype, as part of the therapeutic approach to improve the prognosis of intracerebral haemorrhage.
      PubDate: Thu, 09 Jan 2020 00:00:00 GMT
      DOI: 10.1093/brain/awz393
      Issue No: Vol. 143, No. 5 (2020)
  • Relationship between cortical iron and tau aggregation in
           Alzheimer’s disease
    • Authors: Spotorno N; Acosta-Cabronero J, Stomrud E, et al.
      Pages: 1341 - 1349
      Abstract: AbstractA growing body of evidence suggests that the dysregulation of neuronal iron may play a critical role in Alzheimer’s disease. Recent MRI studies have established a relationship between iron accumulation and amyloid-β aggregation. The present study provides further insight demonstrating a relationship between iron and tau accumulation using magnetic resonance-based quantitative susceptibility mapping and tau-PET in n = 236 subjects with amyloid-β pathology (from the Swedish BioFINDER-2 study). Both voxel-wise and regional analyses showed a consistent association between differences in bulk magnetic susceptibility, which can be primarily ascribed to an increase in iron content, and tau-PET signal in regions known to be affected in Alzheimer’s disease. Subsequent analyses revealed that quantitative susceptibility specifically mediates the relationship between tau-PET and cortical atrophy measures, thus suggesting a modulatory effect of iron burden on the disease process. We also found evidence suggesting the relationship between quantitative susceptibility and tau-PET is stronger in younger participants (age ≤ 65). Together, these results provide in vivo evidence of an association between iron deposition and both tau aggregation and neurodegeneration, which help advance our understanding of the role of iron dysregulation in the Alzheimer’s disease aetiology.
      PubDate: Fri, 24 Apr 2020 00:00:00 GMT
      DOI: 10.1093/brain/awaa089
      Issue No: Vol. 143, No. 5 (2020)
  • In vivo stress granule misprocessing evidenced in a FUS knock-in ALS mouse
    • Authors: Zhang X; Wang F, Hu Y, et al.
      Pages: 1350 - 1367
      Abstract: AbstractMany RNA-binding proteins, including TDP-43, FUS, and TIA1, are stress granule components, dysfunction of which causes amyotrophic lateral sclerosis (ALS). However, whether a mutant RNA-binding protein disrupts stress granule processing in vivo in pathogenesis is unknown. Here we establish a FUS ALS mutation, p.R521C, knock-in mouse model that carries impaired motor ability and late-onset motor neuron loss. In disease-susceptible neurons, stress induces mislocalization of mutant FUS into stress granules and upregulation of ubiquitin, two hallmarks of disease pathology. Additionally, stress aggravates motor performance decline in the mutant mouse. By using two-photon imaging in TIA1-EGFP transduced animals, we document more intensely TIA1-EGFP-positive granules formed hours but cleared weeks after stress challenge in neurons in the mutant cortex. Moreover, neurons with severe granule misprocessing die days after stress challenge. Therefore, we argue that stress granule misprocessing is pathogenic in ALS, and the model we provide here is sound for further disease mechanistic study.
      PubDate: Fri, 01 May 2020 00:00:00 GMT
      DOI: 10.1093/brain/awaa076
      Issue No: Vol. 143, No. 5 (2020)
  • Corticospinal-motor neuronal plasticity promotes exercise-mediated
           recovery in humans with spinal cord injury
    • Authors: Jo H; Perez M.
      Pages: 1368 - 1382
      Abstract: AbstractRehabilitative exercise in humans with spinal cord injury aims to engage residual neural networks to improve functional recovery. We hypothesized that exercise combined with non-invasive stimulation targeting spinal synapses further promotes functional recovery. Twenty-five individuals with chronic incomplete cervical, thoracic, and lumbar spinal cord injury were randomly assigned to 10 sessions of exercise combined with paired corticospinal-motor neuronal stimulation (PCMS) or sham-PCMS. In an additional experiment, we tested the effect of PCMS without exercise in 13 individuals with spinal cord injury with similar characteristics. During PCMS, 180 pairs of stimuli were timed to have corticospinal volleys evoked by transcranial magnetic stimulation over the primary motor cortex arrive at corticospinal-motor neuronal synapses of upper- or lower-limb muscles (depending on the injury level), 1–2 ms before antidromic potentials were elicited in motor neurons by electrical stimulation of a peripheral nerve. Participants exercised for 45 min after all protocols. We found that the time to complete subcomponents of the Graded and Redefined Assessment of Strength, Sensibility and Prehension (GRASSP) and the 10-m walk test decreased on average by 20% after all protocols. However, the amplitude of corticospinal responses elicited by transcranial magnetic stimulation and the magnitude of maximal voluntary contractions in targeted muscles increased on overage by 40–50% after PCMS combined or not with exercise but not after sham-PCMS combined with exercise. Notably, behavioural and physiological effects were preserved 6 months after the intervention in the group receiving exercise with PCMS but not in the group receiving exercise combined with sham-PCMS, suggesting that the stimulation contributed to preserve exercise gains. Our findings indicate that targeted non-invasive stimulation of spinal synapses might represent an effective strategy to facilitate exercise-mediated recovery in humans with different degrees of paralysis and levels of spinal cord injury.
      PubDate: Fri, 01 May 2020 00:00:00 GMT
      DOI: 10.1093/brain/awaa052
      Issue No: Vol. 143, No. 5 (2020)
  • Neural stem cells restore myelin in a demyelinating model of
           Pelizaeus-Merzbacher disease
    • Authors: Gruenenfelder F; McLaughlin M, Griffiths I, et al.
