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，其特征是沟通和社会互动中的障碍以及限制利益和重复行为的存在。 然而，有越来越多的证据表明自闭症代表了由各种神经解剖学，神经生理学，神经免疫学和/或遗传异常引起的重叠神经发育障碍的集合。 自闭症患者中广泛的病因和症状表达的异质性导致猜测实际上有几种“自闭症”，即具有相似行为表现的临床上不同的疾病，但病因，临床病程和治疗方法不同。 PDN研究计划旨在表征这些患者队列的行为和生物学表现，并确定其独特的特征，以促进有效的治疗和预防性干预措施。 在报告期间，该项目主要集中于对105名年幼儿童（1-6岁）进行自闭症，60岁和性别匹配的纵向表 - 调查，通常会发展控制措施，以及一组25名具有非自治发展延迟的儿童。 这些主题已经完成了基线评估，他们正在返回以进行定期随访评估。 现在正在分析来自基线反应的数据，包括检查潜在有意义的患者亚组的检查，例如自闭症儿童的比较具有发育回归的史和没有发展的患者（由社会和/或沟通能力的重大丧失来定义发育回归）。 我们的最初发现表明回归和非退缩亚组之间没有显着差异。实际上，初步分析最引人注目的发现是回归似乎是一个连续的变量，而不是前面描述的二分法类别。 也就是说，具有发展回归史的儿童经常在早期发展中至少有一些延误，而那些具有独特的早期发展延迟的孩子也可能会失去一些社交和沟通能力。 除了行为评估外，该研究还包括全面的医学和发展历史；神经心理学，医学和神经学评估；血液，尿液和脑脊液（CSF）样品的测定；以及各种专业研究，包括常规和夜间脑电图（EEGS）；修改的多症术评估睡眠体系结构；和磁共振成像（MRI扫描）；遗传测定；和畸形评估。 这些评估的初步结果表明，超过一半的儿童患有睡眠结构异常，特别是值得注意的是快速眼动（REM）睡眠所花费的时间的降低。 低REM发现引发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。 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提供病因或发病机理的线索。 表型研究的目的是确定自闭症疾病范围内是否有不同的个体，它们具有共同的生物学和/或行为特征的共同特征。 此类亚组的识别将为自闭症的原因和治疗方法提供新的临床和基础科学研究途径。 有关这项研究的更多信息，请参见： http://clinicalstudies.info.nih.gov/detail/a_2006-m-0102.html 其他三项表型研究也正在进行中。 他们每个人都有一个目标，即对自闭症表型及其与病因，临床过程和结果的关系有更深入的了解。 该小组首次研究的目的从其标题中很明显：“与自闭症症状缓解相关的特征识别”。 这项调查正在比较以前被诊断出患有自闭症的儿童，他们的症状已减轻（部分或完整），同类年龄相似的儿童接受了类似的干预措施，但仍符合自闭症的标准。 该研究旨在确定汇出组中的特定反应预测因素，这将导致为更大的ASD患者的同类群体开发和应用更有效的治疗方法。 该研究正在积极招募具有自闭症及其年龄/性别匹配造影剂的历史的儿童和青少年。 有关汇款自闭症研究的更多信息，请访问：http：//clinicaltrials.gov/ct2/show/nct00938054。 第二项研究是在对ASD和年龄/性别匹配的健康志愿者的社会认知的功能性神经影像学研究中，使用催产素和加压素作为探针。 这项研究利用功能性磁共振成像（fMRI）来评估（盲）给药催产素，加压素或安慰剂对行为和大脑功能的影响，以应对社会认知任务。 根据实验设计，跨组，任务和药物之间的比较将确定自闭症患者与正常对照以及剂量前后的神经肽或安慰剂前和后剂量相比，脑部激活的模式是否不同。 调查将对自闭症社会缺陷的性质有更深入的了解，激活模式可能会为疾病的病理生理提供重要的线索。 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 = autism+oxytocin&rank=3。 最新的PDN表型研究是对由于早期语言延迟的存在而对被认为是ASD危险的幼儿的前瞻性，纵向研究。 这项研究的目的是描述预测ASD的早期交流障碍，并将其与非自动发展延迟的非特异性标记区分开，并研究沟通障碍与大脑结构和功能的相关性，并通过结构性和功能性MRI扫描评估，并过夜。 纵向评估还包括全面的行为评估，这些评估是对交流和其他领域中的特征优势和劣势。 这些评估的目的是确定ASD的特定风险和弹性因素，在3-4岁时的最终评估中进行评估。 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