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: 8556959
• 负责人: Susan Swedo
• 金额: $ 224.13万
• 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/8556959
• 关键词: Adolescent; Affect; Age; Attention; Autistic Disorder; Basic Science; Behavior; Behavior assessment; Behavioral; Behavioral Genetics; Biochemical; Biological; Biological Assay; Blinded; Blood; Brain; Categories; Cerebrospinal Fluid; Characteristics; Child; Clinical; Clinical Sciences; Collection; Communication; Communication impairment; Data; Development; Developmental Delay Disorders; Diagnosis; Diagnostic; Disease; Disease remission; Dose; Dysmorphology; Electroencephalogram; Employee Strikes; Etiology; Evaluation; Experimental Designs; Functional Magnetic Resonance Imaging; Functional disorder; Genetic; Goals; Health Care Costs; Heterogeneity; Impairment; Individual; Intervention; Investigation; Investments; Language Delays; Lead; MRI Scans; Magnetic Resonance Imaging; Medical; Molecular Abnormality; Nature; Neurodevelopmental Disorder; Neurologic; Neuropeptides; Neurosciences; Outcome; Oxytocin; Pathogenesis; Patients; Pattern; Pediatrics; Pharmaceutical Preparations; Phenotype; Placebos; Polysomnography; Preventive Intervention; Public Health; REM Sleep; Recording of previous events; Recruitment Activity; Reporting; Research; Risk; Sampling; Sleep Architecture; Social Interaction; Structure; Subgroup; Support System; Symptoms; Therapeutic Intervention; Therapy Clinical Trials; Time; Toddler; Urine; Variant; Vasopressins; aged; autism spectrum disorder; clinically significant; cohort; disability; effective therapy; follow-up; healthy volunteer; interest; meetings; neuroimaging; neurophysiology; neuropsychological; outcome forecast; programs; prospective; rapid eye movement; resilience; response; sex; skills; social; social cognition; social communication; social communication impairment; young adult

Autism is currently defined as a single disorder characterized by impairments in communication and social interaction and the presence of restricted interests and repetitive behaviors. However, there is mounting evidence that autism represents 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 distinct disorders with similar behavioral presentations but different etiologies, clinical course, and treatments. The PDN research program aims to characterize the behavioral and biological manifestations of these patient cohorts and to identify their unique features in order to facilitate development of effective therapeutic and preventive interventions. During the reporting period, this project focused primarily on a longitudinal, phenotyping investigation of 105 young children (ages 1-6 years) with autism, 60 age and sex-matched typically developing controls and a group of 25 children with non-autistic developmental delays. Baseline evaluations have been completed for these subjects and they are returning for periodic follow-up assessments. Data from the baseline evluations are now being analyzed, including examinations of potentially meaningful subgroups of patients, such as the comparisons of children with autism whow have a history of developmental regression and those without (Developmental regression is defined by a significant loss of social and/or communication skills). Our initial findings indicate no significant differences between the regressive and non-regressive subgroups; indeed the most striking finding of the preliminary analyses was that regression appears to be a continuous variable, rather than the dichotomous categories previously described. That is, children with a history of developmental regression have frequently had at least some delays in their early development and those with distinct early developmental delays may also lose some social and communication skills. In addition to the behavioral assessments, the study includes comprehensive medical and developmental histories; neuropsychological, medical and neurological evaluations; assays of blood, urine and cerebrospinal fluid (CSF) samples; and also a variety of specialized studies, including routine and overnight electroencephalograms(EEGs); modified polysomnography to evaluate sleep architecture; and magnetic resonance imaging (MRI scans); genetic assays; and dysmorphology evaluations. Preliminary results from these evaluations have demonstrated that more than one-half of the children have abnormalities of sleep architecture, particularly notable are reductions in the percentage time spent in Rapid Eye Movement (REM) sleep. The low REM findings prompted a small therapeutic trial which is described in a separate project report (MH002914-04 PDNB). As expected, genetic abnormalities were found in approximately 10% of the subjects and the aberrations are being evaluated for clinical significance (that is, are they a potential etiologic