Childhood Onset Schizophrenia

儿童期发病的精神分裂症

基本信息

批准号：
8342106
负责人：
JUDITH L. RAPOPORT
金额：
$ 156.81万
依托单位：
NATIONAL INSTITUTE OF MENTAL HEALTH
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8342106
关键词：
Address Adolescence Adolescent Adult Affect Age Alleles Anatomy Attention Biological Brain Brain imaging Case Study Catabolism Catechols Chicago Child Child Psychology Childhood Clinical Clinical Research Cognitive Collaborations Corpus striatum structure Depressive disorder Development Differential Diagnosis Disease Dopamine Dose Early Diagnosis Early treatment Exons Family member Follow-Up Studies Future Gene Mutation Genes Genetic Genetic Markers Genetic Polymorphism Goals Growth Hallucinations Heritability Hippocampus (Brain)Impairment Individual Institutes Investigation MRI Scans Measures Medicine Mental disorders Methyltransferase Modality National Institute of Mental Health Nature Neurites Neurobiology Neurons Onset of illness Parents Patients Pediatric Neurology Pediatrics Phenotype Pluripotent Stem Cells Prospective Studies Protocols documentation Rare Diseases Recruitment Activity Relative (related person)Risk Sampling Schizophrenia Severities Shapes Short-Term Memory Siblings Signal Transduction Societies Symptoms Thick Universities Variant childhood bipolar disorder cohort cost early onset exome genetic pedigree gray matter high risk induced pluripotent stem cell meetings neuroimaging neuron development proband prospective

项目摘要

We continue to refine the differential diagnosis of this rare but devastating condition. The best indicator of true disorder compared to pediatric bipolar and depressive disorder is the extreme severity of psychotic symptoms (Gochman et al 2011). In comparison with adult patients, childhood onset patients have a greater number of different modalities of hallucination which appear additive in nature and which are associated with greater intellectual impairment suggesting that these are measures of abnormal cortical brain connectivity (David et al 2011). Cognitive studies have begun within this protocol to obtain prospective measures of working memory and attention for young full siblings of the childhood onset schizophrenia patients. It is hypothesized that earlier cognitive relative deficits will be ameliorated in parallel with temporal and frontal cortical brain/development. Our prospective studies of normal and abnormal brain development have greatly influenced the fields of pediatric neurology, child psychology and pediatrics (Giedd & Rapoport, 2010). Ongoing brain imaging studies find that in a second independent sample, that healthy full siblings have early frontal and temporal cortical brain thinning which normalizes by mid adolescence (Mattai et al 2011). This may represent a healthy phenotype for future genetic studies. Studies of anatomic hippocampal development in the healthy siblings showed no deviance from that seen for the healthy controls indicating that hippocampal abnormalities may be disease related and not genetic markers. Follow up studies in collaboration with the University of Chicago (Dr. Czernansky) are examining hippocampal shape to complete this investigation. Non-psychotic individuals at increased risk for schizophrenia show alterations in fronto-striatal dopamine signaling and cortical gray matter maturation reminiscent of those seen in schizophrenia. We sought to address these issues by relating a functional Val-->Met polymorphism within the gene encoding catechol-o-methyltransferase (COMT)-a key enzymatic regulator of cortical dopamine levels-to longitudinal structural neuroimaging measures of cortical dopamine levels to longitudinal structural neuroimaging measures of cortical gray matter thickness. Brain MRI scans, acquired between 9 and 22 years from patients with childhood-onset schizophrenia (COS), their non-psychotic full siblings, and matched healthy controls were compared. Val allele dose (which confers enhanced dopamine catabolism and is proposed to aggravate cortical deficits in schizophrenia) accelerated adolescent cortical thinning in both schizophrenia probands and their siblings, but lesser cortical thinning in healthy controls. These findings suggest that cortical abnormalities in pedigrees affected by schizophrenia may be contributed to by a disruption of dopaminergic influences on cortical maturation. Several genetic studies are ongoing. Individual case studies from our cohort indicate that exome sequencing studies are likely to be informative as we are already finding unique variants in selected cases e.g. Addington et al 2011, Anderson et al in press, Lee et al in press. To better understand the heritability of schizophrenia, and to identify de novo gene mutations, collaborators at the University of Montreal (Dr. Guy Roulleau) are conducting targeted sequencing of 5,000 brain development-related genes from 30 trios, comprising affected children with schizophrenia and their parents. Using the trios, we are also probing rare variants that may be associated with the disease. Finally, a collaborative study with Drs. Kristin Brennand and Fred Gage of the Salk Institute is studying development of neuronal connectivity and neurite number from iPS derived neurons from our childhood onset schizophrenia patients. Patients with and without rare disease associated copy number variants (CNVs) are included. Contrast groups will include unrelated healthy controls, healthy and affected family members who are carriers of risk CNVs.

