2/3-Brain Chemistry and Genetics in Pediatric Obsessive-Compulsive Disorder

2/3-儿童强迫症的脑化学和遗传学

• 批准号: 8278047
• 负责人: Gregory L. HANNA
• 金额: $ 38.5万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-11 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8278047
• 关键词: Adolescent; Affect; Age; Amygdaloid structure; Anterior; Award; Basal Ganglia; Behavioral Symptoms; Biological; Biology; Brain; Brain Chemistry; Brain imaging; Brain region; Candidate Disease Gene; Child; Childhood; Choline; Chronic; Clinical Services; Clinical assessments; Collaborations; Corpus striatum structure; Creatine; Data; Diagnosis; Disease; Exhibits; Female; Functional disorder; Future; Genes; Genetic; Genetic Polymorphism; Genome; Genotype; Glutamate Receptor; Glutamate Transporter; Glutamates; Glutamine; Goals; Grant; Health; Image; Lead; Left; Light; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measures; Medial; Mediating; Mental disorders; Methods; Michigan; Molecular Genetics; N-acetylaspartate; Neurons; Obsessive-Compulsive Disorder; Occipital lobe; Pathogenesis; Patients; Pediatric Hospitals; Pituitary Gland; Prefrontal Cortex; Principal Investigator; Protons; Psychopathology; Public Health; Receptor Gene; Resolution; Risk; Role; Severities; Site; Symptoms; Temporal Lobe; Testing; Thalamic structure; United States; Universities; Variant; cost; early onset; effective therapy; family genetics; improved; interest; male; neurochemistry; neuroimaging; novel diagnostics; performance site; prevent; programs; sex; translational approach; transmission process; trend

DESCRIPTION (provided by applicant): This is a competitive renewal application of the Wayne State Principal Investigator's (Rosenberg) grant award, R01MH59299. Obsessive compulsive disorder (OCD) is a severe, prevalent, and chronically disabling disorder that emerges during childhood in as many as 50% of all cases. The overall goal of this project, which combines the unique clinical assessment, magnetic resonance imaging, and genetics expertise of three performance sites - Wayne State (neuroimaging of pediatric OCD), University of Michigan (family and molecular genetic studies of early-onset OCD) and University of Toronto (extensive genetic studies of glutamate receptor and transporter genes in OCD) - is to exploit the emerging field of imaging genetics in a critical test of the glutamate hypothesis of OCD. Preliminary studies from Rosenberg's group (R01MH59299, K24MH02037) suggest that a glutamatergically-mediated thalamocortical-striatal dysfunction may serve as a pathophysiological marker in pediatric OCD. Independent findings by the Hanna (R01MH53876, K20MH01065) and the Arnold and Kennedy groups demonstrate a significant association of the glutamate transporter gene, SLC1A1, and glutamate receptor gene, GRIN2B, with early-onset OCD. Building on long-standing existing collaborations among the three sites, exciting new pilot data in pediatric OCD patients demonstrates a significant association between regional brain glutamatergic concentrations, particularly in the anterior cingulate and the GRIN2B-rs1019385 polymorphism. Significant associations between increased left, but not right orbital frontal and increased anterior cingulate volume (R>L) with the rs1805476 variant of GRIN2B were identified in OCD patients. The GRIN2B-rs1019385 variant exhibited a non-significant trend towards association with decreased left but not right caudate volume. The SLC1A1 rs3056-AA genotype was significantly associated with increased right and left thalamic volume. Thus, GRIN2B and SLC1A1 sequence variations may be associated with differences in volume and glutamatergic concentrations within brain regions implicated in the pathogenesis of OCD. High field (3 Tesla) proton magnetic resonance spectroscopy (1H MRS) can uniquely distinguish the subcomponents of the glutamatergic resonance (glutamate and glutamine), as well as measure other compounds including the putative neuronal marker, N-acetyl-aspartate, choline compounds and creatine. Targeted 1H MRS and volumetric imaging at 3T at the Children's Hospital of Michigan at Wayne State will be combined with genotyping of 37 polymorphisms in the genes encoding GRIN2B and SLC1A1 (University of Toronto) to examine the effects of these variants on thalamocortical-striatal circuitry in 200 pediatric OCD patients, 7-19 years, and 200 age and sex-matched healthy controls. The combined study of biological, genetic and behavioral/symptom variables enacts the call for translational approaches to mental illness outlined in PA-07- 092, Collaborative R01s for Clinical and Services Studies of Mental Disorders, which may lead to a better understanding of pediatric OCD and, in turn, to new diagnostic and treatment approaches. PUBLIC HEALTH RELEVANCE: Obsessive-compulsive disorder (OCD) is a chronic and disabling disorder that costs the economy over $2 billion annually and affects approximately one million children and adolescents in the United States, making it a significant public health problem. There is a pressing need for studies that shed light on the biology of the disorder in order to improve our ability to diagnose, treat, and prevent the disorder. By combining brain imaging and genetics, as we do in this proposal, we can better understand the biology of pediatric OCD and, in turn, develop more effective treatments for this severe form of childhood psychopathology.

