Preservation of General Intelligence following Traumatic Brain Injury: Contributions of the Met66 Brain-Derived Neurotrophic Factor

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Abstract

Brain-derived neurotrophic factor (BDNF) promotes survival and synaptic plasticity in the human brain. The Val66Met polymorphism of the BDNF gene interferes with intracellular trafficking, packaging, and regulated secretion of this neurotrophin. The human prefrontal cortex (PFC) shows lifelong neuroplastic adaption implicating the Val66Met BDNF polymorphism in the recovery of higher-order executive functions after traumatic brain injury (TBI). In this study, we examined the effect of this BDNF polymorphism on the preservation of general intelligence following TBI. We genotyped a sample of male Vietnam combat veterans ( n = 156) consisting of a frontal lobe lesion group with focal penetrating head injuries for the Val66Met BDNF polymorphism. Val/Met did not differ from Val/Val genotypes in general cognitive ability before TBI. However, we found substantial average differences between these groups in general intelligence (≈ half a standard deviation or 8 IQ points), verbal comprehension (6 IQ points), perceptual organization (6 IQ points), working memory (8 IQ points), and processing speed (8 IQ points) after TBI. These results support the conclusion that Val/Met genotypes preserve general cognitive functioning, whereas Val/Val genotypes are largely susceptible to TBI.

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Most cited references 52

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The BDNF val66met Polymorphism Affects Activity-Dependent Secretion of BDNF and Human Memory and Hippocampal Function

Michael Egan, Masami Kojima, Joseph Callicott … (2003)

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Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia.

M Egan, T Goldberg, B. S. Kolachana … (2001)

Abnormalities of prefrontal cortical function are prominent features of schizophrenia and have been associated with genetic risk, suggesting that susceptibility genes for schizophrenia may impact on the molecular mechanisms of prefrontal function. A potential susceptibility mechanism involves regulation of prefrontal dopamine, which modulates the response of prefrontal neurons during working memory. We examined the relationship of a common functional polymorphism (Val(108/158) Met) in the catechol-O-methyltransferase (COMT) gene, which accounts for a 4-fold variation in enzyme activity and dopamine catabolism, with both prefrontally mediated cognition and prefrontal cortical physiology. In 175 patients with schizophrenia, 219 unaffected siblings, and 55 controls, COMT genotype was related in allele dosage fashion to performance on the Wisconsin Card Sorting Test of executive cognition and explained 4% of variance (P = 0.001) in frequency of perseverative errors. Consistent with other evidence that dopamine enhances prefrontal neuronal function, the load of the low-activity Met allele predicted enhanced cognitive performance. We then examined the effect of COMT genotype on prefrontal physiology during a working memory task in three separate subgroups (n = 11-16) assayed with functional MRI. Met allele load consistently predicted a more efficient physiological response in prefrontal cortex. Finally, in a family-based association analysis of 104 trios, we found a significant increase in transmission of the Val allele to the schizophrenic offspring. These data suggest that the COMT Val allele, because it increases prefrontal dopamine catabolism, impairs prefrontal cognition and physiology, and by this mechanism slightly increases risk for schizophrenia.

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Brain-derived neurotrophic factor.

Devin K Binder, Helen Scharfman (2004)

Since the purification of BDNF in 1982, a great deal of evidence has mounted for its central roles in brain development, physiology, and pathology. Aside from its importance in neural development and cell survival, BDNF appears essential to molecular mechanisms of synaptic plasticity. Basic activity-related changes in the central nervous system are thought to depend on BDNF modification of synaptic transmission, especially in the hippocampus and neocortex. Pathologic levels of BDNF-dependent synaptic plasticity may contribute to conditions such as epilepsy and chronic pain sensitization, whereas application of the trophic properties of BDNF may lead to novel therapeutic options in neurodegenerative diseases and perhaps even in neuropsychiatric disorders.

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Author and article information

Contributors

Renping Zhou: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2014

Publication date (Electronic): 26 February 2014

Volume: 9

Issue: 2

Electronic Location Identifier: e88733

Affiliations

[1 ]Decision Neuroscience Laboratory, University of Illinois, Urbana, Illinois, United States of America

[2 ]Beckman Institute for Advanced Science and Technology, University of Illinois, Urbana, Illinois, United States of America

[3 ]Department of Internal Medicine, University of Illinois, Champaign, Illinois, United States of America

[4 ]Department of Psychology, University of Illinois, Champaign, Illinois, United States of America

[5 ]Department of Speech and Hearing Science, University of Illinois, Champaign, Illinois, United States of America

[6 ]Neuroscience Program, University of Illinois, Champaign, Illinois, United States of America

[7 ]Universidad Autónoma de Madrid, Fundación CIEN/Fundación Reina Sofía, Madrid, Spain

[8 ]Department of Psychology, University of Delaware, Delaware, Maryland, United States of America

[9 ]Department of Molecular Neuroscience, George Mason University, Virginia, United States of America

[10 ]Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, United States of America

[11 ]Traumatic Brain Injury Research Laboratory, Rehabilitation Institute of Chicago, Chicago, Illinois, United States of America

Rutgers University, United States of America

Author notes

* E-mail: barbey@ 123456illinois.edu (AB); jgrafman@ 123456ric.edu (JG)

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: AKB DG JG. Performed the experiments: AKB CF DG JG. Analyzed the data: AKB RC EJP. Wrote the paper: AKB FK.

Article

Publisher ID: PONE-D-13-44492

DOI: 10.1371/journal.pone.0088733

PMC ID: 3935849

PubMed ID: 24586380

SO-VID: af100955-9b5c-48e4-9aa1-63c94ee8acf7

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This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 30 October 2013

Date accepted : 10 January 2014

Page count

Pages: 8

Funding

This work was supported by funding from the U.S. National Institute of Neurological Disorders and Stroke intramural research program and a project grant from the United States Army Medical Research and Material Command administered by the Henry M. Jackson Foundation (Vietnam Head Injury Study Phase III: a 30-year post-injury follow-up study, grant number DAMD17-01-1-0675). R. Colom was supported by grant PSI2010-20364 from Ministerio de Ciencia e Innovación [Ministry of Science and Innovation, Spain] and and CEMU-2012-004 [Universidad Autonoma de Madrid]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Preservation of General Intelligence following Traumatic Brain Injury: Contributions of the Met66 Brain-Derived Neurotrophic Factor

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Most cited references 52

The BDNF val66met Polymorphism Affects Activity-Dependent Secretion of BDNF and Human Memory and Hippocampal Function

Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia.

Brain-derived neurotrophic factor.

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