Brain Development in Down Syndrome during Fetal, Newborn, and Infant Stages

摘要 唐氏综合征(DS)，又称21三体，是新生儿最常见的染色体疾病。这个 出生时患有DS的婴儿数量正在增加，在美国，每700名婴儿中就有1名出生时患有DS 州(美国)。DS患者携带额外的完整或部分21号染色体，扰乱了许多 过程，包括心脏、消化系统和神经系统，认知障碍是最严重的 显著的特点。DS患者一生中都有学习、记忆和言语/语言方面的问题， 以及阿尔茨海默病的早期发病。鉴于DS患者的寿命比以前更长 改善了医疗保健，鉴于微小抵抗点的概念仍然有效，它是 研究DS患者大脑发育的初始状态的改变对于更好地预测 大脑功能的某些方面将优先和早熟地恶化；这将允许更早和更好的 预防和治疗。然而，详细、全面的皮质发育早期知识 DS患者的解剖和纤维通路仍然缺乏。DS患者的脑异常始于宫内；较少 神经元被产生并迁移到错误的目的地。到怀孕15周(GW)时，患有DS的大脑 皮质厚度异常，体积是正常发育大脑的80%。然而，很多 需要更详细的信息，我们现在有了对胎儿进行直接解剖观察的工具 以及出生后早期的DS大脑。我们在体外和体内都有丰富的经验，磁性 人类大脑的磁共振成像(MRI)。我们已经建立了高角分辨率扩散磁共振成像 具有最佳参数的(Hardi)有可能定义发育中的人类的连接解剖学 胎儿、新生儿和婴儿的大脑。我们已经以前所未有的细节报道了时空发展 大多数轴索束的模式以及神经元迁移路径的区域回归模式 使用弥散磁共振纤维束成像。在胎儿时期，暂时性区域(例如，未来的皮质灰质、皮质板 [CP]；未来白质，中间带[IZ])不断改变其形态，反映神经元 增殖/迁移以及轴突延长、成熟和修剪，并可能为 大脑发育正常/异常。通过最新的初步MRI研究，典型的发展 大脑，我们观察到迁移和轴突路径终止于不同的过渡区，而不是随机的 但具有独特的时空模式。根据已证实的大体形态的异常 DS大脑，连同已知的皮质和白质的度量变化，我们 假设DS的早期大脑发育将表现出区域差异的时空模式，如 与对照组相比。

Abstract Down syndrome (DS), known as trisomy 21, is the most common chromosomal disorder in newborns. The number of babies born with DS is increasing, with about 1 in every 700 babies being born with DS in the United States (US). Patients with DS carry an extra complete or partial chromosome 21, disrupting numerous processes, including cardiac, digestive, and neural systems, with cognitive impairment being one of the most notable features. Patients with DS have problems with learning, memory, and speech/language throughout life, as well as an early onset of Alzheimer’s disease. Given that DS patients live longer than before as a result of improved medical care, and in view of the fact that the concept of locus minoris resistentiae is still valid, it is critical to study the altered initial states of brain development in DS for the purpose of better predicting what aspects of brain function will preferentially and precociously deteriorate; this would allow for earlier and better prevention and treatment. However, detailed, comprehensive knowledge of early development of cortical anatomy and fiber pathways in DS patients is still lacking. The brain abnormalities in DS begin in utero; fewer neurons are generated and migrate to wrong destinations. By 15 gestational weeks (GW), brains with DS have abnormal cortical thickness, with volumes that are 80% of those of typically developing brains. However, much more detailed information is needed, and we now have the tools to make direct anatomical observation on fetal and early postnatal DS brains. We have extensive experience, both in ex vivo and in vivo, magnetic resonance imaging (MRI) of human brains. We have established that high-angular resolution diffusion MRI (HARDI) with optimal parameters has the potential to define the connectional anatomy of developing human fetal, newborn, and infant brains. We have reported, with unprecedented details, spatiotemporal developmental patterns of the majority of axonal tracts, as well as regional regression patterns of neuronal migration pathways using diffusion MRI tractography. In fetal ages, transient zones (e.g., future cortical gray matter, cortical plate [CP]; future white matter, intermediate zone [IZ]) continuously change their morphology, reflecting neuronal proliferation/migration, and axonal elongation, maturation, and pruning, and could provide critical biomarkers for normal/abnormal brain development. Through recent preliminary MRI investigations in typically developing brains, we have observed migration and axonal pathways terminating in different transient zones, not randomly but with unique spatiotemporal patterns. Based on the demonstrated anomalies in the gross morphology of the DS brain, together with what is already known about metric changes in the cortex and white matter, we hypothesize that early brain development in DS will show regionally differential spatiotemporal patterns as compared to that in controls.