MEMBRANE DEFICITS AND OUTCOME IN SCHIZOPHRENIA

精神分裂症的膜缺陷和结果

• 批准号: 6392337
• 负责人: JEFFREY K YAO
• 金额: $ 26.26万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-05 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6392337
• 关键词: arachidonate; blood chemistry; brain metabolism; clinical research; disease /disorder onset; eicosanoid metabolism; erythrocyte membrane; fatty acid metabolism; human middle age (35-64); human subject; longitudinal human study; magnetic resonance imaging; membrane activity; membrane lipids; neuropathology; outcomes research; phosphatidylinositols; phospholipase A2; phospholipids; platelets; psychological tests; schizophrenia; serotonin receptor; unsaturated fatty acids; young adult human (21-34)

Approximately 40 percent of schizophrenic patients have poor outcomes. Although mechanisms that underlie such outcomes are not known, decreased erythrocyte content of a key membrane essential fatty acid (EFA) - arachidonic acid (AA) - has been associated with poor outcome (prominent negative and persistent positive symptoms). AA is a key component of neuronal membrane phospholipids, and is critical to normal neuronal functioning. Increasing AA (by supplementation) is associated with improvement in negative symptoms and generally less severe symptoms, suggesting that clinical outcome parallels AA levels, and more critically, that the levels are modifiable. Previous studies have focused on patients with poor outcome. Since outcome is often determined early, one critical question is whether low membrane AA early in the course of illness is associated with later poor outcome. Another key issue is whether the peripheral membrane abnormalities seen in chronic schizophrenic patients, and hypothesized to be present early in illness, are associated with defects in brain phospholipid metabolism, as determined by 31P magnetic resonance spectroscopy (MRS). To examine these questions, 40 first-episode schizophrenic patients and 40 age- and sex-matched normal subjects will be studied prospectively with repeated assessments. Relations between AA levels and outcome at 2 years follow-up will be examined. Contemporaneous to peripheral membrane determinations, MRS chemical shift imaging will be used to examine brain phospholipid metabolism. This will provide a unique opportunity to investigate simultaneously central and peripheral membrane biochemistry, and relations to clinical measures. Further, putative factors that may contribute to low membrane AA (increased phospholipase A2 and decreased AA incorporation) and its functional consequences (hyperactivity of the phosphoinositide signaling system) will be examined. If findings from these studies show that a membrane defect exists early in the course of illness (suggested by our pilot data of decreased erythrocyte AA in first-episode schizophrenia), and is associated with unfavorable clinical outcome, then the possibility of specific early interventions such as EFA supplementation can be considered. Also, the study will shed light on the significance of peripheral membrane dynamics to central membrane phospholipid metabolism over the early course of illness.

大约 40% 的精神分裂症患者预后不佳。 尽管造成这种结果的机制尚不清楚，但关键膜必需脂肪酸（EFA）——花生四烯酸（AA）的红细胞含量减少与不良结果（显着的阴性症状和持续的阳性症状）相关。 AA 是神经元膜磷脂的关键成分，对神经元的正常功能至关重要。增加 AA（通过补充）与阴性症状的改善以及通常不太严重的症状相关，这表明临床结果与 AA 水平相似，更重要的是，该水平是可以改变的。 先前的研究主要针对预后不佳的患者。 由于结果通常是早期确定的，因此一个关键问题是病程早期的低膜 AA 是否与后来的不良结果相关。 另一个关键问题是，根据 31P 磁共振波谱 (MRS) 测定，慢性精神分裂症患者中观察到的外周膜异常（假设在疾病早期就存在）是否与脑磷脂代谢缺陷相关。 为了研究这些问题，将对 40 名首发精神分裂症患者和 40 名年龄和性别匹配的正常受试者进行前瞻性研究和重复评估。 将检查 AA 水平与 2 年随访结果之间的关系。 在外周膜测定的同时，MRS 化学位移成像将用于检查脑磷脂代谢。 这将为同时研究中枢和外周膜生物化学以及与临床测量的关系提供独特的机会。 此外，还将检查可能导致膜 AA 水平降低（磷脂酶 A2 增加和 AA 掺入减少）的推定因素及其功能后果（磷酸肌醇信号系统的过度活跃）。 如果这些研究结果表明病程早期存在细胞膜缺陷（我们的首发精神分裂症红细胞 AA 减少的试点数据表明），并且与不利的临床结果相关，那么可以考虑采取特定的早期干预措施，例如补充 EFA。 此外，该研究还将阐明疾病早期过程中外周膜动力学对中心膜磷脂代谢的重要性。