Down syndrome: Bridging Genes, Brain and Cognition

描述（由申请人提供）：唐氏综合症（DS）或21号染色体三体，是导致智力迟钝和先天性心脏病的主要原因，在美国影响超过40万人。此外，退行性椎体滑移患者在记忆、语言和神经解剖学上都有缺陷。这项建议的最终目标是阐明与退行性椎体滑移的神经认知缺陷有关的基因、神经解剖学和神经回路。人类基因组测序的最新进展提供了21号染色体基因的完整列表，但直到最近（Korbel, 2009），还没有与任何特定特征相关的基因，也没有成功的治疗认知缺陷的方法。由于缺乏缩小负责认知特征的基因的人类模型，需要对退行性椎体滑移的大脑缺陷进行高分辨率神经成像，以及需要对退行性椎体滑移缺陷进行认知测试，退行性椎体滑移的治疗一直受到阻碍。为了解决这些差距，我们提出了一种创新的多学科方法，将神经影像学、认知测试和遗传学结合起来。在DS和遗传学中，罕见的事件可以阐明共同的过程。罕见的个体由于21号染色体的部分重复而患有退行性痴呆，这为将大脑发育和功能缺陷与相关基因联系起来提供了一个独特的机会。该提案的PI产生了现存最大的队列，由45人组成，其中30人活着，在美国，27个非整倍体，只有21个。最近，这些罕见的病例被用来绘制先天性畸形DS的特定基因亚群，但对大脑或认知知之甚少。此外，一个独特的和罕见的同卵双胞胎不一致的DS，已被确定和研究。为了描述这些群体，一个独特的科学家团队已经成立，具有部分21三体（Korenberg），针对DS的神经认知测试（Nadel, Yurgelun-Todd），磁共振成像和扩散张量成像（Yurgelun- Todd, Gerig），核磁共振光谱学（Renshaw）和基因组组织（Korenberg）的专业知识。该团队将整合完整和罕见的部分21三体的高分辨率成像，以建立DS的区域神经解剖学和神经回路，并将这些与21号染色体基因亚群联系起来。我们将测试三个层次的假设，首先定义DS与正常人，不同的体积和回路大脑结构和认知功能缺陷，包括语言和记忆；第二，将DS内的神经基质与认知特征联系起来；第三，通过使用每个罕见的部分三体，开始解析DS神经和认知特征的基因子集。此外，我们将在DS中测试谷氨酸能或gaba能神经递质系统是否在体内受到干扰。我们提出了两个目标：1)通过认知测试、高分辨率MRI、DTI和MRS对60名正常和完全21三体个体进行表征；2)对罕见的部分21三体DS队列和与目标1中不一致的同卵双胞胎进行表征。这些研究的结果将提供关于DS、GABAergic和glutamatergic通路中大脑发育和功能缺陷的前所未有的知识，以及两者与基因复制的关系。这些结果将有助于阐明退行性痴呆的神经生物学，并为退行性痴呆和其他智力障碍开发新的治疗方法。

DESCRIPTION (provided by applicant): Down syndrome (DS) or trisomy for chromosome 21, is a major cause of mental retardation and congenital heart disease, that affects more than 400,000 individuals in the USA. In addition, people with DS have defects in memory, language and neuroanatomy. The ultimate goal of this proposal is to elucidate the genes, neuroanatomy and neurocircuitry linked to the neurocognitive defects of DS. Recent advances in human genome sequencing provide a complete list of chromosome 21 genes, but until recently (Korbel, 2009), there were no genes linked to any specific feature and no successful treatment for the cognitive deficits. Treatment of DS has been hindered by lack of human models for narrowing the genes responsible for cognitive features, the need for high resolution neuroimaging of the brain defects in DS and the need for cognitive tests focused on DS deficits. To address these gaps, we propose an innovative multidisciplinary approach integrating neuroimaging, cognitive testing and genetics. In DS as in genetics, rare events can illuminate common processes. Rare individuals have DS caused by duplication of only parts of chromosome 21 and provide a unique opportunity to link the defects of brain development and function with the genes responsible. The PI of this proposal has generated the largest cohort in existence, consisting of 45 persons, of whom 30 are alive, in the USA, 27 aneuploid only for 21. Recently, these rare cases were used to map specific gene subsets in DS for congenital malformations but little was known about the brain or cognition. Further, a unique and rare set of identical twins discordant for DS, has been identified and studied. To characterize these cohorts, a unique team of scientists has been created, with expertise in partial trisomy 21 (Korenberg), neurocognitive testing targeted to DS (Nadel, Yurgelun-Todd), Magnetic Resonance Imaging and Diffusion tensor imaging (Yurgelun- Todd, Gerig), NMR Spectroscopy (Renshaw) and genome organization (Korenberg). This team will integrate high resolution imaging of full and rare partial trisomy 21 to establish the regional neuroanatomy and neurocircuitry of DS and to link these to subsets of chromosome 21 genes. We will test three levels of hypotheses, first to define in DS vs normals, distinct volumetric and circuit brain structures and defects of cognitive function, including language and memory; second, to link within DS, neural substrates with cognitive features and third, by using each rare partial trisomy, to begin to parse gene subsets for DS neural and cognitive features. Further, we will test in DS, whether the glutamatergic or, as in mouse, the GABAergic neurotransmitter systems are disturbed in vivo. We propose two aims: 1) to characterize 60 normal and 60 full trisomy 21 individuals with cognitive testing, high resolution MRI, DTI and MRS, 2) to characterize the rare DS cohort with partial trisomy 21 and the unique set of identical twins discordant for DS as in aim 1. The results of these studies will provide unprecedented knowledge of the defects of brain development and function in DS, GABAergic and glutamatergic pathways, and the relationship of both to genes duplicated. These results will help to elucidate the neurobiology of DS and to develop novel treatments for DS and other intellectual disabilities.