Crossing White Matter Fibers as an Endophenotype in First-Episode Psychosis

 描述（由申请人提供）：白色物质连接障碍在精神分裂症和精神病性双相情感障碍中很常见，与当前症状无关，并且由其一级亲属共享。因此，脑连接的测量可能潜在地作为精神障碍的中间表型，其与临床表型相比更接近地反映疾病易感性的生物学效应。对未受影响的兄弟姐妹的研究是一个强有力的设计，以评估精神病的遗传风险，并在健康个体的中等规模家庭研究中提供了大量遗传性的证据。纤维束成像采用扩散张量成像（DTI）显示异常的分数各向异性（FA），特别是在上级纵束（SLF）精神分裂症和精神病性双相障碍。此外，使用概率DTI纤维束成像的224例患者的试验数据提供了证据，与年龄和性别匹配的健康志愿者相比，首次发作和慢性精神病患者的SLF内FA较低，患者组之间的效应量相似，表明这些异常可能是精神病的一种特征相关表现。此外，在有发展为精神病性障碍风险的个体中，这条神经系统的异常是明显的，并且强烈预测神经心理和社会/角色功能的缺陷，使其 一个潜在的重要调查和干预目标。扩散张量的一个极限 然而，基于纤维束成像的缺点在于，它可能不可靠，并且在交叉纤维的区域中导致误导性信息。因此，我们认为该领域需要超越扩散张量框架，最终为治疗临床医生提供临床和生物学相关信息。与扩散张量成像相反，扩散谱成像（DSI）能够实现交叉纤维的分辨率，但是需要显著的扫描时间，这通常不是常规的扫描时间。 在临床人群中可行。在目前的研究中，我们建议使用压缩传感来加速DSI调查交叉白色纤维和额外的DSI参数在交叉白色纤维的区域中的25名抗精神病药物初治的首发精神病患者，25名他们的未受影响的兄弟姐妹和25名健康志愿者。本研究的总体目标是检查使用DSI的推定白色物质完整性的新指标是否可以作为独立于诊断类别的精神病的潜在内表型，以告知精神病现象学的分子基础，而不受抗精神病药物的混淆。此外，在精神病患者的未受影响的兄弟姐妹中识别这些措施可以作为生物标志物，以衡量未来研究中新干预措施的效果。

 DESCRIPTION (provided by applicant): White matter dysconnectivity is common to both schizophrenia and psychotic bipolar disorder, independent of current symptoms and shared by their first-degree relatives. Measures of brain connectivity may therefore potentially serve as an intermediate phenotype for psychotic disorders that more closely reflect the biological effects of illness susceptibility compared to the clinical phenotype. The study of unaffected siblings is a powerful design to assess genetic risk for psychosis with evidence of substantial heritability in moderately large family studies of healthy individuals. Tractography using diffusion tensor imaging (DTI) has revealed abnormalities in fractional anisotropy (FA), especially within the superior longitudinal fasciculus (SLF) both in schizophrenia and psychotic bipolar disorder. In addition, own pilot data in 224 individuals using probabilistic DTI tractography provide evidence for lower FA within the SLF both in first-episode and chronic psychosis patients compared to age- and sex-matched healthy volunteers with similar effect sizes across patient groups suggesting that these abnormalities may be a trait-related manifestation of psychosis. Moreover, abnormalities in this tract are evident among individuals at risk for developing psychotic disorders and strongly predict deficits in neuropsychological and social/role functioning making it a potentially important target for investigation and intervention. A limitation of diffusion tensor based tractography, however, is that it can be unreliable and lead to misleading information in regions of crossing fibers. We therefore believe the field needs to move beyond the diffusion tensor framework to ultimately provide clinically and biologically relevant information to the treating clinician. In contrast to diffusion tensor imaging, diffusion spectrum imaging (DSI) enables resolution of crossing fibers, but requires significant scanning time that is not typically feasible in clinical populations. In the current study, we propose using compressed sensing to accelerate DSI to investigate crossing white matter fibers and additional DSI parameters in regions of crossing white matter fibers in 25 antipsychotic drug-naïve first-episode psychosis patients, 25 of their unaffected siblings and 25 healthy volunteers. The overarching goal of the study is to examine whether novel indices of putative white matter integrity using DSI can serve as potential endophenotypes for psychosis independent of diagnostic category to inform the molecular basis of psychotic phenomenology without the confound of antipsychotic medication. Moreover, identification of such measures in unaffected siblings of patients with psychosis could serve as biomarkers to gauge the effects of novel interventions in future studies.