描述（由申请人提供）：这是韦恩国家主要研究者（罗森博格）补助金R 01 MH 59299的竞争性续期申请。强迫症（OCD）是一种严重的、普遍的、慢性致残性疾病，在儿童时期出现，占所有病例的50%。该项目的总体目标是结合韦恩州立大学三个研究中心独特的临床评估、磁共振成像和遗传学专业知识，（小儿强迫症的神经影像学），密歇根大学（早发强迫症的家族和分子遗传学研究）和多伦多大学（对强迫症中谷氨酸受体和转运蛋白基因的广泛遗传研究）-是利用新兴的成像遗传学领域，对强迫症的谷氨酸假说进行关键性测试。Rosenberg小组的初步研究（R 01 MH 59299，K24 MH 02037）表明，丘脑-纹状体介导的丘脑-皮质-纹状体功能障碍可作为儿童强迫症的病理生理学标志物。Hanna（R 01 MH 53876，K20 MH 01065）和Arnold和Kennedy小组的独立研究结果表明，谷氨酸转运蛋白基因SLC 1A 1和谷氨酸受体基因GRIN 2B与早发性强迫症有显著相关性。基于这三个研究中心之间长期存在的合作，在儿童强迫症患者中令人兴奋的新的试点数据表明，区域脑内多巴胺能浓度之间存在显著关联，特别是在前扣带回和GRIN 2B-rs 1019385多态性中。在强迫症患者中，发现左侧眶额体积增加（而不是右侧眶额）和前扣带回体积增加（R>L）与GRIN 2B的rs 1805476变体之间存在显着相关性。GRIN 2B-rs 1019385变体表现出与左侧尾状核体积减少而非右侧尾状核体积减少相关的非显著趋势。SLC 1A 1 rs3056-AA基因型与左右丘脑体积增加显著相关。因此，GRIN 2B和SLC 1A 1序列变异可能与OCD发病机制中涉及的脑区域内体积和多巴胺能浓度的差异有关。高场（3特斯拉）质子磁共振波谱（1H MRS）可以独特地区分谷氨酸能共振的子成分（谷氨酸和谷氨酰胺），以及测量其他化合物，包括推定的神经元标记物，N-乙酰基-天冬氨酸，胆碱化合物和肌酸。在韦恩州立大学密歇根儿童医院进行的3 T靶向1H MRS和容积成像将与编码GRIN 2B和SLC 1A 1（多伦多大学）的基因中37个多态性的基因分型相结合，以检查这些变体对200名7-19岁儿童强迫症患者和200名年龄和性别匹配的健康对照的丘脑皮质-纹状体回路的影响。生物学、遗传学和行为/症状变量的综合研究，呼吁采用PA-07- 092《精神疾病临床和服务研究协作R 01》中概述的精神疾病转化方法，这可能有助于更好地了解儿童强迫症，进而找到新的诊断和治疗方法。公共卫生相关性：强迫症（OCD）是一种慢性和致残性疾病，每年经济损失超过20亿美元，影响美国约100万儿童和青少年，使其成为一个重大的公共卫生问题。有迫切需要的研究，阐明了生物学的障碍，以提高我们的能力，诊断，治疗和预防疾病。通过结合脑成像和遗传学，就像我们在这个提案中所做的那样，我们可以更好地了解儿童强迫症的生物学，反过来，为这种严重的儿童精神病理学形式开发更有效的治疗方法。