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差。 尽管尚不清楚这种结果的机制，但关键的膜必需脂肪酸（EFA） - 蛛网膜酸（AA）的红细胞含量降低与预后不良有关（显着的负面和持续的阳性症状）。 AA是神经元磷脂的关键成分，对于正常神经元功能至关重要。增加的AA（通过补充）与负面症状的改善和通常严重症状的改善有关，这表明临床结果与AA水平相似，并且更重要的是，这些水平是可修改的。 先前的研究集中在预后差的患者上。 由于结果通常是早期确定的，因此一个关键的问题是，在疾病过程的早期，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看到的周围膜异常是否与疾病早期存在，与脑磷脂代谢中的缺陷有关，如31p磁共振光谱法确定。 为了研究这些问题，将对40例精神分裂症患者和40名年龄和性别匹配的正常受试者进行前瞻性研究。 将检查AA级别和2年随访的结果之间的关系。 同时到周围膜的确定，将使用MRS化学移位成像来检查脑磷脂代谢。 这将提供一个独特的机会，以同时研究中心和周围膜生物化学以及与临床措施的关系。 此外，将检查可能导致低膜AA（增加磷脂酶A2并减少AA掺入）的推定因素及其功能后果（磷酸肌醇信号系统的过度活跃）。 如果这些研究的发现表明在疾病的早期存在膜缺陷（由我们的初期疾病精神分裂症中的红细胞AA降低的试验数据提出），并且与不利的临床结果有关，那么可以考虑特定早期干预措施（例如EFA补充）的可能性。 此外，该研究将阐明周围膜动力学对中央膜磷脂代谢在疾病早期过程中的重要性。