Identifying Brain-Based Biomarkers for ASD & their Biological Subtypes

描述（由申请人提供）：本研究项目的最终目标是使用多模态磁共振成像（MRI）识别自闭症谱系障碍（ASD）和基于生物学的ASD亚型的脑生物标志物。先前对ASD神经生物学的研究提供了与ASD症状严重程度相关的多个神经系统的解剖和功能障碍的证据。我们的研究计划建立在这些发现的基础上，展示了ASD中不同神经系统的干扰如何对应于行为和认知障碍的独特特征。到目前为止，已招募了38名ASD儿童和成人以及39名健康对照，按年龄、性别、种族、智商（IQ）、社会经济状况和利手进行组匹配（目标招募100名ASD和100名对照受试者）。表型分析包括金标准临床工具，以评估ASD核心行为领域的损伤严重程度，沿着智力，程序和陈述性记忆，视觉空间处理和执行功能的测量。参与者在3特斯拉扫描仪中接受高分辨率解剖MRI、功能MRI（fMRI）、扩散张量成像（DTI）和磁共振波谱（MRS）。解剖学测量包括皮质表面、底层白色物质和皮质下灰质核的局部体积的细粒度测量。弥散张量成像提供了白色纤维束的方向和完整性的信息。多平面化学位移成像（MPCSI）提供了非常高质量的代谢物测量，包括神经元密度的测量，在整个大脑的小连续体素。在情绪面部识别任务期间，大脑激活是使用功能磁共振成像结合眼动追踪来测量的。我们使用先进的图像采集、图像处理和统计建模在单个成像空间内分析这些不同形式的数据。这些方法能够精确检测每个体素的个体间和组间变异性，在模态内和跨模态，允许更深入地了解局部体积，功能活性，代谢物浓度和连接之间的关系。我们假设，神经生物学ASD亚型将出现在不同的神经系统，如杏仁核-海马，额纹状体，镜像神经元系统，除其他外，已被证明是改变ASD的干扰的差异模式的基础上。我们之前已经定义了Tourette综合征1，2，注意力缺陷/多动障碍3，4，家族性抑郁症5，成人精神分裂症6和早产儿的神经解剖学特征。我们还开发了基于神经解剖学详细测量的神经精神疾病及其亚型的分类方法。使用这些技术，我们的研究计划将定义ASD的脑生物标志物，基于生物学的ASD亚型，以及这些复杂疾病表型异质性的神经基础。 公共卫生相关性：自闭症谱系障碍（ASD），影响估计150人中的1人，是大脑发育的复杂障碍，导致社交能力，沟通和行为灵活性终身受损，智力残疾和医疗合并症的发生率很高。在ASD患者中识别基于大脑的生物标志物将阐明这种异质性疾病的神经基础，并识别ASD的生物亚型，从而在寻找ASD的脆弱性基因方面产生巨大的好处。我们提出的研究计划将通过制定预防，早期发现和个性化治疗ASD的策略来促进公共卫生。

DESCRIPTION (provided by applicant): The ultimate goal of this research program is to identify brain biomarkers of Autism Spectrum Disorders (ASDs) and biologically-based ASD subtypes using multimodal Magnetic Resonance Imaging (MRI). Previous research into the neurobiology of ASD provides evidence for anatomical and functional disturbances across multiple neural systems that correlate with ASD symptom severity. Our research program builds on these findings by showing how disturbances in different neural systems in ASD correspond to unique profiles of behavioral and cognitive impairment. Thus far, 38 children and adults with ASD and 39 healthy controls, group-matched by age, sex, race, intelligence quotient (IQ), socio-economic status, and handedness, have been enrolled (targeted enrollment 100 ASD and 100 control subjects). Phenotypic profiling includes gold standard clinical instruments to assess the severity of impairment in the core behavioral domains of ASD along with measures of intelligence, procedural and declarative memory, visuospatial processing, and executive functioning. Participants undergo high-resolution anatomical MRI, functional MRI (fMRI), diffusion tensor imaging (DTI), and magnetic resonance spectroscopy (MRS) in a 3 Tesla scanner. Anatomical measures include fine-grained measures of local volumes of the cortical surface, the underlying white matter, and subcortical gray matter nuclei. DTI provides information about the orientation and integrity of white matter fiber tracts. Multiplanar Chemical Shift Imaging (MPCSI) provides extremely high quality measures of metabolites, including measures of neuronal density, in small contiguous voxels throughout the brain. Brain activation during a task of emotional face recognition is measured using fMRI in conjunction with eye-tracking. We analyze these diverse forms of data within a single imaging space using advanced image acquisition, image processing, and statistical modeling. These methods enable the precise detection of inter-individual and inter-group variability at each voxel, within and across modalities, permitting a deeper understanding of the relationships between local volumes, functional activity, metabolite concentrations, and connectivity. We hypothesize that neurobiological ASD subtypes will emerge based on differential patterns of disturbances in distinct neural systems that have been shown to be altered in ASD, such as amygdala-hippocampal, frontostriatal, and the mirror neuron systems, among others. We have previously defined neuroanatomical signatures for Tourette Syndrome1, 2, Attention-Deficit/Hyperactivity Disorder3, 4, familial depression5, adult schizophrenia6, and prematurely born children.7 We have also developed methods that enable the classification of neuropsychiatric disorders and their subtypes based on detailed measures of neuroanatomy. Using these techniques, our research program will define brain biomarkers for ASD, biologically-based ASD subtypes, and the neural bases for the phenotypic heterogeneity of these complex disorders. PUBLIC HEALTH RELEVANCE: Autism Spectrum Disorders (ASDs), affecting an estimated 1 in 150 individuals, are complex disorders of brain development that cause lifelong impairments in social ability, communication and behavioral flexibility with high rates of intellectual disability and medical comorbidities. The identification of brain-based biomarkers in individuals with ASD will illuminate the neural bases of this heterogeneous disorder and identify biological subtypes of ASD thereby yielding enormous benefits in the search for vulnerability genes for ASDs. Our proposed research plan will advance public health by enabling strategies for prevention, early detection, and personalized treatment of ASDs.