Clinical and Behavioral Phenotyping of Autism and Related Disorders

自闭症及相关疾病的临床和行为表型

• 批准号: 8158133
• 负责人: Susan Swedo
• 金额: $ 192.67万
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 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/8158133
• 关键词: Autistic Disorder; Behavior assessment; Behavioral; Clinical; Data Analyses; Diagnosis; Disease; Phenotype

Autism is defined as a single disorder characterized by impairments in communication and social interaction and the presence of restricted interests and repetitive behaviors. The current diagnostic definition is based on behavioral characteristics, but there is mounting evidence that autism may represent a collection of overlapping neurodevelopmental disorders, resulting from a variety of neuroanatomical, neurophysiological, neuroimmunologic and/or genetic abnormalities. The wide range of possible etiologies and the heterogeneity of symptom expression among individuals with autism leads to speculation that there actually are several "autisms", i.e., clinically meaningful subtypes of the disorder that may have distinct causes, symptoms, comorbid conditions and treatments. The PDN research program aims to characterize the behavioral and biological manifestations of these subtypes of autism, and to examine the connection between the two, in an effort to identify unique etiologies and to develop more effective therapeutic and preventive interventions. During the reporting period, this project focused primarily on a longitudinal, phenotyping investigation of young children (ages 1-6 years) with autism. In addition, two new studies were implemented with initial recruitment. The goal of the first is stated in its title: "Identification of Characteristics Associated with Symptom Remission in Autism". This investigation is comparing children who were previously diagnosed with autism, whose symptoms have remitted (partially or completed), with a cohort of similarly aged children who received similar interventions (behavioral, pharmacological and biomedical) but did not significantly improve. It is hoped that specific predictors of response can be identified in the remitted group, which will lead to the development and application of more effective treatmens for the larger cohort of individuals with autism spectrum disorders. The study is actively recruiting children and adolescents with a history of remitted autism and their age-/sex-matched contrast groups. More information about the remitted autism study can be found at: http://clinicaltrials.gov/ct2/show/NCT00938054. The second recently approved study is just beginning to recruit subjects for piloting, which will permit the use of oxytocin and vasopressin as probes in a functional neuroimaging study of social cognition among young adults with autism spectrum disorders and age-/sex-matched healthy volunteers. This investigation utilizes functional magnetic resonance imaging (fMRI) to assess the impact of double-blind single administration of oxytocin, vasopressin or placebo on behavior and brain function in response to tasks of social cognition. Comparisons across groups, tasks and drugs will be made to determine if individuals with autism have different patterns of brain activation compared to normal controls, as well as pre and post dose of neuropeptide or placebo, per the experimental design. The investigation will provide greater understanding of the nature of autism's social deficits and the activation patterns may provide important clues into the pathophysiology of the disorder, which in turn could lead to the development of novel therapeutic strategies. More information about the fMRI study can be found at http://www.clinicaltrials.gov/ct2/show/NCT01093768?term=autism+oxytocin&rank=3. During the reporting period, recruitment continued with the study hitting the mark of enrolling over 100 children with autism. In addition, PDN staff continue to screen children for this natural history study, our enrollment continues to include less than 50 (N=45) individuals with autism and a history of regression. With 100 subjects, we are conducting initial analyses of several of our primary hypotheses, including whether or not there are significant immunological or other differences between children with autism with a history of regression and those without (with developmental regression defined by a significant loss of social and/or communication skills). In addition, we are analyzing the sample of children with autism compared to over 50 typically developing healthy volunteers and 25 children with developmental delays but no significant symptoms of autism. The baseline data we are analyzing include comprehensive behavioral, neuropsychological, medical and neurological evaluations, as well as a routine and overnight electroencephalogram (EEG), neuroimaging with magnetic resonance imaging, modified polysomnography to evaluate sleep architecture, blood and urine samples (and children with autism receive a lumbar puncture to obtain cerebrospinal fluid for analysis), as well as assessments of environmental exposures, early medical history, genetics, genomics, and dysmorphology. Preliminary results from these evaluations have demonstrated genetic abnormalities in a small fraction of the children with autism, while more than half of the children have abnormalities of sleep architecture and/or the presence of abnormal, epileptiform discharges on routine and overnight EEG tracings. The latter findings led to the development of two targeted treatment trials - use of valproic acid to treat epileptiform discharges (recently approved) and use of donepezil to improve Rapid Eye Movement (REM) sleep (closed for recruitment with data analyses underway); described in detail in Project MH002914-02: "Treatment of Medical Conditions among Individuals with Autism Spectrum Disorders" and at http://clinicaltrials.gov/ct2/show/NCT00695136 All children in the phenotyping study are being followed in the NIMH clinic for three years and will have annual evaluations that include behavioral assessments, clinical exams and laboratory studies. At the end of study participation, the comprehensive baseline evaluation will be repeated, including the laboratory assays, EEG, sleep study and MRI scans. Particular attention is being paid to the "N of 1 or 2" findings - unique physical, behavioral, genetic, neuroimaging or biochemical characteristics of children with autism that might provide clues to etiology or pathogenesis. The goal of the investigation is to determine if there are distinct groups of individuals within the spectrum of autistic disorders that share common profiles of biological and/or behavioral characteristics. Identification of such subgroups will provide new avenues for clinical and basic science research into the causes and treatments of autism. Interested parties are invited to learn more about the study at: http://clinicalstudies.info.nih.gov/detail/A_2006-M-0102.html

