Ho Beng-Choon, Milev Peter, O'Leary Daniel S, Librant Amy, Andreasen Nancy C, Wassink Thomas H
Department of Psychiatry, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, USA.
Arch Gen Psychiatry. 2006 Jul;63(7):731-40. doi: 10.1001/archpsyc.63.7.731.
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.
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.
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.
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.
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.
关于精神分裂症认知功能障碍的遗传决定因素，人们了解相对较少。近期研究表明，脑源性神经营养因子（BDNF）前结构域的一个单核苷酸多态性导致缬氨酸（Val）替换为甲硫氨酸（Met），这与健康志愿者及精神分裂症患者的陈述性记忆受损有关。这些研究表明，BDNF（Met）变体可能通过调节细胞内运输和活动依赖性BDNF释放来介导海马体的认知功能。据我们所知，这种功能性单核苷酸多态性影响其他神经认知指标的方式尚未得到研究。其在精神分裂症认知缺陷决定中的作用也未得到系统研究。
描述BDNF Val66Met多态性的神经认知和脑形态学表型相关性，并测试BDNF（Met）变体对精神分裂症认知功能障碍的特异性。
设计、地点和参与者：在一家三级护理大学医院，对144名健康志愿者和293名精神分裂症谱系障碍患者进行了一系列全面的标准化神经心理学测试。大约三分之二的样本还接受了高分辨率磁共振成像脑部扫描。
使用一般线性模型检查基因型效应（Met等位基因携带者与Val纯合子相比）对5个认知领域z评分和磁共振成像灰质脑容量测量值（基于Talairach图谱的脑叶和优化的基于体素的形态测量法）的影响。
在言语记忆方面，存在显著的基因型效应，但不存在基因型×诊断效应。在精神分裂症患者和健康志愿者中，Met等位基因携带者的言语记忆表现均比其Val纯合子对应者差。在视觉空间能力方面，存在显著的基因型和基因型×诊断效应。Met等位基因相关的视觉空间损害在精神分裂症患者中具有特异性，而在健康志愿者中则没有。在已知支持这两个认知领域的脑区内，灰质体积存在显著的基因型效应，Met等位基因携带者的颞叶和枕叶灰质体积较小。优化的基于体素的形态测量法进一步表明，携带Met等位基因的精神分裂症患者的视觉空间损害可能是由顶叶异模态皮质灰质缺陷所致。
我们重复了BDNF（Met）变体与内侧颞叶相关记忆表现不佳之间的关联。我们的认知和脑形态学研究结果的一致性进一步表明，BDNF（Met）变体可能在精神分裂症视觉空间功能障碍的发生中具有特定作用。
