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: 8939987
• 负责人: Susan Swedo
• 金额: $ 182.07万
• 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/8939987
• 关键词: 4 year old; Affect; Age; Algorithms; Area; Attention; Attention deficit hyperactivity disorder; Autistic Disorder; Behavior; Behavior assessment; Behavioral; Biological; Biological Assay; Blood; Brain; Categories; Cerebrospinal Fluid; Child; Clinical; Collaborations; Collection; Communication; Communication impairment; Cross-Sectional Studies; Data; Development; Developmental Delay Disorders; Diagnostic; Disease; Dysmorphology; Electroencephalogram; Employee Strikes; Etiology; Evaluation; Functional Magnetic Resonance Imaging; Functional disorder; Genetic; Goals; Growth; Head; Head circumference; Health Care Costs; Hereditary Disease; Heterogeneity; Image; Impairment; Individual; Investigation; Investments; Language Delays; Literature; MRI Scans; Magnetic Resonance Imaging; Measurement; Medical; Molecular Abnormality; National Human Genome Research Institute; Natural History; Near-Infrared Spectroscopy; Neurodevelopmental Disorder; Neurologic; Neurosciences; Nursery Schools; Outcome; Patients; Pattern; Pediatrics; Phenotype; Polysomnography; Preventive Intervention; Procedures; Process; Protocols documentation; Public Health; REM Sleep; Recording of previous events; Records; Relative (related person); Reporting; Research; Risk; Sampling; Signal Transduction; Sleep Architecture; Smith-Lemli-Opitz Syndrome; Structure; Subgroup; Support System; Symptoms; Syndrome; Therapeutic Intervention; Therapy Clinical Trials; Time; Toddler; Treatment Protocols; Urine; Validation; Variant; autism spectrum disorder; clinically significant; cohort; comparison group; design; disability; exome sequencing; follow-up; instrument; interest; myelination; neuroimaging; neurophysiology; neuropsychological; outcome forecast; programs; prospective; resilience; restrictive repetitive behavior; sex; skills; social communication; white matter

Autism is currently defined as a single disorder characterized by impairments in social communication 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 differing presentations of autism 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 continuing 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 (Protocol 06-M-0102, NCT 00298246). Baseline evaluations have been completed for these subjects and they are returning for periodic follow-up assessments. Data from the baseline evaluations are now being analyzed, including examinations of potentially meaningful subgroups of patients, such as the comparisons of children with autism who have a history of developmental regression and those without. Interestingly, one of the most striking findings 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. We have also recently explored the measurement of restrictive and repetitive behavior in this cohort, finding that these children are reported to have significantly more restrictive and repetitive behavior than found in similar samples, and that this behavior remains stable over a one year period. Finally, data from this project have also been used to continue validation of appropriate algorithms of diagnostic instruments for children in the preschool age range. 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 relative reductions in the percentage time spent in Rapid Eye Movement (REM) sleep. The finding prompted a therapeutic trial which is described in a separate project report (MH002914-04 PDNB). We also analyzed cross-sectional data from MRI scans, which found signals of abnormal myelination in specific brain areas of autism, as well as other indicators of abnormalities in brain white matter and relative cortical thinning in specific key regions in the brain. Evidence of previously reported abnormalities of early brain growth was also investigated, both through imaging as well as head circumference records, with data indicating previous findings may have spuriously overestimated increased head size in autism due to inadequate norms (see Raznahan et al, 2013). As expected, genetic abnormalities were found in approximately 10% of the subjects and the aberrations are being evaluated for clinical significance. Further, we are engaged in a collaboration to conduct whole exome sequencing of the cohort, and are in the process of analyzing the relationship of sequencing data and phenotypic variations. More information about this study (Protocol 06-M-0102, NCT 00298246) may be found at http://clinicalstudies.info.nih.gov/detail/A_2006-M-0102.html Other phenotyping studies are also underway or have been recently completed. 