      Pages: 1383 - 1399
      Abstract: AbstractPelizaeus-Merzbacher disease is a fatal X-linked leukodystrophy caused by mutations in the PLP1 gene, which is expressed in the CNS by oligodendrocytes. Disease onset, symptoms and mortality span a broad spectrum depending on the nature of the mutation and thus the degree of CNS hypomyelination. In the absence of an effective treatment, direct cell transplantation into the CNS to restore myelin has been tested in animal models of severe forms of the disease with failure of developmental myelination, and more recently, in severely affected patients with early disease onset due to point mutations in the PLP1 gene, and absence of myelin by MRI. In patients with a PLP1 duplication mutation, the most common cause of Pelizaeus-Merzbacher disease, the pathology is poorly defined because of a paucity of autopsy material. To address this, we examined two elderly patients with duplication of PLP1 in whom the overall syndrome, including end-stage pathology, indicated a complex disease involving dysmyelination, demyelination and axonal degeneration. Using the corresponding Plp1 transgenic mouse model, we then tested the capacity of transplanted neural stem cells to restore myelin in the context of PLP overexpression. Although developmental myelination and axonal coverage by endogenous oligodendrocytes was extensive, as assessed using electron microscopy (n = 3 at each of four end points) and immunostaining (n = 3 at each of four end points), wild-type neural precursors, transplanted into the brains of the newborn mutants, were able to effectively compete and replace the defective myelin (n = 2 at each of four end points). These data demonstrate the potential of neural stem cell therapies to restore normal myelination and protect axons in patients with PLP1 gene duplication mutation and further, provide proof of principle for the benefits of stem cell transplantation for other fatal leukodystrophies with ‘normal’ developmental myelination.
      PubDate: Mon, 18 May 2020 00:00:00 GMT
      DOI: 10.1093/brain/awaa080
      Issue No: Vol. 143, No. 5 (2020)
  • Early clinical markers of aggressive multiple sclerosis
    • Authors: Malpas C; , Manouchehrinia A, et al.
      Pages: 1400 - 1413
      Abstract: AbstractPatients with the ‘aggressive’ form of multiple sclerosis accrue disability at an accelerated rate, typically reaching Expanded Disability Status Score (EDSS) ≥ 6 within 10 years of symptom onset. Several clinicodemographic factors have been associated with aggressive multiple sclerosis, but less research has focused on clinical markers that are present in the first year of disease. The development of early predictive models of aggressive multiple sclerosis is essential to optimize treatment in this multiple sclerosis subtype. We evaluated whether patients who will develop aggressive multiple sclerosis can be identified based on early clinical markers. We then replicated this analysis in an independent cohort. Patient data were obtained from the MSBase observational study. Inclusion criteria were (i) first recorded disability score (EDSS) within 12 months of symptom onset; (ii) at least two recorded EDSS scores; and (iii) at least 10 years of observation time, based on time of last recorded EDSS score. Patients were classified as having ‘aggressive multiple sclerosis’ if all of the following criteria were met: (i) EDSS ≥ 6 reached within 10 years of symptom onset; (ii) EDSS ≥ 6 confirmed and sustained over ≥6 months; and (iii) EDSS ≥ 6 sustained until the end of follow-up. Clinical predictors included patient variables (sex, age at onset, baseline EDSS, disease duration at first visit) and recorded relapses in the first 12 months since disease onset (count, pyramidal signs, bowel-bladder symptoms, cerebellar signs, incomplete relapse recovery, steroid administration, hospitalization). Predictors were evaluated using Bayesian model averaging. Independent validation was performed using data from the Swedish Multiple Sclerosis Registry. Of the 2403 patients identified, 145 were classified as having aggressive multiple sclerosis (6%). Bayesian model averaging identified three statistical predictors: age > 35 at symptom onset, EDSS ≥ 3 in the first year, and the presence of pyramidal signs in the first year. This model significantly predicted aggressive multiple sclerosis [area under the curve (AUC) = 0.80, 95% confidence intervals (CIs): 0.75, 0.84, positive predictive value = 0.15, negative predictive value = 0.98]. The presence of all three signs was strongly predictive, with 32% of such patients meeting aggressive disease criteria. The absence of all three signs was associated with a 1.4% risk. Of the 556 eligible patients in the Swedish Multiple Sclerosis Registry cohort, 34 (6%) met criteria for aggressive multiple sclerosis. The combination of all three signs was also predictive in this cohort (AUC = 0.75, 95% CIs: 0.66, 0.84, positive predictive value = 0.15, negative predictive value = 0.97). Taken together, these findings suggest that older age at symptom onset, greater disability during the first year, and pyramidal signs in the first year are early indicators of aggressive multiple sclerosis.
      PubDate: Sat, 09 May 2020 00:00:00 GMT
      DOI: 10.1093/brain/awaa081
      Issue No: Vol. 143, No. 5 (2020)
  • NLRP3 inflammasome as prognostic factor and therapeutic target in primary
           progressive multiple sclerosis patients
    • Authors: Malhotra S; Costa C, Eixarch H, et al.
