Biomarkers for Psychosis in Velocardiofacial Syndrome

描述(申请人提供)：血管心面综合征(VCFS)，也被称为22q11.2缺失综合征，与先天性畸形、神经认知障碍有关，在患有这种综合征的成年人中，高达30%与精神分裂症(SZ)有关。在这项竞争性更新申请中，我们建议继续我们从2002年开始的对VCFS中精神障碍生物标志物的纵向研究。在2007-2011年的资助周期中，我们已经开始绘制患有VCFS儿童的认知、精神和神经解剖学发展轨迹，并确定这些因素中的哪些可以预测精神病的前驱症状。来自这一资助周期的数据显示，在患有VCFS的青少年的青春期中期，对精神病先兆症状最有力的预测因子是言语学习、视觉工作记忆和执行功能的纵向认知衰退，以及前额叶皮质、颞叶灰质和海马体体积的神经解剖萎缩。然而，我们样本中的年轻人刚刚达到他们最容易患上SZ的年龄。因此，我们继续跟踪队列以确定与SZ发病相关的因素，并可能预测SZ的发病，这一点至关重要。拟议项目的目标是通过第四阶段的数据收集扩大我们对这一大样本的调查，该阶段将涵盖患有VCFS的青少年患上SZ的最高风险的年龄范围(18-24岁)。基于我们在当前资金周期中的发现，并了解到在非VCFS患者中，当SZ症状开始出现时，额叶和颞叶的快速髓鞘形成正在发生，我们建议在这个时间点应用扩散张量成像来研究VCFS中白质束的完整性。因此，我们建议通过应用最先进的方法来调查VCFS中微结构白质的异常与严重精神疾病的易感性的程度，从而将这一项目带入一个新的、创新的方向。我们的具体目标是：1)继续调查(跨越时间点1、2和3)额叶和颞叶感兴趣区域在时间4的精神疾病发展中的轨迹；2)研究额颞束、额顶枕束和放射冠纤维束在VCFS中的完整性；3)研究额颞束和额顶枕束结构连通性与构成精神病功能缺陷的认知、社会和调节过程之间的联系(利用NIMH研究领域标准项目的结构)；4)研究22q11.2基因座7个候选基因的10个功能性单核苷酸多态(SNP)等位基因变异对额颞白质通路和额枕白质通路改变的影响；5)寻找适用于VCFS青少年精神病的预测因子。我们从这项研究中获得的知识将通过阐明和明确VCFS对SZ易感性的神经生物学基础来推动这一领域的发展，从而为早期识别和治疗VCFS铺平道路。 青少年患精神病的风险最高。

DESCRIPTION (provided by applicant): Velocardiofacial syndrome (VCFS), also known as 22q11.2 deletion syndrome, is associated with congenital anomalies, neurocognitive deficits, and, in up to 30 percent of adults with this syndrome, schizophrenia (SZ). In this competitive renewal application, we are proposing to continue our longitudinal study of biomarkers for psychosis in VCFS that we began in 2002. During the 2007-2011 funding cycle, we have begun to map the trajectory of cognitive, psychiatric and neuroanatomic development in children with VCFS, and to determine which of these factors predict prodromal symptoms of psychosis. Data from this funding cycle have revealed that within the developmental window of mid-adolescence in youth with VCFS, the most robust predictors to prodromal symptoms of psychosis were longitudinal cognitive decrements in verbal learning, visual working memory and executive function, and neuroanatomic decrements in the volumes of prefrontal cortex, temporal lobe gray matter and hippocampus. However, the youth in our sample are just reaching the age at which they are most vulnerable to the onset of SZ. Accordingly, it is critical that we continue follow ths cohort in order to identify the factors that are associated with, and may be predictive of, the onset of SZ. The goal of the proposed project is to extend our investigation of this large sample through a fourth phase of data collection, which will span the age range (18 - 24 years) during which youth with VCFS are at the highest risk of developing SZ. Based on our findings from the current funding cycle, and the knowledge that in non-VCFS individuals, rapid myelination of frontal and temporal lobes is occurring at a time when symptoms of SZ are beginning to appear, we propose to apply diffusion tensor imaging to investigate the integrity of the white matter tracts in VCFS at this timepoint. Accordingly, we propose to take this project in a new, innovative direction by applying state-of-the-art methods to investigate the extent to which anomalies in microstructural white matter in VCFS are associated with vulnerability to severe psychiatric illness. Our specific aims are: 1) to continue to investigate the trajectory (across Timepoints 1, 2, and 3) of frontal and temporal lobe regions of interest on the development of psychosis at Time 4; 2) to investigate the integrity of fronto-temporal, fronto-parieto-occipital, and corona radiata fiber bundles in VCFS; 3) to investigate the association between structural connectivity in fronto-temporal and fronto-parieto-occipital tracts and cognitive, social and regulatory processes that comprise functional deficits in psychotic illness (utilizing constructs from the NIMH Research Domain Criteria Project); 4) to investigate the effect of allelic variation in ten functional single nucleotide polymorphisms (SNP's) of seven Candidate genes at the 22q11.2 locus on alterations in fronto-temporal and fronto-parieto-occipital white matter pathways; and 5) to develop useful predictors of psychosis for VCFS youth. The knowledge we gain from this study will move the field forward by elucidating and specifying the neurobiological basis of vulnerability to SZ in VCFS, thus paving the way for early identification and treatment of youth at highest risk for psychosis.