Institute of Psychiatry, School of Medicine, University of São Paulo (IPq-FMUSP), São Paulo, Brazil.
Genetics and Pharmacogenetics Unit (PROGENE), Institute of Psychiatry, School of Medicine, University of São Paulo (IPq-FMUSP), São Paulo, Brazil.
Brain Imaging Behav. 2023 Jun;17(3):282-293. doi: 10.1007/s11682-023-00757-7. Epub 2023 Jan 11.
Brain-derived neurotrophic factor (BDNF) is the most abundant brain neurotrophin and plays a critical role in neuronal growth, survival and plasticity, implicated in the pathophysiology of Bipolar Disorders (BD). The single-nucleotide polymorphism in the BDNF gene (BDNF rs6265) has been associated with decreased hippocampal BDNF secretion and volume in met carriers in different populations, although the val allele has been reported to be more frequent in BD patients. The anterior cingulate cortex (ACC) is a key center integrating cognitive and affective neuronal connections, where consistent alterations in brain metabolites such as Glx (Glutamate + Glutamine) and N-acetylaspartate (NAA) have been consistently reported in BD. However, little is known about the influence of BDNF rs6265 on neurochemical profile in the ACC of Healthy Controls (HC) and BD subjects. The aim of this study was to assess the influence of BDNF rs6265 on ACC neurometabolites (Glx, NAA and total creatine- Cr) in 124 euthymic BD type I patients and 76 HC, who were genotyped for BDNF rs6265 and underwent a 3-Tesla proton magnetic resonance imaging and spectroscopy scan ( H-MRS) using a PRESS ACC single-voxel (8cm) sequence. BDNF rs6265 polymorphism showed a significant two-way interaction (diagnosis × genotype) in relation to NAA/Cr and total Cr. While met carriers presented increased NAA/Cr in HC, BD-I subjects with the val allele revealed higher total Cr, denoting an enhanced ACC metabolism likely associated with increased glutamatergic metabolites observed in BD-I val carriers. However, these results were replicated only in men. Therefore, our results support evidences that the BDNF rs6265 polymorphism exerts a complex pleiotropic effect on ACC metabolites influenced by the diagnosis and sex.
脑源性神经营养因子（BDNF）是最丰富的脑神经营养因子，在神经元的生长、存活和可塑性中发挥着关键作用，与双相情感障碍（BD）的病理生理学有关。BDNF 基因中的单核苷酸多态性（BDNF rs6265）与不同人群中 met 携带者的海马 BDNF 分泌和体积减少有关，尽管 val 等位基因在 BD 患者中更为常见。前扣带皮层（ACC）是整合认知和情感神经元连接的关键中心，在 BD 中一致报道了脑代谢物如 Glx（谷氨酸+谷氨酰胺）和 N-乙酰天门冬氨酸（NAA）的一致改变。然而，关于 BDNF rs6265 对健康对照（HC）和 BD 受试者 ACC 神经化学特征的影响知之甚少。本研究旨在评估 BDNF rs6265 对 124 名心境稳定的 BD 型 I 患者和 76 名 HC 的 ACC 神经代谢物（Glx、NAA 和总肌酸-Cr）的影响，这些患者进行了 BDNF rs6265 基因分型，并进行了 3-Tesla 质子磁共振成像和光谱扫描（H-MRS）使用 PRESS ACC 单体素（8cm）序列。BDNF rs6265 多态性在 NAA/Cr 和总 Cr 方面表现出显著的双向交互作用（诊断×基因型）。虽然 met 携带者在 HC 中表现出 NAA/Cr 增加，但 val 等位基因的 BD-I 受试者显示出更高的总 Cr，表明 ACC 代谢增强，这可能与 BD-I val 携带者中观察到的谷氨酸代谢物增加有关。然而，这些结果仅在男性中得到复制。因此，我们的结果支持证据表明，BDNF rs6265 多态性对 ACC 代谢物产生复杂的多效性影响，受诊断和性别影响。