      Pages: 1414 - 1430
      Abstract: AbstractPrimary progressive multiple sclerosis is a poorly understood disease entity with no specific prognostic biomarkers and scarce therapeutic options. We aimed to identify disease activity biomarkers in multiple sclerosis by performing an RNA sequencing approach in peripheral blood mononuclear cells from a discovery cohort of 44 untreated patients with multiple sclerosis belonging to different clinical forms and activity phases of the disease, and 12 healthy control subjects. A validation cohort of 58 patients with multiple sclerosis and 26 healthy control subjects was included in the study to replicate the RNA sequencing findings. The RNA sequencing revealed an interleukin 1 beta (IL1B) signature in patients with primary progressive multiple sclerosis. Subsequent immunophenotyping pointed to blood monocytes as responsible for the IL1B signature observed in this group of patients. Functional experiments at baseline measuring apoptosis-associated speck-like protein containing a CARD (ASC) speck formation showed that the NOD-leucine rich repeat and pyrin containing protein 3 (NLRP3) inflammasome was overactive in monocytes from patients with primary progressive multiple sclerosis, and canonical NLRP3 inflammasome activation with a combination of ATP plus lipopolysaccharide was associated with increased IL1B production in this group of patients. Primary progressive multiple sclerosis patients with high IL1B gene expression levels in peripheral blood mononuclear cells progressed significantly faster compared to patients with low IL1B levels based on the time to reach an EDSS of 6.0 and the Multiple Sclerosis Severity Score. In agreement with peripheral blood findings, both NLRP3 and IL1B expression in brain tissue from patients with primary progressive multiple sclerosis was mainly restricted to cells of myeloid lineage. Treatment of mice with a specific NLRP3 inflammasome inhibitor attenuated established experimental autoimmune encephalomyelitis disease severity and improved CNS histopathology. NLRP3 inflammasome-specific inhibition was also effective in reducing axonal damage in a model of lipopolysaccharide-neuroinflammation using organotypic cerebellar cultures. Altogether, these results point to a role of IL1B and the NLRP3 inflammasome as prognostic biomarker and potential therapeutic target, respectively, in patients with primary progressive multiple sclerosis.
      PubDate: Mon, 13 Apr 2020 00:00:00 GMT
      DOI: 10.1093/brain/awaa084
      Issue No: Vol. 143, No. 5 (2020)
  • Myelin oligodendrocyte glycoprotein antibody-associated disease: an
           immunopathological study
    • Authors: Takai Y; Misu T, Kaneko K, et al.
      Pages: 1431 - 1446
      Abstract: AbstractConformation-sensitive antibodies against myelin oligodendrocyte glycoprotein (MOG) are detectable in patients with optic neuritis, myelitis, opticomyelitis, acute or multiphasic disseminated encephalomyelitis (ADEM/MDEM) and brainstem/cerebral cortical encephalitis, but are rarely detected in patients with prototypic multiple sclerosis. So far, there has been no systematic study on the pathological relationship between demyelinating lesions and cellular/humoral immunity in MOG antibody-associated disease. Furthermore, it is unclear whether the pathomechanisms of MOG antibody-mediated demyelination are similar to the demyelination patterns of multiple sclerosis, neuromyelitis optica spectrum disorders (NMOSD) with AQP4 antibody, or ADEM. In this study, we immunohistochemically analysed biopsied brain tissues from 11 patients with MOG antibody-associated disease and other inflammatory demyelinating diseases. Patient median onset age was 29 years (range 9–64), and the median interval from attack to biopsy was 1 month (range 0.5–96). The clinical diagnoses were ADEM (n = 2), MDEM (n = 1), multiple brain lesions without encephalopathy (n = 3), leukoencephalopathy (n = 3) and cortical encephalitis (n = 2). All these cases had multiple/extensive lesions on MRI and were oligoclonal IgG band-negative. Most demyelinating lesions in 10 of 11 cases showed a perivenous demyelinating pattern previously reported in ADEM (153/167 lesions) and a fusion pattern (11/167 lesions) mainly in the cortico-medullary junctions and white matter, and only three lesions in two cases showed confluent demyelinated plaques. In addition, 60 of 167 demyelinating lesions (mainly in the early phase) showed MOG-dominant myelin loss, but relatively preserved oligodendrocytes, which were distinct from those of AQP4 antibody-positive NMOSD exhibiting myelin-associated glycoprotein-dominant oligodendrogliopathy. In MOG antibody-associated diseases, MOG-laden macrophages were found in the perivascular spaces and demyelinating lesions, and infiltrated cells were abundant surrounding multiple blood vessels in and around the demyelinating lesions, mainly consisting of macrophages (CD68; 1814 ± 1188 cells/mm2), B cells (CD20; 468 ± 817 cells/mm2), and T cells (CD3; 2286 ± 1951 cells/mm2), with CD4-dominance (CD4+ versus CD8+; 1281 ± 1196 cells/mm2 versus 851 ± 762 cells/mm2, P < 0.01). Humoral immunity, evidenced by perivascular deposits of activated complements and immunoglobulins, was occasionally observed in some MOG antibody-associated demyelinating lesions, and the frequency was much lower than that in AQP4 antibody-positive NMOSD. Subpial lesions with perivenous demyelination were observed in both ADEM and cortical encephalitis. Our study suggests that ADEM-like perivenous inflammatory demyelination with MOG-dominant myelin loss is a characteristic finding of MOG antibody-associated disease regardless of whether the diagnostic criteria of ADEM are met. These pathological features are clearly different from those of multiple sclerosis and AQP4 antibody-positive NMOSD, suggesting an independent autoimmune demyelinating disease entity.
      PubDate: Fri, 15 May 2020 00:00:00 GMT
      DOI: 10.1093/brain/awaa102
      Issue No: Vol. 143, No. 5 (2020)
  • Bi-allelic GAD1 variants cause a neonatal onset syndromic developmental
           and epileptic encephalopathy
    • Authors: Chatron N; Becker F, Morsy H, et al.
