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Cognitive and magnetic resonance imaging brain morphometric correlates of brain-derived neurotrophic factor Val66Met gene polymorphism in patients with schizophrenia and healthy volunteers.

Abstract

CONTEXT

Relatively little is known about genetic determinants of cognitive dysfunction in schizophrenia. Recent studies suggest that a brain-derived neurotrophic factor (BDNF) prodomain single nucleotide polymorphism resulting in a valine (Val)-to-methionine (Met) substitution is associated with impaired declarative memory in healthy volunteers and patients with schizophrenia. These studies indicate that the BDNF(Met) variant may mediate hippocampal cognitive functions by modulating intracellular trafficking and activity-dependent BDNF release. To our knowledge, the way in which this functional single nucleotide polymorphism affects other neurocognitive measures has not been examined. Its role in determining cognitive deficits in schizophrenia has also not been systematically studied.

OBJECTIVES

To characterize the neurocognitive and brain morphometric phenotypic correlates of the BDNF Val66Met polymorphism and to test the specificity of the BDNF(Met) variant on cognitive dysfunction in schizophrenia.

DESIGN, SETTING, AND PARTICIPANTS

A comprehensive battery of standardized neuropsychological tests was administered to 144 healthy volunteers and 293 patients with schizophrenia spectrum disorder at a tertiary care university hospital. Approximately two thirds of the sample also underwent high-resolution magnetic resonance imaging brain scans.

MAIN OUTCOME MEASURES

Genotype effects (in Met allele carriers vs Val homozygotes) on 5 cognitive domain z scores and magnetic resonance imaging gray matter brain volume measures (Talairach atlas-based cerebral lobes and optimized voxel-based morphometry) were examined using general linear models.

RESULTS

On verbal memory, there was a significant genotype effect but no genotype x diagnosis effects. In both patients with schizophrenia and healthy volunteers, Met allele carriers had poorer verbal memory performance than their Val-homozygous counterparts. On visuospatial abilities, there were significant genotype and genotype x diagnosis effects. Met allele-associated visuospatial impairment was specific to patients with schizophrenia but not healthy volunteers. There were significant genotype effects on gray matter volumes within brain regions known to subserve these 2 cognitive domains, with Met allele carriers having smaller temporal and occipital lobar gray matter volumes. Optimized voxel-based morphometry further suggests that parietal heteromodal cortical gray matter deficits may underlie visuospatial impairment in patients with schizophrenia carrying the Met allele.

CONCLUSIONS

We replicated the association between the BDNF(Met) variant and poor medial temporal lobe-related memory performance. The consonance of our cognitive and brain morphology findings further suggests that the BDNF(Met) variant may have a specific role in conferring visuospatial dysfunction in schizophrenia.

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  • Authors+Show Affiliations

    ,

    Department of Psychiatry, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, USA.

    , , , ,

    Source

    Archives of general psychiatry 63:7 2006 Jul pg 731-40

    MeSH

    Adult
    Brain
    Brain Mapping
    Brain-Derived Neurotrophic Factor
    Cognition Disorders
    Female
    Genetic Variation
    Genotype
    Hippocampus
    Humans
    Image Processing, Computer-Assisted
    Magnetic Resonance Imaging
    Male
    Methionine
    Neuropsychological Tests
    Polymorphism, Genetic
    Polymorphism, Single Nucleotide
    Schizophrenia
    Schizophrenic Psychology
    Temporal Lobe
    Valine

    Pub Type(s)