自闭症被定义为一种单一疾病，其特征是沟通和社会互动障碍以及兴趣受限和重复行为。 目前的诊断定义基于行为特征，但越来越多的证据表明自闭症可能代表一系列重叠的神经发育障碍，由各种神经解剖学、神经生理学、神经免疫学和/或遗传异常引起。 自闭症患者的可能病因多种多样，症状表现也存在异质性，因此人们推测实际上存在多种“自闭症”，即具有临床意义的疾病亚型，可能具有不同的病因、症状、共病状况和治疗方法。 PDN 研究计划旨在表征这些自闭症亚型的行为和生物学表现，并检查两者之间的联系，以努力确定独特的病因并开发更有效的治疗和预防干预措施。 在报告期内，该项目主要侧重于对患有自闭症的幼儿（1-6岁）进行纵向表型调查。 此外，在初次招募时还实施了两项新研究。 第一个的目标在其标题中阐明：“识别与自闭症症状缓解相关的特征”。 这项调查将之前被诊断为自闭症且症状已缓解（部分或完全）的儿童与接受类似干预（行为、药理学和生物医学）但未显着改善的年龄相仿的儿童进行比较。 希望能够在缓解组中确定反应的具体预测因子，这将导致为更大的自闭症谱系障碍患者群体开发和应用更有效的治疗方法。 该研究正在积极招募有自闭症缓解史的儿童和青少年以及年龄/性别匹配的对照组。 有关缓解自闭症研究的更多信息，请访问：http://clinicaltrials.gov/ct2/show/NCT00938054。 最近批准的第二项研究刚刚开始招募试点受试者，这将允许使用催产素和加压素作为探针，对患有自闭症谱系障碍的年轻人和年龄/性别匹配的健康志愿者进行社会认知的功能性神经影像研究。 这项研究利用功能磁共振成像 (fMRI) 来评估双盲单次施用催产素、加压素或安慰剂对响应社会认知任务的行为和大脑功能的影响。 根据实验设计，将进行组别、任务和药物之间的比较，以确定自闭症患者与正常对照组相比，以及神经肽或安慰剂给药前后是否有不同的大脑激活模式。 这项研究将有助于更好地了解自闭症社交缺陷的本质，而激活模式可能会为该疾病的病理生理学提供重要线索，进而可能导致新的治疗策略的开发。 有关功能磁共振成像研究的更多信息，请访问 http://www.clinicaltrials.gov/ct2/show/NCT01093768?term=autism+oxytocin&rank=3。 报告期内，招募工作仍在继续，研究已招募超过 100 名自闭症儿童。此外，PDN 工作人员继续筛选儿童进行这项自然历史研究，我们的注册人数继续包括不到 50 名（N = 45）名患有自闭症和有退行史的人。 我们正在对 100 名受试者进行初步分析，其中包括几个主要假设，包括有退行史的自闭症儿童与没有退行史的自闭症儿童（发育退行定义为社交和/或沟通技能显着丧失）之间是否存在显着的免疫学或其他差异。 此外，我们还分析了自闭症儿童样本，与 50 多名正常发育的健康志愿者和 25 名发育迟缓但没有明显自闭症症状的儿童进行比较。 我们正在分析的基线数据包括全面的行为、神经心理学、医学和神经学评估，以及常规和夜间脑电图 (EEG)、磁共振成像神经成像、评估睡眠结构的改良多导睡眠图、血液和尿液样本（自闭症儿童接受腰椎穿刺以获取脑脊液进行分析）以及环境评估 暴露、早期病史、遗传学、基因组学和畸形学。 这些评估的初步结果表明，一小部分自闭症儿童存在遗传异常，而超过一半的儿童在常规和夜间脑电图描记中存在睡眠结构异常和/或存在异常癫痫样放电。 后者的发现导致了两项靶向治疗试验的发展——使用丙戊酸治疗癫痫样放电（最近获得批准）和使用多奈哌齐改善快速眼动（REM）睡眠（已关闭招募，数据分析正在进行中）；详细描述见项目 MH002914-02：“自闭症谱系障碍患者的医疗状况治疗”和 http://clinicaltrials.gov/ct2/show/NCT00695136 参与表型分析研究的所有儿童都将在 NIMH 诊所接受为期三年的跟踪，并将进行年度评估，包括行为评估、临床检查和实验室研究。 在研究参与结束时，将重复进行全面的基线评估，包括实验室分析、脑电图、睡眠研究和 MRI 扫描。 人们特别关注“1 或 2 中的 N”发现——自闭症儿童独特的身体、行为、遗传、神经影像或生化特征，这些特征可能为病因或发病机制提供线索。 调查的目的是确定自闭症谱系中是否存在具有共同生物学和/或行为特征的不同个体群体。 这些亚组的识别将为自闭症病因和治疗的临床和基础科学研究提供新途径。 欢迎有兴趣的人士了解有关该研究的更多信息： http://clinicalstudies.info.nih.gov/detail/A_2006-M-0102.html