      Pages: 1447 - 1461
      Abstract: AbstractDevelopmental and epileptic encephalopathies are a heterogeneous group of early-onset epilepsy syndromes dramatically impairing neurodevelopment. Modern genomic technologies have revealed a number of monogenic origins and opened the door to therapeutic hopes. Here we describe a new syndromic developmental and epileptic encephalopathy caused by bi-allelic loss-of-function variants in GAD1, as presented by 11 patients from six independent consanguineous families. Seizure onset occurred in the first 2 months of life in all patients. All 10 patients, from whom early disease history was available, presented with seizure onset in the first month of life, mainly consisting of epileptic spasms or myoclonic seizures. Early EEG showed suppression-burst or pattern of burst attenuation or hypsarrhythmia if only recorded in the post-neonatal period. Eight patients had joint contractures and/or pes equinovarus. Seven patients presented a cleft palate and two also had an omphalocele, reproducing the phenotype of the knockout Gad1−/− mouse model. Four patients died before 4 years of age. GAD1 encodes the glutamate decarboxylase enzyme GAD67, a critical actor of the γ-aminobutyric acid (GABA) metabolism as it catalyses the decarboxylation of glutamic acid to form GABA. Our findings evoke a novel syndrome related to GAD67 deficiency, characterized by the unique association of developmental and epileptic encephalopathies, cleft palate, joint contractures and/or omphalocele.
      PubDate: Mon, 13 Apr 2020 00:00:00 GMT
      DOI: 10.1093/brain/awaa085
      Issue No: Vol. 143, No. 5 (2020)
  • Bidirectional gut-to-brain and brain-to-gut propagation of synucleinopathy
           in non-human primates
    • Authors: Arotcarena M; Dovero S, Prigent A, et al.
      Pages: 1462 - 1475
      Abstract: AbstractIn Parkinson’s disease, synucleinopathy is hypothesized to spread from the enteric nervous system, via the vagus nerve, to the CNS. Here, we compare, in baboon monkeys, the pathological consequences of either intrastriatal or enteric injection of α-synuclein-containing Lewy body extracts from patients with Parkinson’s disease. This study shows that patient-derived α-synuclein aggregates are able to induce nigrostriatal lesions and enteric nervous system pathology after either enteric or striatal injection in a non-human primate model. This finding suggests that the progression of α-synuclein pathology might be either caudo-rostral or rostro-caudal, varying between patients and disease subtypes. In addition, we report that α-synuclein pathological lesions were not found in the vagal nerve in our experimental setting. This study does not support the hypothesis of a transmission of α-synuclein pathology through the vagus nerve and the dorsal motor nucleus of the vagus. Instead, our results suggest a possible systemic mechanism in which the general circulation would act as a route for long-distance bidirectional transmission of endogenous α-synuclein between the enteric and the central nervous systems. Taken together, our study provides invaluable primate data exploring the role of the gut-brain axis in the initiation and propagation of Parkinson’s disease pathology and should open the door to the development and testing of new therapeutic approaches aimed at interfering with the development of sporadic Parkinson’s disease.
      PubDate: Thu, 07 May 2020 00:00:00 GMT
      DOI: 10.1093/brain/awaa096
      Issue No: Vol. 143, No. 5 (2020)
  • Microglial exosomes facilitate α-synuclein transmission in
           Parkinson’s disease
    • Authors: Guo M; Wang J, Zhao Y, et al.
      Pages: 1476 - 1497
      Abstract: AbstractAccumulation of neuronal α-synuclein is a prominent feature in Parkinson’s disease. More recently, such abnormal protein aggregation has been reported to spread from cell to cell and exosomes are considered as important mediators. The focus of such research, however, has been primarily in neurons. Given the increasing recognition of the importance of non-cell autonomous-mediated neurotoxicity, it is critical to investigate the contribution of glia to α-synuclein aggregation and spread. Microglia are the primary phagocytes in the brain and have been well-documented as inducers of neuroinflammation. How and to what extent microglia and their exosomes impact α-synuclein pathology has not been well delineated. We report here that when treated with human α-synuclein preformed fibrils, exosomes containing α-synuclein released by microglia are fully capable of inducing protein aggregation in the recipient neurons. Additionally, when combined with microglial proinflammatory cytokines, these exosomes further increased protein aggregation in neurons. Inhibition of exosome synthesis in microglia reduced α-synuclein transmission. The in vivo significance of these exosomes was demonstrated by stereotaxic injection of exosomes isolated from α-synuclein preformed fibrils treated microglia into the mouse striatum. Phosphorylated α-synuclein was observed in multiple brain regions consistent with their neuronal connectivity. These animals also exhibited neurodegeneration in the nigrostriatal pathway in a time-dependent manner. Depleting microglia in vivo dramatically suppressed the transmission of α-synuclein after stereotaxic injection of preformed fibrils. Mechanistically, we report here that α-synuclein preformed fibrils impaired autophagy flux by upregulating PELI1, which in turn, resulted in degradation of LAMP2 in activated microglia. More importantly, by purifying microglia/macrophage derived exosomes in the CSF of Parkinson’s disease patients, we confirmed the presence of α-synuclein oligomer in CD11b+ exosomes, which were able to induce α-synuclein aggregation in neurons, further supporting the translational aspect of this study. Taken together, our study supports the view that microglial exosomes contribute to the progression of α-synuclein pathology and therefore, they may serve as a promising therapeutic target for Parkinson’s disease.
      PubDate: Fri, 01 May 2020 00:00:00 GMT
      DOI: 10.1093/brain/awaa090
      Issue No: Vol. 143, No. 5 (2020)
  • Cognitive load amplifies Parkinson’s tremor through excitatory network
           influences onto the thalamus
    • Authors: Dirkx M; Zach H, van Nuland A, et al.
