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

 描述(由申请人提供)：白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，并由他们的一级亲属共享。因此，脑连通性的测量可能潜在地作为精神障碍的中间表型，与临床表型相比，更接近地反映疾病易感性的生物效应。对未受影响的兄弟姐妹的研究是一项强大的设计，旨在评估精神病的遗传风险，并在中等规模的健康个体家庭研究中提供大量遗传力的证据。应用弥散张量成像(DTI)的纤维束成像显示了分数各向异性(FA)的异常，特别是在精神分裂症和精神病性双相情感障碍的上纵束(SLF)内。此外，在224名个体中使用概率DTI气管造影术的自己的试点数据提供了证据，表明与年龄和性别匹配的健康志愿者相比，首发和慢性精神病患者SLF中的FA较低，这些患者组的效果大小相似，这表明这些异常可能是精神病的一种与特征相关的表现。此外，这个区域的异常在有精神障碍风险的个体中是明显的，并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，基于纤维束成像技术可能是不可靠的，并导致交叉纤维区域的误导性信息。因此，我们认为该领域需要超越扩散张量框架，以最终向治疗临床医生提供临床和生物相关信息。与扩散张量成像不同，扩散光谱成像(DSI)能够分辨交叉纤维，但需要大量的扫描时间，这通常不是 在临床人群中是可行的。在目前的研究中，我们建议使用压缩传感加速DSI来研究25名服用抗精神病药物的幼稚首发精神病患者、25名未受影响的同胞和25名健康志愿者的交叉白质纤维和交叉白质纤维区域的额外DSI参数。这项研究的首要目标是检查使用DSI推测的白质完整性的新指数是否可以作为独立于诊断类别的精神病的潜在内表型，以便在不混淆抗精神病药物的情况下提供精神病现象学的分子基础。此外，在精神病患者未受影响的兄弟姐妹中识别这些措施可以作为生物标记物，在未来的研究中衡量新干预措施的效果。

 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.