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 first of these is a prospective, longitudinal investigation of toddlers considered to be at-risk for ASD because of the presence of early language delays (Protocol 11-M-0144, NCT01339767). This study aims to delineate early communicative impairments that predict ASD and to distinguish these from non-specific markers of (non-autistic) developmental delays. The investigation also examines the relationship of communication impairments to abnormalities of brain structure and function assessed by electroencephalograms (EEGs), structural MRIs, and functional MRI scans. The longitudinal assessments also include comprehensive behavioral assessments designed 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. More information about this study may be found at: http://www.clinicaltrials.gov/ct2/show/NCT01339767?term=toddlers+autism&rank=2 A related investigation uses near-infrared spectroscopy (NIRS) to perform functional neuroimaging in children who are too young or behaviorally-challenged to tolerate functional MRI scanning procedures -- a key group that is missing from much of the neuroimaging literature on autism. Using tasks of inhibition and including comparison groups of children with attention-deficit hyperactivity disorder and typically developing children, this study seeks to obtain reliable and informative brain activation data on children with autism as young as 4 years old. A final area of phenotyping investigation involves behavioral assessments of individuals with specific genetic disorders purported to be highly associated with autism, such as Phelan McDermid Syndrome, Smith-Lemli-Opitz Syndrome and others. Additionally, through a collaboration with the Undiagnosed Diseases Program of NHGRI, subjects with serious rare and potentially genetic disorders are evaluated to find common and unique patterns of developmental and behavioral strengths and weaknesses. The behavioral assessments are conducted as part of PDN's "Natural History" investigation (Protocol 13-M-0028, NCT01778504), which is described at: http://clinicalstudies.info.nih.gov/cgi/detail.cgi?A_2013-M-0028.html

自闭症目前被定义为一种单一疾病，其特征是社会交流中的障碍以及受限制的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研究计划旨在表征自闭症不同表现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，该项目主要集中于继续对105名自闭症，60岁和性别匹配的纵向表型调查（1-6岁），通常会发展对照，以及一组25名具有非独立发展延迟的儿童（协议06-M-0102，NCT 00298246）。 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评估的数据，包括对患者的潜在有意义的亚组进行检查，例如具有发育回归史的自闭症儿童的比较以及没有发育史的儿童。 有趣的是，初步分析的最引人注目的发现之一是回归似乎是连续的变量，而不是先前描述的二分法类别。 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。我们最近还探索了该队列中限制性和重复行为的测量，发现这些孩子的限制性和重复性行为比在类似样本中的限制性和重复性明显高得多，并且这种行为在一年中保持稳定。 最后，该项目的数据还用于继续验证学龄前年龄范围内儿童诊断工具的适当算法。 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相对减少。 该发现促使了一项治疗试验，该试验在单独的项目报告（MH002914-04 PDNB）中进行了描述。 我们还分析了MRI扫描中的横截面数据，该数据发现了自闭症特定大脑区域中异常髓鞘形成的信号，以及大脑白质和大脑特定关键区域的其他异常指标。 先前报道的早期大脑生长异常的证据也通过成像和头围记录进行了研究，数据表明先前的发现可能微不足道地高估了由于规范不足而导致自闭症的头部大小增加（参见Raznahan等人，参见Raznahan等，2013年）。 不出所料，在大约10％的受试者中发现了遗传异常，并且正在评估临床意义的畸变。 此外，我们还进行了协作以进行队列的整个外显子组测序，并正在分析测序数据和表型变化的关系。有关这项研究的更多信息（协议06-M-0102，NCT 00298246），请访问http://clinicalstudies.info.nih.gov/detail/a_2006-m-0102.html 其他表型研究也正在进行中或最近已经完成。 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。 首先是对被认为是ASD高风险的幼儿的前瞻性，纵向研究，因为早期语言延迟的存在（协议11-M-0144，NCT01339767）。 这项研究旨在描述预测ASD并将其与（非自动）发育延迟的非特异性标记区分开的早期交流障碍。 该研究还研究了通过脑结构和功能异常的沟通障碍与通过脑结构（EEG），结构MRIS和功能性MRI扫描评估的功能的关系。 纵向评估还包括旨在介绍通信和其他领域中的优势和劣势的全面行为评估。 这些评估的目的是确定ASD的特定风险和弹性因素。 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 一项相关的研究使用近红外光谱法（NIR）在太年轻或受到行为挑战的儿童中进行功能性神经影像学，无法耐受功能性MRI扫描程序 - 这是一个关键组，这是许多自闭症文献中许多神经影像中缺少的关键群体。 该研究使用抑制任务，包括注意缺陷多动障碍的儿童的比较组，通常是患有儿童的儿童，该研究旨在获取有关自闭症儿童年仅4岁的自闭症儿童的可靠且内容丰富的大脑激活数据。 表型研究的最终领域涉及对特定遗传疾病的个体的行为评估，该评估据称与自闭症高度相关，例如菲兰·麦克德米德综合症，史密斯 - 莱姆利 - 奥皮茨综合征等。 此外，通过与未诊断的NHGRI疾病计划的合作，评估患有严重罕见且潜在的遗传疾病的受试者，以找到发育和行为优势和劣势的共同和独特的模式。 行为评估是作为PDN的“自然历史”调查（协议13-M-0028，NCT01778504）的一部分进行的，该研究如下：