      Pages: 1498 - 1511
      Abstract: AbstractParkinson’s tremor is related to cerebral activity in both the basal ganglia and a cerebello-thalamo-cortical circuit. It is a common clinical observation that tremor markedly increases during cognitive load (such as mental arithmetic), leading to serious disability. Previous research has shown that this tremor amplification is associated with reduced efficacy of dopaminergic treatment. Understanding the mechanisms of tremor amplification and its relation to catecholamines might help to better control this symptom with a targeted therapy. We reasoned that, during cognitive load, tremor amplification might result from modulatory influences onto the cerebello-thalamo-cortical circuit controlling tremor amplitude, from the ascending arousal system (bottom-up), a cognitive control network (top-down), or their combination. We have tested these hypotheses by measuring concurrent EMG and functional MRI in 33 patients with tremulous Parkinson’s disease, OFF medication, during alternating periods of rest and cognitive load (mental arithmetic). Simultaneous heart rate and pupil diameter recordings indexed activity of the arousal system (which includes noradrenergic afferences). As expected, tremor amplitude correlated with activity in a cerebello-thalamo-cortical circuit; and cognitive load increased tremor amplitude, pupil diameter, heart rate, and cerebral activity in a cognitive control network distributed over fronto-parietal cortex, insula, thalamus and anterior cingulate cortex. The novel finding, obtained through network analyses, indicates that cognitive load influences tremor by increasing activity in the cerebello-thalamo-cortical circuit in two different ways: by stimulating thalamic activity, likely through the ascending arousal system (given that this modulation correlated with changes in pupil diameter), and by strengthening connectivity between the cognitive control network and the cerebello-thalamo-cortical circuit. We conclude that both the bottom-up arousal system and a top-down cognitive control network amplify tremor when a Parkinson’s patient experiences cognitive load. Interventions aimed at attenuating noradrenergic activity or cognitive demands may help to reduce Parkinson’s tremor.
      PubDate: Fri, 01 May 2020 00:00:00 GMT
      DOI: 10.1093/brain/awaa083
      Issue No: Vol. 143, No. 5 (2020)
  • Isolation of infectious, non-fibrillar and oligomeric prions from a
           genetic prion disease
    • Authors: Vanni I; Pirisinu L, Acevedo-Morantes C, et al.
      Pages: 1512 - 1524
      Abstract: AbstractPrions are transmissible agents causing lethal neurodegenerative diseases that are composed of aggregates of misfolded cellular prion protein (PrPSc). Despite non-fibrillar oligomers having been proposed as the most infectious prion particles, prions purified from diseased brains usually consist of large and fibrillar PrPSc aggregates, whose protease-resistant core (PrPres) encompasses the whole C-terminus of PrP. In contrast, PrPSc from Gerstmann-Sträussler-Scheinker disease associated with alanine to valine substitution at position 117 (GSS-A117V) is characterized by a small protease-resistant core, which is devoid of the C-terminus. We thus aimed to investigate the role of this unusual PrPSc in terms of infectivity, strain characteristics, and structural features. We found, by titration in bank voles, that the infectivity of GSS-A117V is extremely high (109.3 ID50 U/g) and is resistant to treatment with proteinase K (109.0 ID50 U/g). We then purified the proteinase K-resistant GSS-A117V prions and determined the amount of infectivity and PrPres in the different fractions, alongside the morphological characteristics of purified PrPres aggregates by electron microscopy. Purified pellet fractions from GSS-A117V contained the expected N- and C-terminally cleaved 7 kDa PrPres, although the yield of PrPres was low. We found that this low yield depended on the low density/small size of GSS-A117V PrPres, as it was mainly retained in the last supernatant fraction. All fractions were highly infectious, thus confirming the infectious nature of the 7 kDa PrPres, with infectivity levels that directly correlated with the PrPres amount detected. Finally, electron microscopy analysis of these fractions showed no presence of amyloid fibrils, but only very small and indistinct, non-fibrillar PrPresparticles were detected and confirmed to contain PrP via immunogold labelling. Our study demonstrates that purified aggregates of 7 kDa PrPres, spanning residues ∼90–150, are highly infectious oligomers that encode the biochemical and biological strain features of the original sample. Overall, the autocatalytic behaviour of the prion oligomers reveals their role in the propagation of neurodegeneration in patients with Gerstmann-Sträussler-Scheinker disease and implies that the C-terminus of PrPSc is dispensable for infectivity and strain features for this prion strain, uncovering the central PrP domain as the minimal molecular component able to encode infectious prions. These findings are consistent with the hypothesis that non-fibrillar prion particles are highly efficient propagators of disease and provide new molecular and morphological constraints on the structure of infectious prions.
      PubDate: Fri, 17 Apr 2020 00:00:00 GMT
      DOI: 10.1093/brain/awaa078
      Issue No: Vol. 143, No. 5 (2020)
  • Acute ischaemic stroke alters the brain’s preference for distinct
           dynamic connectivity states
    • Authors: Bonkhoff A; Espinoza F, Gazula H, et al.
      Pages: 1525 - 1540
      Abstract: AbstractAcute ischaemic stroke disturbs healthy brain organization, prompting subsequent plasticity and reorganization to compensate for the loss of specialized neural tissue and function. Static resting state functional MRI studies have already furthered our understanding of cerebral reorganization by estimating stroke-induced changes in network connectivity aggregated over the duration of several minutes. In this study, we used dynamic resting state functional MRI analyses to increase temporal resolution to seconds and explore transient configurations of motor network connectivity in acute stroke. To this end, we collected resting state functional MRI data of 31 patients with acute ischaemic stroke and 17 age-matched healthy control subjects. Stroke patients presented with moderate to severe hand motor deficits. By estimating dynamic functional connectivity within a sliding window framework, we identified three distinct connectivity configurations of motor-related networks. Motor networks were organized into three regional domains, i.e. a cortical, subcortical and cerebellar domain. The dynamic connectivity patterns of stroke patients diverged from those of healthy controls depending on the severity of the initial motor impairment. Moderately affected patients (n = 18) spent significantly more time in a weakly connected configuration that was characterized by low levels of connectivity, both locally as well as between distant regions. In contrast, severely affected patients (n = 13) showed a significant preference for transitions into a spatially segregated connectivity configuration. This configuration featured particularly high levels of local connectivity within the three regional domains as well as anti-correlated connectivity between distant networks across domains. A third connectivity configuration represented an intermediate connectivity pattern compared to the preceding two, and predominantly encompassed decreased interhemispheric connectivity between cortical motor networks independent of individual deficit severity. Alterations within this third configuration thus closely resembled previously reported ones originating from static resting state functional MRI studies post-stroke. In summary, acute ischaemic stroke not only prompted changes in connectivity between distinct networks, but it also caused characteristic changes in temporal properties of large-scale network interactions depending on the severity of the individual deficit. These findings offer new vistas on the dynamic neural mechanisms underlying acute neurological symptoms, cortical reorganization and treatment effects in stroke patients.
