Biomarkers for Psychosis in Velocardiofacial Syndrome

描述(申请人提供)：由染色体22q11.2上的微缺失引起的心血管面部综合征(VCFS)，影响1：4000人，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。我们只是刚刚开始确定预测患有这种遗传疾病的深圳人的因素。在这项申请中，我们建议继续我们从2001年2月开始的对VCFS中精神障碍危险因素的纵向研究。在过去的5年里，我们在两个时间点收集了大量的神经解剖学、认知和精神病学数据，涉及83名患有VCFS的青年、33名未受影响的兄弟姐妹和38名社区对照。这些数据使我们能够开始绘制患有VCFS的儿童的认知、精神和神经解剖学发展轨迹，并确定这些因素中的哪些因素在第二时间预测精神功能不佳。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，我们继续跟踪这一队列，以确定与SZ发病相关的神经解剖学和神经心理学因素，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三阶段数据收集扩大我们对这一大样本的调查，该阶段将跨越患有VCFS的青少年易受SZ发病影响的年龄范围(15-21岁)。我们建议应用先进的计算工具来分析我们已经发现的患有VCFS的青年患者特定大脑区域的皮质厚度和皮质形态，这可能与精神功能低下有关。然后，我们将研究基因、脑体积、皮质表面形态/厚度和神经认知功能对精神疾病结局的影响。我们的具体目标是：1)绘制患有VCFS的青年患者的神经解剖学、神经认知和精神轨迹；确定2)特定脑体积、皮质表面形态和皮质厚度、3)神经心理功能和4)精神障碍与SZ病前症状或阳性症状3)相关的发育轨迹；5)确定Val158Met COMT多态等位基因变异是否可以预测3岁时SZ的病前症状或阳性症状。VCFS中SZ的高发生率构成了对家庭和社会的重大公共卫生问题。找出那些使患有VCFS的青少年处于SZ最高风险的因素，将对患有VCFS的精神受损儿童和青少年的早期预防性干预和治疗产生积极影响，从而减少其对家庭和社会的影响。

DESCRIPTION (provided by applicant): Velocardiofacial syndrome (VCFS), caused by a microdeletion on chromosome 22q11.2 and affecting 1:4000 individuals, is associated with congenital anomalies, neurocognitive deficits, and, in up to 30% of adults with this syndrome, schizophrenia (SZ). We are only beginning to identify the factors that predict SZ n individuals with this genetic disorder. In this application, we are proposing to continue our longitudinal study of risk factors for psychosis in VCFS that we began in February of 2001. During the past 5 years, we have collected extensive neuroanatomic, cognitive, and psychiatric data at two time points on 83 youth with VCFS, 33 of their unaffected siblings and 38 community controls. These data have permitted us to begin to map the trajectory of cognitive, psychiatric and neuroanatomic development in children with VCFS, and to determine which of these factors predict poor psychiatric function at Time 2. 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 this cohort in order to identify the neuroanatomic and neuropsychological 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 third phase of data collection, which will span the age range (15-21 years) during which youth with VCFS become vulnerable to the onset of SZ. We are proposing to apply advanced computational tools to analyze the cortical thickness and cortical morphology of the specific brain regions that we have found are altered in youth with VCFS and that may be associated with poor psychiatric function. We will then examine the effect of genotype, brain volumes, cortical surface morphology / thickness and neurocognitive function on psychiatric outcome. Our specific aims are: 1) to map the neuroanatomic, neurocognitive and psychiatric trajectory in youth with VCFS; to determine the extent to which the developmental trajectories of 2) specific brain volumes, cortical surface morphology and cortical thickness, 3) neuropsychological function, and 4) psychiatric disorders are associated with either premorbid or positive symptoms of SZ at Time 3; and 5) to determine whether allelic variation in the Val158Met COMT polymorphism predicts either premorbid or positive symptoms of SZ at Time 3. The high rate of SZ in VCFS constitutes a significant public health concern for both families and society. Identifying those factors that place youth with VCFS at the highest risk for SZ 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.