Biomarkers for Psychosis in Velocardiofacial Syndrome

描述（由申请人提供）：速度心面综合征（VCFS），也称为22q11.2缺失综合征，与先天性异常、神经认知缺陷有关，在多达30%的患有该综合征的成年人中，与精神分裂症（SZ）有关。在这个竞争性更新申请中，我们建议继续我们2002年开始的VCFS精神病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。来自该资助周期的数据显示，在患有VCFS的青少年中青春期中期的发育窗口内，精神病前驱症状的最有力预测因素是言语学习，视觉工作记忆和执行功能的纵向认知递减，以及前额叶皮层，颞叶灰质和海马体积的神经解剖学递减。然而，我们样本中的年轻人刚刚达到他们最容易发生SZ的年龄。因此，我们必须继续跟踪这一队列，以确定与SZ发病相关的因素，并可能预测SZ的发病。拟议项目的目标是通过第四阶段的数据收集来扩展我们对这一大样本的调查，该阶段将涵盖年龄范围（18 - 24岁），在此期间，VCFS青年发展SZ的风险最高。根据我们从当前的资金周期的研究结果，以及在非VCFS个体中，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的知识，我们建议应用扩散张量成像来调查VCFS中白色物质束在这个时间点的完整性。因此，我们建议采取这个项目在一个新的，创新的方向，通过应用国家的最先进的方法来调查在何种程度上异常的微结构白色的问题在VCFS与严重的精神疾病的脆弱性。我们的具体目标是：1）继续调查轨迹（跨时间点1、2和3）额叶和颞叶感兴趣区域对时间4精神病发展的影响; 2）研究VCFS中额颞叶、额顶枕叶和放射冠纤维束的完整性; 3）探讨额颞束和额顶枕束的结构连接与认知功能的关系，包括精神病功能缺陷的社会和调节过程（利用NIMH研究领域标准项目的结构）; 4）研究22q11.2位点上7个候选基因的10个功能性单核苷酸多态性（SNP）等位变异对额-额-额颞叶和额顶枕部白色物质通路; 5）开发VCFS青少年精神病的有用预测因子。我们从这项研究中获得的知识将通过阐明和详细说明VCFS中SZ脆弱性的神经生物学基础来推动该领域的发展，从而为早期识别和治疗 精神病风险最高的年轻人

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.