Psychotic Disorders Division, McLean Hospital, Belmont, Massachusetts2Department of Psychiatry, Harvard Medical School, Boston, Massachusetts.
Psychotic Disorders Division, McLean Hospital, Belmont, Massachusetts.
JAMA Psychiatry. 2014 Jan;71(1):19-27. doi: 10.1001/jamapsychiatry.2013.2287.
Abnormalities in neural activity and cerebral bioenergetics have been observed in schizophrenia (SZ). Further defining energy metabolism anomalies would provide crucial information about molecular mechanisms underlying SZ and may be valuable for developing novel treatment strategies.
To investigate cerebral bioenergetics in SZ via measurement of creatine kinase activity using in vivo 31P magnetization transfer spectroscopy.
DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional case-control study in the setting of clinical services and a brain imaging center of an academic psychiatric hospital. Twenty-six participants with chronic SZ (including a subgroup diagnosed as having schizoaffective disorder) and 26 age-matched and sex-matched healthy control subjects (25 usable magnetic resonance spectroscopy data sets from the latter).
31P magnetization transfer spectroscopy.
The primary outcome measure was the forward rate constant (k(f)) of the creatine kinase enzyme in the frontal lobe. We also collected independent measures of brain intracellular pH and steady-state metabolite ratios of high-energy phosphate-containing compounds (phosphocreatine and adenosine triphosphate [ATP]), inorganic phosphate, and the 2 membrane phospholipids phosphodiester and phosphomonoester.
A substantial (22%) and statistically significant (P = .003) reduction in creatine kinase kf was observed in SZ. In addition, intracellular pH was significantly reduced (7.00 in the SZ group vs 7.03 in the control group, P = .007) in this condition. The phosphocreatine to ATP ratio, inorganic phosphate to ATP ratio, and phosphomonoester to ATP ratio were not substantially altered in SZ, but a significant (P = .02) reduction was found in the phosphodiester to ATP ratio. The abnormalities were similar between SZ and schizoaffective disorder.
Using a novel 31P magnetization transfer magnetic resonance spectroscopy approach, we provide direct and compelling evidence for a specific bioenergetic abnormality in SZ. Reduced kf of the creatine kinase enzyme is consistent with an abnormality in storage and use of brain energy. The intracellular pH reduction suggests a relative increase in the contribution of glycolysis to ATP synthesis, providing convergent evidence for bioenergetic abnormalities in SZ. The similar phosphocreatine to ATP ratios in SZ and healthy controls suggest that the underlying bioenergetics abnormality is not associated with change in this metabolite ratio.
精神分裂症（SZ）患者的神经活动和脑生物能量已出现异常。进一步确定能量代谢异常将为 SZ 潜在的分子机制提供重要信息，并且可能对开发新的治疗策略具有重要价值。
通过使用体内 31P 磁化转移光谱测量肌酸激酶活性，来研究 SZ 的脑生物能量。
设计、地点和参与者：在临床服务和学术精神病学医院的脑成像中心进行的横断面病例对照研究。26 名患有慢性 SZ 的参与者（包括诊断为患有分裂情感障碍的亚组）和 26 名年龄和性别匹配的健康对照者（后者有 25 个可使用的磁共振波谱数据组）。
31P 磁化转移光谱。
主要观察指标是额叶肌酸激酶的正向速率常数（k（f））。我们还收集了脑细胞内 pH 值和高能磷酸化合物（磷酸肌酸和三磷酸腺苷[ATP]）、无机磷和 2 种膜磷脂磷酸二酯和磷酸单酯的稳态代谢物比的独立测量值。
在 SZ 中观察到肌酸激酶 k（f）显著降低（22%，P = .003）。此外，在这种情况下细胞内 pH 值显著降低（SZ 组为 7.00，对照组为 7.03，P = .007）。磷酸肌酸与 ATP 比、无机磷与 ATP 比、磷酸单酯与 ATP 比在 SZ 中均无明显改变，但磷酸二酯与 ATP 比明显降低（P = .02）。SZ 和分裂情感障碍之间存在相似的异常。
使用新型 31P 磁化转移磁共振波谱方法，我们为 SZ 中的特定生物能量异常提供了直接而有力的证据。肌酸激酶酶的 kf 降低与脑能量的储存和利用异常一致。细胞内 pH 值降低表明糖酵解对 ATP 合成的相对贡献增加，为 SZ 中的生物能量异常提供了一致的证据。SZ 和健康对照组的磷酸肌酸与 ATP 比值相似，表明潜在的生物能量异常与该代谢物比值的变化无关。
