MEMBRANE DEFICITS AND OUTCOME IN SCHIZOPHRENIA

精神分裂症的膜缺陷和结果

• 批准号: 6528493
• 负责人: JEFFREY K YAO
• 金额: $ 23.73万
• 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/6528493
• 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良。 虽然这些结果的机制尚不清楚，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局（显著的阴性和持续的阳性症状）相关。 AA是神经元膜磷脂的关键组分，并且对正常神经元功能至关重要。增加AA（通过补充）与阴性症状的改善和一般不太严重的症状有关，这表明临床结果与AA水平平行，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良的患者身上。 由于结果往往是早期确定的，一个关键的问题是是否低膜AA在病程早期与后来的不良结果。 另一个关键问题是，慢性精神分裂症患者的外周膜异常是否与脑磷脂代谢缺陷有关，这一点被假设为在疾病早期就存在，这一点由31 P磁共振波谱（MRS）确定。 为了研究这些问题，40例首发精神分裂症患者和40例年龄和性别匹配的正常受试者将进行前瞻性研究，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，将使用MRS化学位移成像检查脑磷脂代谢。 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，和临床措施的关系。 此外，将检查可能导致低膜AA（磷脂酶A2增加和AA掺入减少）及其功能后果（磷酸肌醇信号系统活性过高）的推定因素。 如果这些研究的结果表明，膜缺陷存在于病程早期（我们的初步数据表明，首发精神分裂症患者红细胞AA减少），并与不利的临床结局相关，那么可以考虑特定的早期干预措施，如补充EFA。 此外，这项研究将阐明外周膜动力学的意义，中央膜磷脂代谢在疾病的早期过程。