      PubDate: Fri, 01 May 2020 00:00:00 GMT
      DOI: 10.1093/brain/awaa101
      Issue No: Vol. 143, No. 5 (2020)
  • A unified model of post-stroke language deficits including discourse
           production and their neural correlates
    • Authors: Alyahya R; Halai A, Conroy P, et al.
      Pages: 1541 - 1554
      Abstract: AbstractThe clinical profiles of individuals with post-stroke aphasia demonstrate considerable variation in the presentation of symptoms. Recent aphasiological studies have attempted to account for this individual variability using a multivariate data-driven approach (principal component analysis) on an extensive neuropsychological and aphasiological battery, to identify fundamental domains of post-stroke aphasia. These domains mainly reflect phonology, semantics and fluency; however, these studies did not account for variability in response to different forms of connected speech, i.e. discourse genres. In the current study, we initially examined differences in the quantity, diversity and informativeness between three different discourse genres, including a simple descriptive genre and two naturalistic forms of connected speech (storytelling narrative, and procedural discourse). Subsequently, we provided the first quantitative investigation on the multidimensionality of connected speech production at both behavioural and neural levels. Connected speech samples across descriptive, narrative, and procedural discourse genres were collected from 46 patients with chronic post-stroke aphasia and 20 neurotypical adults. Content analyses conducted on all connected speech samples indicated that performance differed across discourse genres and between groups. Specifically, storytelling narratives provided higher quantities of content words and lexical diversity compared to composite picture description and procedural discourse. The analyses further revealed that, relative to neurotypical adults, patients with aphasia, both fluent and non-fluent, showed reduction in the quantity of verbal production, lexical diversity, and informativeness across all discourses. Given the differences across the discourses, we submitted the connected speech metrics to principal component analysis alongside an extensive neuropsychological/aphasiological battery that assesses a wide range of language and cognitive skills. In contrast to previous research, three unique orthogonal connected speech components were extracted in a unified model, reflecting verbal quantity, verbal quality, and motor speech, alongside four core language and cognitive components: phonological production, semantic processing, phonological recognition, and executive functions. Voxel-wise lesion-symptom mapping using these components provided evidence on the involvement of widespread cortical regions and their white matter connections. Specifically, left frontal regions and their underlying white matter tracts corresponding to the frontal aslant tract and the anterior segment of the arcuate fasciculus were particularly engaged with the quantity and quality of fluent connected speech production while controlling for other co-factors. The neural correlates associated with the other language domains align with existing models on the ventral and dorsal pathways for language processing.
      PubDate: Fri, 24 Apr 2020 00:00:00 GMT
      DOI: 10.1093/brain/awaa074
      Issue No: Vol. 143, No. 5 (2020)
  • Redefining the multidimensional clinical phenotypes of frontotemporal
           lobar degeneration syndromes
    • Authors: Murley A; Coyle-Gilchrist I, Rouse M, et al.
      Pages: 1555 - 1571
      Abstract: AbstractThe syndromes caused by frontotemporal lobar degeneration have highly heterogeneous and overlapping clinical features. There has been great progress in the refinement of clinical diagnostic criteria in the past decade, but we propose that a better understanding of aetiology, pathophysiology and symptomatic treatments can arise from a transdiagnostic approach to clinical phenotype and brain morphometry. In a cross-sectional epidemiological study, we examined 310 patients with a syndrome likely to be caused by frontotemporal lobar degeneration, including behavioural variant frontotemporal dementia, non-fluent, and semantic variants of primary progressive aphasia (PPA), progressive supranuclear palsy and corticobasal syndrome. We included patients with logopenic PPA and those who met criteria for PPA but not a specific subtype. To date, 49 patients have a neuropathological diagnosis. A principal component analysis identified symptom dimensions that broadly recapitulated the core features of the main clinical syndromes. However, the subject-specific scores on these dimensions showed considerable overlap across the diagnostic groups. Sixty-two per cent of participants had phenotypic features that met the diagnostic criteria for more than one syndrome. Behavioural disturbance was prevalent in all groups. Forty-four per cent of patients with corticobasal syndrome had progressive supranuclear palsy-like features and 30% of patients with progressive supranuclear palsy had corticobasal syndrome-like features. Many patients with progressive supranuclear palsy and corticobasal syndrome had language impairments consistent with non-fluent variant PPA while patients with behavioural variant frontotemporal dementia often had semantic impairments. Using multivariate source-based morphometry on a subset of patients (n = 133), we identified patterns of covarying brain atrophy that were represented across the diagnostic groups. Canonical correlation analysis of clinical and imaging components found three key brain-behaviour relationships, with a continuous spectrum across the cohort rather than discrete diagnostic entities. In the 46 patients with follow-up (mean 3.6 years) syndromic overlap increased with time. Together, these results show that syndromes associated with frontotemporal lobar degeneration do not form discrete mutually exclusive categories from their clinical features or structural brain changes, but instead exist in a multidimensional spectrum. Patients often manifest diagnostic features of multiple disorders while deficits in behaviour, movement and language domains are not confined to specific diagnostic groups. It is important to recognize individual differences in clinical phenotype, both for clinical management and to understand pathogenic mechanisms. We suggest that a transdiagnostic approach to the spectrum of frontotemporal lobar degeneration syndromes provides a useful framework with which to understand disease aetiology, progression, and heterogeneity and to target future treatments to a higher proportion of patients.
