Lewy body dementia pathway and biomarker discovery

项目总结/摘要 路易体痴呆症（LBD），包括帕金森病痴呆症（PDD）和路易体痴呆症 阿尔茨海默病（AD）相关痴呆的常见形式，占高达30%， 所有痴呆症病例中。LBD的病理学标志是神经元内皮质α-突触核蛋白聚集， 细胞体和神经元突起分别称为路易体和路易神经突。LBD患者 患有认知障碍、神经精神症状和帕金森运动症状。临床 DLB与PDD的区分基于任意定义的“一年规则”： 在运动症状发作之前或之后一年内的痴呆被定义为DLB，而 在最初诊断为帕金森病（PD）一年后发展为痴呆的患者是 分类为PDD。DLB与PDD是相同还是不同的临床证候， 争论，以及我们对这些疾病发病机制的分子共性和差异的认识， 两种LBD亚型是有限的。此外，由于临床诊断的敏感性低，LBD被诊断不足。 LBD与AD的临床鉴别诊断标准和挑战。目前，没有可靠的 用于LBD诊断的生物标志物，并且没有有效的预防或疾病改善治疗手段， 强调需要更好地了解LBD的发病机制。该项目将解决一个 痴呆症研究的重要但未充分研究的领域，并使用创新的多路复用平台， 整合蛋白质组学、糖蛋白质组学和糖组学，以发现致病途径和分子 LBD诊断和治疗开发的目标。拟议的研究将调查和 发现存储在几乎未被探索的人类LBD大脑蛋白质组中的有用生物信息， 糖蛋白质组和糖组，并鉴定参与LBD发病机制的分子和途径。 此外，该项目将使用系统生物学方法来确定是否已确定LBD相关 分子、网络和途径与阿尔茨海默病的分子、网络和途径相似或不同。结果 这项研究将提高我们对LBD发病机制的认识， 发现治疗LBD和其他神经退行性痴呆包括阿尔茨海默病的治疗方法。

Project Summary / Abstract Lewy body dementia (LBD), which includes Parkinson disease dementia (PDD) and dementia with Lewy bodies (DLB), is a common form of Alzheimer disease (AD)-related dementia that accounts for up to 30% of all dementia cases. The pathological hallmarks of LBD are cortical α-synuclein aggregates in neuronal cell body and neuronal processes termed Lewy bodies and Lewy neurites, respectively. Patients with LBD suffer from cognitive impairment, neuropsychiatric symptoms, and Parkinsonian motor symptoms. Clinical differentiation of DLB from PDD is based on an arbitrarily defined “one-year rule”: patients who develop dementia before or within one year after the onset of motor symptoms are defined as DLB, whereas patients who develop dementia after one year of the original diagnosis of Parkinson disease (PD) are classified as PDD. Whether DLB and PDD are the same or different clinical syndromes remains hotly debated, and our knowledge of the molecular commonalities and differences in the pathogenesis of these two LBD subtypes is limited. Furthermore, LBD is underdiagnosed, due to the low sensitivity of the clinical diagnosis criteria and challenges in clinical differentiation of LBD from AD. Currently, there is no reliable biomarker for LBD diagnosis and no effective means of prevention or disease-modifying treatment, highlighting the need to better understanding the pathogenesis of LBD. This project will address an important yet understudied area of dementia research and use an innovative multiplex platform of integrative proteomics, glycoproteomics, and glycomics to discover pathogenic pathways and molecular targets for LBD diagnostic and therapeutic development. The proposed research will investigate and uncover useful biological information stored in virtually unexplored, human LBD brain proteome, glycoproteome, and glycome and identify molecules and pathways involved in LBD pathogenesis. Furthermore, this project will use a systems biology approach to determine if the identified LBD-associated molecules, networks, and pathways are similar to or distinct from those of Alzheimer disease. Results from the proposed research will advance our knowledge of LBD pathogenesis and help accelerate the effort to discover curative therapies for LBD and other neurodegenerative dementia including Alzheimer disease.