Biomarkers for Psychosis in Velocardiofacial Syndrome

描述（由申请人提供）：心面快速综合征（VCFS），也称为22q11.2缺失综合征，与先天性异常、神经认知缺陷以及高达30%的患有该综合征的成人精神分裂症（SZ）相关。在这个竞争性更新申请中，我们建议继续我们在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，并确定哪些因素可以预测精神病的前驱症状。来自该资助周期的数据显示，在青少年VCFS的青春期中期发育窗口内，最可靠的精神病前驱症状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，以及前额皮质、颞叶灰质和海马体积的神经解剖衰退。然而，我们样本中的年轻人正处于他们最容易患上SZ的年龄。因此，至关重要的是，我们继续跟踪这一队列，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大我们对这个大样本的调查，这将跨越年龄范围（18 - 24岁），在这个年龄范围内，患有VCFS的年轻人患SZ的风险最高。基于我们当前资助周期的发现，以及在非VCFS个体中，额叶和颞叶的快速髓鞘形成发生在SZ症状开始出现的时候，我们建议应用弥散张量成像来研究VCFS在这个时间点的白质束完整性。因此，我们建议通过应用最先进的方法来研究VCFS微结构白质异常与严重精神疾病易感性的关联程度，从而将该项目引入一个新的创新方向。我们的具体目标是：1)继续研究（跨越时间点1、2和3）在时间点4时，感兴趣的额叶和颞叶区域在精神病发展中的轨迹；2)研究VCFS中额颞、额顶枕和辐射冠纤维束的完整性；3)研究额颞叶束和额顶枕束的结构连通性与包括精神病患者功能缺陷的认知、社会和调节过程之间的关系（利用NIMH研究领域标准项目的结构）；4)研究22q11.2位点7个候选基因的10个功能性单核苷酸多态性（SNP）等位基因变异对额-颞叶和额-顶叶-枕叶白质通路改变的影响；5)开发有用的VCFS青少年精神病预测指标。我们从本研究中获得的知识将通过阐明和明确VCFS中SZ易感性的神经生物学基础推动该领域的发展，从而为早期识别和治疗铺平道路

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. PUBLIC HEALTH RELEVANCE: Up to 30 percent of adults with the genetic disorder, velo-cardio-facial syndrome (VCFS; also known as 22q11.2 deletion syndrome) develop schizophrenia. The continuation of our longitudinal study of biomarkers for psychosis in VCFS, in which we will investigate neuroanatomic alterations with anatomic magnetic resonance imaging and diffusion tensor imaging, will permit us to elucidate the neurobiological basis of vulnerability to psychosis in youth with this genetic disorder. The high rate of schizophrenia in VCFS constitutes a significant public health concern for both families and society. Identifying those neurobiological factors that place youth with VCFS at the highest risk for schizophrenia will impact positively on the early, preventative intervention and treatment of psychiatrically impaired children and youth with VCFS, thus reducing its toll on families and society.