Department of General Neurology, Cognitive and Aging Center, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, #123, Ta-Pei Road, Niaosung, Kaohsiung County, 833, Taiwan.
Institute of Human Resource Management, National Sun Yat-Sen University, Kaohsiung, Taiwan.
Mol Neurobiol. 2019 Jun;56(6):4518-4529. doi: 10.1007/s12035-018-1394-0. Epub 2018 Oct 18.
Functional polymorphisms in the promoter region of the monoamine oxidase A (MAOA) gene are associated with brain MAOA activity and transcriptional efficiency in patients with Alzheimer's disease (AD). This study investigated structural covariance networks mediated by MAOA-variable number tandem repeat (VNTR) genotypes in patients with AD, and assessed whether this effect was associated with sex. A total of 193 patients with AD were classified into four genotype groups based on MAOA transcriptional efficiency (female low [L], low-high + high activity groups [LH + H]; male L, male H groups). Structural covariance networks were constructed focusing on triple-network and striatal networks. Covariance strength was analyzed in the four groups, and the genotype and sex main effects and their interactions were analyzed. Significant peak cluster volumes were correlated with neurobehavioral scores to establish the clinical significance. MAOA genotypes mediated the structural covariance strength on the dorsolateral prefrontal cortex (dLPFC)-caudate axis in both sexes, but a higher covariance strength was shown in the female L group and male H group. The independent effect of male sex was related to higher covariance strength in the frontal medial superior region in the dLPFC, dorsal caudate (DC), and ventral superior striatum (VSs) seeds. In contrast, female sex had higher covariance strength in the frontal opercular areas anchored by the dLPFC, DC, and VSs seeds. Topographies showing higher covariance strength with sex interactions were found in the male H group and female L group in the dLPFC supplementary motor axis, DC-SMA, and DC-precentral axis. In our patients with AD, MAOA-VNTR polymorphisms and sex had independent and interactive effects on structural covariance networks, of which the dLPFC-, VSs-, and DC-anchored networks represented major endophenotypes that determined cognitive outcomes. The sex-genotype interaction model suggested that male high activity and female low activity may modulate brain morphometric connectivity and determine cognitive scores.
单胺氧化酶 A（MAOA）基因启动子区域的功能多态性与阿尔茨海默病（AD）患者大脑 MAOA 活性和转录效率相关。本研究调查了 AD 患者中 MAOA-可变数目串联重复（VNTR）基因型介导的结构协变网络，并评估了这种效应是否与性别相关。共有 193 名 AD 患者根据 MAOA 转录效率分为 4 种基因型组（女性低 [L]、低高+高活性组 [LH+H]；男性 L、男性 H 组）。构建了以三网络和纹状体网络为重点的结构协变网络。在四组中分析了协变强度，分析了基因型和性别主效应及其相互作用。对显著峰簇体积与神经行为评分进行相关性分析，以确定其临床意义。MAOA 基因型介导了两性的背外侧前额叶皮层（dLPFC）-尾状核轴的结构协变强度，但女性 L 组和男性 H 组的协变强度更高。男性性别的独立作用与 dLPFC 中的额内侧上区、背侧尾状核（DC）和腹侧上纹状体（VSs）种子的更高协变强度有关。相反，女性在 dLPFC、DC 和 VSs 种子锚定的额眶区具有更高的协变强度。在男性 H 组和女性 L 组的 dLPFC 辅助运动轴、DC-SMA 和 DC-中央前回轴中发现了具有性别相互作用的更高协变强度的拓扑结构。在我们的 AD 患者中，MAOA-VNTR 多态性和性别对结构协变网络具有独立和交互作用，其中 dLPFC、VSs 和 DC 锚定网络代表了决定认知结果的主要表型。性别-基因型相互作用模型表明，男性高活性和女性低活性可能调节大脑形态计量连接并决定认知评分。