factor or merely a clinically insignificant variation.) As the baseline data are being examined, particular attention is being paid to interesting "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 phenotyping 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 researchh into the causes and treatments of autism. More information about this study may be found at: http://clinicalstudies.info.nih.gov/detail/A_2006-M-0102.html Three other phenotyping studies are also underway. Each of them shares the goal of providing a deeper understanding of the autism phenotype and its relationship to etiology, clinical course and outcome. The goal of the first study in this group is obvious from its title: "Identification of Characteristics Associated with Symptom Remission in Autism". This investigation is comparing children previously diagnosed with autism, whose symptoms have remitted (partially or completed), with a cohort of similarly aged children who received similar interventions but continued to meet criteria for autism. The study aims to identify specific predictors of response in the remitted group, which will lead to the development and application of more effective treatments for the larger cohort of individuals with ASD. 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 study is using oxytocin and vasopressin as probes in a functional neuroimaging study of social cognition among young adults with ASD and age-/sex-matched healthy volunteers. This investigation utilizes functional magnetic resonance imaging (fMRI) to assess the impact of the (blinded) 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 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. More information about the fMRI study can be found at http://www.clinicaltrials.gov/ct2/show/NCT01093768?term=autism+oxytocin&rank=3. The most recent PDN phenotyping study is a prospective, longitudinal investigation of toddlers considered to be at-risk for ASD because of the presence of early language delays. This study aims to delineate early communicative impairments that predict ASD and to distinguish these from non-specific markers of non-autistic developmental delays, as well as examining how communication impairments correlate with brain structure and function, as assessed with structural and functional MRI scans, and overnight EEGs. The longitudinal assessments also include comprehensive behavioral assessments desifned to profile strengths and weaknesses in communication and other domains. The goal of these assessments is to identify specific risk and resilience factors for ASD, assessed at the final evaluation at age 3 - 4 years. More information about this study may be found at: http://www.clinicaltrials.gov/ct2/show/NCT01339767?term=toddlers+autism&rank=2

自闭症目前被定义为一种单一疾病，其特征是沟通和社交互动障碍以及兴趣受限和重复行为。 然而，越来越多的证据表明自闭症代表了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。 自闭症患者可能的病因多种多样，症状表达也存在异质性，因此人们推测实际上存在多种“自闭症”，即临床上不同的疾病，具有相似的行为表现，但病因、临床病程和治疗方法不同。 PDN 研究计划旨在描述这些患者群体的行为和生物学表现，并确定他们的独特特征，以促进有效的治疗和预防干预措施的开发。 在报告期内，该项目主要侧重于对 105 名患有自闭症的幼儿（1-6 岁）、60 名年龄和性别匹配的典型发育对照儿童以及一组 25 名非自闭症发育迟缓儿童进行纵向表型调查。 这些受试者的基线评估已经完成，他们将返回进行定期后续评估。 目前正在分析基线评估的数据，包括对潜在有意义的患者亚组进行检查，例如对有发育退化史的自闭症儿童与没有发育退化史的儿童进行比较（发育退化的定义是社交和/或沟通技能的显着丧失）。 我们的初步研究结果表明，回归亚组和非回归亚组之间没有显着差异；事实上，初步分析中最引人注目的发现是回归似乎是一个连续变量，而不是之前描述的二分类别。 也就是说，有发育倒退史的儿童在早期发育中经常至少有一些延迟，而那些有明显早期发育延迟的儿童也可能会失去一些社交和沟通技能。 除了行为评估之外，该研究还包括全面的医学和发育史；神经心理学、医学和神经学评估；血液、尿液和脑脊液 (CSF) 样本的化验；以及各种专业研究，包括常规和夜间脑电图 (EEG)；改良多导睡眠图以评估睡眠结构；和磁共振成像（MRI 扫描）；基因检测；和畸形评估。 这些评估的初步结果表明，超过一半的儿童存在睡眠结构异常，尤其值得注意的是快速眼动 (REM) 睡眠时间百分比的减少。 低 REM 发现促使进行了一项小型治疗试验，该试验在单独的项目报告 (MH002914-04 PDNB) 中进行了描述。 正如预期的那样，在大约 10% 的受试者中发现了遗传异常，并且正在评估这些畸变的临床意义（即，它们是潜在的病因还是仅仅是临床上不显着的变异。）在检查基线数据时，我们特别关注有趣的“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，这些特征可能会导致 提供病因学或发病机制的线索。 表型研究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的病因和治疗的临床和基础科学研究提供新的途径。 有关这项研究的更多信息可以在以下位置找到： http://clinicalstudies.info.nih.gov/detail/A_2006-M-0102.html 其他三项表型研究也在进行中。 他们每个人的共同目标是更深入地了解自闭症表型及其与病因、临床过程和结果的关系。 该小组第一项研究的目标从其标题中显而易见：“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措施但仍符合自闭症标准的年龄相仿的儿童进行比较。 该研究旨在确定缓解组反应的具体预测因素，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。 第二项研究是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功能神经影像学研究。 这项研究利用功能磁共振成像 (fMRI) 来评估（盲法）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，对各组、任务和药物进行比较，将确定自闭症患者与正常对照相比，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。 这项调查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。 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。 最近的 PDN 表型研究是一项前瞻性纵向调查，对象是因早期语言发育迟缓而被认为具有自闭症谱系障碍 (ASD) 风险的幼儿。 本研究旨在描述预测自闭症谱系障碍的早期沟通障碍，并将其与非自闭症发育迟缓的非特异性标志物区分开来，并通过结构和功能 MRI 扫描以及夜间脑电图评估，研究沟通障碍如何与大脑结构和功能相关。 纵向评估还包括旨在分析沟通和其他领域的优势和劣势的综合行为评估。 这些评估的目标是确定 ASD 的具体风险和复原力因素，并在 3 - 4 岁时进行最终评估。 有关这项研究的更多信息，请访问：http://www.clinicaltrials.gov/ct2/show/NCT01339767?term=toddlers+autism&rank=2