我们继续完善这种罕见但具有破坏性的疾病的鉴别诊断。与儿科双相情感障碍和抑郁症相比，真正的疾病的最佳指标是精神病症状的极端严重性（Gochman et al 2011）。与成年患者相比，儿童期发病的患者有更多不同形式的幻觉，这些幻觉本质上是累加性的，并且与更大的智力障碍相关，表明这些是异常皮质脑连接的衡量标准（David et al 2011）。在该方案中已经开始认知研究，以获得儿童期精神分裂症患者的年轻同胞兄弟姐妹的工作记忆和注意力的前瞻性测量。据推测，早期认知相对缺陷将随着颞叶和额叶皮层大脑/发育的同时得到改善。我们对正常和异常大脑发育的前瞻性研究极大地影响了儿科神经病学、儿童心理学和儿科领域（Giedd & Rapoport，2010）。正在进行的脑成像研究发现，在第二个独立样本中，健康的同胞兄弟姐妹的大脑额叶和颞叶皮质较早变薄，并在青春期中期正常化（Mattai et al 2011）。这可能代表了未来遗传学研究的健康表型。对健康兄弟姐妹海马发育的解剖学研究表明，与健康对照相比，海马发育没有任何偏差，这表明海马异常可能与疾病有关，而不是遗传标记。与芝加哥大学（Czernansky 博士）合作的后续研究正在检查海马形状以完成这项调查。精神分裂症风险增加的非精神病个体表现出额纹状体多巴胺信号传导和皮质灰质成熟的改变，让人想起精神分裂症中所见的变化。我们试图通过将儿茶酚邻甲基转移酶（COMT）编码基因内的功能性 Val-->Met 多态性（皮质多巴胺水平的关键酶调节因子）与皮质多巴胺水平的纵向结构神经影像测量联系起来来解决这些问题。皮质灰质厚度的神经影像测量。对儿童期精神分裂症 (COS) 患者、其非精神病同父异母兄弟姐妹以及匹配的健康对照者 9 至 22 岁时获得的脑部 MRI 扫描进行了比较。 Val等位基因剂量（可增强多巴胺分解代谢，并被认为会加剧精神分裂症的皮质缺陷）加速了精神分裂症先证者及其兄弟姐妹的青少年皮质变薄，但在健康对照中皮质变薄程度较小。这些发现表明，受精神分裂症影响的家系中的皮质异常可能是由于多巴胺能对皮质成熟的影响被破坏所致。多项遗传学研究正在进行中。我们队列中的个别案例研究表明，外显子组测序研究可能会提供丰富的信息，因为我们已经在选定的案例中发现了独特的变异，例如Addington 等人 2011，Anderson 等人正在出版，Lee 等人正在出版。为了更好地了解精神分裂症的遗传性，并识别从头基因突变，蒙特利尔大学的合作者（Guy Roulleau 博士）正在对来自 30 个三人组的 5,000 个大脑发育相关基因进行靶向测序，这些三人组包括患有精神分裂症的儿童及其家人。父母。利用这三者，我们还探索可能与该疾病相关的罕见变异。最后，与博士的合作研究。索尔克研究所的 Kristin Brennand 和 Fred Gage 正在研究来自儿童期发病的精神分裂症患者的 iPS 衍生神经元的神经元连接和神经突数量的发育。患有或不患有罕见病相关拷贝数变异 (CNV) 的患者均包括在内。对照组将包括不相关的健康对照、健康和受影响的家庭成员，他们是风险 CNV 的携带者。