Identifying Brain-Based Biomarkers for ASD & their Biological Subtypes

描述(申请人提供)：本研究计划的最终目标是利用多模式磁共振成像(MRI)识别自闭症谱系障碍(ASD)的脑生物标记物和基于生物学的ASD亚型。先前对ASD神经生物学的研究为多个神经系统的解剖学和功能障碍提供了证据，这些障碍与ASD症状的严重程度相关。我们的研究项目建立在这些发现的基础上，通过展示ASD不同神经系统的障碍如何对应于行为和认知障碍的独特特征。到目前为止，38名患有自闭症的儿童和成人和39名健康对照已经入选(定向登记100名自闭症受试者和100名对照受试者)，他们在年龄、性别、种族、智商(IQ)、社会经济地位和利手方面进行了分组匹配。表型分析包括评估ASD核心行为领域损害严重程度的黄金标准临床工具，以及智力、程序性和陈述性记忆、视觉空间处理和执行功能的测量。受试者在3Tesla扫描仪上接受高分辨率解剖MRI、功能MRI(FMRI)、扩散张量成像(DTI)和磁共振波谱(MRS)检查。解剖学测量包括对皮质表面、下层白质和皮质下灰质核局部体积的细粒度测量。DTI提供有关白质纤维束的方向和完整性的信息。多平面化学位移成像(MPCSI)提供了极高质量的代谢物测量，包括整个大脑中连续小体素的神经元密度测量。情绪面孔识别任务中的大脑激活是使用功能磁共振结合眼球跟踪来测量的。我们使用先进的图像采集、图像处理和统计建模技术，在一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，无论是在模式内还是跨模式，从而允许更深入地了解局部体积、功能活动、代谢物浓度和连接性之间的关系。我们假设，神经生物学的ASD亚型将出现在不同神经系统的不同干扰模式的基础上，这些神经系统已被证明在ASD中发生改变，如杏仁核-海马体、额纹状体和镜像神经系统等。我们之前已经定义了抽动秽语综合征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。7我们还开发了能够基于神经解剖学的详细测量对神经精神障碍及其亚型进行分类的方法。使用这些技术，我们的研究计划将定义ASD的脑生物标记物，基于生物学的ASD亚型，以及这些复杂疾病的表型异质性的神经基础。 公共卫生相关性：据估计，每150人中就有1人患有自闭症谱系障碍(ASD)，是一种复杂的大脑发育障碍，会导致社交能力、沟通和行为灵活性的终身障碍，智力残疾和医学并存的比例很高。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的生物学亚型，从而在寻找ASD易感基因方面产生巨大的好处。我们拟议的研究计划将通过支持ASD的预防、早期发现和个性化治疗的战略来促进公共健康。

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.