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.

我们继续完善对这种罕见但毁灭性疾病的鉴别诊断。与小儿双极和抑郁症相比，真正疾病的最佳指标是精神病症状的极端严重程度（Gochman等人，2011年）。与成年患者相比，儿童时期患者具有更多不同的幻觉方式，这些幻觉本质上似乎是加性的，并且与更大的智力障碍有关，这表明这些是皮质脑连接异常的措施（David等人，2011年）。认知研究已经开始在该方案中开始，以获得童年开始精神分裂症患者的年轻兄弟姐妹的前瞻性措施。假设早期的认知相对缺陷将与时间和额叶皮质大脑/发育平行改善。我们对正常和异常脑发育的前瞻性研究极大地影响了儿科神经病学，儿童心理学和儿科的领域（Giedd＆Rapoport，2010年）。正在进行的大脑成像研究发现，在第二个独立的样本中，健康的全兄弟姐妹具有早期额叶和颞皮质脑稀疏，到青春期中期正常化（Mattai等，2011）。这可能代表了未来遗传研究的健康表型。健康兄弟姐妹中解剖学海马发育的研究表明，对于健康对照组，没有偏见，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研究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患者表明，额纹状体多巴胺信号传导和皮质灰质成熟的改变，让人联想到精神分裂症中看到的人。我们试图通过在编码Catechol-O-甲基转移酶（COMT）的基因中将功能性阀（> MET多态性）联系起来来解决这些问题，这是皮质多巴胺水平的关键酶促调节剂与纵向结构性神经模拟型纵向多巴胺水平的纵向灰色结构型纵向纵向较大的神经膜化度量。比较了脑部MRI扫描，从儿童期精神分裂症患者（COS），非精神病性全兄弟姐妹和匹配的健康对照组中获得了9至22年的范围。 VAL等位基因剂量（增强了多巴胺分解代谢，并提议加重精神分裂症的皮质缺陷）在精神分裂症概率及其兄弟姐妹中加速了青少年皮质稀疏，但健康对照中的皮质稀疏较少。这些发现表明，受精神分裂症影响的血统的皮质异常可能是由于多巴胺能对皮质成熟的影响而造成的。几项遗传研究正在进行中。我们队列中的个体案例研究表明，外显子测序研究可能是有益的，因为我们已经在选定的案例中找到了独特的变体。 Addington等人2011年，Anderson等人在印刷中，印刷中。为了更好地了解精神分裂症的遗传力，并确定从头基因突变，蒙特利尔大学（Guy Roulleau博士）的合作者正在对30个三个三个三重奏的5,000个与脑发育相关的基因进行有针对性的测序，其中包括受影响的儿童与Schizophrenia及其父母。使用三重奏，我们还探测了可能与该疾病有关的稀有变体。最后，与Drs的合作研究。 Salk Institute的Kristin Brennand和Fred Gage正在研究来自我们童年的精神分裂症患者的IPS神经元的神经元连通性和神经突的发展。包括有或没有罕见疾病相关的拷贝数变体（CNV）的患者。对比组将包括无关的健康对照，健康和受影响的家庭成员，这些家庭成员是风险CNV的载体。