      PubDate: Fri, 01 May 2020 00:00:00 GMT
      DOI: 10.1093/brain/awaa097
      Issue No: Vol. 143, No. 5 (2020)
  • Tau immunophenotypes in chronic traumatic encephalopathy recapitulate
           those of ageing and Alzheimer’s disease
    • Authors: Arena J; Smith D, Lee E, et al.
      Pages: 1572 - 1587
      Abstract: AbstractTraumatic brain injury (TBI) is a risk factor for neurodegenerative disease, including chronic traumatic encephalopathy (CTE). Preliminary consensus criteria define the pathognomonic lesion of CTE as patchy tau pathology within neurons and astrocytes at the depths of cortical sulci. However, the specific tau isoform composition and post-translational modifications in CTE remain largely unexplored. Using immunohistochemistry, we performed tau phenotyping of CTE neuropathologies and compared this to a range of tau pathologies, including Alzheimer’s disease, primary age-related tauopathy, ageing-related tau astrogliopathy and multiple subtypes of frontotemporal lobar degeneration with tau inclusions. Cases satisfying preliminary consensus diagnostic criteria for CTE neuropathological change (CTE-NC) were identified (athletes, n = 10; long-term survivors of moderate or severe TBI, n = 4) from the Glasgow TBI Archive and Penn Neurodegenerative Disease Brain Bank. In addition, material from a range of autopsy-proven ageing-associated and primary tauopathies in which there was no known history of exposure to TBI was selected as non-injured controls (n = 32). Each case was then stained with a panel of tau antibodies specific for phospho-epitopes (PHF1, CP13, AT100, pS262), microtubule-binding repeat domains (3R, 4R), truncation (Tau-C3) or conformation (GT-7, GT-38) and the extent and distribution of staining assessed. Cell types were confirmed with double immunofluorescent labelling. Results demonstrate that astroglial tau pathology in CTE is composed of 4R-immunoreactive thorn-shaped astrocytes, echoing the morphology and immunophenotype of astrocytes encountered in ageing-related tau astrogliopathy. In contrast, neurofibrillary tangles of CTE contain both 3R and 4R tau, with post-translational modifications and conformations consistent with Alzheimer’s disease and primary age-related tauopathy. Our observations establish that the astroglial and neurofibrillary tau pathologies of CTE are phenotypically distinct from each other and recapitulate the tau immunophenotypes encountered in ageing and Alzheimer’s disease. As such, the immunohistochemical distinction of CTE neuropathology from other mixed 3R/4R tauopathies of Alzheimer’s disease and ageing may rest solely on the pattern and distribution of pathology.
      PubDate: Mon, 11 May 2020 00:00:00 GMT
      DOI: 10.1093/brain/awaa071
      Issue No: Vol. 143, No. 5 (2020)
  • Microglial activation and tau burden predict cognitive decline in
           Alzheimer’s disease
    • Authors: Malpetti M; Kievit R, Passamonti L, et al.
      Pages: 1588 - 1602
      Abstract: AbstractTau pathology, neuroinflammation, and neurodegeneration are key aspects of Alzheimer’s disease. Understanding whether these features predict cognitive decline, alone or in combination, is crucial to develop new prognostic measures and enhanced stratification for clinical trials. Here, we studied how baseline assessments of in vivo tau pathology (measured by 18F-AV-1451 PET), neuroinflammation (measured by 11C-PK11195 PET) and brain atrophy (derived from structural MRI) predicted longitudinal cognitive changes in patients with Alzheimer’s disease pathology. Twenty-six patients (n = 12 with clinically probable Alzheimer’s dementia and n = 14 with amyloid-positive mild cognitive impairment) and 29 healthy control subjects underwent baseline assessment with 18F-AV-1451 PET, 11C-PK11195 PET, and structural MRI. Cognition was examined annually over the subsequent 3 years using the revised Addenbrooke’s Cognitive Examination. Regional grey matter volumes, and regional binding of 18F-AV-1451 and 11C-PK11195 were derived from 15 temporo-parietal regions characteristically affected by Alzheimer’s disease pathology. A principal component analysis was used on each imaging modality separately, to identify the main spatial distributions of pathology. A latent growth curve model was applied across the whole sample on longitudinal cognitive scores to estimate the rate of annual decline in each participant. We regressed the individuals’ estimated rate of cognitive decline on the neuroimaging components and examined univariable predictive models with single-modality predictors, and a multi-modality predictive model, to identify the independent and combined prognostic value of the different neuroimaging markers. Principal component analysis identified a single component for the grey matter atrophy, while two components were found for each PET ligand: one weighted to the anterior temporal lobe, and another weighted to posterior temporo-parietal regions. Across the whole-sample, the single-modality models indicated significant correlations between the rate of cognitive decline and the first component of each imaging modality. In patients, both stepwise backward elimination and Bayesian model selection revealed an optimal predictive model that included both components of 18F-AV-1451 and the first (i.e. anterior temporal) component for 11C-PK11195. However, the MRI-derived atrophy component and demographic variables were excluded from the optimal predictive model of cognitive decline. We conclude that temporo-parietal tau pathology and anterior temporal neuroinflammation predict cognitive decline in patients with symptomatic Alzheimer’s disease pathology. This indicates the added value of PET biomarkers in predicting cognitive decline in Alzheimer’s disease, over and above MRI measures of brain atrophy and demographic data. Our findings also support the strategy for targeting tau and neuroinflammation in disease-modifying therapy against Alzheimer’s disease.
