MEMBRANE DEFICITS AND OUTCOME IN SCHIZOPHRENIA

精神分裂症的膜缺陷和结果

• 批准号: 6186474
• 负责人: JEFFREY K YAO
• 金额: $ 24.56万
• 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/6186474
• 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%的精神分裂症患者的预后很差。尽管导致这种结果的机制尚不清楚，但红细胞中一种关键的细胞膜必需脂肪酸(EFA)-花生四烯酸(AA)的含量下降与不良结果(显著的阴性和持续的阳性症状)有关。AA是神经细胞膜磷脂的关键成分，对神经元的正常功能至关重要。增加AA(通过补充)与阴性症状的改善和一般不那么严重的症状有关，这表明临床结果与AA水平平行，更关键的是，这些水平是可以改变的。此前的研究主要集中在预后不佳的患者身上。由于预后通常是早期确定的，一个关键的问题是，病程早期的低膜AA是否与后来的不良预后相关。另一个关键问题是，如31P磁共振波谱(MRS)所确定的那样，在慢性精神分裂症患者中看到的外周细胞膜异常，并假设在疾病早期存在，是否与大脑磷脂代谢缺陷有关。为了检验这些问题，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将被前瞻性地研究，并进行重复评估。AA水平和两年随访结果之间的关系将被研究。与外周膜同时测定，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措施的关系提供一个独特的机会。此外，可能导致细胞膜AA降低的可能因素(磷脂酶A2增加和AA掺入减少)及其功能后果(磷脂酰肌醇信号系统的过度活跃)将被研究。如果这些研究的结果表明，在病程早期就存在膜缺陷(我们的初步数据表明，首发精神分裂症患者的红细胞AA减少)，并与不良的临床结果有关，那么可以考虑采取特定的早期干预措施，如补充全民教育。此外，这项研究还将阐明外周细胞膜动力学对疾病早期中枢膜磷脂代谢的意义。