Proteomics of mild cognitive impairment in the elderly

描述（由申请人提供）： 痴呆症的研究越来越多地集中在阿尔茨海默病（AD）的前驱阶段。阐明疾病的发病机制和可靠的识别人在早期阶段的认知能力下降将是至关重要的发展有效的治疗AD。最近，一个临床实体称为轻度认知功能障碍（MCI）已被公认为之间的过渡状态的认知变化，在正常老化和AD。MCI的患病率是痴呆的两倍多，并且在许多情况下MCI可能是前驱AD。因此，MCI是探索AD发病机制的神经生物学基础的合适条件。有一个病理和生物标志物的数据，以区分与健康的老年人MCI个体的匮乏。为了研究MCI的病理生物学标志物，我们将采用一种新的双层，基于发现的蛋白质组学方法。首先，我们将使用二维凝胶电泳（2DGE）和液相色谱-串联质谱（LCMS/ MS），以确定在没有认知障碍（NCI），MCI，或早期/轻度AD的受试者的内嗅皮层（EC）的蛋白质水平的具体变化。EC是MCI的起始变性部位，是研究MCI发病机制的理想区域。其次，我们将使用新的表面增强激光解吸/电离飞行时间质谱（SELDI-TOF MS）蛋白芯片技术来评估这些相同个体的脑脊液（CSF）的变化。组织和体液样本将从我们正在进行的由美国国立卫生研究院资助的衰老和AD纵向研究，即宗教秩序研究（ROS）中获得。拟议的研究将有望发现参与AD发病机制的新蛋白质和新的生物标志物，以便及时诊断这种毁灭性疾病的早期阶段。这两个因素将是至关重要的神经保护策略的发展，以减缓或预防老年人的认知能力下降。

DESCRIPTION (provided by applicant): Dementia research has become increasingly focused on the prodromal stages of Alzheimer's disease (AD). Elucidating the mechanisms of disease pathogenesis and the reliable identification of people in early stages of cognitive decline will be critical to the development of efficacious therapies for AD. Recently, a clinical entity termed mild cognitive impairment (MCI) has been recognized as a transitional state between the cognitive changes seen in normal aging and AD. The prevalence of MCI is more than double that of dementia and in many cases MCI may be prodromal AD. Therefore, MCI is a suitable condition for exploring the neurobiology underlying AD pathogenesis. There is a paucity of data on pathological and biological markers that distinguish individuals with MCI from healthy aged individuals. To investigate pathobiological markers for MCI, we will employ a novel two-tiered, discovery-based proteomics approach. First, we will use two-dimensional gel electrophoresis (2DGE) and liquid chromatography-tandem mass spectrometry (LCMS/ MS) to identify specific alterations in protein levels in the entorhinal cortex (EC) of subjects with no cognitive impairment (NCI), MCI, or early stage/mild AD. The EC is the initial site of degeneration in MCI and is an ideal area to explore MCI pathogenesis. Second, we will use new surface-enhanced laser desorption/ionization-time of flight MS (SELDI-TOF MS) protein chip technology to evaluate the changes in the cerebrospinal fluid (CSF) of these same individuals. Both tissue and fluid samples will be obtained from our ongoing NIA-funded longitudinal study of aging and AD, the Religious Orders Study (ROS). The proposed studies will hopefully lead to the discovery of new proteins involved in the pathogenesis of AD and new biomarkers for the timely diagnosis of persons in the earliest stages of this devastating disease. Both of these factors will be critical for the development of neuroprotective strategies for slowing or preventing cognitive decline in the elderly.