      PubDate: Thu, 07 May 2020 00:00:00 GMT
      DOI: 10.1093/brain/awaa088
      Issue No: Vol. 143, No. 5 (2020)
  • Deep brain stimulation modulates directional limbic connectivity in
           obsessive-compulsive disorder
    • Authors: Fridgeirsson E; Figee M, Luigjes J, et al.
      Pages: 1603 - 1612
      Abstract: AbstractDeep brain stimulation is effective for patients with treatment-refractory obsessive-compulsive disorder. Deep brain stimulation of the ventral anterior limb of the internal capsule rapidly improves mood and anxiety with optimal stimulation parameters. To understand these rapid effects, we studied functional interactions within the affective amygdala circuit. We compared resting state functional MRI data during chronic stimulation versus 1 week of stimulation discontinuation in patients, and obtained two resting state scans from matched healthy volunteers to account for test-retest effects. Imaging data were analysed using functional connectivity analysis and dynamic causal modelling. Improvement in mood and anxiety following deep brain stimulation was associated with reduced amygdala-insula functional connectivity. Directional connectivity analysis revealed that deep brain stimulation increased the impact of the ventromedial prefrontal cortex on the amygdala, and decreased the impact of the amygdala on the insula. These results highlight the importance of the amygdala circuit in the pathophysiology of obsessive-compulsive disorder, and suggest a neural systems model through which negative mood and anxiety are modulated by stimulation of the ventral anterior limb of the internal capsule for obsessive-compulsive disorder and possibly other psychiatric disorders.
      PubDate: Thu, 30 Apr 2020 00:00:00 GMT
      DOI: 10.1093/brain/awaa100
      Issue No: Vol. 143, No. 5 (2020)
  • Neurology and what'
    • Authors: Scolding N.
      Pages: 1613 - 1615
      PubDate: Fri, 01 May 2020 00:00:00 GMT
      DOI: 10.1093/brain/awaa132
      Issue No: Vol. 143, No. 5 (2020)
  • A multiomics approach to heterogeneity in Alzheimer’s disease:
           focused review and roadmap
    • Authors: Badhwar A; McFall G, Sapkota S, et al.
      Pages: 1315 - 1331
      Abstract: AbstractAetiological and clinical heterogeneity is increasingly recognized as a common characteristic of Alzheimer’s disease and related dementias. This heterogeneity complicates diagnosis, treatment, and the design and testing of new drugs. An important line of research is discovery of multimodal biomarkers that will facilitate the targeting of subpopulations with homogeneous pathophysiological signatures. High-throughput ‘omics’ are unbiased data-driven techniques that probe the complex aetiology of Alzheimer’s disease from multiple levels (e.g. network, cellular, and molecular) and thereby account for pathophysiological heterogeneity in clinical populations. This review focuses on data reduction analyses that identify complementary disease-relevant perturbations for three omics techniques: neuroimaging-based subtypes, metabolomics-derived metabolite panels, and genomics-related polygenic risk scores. Neuroimaging can track accrued neurodegeneration and other sources of network impairments, metabolomics provides a global small-molecule snapshot that is sensitive to ongoing pathological processes, and genomics characterizes relatively invariant genetic risk factors representing key pathways associated with Alzheimer’s disease. Following this focused review, we present a roadmap for assembling these multiomics measurements into a diagnostic tool highly predictive of individual clinical trajectories, to further the goal of personalized medicine in Alzheimer’s disease.
      PubDate: Fri, 13 Dec 2019 00:00:00 GMT
      DOI: 10.1093/brain/awz384
      Issue No: Vol. 143, No. 5 (2019)
  • Disrupted glycosylation of lipids and proteins is a cause of
    • Authors: Moll T; Shaw P, Cooper-Knock J.
      Pages: 1332 - 1340
      Abstract: AbstractGlycosyltransferases represent a large family of enzymes that catalyse the biosynthesis of oligosaccharides, polysaccharides, and glycoconjugates. A number of studies have implicated glycosyltransferases in the pathogenesis of neurodegenerative diseases but differentiating cause from effect has been difficult. We have recently discovered that mutations proximal to the substrate binding site of glycosyltransferase 8 domain containing 1 (GLT8D1) are associated with familial amyotrophic lateral sclerosis (ALS). We demonstrated that ALS-associated mutations reduce activity of the enzyme suggesting a loss-of-function mechanism that is an attractive therapeutic target. Our work is the first evidence that isolated dysfunction of a glycosyltransferase is sufficient to cause a neurodegenerative disease, but connection between neurodegeneration and genetic variation within glycosyltransferases is not new. Previous studies have identified associations between mutations in UGT8 and sporadic ALS, and between ST6GAL1 mutations and conversion of mild cognitive impairment into clinical Alzheimer’s disease. In this review we consider potential mechanisms connecting glycosyltransferase dysfunction to neurodegeneration. The most prominent candidates are ganglioside synthesis and impaired addition of O-linked β-N-acetylglucosamine (O-GlcNAc) groups to proteins important for axonal and synaptic function. Special consideration is given to examples where genetic mutations within glycosyltransferases are associated with neurodegeneration in recognition of the fact that these changes are likely to be upstream causes present from birth.
      PubDate: Thu, 14 Nov 2019 00:00:00 GMT
      DOI: 10.1093/brain/awz358
      Issue No: Vol. 143, No. 5 (2019)
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