Isomura Yoshiaki, Ohno Mikiko, Sudo Satoshi, Ono Mayuko, Kaminishi Yuki, Sumi Yukiyoshi, Yoshimura Atsushi, Fujii Kumiko, Akiyama Kazufumi, Nishi Eiichiro, Ozeki Yuji
Department of Psychiatry, Shiga University of Medical Science, Japan.
Department of Pharmacology, Shiga University of Medical Science, Japan.
Heliyon. 2024 Apr 25;10(9):e30193. doi: 10.1016/j.heliyon.2024.e30193. eCollection 2024 May 15.
Several hypotheses regarding the pathomechanisms of schizophrenia have been proposed. If schizophrenia is a unitary disease, then these pathological processes must be linked; however, if such links do not exist, schizophrenia may best be considered a group of disorders. Only a few studies have examined the relationships among these pathomechanisms. Herein, we examined the relationships among deficient myelination, NMDA receptor hypofunction, and metabolic dysregulation by measuring various plasma markers and examining their correlations.
Plasma samples were collected from 90 patients with schizophrenia and 68 healthy controls. Concentrations of nardilysin (N-arginine dibasic convertase, NRDC), a positive regulator of myelination, the NMDA receptor co-agonist d-serine and glycine, various additional amino acids related to NMDA receptor transmission (glutamate, glutamine, and l-serine), and homocysteine (Hcy), were measured. Concentrations were compared using independent samples -test or logistic regression, and associations were evaluated using Pearson's correlation coefficients.
Plasma glycine (t = 2.05, p = 0.042), l-serine (t = 2.25, p = 0.027), and homocysteine (t = 3.71, p < 0.001) concentrations were significantly higher in patients with schizophrenia compared to those in healthy controls. Logistic regression models using age, sex, smoking status, glutamine, glutamate, glycine, l-serine, d-serine, homocysteine, and NRDC as independent variables revealed significantly lower plasma d-serine (p = 0.024) and NRDC (p = 0.028), but significantly higher l-serine (p = 0.024) and homocysteine (p = 0.001) in patients with schizophrenia. Several unique correlations were found between NMDA receptor-related amino acids and NRDC in patients with schizophrenia compared to those in healthy controls, while no correlations were found between plasma homocysteine and other markers. No associations were found between plasma marker concentrations and disease status or cognitive function in patients with schizophrenia, except for a significant correlation between plasma glycine and full intelligence quotient.
Reduced myelination and NMDA receptor hypofunction may be related to pathological mechanisms in schizophrenia, while homocysteine dysregulation appears to be an independent pathological process. These results suggest that schizophrenia may be a group of disorders with unique or partially overlapping etiologies.
关于精神分裂症的发病机制已提出了几种假说。如果精神分裂症是一种单一疾病，那么这些病理过程必然相互关联；然而，如果不存在这种关联，精神分裂症可能最好被视为一组疾病。仅有少数研究探讨了这些发病机制之间的关系。在此，我们通过测量各种血浆标志物并检查它们之间的相关性，研究了髓鞘形成不足、N-甲基-D-天冬氨酸（NMDA）受体功能低下和代谢失调之间的关系。
收集了90例精神分裂症患者和68例健康对照者的血浆样本。测量了髓鞘形成的正向调节因子纳尔迪溶素（N-精氨酸双基转化酶，NRDC）、NMDA受体协同激动剂D-丝氨酸和甘氨酸、与NMDA受体传递相关的各种其他氨基酸（谷氨酸、谷氨酰胺和L-丝氨酸）以及同型半胱氨酸（Hcy）的浓度。使用独立样本t检验或逻辑回归比较浓度，并使用Pearson相关系数评估相关性。
与健康对照者相比，精神分裂症患者血浆甘氨酸（t = 2.05，p = 0.042）、L-丝氨酸（t = 2.25，p = 0.027）和同型半胱氨酸（t = 3.71，p < 0.001）浓度显著更高。以年龄、性别、吸烟状况、谷氨酰胺、谷氨酸、甘氨酸、L-丝氨酸、D-丝氨酸、同型半胱氨酸和NRDC作为自变量的逻辑回归模型显示，精神分裂症患者血浆D-丝氨酸（p = 0.024）和NRDC（p = 0.028）显著降低，但L-丝氨酸（p = 0.024）和同型半胱氨酸（p = 0.001）显著升高。与健康对照者相比，精神分裂症患者中发现了几种NMDA受体相关氨基酸与NRDC之间独特的相关性，而血浆同型半胱氨酸与其他标志物之间未发现相关性。除了血浆甘氨酸与全智商之间存在显著相关性外，未发现精神分裂症患者血浆标志物浓度与疾病状态或认知功能之间存在关联。
髓鞘形成减少和NMDA受体功能低下可能与精神分裂症的病理机制有关，而同型半胱氨酸失调似乎是一个独立的病理过程。这些结果表明，精神分裂症可能是一组病因独特或部分重叠的疾病。