    Comparative Study
    Journal Article
    Research Support, N.I.H., Extramural

    Language

    eng

    PubMed ID

    16818862

    Citation

    Ho, Beng-Choon, et al. "Cognitive and Magnetic Resonance Imaging Brain Morphometric Correlates of Brain-derived Neurotrophic Factor Val66Met Gene Polymorphism in Patients With Schizophrenia and Healthy Volunteers." Archives of General Psychiatry, vol. 63, no. 7, 2006, pp. 731-40.
    Ho BC, Milev P, O'Leary DS, et al. Cognitive and magnetic resonance imaging brain morphometric correlates of brain-derived neurotrophic factor Val66Met gene polymorphism in patients with schizophrenia and healthy volunteers. Arch Gen Psychiatry. 2006;63(7):731-40.
    Ho, B. C., Milev, P., O'Leary, D. S., Librant, A., Andreasen, N. C., & Wassink, T. H. (2006). Cognitive and magnetic resonance imaging brain morphometric correlates of brain-derived neurotrophic factor Val66Met gene polymorphism in patients with schizophrenia and healthy volunteers. Archives of General Psychiatry, 63(7), pp. 731-40.
    Ho BC, et al. Cognitive and Magnetic Resonance Imaging Brain Morphometric Correlates of Brain-derived Neurotrophic Factor Val66Met Gene Polymorphism in Patients With Schizophrenia and Healthy Volunteers. Arch Gen Psychiatry. 2006;63(7):731-40. PubMed PMID: 16818862.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Cognitive and magnetic resonance imaging brain morphometric correlates of brain-derived neurotrophic factor Val66Met gene polymorphism in patients with schizophrenia and healthy volunteers. AU - Ho,Beng-Choon, AU - Milev,Peter, AU - O'Leary,Daniel S, AU - Librant,Amy, AU - Andreasen,Nancy C, AU - Wassink,Thomas H, PY - 2006/7/5/pubmed PY - 2006/8/4/medline PY - 2006/7/5/entrez SP - 731 EP - 40 JF - Archives of general psychiatry JO - Arch. Gen. Psychiatry VL - 63 IS - 7 N2 - CONTEXT: Relatively little is known about genetic determinants of cognitive dysfunction in schizophrenia. Recent studies suggest that a brain-derived neurotrophic factor (BDNF) prodomain single nucleotide polymorphism resulting in a valine (Val)-to-methionine (Met) substitution is associated with impaired declarative memory in healthy volunteers and patients with schizophrenia. These studies indicate that the BDNF(Met) variant may mediate hippocampal cognitive functions by modulating intracellular trafficking and activity-dependent BDNF release. To our knowledge, the way in which this functional single nucleotide polymorphism affects other neurocognitive measures has not been examined. Its role in determining cognitive deficits in schizophrenia has also not been systematically studied. OBJECTIVES: To characterize the neurocognitive and brain morphometric phenotypic correlates of the BDNF Val66Met polymorphism and to test the specificity of the BDNF(Met) variant on cognitive dysfunction in schizophrenia. DESIGN, SETTING, AND PARTICIPANTS: A comprehensive battery of standardized neuropsychological tests was administered to 144 healthy volunteers and 293 patients with schizophrenia spectrum disorder at a tertiary care university hospital. Approximately two thirds of the sample also underwent high-resolution magnetic resonance imaging brain scans. MAIN OUTCOME MEASURES: Genotype effects (in Met allele carriers vs Val homozygotes) on 5 cognitive domain z scores and magnetic resonance imaging gray matter brain volume measures (Talairach atlas-based cerebral lobes and optimized voxel-based morphometry) were examined using general linear models. RESULTS: On verbal memory, there was a significant genotype effect but no genotype x diagnosis effects. In both patients with schizophrenia and healthy volunteers, Met allele carriers had poorer verbal memory performance than their Val-homozygous counterparts. On visuospatial abilities, there were significant genotype and genotype x diagnosis effects. Met allele-associated visuospatial impairment was specific to patients with schizophrenia but not healthy volunteers. There were significant genotype effects on gray matter volumes within brain regions known to subserve these 2 cognitive domains, with Met allele carriers having smaller temporal and occipital lobar gray matter volumes. Optimized voxel-based morphometry further suggests that parietal heteromodal cortical gray matter deficits may underlie visuospatial impairment in patients with schizophrenia carrying the Met allele. CONCLUSIONS: We replicated the association between the BDNF(Met) variant and poor medial temporal lobe-related memory performance. The consonance of our cognitive and brain morphology findings further suggests that the BDNF(Met) variant may have a specific role in conferring visuospatial dysfunction in schizophrenia. SN - 0003-990X UR - https://www.unboundmedicine.com/medline/citation/16818862/Cognitive_and_magnetic_resonance_imaging_brain_morphometric_correlates_of_brain_derived_neurotrophic_factor_Val66Met_gene_polymorphism_in_patients_with_schizophrenia_and_healthy_volunteers_ L2 - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&PAGE=linkout&SEARCH=16818862.ui DB - PRIME DP - Unbound Medicine ER -