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%的精神分裂症患者预后不佳。虽然这些结果背后的机制尚不清楚，但红细胞中关键膜必需脂肪酸(EFA) -花生四烯酸（AA）含量的降低与不良结果（明显的阴性和持续的阳性症状）有关。AA是神经元膜磷脂的重要组成部分，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通常较轻的症状相关，这表明临床结果与AA水平相似，更重要的是，AA水平是可以改变的。以前的研究主要集中在预后不佳的患者身上。由于预后通常在早期确定，一个关键的问题是疾病早期低膜AA是否与后来的不良预后有关。另一个关键问题是，在慢性精神分裂症患者中观察到的外周膜异常，并假设在疾病早期出现，是否与脑磷脂代谢缺陷有关，这是由31P磁共振波谱（MRS）确定的。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通过重复评估进行前瞻性研究。AA水平与2年随访结果的关系将被检查。与外周膜测定同时，MRS化学移位成像将用于检查脑磷脂代谢。这将提供一个独特的机会，同时调查中央和外周膜生物化学，并与临床措施的关系。此外，可能导致低膜AA的因素（磷脂酶A2增加和AA掺入减少）及其功能后果（磷酸肌苷信号系统的过度活跃）将被检查。如果这些研究结果表明，在病程早期存在膜缺陷（我们的首发精神分裂症患者红细胞AA降低的试点数据表明），并且与不利的临床结果相关，那么可以考虑特定的早期干预措施，如补充EFA。此外，该研究将阐明外周膜动力学对疾病早期中央膜磷脂代谢的意义。