The Development of Brain Anatomy and Connectivity in Males and Females with Autism Spectrum Disorder during Adolescence

自闭症谱系障碍（ASD）是一种以社会互惠、社会沟通和重复/刻板行为缺陷为特征的终身神经发育障碍。尽管ASD患者在病因和表型上存在相当大的异质性，但研究一致认为，ASD伴随着非典型的大脑成熟轨迹和大脑连接的改变。儿童早期的非典型神经发育轨迹在ASD中有很好的特征。然而，介导ASD青少年期大脑成熟的神经生物学机制仍然知之甚少。现在人们普遍认为，大脑在青春期到成年早期继续成熟，尤其是成熟较晚的额叶和颞叶系统，它们在ASD中典型的社交和情感行为的发展中起着至关重要的作用。青春期也是成人神经发育和行为形成的时期。因此，了解青春期早期ASD各自的神经病理学可以为青春期晚期和成年早期临床结果的发展提供重要的预测信息。因此，本研究的第一个主要目的是建立ASD从儿童晚期到成年早期大脑成熟的神经病理机制，并开发青春期早期的生物标志物，以预测青春期晚期的临床结果。初步证据还表明，ASD在生理性别方面表现不同，男性和女性ASD患者在各自的行为和神经病理表型方面存在差异。然而，目前尚不清楚与神经正常对照相比，青春期是否对男性和女性ASD患者的神经病理学和症状特征产生不同的影响。因此，本研究的第二个目的是确定青春期ASD的皮层病理和神经发育轨迹在多大程度上受生理性别的调节，并检查青春期可能调节成年早期自闭症症状严重程度的潜在神经保护因素。我们提出的研究结果将为青少年ASD的神经病理学提供重要的新见解，并阐明神经生物学和临床ASD表型的性别差异，这可能为未来的青少年ASD诊断和治疗方法提供信息。然而，最重要的是，我们的研究将为ASD早期体内生物标志物的开发做出重大贡献，这些生物标志物可用于预测以后的临床结果，从而增加了正在进行的全球研究工作，将研究成果转化为临床实践。

Autism Spectrum Disorder (ASD) is a life-long neurodevelopmental disorder characterized by deficits in social reciprocity, social communication, and repetitive/stereotypic behaviours. While there is considerable heterogeneity among individuals with ASD, both causative and phenotypic, research agrees that ASD is accompanied by an atypical trajectory of brain maturation and altered brain connectivity. The atypical neurodevelopmental trajectory during early childhood is well characterized in ASD. However, the neurobiological mechanisms that mediate brain maturation during adolescence in ASD remain poorly understood. It is now widely accepted that the brain continues to mature through adolescence until early adulthood, particularly in late maturing frontal and temporal lobe systems, which play a crucial role in the development of the social and emotional behaviors typically impaired in ASD. Adolescence is also a time where the course for adult neurodevelopment and behavior is set. Insights into the respective neuropathology of ASD during early adolescence could therefore provide important predictive information for the development of clinical outcomes during late adolescence and early adulthood. The first main aim of the proposed research is thus to establish the neuropathological mechanisms mediating brain maturation from late childhood to early adulthood in ASD, and to develop early adolescence biomarkers that could predict clinical outcomes during late adolescence. Preliminary evidence also suggests that ASD manifests differently as a function of biological sex, and that males and females with ASD differ in terms of their respective behavioural and neuropathological phenotypes. However, it is currently unknown whether adolescence exerts a differential effect on the neuropathology and symptom profiles in males and females with ASD, compared to neurotypical controls. The second aim of the study is thus to establish the extend to which the cortical pathology and neurodevelopmental trajectory of ASD during adolescence is modulated by biological sex, and to examine potential neuroprotective factors in adolescence that could modulate the severity of autistic symptoms in early adulthood. The outcomes of our proposed work will provide important novel insights into the neuropathology of ASD during adolescence, and elucidate gender-differences in the neurobiological and clinical ASD phenotype, which may inform future approaches to diagnosing and treating ASD during adolescence. Most importantly, however, our research will significantly contribute to the development of early in vivo biomarkers for ASD that could be utilized in the prediction of clinical outcomes later on, and thus adds to ongoing global research efforts towards translating research findings into clinical practice.